State of the world’s

vaccines and immunization
Third edition
Suggested citation: WHO, UNICEF, World Bank. State of the world’s vaccines and
immunization, 3
rd
ed. Geneva, World Health Organization, 2009.
This book is dedicated to all those individuals who work tirelessly to improve and
save lives through vaccines and immunization.
WHO Library Cataloguing-in-Publication Data
State of the world's vaccines and immunization. -- 3
rd
ed.
1.Immunization programs 2.Immunization 3.Vaccines 4.Biomedical research
5.Child 6.Infant 7.Interinstitutional relations 8.International cooperation
9.Developing countries I.World Health Organization.
ISBN 978 92 4 156386 4 (NLM classification: WA 110)
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Printed in France
1


CORRIGENDA


State of the world's vaccines and immunization. Third edition

ISBN 978 92 4 156386 4

Please note the following:


Page 38:

Innovative regulatory pathways

Traditionally, when a national regulatory authority in a developing country considers whether to host
clinical trials of a new vaccine produced in another country, or whether to adopt a new vaccine in its
country’s immunization programme, it would be favourably influenced if the vaccine had been approved
for human use by the European Medicines Agency or the FDA. However, in 2004 and 2007, respectively,
both agencies decided to no longer accept vaccines for marketing approval where they are intended for
use exclusively outside their geographical jurisdictions. This decision raised a fear that the supply of new
life-saving vaccines to developing countries may be hindered or delayed for lack of authoritative
marketing approval.

In 2005, therefore, the European Medicines Agency introduced a mechanism, known as “Article 58”,
whereby it issues a “scientific opinion” based on the customary Agency process but with the addition of
an evaluation of the vaccine by WHO-appointed experts from countries where the vaccine is intended to
be used. This mechanism, although stopping short of formally granting a licence, involves all the steps of
a regular licensing procedure. It carries enough weight to allay fears that vaccines may be introduced
without having been assessed for safety and quality. Moreover, the FDA and the European Medicines
Agency have agreed to work with national regulatory authorities or with networks of regulators in the
regions, to provide advice on vaccine safety and efficacy as well as on clinical trial protocols. Similar
collaborative agreements are being forged in other parts of the world, notably in Asia.

2
should read:

Innovative regulatory pathways

Traditionally, when a national regulatory authority in a developing country considers whether to adopt a
new vaccine in its country’s immunization programme, it would be favourably influenced if the vaccine
had been approved for human use by the European Medicines Agency (EMEA) or the FDA. However, in
2004, the EMEA decided to no longer issue marketing authorization for vaccines intended exclusively for
use outside the European Union. This decision raised a fear that the supply of new life-saving vaccines to
developing countries may be hindered or delayed for lack of authoritative marketing approval.

In 2005, therefore, the EMEA introduced a mechanism, known as “Article 58”, whereby it issues a
“scientific opinion” based on the customary Agency process but with the added input of experts —
proposed by WHO to the EMEA — from countries where the vaccine is intended for use. This
mechanism, although stopping short of formally granting a licence, involves all the steps of a regular
licensing procedure. It carries enough weight to allay fears that vaccines may be introduced without
having been assessed for quality, safety and efficacy for the intended population. Moreover, the national
regulatory authorities in Europe and the United States have agreed to work with global and regional
networks of regulators. Collaborative agreements are being established to promote expert advice from the
European and United States regulators to regulatory authorities of developing countries hosting clinical
trials or reviewing registration dossiers of vaccines manufactured under the jurisdiction of the former.


Pages 49-50

By mid-2005, 53 countries, mostly in Africa and Asia, had begun implementing the RED strategy to
varying degrees (see Fig. 6) (32). In 2005, an evaluation of five countries in Africa that had implemented
RED found that the proportion of districts with over 80% of children fully immunized with DTP vaccine
had more than doubled (33). More recently, a nine-country evaluation carried out by the CDC in 2007
found that the RED strategy had been adopted by 90% of all districts within these countries.

However, few of the nine countries were implementing all five components of the strategy (see Box 11).
The CDC evaluation noted that further studies would be needed over a longer period to assess the
effectiveness and sustainability of the strategy.

should read:

By mid-2005, 53 countries, mostly in Africa and Asia, had begun implementing the RED strategy to
varying degrees (see Fig. 6) (32). In 2005, an evaluation in five countries in Africa that had implemented
RED carried out by staff from WHO's Regional Office for Africa, with the support of UNICEF, the
IMMUNIZATIONbasics project, and the United States Centers for Disease Control and Prevention found
that the proportion of districts with over 80% of children fully immunized with DTP vaccine had more
than doubled (33). A nine-country in-depth evaluation carried out by the same groups in 2007 found that
the RED strategy had been adopted by 90% of all districts within these countries.

However, few of the nine countries were implementing all five components of the strategy (see Box 11).
The in-depth evaluation noted that further studies would be needed over a longer period to assess the
effectiveness and sustainability of the strategy.

3
Page 105

The search for a safer, more effective cholera vaccine produced three new-generation vaccines, of which
only one is available for widespread use today. This vaccine, first licensed in Argentina in 1997 and code-
named WC/rBS, is made from the whole-cell V. cholerae linked to a genetically engineered
(recombinant) fragment (B-subunit) of the cholera toxin.

should read:

The search for a safer, more effective cholera vaccine produced three new-generation vaccines, of which
only one is available for widespread use today. This vaccine, first licensed in Argentina in 1997 and code-
named WC/rBS, is made from the whole-cell V. cholerae and a genetically engineered (recombinant)
fragment (B-subunit) of the cholera toxin.


Page 107

These observations have prompted countries where diphtheria is no longer endemic to extend vaccination
protection beyond the primary three-dose series for infants by administering one, or sometimes two,
booster doses every 10 years to adults through the diphtheria-tetanus (dT – low content of diphtheria)
combination vaccine (67).

should read:

These observations have prompted countries where diphtheria is no longer endemic to extend vaccination
protection beyond the primary three-dose series for infants by administering one booster dose every 10
years to adults through the diphtheria-tetanus (dT – low content of diphtheria) combination vaccine (67).


Page 108

Notwithstanding clear evidence of the vaccine’s efficacy, by 1997 only 29 countries were using it
routinely, prompting WHO to recommend its inclusion in the routine immunization programmes of all
countries where Hib was recognized as a public health burden and where the cost of the vaccine was not
prohibitive (70).

should read:

Notwithstanding clear evidence of the vaccine’s efficacy, by 1997 only 26 countries were using it
routinely, prompting WHO to recommend its inclusion in the routine immunization programmes of all
countries where Hib was recognized as a public health burden and where the cost of the vaccine was not
prohibitive (70).


4
Page 111

At the present time, therefore, there are no compelling reasons for recommending a fourth dose of vaccine
outside of the routine immunization programme.

should read:

At the present time, therefore, there are no compelling reasons for recommending a systematic booster
dose.


Page 127

To date, there are no licensed vaccines against the group B meningococcus, but several vaccine
manufacturers have products that are being evaluated clinically. For example, group B vaccines that have
been custom-made against specific epidemic strains have been successfully used to control specific
outbreaks in Brazil, Chile, Cuba, France, New Zealand, and Norway.

should read:

To date, there are few licensed vaccines against the group B meningococcus. Those vaccines that have
been available during the past years were custom-made against specific epidemic strains and have been
used to control outbreaks in Brazil, Chile, Cuba, France, New Zealand, and Norway.


Page 132

Death from pertussis still occurs in industrialized countries (less than 1 per 1000 cases (111)), but more
rarely than in developing countries (40 per 1000 infants, and 10 per 1000 in older children (111)).

Should read:

Death from pertussis still occurs in industrialized countries (less than 1 per 1000 cases (111)), but more
rarely than in developing countries (40 per 1000 cases in infants, and 10 per 1000 cases in older children
(111)).



State of the world’s
vaccines and immunization
Third edition
State of the world’s vaccines and immunization
III
Acknowledgements
Writers
The principal writer of the 3
rd
edition of the State of the world’s vaccines and
immunization was John Maurice. Special thanks to John for his extensive research
and writing and editing of many drafts of the document. The secondary writer was
Sheila Davey, who took over the writing during the last months of revisions. Her
assiduity in dealing with the comments of multiple reviewers, at tight deadlines, is
much appreciated.
Contributors
Contributions to the text were provided by Jeffrey Bates (for communications sections
in Chapter 3), Julian Bilous (hepatitis B control in China), Logan Brenzel (Chapter 4),
Michel Greco (for section on vaccine industry in Chapter 2), Patrick Lydon (Chapter
4), and Rob Matthews (on vaccine supply issues).
Editorial Committee
An Editorial Committee composed of Amie Batson, Brent Burkholder, Peter Folb,
Rehan Hafiz, Tatu Kamau, Ruth Levine, and Kevin Reilly provided invaluable advice in
the early stages of drafting. The main contributions of the Committee were provided
during a two-day retreat in Switzerland. Written comments on drafts were also provided.
Reviewers
Gratitude is extended to the many individuals who invested considerable time
reviewing the document: Teresa Aguado, Mercy Ahun, Bruce Aylward, Sona Bari,
Madeline Beal, Lahouari Belgharbi, Adwoa Bentsi-Enchill, Janice Bernat, Julian
Bilous, Bjarne Bjorvatn, David Bloom, Rob Breiman, Julie Buss, Logan Brenzel, Peter
Carrasco, Diana Chang-Blanc, Thomas Cherian, Liliana Chocarro, John Clemens,
Alejandro Costa, Maritel Costales, Alya Dabbagh, Nora Dellepiane, Philippe Duclos,
Laure Dumolard, Tony Dutson, Chris Dye, Linda Eckert, Rudi Eggers, Chris Elias,
Godwin Enwere, Armin Fidler, Martin Friede, Uli Fruth, Marta Gacic-Dobo, François
IV
Acknowledgements
Gasse, Tracey Goodman, Judy Heck (graphics), Melinda Henry, Edward Hoekstra,
Joachim Hombach, Maria Ieroianni, Bernard Ivanoff, Suresh Jadhav, Naroesha
Jagessar, Steve Jarrett, Miloud Kaddar, Umit Kartoglu, Marie-Paule Kieny, Benny
Kim, Nicole King, Ivana Knezevic, Ryoko Krause, Patience Kuruneri, Marc LaForce,
Rama Lakshiminarayana, Eric Laurent, Daniel Lavanchy, Orin Levine, Julian Lob-Levyt,
Patrick Lydon, Ahmed Magan, Carsten Mantel, Eric Mast, Rob Matthews, Gill Mayers,
Pankaj Mehta, Bjorn Melgaard, Lalitha Mendis, François-Xavier Meslin, Julie Milstien,
Haydar Nasser, Jennifer O’Brien, Alex Palacios, Georges Peter, Marie-Pierre Preziosi,
Lois Privor-Dumm, Eileen Quinn, Oliver Rosenbauer, Alison Rowe, Jeffrey Rowland,
Peter Salama, Sarah Schmitt, Nina Schwalbe, Craig Shapiro, Peter Smith, Thomas
Sorensen, Duncan Steele, Robert Steinglass, Peter Strebel, Roland Sutter, Daniel
Tarantola, Teresa Taube, Christiana Toscana, Nikki Turner, Pierre van Damme, Maya
Vandenent, Steve Wiersma, Scott Wittet, David Wood, Simon Wreford-Howard, Mark
Young, Patrick Zuber.
Editor
Thanks are extended to Cathy Needham for her careful editing of final drafts.
Graphic design
Mise en oeuvre, www.allmeo.com, Switzerland.
Photography
Front cover: Marc-André Marmillod; p.2 Jean-Marc Giboux; p.9 Courtesy of the
PneumoADIP, photo by Adrian Books; p.14 Corbis; p.25 MVI/David Poland; p.36
Department of Medical Sciences, Ministry of Public Health, Thailand; p.40 Jean-
Marc Giboux; p.52 WHO/H.Hasan; p.61 WHO/U. Kartoglu; p.64 WHO/H.Hasan; p.72
Istockphoto; p.92 Amélie Coulombel; p.95 Jim Lin.
State of the world’s vaccines and immunization
V
Steering Group
Alison Brunier, Osman Mansoor, Anthony Measham, Jean-Marie Okwo-Bele, Jos
Vandelaer, and Michel Zaffran oversaw the production of the document from inception
to publication, providing input and direction on content at all stages of drafting.
Vaccines
“With the exception of safe water, no other
modality, not even antibiotics, has had such
a major effect on mortality reduction…”
(1)
State of the world’s vaccines and immunization
VII
Contents
Foreword XIV
Executive summary XVII
PART 1: Progress and challenges in meeting global goals 1

1. Immunization and human development 2
2. A new chapter in vaccine development 14
A vaccine boom 17
Explaining the new momentum 17
Technology comes of age 18
Reverse technology 19
Conjugation technology 20
Adjuvants 21
Cell substrates 21
New licensed vaccines 23
Vaccines in the pipeline 24
Supplying vaccines for a changing world 27
A rapidly expanding market 27
A concentrated industry 27
Planning, producing, protecting 28
Towards vaccines of assured quality 31
Making and meeting standards of quality and safety 31
Strengthening national regulatory authorities 34
A regulators’ network for developing countries 35
Harmonizing and standardizing vaccine regulation 36
Innovative regulatory pathways 38
VIII
Contents
3. Immunization: putting vaccines to good use 40
The unfinished immunization agenda 45
Extending the benefits of immunization equitably within countries 49
Reaching more children through campaign strategies 51
Greater awareness fuels demand 54
Surveillance and monitoring: essential health system functions 56
Optimizing the delivery of vaccines 59
Linking interventions for greater impact 62
Combating fear with knowledge and evidence 66
Remarkable progress, huge challenges 68
4. Investing in immunization 72
What does immunization cost? 75
Is the investment worth making? 79
Who pays the bill and how? 81
National governments 81
Multilateral, bilateral, and other donors 85
The Global Polio Eradication Initiative 85
The GAVI Alliance 87
New financing mechanisms 89
The International Finance Facility for Immunisation 89
Advance Market Commitment 90
A concluding conundrum 91
5. The view from the future 92
State of the world’s vaccines and immunization
IX
PART 2: Diseases and their vaccines 103
Cholera – exploring the use of available vaccines 104
Diphtheria – controlled by vaccines but waiting to resurface 106
Haemophilus influenzae type b (Hib) – increased attention for this little
known but lethal disease 108
Hepatitis A – paradox and potential 111
Hepatitis B – the first vaccine against cancer 112
Human papillomavirus – a second cancer vaccine 115
Influenza – keeping scientists guessing 118
Japanese encephalitis – a regional scourge, waning but still present 122
Measles – record progress but risk of resurgence is high 123
Meningococcal disease – still a deadly menace across Africa 126
Mumps – not always mild, not yet conquered 130
Pertussis – too many children not being vaccinated, too many
uncounted deaths 132
Pneumococcal disease – many deaths from many strains, many hopes
from new vaccines 134
Polio – a tough end-game 137
Rabies – a terrible but vaccine-preventable death 139
Rotavirus – vaccines set to prevent half a million child deaths a year 142
Rubella – eliminating a threat to the unborn 144
Tetanus, neonatal and maternal – victory in sight 145
Tuberculosis – waiting for a better vaccine 149
Typhoid fever – vaccines ready and waiting 150
Varicella and herpes zoster – a single virus that can linger for a lifetime 152
Yellow fever – defusing a bomb waiting to explode 156
X
Contents
Boxes
1. Global Immunization Vision and Strategy (GIVS) goals 11
2. What’s so special about vaccines? 13
3. AIDS and malaria defy science 19
4. The role of industry in vaccine research and development 22
5. Product development partnerships 26
6. Vaccine security 29
7. How good is a national regulatory authority? 33
8. Prequalification – flagging vaccines fit for public purchase 39
9. The impact of immunization 44
10. Strengthening health systems – the six building blocks 48
11. Reaching Every District (RED) 50
12. Mass mobilization to extend the reach of immunization 53
13. Reaching out to communities 56
14. What it takes to run a successful national immunization programme 59
15. Vaccine Safety Net for quality web sites 68
16. Strengthening post-marketing surveillance of newly licensed vaccines 70
17. The future of immunization 97
18. Hepatitis B control in China: reducing disparities 114
19. Pandemic influenza – the H5N1 threat 120
20. Pandemic influenza – the H1N1 threat 121
21. A new meningococcal vaccine to control meningitis in Africa 129
22. Herpes zoster – the same virus, a different disease 154
State of the world’s vaccines and immunization
XI
State of the world’s vaccines and immunization
Figures
1. Trends in global mortality in children under five years old 6
2. Leading causes of vaccine-preventable death in children
under five years old, 2004 7
3. Quantities of WHO-prequalified vaccines offered to UNICEF 30
4. Global three-dose DTP coverage for 1980–2007 and
goals for 2008–2010 43
5. Immunization coverage and density of health workers 46
6. Countries implementing the RED strategy in 2005 51
7. More comprehensive health centres have better
vaccination coverage 63
8. Relation between the number of WHO Member States using
hepatitis B vaccine and the UNICEF weighted average
price for the monovalent vaccine 77
9. Government funding of vaccines for routine immunization, 2007 84
10. Countries introducing Hib vaccine 1997 to 2008 110
11. Estimated measles deaths 2000–2007 125
12. Status of elimination of maternal and neonatal tetanus 148
XII
Acronyms
Acronyms
AIDS Acquired immunodeficiency syndrome
AMC Advance Market Commitment
BCG Bacille Calmette-Guérin [vaccine]
CDC Centers for Disease Control and Prevention
cMYP Comprehensive multi-year plan for immunization
CRS Congenital rubella syndrome
cVDPV Circulating vaccine-derived poliovirus
DALY Disability-adjusted life year
DTP Diphtheria-tetanus-pertussis [vaccine]
EPI Expanded Programme on Immunization
FDA United States Food and Drug Administration
GIVS Global Immunization Vision and Strategy
GMP Good manufacturing practice
GNI Gross national income
GPEI Global Polio Eradication Initiative
HAV Hepatitis A virus
HBV Hepatitis B virus
Hib Haemophilus influenzae type b
HIV Human immunodeficiency virus
HPV Human papillomavirus
IFFIm International Finance Facility for Immunisation
IPV Inactivated polio vaccine
MDG Millennium Development Goal
MDG 1 The first Millennium Development Goal
MDG 4 The fourth Millennium Development Goal
MMR Measles-mumps-rubella [vaccine]
MNT Maternal and neonatal tetanus
OPV Oral polio vaccine
PAHO Pan American Health Organization
R&D Research and development
RED Reaching Every District [strategy]
SAGE WHO Strategic Advisory Group of Experts [on Immunization]
TAT Toxin-antitoxin
UCI Universal child immunization
UNICEF United Nations Children’s Fund
VPPAG Vaccine Presentation and Packaging Advisory Group
VLP Virus-like particle
WHA World Health Assembly
WHO World Health Organization
State of the world’s vaccines and immunization
XIII
XIV
Foreword
Margaret Chan
Director-General,
WHO
Graeme Wheeler
Managing Director,
The World Bank Group
Ann M. Veneman
Executive Director,
UNICEF
Foreword
Immunization is one of the most powerful and cost-effective of all health interventions.
It prevents debilitating illness and disability, and saves millions of lives every year. It
is also key to achieving the Millennium Development Goals (MDGs) – commitments
made by world leaders in 2000 to reduce poverty and improve human development.
The contribution of immunization is especially critical to achieving the goal to reduce
deaths among children under five years old (MDG 4).
Vaccines have the power not only to save, but also to transform, lives – giving
children a chance to grow up healthy, go to school, and improve their life prospects.
When vaccines are combined with other health interventions – such as vitamin A
supplementation, provision of deworming medicine and bednets to prevent malaria
– immunization becomes a major force for child survival.
State of the world’s vaccines and immunization
XV
Since 2000, efforts have been scaled up to meet the MDGs and the supporting
goals of the Global Immunization Vision and Strategy (GIVS), developed by WHO
and UNICEF. With financial support from the GAVI Alliance and other partners, more
children are being immunized than ever before – over 100 million children a year in
recent years. And more vaccines are increasingly being made available to protect
adolescents and adults. These include vaccines that protect against life-threatening
diseases such as influenza, meningitis, and cancers that occur in adulthood.
At the same time, access to vaccines and immunization is becoming more equitable.
Pneumococcal and rotavirus vaccines, now available to GAVI-eligible countries,
prevent the leading causes of the two main child-killers – pneumonia and diarrhoea.
Their introduction provides an opportunity to scale up the use of other interventions
for the prevention and treatment of pneumonia and diarrhoea to achieve better
overall disease control.
Despite the progress, more must be done to target the 24 million children, mainly in
developing countries, who are proving difficult to reach with vaccines. Identifying and
implementing strategies to overcome the barriers to access must be a top priority,
given the right of every child to protection from preventable diseases.
Innovative funding mechanisms are being put in place to help developing countries
increase immunization coverage and provide new vaccines that can save even
more lives. Governments too have stepped up to the mark, with increasing
spending on vaccines and immunization since the year 2000. Many governments
are demonstrating strong and effective leadership and national ownership of their
immunization programmes – a key requisite for ensuring the long-term sustainability
of immunization investments.
These are impressive achievements. But they need to be sustained and improved.
New and improved vaccines are urgently needed to prevent the unacceptable toll
XVI
Foreword
Margaret Chan
Director-General,
WHO
Graeme Wheeler
Managing Director,
The World Bank Group
Ann M. Veneman
Executive Director,
UNICEF
of sickness and deaths from diseases such as malaria, tuberculosis, and AIDS.
Continued investments are essential to ensure the breakthroughs needed in the
research and development (R&D) of these next-generation vaccines.
Major efforts will be needed in the coming months and years to ensure that, during
the current global financial and economic crisis, hard-won gains in immunization
are protected, and the development of new vaccines that could save millions of
additional lives every year does not slow down.
Experience shows that economic crises can lead to government cuts in social sector
spending, a decline in international development assistance, an increase in poverty,
and an upsurge in deaths among children under five years old.
This must not be allowed to happen again.
The global goals have not changed. Poverty, illness, and premature deaths have not
gone away. Equity and social justice are still to be achieved. These are promises to
be kept.
This report is a call to action to governments and donors to sustain and increase
funding for immunization in order to build upon the progress made so far in meeting
the global goals. The price of failure will be counted in children’s lives.
State of the world’s vaccines and immunization
XVII
Executive summary
Executive summary
XVIII
Overview
Since the Millennium Summit in 2000, immunization has moved centre stage as
one of the driving forces behind efforts to meet the Millennium Development Goals
(MDGs) – in particular, the goal to reduce deaths among children under five years
old (MDG 4).
More children than ever before are being reached with immunization: over 100 million
children a year in 2005–2007. And the benefits of immunization are increasingly being
extended to adolescents and adults – providing protection against life-threatening
diseases such as influenza, meningitis, and cancers that occur in adulthood.
In developing countries, more vaccines are available and more lives are being saved.
For the first time in documented history the number of children dying every year has
fallen below 10 million – the result of improved access to clean water and sanitation,
increased immunization coverage, and the integrated delivery of essential health
interventions.
More vaccines have been developed and others are already in the late stages of
clinical trials, making this decade the most productive in the history of vaccine
development. More money is available for immunization through innovative financing
mechanisms. And more creative energy, knowledge, and technical know-how is
being put to use through the development of public-private partnerships – forged to
help advance the immunization-related global goals.
Yet despite extraordinary progress in immunizing more children over the past decade,
in 2007, 24 million children – almost 20% of the children born each year – did not
get the complete routine immunizations scheduled for their first year of life. Reaching
these vulnerable children – typically in poorly-served remote rural areas, deprived
urban settings, fragile states, and strife-torn regions – is essential if the MDGs are to
be equitably met.
State of the world’s vaccines and immunization
XIX
In response, a major global push is under way to ensure that these difficult-to-reach
children – most of them in Africa and Asia – are immunized. At the same time, new
initiatives have been launched to accelerate both the development and deployment
of new life-saving vaccines.
The stakes are high. WHO has estimated that if all the vaccines now available against
childhood diseases were widely adopted, and if countries could raise vaccine
coverage to a global average of 90%, by 2015 an additional two million deaths
a year could be prevented among children under five years old. This would have
a major impact on meeting the global goal to reduce child deaths by two-thirds
between 1990 and 2015 (MDG 4). It would also greatly reduce the burden of illness
and disability from vaccine-preventable diseases, and contribute to improving child
health and welfare, as well as reducing hospitalization costs.
But even when the global goals have been met, success will be measured against
an additional benchmark – whether the achievements are sustainable. Solid building
blocks are being put in place – strengthening of health systems and immunization
programmes, new public-private partnerships for vaccine development and
immunization, new long-term global financing mechanisms, innovative and
sustainable delivery strategies, and improved advocacy and communication
strategies – to ensure that long-term progress is not sacrificed for short-term gains.
In addition, continued investments will be needed to accelerate the research
and development of urgently needed vaccines against diseases such as malaria,
tuberculosis, and acquired immunodeficiency syndrome (AIDS), which together
account for over four million deaths a year and a high burden of disease, mainly in
developing countries.
This edition of the State of the world’s vaccines and immunization focuses on the
major developments in vaccines and immunization since 2000. Part 1 (Chapters 1–5)
examines the impact of immunization on efforts to meet the MDGs, especially the
Executive summary
XX
goal to reduce deaths among children under five. It looks at the development and
use of vaccines and at the safeguards that have been put in place to ensure their
safety, efficacy, and quality. It sets out the progress and challenges in meeting the
immunization-related global goals, and looks at the cost of scaling up immunization
coverage to meet these goals, and efforts to ensure that the achievements are
sustainable in the long term. Finally, it looks beyond 2015 to likely changes in the
immunization landscape.
Part 2 focuses on over 20 vaccine-preventable diseases and reviews progress since
2000 in efforts to protect populations against these diseases through the use of
vaccines.
Immunization and human development
Chapter 1 outlines the progress in vaccines and immunization over the past decade
against the backdrop of a changing health and development landscape.
In September 2000, leaders of more than 190 countries signed the United Nations
Millennium Declaration, which committed the international community to eight
development goals aimed at reducing poverty and improving human development.
One of these goals calls for a massive reduction in deaths among children under five
years old – a two-thirds drop in the under-five mortality rate between 1990 and 2015.
Most of the effort in achieving these goals is focused on developing countries, which
account for over 90% of deaths among children in this age group.
In 2005, the World Health Organization (WHO) and the United Nations Children’s
Fund (UNICEF) published the Global Immunization Vision and Strategy (GIVS) for
the decade 2006–2015. With an overriding focus on the need to ensure equity
in access to vaccines and immunization, the strategy sets out the steps that the
immunization community needs to take in order to contribute fully to the attainment
State of the world’s vaccines and immunization
XXI
of the MDG mortality reduction targets. Implementing the strategy calls for four main
approaches: protecting more people; introducing new vaccines and technologies;
integrating immunization with other components in the health system context; and
immunizing in the context of global interdependence.
The global goals have added a sense of urgency to vaccine-related activities and
spurred renewed efforts to complete, as far as possible, what the GIVS refers to as
“the unfinished immunization agenda”. The chapters which follow chart the progress
made so far in completing this agenda and in meeting the global goals.
A new chapter in vaccine development
Chapter 2 highlights the surge in vaccine development over the past decade and
outlines the reasons for this. It documents the unprecedented growth in the volume
of traditional childhood vaccines now being produced by manufacturers in developing
countries. And it reports on progress in efforts to assure the quality, safety, and
effectiveness of vaccines.
The first decade of this century has been the most productive in the history of vaccine
development. New life-saving vaccines have been developed for meningococcal
meningitis, rotavirus diarrhoeal disease, avian influenza caused by the H5N1 virus,
pneumococcal disease, and cervical cancer caused by human papillomavirus
(HPV).
The vaccine industry is experiencing a new, more dynamic period. Since the year
2000, the global vaccine market has almost tripled – reaching over US$ 17 billion
in global revenue by mid-2008, and making the vaccine industry one of the fastest
growing sectors of industry. Most of this expansion comes from sales in industrialized
countries of newer, more costly vaccines, which account for more than half of the
total value of vaccine sales worldwide.
Executive summary
XXII
The recent surge in new vaccine development is largely due to three key factors:
the use of innovative manufacturing technology, growing support from public-private
product development partnerships, and new funding resources and mechanisms
(see Chapter 4).
At the same time, there has been unprecedented growth in the capacity of
manufacturers in developing countries to contribute to the supply of the traditional
childhood vaccines. Overall, the demand for these traditional vaccines has also
grown since 2000, partly to meet the massive needs of the major initiatives put in
place to eradicate polio, and reduce the burden of measles and of neonatal and
maternal tetanus.
Since the early 1990s, the vaccine market has changed. Growing divergence
between the vaccines used in developing and industrialized countries, a drop in the
number of suppliers in industrialized countries, and a reduction in excess production
capacity led to a vaccine supply crisis beginning in the late-1990s. In response,
UNICEF – which procures vaccines to reach more than half (55%) of the world’s
children – established the Vaccine Security Strategy to ensure the uninterrupted and
sustainable supply of vaccines that are both affordable and of assured quality. While
the strategy succeeded in reversing the fall-off in the supply of vaccines to UNICEF,
vaccine supply remains heavily reliant on a limited number of vaccine manufacturers
and continued vigilance is needed.
Making sure that vaccines are safe, effective, and of good quality is a pivotal element
of vaccine development and deployment. It begins with the “infancy” of the vaccine,
usually in the laboratory, where its components are tested for criteria such as purity and
potency. It continues with clinical testing for safety and efficacy in humans, followed,
after licensure, by post-marketing testing of vaccine batches for consistency of the
production process, as well as surveillance to identify any potential cases of vaccine-
related adverse events.
State of the world’s vaccines and immunization
XXIII
Licensure, or approval for human use, is the most crucial step in the process. The
official body that grants the licence – the national regulatory authority – is the arbiter
of whether established standards have been met to ensure that a vaccine is of
assured quality.
All industrialized countries have a reliable, properly functioning vaccine regulatory
system, but only about one quarter of developing countries do. The international
health community has launched a series of initiatives, spearheaded by WHO, to
ensure that vaccines used in national immunization programmes are “vaccines of
assured quality”. The initiatives include a prequalification system established by
WHO to advise UN vaccine procurement agencies on the acceptability, in principle,
of vaccines available for purchase, and efforts to ensure that every country has a
reliable, properly functioning national regulatory authority.
Immunization: putting vaccines to good use
Chapter 3 highlights the achievements of immunization over the past decade and
reports on progress and challenges in efforts to reach more people with more
vaccines, to boost immunization coverage at the district level, and to target difficult-
to-reach children who have not been immunized. It also sets out some of the key
elements of an effective immunization programme.
Over the past decade, immunization programmes have added new and underused
vaccines to the original six – diphtheria, tetanus, pertussis, measles, polio, and
tuberculosis – given to young children. They include vaccines against hepatitis B,
Haemophilus influenzae type b (Hib) disease, mumps, pneumococcal disease,
rotavirus, rubella, and – in countries where needed – yellow fever and Japanese
encephalitis.
Executive summary
XXIV
Immunization averts an estimated 2.5 million child deaths a year, but despite the
successes, millions of children in developing countries – almost 20% of all children
born every year – do not get the complete immunizations scheduled for their first
year of life.
Reaching these children will require overcoming a number of critical barriers that have
slowed progress. A major barrier is the underlying weakness of the health system
in many developing countries. Another is the difficulty in delivering vaccines through
an infrastructure and logistical support system that is often overloaded. Yet another
is a lack of understanding about the importance of vaccines – especially among
the poorest populations – and a failure to actively demand access to immunization
services. The threat posed by false or unsubstantiated rumours about vaccine safety
is also a barrier to progress, as is the projected shortfall in funding needed to reach
the global immunization-related goals (see Chapter 4).
Efforts under way to overcome the barriers to expanded immunization include the
use of immunization campaigns and “outreach” operations that seek out population
groups not adequately covered by routine immunization programmes. In addition,
special initiatives, such as the Optimize project, have been launched to help countries
manage the growing complexity of immunization logistics (delivery and storage of
vaccines, for example) underpinning immunization activities.
The Reaching Every District (RED) strategy, launched in 2002, is designed to
strengthen immunization delivery at the district level, by encouraging district-level
immunization officials to adopt the principles of “good immunization practice”, such
as the identification and resolution of local problems, the organization of regular
outreach vaccine delivery services, and the involvement of communities in ensuring
adequate functioning of immunization services.
Another strategy aims to integrate immunization activities with other services
provided by the health system. Any contact that a health worker has with a child or
State of the world’s vaccines and immunization
XXV
mother at a health facility is also an opportunity to check immunization status and,
if need be, to administer vaccines. Conversely, a mobile team offering immunization
to a community can also distribute medicines, antimalarial bednets, and other health
commodities or interventions.
Community participation is a key factor in raising vaccine coverage. Creating
awareness of, and public demand for, the benefits of immunization is an essential
component of an active immunization programme. However, it is also important to
ensure that demand can be reliably met.
The availability of new vaccines against pneumococcal disease and rotavirus is
expected to have a rapid and major impact in global efforts to reduce child deaths
(MDG 4), prevent sickness, and, for pneumococcal disease, prevent disability. At the
same time, vaccination against these diseases provides a key opportunity to actively
promote the prevention and treatment of pneumonia and diarrhoea, which together
account for over one third of all deaths among children under five years old.
Surveillance and monitoring are the cornerstones of immunization programmes,
playing a key role in programme planning, priority setting, and mobilization of
resources, as well as in monitoring trends in disease burden, and assessing the
impact of disease control programmes and progress towards global goals. Since
2000, the increase in data-driven immunization initiatives (such as the RED strategy)
and the need for disease data to monitor the impact of new vaccines have highlighted
the need to strengthen surveillance and monitoring at all levels.
Disease surveillance systems are also expected to provide an early warning of
impending or ongoing outbreaks of disease. The revised International Health
Regulations, which entered into force in 2007, require WHO Member States to
establish and maintain core capacities for surveillance at the local, intermediate, and
national levels.
Executive summary
XXVI
Over the past decade, progress has been made in setting up or improving surveillance
systems for vaccine-preventable diseases. An example of a high-performance
surveillance system is the polio surveillance network, which enables rapid detection
of polio cases worldwide, and has been expanded in some countries to include
measles, neonatal tetanus, yellow fever, and other vaccine-preventable diseases.
Meanwhile, as vaccine coverage has increased and the incidence of vaccine-
preventable diseases has fallen – particularly in industrialized countries – there has
been an increase in concern about the potential side-effects of vaccines.
Making sure vaccines are made, used, and tested in accordance with internationally
accepted standards is one part of the effort to reduce the likelihood of a vaccine
producing an adverse event (see Chapter 2). The other part is having an efficient
post-marketing surveillance and investigation system in place that will rapidly pick
up and verify any rumours or reports of adverse events allegedly related to the use
of a vaccine.
Most industrialized countries have such a system, but many developing countries
lack the resources or experience required. To address this, WHO has established
a Global Advisory Committee on Vaccine Safety, made up of independent experts,
to assess and respond to reports and rumours about vaccine safety. In addition, in
2009, WHO established a Global Network for Post-marketing Surveillance of Newly
Prequalified Vaccines which have recently been introduced into national immunization
programmes.
State of the world’s vaccines and immunization
XXVII
Investing in immunization
Chapter 4 looks at the costs involved in scaling up immunization since 2000, and
examines the response of both new and established sources of immunization
funding.
Immunization is among the most cost-effective health interventions, but what does it
cost, and is the investment worth making? In the 1980s, total annual expenditure on
immunization in developing countries averaged out at an estimated US$ 3.50–5.00
per live birth. By 2000, the figure had risen only slightly to about US$ 6.00 per live
birth. Since 2000, GAVI Alliance (formerly known as the "Global Alliance for Vaccines
and Immunisation") support for immunization enabled many low-income countries
to strengthen their routine vaccine delivery systems and introduce underused
vaccines, such as hepatitis B, Hib, and yellow fever. Not unexpectedly, immunization
expenditure began to rise again.
By 2010, the average cost of immunizing a child is projected to rise to about
US$ 18.00 per live birth. Beyond 2010, scaling up vaccine coverage with new
vaccines – such as pneumococcal and rotavirus vaccines – to meet the MDGs and
the GIVS goals is likely to raise the cost above US$ 30.00 per live birth.
There are several reasons for these rising costs. For a start, new and underused
vaccines cost more than the traditional vaccines, although as the market and
demand expands, their costs should fall. A second reason is that the increased
quantities of vaccines place considerable pressure on the existing vaccine supply
chain, requiring expanded storage facilities and more frequent delivery of supplies. A
third is the “hidden” costs of introducing a new vaccine into a national immunization
programme, such as the costs of staff training, public information, and expanded
surveillance and monitoring. Fourth, is the increased cost of providing immunization
services for difficult-to-reach children.
Executive summary
XXVIII
Meeting the goals of the GIVS will mean protecting children against 14 diseases –
diphtheria, pertussis, tetanus, measles, polio, tuberculosis, hepatitis B, Hib, rubella,
meningococcal disease, pneumococcal disease, rotavirus, and (where needed)
Japanese encephalitis and yellow fever. If all countries immunize 90% of children
under five years of age with these vaccines, it is estimated that immunization could
prevent an additional two million deaths a year in this age group – making a major
contribution to the achievement of MDG 4.

A WHO-UNICEF analysis published in 2008 estimated how much it would cost
to attain the GIVS goals in 117 WHO low- and lower-middle-income Member
States between 2006 and 2015. The total bill came to US$ 76 billion, including
US$ 35 billion for the 72 countries that have a gross national income (GNI) per capita
below US$ 1000 (as of 2006). These countries are eligible for GAVI Alliance funding
and have received support for introducing underused and new vaccines as well as
support to strengthen their immunization systems.
Is the investment worth making? Data on the cost-effectiveness of immunization
confirm that it is. For example, the global eradication of smallpox, which cost
US$ 100 million over a 10-year period up to 1977, has resulted in savings of
US$ 1.3 billion a year in treatment and prevention costs ever since.
In addition to being a significant contributor to childhood deaths, vaccine-preventable
diseases also constitute a major cause of illness and long-term disabilities among
children both in industrialized and developing countries. The classic example of
prevention of serious disability has been the prevention of paralytic polio in hundreds
of thousands of children since the advent of the Global Polio Eradication Initiative
(GPEI).
Of the new vaccines, the pneumococcal vaccine has been shown to be associated
with a 39% reduction in hospital admissions due to pneumonia from any cause.
Among children who survive an episode of pneumococcal meningitis, a large
State of the world’s vaccines and immunization
XXIX
proportion are left with long-term disabilities. Similarly, the rotavirus vaccine has
been shown to reduce clinic visits and hospitalizations due to rotavirus diarrhoea by
95%.
Thus, while the impact on child deaths alone would be sufficient justification for the use
of vaccines in children in developing countries, the reduction of long-term disability
among children and the savings from reductions in clinic visits and hospitalization
more than justify their use in children everywhere.
Immunization has other far-reaching benefits beyond the positive impact on individual
and community health. A recent study by a Harvard School of Public Health team
found that by keeping children healthy and in school, immunization helps extend
life expectancy and the time spent on productive activity – thereby contributing to
poverty reduction (MDG 1).
Who pays the bill and how? In 2007, WHO’s 193 Member States were funding an
average 71% of their vaccine costs (33% in low-income countries). Of these, 86%
of countries reported having a separate line item for vaccines within their national
budget – a measure associated with increased budget allocations to vaccines and
immunization and with long-term political commitment to immunization. From the
WHO-UNICEF costing analysis, it is estimated that 40% of the costs of immunization
for the period 2006–2015 will be met by national governments.
Since 2000, immunization funding from multilateral, bilateral, and other funding
sources has increased by 13% (not adjusted for inflation). At the same time, there
has been a shift both in the way funds are channeled and in the way they are used.
At the global level, some bilateral donors have increasingly used the GAVI Alliance
as a channel for funding. At a country level, there has been a move away from a
project-based approach to the use of broad-based funding mechanisms to support
the health sector as a whole.
Executive summary
XXX
Health and immunization systems benefit substantially from targeted immunization
efforts such as the GPEI. A substantial proportion of the investment in polio eradication
has been spent on strengthening routine immunization and health systems, and on
achieving the goals of the GIVS.
In recent years, several innovative public-private partnerships and new financing
mechanisms have been introduced to provide predictable and sustainable
external financial support to help countries meet the immunization-related global
goals. The GAVI Alliance is a public-private global health partnership that provides
support to countries with a GNI per capita below US$ 1000, to strengthen their
health systems and immunization programmes, increase routine immunization
coverage, and introduce new and underused vaccines. As of the end of
2008, the Alliance had received a total of US$ 3.8 billion in cash and pledges
from public and private sector donors, and disbursed US$ 2.7 billion to eligible
countries. Over the period up to 2015, the Alliance has an estimated US$ 3 billion
funding gap out of the estimated US$ 8.1 billion total funding needed.
During its first phase (2000–2005), the GAVI Alliance focused on the introduction
of new and underused vaccines (hepatitis B, Hib, and yellow fever). During the
second phase (2006–2015) support is being expanded to new vaccines (rotavirus
and pneumococcal vaccines). In addition, the GAVI Alliance Board has approved
for possible future support a further package of vaccines to be offered to countries,
including HPV, Japanese encephalitis, rubella, and typhoid.
To meet concerns about financial sustainability, all GAVI-supported countries were
required to prepare a comprehensive multi-year plan for immunization, or cMYP. In
2007, the Alliance introduced a new co-financing system, which requires countries
to pay a gradually increasing share of the cost of their new vaccines, based on a
country’s GNI per capita. By the end of 2008, 30 countries had begun using this
system to pay for the introduction of the pentavalent vaccine (DTP-Hepatitis B-Hib),
rotavirus vaccine, and pneumococcal vaccine.
State of the world’s vaccines and immunization
XXXI
A new, innovative source of funding is the International Finance Facility for
Immunisation (IFFIm), which uses long-term legally binding commitments by donors
to issue bonds on the international capital markets. The sale of these bonds
provides cash that can be used by the GAVI Alliance to fund programmes. As of
early 2008, the bonds had raised US$ 1.2 billion from investors worldwide.
Another innovative financing mechanism is the Advance Market Commitment (AMC)
– a new approach to public health funding designed to accelerate the development
and manufacture of vaccines for developing countries. Conceived in 2005 by the
Center for Global Development, a pilot AMC for pneumococcal vaccine was launched
in 2007 by the Governments of Canada, Italy, Norway, the Russian Federation,
and the United Kingdom of Great Britain and Northern Ireland; the Bill & Melinda
Gates Foundation; the GAVI Alliance; and the World Bank; with an investment of
US$ 1.5 billion.
The good news is that more investment is being made in immunization and projected
trends indicate growing financing in the future. Yet, without further growth, expected
future funding from governments and donors will not be enough to sustain the gains
already achieved towards GIVS goals and the MDGs. “The real challenge,” the WHO-
UNICEF 2008 analysis report concluded, “will hinge on how national governments,
and the international community at large manage their roles and responsibilities in
reaching and financing the goals of the GIVS until 2015.”
Executive summary
XXXII
The view from the future
Chapter 5 looks forward over the next decade and considers how the immunization
landscape may have changed by 2020.
By the 2020s, the strategies put in place to reach the MDGs should have brought
deaths among children under five years old to an all-time low. Polio should be
eradicated, and measles eliminated in all countries. Neonatal and maternal tetanus
should no longer be exerting such a heavy toll on babies and mothers, and today’s
underused vaccines (against Hib disease, hepatitis B, and yellow fever) may have rid
the world of the lethal burden of these diseases. The use of new vaccines against
pneumococcal, rotavirus, meningococcal, and HPV disease may have inspired a
new, more ambitious set of international health and development goals. Vaccines
may have been developed that can turn the tide against malaria, tuberculosis, and
AIDS.
Over the next decade or so, an increasing number of developing countries will be
using the new vaccines coming onto the market. Some of these (such as the HPV
vaccine) will be given to adolescents; others (such as the influenza vaccine) will be
given to adults. However, there is as yet little knowledge or experience of reaching
older age groups in developing countries, except through special immunization
campaigns. School-based immunization is one possible solution, especially since
school attendance is increasing in many developing countries.
New vaccine delivery systems are also anticipated. Devices that use needles may
have been largely replaced with new approaches such as aerosol formulations
sprayed in the nose (already available for an influenza vaccine) or lungs (currently
being tested for several vaccines); adhesive skin patches; drops under the tongue;
and oral pills.
State of the world’s vaccines and immunization
XXXIII
Another potential breakthrough is the development of an increasing number of
vaccines that are heat-stable. When supplied with a vaccine vial monitor to check
exposure to heat, these vaccines should be available for use outside the cold chain
– greatly relieving the pressure on the cold chain and logistics.
By 2020, manufacturers in developing countries may have acquired the capacity to
make their own state-of-the-art vaccines tailored to meet their own specific needs.
Moreover, their contribution to global vaccine supply may be on a more equal footing
with the industrialized countries – a development likely to increase competition.
But the world will face fresh challenges. As of early 2009, countries throughout the
world are facing economic recession and financial turmoil, which threaten to unravel
hard-won gains. Climate change looms large and is likely to alter the epidemiological
landscape in which vaccines and immunization operate – bringing new health
challenges.
Despite this, the overall picture is one of cautious optimism, enthusiasm, energy,
and dedication. Vaccines can make a major contribution to achieving the MDGs.
Vaccine development is in a dynamic phase and more people are being reached
with vaccines. New public-private partnerships and product development groups
are becoming important drivers of vaccine development and deployment. And over
the next two decades, public demand for vaccines and immunization is expected
to rise. As it does so – and far into the future – there is every reason to believe that
immunization will continue to be a mainstay of public health.
State of the world’s vaccines and immunization
1
Part 1:
Progress and challenges in
meeting global goals
State of the world’s vaccines and immunization
Chapter 1. Immunization and human development
2
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3
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33
Immunization and
human development
Chapter 1
Chapter 1. Immunization and human development
4 4
Chapter 1. Immunization and human development
Key messages
• Immunization is key to achieving the Millennium
Development Goals (MDGs), especially the goal to reduce
deaths among children under five years old (MDG 4).
• Vaccines prevent more than 2.5 million child deaths a year.
• Available vaccines could prevent an additional two million
deaths a year among children under five years old.
• The introduction of new vaccines against pneumococcal
disease and rotavirus could have a rapid impact – within
three to five years – on reducing the high toll of sickness,
disability, and deaths among children under five years old.
• Over 100 million children are immunized every year before
their first birthday.
• Around 24 million children under one year old – almost
20% of the children born every year – are not being
reached with vaccines.
State of the world’s vaccines and immunization
5
Since the turn of the century, several positive changes have occurred in the world
of human development. People are living longer, bringing the global average life
expectancy at birth to 69 years for women and 65 years for men (2). For the first
time in documented history, the number of children under five years old dying every
year has fallen below 10 million (3). Investment in health has taken off in earnest
within the donor community – a trend reflected in the birth of several major global
partnerships, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria; the
GAVI Alliance; and the International Health Partnership.
Too many problem areas, though, are still waiting for change. Inequalities and
inequities still roam freely across the globe. About nine million children under
five years old are still dying every year – most of them in developing countries.
Undernutrition is an underlying factor in about one third of all deaths in children.
Among all age groups, AIDS, tuberculosis, and malaria kill more than four million
people a year; lower respiratory infections (mainly pneumonia) account for over four
million deaths, and diarrhoeal diseases account for over two million deaths (4). And
every year more than half a million women – almost all (99%) in developing countries
– die from pregnancy-related causes (5). And these are only a few examples.
The year 2000 marked a turning point in the world’s reaction to these inequities.
In September of that year, leaders of more than 190 countries signed the United
Nations Millennium Declaration, which committed the international community to
the task of removing the “abject and dehumanizing conditions” holding more than
one billion of the world’s population in the grip of poverty, disease, and premature
death. Alleviating the inequity of that burden is part of the task. Reducing the toll of
deaths among children under five years old is another. Yet another is to seek out and
remedy the preventable poverty, disease and death among neglected population
groups that is hidden beneath promising regional or national indicators of progress.
One of the eight MDGs that emerged from the Millennium Declaration calls for a
drastic reduction in deaths among children under five years of age, specifically, a
Chapter 1. Immunization and human development
6
two-thirds drop in the under-five mortality rate between 1990 and 2015 (MDG 4).
Most of the effort in achieving this goal focuses on developing countries, which
account for over 90% of child deaths.
Immunization is key to achieving the MDGs, especially the goal to reduce deaths
among children under five years old (MDG 4). Reducing these deaths means
providing more children, not only with vaccines, but also with life-saving drugs,
antimalarial bednets, schooling, sanitary living conditions, clean water, and other
essentials that are mostly taken for granted in the better-off parts of the world. It also
means addressing the global imbalance in spending on health, where developing
countries – with 85% of the world’s population – account for only 12% of global
spending on health (6).
18
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Year
16
14
12
10
8
6
4
2
1970
17.0
1980
14.1
1990
12.8
1995
11.9
2000
10.5
2005
9.6
2007
9.2
2015
4.3
0
Figure 1
Trends in global mortality in children under five years old
Source: UNICEF Programme Division, 2009
State of the world’s vaccines and immunization
7

One change, however, that could seriously imperil efforts to battle inequity,
preventable disease, death, and poverty, is the collapse of global financial markets
in the last months of 2008, and the economic slowdown that has since swept
over the world. United Nations Secretary-General Ban Ki-moon has expressed
deep concern about the impact of the crisis “particularly on the poorest of the poor
and the serious setback this is likely to have on efforts to meet major goals”.
Much will depend on the continued commitment of governments and the
international community to sustain and build on their efforts to improve child
survival and meet the MDGs. With the renewed energy and enthusiasm that now
pervades the vaccine landscape, the time is ripe for accelerating the role of life-saving
N
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800
700
600
500
400
300
200
100
Pneumococcal
diseases*
Rotavirus* Measles Hib* Pertussis Tetanus
(neonatal and
non-neonatal)
0
Figure 2
Leading causes of vaccine-preventable death in children under
five years old, 2004
* WHO/Department of Immunization, Vaccines and Biologicals estimates based on
Global Burden of Disease, 2004 estimates. Pneumococcal diseases and Hib
estimates are for the year 2000.
Source: (4)
Chapter 1. Immunization and human development
8
vaccines and other linked health interventions in global efforts to achieve the MDGs.
At the same time, efforts are needed to ensure that the benefits of immunization are
increasingly extended to adolescents and adults, to protect against diseases such
as influenza, meningitis, and vaccine-preventable cancers that occur in adulthood.
In addition, ongoing vaccine research and development efforts must be intensified
to accelerate the development of urgently needed vaccines against diseases such
as malaria, tuberculosis, and AIDS, which affect millions of people every year and
contribute to increasing poverty.

All countries have national immunization programmes, and in most developing
countries, children under five years old are immunized with the standard WHO-
recommended vaccines that protect against eight diseases – tuberculosis,
diphtheria, tetanus (including neonatal tetanus through immunization of mothers),
pertussis, polio, measles, hepatitis B, and Hib. These vaccines are preventing more
than 2.5 million child deaths each year. This estimate is based on assumptions of
no immunization and current incidence and mortality rates in children not immunized
(World Health Organization, Department of Immunization, Vaccines and Biologicals,
unpublished).
Today, over 100 million children under one year of age are immunized every year with
the required three doses of diphtheria-tetanus-pertussis (DTP) vaccine. However,
24 million children are not being reached with vaccines: in 2007, over 10% of
children under one year old in developing countries were not receiving even one
dose of DTP vaccine, compared with 2% in industrialized countries.
Most of these 24 million unimmunized or incompletely immunized children live in
the poorest countries, where many factors combine to thwart attempts to raise
vaccine coverage rates – fragile or non-existent health service infrastructure, difficult
geographical terrain, and armed conflict, to mention just three. Other unimmunized
children live in countries that can afford, but have not given priority to, acquiring or
maintaining the infrastructure and human resources required to deliver immunization.
State of the world’s vaccines and immunization
9
And others are refugees or homeless children, beyond the reach of routine
immunization. Failure to reach these different groups of children with vaccines is
jeopardizing the massive efforts and funding being invested in expanding the
use of currently underused vaccines (such as the Hib, hepatitis B, and yellow
fever vaccines), as well as in major disease-defeating drives, such as eradicating
polio, reducing child deaths from measles, and eliminating maternal and neonatal
tetanus.
The good news is that strategies are being implemented to overcome these
obstacles to immunization. Some strategies aim at strengthening the ability of health
systems to deliver health care, including immunization; others use immunization
campaigns and similar approaches to bring immunization to more people in districts
where vaccine coverage is low.
Good news comes also from the vaccine development area. Since 2000, for
example, the global vaccine supply landscape has changed. Manufacturers
in developing countries are emerging as a significant presence on the vaccine
market, with a perceptibly positive impact on the affordability of vaccines and the
sustainability of vaccine supply. Manufacturers based in industrialized countries are
Nurse Justina Munoz Gonzalez
about to vaccinate four-month
old Olga Damaris outside her
home near the remote village
of San Pablo near Murra in
the Nueva Segovia state of
Nicaragua.
Chapter 1. Immunization and human development
10
expanding their presence in developing countries and are working increasingly with
international health organizations to make vaccines that are designed for use in
developing countries and affordable by these countries. In addition, the development
of new vaccines, and efforts to put these vaccines into use in the poorer countries,
are receiving a substantial boost from more than a dozen new public-private
partnerships created specifically for this purpose. And, most encouragingly,
underpinning the new vaccine landscape is an influx of new financial resources and
an array of new strategies and mechanisms for sustaining and managing these
resources. The overall effect of these changes is to stimulate and revitalize all facets
of the vaccine arena – demand, supply, and use.
Over the past decade, new vaccines have become available that protect against
three organisms – the pneumococcus, rotavirus, and human papillomavirus (HPV).
While HPV is a cause of premature deaths from cancers that occur in adulthood,
pneumococcal disease and rotavirus diarrhoea together account for 1.3 million
deaths among children under five years old – 12% of all deaths among this age
group – as well as high rates of sickness and, for pneumococcal disease, disability.
In a recent analysis (7), WHO estimated that if all the vaccines currently available
against childhood diseases are widely adopted, and if immunization programmes
can raise vaccine coverage to a global average of 90%, vaccines would prevent
an additional two million deaths a year among children under five by 2015 – making
a major contribution to MDG 4. This projection is based on unpublished WHO
estimates of the expected future cohort of children under five, and assumptions of no
immunization and current incidence and mortality rates in children not immunized.
For any country, however, the decision to adopt a new vaccine cannot be taken
lightly: there are issues of cost, logistics (storage space and transportation,
etc.), staff training, sustainability, and other considerations. However, immunization
– even with the addition of the new, more costly vaccines – remains one of the most
State of the world’s vaccines and immunization
11
Box 1
Global Immunization Vision and Strategy (GIVS) goals
By 2010 or earlier:
• Increase coverage. Countries will reach at least 90% national vaccination coverage
and at least 80% vaccination coverage in every district or equivalent administrative
unit.
• Reduce measles mortality. Globally, mortality due to measles will have been
reduced by 90% compared to the 2000 level.
By 2015 or earlier:
• Sustain coverage. The vaccination coverage goal reached in 2010 will have been
sustained.
• Reduce morbidity and mortality. Global childhood morbidity and mortality due
to vaccine-preventable diseases will have been reduced by at least two thirds
compared to 2000 levels.
• Ensure access to vaccines of assured quality. Every person eligible for
immunization included in national programmes will have been offered vaccination
with vaccines of assured quality according to established national schedules.
• Introduce new vaccines. Immunization with newly introduced vaccines will have
been offered to the entire eligible population within five years of the introduction of
these new vaccines in national programmes.
• Ensure capacity for surveillance and monitoring. All countries will have
developed the capacity at all levels to conduct case-based surveillance of vaccine-
preventable diseases, supported by laboratory confirmation where necessary, in
order to measure vaccine coverage accurately and use these data appropriately.
cost-effective health interventions. The challenge is to get vaccines into use in the
countries where they are most needed, and to do so quickly.
Responding to this challenge, in 2005, WHO and UNICEF published the Global
Immunization Vision and Strategy (GIVS) for the decade 2006 to 2015 (8).
Chapter 1. Immunization and human development
12
Equality and equity are central to the GIVS vision. The GIVS strategy foresees a
world in which “every child, adolescent and adult has equal access to immunization”,
and where “solidarity among the global community guarantees equitable access
for all people to the vaccines they need”. Implementing the strategy calls for four
main approaches: i) protecting more people; ii) introducing new vaccines and
technologies; iii) integrating immunization with other components in the health
systems context; and iv) immunizing in the context of a globally inter-linked,
interdependent health and development system.
This report chronicles the efforts being made since 2000 to complete, as far as
possible, what the GIVS calls the “unfinished immunization agenda”. It is unlikely,
however, that the unfinished agenda will ever be finished as new infections will
undoubtedly emerge; new vaccines will continually be needed; new ways of
overcoming obstacles to making use of new vaccines will have to be found; and
new global crises – such as the financial crisis that has engulfed the world since the
last months of 2008 – may threaten the sustainability of funding for vaccine-related
activities. Nevertheless, as of early-2009, and despite the economic downturn, the
vaccine community allows itself a degree of cautious optimism. If the optimism turns
out to be justified, vaccines and immunization will have a good chance of realizing
their potential to help make the world a safer, more equitable, place for all – not only
for people alive today, but also for future generations.
• Strengthen systems. All national immunization plans will have been formulated
as an integral component of sector-wide plans for human resources, financing and
logistics.
• Assure sustainability. All national immunization plans will have been formulated,
costed and implemented so as to ensure that human resources, funding and
supplies are adequate.
Source: (8)
State of the world’s vaccines and immunization
13
Box 2
What’s so special about vaccines?
Vaccines are special.
First, unlike many other health interventions, they help healthy people stay healthy and
in doing so help to remove a major obstacle to human development.
Second, they benefit not only individuals but also communities, and even entire
populations (the eradication of smallpox is a case in point).
Third, for most vaccines, their impact on communities and populations is more rapid than
that of many other health interventions: between 2000 and 2007, for example, global
mortality from measles was reduced by 74% (from 750 000 to 197 000 (9)). Today, it is
estimated that new vaccines against pneumococcal disease and rotavirus could have
a rapid impact – within three to five years – in reducing the high burden of sickness,
disability (from pneumococcal disease), and deaths among children under five years old.
Finally, vaccines are both life- and cost-saving. Recent data show that immunization, even
with more expensive vaccines, continues to be good value for money (see Chapter 4).
Not surprisingly, the United States’ Centers for Disease Control and Prevention (CDC)
put vaccination at the top of its list of ten great public health achievements of the
20
th
century. Furthermore, in 2008, a panel of distinguished economists convened
by the Copenhagen Consensus Center – an international think-tank that advises
governments and philanthropists how best to spend aid and development money –
put expanded immunization coverage for children in fourth place on a list of 30 cost-
effective ways of advancing global welfare (see Table).
Table: The ten most cost-effective solutions to major global challenges, Copenhagen
Consensus 2008
Source: The Copenhagen Consensus 2008 (10)
Solution Challenge
1 Micronutrient supplements for children (vitamin A and zinc) Malnutrition
2 The Doha development agenda Trade
3 Micronutrient fortification (iron and salt iodization) Malnutrition
4 Expanded immunization coverage for children Diseases
5 Biofortification Malnutrition
6 Deworming and other nutrition programmes at school Malnutrition & Education
7 Lowering the price of schooling Education
8 Increase and improve girls’ schooling Women and development
9 Community-based nutrition promotion Malnutrition
10 Provide support for women’s reproductive role Women and development
Chapter 1. Immunization and human development
14
Ch Ch Ch Chap ap ptte teerrr 11. 11. IImm mmunization and human deeve velo loo lopm pm pm pm pmen en en en enttttttt
1444
State of the world’s vaccines and immunization
15
State of the world’s vaccines and immunization
115 115 15
A new chapter
in vaccine development
Chapter 2
Chapter 2. A new chapter in vaccine development
16
Key messages
• The first decade of the 21
st
century has been the most
productive in the history of vaccine development.
• New life-saving vaccines have been developed, and others
will soon be available.
• New vaccines are urgently needed to reduce illness
and deaths from high-burden diseases such as malaria,
tuberculosis, and AIDS.
• Most low-cost traditional vaccines are now produced by
vaccine manufacturers in developing countries.
• Public-private partnerships are accelerating the availability
of new vaccines.
• Systems have been put in place to ensure the safety,
effectiveness, and quality of all vaccines.

State of the world’s vaccines and immunization
17
State of the world’s vaccines and immunization
A vaccine boom
Since the turn of the century, the mood in the vaccine community has been
decidedly enthusiastic – and for good reason. Two diseases have been added to
the list of vaccine-preventable diseases, bringing the total number to a record of
over 30. In addition, the vaccine industry has put 25 new vaccine formulations
on the market – several specifically designed for use in age groups (adolescents
and elderly people, for example) and in populations (in developing countries, for
example), that have in the past not been priority targets for vaccine developers.
By the end of 2008, according to recent unpublished data, the total number of
vaccine “products” (all formulations combined) had reached a record of over 120,
making the first decade of this century the most productive in the history of vaccine
development.
Enthusiasm also stems from the exceptionally large number of candidate vaccines
in the late stages of research and development (R&D) – over 80 according to recent
unpublished data. Furthermore, about 30 of these candidates aim to protect against
diseases for which there are no vaccines currently available (11).
Explaining the new momentum
Compared with the recent past, an increase in the use of innovative vaccine
technology by the R&D-based vaccine industry, and a greater sharing of technology
between manufacturers in industrialized countries and emerging market producers,
have played a substantial role in the current upswing in productivity of the
global vaccine industry. Another stimulus to vaccine development has come from
public-private product development partnerships, whose numbers have grown
significantly over the past decade: there are now close to 30, of which half have
appeared since the year 2000. The current surge in vaccine development is also
the result of new funding resources and new funding mechanisms (see Chapter 4).
18

Chapter 2. A new chapter in vaccine development
Their arrival on the scene reflects a new concern of the global health and
development community over the unmet needs of developing countries for vaccines
and immunization.
The unparalleled growth in vaccine development, however, has been achieved in
the face of several constraints. For example, some vaccines under development
against particularly complex pathogens, such as the malaria parasite and the AIDS
virus, require the application of innovative research and manufacturing technologies
that have only recently become available (see Box 3). The rising cost of producing a
vaccine – upwards of US$ 500 million (1) – is also a constraining factor, due partly
to increasingly stringent regulatory oversight and the resulting greater industry
investment in more complex and more costly manufacturing technology. Vaccine
manufacturers also face a high risk of failure: only one in four to five candidate
vaccines ends up as a marketable vaccine (12).
Technology comes of age
Vaccine industry executives attribute much of the surge in new vaccine development
to the “maturing” of breakthroughs in biotechnology that occurred in the 1980s
and 1990s. A recent analysis (13) points to a “technological revolution [which has]
removed most of the technical barriers that formerly limited vaccine developers”
and to the fact that “biotechnology in the current era of vaccine development has
enabled totally unprecedented advancements in the development of vaccines”.
19

State of the world’s vaccines and immunization
Reverse vaccinology
The science of genomics has provided scientists with the complete genome
sequences of more than 300 bacterial species – most of them responsible for
human disease (14). Researchers use an organism’s genome to pick out the genes
most likely to correspond to conserved antigens that could be used in a vaccine.
Once identified, the genes can be combined and inserted into a different, rapidly
multiplying organism – such as yeast – to produce candidate antigens, which
are then screened for their ability to produce protective immune responses. This
Box 3
AIDS and malaria defy science
The plasmodium parasite that causes malaria and the human immunodeficiency virus
(HIV) that causes AIDS are both adept at evading human immune defences. Both are
able to alter the configuration of the immunity-stimulating molecules (antigens) they
carry and that would otherwise signal their presence to their host’s immune system.
This antigenic variability occurs not only within a single person but also between
different people, different population groups, and different geographical locations.
The malaria parasite also has an additional immunity-evading capability. As it passes
through the different anatomical parts of its human and mosquito hosts, it turns into
a different biological life-stage, presenting its host’s immune system each time with
a different set of antigens.
One of the most devastating properties of HIV is that it attacks its host’s immune
system – the very system designed to protect the human host against infections.
HIV is characterized by extremely high levels of genetic variability and rapid evolution.
HIV strains can easily recombine giving birth to complex recombinant or mosaic
viruses – called “circulating recombinant forms” or CRFs – some of which can play
an important role in regional sub-epidemics. To date, more than a dozen genetic
HIV subtypes and up to 24 different recombinant forms have been reported. The
impact of such enormous genetic variability on the biological properties of the virus,
its transmissibility, pathogenic properties, as well as vaccine development remains
unclear and complicates significantly the development of broadly effective novel
prevention tools.
20

Chapter 2. A new chapter in vaccine development
approach is known as “reverse vaccinology”: it starts with a genetic blueprint of
an organism and rapidly generates antigens of interest.
In contrast, the more time-consuming conventional approach starts with the
pathogenic organism itself, which is grown in the laboratory (a lengthy process
made more complex by the fact that some pathogens cannot easily be grown in
a laboratory), and from which a limited number of antigens are isolated. These are
then tested for their ability to induce potentially protective immune responses.
Reverse vaccinology has not yet produced a licensed vaccine but researchers have
used it to develop several candidate vaccines, some of which are currently in the
late stages of clinical testing (for example, a candidate vaccine against group B
meningococcus).
Conjugation technology
Conjugation technology has also spurred vaccine development. First used in
the 1980s, conjugation allows scientists to link (conjugate) the sugar molecules
on the outer envelopes of certain bacteria – such as the pneumococcus, the
meningococcus, and the Hib bacterium – to strongly immunogenic “carrier” proteins.
Older vaccines of this type relied on the sugar molecules to stimulate immunity,
but usually failed to elicit protective immunity in children under two years of age.
The new conjugate vaccines, however, do protect young children. In addition,
unlike the older vaccines, the new conjugate vaccines stimulate the type of immune
cells needed to create a long-lasting memory of the pathogen: the immunity
from those cells can thus be boosted by subsequent vaccine doses or by exposure
to the pathogen itself. Again, unlike the older vaccines, conjugate vaccines have
even been shown to reduce the numbers of healthy carriers of the pathogen in
a community, thereby producing a so-called “herd immunity” that protects
even unvaccinated people from the pathogen. A case in point is the use of the
21

State of the world’s vaccines and immunization
pneumococcal conjugate vaccine in the United States of America: one year after its
introduction, the incidence of invasive pneumococcal disease fell by 69% among
vaccinated children under two years of age – but also by 32% in adults (aged 20–39
years) and by 18% among older age groups (aged over 65 years), none of whom
had ever received the vaccine (15).
Adjuvants
Adjuvant technology, too, has evolved. Adjuvants are substances that help a
vaccine to produce a strong protective response. They can also reduce the
time the body takes to mount a protective response and can make the immune
response more broadly protective against several related pathogens. Progress in
understanding how the human immune system recognizes the molecules carried
by pathogens has led to the development of a host of adjuvants. Up to now, only
five of the 20 or so types of adjuvants under development have been licensed
for use in vaccines administered to humans (16). Several vaccine manufacturers
have invested heavily in the search for safe and effective adjuvants, notably for
vaccines against pandemic influenza and HPV. The malaria candidate vaccine –
RTS,S/AS01 – which is due to enter advanced (Phase 3) clinical trials in Africa in
2009, has also benefited from a 15-year research programme undertaken by its
manufacturer to produce an innovative adjuvant system comprising three types of
adjuvant.
Cell substrates
Cells derived from humans and from animals (such as monkey kidney cells or
chicken embryo cells), have been used for over 50 years as “substrates” on which
the viruses used to make vaccines against viral diseases (influenza, measles, and so
on) are grown. Recent advances in technology and research have led manufacturers
22

Chapter 2. A new chapter in vaccine development
to explore a broad array of new cell substrates that use, for example, cells from
dogs, rodents, insects, plants, and other living organisms. Some of these substrates
are “immortal” – continuous cell lines that avoid the ongoing use of animals. The
ultimate aim is to find technologies that will produce greater yields of vaccine virus
and facilitate their harvesting from these cell substrates.
Box 4
The role of industry in vaccine research and development
The role of industry in vaccine R&D involves at least four groups of actors:
Big Pharma – with regard to vaccine production – is a group of five major
pharmaceutical companies. These firms do not invest in in-house basic research
(which is conducted mainly by academic institutions), and are only minor players in
the applied research area. Their main role is in vaccine evaluation. They are powerful
engines for the development, industrialization, registration, and marketing of vaccines,
but are increasingly outsourcing some of these functions.
Biotechs concentrate on applied research, pre-clinical development, and clinical
development up to Phase 2 clinical trials. They constitute the main source of innovation
and account for nearly 50% of Big Pharma’s financial investment in R&D. Although
these companies are expected to play an increasingly important role in vaccine R&D,
their ability to penetrate downstream functions such as Phase 3 clinical trials, and
the industrialization and commercialization of vaccines, is often limited by structural,
financial, and human constraints. As the recent case of Roche taking over Genentech
in 2009 has demonstrated, the largest Biotech companies that manage to make their
way to the market are usually taken over and absorbed by Big Pharma.
Producers in emerging markets and developing countries have in recent years
become major suppliers of traditional children’s vaccines and of a few combination
vaccines. Some companies have even contributed to the development of new
products. They have strengthened their industrial capability and become credible
players, prompting Big Pharma to seek alliances and partnerships with them, even
though their innovation potential is still limited by their regulatory environment and
financial capacity. This situation is likely to evolve.
Sub-contractors are increasingly engaged in all sectors of the pharmaceutical
industry, including the vaccine business. One major development is the emergence
23

State of the world’s vaccines and immunization
of large sub-contractors capable of large-scale production on behalf of Biotechs
and even of Big Pharma. Strategic restructuring may in the future enable some
sub-contractor companies to become vaccine producers and suppliers in their own
right.
Big Pharma is expected to remain a major and indispensable driver of innovation in
the field of vaccines and immunization. This is because the companies in question
have:
• the ability to rapidly mobilize large financial resources
• skilled technical and regulatory expertise in many domains
• a large workforce that is generally competent and well trained
• management tools which increase global competitiveness.
Although this situation is not static, fundamental change will take time. In the meantime,
it is critical that non-industrial actors – while recognizing the unique role played by
the vaccine industry – should be able to fully engage in dialogue and collaborate
more effectively with the private sector, in particular in the context of public-private
partnerships.
New licensed vaccines
Several new vaccines and new vaccine formulations have become available since
the year 2000. These include:
• the first conjugate vaccine against the pneumococcus, a bacterium which,
according to WHO estimates of the year 2000, causes more than 14.5 million
episodes of serious pneumococcal disease and more than 800 000 deaths
annually among children under five years old, as well as high rates of meningitis-
related disability among children who survive (including mental retardation,
seizures, and deafness);
• two new vaccines against rotavirus (replacing a previous vaccine withdrawn from
the market because of adverse events) – a virus which, according to WHO 2004
estimates, accounts annually for an estimated two million hospitalized cases of
severe diarrhoeal disease in children (17) and kills an estimated 527 000 children
a year;
24

Chapter 2. A new chapter in vaccine development
• the first two vaccines against HPV, a virus which causes cervical cancer.
According to GLOBOCAN estimates, there were 493 000 new cases of cervical
cancer and 274 000 related deaths in 2002 (18). The HPV genotypes 16 and 18,
included in both vaccines, are responsible for 70% of cervical cancer and also
cause cancers of the vulva, vagina, anus, penis, head and neck;
• the first DTP combination vaccines specifically formulated for adolescents and
adults;
• the first vaccines for human use against avian influenza caused by the H5N1
virus, responsible since 2003 for the deaths and culling of tens of millions of birds,
and for over 400 reported cases among people in 16 countries as of May 2009,
of whom more than 60% have died (19). These vaccines are not envisaged at the
time of writing for use in large population groups.
Vaccines in the pipeline
A large number of vaccine products are currently in the pipeline and are expected
to become available by 2012. According to recent unpublished data, more than
80 candidate vaccines are in the late stages of clinical testing. About 30 of these
candidate vaccines aim to protect against major diseases for which no licensed
vaccines exist, such as malaria and dengue. If Phase 3 trials of the RTS,S/AS01
candidate vaccine against malaria go well, this vaccine could be licensed by 2012.
If successful, it would be the first vaccine against a parasite that causes disease
in humans. Several candidate vaccines are also under development against dengue,
another mosquito-borne disease of major public health concern. There is no specific
treatment for dengue fever – a severe influenza-like illness that can occur in more
serious forms, including dengue haemorrhagic fever. Two candidate vaccines
against dengue virus have been evaluated in children, and one candidate vaccine is
currently being evaluated in a large-scale trial. A successful vaccine needs to confer
25

State of the world’s vaccines and immunization
immunity against all four circulating dengue viruses, and evaluation of the vaccines
is complex. However, researchers are hopeful that dengue vaccines will become
available in the coming years.
About 50 candidate vaccines target diseases for which vaccines already exist,
such as pneumococcal disease, Japanese encephalitis, hepatitis A, and cholera:
however, these candidates hold the promise of being more effective, more easily
administered, and more affordable than the existing vaccines.
Phase 3 malaria vaccine
trial participants and their
mothers (on bench) with Dr
Salim Abdulla (standing left)
and vaccination staff at the
Bagamoyo Research and
Training Centre of the Ifakara
Health Institute in the United
Republic of Tanzania.
26

Chapter 2. A new chapter in vaccine development
Box 5
Product development partnerships
Product development partnerships are typically not-for-profit entities mandated to
accelerate the development and introduction of a product, such as a vaccine. They
are funded by donors to promote research and development, often through links
between developing country academic programmes, biotechnology companies,
and vaccine manufacturers. Product development partnerships have encouraged
investment in various aspects of vaccine development, including large-scale clinical
trials of vaccines against diseases prevalent in the poorest countries of the world.
Examples of product development partnerships concerned primarily with vaccine
development are the:
• International AIDS Vaccine Initiative (launched in 1996)
• Global HIV Vaccine Enterprise (launched in 2004)
• Aeras Global TB Vaccine Foundation (launched in 1997)
• European Malaria Vaccine Initiative (launched in 1998)
• PATH Malaria Vaccine Initiative (launched in 1999).
Product development partnerships that lean more towards vaccine introduction than
development are the:
• GAVI-funded Pneumococcal Accelerated Development and Introduction Plan
(PneumoADIP)
• Rotavirus Accelerated Development and Introduction Plan (RotaADIP)
• Hib Initiative
Each of these three partnerships is ending in 2009.
The Meningitis Vaccine Project (launched in 2001) is involved in both vaccine
development and introduction.
27

State of the world’s vaccines and immunization
Supplying vaccines for a changing world
A rapidly expanding market
Over the first eight years of this century, the global vaccine market almost tripled,
reaching over US$ 17 billion in global revenue by mid-2008, according to recent
estimates (20). This increase represents a 16% annual growth rate, making the
vaccine market one of the fastest-growing sectors of industry generally – more than
twice as fast as that of the therapeutic drugs market. Most of the expansion comes
from sales in industrialized countries of newer, relatively more expensive vaccines,
which account for more than half of the total value of vaccine sales worldwide
(20). These vaccines include the two second-generation rotavirus vaccines, two
recombinant HPV vaccines, a varicella zoster (shingles) vaccine, and a conjugate
pneumococcal vaccine (which alone totalled US$ 2 billion in sales between 2000
and 2007). The commercial success of these products, according to a recent
vaccine market analysis (21), “is sparking renewed interest and investment in the
vaccine industry, which had appeared moribund in the 1980s”.
A concentrated industry
The vaccine supply scene is dominated by a small number of multinational
manufacturers based in industrialized countries. As of mid-2008, five major firms
producing vaccines – all Big Pharma companies – account for more than 80% of
global vaccine revenue. The remaining revenue is divided among more than 40
manufacturers in developing countries.
By contrast, in terms of volume, only 14% of the vaccine required to meet global
vaccine demand comes from suppliers in industrialized countries. The remaining
86% is met by suppliers based in developing countries. The striking disparity
28

Chapter 2. A new chapter in vaccine development
between revenue and volume reflects the large volume of low-cost, mainly traditional
vaccines produced by these developing country suppliers, primarily for use in their
own or in other low- and middle-income countries – a market that represents 84%
of the world’s population.
The growth in the manufacturing capacity of suppliers in developing countries is
also a response to increasing demand from the two United Nations public-sector
procurement entities – the Pan American Health Organization (PAHO) and UNICEF
(which also buys vaccines on behalf of the GAVI Alliance). The purchases of these
agencies account for about 5–10% of the value of all vaccine doses produced in
the world. UNICEF alone bought 3.2 billion vaccine doses in 2007 at a value of
US$ 617 million (22) – mainly the traditional vaccines intended for use in developing
countries. In 2000, 39% of vaccine doses purchased by these agencies came from
suppliers in developing countries. By 2007, that proportion had soared to 60%.
A good part of the increase is due to the vaccine requirements of the initiatives
mounted to eradicate polio, eliminate neonatal tetanus and maternal tetanus, and
reduce deaths from measles.
Planning, producing, protecting
Up to the mid-to-late 1990s, manufacturers in industrialized countries were supplying
UNICEF and PAHO with large volumes of vaccines at a low price for use in developing
countries. Most of these vaccines were the traditional vaccines recommended by WHO’s
Expanded Programme on Immunization (EPI) against the basic cluster of six childhood
vaccine-preventable diseases – diphtheria, pertussis, tetanus, polio, measles, and
tuberculosis. The manufacturers were able to supply these vaccines at a low price for at
least three reasons. First, at that time, the richest and poorest countries were using much
the same vaccines: by selling the same vaccines at higher prices to the richer countries
and at lower prices to the poorer countries (i.e. via UNICEF and PAHO through a tiered,
or differential, pricing arrangement), manufacturers were able to recoup their production
29

State of the world’s vaccines and immunization
costs. Second, manufacturers tended to keep an excess production capacity for many
of the traditional vaccines, which enabled them to supply vaccines at a low price to
developing countries without having to invest in expanding production capacity. And
third, up to the 1980s, there were enough vaccine suppliers to sustain competition
among them, which kept vaccine prices low.
The vaccine market has since changed. The three factors conducive to low vaccine
prices have evaporated. No longer do industrialized and developing countries
use the same vaccines. Industrialized countries increasingly favour second-
generation vaccines such as the acellular pertussis vaccine; combination vaccines
such as the measles-mumps-rubella combination; and new vaccines such as the
pneumococcal conjugate or HPV vaccines. No longer do manufacturers maintain
excess production capacity: supply must be equivalent to demand, since the newer
vaccines are more costly to make, and too costly or too perishable to keep. And in
the traditional markets, with the exception of hepatitis B, there is no longer enough
competition among suppliers to keep prices down: there are now far fewer suppliers
from industrialized countries than before and those that remain tend increasingly to
protect their products from competition through a system of patents and royalties.
Box 6
Vaccine security
In the late 1990s, a vaccine supply crisis began, which highlighted the need for a new
approach to ensure the uninterrupted and sustainable supply of vaccines of assured
quality. In the run-up to this period, quantities of WHO-prequalified vaccines offered
to UNICEF declined significantly, threatening immunization programmes in the 80–
100 countries supported by UNICEF procurement, including over 50% of the routine
vaccine requirements for the poorest countries. With growing divergence between
the vaccines used in developing and industrialized countries, some manufacturers
stopped production of the traditional vaccines and supplies plummeted. A critical
shortage of oral polio vaccine (OPV) for immunization campaigns signaled the need
for a new approach to doing business with the vaccine manufacturers.
30

Chapter 2. A new chapter in vaccine development
In response, UNICEF, in consultation with vaccine manufacturers and partners,
developed the Vaccine Security Strategy (23). The aim is to ensure the uninterrupted
and sustainable supply of vaccines that are both affordable and of assured quality.
The strategy includes a focus on developing a healthy vaccine market through
implementing specific vaccine procurement strategies and ensuring that the key
elements of accurate forecasting, timely funding, and appropriate contracts are in
place. Industry reacted positively to the changes and the trend of decreasing vaccine
availability was reversed.
But while the strategy succeeded in reversing the fall-off in the supply of vaccines
to UNICEF, vaccine supply remains heavily reliant on a limited number of vaccine
manufacturers and continued vigilance is needed.
Today, UNICEF is the world’s largest vaccine buyer for developing countries, providing
a critical pooled procurement function securing vaccines for the world’s poorest
children. Through its Supply Division based in Copenhagen, Denmark, UNICEF
procures vaccines to reach more than half (55%) of the world’s children. The Supply
Division is also responsible for procuring vaccines on behalf of the GAVI Alliance. In
2007, for example, UNICEF procurement on behalf of GAVI increased by 76% to over
US$ 230 million. Procurement of OPV also remains very high, with 2.3 billion doses of
vaccine purchased for the Global Polio Eradication Initiative (GPEI) in 2007.
600
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Source: UNICEF Supply Division, 2009
31

State of the world’s vaccines and immunization
Towards vaccines of assured quality
Making and meeting standards of quality and safety
An internationally accepted system of testing vaccines for their efficacy, quality, and
safety has gradually developed over the past century. In the early 1900s, the United
States Food and Drug Administration (FDA) in the United States, and the Paul-
Ehrlich Institute in Germany, were the first regulatory agencies created to ensure the
safety of biological products, including vaccines.
Today, the system in use in all industrialized countries and in a growing number
of developing countries covers three main testing phases: preclinical laboratory
testing, including animal tests; clinical trials in humans; and surveillance following
regulatory approval for marketing.
During the preclinical laboratory phase, a vaccine undergoes biochemical testing
and evaluation in laboratory animals for, among other things, characterization of its
biochemical components, potency, purity, genetic and biochemical stability, and
safety in animals. The clinical (i.e. human) trial stage covers three phases. In Phase 1,
the vaccine is tested in a few volunteers for safety and efficacy (immunogenicity),
and for an initial indication of the appropriate dose to be used (dose-ranging). Phase
2 tests for safety, immunity-stimulating capacity (immunogenicity), dose-ranging,
and efficacy in up to several hundred volunteers. Phase 3 tests for efficacy and
safety in several thousand volunteers.
A vaccine that has successfully completed the preclinical and clinical trial stages
is ready to be submitted to a regulatory authority for licensure – or approval for
human use. A regulatory authority will, among many other things, undertake a
review of how the preclinical and clinical tests were conducted and what they found.
The regulators will also inspect the production site and make a detailed review of
32

Chapter 2. A new chapter in vaccine development
how the vaccine was produced, starting with the raw materials and ending with
the finished product, and will even check the qualifications of the manufacturer’s
staff.
Following licensure, post-marketing evaluation (Phase 4) involves surveillance for
any adverse events. The post-marketing stage also includes testing of vaccine
batches for consistency of the production process, and routine inspection of the
manufacturing process to ensure continuing conformity to standards of good
manufacturing practice (GMP). These inspections can take place at any stage in
a vaccine’s life-cycle. During the life cycle of a product, a manufacturer may wish
to, or have to, introduce variations to the production process. In such cases, the
variations are reported to the national regulatory authority for review and approval.
WHO’s efforts to ensure the safety and quality of vaccines uses a system that first
establishes international standards of vaccine efficacy, safety and quality, and then
monitors the extent to which a given licensed vaccine meets those standards.
Setting international standards is the role of WHO’s Expert Committee on Biological
Standardization. Monitoring how fully a vaccine made or used in a given country
complies with these standards is the role of the country’s national regulatory
authority. In 1981, the Expert Committee on Biological Standardization called upon
all countries to have a national regulatory authority.
All industrialized countries have a reliable, properly functioning vaccine regulatory
system, but only about one quarter of developing countries do. Having an
independent and functional national regulatory authority is a good start for a country
wishing to ensure that the vaccines it uses meet internationally agreed standards
of safety, efficacy, and quality. Vaccines that have successfully emerged from the
six-function national regulatory authority oversight (see Box 7) with no “unresolved
confirmed reports of quality-related problems” are regarded by WHO as “vaccines of
assured quality”. In 2008, about 70% of vaccines met the WHO criteria for assured
quality.
33

State of the world’s vaccines and immunization
Box 7
How good is a national regulatory authority?
For a country using or making vaccines, simply having a national regulatory authority
is not enough. The national regulatory authority must be able to work independently
(of vaccine manufacturers and of the government, for example); it must have the legal
basis that defines its mandate and enforcement power; and it should perform between
two and six core functions, depending on how the country acquires its vaccines.
For countries that procure their vaccines through UN agencies (UNICEF, WHO, or
PAHO), core functions of the national regulatory authorities are:
(1) issuing a marketing authorization, and licensing vaccine production facilities and
vaccine distribution facilities;
(2) ensuring that post-marketing surveillance is carried out, with a focus on
detecting, investigating and responding to unexpected adverse events following
immunization.
Two additional core functions for countries that procure their vaccines directly in the
domestic or international market are:
(3) verifying consistency of the safety and quality of different batches of vaccine
coming off the production line (lot release);
(4) accessing, as needed, a national control laboratory in order to test vaccine
samples.
For countries that manufacture vaccines, two additional functions are required.
The sixth function is also recommended for any countries that host clinical trials of
vaccines:
(5) inspecting vaccine manufacturing sites and distribution channels;
(6) authorizing and monitoring clinical trials to be held in the country.
34

Chapter 2. A new chapter in vaccine development
The problem, however, is that in some countries the national regulatory authority
lacks the capacity – the human and material resources, the experience, the
know-how, or the political backing – to assess and monitor whether a vaccine
is of assured quality (i.e. compliant with GMP, safe, and effective). To address this
problem, WHO launched an initiative in 1997 to strengthen the capacity of national
regulatory authorities.
Strengthening national regulatory authorities
The ultimate objective of WHO’s initiative to strengthen the regulatory capacity of
countries is for all countries to have a reliable, properly functioning national regulatory
authority. To achieve its objectives, the initiative undertakes a five-step capacity-
development process tailor-made to the requirements of each individual country.
1. Defining and then regularly updating benchmarks and other tools used to assess
whether a national regulatory system is capable of ensuring that the vaccines
used and/or made in its country are of the required standards of quality, efficacy,
and safety.
2. Using benchmark indicators and other pertinent tools to assess the national
regulatory system.
3. Working with the country’s regulators and other health officials in drawing up an
institutional development plan for dealing with any shortcomings in the country’s
regulatory system and for building upon the existing regulatory strengths in the
country.
4. Implementing the institutional development plan, which may involve technical
support or staff training to perform regulatory functions.
5. Re-assessing the national regulatory authority within two years to evaluate progress.
When the initiative started in 1997, only 37 (19%) of WHO’s 190 Member States,
had a reliable, fully functioning national regulatory authority. By the end of 2008, the
35

State of the world’s vaccines and immunization
number had risen to 58 (30%) of WHO’s 193 Member States. Priority countries for
the initiative are those that have vaccine manufacturers and thus contribute to the
world’s vaccine supply. In 1997, 20 (38%) of the 52 vaccine producing countries had
a reliable, functioning national regulatory authority. By the end of 2008, the numbers
had risen to 33 (69%) of 48 vaccine producing countries.
A regulators’ network for developing countries
The power of networking is being applied to the quest for stronger regulatory
oversight in countries where regulation is lacking or inadequate. These countries are
increasingly being asked by vaccine manufacturers to host clinical trials of vaccines
intended for use in developing countries. Clearly, these vaccines must be tested for
their safety and efficacy in the “real-life” conditions of these developing countries.
The danger is that in countries with little or no regulatory capacity, the trials may take
place without due respect for international standards of good clinical practice, of
ethics, and of vaccine safety, quality, and efficacy.
In 2004, therefore, WHO launched the Developing Countries Vaccine Regulators
Network, aimed at strengthening the regulatory capacity of developing countries
to assess clinical trial proposals and to oversee ongoing clinical trials. The network
allows members to share expertise and information – particularly information about
problems of vaccine safety and efficacy that may have surfaced during a clinical trial.
Network participants also inspect clinical trials for their adherence to good clinical
practice.
In 2006, the African Vaccine Regulatory Forum was established, and is working
in much the same way as the developing countries’ network – clinical trials on
candidate vaccines against diseases including AIDS, malaria, and meningitis
are under way in the 19 Forum countries, where regulatory oversight is weak or
altogether absent.
36

Chapter 2. A new chapter in vaccine development
Harmonizing and standardizing vaccine regulation
Strengthening regulatory capacity also means bringing some uniformity to the
way regulatory oversight is practised in different countries and, more importantly,
to the standards of safety, efficacy, and quality they apply to vaccines. At the end
of 2008, 58 countries possessed a reliable national regulatory authority, but not all
were applying the same regulatory standards for vaccine licensure. The problem
is that vaccine manufacturers – both in developing and in industrialized countries
– are increasingly seeking a global market for their products. Clearly, the diversity
of regulatory standards from one country to another can seriously complicate
international trade in vaccines. It can also force manufacturers to obtain separate
authorizations for each intended market – a long, costly, and uncertain process
that runs counter to current endeavours to accelerate the introduction of new
vaccines into countries’ immunization programmes. Hence the need for regulatory
harmonization.
Vaccine quality testing by the
Division of Biological Products
at the Department of Medical
Sciences, Ministry of Public
Health, Thailand.
37

State of the world’s vaccines and immunization
In the Americas, a Vaccines Working Group of the Pan American Network on Drug
Regulatory Harmonization was set up in 2005 to work with regulatory officials from
PAHO Member countries in establishing guidelines on regulatory standards for
licensure of vaccines to be used in the region. In Europe, harmonization is a major
objective of the European Medicines Agency, a regional regulatory authority. At
present, vaccines for use in the European Union are regulated either by the European
Medicines Agency itself or by a European Union Member State, in which case the
licensure of the vaccine is recognized, through a mutual recognition agreement, by
all other European Union states.
Another entity whose objectives include greater regulatory harmonization is the WHO
International Conference of Drug Regulatory Authorities, which, since 1980, has
provided regulatory authorities of WHO Member States with a forum for discussion
and collaboration on the regulation of medicinal products, including vaccines.
In 1989, the WHO International Conference of Drug Regulatory Authorities laid
plans for an international harmonization initiative run jointly by regulatory authorities
together with pharmaceutical industry input. A year later, the International Conference
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) was born. The Conference, held every two years, brings together
the regulatory authorities and pharmaceutical industry experts of Europe, Japan,
and the United States. Their aim is to harmonize technical guidelines and licensing
requirements for pharmaceutical products, including vaccines. Topics chosen for
harmonization relate to criteria for assessing the safety, quality, and efficacy of
these products. The Conference is credited with achieving substantial progress in
harmonizing technical guidelines and applications for licensing.
Generally speaking, progress towards harmonization of standards is slow but steady.
An encouraging sign is that the recommendations of the WHO Expert Committee
on Biological Standardization on regulatory standards for pneumococcal conjugate
vaccines and vaccines against pandemic influenza – published in 2005 and 2008,
38

Chapter 2. A new chapter in vaccine development
respectively – are being applied by virtually all national regulatory authorities in the
world.
Innovative regulatory pathways
Traditionally, when a national regulatory authority in a developing country considers
whether to host clinical trials of a new vaccine produced in another country, or
whether to adopt a new vaccine in its country’s immunization programme, it would
be favourably influenced if the vaccine had been approved for human use by the
European Medicines Agency or the FDA. However, in 2004 and 2007, respectively,
both agencies decided to no longer accept vaccines for marketing approval where
they are intended for use exclusively outside their geographical jurisdictions. This
decision raised a fear that the supply of new life-saving vaccines to developing
countries may be hindered or delayed for lack of authoritative marketing approval.
In 2005, therefore, the European Medicines Agency introduced a mechanism,
known as “Article 58”, whereby it issues a “scientific opinion” based on the
customary Agency process but with the addition of an evaluation of the vaccine by
WHO-appointed experts from countries where the vaccine is intended to be used.
This mechanism, although stopping short of formally granting a licence, involves all
the steps of a regular licensing procedure. It carries enough weight to allay fears that
vaccines may be introduced without having been assessed for safety and quality.
Moreover, the FDA and the European Medicines Agency have agreed to work
with national regulatory authorities or with networks of regulators in the regions, to
provide advice on vaccine safety and efficacy as well as on clinical trial protocols.
Similar collaborative agreements are being forged in other parts of the world, notably
in Asia.
39

State of the world’s vaccines and immunization
Box 8
Prequalification – flagging vaccines fit for public purchase
In 1987, a prequalification system was established by WHO to advise United Nations
vaccine procuring agencies on the acceptability, in principle, of vaccines available for
purchase by these agencies.
In order to be included in the list of WHO prequalified vaccines (24), a vaccine
must, inter alia, be licensed and be under continuous regulatory oversight by an
independent, fully functioning national regulatory authority in the country where the
vaccine is manufactured.
The United Nations procuring agencies invite tenders only for vaccines on WHO’s list
of prequalified vaccines. In addition, many countries that do not use these procuring
agencies but buy vaccines directly from manufacturers also use the WHO list to select
vaccines for purchase.
The prequalification process, in addition to assessing individual vaccines, also
determines how well the national regulatory authority of the country where the vaccine
is made is fulfilling its regulatory role in enforcing manufacturers’ compliance with
WHO recommended standards.
Prequalification status normally lasts for two years, after which the vaccine is
reassessed to determine if it – and the manufacturer – still meet the standards required
to retain prequalification status.
The prequalification system is widely credited with contributing to the growing number
and proportion of quality vaccines being supplied by manufacturers in developing
countries, such as Brazil, Cuba, India, Indonesia, and Senegal. In the early 1990s,
for example, manufacturers in industrialized countries were supplying all the vaccines
purchased through United Nations agencies. By 2008, more than half were coming
from manufacturers in developing countries.
Not surprisingly, applications for prequalification evaluation have escalated in recent
years. They are coming not only from manufacturers in developing countries, but
also from those in industrialized countries. As of mid-2008, all five major multinational
companies of the Big Pharma marketed products that had passed a prequalification
assessment.
Chapter 3. Immunization: putting vaccines to good use
40
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State of the world’s vaccines and immunization
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Immunization :
putting vaccines
to good use
Chapter 3
Chapter 3. Immunization: putting vaccines to good use
42
42
Chapter 3. Immunization: putting vaccines to good use
Key messages
• From 2000 to 2007, intensified vaccination campaigns
resulted in a 74% reduction in measles deaths globally.
• Polio has been eradicated in three of WHO’s six regions
and is today endemic in only four countries – down from
125 countries in 1988.
• Integrating immunization with the delivery of other health
interventions can boost immunization coverage and
accelerate the achievement of MDG 4.
• Targeted immunization strategies for difficult-to-reach
populations increase equity in access to vaccines.
• Weak health systems are a major constraint
on the effectiveness of immunization programmes.
• Strong and effective leadership, and national ownership
of immunization programmes, are key components
of a successful national immunization programme.
• There is a need to foster increased public demand for
vaccines.
• Disease surveillance and monitoring programmes need
to be strengthened at all levels.
• False or unsubstantiated rumours about vaccine safety
can undermine immunization programmes and cost lives.
43
State of the world’s vaccines and immunization
Year after year, immunization programmes the world over have been administering
vaccines to young children to protect them against a cluster of common childhood
diseases – diphtheria, tetanus (including tetanus in mothers and newborns),
pertussis, measles, polio, and tuberculosis. Increasingly, with the development of
new and improved vaccines (see Chapter 2) more diseases are being added to this
traditional childhood cluster of vaccine-preventable diseases. They include hepatitis
A, hepatitis B, Hib disease, mumps, pneumococcal and meningococcal disease,
rubella, and more recently, rotavirus diarrhoea, and cancers due to HPV. In addition,
immunization programmes are increasingly reaching out to other population groups
– older children and adolescents (for meningococcal disease and HPV disease),
elderly people (for pneumonia, shingles, and influenza), and people exposed to
locally prevalent diseases (for yellow fever and Japanese encephalitis).
The main focus, though, of national immunization programmes and of the
EPI, which WHO created in 1974 to establish and coordinate the work of these
100
80
60
40
20
0
Figure 4
Global three-dose DTP coverage for 1980−2007 and
goals for 2008−2010
C
o
v
e
r
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(
%
)
Year
1
9
8
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0
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2
0
0
0
2
0
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2
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9
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Source: (31)
Chapter 3. Immunization: putting vaccines to good use
44
Box 9
The impact of immunization
The selected data below testify to the impact of immunization in achieving its main
objective: to reduce the number of children dying, falling ill, or being disabled as a
result of diseases that can be prevented by vaccines.
• Every year immunization averts an estimated 2.5 million deaths among children
under five years old.
• Between 2000 and 2007, the number of children dying from measles dropped by
74% worldwide, from an estimated 750 000 to an estimated 197 000 children (9).
In addition, immunization prevents sickness as well as lifelong disability, including
measles-related deafness, blindness, and mental disability.
• In 1988, polio was endemic in 125 countries and paralyzing an estimated 350 000
children every year (close to 1000 cases a day) (25). By the end of 2007, polio
had been eradicated in three of WHO’s six regions – the Region of the Americas,
the European Region, and the Western Pacific Region. In mid 2009, indigenous
poliovirus remained endemic in only four countries: Afghanistan, India, Nigeria and
Pakistan. The numbers of new cases reported for these four countries in 2009 as
at end June were: Afghanistan: 10; India: 89; Nigeria: 321; and Pakistan: 20 (26).
• Following implementation of the rubella elimination strategy in the Americas, the
number of reported cases of rubella declined by 98% between 1998 and 2006 (27).
• By 2000, 135 countries had eliminated neonatal tetanus (25) and by 2004, annual
deaths from neonatal tetanus had fallen to an estimated 128 000, down from
790 000 deaths in 1988 (28, 4).
programmes, is still on infants. As of 2007, about 80% of children under one
year old were receiving the full three-dose schedule of the DTP vaccine, which
serves as a measure of how well immunization programmes are functioning (see
Fig. 4). The life-saving impact of national immunization programmes is impressive
(see Box 9).
45
State of the world’s vaccines and immunization
The unfinished immunization agenda
Remarkable progress has been made in reducing disease incidence and deaths
from vaccine-preventable diseases. But a lot remains to be done in order to achieve
the targets of the GIVS set by WHO and UNICEF (see Chapter 1). Those targets
call, among other things, for all countries to be immunizing by 2010 at least 90% of
their total child population under five years old, and at least 80% of children under
five in every district throughout the country.
Achieving these targets will not be easy. One critical barrier is the underlying
weakness of the health systems in many developing countries. The ability of health
systems to deliver services such as immunization is often constrained by a lack of
political and financial commitment, poor management skills, and weak monitoring
and information systems. This is compounded by a severe shortage of health
workers, due to high rates of sickness and deaths, and the loss of health workers
to higher-paid jobs overseas. Many health workers that remain are often poorly
distributed across the country, inadequately trained and unsupervised, badly paid,
unmotivated, and often have skills that are ill-matched to the work they have been
assigned to do.
Recent reports by WHO (29,30) have warned that countries experiencing the
greatest difficulties in meeting the MDGs – mainly in sub-Saharan Africa – face
absolute shortfalls in their workforce. Of the 57 countries worst affected by extreme
shortages of health workers, 36 are in Africa, where AIDS and worker migration have
depleted the health workforce. Countries in Africa account for 24% of the global
disease burden but have only 3% of the world’s health workers. Figure 5 illustrates
how immunization coverage is affected by the density of health workers.
Chapter 3. Immunization: putting vaccines to good use
46
In a poorly functioning health system it is difficult to ensure equity in access
to immunization, and as a result, there may be a high degree of variability in
immunization coverage. There are unreached populations and immunization failures
in every country but 73% of the children currently unreached with three doses of
DTP immunization live in just 10 countries – all in Asia and Africa (31).
Many of the unimmunized children live in isolated rural areas without easy access
to health facilities. Some live in fragile states where public services are weak or
non-existent and where access to health facilities may be severely restricted due
to ongoing conflict. Others live in poor, densely populated urban areas and informal
settlements, or among displaced populations that are on the move and especially
difficult to reach. Some – like the children of “illegal” immigrants in urban areas, or
the many children whose births go unregistered – may not even officially “exist”. In
India, recent studies have also highlighted a number of social factors that may inhibit
mothers from seeking immunization, including gender, religion, and social status
(caste). Additional operational research is needed in other regions to confirm these
findings.
100
90
70
50
30
10
80
60
40
20
0
Figure 5
Immunization coverage and density of health workers
C
o
v
e
r
a
g
e

(
%
)
Density (per 100 000)
1 10
Human resources for health
Doctors
Nurses
100 1000
Source: (29)
47
State of the world’s vaccines and immunization
In addition to a weak health system, another barrier to achieving the GIVS targets,
also rooted in the overall health system, is the difficulty of delivering vaccines –
especially the newer vaccines – through an infrastructure and logistical support
system that in many developing countries is characterized by poor vaccine stock
management, poor vaccine handling and storage, and high wastage. Against this
backdrop, the introduction of new vaccines, some with non-standard characteristics
– i.e. single dose in pre-filled glass syringes as opposed to multi-dose vials – require
new vaccine management strategies and increased storage capacity, putting a
huge strain on an already weak supply chain.
A third barrier – especially among the poorest populations – is a lack of information
and understanding about the importance of vaccines and immunization. In some
communities, the value of an intervention that “helps healthy people to stay healthy”
may suffer in comparison with medicines that can visibly heal the sick. And where
parents lack a basic understanding of how vaccines work, children may be vaccinated
once but fail to return for the required follow-up doses. To counter these and other
misconceptions, well-targeted information and social mobilization campaigns are
needed to transform a community’s “passive acceptance” of immunization into
a well-informed demand for vaccines that can protect their children against life-
threatening diseases.
A fourth barrier relates to the fear of immunization, fanned by reports of adverse
events that are rumoured or suspected of being related to vaccines. With ever-
increasing access to Internet-based information, an unsubstantiated rumour about
vaccines can rapidly circle the globe and undermine immunization services, sparking
outbreaks of disease and untold deaths. Since fear of vaccines and immunization
often stems from a lack of information, people need to know how safe a vaccine is
and how it can reduce disease and deaths.
A fifth barrier, addressed in Chapter 4, is the need to secure additional financing
to meet a projected shortfall in funding needed to achieve the global immunization
Chapter 3. Immunization: putting vaccines to good use
48
Box 10
Strengthening health systems – the six building blocks
In an effort to promote a common understanding of what a health system is, WHO
has defined six “building blocks” that make up a health system (30). The aim is to
clarify the essential functions of a health system and set out what a health system
should have the capacity to do.
• Good health services are those which deliver effective, safe, quality personal
and non-personal health interventions to those who need them, when and where
needed, with minimum waste of resources.
• A well-performing health workforce is one that works in ways that are
responsive, fair and efficient to achieve the best health outcomes possible,
given available resources and circumstances (i.e. there are sufficient staff, fairly
distributed; they are competent, responsive and productive).
• A well-functioning health information system is one that ensures the production,
analysis, dissemination and use of reliable and timely information on health
determinants, health system performance and health status.
• A well-functioning health system ensures equitable access to essential medical
products, vaccines and technologies of assured quality, safety, efficacy and
cost-effectiveness, and their scientifically sound and cost-effective use.
• A good health financing system raises adequate funds for health, in ways
that ensure people can use needed services, and are protected from financial
catastrophe or impoverishment associated with having to pay for them. It provides
incentives for providers and users to be efficient.
• Leadership and governance involves ensuring strategic policy frameworks exist
and are combined with effective oversight, coalition-building, regulation, attention
to system-design and accountability.
goals. This comes amid growing concern that the current global financial and
economic crisis may have an adverse effect on the funds available for development
assistance, including for immunization.
The following sections outline the steps being taken to overcome the barriers
to achieving global immunization goals.
49
State of the world’s vaccines and immunization
Extending the benefits of immunization equitably within
countries
In 2002, 135 of WHO’s Member States were reaching a national average of
more than 80% of children under one year old with the full three doses of the
DTP vaccine. A closer look, though, found that in some of these countries, there
were districts where fewer than 50% of the children were receiving the full three
doses of this vaccine.
In 2002, therefore, WHO, UNICEF, and other partners devised the Reaching Every
District (RED) strategy, which takes the district as its primary focus and aims to
improve equity in access to immunization by targeting difficult-to-reach populations.
The strategy provides support – including training – to ensure that district-level
immunization managers apply the principles of “good immunization practice”.
These principles call for district health officials to identify local immunization-related
problems and oversee remedial action, while ensuring that vaccines are delivered
regularly in all districts. “Outreach” staff take vaccines to hard-to-reach villages and
make sure that all the children are vaccinated. The RED strategy also calls for timely
collection of data on vaccine coverage and other vaccine-related activities (logistics,
supply, and surveillance), proper supervision of immunization health workers, and
involvement of communities in the planning and delivery of immunization services.
The expertise, knowledge, and human resources of the GPEI were used to plan and
implement the RED approach in many countries, working in close collaboration with
national immunization programmes and key partners, notably the GAVI Alliance.
By mid-2005, 53 countries, mostly in Africa and Asia, had begun implementing the
RED strategy to varying degrees (see Fig. 6) (32). In 2005, an evaluation of five
countries in Africa that had implemented RED found that the proportion of districts
with over 80% of children fully immunized with DTP vaccine had more than doubled
(33). More recently, a nine-country evaluation carried out by the CDC in 2007 found
that the RED strategy had been adopted by 90% of all districts within these countries.
Chapter 3. Immunization: putting vaccines to good use
50
Box 11
Reaching Every District (RED)
The Reaching Every District (RED) strategy aims to improve equity in access to
immunization by targeting difficult-to-reach populations. It involves:
• re-establishment of regular outreach services;
• supportive supervision and on-site training;
• community links with service delivery;
• monitoring and use of data for action;
• better planning and management of human and financial resources.
Special measures are needed to ensure that difficult-to-reach populations are reached
with vaccines and other health interventions. These include efforts to:
• map (geographically, socially, and culturally) the entire population – through micro-
planning at the district or local level – in order to identify and reach the target
populations at least four times a year;
• reduce the number of immunization drop-outs (incomplete vaccination) through
improved management, defaulter tracing, and social mobilization and communication
during immunization contacts, and by avoiding missed opportunities to vaccinate;
• strengthen the managerial skills of national and district immunization providers and
managers, and develop and update supervisory mechanisms and tools;
• provide timely funding, logistics support, and supplies for programme implementation
in every district.
However, few of the nine countries were implementing all five components of the
strategy (see Box 11). The CDC evaluation noted that further studies would be needed
over a longer period to assess the effectiveness and sustainability of the strategy.
51
State of the world’s vaccines and immunization
Reaching more children through campaign strategies
Immunization is mostly delivered by health workers as a pre-defined series of
vaccines, administered in a given schedule to children of a given age. In many
countries, tetanus toxoid vaccine is also provided to pregnant women, in order
to prevent maternal and neonatal tetanus. It is mostly during contacts in health
centres that such vaccines are given, or in the case of pregnant women, during
antenatal care visits. In remote areas, where access to health centres is very limited,
immunization may be partly, or entirely, provided through outreach services. In some
very isolated villages, access may only be possible during certain periods of the
year, and mobile teams are needed to deliver vaccines and other essential health
interventions.
Figure 6
Countries implementing the RED strategy in 2005
Source: (32)
Chapter 3. Immunization: putting vaccines to good use
52
In countries with well-functioning health systems and where the populations have
good access to the system, routine immunization contacts may be sufficient
to control vaccine-preventable diseases. However, so-called “supplementary
immunization activities” may be needed to improve protection at population levels
– for example, to achieve some of the global elimination or eradication goals, or to
stem outbreaks. In these scenarios, a mass-mobilization campaign-style approach
is adopted, during which all individuals receive a certain vaccine, often regardless
of prior immunization. Efforts to eradicate polio, eliminate measles, and eliminate
maternal and neonatal tetanus all rely on this approach – in addition to routine
immunization – either nationwide or targeted at selected high-risk areas only. For
example, measles “catch-up” campaigns are used to reach children who may
have missed out on measles immunization during their first year of life and children
who may not have developed a protective immune response when immunized the
first time round. Campaigns have also been used to control outbreaks of measles,
yellow fever, diphtheria, and epidemic meningococcal meningitis.
A health worker marks a child's
finger to show that measles
vaccine has been administered
— during measles vaccination
campaign in Côte d'Ivoire in
November 2008.
53
State of the world’s vaccines and immunization
A campaign has the potential to rapidly reach more children, especially those missed
by routine immunization. And they tend to cover more equitably all socioeconomic
sections of the target population. Uptake of measles vaccine in a campaign in
Kenya showed equal uptake of over 90% in all wealth quintiles, compared to routine
immunization that reached less – only 60% – of the poorest wealth quintile (34).
Box 12
Mass-mobilization to extend the reach of immunization
Through mass-mobilization, the campaign-style approach to immunization often
manages to reach more people than can be reached through the regular immunization
contacts. The “immunization weeks” in many American and European countries,
and the “child health days” in numerous African countries, have been using mass-
mobilization techniques to ensure universal coverage as much as possible.
The child health days were originally introduced by UNICEF to deliver vitamin
A supplementation, but now offer an integrated package of preventive services that
can include, depending on local needs, vitamin A, immunization, deworming tablets,
growth monitoring, and insecticide-treated bednets. They are usually conducted
twice a year and target a large proportion of the population. During 2008, over
52 countries conducted child health days, compared with 28 countries in 2005.
Over the same period, the number of countries conducting child health days in east
and southern Africa almost doubled from 10 to 18, and tripled in west and central
Africa from 5 to 16.
Immunization weeks in the Americas have proved particularly effective in reaching
difficult-to-reach people, such as those living in isolated border communities where
immunization coverage is limited. Debates, workshops, training sessions, exhibitions,
and media events are among the activities on the agendas of these weekly campaigns.
In Europe, immunization weeks have mainly had a social mobilization function.
Immunization weeks are now organized in 30 countries in Europe – up from 9 in
2003; immunization weeks in the Americas are now organized in 45 countries – up
from 19 in 2003.
All this requires a strong support system, from micro-planning logistics to well-trained
health workers, supported by adapted communications and monitoring mechanisms.
These are very much the same components that are the basis of any health care
system or any other public health programme.
Chapter 3. Immunization: putting vaccines to good use
54
Greater awareness fuels demand
Renewed efforts are needed to ensure that the public, policy-makers, and health
workers understand the vital importance of immunization for both children and
adults. This is critical in maintaining support for national immunization programmes
and in providing information about the introduction of new vaccines and technologies
to a national immunization schedule.
Parents in particular need to understand why they should seek immunization. In
some cases mothers may understand why their children need to be immunized, but
they may lack awareness of the need for follow-up doses to complete the schedule.
Others may refuse immunization for social or cultural reasons.
There is a need for grass-roots mobilization for immunization at community level,
especially in areas where there is high illiteracy and poor access to the media.
Countries need to ensure that innovative methods are used to reach these
communities – for example, through engaging a network of community leaders
such as religious leaders, women’s associations, and village volunteers. The active
involvement of community members to assist health workers – by informing the
community about an upcoming immunization session, helping to track children
who are due for their next dose of vaccine, and helping to identify newborns or
pregnant women, for example – is one way of building up trust, and ensuring that
the community is motivated to demand immunization and is fully engaged as a
partner, not just a recipient of vaccines.
Creating demand in communities, though, is only one side of the coin. The health
system – particularly the health workers who vaccinate community members – must
also be able to reliably meet that demand. Weak immunization performance and
a failure to deliver services due to transport problems, staff shortages, inadequate
supplies, or a break in the cold chain, can lead to a loss of confidence and fall-off in
demand for immunization.
55
State of the world’s vaccines and immunization
Despite longstanding efforts by the international community, particularly UNICEF,
to create awareness of and demand for vaccination among community members,
many communities still do not actively seek immunization. Low demand persists
because of poor understanding about the benefits of vaccines, misconceptions
about vaccine safety, perceived inconvenience or difficulty in accessing services,
and low prioritization of immunization – especially among people who are barely
surviving.
The basic message so far has been relatively simple: Diseases are a threat. Take the
vaccine and prevent the disease. But for some of the newer vaccines the situation
is more complex. Rotavirus and pneumococcal vaccines, for example, will only
prevent a proportion of all cases of diarrhoea and pneumonia respectively, because
not all causes of diarrhoea and pneumonia are vaccine-preventable. But even
though the message is not so simple, immunization against these diseases creates
an opportunity to actively promote the prevention and treatment of diarrhoea and
pneumonia, which together account for over 36% of deaths among children under
five. This includes early and exclusive breastfeeding, access to community case
management, zinc supplementation, reduction of malnutrition, hand-washing with
soap, and control of environmental risk factors such as water and sanitation (for
diarrhoea) and indoor air pollution (for pneumonia).
Chapter 3. Immunization: putting vaccines to good use
56
Surveillance and monitoring: essential health system
functions
In addition to its key role in programme planning and monitoring, priority setting,
and mobilization and allocation of resources, an effective disease surveillance
system provides the critical intelligence that is needed to guide an immunization
programme. It provides the information needed to monitor trends in disease burden
Box 13
Reaching out to communities
In an effort to increase demand for immunization among community members,
UNICEF has identified some fundamental communication approaches to help health
workers and local public health officials provide information about vaccines.
• Improve the quality of vaccine delivery services before trying to convince community
members of the need to use them.
• Adapt immunization services to the local culture so that community members can
come to trust them.
• Engage local leaders as spokespersons for immunization, especially traditional and
religious leaders, who usually have high credibility and a large following among
community members.
• Identify strategies for reaching women: they are the primary caretakers of young
children but usually have less access to mass media and often face obstacles to
accessing health services.
• Emphasize that the disease constitutes a threat but a threat that can be reduced by
vaccination, as well as by key behaviours such as breastfeeding.
• Explain how to access local immunization services.
• Engage marginalized or underserved communities, which often suffer greater
disease burdens than other segments of society.
• Evaluate the impact of the communications strategy on vaccine coverage rates and
on efforts to improve knowledge of, and trust in immunization services.
57
State of the world’s vaccines and immunization
and the impact of disease control programmes, as well as the data needed to guide
public health policy and to monitor progress towards global goals.
The GIVS goal to vaccinate 90% of children at the national level and 80%
in each district by 2010 (see Chapter 1), and related approaches, such as
the RED strategy, that rely heavily on the use of data to drive strategic interventions,
have highlighted the need to strengthen routine surveillance and monitoring at
all levels.
Over the past decade, progress has been made in setting up or improving regional,
national, and global systems for the surveillance of vaccine-preventable diseases.
An example of an outstanding, high-performance surveillance system is the global
polio surveillance network, which enables rapid detection of polio cases throughout
the world, especially in developing countries. In many developing countries where
disease surveillance systems are weak, polio surveillance systems have been
expanded to include reporting on other vaccine-preventable diseases such as
measles, neonatal tetanus, and yellow fever.
In addition to the need to improve case-based surveillance and outbreak response for
diseases such as measles and polio, surveillance systems need to be strengthened
for other vaccine-preventable diseases. The availability of new vaccines to combat
diseases such as Hib, meningococcal disease, pneumococcal disease, and
rotavirus diarrhoea provides the potential to significantly reduce childhood illness
and deaths. Effective surveillance systems are indispensable in guiding the decision-
making process for the introduction of new vaccines, monitoring the impact of these
new vaccines on disease patterns, and conducting post-marketing surveillance to
ensure the safety of all newly introduced vaccines.
Disease surveillance and monitoring systems are also expected to give an early
warning of impending or ongoing disease outbreaks – providing a first line of
defence against the threat of emerging or pandemic diseases, including influenza.
Chapter 3. Immunization: putting vaccines to good use
58
The revised International Health Regulations, which entered into force in mid-2007,
require Member States to establish and maintain core capacities for surveillance at
the local, intermediate, and national levels. The regulations stipulate that countries
should be able to detect, provide notification of, and take initial steps to control
outbreaks of diseases of global health importance. This intelligence provides a
platform for high-level advocacy for surveillance support within countries, and a
new opportunity to build on synergies between different existing surveillance systems.
In 2007, the WHO Strategic Advisory Group of Experts on Immunization (SAGE)
endorsed a new Global Framework for Immunization Monitoring and Surveillance.
This framework calls for: alleviating health system barriers to surveillance; building
capacity for surveillance at national, regional, district, and health facility levels as well
as in sentinel sites, where appropriate; assuring quality data; and linking surveillance
of vaccine-preventable diseases and immunization monitoring with other national
surveillance systems.
Efforts to strengthen immunization surveillance, monitoring, and evaluation can
also help alleviate “system-wide” barriers, through providing better data to improve
health system management. For example, immunization surveillance data on
coverage and drop-out rates can be used as an indicator of the equity of health
system performance – a measure of its ability to continue to provide health services
to difficult-to-reach populations (35).
59
State of the world’s vaccines and immunization
Optimizing the delivery of vaccines
Box 14
What it takes to run a successful national
immunization programme
• Political motivation.
• Strong and effective leadership and national ownership of immunization
programmes.
• Country-driven policies, planning, monitoring, and reporting.
• An effective National Immunization Technical Advisory Committee to help facilitate
evidence-based decision-making at country level.
• Sound decision-making on which vaccines to schedule, based on local, regional,
and global data.
• Use of routine surveillance data (immunization coverage, vaccine use and wastage,
and incidence of diseases) for programme management.
• The capacity for efficient financial planning, including multi-year planning and a
budget line for immunization in the national health budget, as well as knowledge of
available international funding mechanisms.
• A well-functioning national regulatory authority.
• A motivated, well trained, and well supervised staff.
• A surveillance system for detecting, investigating, and responding to adverse events
following immunization.
• Cold-chain facilities and logistics.
• A well-functioning health system that facilitates the delivery of immunization to all
communities.
As new vaccines come on the scene (see Chapter 2) and as more vaccine doses are
needed to immunize more people in more age groups, the logistics and infrastructure
needed to transport vaccines safely and efficiently from the manufacturer to the
Chapter 3. Immunization: putting vaccines to good use
60
end user – without jeopardizing their potency – have in many countries become
increasingly complex. In some regions, cold storage facilities are inadequate to cope
with the massive increase in the volume of vaccine being shipped, which is now
greatly inflated by the high-volume packaging of the new vaccines. This logistical
challenge, coupled with the rising cost of vaccines, means that managers must be
able to maintain lower levels of vaccine stocks, accurately forecast vaccine demand,
reduce wastage, and prevent break-downs in cold-chain equipment, which can
interrupt the supply of vaccines and entail major financial losses.
In some cases, the increased volume of packaging used for a new vaccine exceeds
the cold storage space available at the country level. In addition, there are major
implications for the cost and logistics of international transport. For example, the
first shipment of pneumococcal conjugate vaccine (679 500 doses) to Rwanda in
March 2009, required over 40 cubic metres of storage space in the national cold
storage. But the shipping volume was even higher at 370 cubic metres. As a result,
a plane had to be chartered to deliver the vaccine to Rwanda.
In addition, the packaging and presentation of these new vaccine products
– often single-dose presentation, pre-filled glass syringes, and bulky packaging –
have implications not only for storage but for service delivery strategies, waste
disposal, and the need for training and supportive supervision.
In 2007, WHO and a non-profit organization, PATH, with the support of the Bill &
Melinda Gates Foundation, launched Optimize – a global effort to help countries
manage the growing complexity of immunization logistics. Optimize aims to make
use of technological and scientific advances to help guide the development of new
products and ensure maximum efficiency and safety in the field.
For 30 years, countries have relied on the same system to store and transport
vaccines safely from manufacturers to recipients – the cold chain – which keeps
vaccines at controlled temperatures throughout. As long as vaccines could be
61
State of the world’s vaccines and immunization
acquired at low cost and in large quantities, this system worked, despite high
wastage rates (more than 50% for some vaccines) and high maintenance costs.
Today, as new, more costly vaccines arrive on the market, the landscape is changing.
In addition, technology innovations that protect these vaccines and reduce waste –
such as single-dose vials and prefilled syringes – require significantly more space
on trucks and in refrigerators, putting even more pressure on the system. However,
there is relief in other areas: some of the vaccines that currently pass through the
system are now heat-stable, and the addition of the vaccine vial monitor – a small
sticker that indicates exposure to heat – may mean that these vaccines can move
out of the cold chain altogether.
Optimize is working directly with manufacturers and countries to identify problems
and test solutions that could have a global application. One possible solution could
be to use the passively cooled carts used to deliver fruit and vegetables to European
supermarkets, to transport vaccines within developing countries. These carts use
no electricity as they are charged with well-insulated plates that have been pre-
refrigerated or frozen and that maintain consistently cool temperatures for long
periods of time. They are also are capable of carrying a significantly higher volume
than traditional vaccine cold boxes, and could help reduce costs.
Tetanus toxoid vaccines,
with vaccine vial monitors
attached, being packed at a
vaccine manufacturing facility in
Bandung, Indonesia.
Chapter 3. Immunization: putting vaccines to good use
62
Elsewhere, in response to the high energy costs and unreliable power supply in
developing countries, Optimize is examining the use of battery-free solar refrigerators
as a possible means of improving the reliability and efficiency of refrigeration systems
at health centres and clinics.
Another initiative is the establishment of an inter-agency advisory group to
recommend vaccine presentations and packaging for use by developing countries.
The Vaccine Presentation and Packaging Advisory Group (VPPAG) provides a
forum for representatives of UN agencies, experts involved in public sector delivery
of vaccines, and industry representatives – both the International Federation of
Pharmaceutical Manufacturers Association (IFPMA) and the Developing Country
Vaccine Manufacturer’s Network (DCVMN) – to discuss vaccine presentation and
packaging issues in order to support the development of products tailored for use
in developing country settings.
VPPAG was established in 2007 by the GAVI Alliance to respond to industry requests
in relation to the packaging and presentation of the pneumococcal conjugate vaccine
and rotavirus vaccine. In 2008, WHO took over the role of convening VPPAG, and the
work of the group was broadened to look at presentation and packaging formats for
the HPV vaccine, as well as to develop a more generic presentation and packaging
guideline to address the range of potential new vaccines in the development pipeline.
Linking interventions for greater impact
The primary health care approach, as an efficient, fair, and cost-effective way to
organize the development of health systems, is back on centre stage. Immunization,
as one of many components of a country’s health system, is well-placed to benefit
from this increased visibility. This is because in many countries, immunization has
always been an integral part of the health system and has benefited from the health
system’s synergistic potential. There is clear evidence, for example, that where
health centres offer a range of services, vaccine coverage rates tend to be higher.
63
State of the world’s vaccines and immunization
For years, immunization programme managers have urged health workers to use
any and every contact with a child in a health centre to check the child’s (and
mother’s) immunization status and to vaccinate if needed. Conversely, immunization
can benefit the delivery of other health interventions. For people with limited access
to health centres, an immunization outreach or mobile team may offer the only
contact they have with the health system: providing more health commodities (such
100
80
120
60
40
20
0
Figure 7
More comprehensive health centres have better
vaccination coverage
a,b
DTP3 vaccination coverage (%)
Democratic Republic of the Congo (380 health centres, 2004)
Madagascar (534 health centres, 2006)
Weighted average of coverage in each country quintile
Rwanda (313 health centres, 1999)
Facility performance score
D
T
P

t
h
r
e
e
-
d
o
s
e

v
a
c
c
i
n
a
t
i
o
n

c
o
v
e
r
a
g
e

(
%
)
20% health centres
with lowest overall
performance
Quintile 2 Quintile 3 Quintile 4 20% health centres
with highest overall
performance
a
Total 1227 health centres, covering a population of 16 million people.
b
Vaccination coverage was not included in the assessment of overall health-centre
performance across a range of services.
c
Includes vaccination of children not belonging to target population.
c
Source: (36)
Chapter 3. Immunization: putting vaccines to good use
64
as medicines, bednets, and nutritional supplements) or health services (such as
checking children’s growth and giving antenatal advice) to these people, who are
often among the least served by the health services, can have a positive health
impact. Immunization campaigns, too, bring together large numbers of children and
their parents into a limited place over a limited time, and can offer interventions to
many people that they have previously missed out on.
In addition to the direct health benefits, there are other advantages in combining
targeted health interventions. The provision of a range of preventive and curative
services may result in increased trust in the health system by the community, as more
of their demands are met. Meanwhile, well-planned linkages between interventions
may involve the pooling of human and financial resources, joint training, improved
management, and a reduction in costs through shared transport and distribution
mechanisms. However, experience has shown that platforms offering multiple
interventions can have a negative impact on coverage unless the interventions are
well-targeted; good logistics systems are in place to ensure accurate forecasting,
supply, and delivery; human resources are adequate; and there is good monitoring
and evaluation.
Child collecting an insecticide
treated net to protect against
malaria during measles
vaccination campaign in Côte
d'Ivoire in November 2008.
65
State of the world’s vaccines and immunization
Examples of linked interventions include the following.
• Since 2001, routine and supplementary polio and measles immunization activities
have been used to deliver insecticide-treated bednets (which, when used properly,
substantially reduce malaria).
• In 2008, integrated supplementary immunization activities against measles
resulted in the distribution of over 35 million doses of vitamin A, 30 million doses
of deworming medicine, and more than 5.6 million insecticide-treated bednets
(37). Distributing these interventions as part of measles immunization campaigns
can serve to rapidly increase demand for measles immunization, while targeting
hard-to-reach people with additional interventions capable of reducing mortality
in children under five years old.
• The GPEI calculated that by the end of 2006, using its OPV immunization activities
to deliver vitamin A tablets had helped to avert 1.25 million deaths worldwide
(38).
• The Accelerated Child Survival and Development programme – set up in 2002
and managed with support from UNICEF and the Canadian International
Development Agency (CIDA) – was established to help increase the delivery of a
package of key health interventions in districts of 11 African countries with high
under-five mortality rates. A 2008 evaluation found that rapid impact on mortality
rates could be achieved through the package of interventions – especially through
the distribution of vitamin A and bednets.
Chapter 3. Immunization: putting vaccines to good use
66
Combating fear with knowledge and evidence
As vaccine coverage has increased and the incidence of vaccine-preventable
diseases has fallen – particularly in industrialized countries – immunization has
become a victim of its own success. As the diseases prevented by immunization
have become less frequent and less visible, concern about the potential side-
effects of vaccines has increased.
In both developing and industrialized countries, loss of public confidence in a vaccine
due to real or spurious links to adverse events can curtail or even halt immunization
activities, with potentially disastrous consequences. For example, a scientifically
flawed, but widely publicized 1999 British study (39) linking the measles-mumps-
rubella (MMR) combination vaccine to autism, has fuelled continuing anxieties
among parents about the safety of the vaccine and has caused a decline in vaccine
coverage in many countries: ten years later, measles is making a comeback in
several industrialized countries, including Austria, Israel, Italy, Switzerland, and the
United Kingdom. The CDC reported record numbers of measles cases in the United
States for the first seven months of 2008 – many in children whose parents had
refused vaccination. Another well-known case in point concerns Nigeria, where in
2002–2003 rumours that the OPV was being used to lower the fertility of young
girls brought polio immunization to a halt for 12 months in several states: the result
was a nationwide polio epidemic that ultimately spread to 20 previously polio-free
countries in Africa, Asia, and the Middle East.
Dealing with such rumours and with adverse events following immunization
requires an efficient post-marketing surveillance and investigation system that can
assess whether these events are truly caused by vaccines. Part of that system
should provide for communication of the findings to health workers, health officials,
parents, and the general public. Communication has to be truthful without fanning
fears that could compromise future vaccination activities and diminish their
benefits. Most industrialized countries have such a post-marketing surveillance and
67
State of the world’s vaccines and immunization
investigation system. Developing countries are, on the whole, making progress in
detecting and dealing with reports of adverse events. There are still many countries,
though, that do not have the experience or resources needed to investigate
rumours or reports of adverse events following immunization and to restore public
confidence.
In 1999, WHO set up a Global Advisory Committee on Vaccine Safety, made up
of independent experts, to respond promptly, efficiently, and with scientific rigour,
to rumours and reports related to vaccine safety. Recent topics dealt with by the
Committee include:
• alleged links between the hepatitis B vaccine and multiple sclerosis (“no evidence
found of such a link”, the Committee observed);
• alleged links between thiomersal, a vaccine preservative (known as thimerosal
in some countries), and autism in children (“no evidence of toxicity in children or
adults exposed to thiomersal in vaccines”);
• a higher than normal risk of Bacille Calmette-Guérin (BCG)-related disease in HIV-
positive children vaccinated with BCG (“evidence suggests a higher risk and that
BCG vaccine should not be used in HIV-positive children”);
• the risk of administration of multiple vaccines overloading a child’s immune
system (“no evidence to support any risk of immune overload”);
• the safety of newly licensed rotavirus vaccines (“pre-licensing safety profiles
reassuring but careful post-marketing surveillance required at country level”).
Chapter 3. Immunization: putting vaccines to good use
68
Remarkable progress, huge challenges
The immunization achievements are immense but so too are the challenges
that lie ahead in meeting the immunization-related MDGs and those of the GIVS
(in particular, the GIVS goal to reach 90% immunization coverage nationally and
at least 80% in each district by 2010 – see Chapter 1). Reaching the 24 million
children a year who remain unvaccinated will not be easy. Success will depend
on better use of surveillance and monitoring data at the local level to identify and
target these difficult-to-reach children. It will also require the use of operational
research to help identify innovative approaches and solutions that are tailored to
local needs.
Box 15
Vaccine Safety Net for quality web sites
“Is this new rotavirus vaccine likely to produce side-effects in my baby?”
“Can a pregnant woman be vaccinated against tetanus without risking health problems
for herself and her unborn baby?”
“How safe is the new vaccine against the human papillomavirus?”
To find answers to such questions, members of the general public, health officials, and
health practitioners may well turn to the Internet. The web sites they find are as likely
to present inaccurate, unbalanced, misleading, or unjustifiably alarming information as
they are reliable information. In 2003, to tip the balance in favour of reliable information,
WHO, prompted by its Global Advisory Committee on Vaccine Safety and other
members of the health and development community, began a “Vaccine Safety Net”
service, which lists web sites that contain vaccine safety information and that a WHO
team has approved as being sound and credible. To meet the required standards, web
sites must, among other requirements, disclose their ownership and their sponsors,
as well as their sources of information and their data protection policy.
As of March 2009, the Vaccine Safety Net listed 29 web sites (40).
69
State of the world’s vaccines and immunization
Efforts to reach the global goals have focused on overcoming some of the main
barriers to increasing immunization coverage. These barriers include the constraints
in some countries of weak health systems, the difficulty of delivering vaccines,
the failure of many governments to mobilize populations and establish a well-
informed demand for vaccines, the global threat posed by false or unsubstantiated
rumours about the safety of vaccines, and the projected shortfalls in funding. New
global alliances have been forged to help address these and other challenges
– attracting new financing for immunization and bringing together people from the
public and private sector and civil society with the collective knowledge, experience,
technical know-how, and problem-solving ingenuity needed to get the job done.
But even when the global goals have been met, success will be measured against
an additional benchmark – ensuring that the achievements are sustainable. The
solid building blocks that are being put in place – health system and immunization
programme strengthening, new long-term global financing mechanisms for
immunization (see Chapter 4), dynamic global health alliances and public-private
partnerships, and more responsive information and communication strategies –
should help to ensure that long-term progress has not been sacrificed for short-
term gains.
Chapter 3. Immunization: putting vaccines to good use
70
Box 16
Strengthening post-marketing surveillance of newly
licensed vaccines
In recent years, concern has been growing over the possibility that the investigation
of an adverse event following the routine use of a newly licensed vaccine may not be
undertaken as rapidly or reliably in the sometimes difficult conditions of developing
countries as it is in industrialized countries. This concern prompted WHO to set up
in 2009 a Global Network for Post-marketing Surveillance of Newly Prequalified
Vaccines. This Network brings together selected developing countries to share
information about adverse events following immunization, through a harmonized
approach. Member countries will submit data on adverse events to a common
database housed at the Uppsala Monitoring Centre – a WHO Collaborating Centre
– in Sweden. They will share among themselves information about adverse events
following immunization, and will forge strong links between their national immunization
programmes, regulatory authorities, and national pharmacovigilance centres. The
Network will share safety data among member countries and, on a wider scale,
data will be shared with other countries, vaccine manufacturers, and United Nations
vaccine supply agencies.
In 2006, PAHO set up a surveillance network comprising five member countries
– Argentina, Brazil, Mexico, Panama and the Bolivarian Republic of Venezuela – that
operates on much the same lines as the global network.
71
State of the world’s vaccines and immunization
Chapter 4. Investing in immunization
72
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State of the world’s vaccines and immunization
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Investing in
immunization
Chapter 4
Chapter 4. Investing in immunization
74
Key messages
• Immunization remains one of the most cost-effective
health interventions, even with newer, more expensive
vaccines.
• By keeping children healthy, immunization helps extend
life expectancy and the time spent on productive activity,
thereby contributing to poverty reduction (MDG 1).
• Since the year 2000, government spending on vaccines
and immunization has been increasing.
• Since 2000, the level of development assistance for
immunization has increased by about 13%.
• Since 2005, bilateral donors are making use of broad-
based funding mechanisms and partnerships to support
the health sector as a whole.
• New sources of funding and innovative funding
mechanisms are providing long-term, predictable funding
for immunization.
• There remain funding shortfalls to be addressed if global
goals are to be reached.
Chapter 4. Investing in immunization
74
75
State of the world’s vaccines and immunization
First came the vaccines: by the early 1970s, vaccines against about 20 diseases had
become available, and in most countries were being used for high-risk population
groups (travellers, the military, and so on), or for occasional mass campaigns,
but not routinely in a systematic organized manner. Then, starting in the mid-
1970s, came the EPI – set up to establish and coordinate, on a global scale, the
systematic use of vaccines by national immunization programmes and thereby to
protect as many children as possible in the world against six infectious diseases
(diphtheria, tetanus, pertussis, measles, polio, and tuberculosis). In the mid-1980s,
came the evidence that these immunization programmes could, in a matter of a
few years, protect millions of children from disease and death (41). By the early
1990s, the drive for universal child immunization (UCI) launched by UNICEF, WHO,
and other partners, had helped raise immunization coverage to a global average
of about 80%.
Throughout this sequence, though, and to this day, questions have arisen about the
economics of immunization. Immunization is clearly effective, but what does it cost ?
Is it cost-effective? And who pays for it ?
These questions are being asked with growing insistence as new vaccines are
becoming available; as new funding sources and resources are materializing; and
as new goals, such as the MDGs and the GIVS goals (see Chapter 1, page 2), are
calling for large reductions in child and maternal mortality, and thereby stepping up
the pressure to maximize the life-saving potential of immunization.
What does immunization cost?
In the 1980s, total annual expenditure on immunization for low-income countries
averaged US$ 3.50–5.00 per live birth. By 2000, the figure had risen only slightly
to about US$ 6.00 per live birth. Support for immunization from the GAVI Alliance,
which began in that year, allowed many of the poorest countries of the world to
Chapter 4. Investing in immunization
76
strengthen their routine vaccine delivery systems and to introduce underused
vaccines, such as those against yellow fever, hepatitis B, and Hib into their
immunization programmes. Not unexpectedly, immunization expenditure began to
rise again.
By 2010, the cost per live birth for immunization with the traditional vaccines
plus the hepatitis B and Hib vaccines is likely to reach US$ 18.00 per live birth.
Beyond 2010, scaling up vaccine coverage with newer vaccines to the levels
needed to meet the MDGs and the GIVS goals is likely to exceed US$ 30.00 per
live birth.
There are several reasons for the rising costs of immunization. First, the price of new
and underused vaccines is higher than the older vaccines – the prices of these new
and underused vaccines are in the dollars per dose compared with a few cents per
dose for the traditional ones. Vaccines (and injection equipment) have now replaced
human resources and operational costs as the most expensive component of
immunization. In the 1980s, human resources and operational costs accounted
for the bulk of immunization costs, compared with only about 15% for the costs
of vaccines. Today, efforts to accelerate the adoption by developing countries of
the most recently developed vaccines (the pneumococcal conjugate vaccine, the
rotavirus vaccine, and the HPV vaccine, for example) could bring the share of the
vaccine component to 60% of the total costs. However, the vaccine costs should fall
as these newer vaccines become more widely used, as vaccine production methods
become more efficient, as the market and demand for these vaccines expands, and
as multiple suppliers (including manufacturers from developing countries) enter the
market. The price of the hepatitis B vaccine, for example, has fallen steeply over the
past decade or so (see Fig. 8).
Chapter 4: Investing in immunization
77
State of the world’s vaccines and immunization
Second, because vaccines are temperature sensitive, the expansion of immunization
schedules with underused and new vaccines (particularly the pneumococcal
conjugate vaccine, rotavirus vaccine, and HPV vaccine), will increase the quantities
of vaccines that need to be stored in the cold chain. The increased quantities of
vaccines need to be managed, stored, and transported, and will place considerable
pressure on existing national vaccine supply chains. As such, the immunization
system will require additional investments to cope.
Third, introducing underused and new vaccines come with additional costs of
training staff to safely administer and dispose of the waste, costs of updating and
printing new vaccination cards, and costs associated with expanding surveillance
and monitoring activities to cover the added disease or diseases, and informing
communities about the benefits of the vaccines.
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Number of WHO Member States
using hepatitis B vaccine
UNICEF weighted average price of
monovalent hepatitis B vaccine in US$
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Figure 8
Relation between the number of WHO Member States
using hepatitis B vaccine and the UNICEF weighted
average price for the monovalent vaccine
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Chapter 4. Investing in immunization
78
Fourth, reaching the 20% hard-to-reach children who are not receiving the full three-
dose schedule of the DTP vaccine is increasingly difficult and costly, as many of
them are hard to reach for reasons of geography, civil strife, or lack of sufficient
health service resources (see Chapter 3). In addition, to reach more children with
vaccines, many countries need to rely on outreach services and supplementary
immunization activities, such as mass vaccination campaigns and child health days.
These strategies require increasing investments in immunization.
To put a price tag to these rising costs for immunization, a WHO and UNICEF
analysis, published in 2008 (7), calculated how much it would cost to attain the
GIVS goals in 117 WHO low- and lower-middle-income Member States between
2006 and 2015. The total bill came to US$ 76 billion. For the 72 poorest countries,
the bill came to US$ 35 billion – enabling them to protect more than 70 million
children. These countries however, are eligible for GAVI Alliance funding and have
received support for introducing underused and new vaccines, as well as support to
strengthen their immunization systems.
The remaining 45 countries are those whose GNI per capita classify them as lower-
middle-income countries according to the World Bank classification (42). Thirty-five of
these countries are unable to benefit from GAVI Alliance funding and face increasing
difficulties in financing the introduction of underused and new vaccines. The total
population in these lower-middle-income countries is nearly two billion, including
about 30 million children. In some of these countries, many people live on less than
US$ 2 per day and require support from national authorities and the international
community to meet their basic needs, including immunization. There are a number
of strategies that could help to assist the lower-middle-income countries to access
new and underused vaccines, including technical assistance in disease surveillance,
evaluation, prioritization, and decision-making; enhanced participation of the private
health sector in provision of immunization services; identification of new financing
opportunities; and inter-country collaboration to address the challenge of vaccine
procurement, manufacturing, and vaccine quality assurance.
79
State of the world’s vaccines and immunization
Is the investment worth making?
The investments in immunization continue to increase, and efforts to meet
internationally accepted goals will add substantially to the cost of immunization. For
WHO and UNICEF, the GIVS goals are necessary stepping stones to achieving MDG 4.
Meeting the GIVS goals (see Chapter 1, page 2), would mean protecting children
against 14 diseases – diphtheria, pertussis, tetanus, measles, polio, tuberculosis,
hepatitis B, Hib, rubella, meningococcal disease, pneumococcal disease, rotavirus
diarrhoea, and (in certain areas) Japanese encephalitis and yellow fever.
Yet, is the investment worth making? If all countries manage to reach 90% of
children under five years old with these vaccines, then by 2015 immunization could
prevent an additional two million deaths a year in this age group, making a major
contribution to meeting MDG 4. This would represent a major reduction (60–70%)
since 2000 in the number of under-five deaths from vaccine-preventable diseases.
In addition, recent data show that immunization, even with more expensive vaccines,
continues to be good value for money and a proven cost-effective health intervention
(43, 44, 45, 46, 47, 48, 49). An extreme example is its ability to remove a disease
altogether from the world’s public health landscape, as in the case of smallpox,
or from vast areas of the world, as in the case of polio. Eradicating smallpox cost
US$ 100 million over a 10-year period up to 1977. That investment, according to
one estimate (50), has since been saving the world about US$ 1.3 billion a year in
treatment and prevention costs.
In addition to being a significant contributor to child deaths, vaccine-preventable
diseases also constitute a major cause of illness and disabilities among children
both in industrialized and developing countries. The classic example of vaccines
preventing serious disability has been the prevention of paralytic polio in hundreds
of thousands of children since the advent of the GPEI. In addition, prior to the
widespread use of the measles vaccine, measles was the leading cause of
Chapter 4. Investing in immunization
80
blindness in children in developing countries, accounting for an estimated 15 000–
60 000 cases of blindness every year (51). Other complications of measles that
result in severe neurological disabilities are the post-infectious encephalitis and
the subacute sclerosing panencephalitis (SSPE). Congenital rubella also, which
is associated with deafness, blindness, and severe mental retardation, can be
prevented through immunization.
Among the newer vaccines, the pneumococcal vaccine has been shown to reduce
severe acute otitis media – one of the commonest childhood illnesses that requires
medical attention in industrialized countries. More recently, use of the pneumococcal
vaccine was shown to be associated with a 39% reduction in hospital admissions
due to pneumonia from any cause (52). A large proportion of children who survive
an episode of pneumococcal meningitis are left with long-term disabilities: a recent
study in Bangladesh showed that close to half the children had either a neurological
deficit, such as hearing or visual loss, or a developmental deficit (53).
Similarly, rotavirus diarrhoea is a common cause of clinic visits or hospitalization
among children in both industrialized and developing countries. In a large clinical trial
conducted in 11 countries in North America and Europe, use of the rotavirus vaccine
was shown to reduce clinic visits and hospitalizations due to rotavirus diarrhoea by
95% (54). In Africa, for every 100 vaccinees, rotavirus vaccine prevented three cases
of severe rotavirus diarrhoea that required hospitalization (55).
Thus, while the impact on child deaths alone would be sufficient justification for the
use of vaccines in developing countries, the reduction of long-term disability among
children and the cost savings from reduction in clinic visits and hospitalization more
than justify their use in children everywhere.
The cost-effectiveness equation for immunization, however, should take into
account more than its positive impact on individual and community health. By
keeping children healthy, immunization lengthens life expectancy and the time
81
State of the world’s vaccines and immunization
spent on productive activity, and thereby contributes to a reduction in poverty (the
first Millennium Development Goal, MDG 1). As a Harvard School of Public Health
team recently found in a study on the economics of immunization in countries
receiving GAVI Alliance support, “Healthy children perform better at school, and
healthy adults are both more productive at work and better able to tend to the
health and education of their children. Healthy families are also more likely to save
for the future; since they tend to have fewer children, resources spent on them go
further, thereby improving their life prospects” (56).
Who pays the bill and how?
The WHO and UNICEF analysis to calculate how much it would cost to attain the
GIVS goals (7), not only estimated the total price tag, but also matched this against
estimated future funding, and calculated the estimated shortfalls between 2006 and
2015. For the 72 poorest countries, an estimated funding flow of US$ 25 billion to
support immunization is expected to become available from government, multilateral,
and other sources (including the GAVI Alliance). Against a total immunization bill of
US$ 35 billion in these countries, this leaves an unfunded mandate and funding gap
of US$ 10 billion. Hence, about a US$ 1 billion shortfall needs to be financed every
year if the GIVS goals and MDG 4 are to be achieved.
In order to get a clearer understanding of who pays the immunization bill, it is useful
to look at each funding source separately.
National governments
Since the launch of the EPI in 1974, the financing of vaccines and immunization
in developing countries has largely been made possible through support from the
global international health community – primarily from multilateral and bilateral
Chapter 4. Investing in immunization
82
sources and from international development banks. In the 1970s and 1980s, huge
investments were made to reach the 1990 goal of universal child immunization (UCI),
including important investments in equipment and infrastructure.
However, after 1990, donor funding to sustain routine immunization services began
to dwindle, with most of the funding for vaccines and immunization focused toward
disease control and eradication initiatives. At the same time, many governments
of developing countries became complacent about the need to use their own
domestic resources to pay for their basic vaccines and immunization. As a result,
immunization performance suffered and vaccination coverage stagnated throughout
the 1990s.
Notable exceptions to this were the countries in the Americas, which already had
access to a regional funding mechanism for vaccines. In 1979, PAHO established
a revolving fund to help all countries in the region become more self-sufficient in
the purchase of vaccines for routine immunization. The pooled fund is able to
secure low vaccine prices through large volume contracts with manufacturers. The
mechanism enables participating countries to buy vaccines, using local currencies,
with payment not due until up to 60 days after delivery. As a result, the majority of
countries in the Americas are today almost entirely self-sufficient in the financing of
vaccines and immunization – with over 90% of immunization costs paid for out of
national government resources.
Another part of the success of the PAHO model for financing immunization was the
requirement that countries create a specific budget line item in the national budget
for the purchasing of vaccines. The presence of this separate budget line within a
country’s national health budget contributed significantly to increasing government
financing of vaccines and routine immunization in the Americas, the reason being
that budget line items give visibility to immunization as a permanent presence
within the national planning and budgeting process. Budget line items also facilitate
resource tracking and allow for greater accountability of expenditures. And, most
83
State of the world’s vaccines and immunization
importantly, they signal a long-term political commitment that could protect budget
allocations for immunization during economic downturns.
A WHO analysis of immunization financing indicators from 185 countries collected
through a joint WHO and UNICEF monitoring system, confirmed that breaking
out vaccine purchases as a line item in the national health budget is indeed
associated with increased governmental budget allocations to vaccines and routine
immunization (57).
In 2007, WHO’s 193 Member States were funding an average 71% of their vaccine
costs (33% in low- and lower-middle-income countries). Of these, 86% of countries
reported having a line item for vaccines within their national health budgets (75% of
the 117 low- and lower-middle-income countries).
From the 2008 WHO-UNICEF costing analysis (7), it is estimated that 40% of
the costs of immunization for the period 2006–2015 will be met by national
governments. Other studies have shown that since the year 2000, governments’
spending on vaccines and immunization has been increasing at a steady rate.
Chapter 4. Investing in immunization
84
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85
State of the world’s vaccines and immunization
Multilateral, bilateral, and other donors
If the 2015 Millennium Development Goals are to have any chance of being achieved,
international development assistance, according to a widely quoted estimate (58),
needs to double from the current US$ 50 billion per year. Moreover, it should be
spent primarily on the poorest countries. As mentioned above, immunization alone
will require an additional US$ 1 billion a year over the decade 2006–2015, in order
to help meet the MDGs. Many donor governments have pledged to raise their
development assistance to 0.7% of their gross domestic product, but few have
fulfilled that pledge.
Since the start of GAVI support in 2000, funding for immunization from multilateral,
bilateral, and other funding sources increased by 13% (not adjusted for inflation),
from an average of US$ 2.6 per infant to US$ 3.0 per infant. Overall financing from
multilateral, bilateral, and other external donor sources is projected to average
US$ 2.7 per infant between 2005 and 2010, remaining more or less at its baseline
level.
Starting in 2005, however, the donor funding environment began to change. At
a global level, bilateral donors began to increasingly use the GAVI Alliance as a
channel for funding. At a country level, they started moving away from providing
direct support to individual projects or interventions, and were making increasing
use of broad-based funding mechanisms, or partnerships, to support the health
sector as a whole.
The Global Polio Eradication Initiative
In addition to the broader immunization financing mechanisms, a number of public-
private partnerships have been established to deliver targeted immunization goals.
Such targeted efforts offer substantial benefits for broader immunization objectives –
Chapter 4. Investing in immunization
86
a contribution which often goes unrecognized. A striking example of this is the wide-
ranging impact of the worldwide investment in the Global Polio Eradication Initiative
(GPEI), a public-private partnership launched in 1988 and spearheaded by WHO,
Rotary International, the CDC, and UNICEF.
Since 1988, more than US$ 6 billion in international resources has been invested
in the GPEI, in addition to an estimated equal amount in the form of in-kind
contributions at the national level. A substantial proportion of this amount has
been allocated to the strengthening of routine immunization and health systems,
and towards meeting the GIVS goals (see Chapter 1). About 50% of the annual
GPEI budget is spent on polio supplementary immunization activities such as the
purchase of polio vaccine and transport of vaccinators. However, the remaining
50% is used for training of health staff, district-level micro-planning, refurbishment of
vaccine cold-chain systems, and for scaling up the technical capacity of networks
for surveillance and monitoring of vaccine-preventable diseases.
The GPEI is increasingly funded through innovative financing mechanisms. In addition
to ongoing support through traditional donor engagement, such mechanisms
include innovative funding partnerships between Rotary International and the Bill &
Melinda Gates Foundation; a one-time contribution in 2007 from the International
Finance Facility for Immunisation (IFFIm); and a budget allocation from the G8 Group
of countries, which includes not only development aid but also domestic resources.
Another funding mechanism is the Investment Partnership for Polio, launched in
2003 by the World Bank, Bill & Melinda Gates Foundation, Rotary International,
and the UN Foundation. This involves the use of long-term “soft loans” issued
by the International Development Association (IDA) – the concessionary
lending arm of the World Bank – to enable countries to buy oral polio vaccine.
When the recipient country’s polio eradication programme has been completed,
the Investment Partnership for Polio will then “buy down” the loans – effectively
turning them into grants – through the use of a trust fund established by the
87
State of the world’s vaccines and immunization
Bill & Melinda Gates Foundation, Rotary International, and the UN Foundation.
As of early 2009, two countries – Nigeria and Pakistan – are making use of this
funding mechanism.
The GAVI Alliance
The GAVI Alliance is a public-private global health partnership that includes
governments in industrialized and developing countries, international organizations
(UNICEF, WHO, and the World Bank), foundations (notably, the Bill & Melinda Gates
Foundation), non-governmental organizations, vaccine manufacturers from industrialized
and developing countries, civil society, and public health and research institutions.
All the partners have signed the Alliance’s declared mission “to save children’s
lives and protect people’s health by increasing access to immunization in poor
countries”.
The GAVI Alliance offers all eligible countries support, primarily for vaccines and
immunization, but also to strengthen health systems and the work of civil society
organizations, and to ensure the safety of immunization. To be eligible for GAVI
Alliance support, countries must have a GNI per capita of less than US$ 1000. They
must also have a costed comprehensive multi-year plan for immunization (cMYP).
Up to 2005, 75 countries were eligible for GAVI Alliance support. In 2003, the
number of countries dropped to 72, due to changes in GNI per capita.
As of the end of 2008, the GAVI Alliance had received a cumulative total of
US$ 3.8 billion in cash and pledges from public and private sector donors (including
US$ 1.2 billion from the sale of IFFIm bonds), and had disbursed US$ 2.7 billion to
eligible countries. Over the period up to 2015, the Alliance has an estimated funding
gap of US$ 3 billion out of the estimated US$ 8.1 billion total funding needed.
Chapter 4. Investing in immunization
88
During its first phase, from 2000 to 2005, the GAVI Alliance focused on vaccines
against hepatitis B and Hib – especially those used in combination with the DTP
vaccine. The Alliance also focused on yellow fever vaccine in areas at risk for this
disease. The GAVI-supported vaccines, which are recommended by WHO because
they are safe, cost-effective, and known to have significant public health benefits,
had previously remained largely unavailable to poor countries. During the Alliance’s
second phase, which runs from 2006 to 2015, the focus of financial support has
expanded to include rotavirus and pneumococcal vaccines.
By the end of 2008, thanks to GAVI Alliance support, it is estimated that over
192 million children had been immunized against hepatitis B; nearly 42 million
against Hib disease; and 35.6 million against yellow fever. GAVI Alliance support
for these underused vaccines and for vaccination against diphtheria, tetanus, and
pertussis had, according to GAVI Alliance and WHO estimates, averted 3.4 million
premature deaths.
Under the GAVI Alliance’s “immunization services support” programme, launched
in 2000, countries receive funds over a two-year period – the so-called “investment
phase”. In the third year, they receive a bonus of US$ 20 per additional child
vaccinated compared with the previous year. An evaluation exercise conducted by
the Alliance in 2007 estimated that about 2.4 million children had been immunized
with the full three doses of DTP vaccine – children who would not have immunized
without the Alliance’s immunization support programme.
To meet concerns about financial sustainability, all GAVI-supported countries were
required to prepare a financial sustainability plan (now replaced by a cMYP). An
analysis of 50 of the financial sustainability plans reveals an upward trend since 2000
in both national and external sources of funding for routine immunization.
In 2007, as part of its second phase, the GAVI Alliance introduced a co-financing
system, whereby countries eligible for support are required to pay a gradually
89
State of the world’s vaccines and immunization
increasing share of the cost of the vaccines provided through the Alliance, based on
their GNI per capita. The aim is not only to assist countries on the path to greater
financial sustainability, but also to encourage them to base their decisions about
vaccine introduction on solid evidence about the burden of disease targeted by a
vaccine, and the affordability and likely cost-effectiveness of using the vaccine. By
the end of 2008, 30 countries were using the co-financing system to pay for the
introduction of the pentavalent (DTP-Hepatitis B-Hib) vaccine, rotavirus vaccine, and
pneumococcal vaccine.
New financing mechanisms
The International Finance Facility for Immunisation
The International Finance Facility for Immunisation (IFFIm) is a multilateral
development institution created to accelerate the availability of predictable, long-
term funds for health and immunization programmes through the GAVI Alliance in
70 of the poorest countries in the world.
Launched in 2006 as a pilot project of the International Finance Facility (IFF), and
promoted by the United Kingdom Government, IFFIm was created as a development
financing tool to help the international community achieve the MDGs. Donors
contribute to the IFFIm by making long-term legally binding commitments or grants
to support immunization activities in poor countries. As of the end of 2008, seven
countries – France, Italy, Norway, South Africa, Spain, Sweden, and the United
Kingdom – had made commitments totalling US$ 5.3 billion over a 20-year period.
The World Bank acts as financial adviser and treasury manager to the project.
The IFFIm uses these commitments to issue bonds on the international capital
markets. The sale of these bonds provides cash that the IFFIm gives to the GAVI
Alliance and that can be used immediately to fund the Alliance’s programmes. The
Chapter 4. Investing in immunization
90
IFFIm’s first bond offering, in November 2006, raised US$ 1 billion from institutional
investors worldwide. A second offering, in March 2008, raised US$ 223 million from
private investors in Japan.
Advance Market Commitment
Conceived in 2005 by the Center for Global Development, and carried forward by five
bilateral donor governments, the Bill & Melinda Gates Foundation, the GAVI Alliance,
and the World Bank, the Advance Market Commitment (AMC) is a new approach
to public health funding. Its aim is to stimulate the development and manufacture of
vaccines specially suited to developing countries.
Through an AMC, donors commit money to guarantee the price of vaccines once
they have been developed, thus creating the potential for a viable future market.
However, donor funds are not provided until after the proposed vaccines have
met stringent, pre-agreed technical criteria, and developing countries request
them. These commitments provide vaccine makers with the incentive to invest the
considerable sums required to conduct research and build manufacturing capacity.
Companies that participate in an AMC make legally binding commitments to supply
the vaccines at lower and sustainable prices after the donor funds made available
for the initial fixed price are spent. As a result, governments of developing countries
are able to plan and budget for their immunization programmes – with the assurance
that vaccines will be available in sufficient quantity, at a price they can afford, for the
long term.
The Governments of Canada, Italy, Norway, the Russian Federation, and the United
Kingdom, together with the Bill & Melinda Gates Foundation, have committed
US$ 1.5 billion to a pilot AMC targeting pneumococcal disease. It is estimated that
pneumococcal vaccines – if made widely available in developing countries – could
save over seven million lives by 2030.
91
State of the world’s vaccines and immunization
A concluding conundrum
If children’s lives are worth saving – and who would doubt that they are; if vaccines
save lives – and the evidence is clear that they do; and if the world has the means
of making, buying, and using vaccines, as it surely does: then why are children still
dying from diseases that vaccines can prevent ?
The answer to this conundrum lies perhaps in the difficulty of choosing between
conflicting priorities. The choices are made primarily by governments. Between
2006 and 2015, some 40% of all funding for routine immunization is estimated to
come from national government funds. As the current economic downturn unfolds,
it will be important for governments to sustain and, when possible, increase these
investments in immunization.
For a government faced with competing priorities, choosing is not easy.
Vaccines will not prevent all diseases or all child deaths. But vaccines can prevent
much of the needless suffering caused by infectious diseases – enough to help
create a space where families can busy themselves with things other than sheer
survival.
The good news is that more investment is being made in immunization, and the
future projections indicate increasing financing. Today, as never before, governments
have an unprecedented number of partners willing to help pay for vaccines and
immunization. Yet, expected future funding from governments and donors will not
be enough to sustain the gains already achieved towards GIVS goals and the
MDGs. “The real challenge,” the WHO-UNICEF analysis report (7) concluded, “will
hinge on how national governments, and the international community at large
manage their roles and responsibilities in reaching and financing the goals of the
GIVS until 2015.”
Chapter 5. The view from the future
92
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State of the world’s vaccines and immunization
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The view
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Chapter 5. The view from the future
94
Key messages
By the 2020s:
• child deaths from infectious diseases are expected to be
at an all-time low;
• polio should be eradicated, and measles eliminated in all
countries;
• today’s new vaccines against pneumococcal disease,
rotavirus, meningococcal disease, and HPV are expected
to have inspired new health and development goals;
• hopes remain high that new vaccines will be available to
combat malaria, tuberculosis, AIDS, and other diseases.
Chapter 5. The view from the future
94
95
State of the world’s vaccines and immunization
This report paints a picture of where the many and diverse activities relating to
vaccines and immunization stand today. Some of these activities are well on the way
to achieving their objectives. Others are stalling, for one reason or another. But the
overall picture is one of cautious optimism, enthusiasm, energy, and dedication.
Clearly, vaccines and immunization can make a major contribution to achieving
the MDGs and thereby reduce the gross inequities that create an ever wider gap
between the haves and have-nots (Chapter 1). The vaccine world, too, has set a
number of goals: its GIVS identifies the targets to be reached if immunization is to
lend its full potential to achieving the MDGs.
Vaccine development presents a dynamic picture (Chapter 2) – safer and more
effective vaccines coming off an exceptionally rich pipeline; more efficient ways
of making vaccines; more vaccine producers in developing countries; innovative
regulatory mechanisms; more efficient ways of ensuring maximum vaccine safety
and efficacy; and more partnerships harnessing the combined strengths of the
public and private sectors to spur development of even better vaccines.
Administration of measles
vaccine through the aerosol
route could facilitate measles
immunization efforts, especially
mass campaigns.
Chapter 5. The view from the future
96
To meet the goals of the GIVS, more people need to benefit from the life-saving,
disease-preventing power of vaccines. A groundswell of activities and projects –
some new and some newly revitalized – are working to achieve this goal (Chapter
3). More people are being reached with vaccines, including groups – such as
adolescents, elderly people, women outside child-bearing age – and members
of hard-to-reach communities – who have been neglected to some degree by
traditional immunization policies, where the main focus has been on infants and
young children.
New strategies have also been put in place to accelerate the integration of
immunization programmes within the health systems of countries, and to expand
the use of these programmes to deliver other health interventions. When linked with
other health interventions – to prevent and treat childhood pneumonia, diarrhoea,
and malaria, for example – immunization becomes a driving force for child survival
and for meeting MDG 4.
A new, ambitious plan to create a global network for the surveillance and monitoring
of vaccine-preventable diseases is also taking shape. And less recent, but no less
exciting, are the achievements of major thrusts to remove the burden of three
diseases: polio is close to being eradicated, deaths from measles have plunged
to record lows, and maternal and neonatal tetanus is well on the way to being
eliminated (see Box 17).
Funding to pay for all these activities is clearly on a more solid footing than it was
a decade ago (Chapter 4). Innovative mechanisms for mobilizing and channeling
donor funds have created new incentives among almost all players on the vaccine
and immunization stage, from the vaccine industry to the health ministry. Donors
– both multilateral and bilateral – have increased their generosity and are currently
financing about a fifth of immunization costs worldwide. Governments – even of
some of the poorest countries – are spending more on vaccines and immunization.
To some extent, the entire field of vaccines and immunization is buoyed by an
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State of the world’s vaccines and immunization
Box 17
The future of immunization
How will immunization change over coming decades?
Today, in most developing countries, routine immunization schedules have gone
beyond the six traditional childhood vaccines – diphtheria, tetanus, pertussis, measles,
polio, and tuberculosis. Vaccines against hepatitis B, Hib, rubella, pneumococcal
disease, and rotavirus – and, in areas where they are needed, vaccines against yellow
fever and Japanese encephalitis – are being used in a growing number of countries.
Over the next decade or so, increasing numbers of developing countries should be
using the new vaccines coming onto the market. Some of these vaccines (such as
the HPV vaccine) will be given to adolescents; others (such as the influenza vaccine)
to adults. Moreover, booster doses of some of the traditional vaccines, such as those
against tetanus, diphtheria, and pertussis, will be given to older children, adolescents,
and adults, and will need to be integrated into the immunization schedules of
developing countries (as they are today in industrialized countries). In many countries,
second doses of the measles vaccine will be offered through routine immunization
programmes to children beyond their first birthday.
The problem is that, with the exception of special immunization campaigns, there is
little knowledge or experience about how to reach older age groups in developing
countries. School-based immunization is a possibility, especially as school attendance
is growing in many developing countries.
Over the next decade, delivering vaccines into the human body may, to a large
extent, have done away with devices that use needles. Some needle-free approaches
are already appearing, and others are still in the experimental phase. They include
vaccines in aerosol formulations that are sprayed into the nose (already available
for an influenza vaccine), or lungs (currently being tested in humans with a measles
vaccine, and in monkeys with an HIV or HPV vaccine); adhesive skin patches; drops
under the tongue; and oral pills.
Another potential breakthrough is the development of an increasing number of
vaccines that are heat-stable. When supplied with a vaccine vial monitor to check
exposure to heat, these vaccines should be available for use outside the cold chain –
greatly relieving the pressure on the cold chain and logistics.
Chapter 5. The view from the future
98
unprecedented influx of new wealth. However rough the path into the future may
be in some places, today’s vaccines and immunization scene clearly bears the mark
of progress.
The world, as it enters the final years of this decade, is facing a massive financial and
economic crisis, which raises the question: How long can the dynamo that drives
progress in the vaccine arena continue to function? A look at the forces driving the
dynamo may hold some clues.
More funds from more sources are clearly a driving force for all areas of work on
vaccines and immunization. The effects of these funds have rarely been so visible.
Since 2000, health aid has doubled, according to one report (59). As of early 2009,
with the financial world in turmoil, cash is scarce. Views differ about the potential
impact of the economic downturn on future donor health funding. Optimists remain
hopeful that the MDGs will exert a strong enough “pull” on the donor community
to provide predictable, sustainable funding; that the current momentum within the
vaccine community and the current soaring trends in the life-saving achievements
of vaccines will motivate the donor community to keep immunization high on their
priority lists; and that it will encourage donors to sustain and even increase financial
support well beyond the 2015 deadline for achieving the MDGs.
Increasingly, partnerships are becoming important drivers of vaccine development
and deployment. The GAVI Alliance – a public-private global health partnership – is a
prime example of this trend. Its partners span almost the entire spectrum of vaccine
and immunization activities: private foundations and governments of industrialized
countries; industry, in both developing and industrialized countries; civil society
organizations; and international health and development organizations (WHO,
UNICEF, the World Bank, and others). Perhaps the most crucial partners are the
developing countries, whose governments are responsible for choosing and using
the vaccines that are available. Current efforts, that should bear fruit in the future, are
being made to assist these governments in making decisions about vaccines and
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State of the world’s vaccines and immunization
immunization – decisions that should be made on the strength of sound evidence.
In the long term, government ownership of national immunization programmes,
including country-driven policies, strategies, monitoring, and reporting, should
ensure the sustainability of today’s investments in immunization.
Another force likely to drive future vaccine development and expand immunization
coverage is public demand for vaccines and immunization services. Over the next
two decades that demand should rise. For one thing, more vaccines are likely
to become available against more diseases, thereby boosting the popularity of
immunization. For another, more people are likely to have access to more education
and to have a greater awareness of the benefits of immunization. Their claim to
a share of these benefits is likely to become bolder. Public demand in developing
countries is likely in the future to be as strong as it is today in industrialized countries.
But growing awareness of the benefits of vaccines is also likely to increase concerns
over their safety. Vaccine producers and regulators will no doubt feel increasing
pressure to ensure that vaccines are safe, and vaccine advocates will feel the need
to offset rumours and doubts with even more timely, accurate information than they
provide today.
Certainly, the vaccine supply landscape is likely to have changed by 2020. Judging
from current trends, developing countries may well have acquired the capacity to
make their own state-of-the-art vaccines that meet their own specific needs. And
their contribution to global vaccine supply may well be on a much more equal
footing with industrialized countries than it is today – a development likely to increase
competition.
As for vaccine development, one driving factor is the progress being made in
devising, adapting, and using advances in vaccine science and technology. Will
those advances continue? And will they justify the setting of new goals for combating
vaccine-preventable diseases and deaths? Looking into the 2020s, the MDGs
should have brought child deaths from infectious diseases to an all-time low. Polio
Chapter 5. The view from the future
100
should be a thing of the past, and measles eliminated in all countries. Neonatal and
maternal tetanus should no longer be exerting such a heavy toll on babies and their
mothers. Today’s underused vaccines – against Hib disease, hepatitis B, and yellow
fever – may well have rid the world of the lethal burden of these diseases. Surely
today’s new vaccines – against pneumococcal, rotavirus, meningococcal, and HPV
disease – will have inspired tomorrow’s new goals for going beyond the life-saving
achievements of the current international health and development goals. And surely,
vaccine science and industrial inventiveness will have produced high-performance
vaccines capable of turning the tide against malaria, tuberculosis, AIDS and other
diseases that seem, today, unconquerable.
But, of course, new goals will likely face new challenges. The world is currently facing
the challenges of economic recession and financial turmoil. Climate change is already
a major challenge and is likely, over coming decades, to alter the epidemiological
landscape in which vaccines and immunization operate.
“The business of predicting,” as Nobel laureate Niels Bohr is often quoted as saying,
“is very difficult, especially when it’s about the future”. Which is another way of
saying: the future holds more questions than answers. About one thing, though,
there is no question. Immunization works. It has worked in the past. It is working in
the present. And short of a radical change in human biology, there is every reason
to believe that immunization will continue far into the future to be a mainstay of
human health.
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State of the world’s vaccines and immunization
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Part 2:
Diseases and their vaccines
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Part 2: Diseases and their vaccines
Cholera – exploring the use of available vaccines
Often referred to as one of humankind’s “most devastating diseases”, cholera was for
centuries a permanent feature of life in the slums and poverty-stricken villages of India,
where outbreaks have occurred since the early 1800s. Ships sailing from the Bay of
Bengal during an 1817 epidemic are believed to have brought the disease to Europe in
bilge water contaminated with the causative organism, Vibrio cholerae. From there, the
disease spread eastwards throughout Europe and Asia, and westwards to the Americas.
Since 1817, there have been seven major cholera pandemics in areas of South America,
Africa, Europe, and Asia (60). The seventh pandemic, which is still ongoing, began in
1961 in Indonesia, then spread through Asia and Africa, and finally reached Latin America
early in 1991 (60).
V. cholerae is transmitted by contaminated water and food and, like typhoid fever, is
associated with poverty, poor hygiene, and inadequate sanitation. The disease typically
begins with an acute attack of diarrhoea and copious vomiting, rapidly followed by
dehydration, and, in the absence of treatment, renal failure and death (1). About 80% of
cholera episodes are of mild-to-moderate severity. Cholera usually responds to prompt
administration of oral rehydration salts to replace lost fluids. In the past, before the advent
of fluid replacement therapy, up to 50% of infected people died from the disease. Today,
the risk of death is less than 3%, on a global average (61).
The number of cholera cases reported to WHO annually has remained relatively constant
since 1995, varying from 100 000 to 300 000 cases per year, with Africa accounting for
more than 94% of the total. In 2006, a total of 236 896 cases were notified to WHO from
52 countries: 31 out of 46 African countries experienced an outbreak of cholera and
reported a total number of 202 407 cases with 5259 deaths (62). Globally, the actual
number of cholera cases is known to be much higher; the discrepancy is the result of
underreporting due to fear of unjustified travel and trade-related sanctions, limitations
of surveillance systems, such as inconsistency in the case definition and a lack of a
standard vocabulary (61), and this perhaps represents 10-20% of all cases (63). The
problem may be less acute following the change, in 2005, in the International Health
Regulations (IHR) that replaces compulsory public notification of cholera with a more
discreet outbreak response arrangement between affected countries and WHO. Today,
no country requires proof of cholera vaccination as a condition for entry.
The causative agent of cholera was first discovered in 1854 by the Italian scientist
Filippo Pasini, and “re-discovered”, seemingly independently, in 1884 by the German
microbiologist Robert Koch. In that year, the first cholera vaccine was made and
began to be used in Spain. It consisted of the killed whole cholera bacterium and was
administered by injection. Over subsequent years, several injectable whole-cell cholera
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State of the world’s vaccines and immunization
vaccines made their appearance and were used in millions of people in several countries,
including India and Russia. Reported efficacy of these early vaccines varied widely.
The year 1959 saw licensure of the first cholera vaccine to benefit from modern
manufacturing technology, and the first to be submitted to reliable scientific scrutiny.
However, several well-designed studies in Asia found that the vaccine possessed only
limited efficacy and caused a significant number of side-effects.
The search for a safer, more effective cholera vaccine produced three new-generation
vaccines, of which only one is available for widespread use today. This vaccine, first
licensed in Argentina in 1997 and code-named WC/rBS, is made from the whole-cell
V. cholerae linked to a genetically engineered (recombinant) fragment (B-subunit) of the
cholera toxin. Field trials in Bangladesh, Mozambique, and Peru found the vaccine to be
effective and safe. It does have shortcomings, though. First, it requires two doses given
one week apart and taken with liquid (a buffer solution to neutralize stomach acid) – two
factors that complicate its use, particularly in epidemics. Second, its protective capability
takes about three weeks to develop after administration of the first dose. Protection is
highest during the first six months after vaccination but lasts for up to three years (64).
Third, it is effective only against the 01 V. cholerae strain (serogroup): until recently, this
strain was the most frequent cause of epidemics but in 1992 a second serogroup, 0139,
was identified as the cause of epidemics in Bangladesh and India, and has since been
implicated in a growing number of outbreaks in Asia.
From a public health standpoint, the WC/rBS vaccine, despite its shortcomings, is the
only new-generation cholera vaccine recommended for use by travellers to cholera-
endemic areas, and the only one to have been used in mass vaccination campaigns.
Over the period 2003–2006, it was successfully deployed in mass campaigns carried out
in Indonesia, Mozambique, and the Sudan. Since 2006, WHO has recommended that in
complex emergencies, the use of cholera vaccine should be considered by governments
in the context of other public health priorities (61, 65).
As of mid-2008, WHO’s cholera control policy (61) calls, in the first instance, for the
improvement of basic sanitary conditions and hygiene. Guided by its Global Task Force
on Cholera Control, WHO is weighing how best vaccines might be used to supplement
these basic measures, particularly in areas, such as urban slums, or in conditions, such
as epidemics, where these measures are particularly difficult to apply.
Meanwhile, the vaccine R&D pipeline holds the promise of several new vaccines which,
if they fulfil their promise, would confer long-lasting immunity against all predominant
strains of V. cholerae after oral administration of a single dose, would be affordable by
developing countries, and would not require or overload current cold-chain facilities.
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Diphtheria – controlled by vaccines but waiting to resurface
Diphtheria is a disease of the upper respiratory tract caused by the bacterium
Corynebacterium diphtheriae. Most cases run a mild course with only sore throat and
fever, and often no symptoms at all. The organism, however, secretes a toxin that can
cause inflammation of the pharynx, larynx, and trachea, and when the toxin travels in
the blood or lymph system, it can attack just about any organ in the body, including the
heart (resulting in myocarditis) and nervous system (resulting in polyneuritis) (1). In more
than 10% of cases, the disease is fatal (66). The latest WHO estimates for 2004 put
the number of deaths worldwide at 5000, of which 4000 are in children under five (4).
Corynebacterium diphtheriae also causes a cutaneous infection that is a further source
of transmission, and may confer some protection against the respiratory disease.
The hallmark of diphtheria is a greyish-white membrane (a pseudomembrane) that forms
on throat tissue. When this membrane spreads downwards into the larynx, it can cause
death by suffocation. French physician Pierre Bretonneau, who in 1825 performed the
first successful tracheotomy to save the life of a patient threatened by suffocation from the
leathery membrane, gave the name “diphtheria” to the disease (from the Greek word for
“leather”) (1). However, the earliest detailed descriptions of the disease date from ancient
Syrian, Egyptian, and Greek writings (1). Two millennia later, in 1883, Corynebacterium
diphtheriae was identified in a German laboratory as the causative agent.
Diphtheria is highly contagious. The organism spreads through direct physical contact
or air-borne droplets. Throughout history, devastating epidemics have made diphtheria
one of the most feared childhood diseases (67). Known as “the strangler” in Spain and
“the gullet disease” in Italy, diphtheria swept across Europe in the 17
th
century. Towards
the end of the following century, a major epidemic occurred in Europe and spread to the
United States, killing about 50% of infected people. By the beginning of the 20
th
century,
the disease was causing about 150 000 cases and 13 000 deaths annually in the United
States, mostly in infants and young children. Diphtheria epidemics continued to ravage
Europe over subsequent decades: in 1943, about one million cases and 50 000 deaths
occurred, and a similar number of cases and deaths were believed to be occurring every
year in developing countries at the time (67).
Meanwhile, in 1907, experiments had begun on using a toxin–antitoxin (TAT) solution to
induce protective immunity. The rationale was that the toxin would stimulate immunity
and the antitoxin (antibodies) would counteract the toxicity of the toxin and prevent it
from causing disease in the recipient (1). Starting in 1910, several cities in Europe and
the United States set up immunization programmes to administer the TAT complex.
Thanks to this prophylaxis, the average death rate among infected people declined from
about 50% to under 15%.
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State of the world’s vaccines and immunization
In the early 1920s, researchers discovered that they could attenuate the diphtheria
toxin by exposing it to certain chemicals or to heat, without depriving it of its immune-
stimulating (immunogenic) properties. The resulting product was a safer vaccine, less
likely to cause allergic reactions than the TAT complex. To this day the toxoid has
remained, with only minor modifications, the standard diphtheria vaccine and one of the
safest and effective in the immunological arsenal.
In 1974, national routine immunization programmes working with WHO’s newly created
EPI, began using the diphtheria toxoid as one of the components of the DTP combination
vaccine. By 1980, 20% of the infant population was receiving the full three-dose series
of DTP (41). By the end of 2007, 81% of all infants worldwide were protected with
three doses of DTP (41). Over the same period, reported cases worldwide fell by
more than 95%, from 97 774 to 4273 (41) (reported case numbers rarely reflect true
numbers but the trend certainly shows a convincing inverse relationship to vaccination
coverage).
Diphtheria is no longer endemic, and high vaccine coverage rates in most countries have
mostly eliminated the risk of epidemics. However, in countries with low (<50%) routine
immunization coverage the risk of epidemics is still high. In the 1990s, a particularly
alarming epidemic broke out in countries of the former Union of Soviet Socialist
Republics following a drop in vaccination coverage. If nothing else, this outbreak served
as an object lesson in the risk countries face when they lower their vaccination guard.
Since 1990, diphtheria outbreaks have also occurred in Africa, the Middle East, Asia,
and South America (41). Paradoxically, some of the affected countries had relatively
high reported vaccination coverage rates (67). The paradox is still the subject of debate.
Another observation fuelling debate is the high percentage of adult cases in these
epidemics, even where infant vaccination coverage was high and adults were receiving
booster vaccine doses.
These observations have prompted countries where diphtheria is no longer endemic
to extend vaccination protection beyond the primary three-dose series for infants by
administering one, or sometimes two, booster doses every 10 years to adults through
the diphtheria-tetanus (dT – low content of diphtheria) combination vaccine (67).
Some countries with high infant vaccination coverage rates are giving booster doses
of diphtheria toxoid to older children to compensate for the loss of natural immunity
that they would have acquired from exposure to the bacterium had it still been
circulating. Re-vaccination of health-care workers and using the dT combination vaccine
(rather than the tetanus toxoid alone), for prophylaxis against tetanus following injury
are additional safeguards some countries are adopting to lower the risk of a diphtheria
outbreak (67).
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Haemophilus influenzae type b (Hib) – increased attention for
this little known but lethal disease
Since the mid-20
th
century, Haemophilus influenzae type b, or Hib, has been known by
epidemiologists to cause meningitis, pneumonia, and other serious infections in infants
and young children. WHO estimates of the year 2000 attribute to this bacterium an
annual toll among the under-fives of nearly 8.1 million cases of invasive disease and
pneumonia of which 363 000
1
are fatal (68). Hib also causes potentially severe
inflammatory infections of the face, mouth, blood, epiglottis, joints, heart, bones,
peritoneum, and trachea.
Yet, beyond the epidemiologists and public health analysts of the vaccine community,
the burden of Hib disease is still not widely appreciated. One reason is the difficulty
in detecting this bacterium as a common cause of pneumonia and meningitis cases,
especially in developing countries. The problem is complicated by the fact that in many
parts of the world, clinicians have treated these diseases with antibiotics, thereby
masking the role of Hib.
Since the early 1980s, researchers used conjugation technology to develop several
vaccine products that were highly immunogenic and conferred protection on all age
groups. Wide use of this Hib “conjugate” vaccine enabled several countries – both
industrialized and developing – to virtually wipe out Hib disease. Moreover, large-scale
studies in Africa and Latin America, and more recently also in Asia, found a substantial
reduction in the burden of pneumonia and meningitis in countries that had used the
vaccine widely. One African trial, in particular, showed a drop in pneumonia incidence of
just over 20% in Gambian children (69).
Notwithstanding clear evidence of the vaccine’s efficacy, by 1997 only 29 countries were
using it routinely, prompting WHO to recommend its inclusion in the routine immunization
programmes of all countries where Hib was recognized as a public health burden
and where the cost of the vaccine was not prohibitive (70). Over the next few years,
however, both these conditions were to prove deterrents to Hib introduction for many
countries.
Following the WHO global recommendation, and with growing demand for the vaccine
together with increasing supply, the cost of the three doses of the single-antigen Hib
vaccine had fallen to approximately US$ 10, and is now beginning to see even more
1
reflects only deaths in HIV-negative children; an additional 8000 deaths are estimated to
occur in HIV-infected children.
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State of the world’s vaccines and immunization
significant declines. In 2000, the GAVI Alliance began offering financial support for
procurement of the vaccine to its then-75 eligible countries (i.e. those with a per capita
gross national income of less than US$ 1000). The year 2005 also saw the birth of the
Hib Initiative, a consortium of four public health entities (WHO, Johns Hopkins Bloomberg
School of Public Health, the London School of Hygiene and Tropical Medicine, and the
CDC), that was set up, with GAVI Alliance support, to speed up the adoption of Hib
vaccine (70).
By late 2008, 135 countries had adopted the vaccine in their routine immunization
programmes (Fig. 10) and a further 25 countries are expected to do so before the end of
2009, bringing the total to 160 countries, or 83% of all 193 WHO Member States (71).
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Part 2: Diseases and their vaccines
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State of the world’s vaccines and immunization
Hib vaccines are administered at the same time as DTP, often in combination vaccines
that also include the DTP and hepatitis B antigens. In industrialized countries, the infant
vaccination schedule with Hib conjugate vaccines is usually followed by one further dose
during the second year of life. In most other countries, the Hib vaccine is only used for
younger infants. Recent data from Latin America and Africa suggest that Hib disease
can be eliminated with a three-dose regimen. At the present time, therefore, there are
no compelling reasons for recommending a fourth dose of vaccine outside of the routine
immunization programme. However, it is not yet known whether the protection conferred
by the primary three doses will last a lifetime or if susceptibility to Hib infection could
appear later in life. To help dispel such doubts, countries using Hib vaccines need to
sustain surveillance for bacterial meningitis. Prompt detection of a resurgence of Hib
disease could enable an appropriate vaccination response to be made.
Hepatitis A – paradox and potential
Hepatitis A is an acute illness caused by a virus (HAV) transmitted through the faecal-
oral route. It is characterized by jaundice, dark urine, fever, anorexia, and abdominal
discomfort, with the symptoms related to age. Infection with HAV does not become
chronic. Most people recover after a few weeks. Severe complications are rare, but the
risk of death increases with age, and case fatality may range from zero in children under
5 years old to 1.5% in people aged over 60.
The paradox of hepatitis A is that the very countries in which the disease is most
prevalent are those where it has least visibility; in countries where its incidence is lower,
outbreaks of the disease are very evident. In developing countries, HAV infects more
than 80% of the population before adolescence, and 70% of children under six years of
age may have no symptoms. In contrast, in industrialized countries with better sanitation,
young children may not be infected, but during outbreaks, older children and adults who
do not have immunity, may be ill with jaundice for up to two months, with the result that
the disease is the most commonly reported of vaccine-preventable diseases in these
countries. But this paradox also defines the potential: when countries improve their
socioeconomic conditions, hepatitis A becomes more visible and controlling the disease
through vaccination becomes a possibility.
Inactivated hepatitis A vaccines were licensed in the United States in 1996, where their
use led to a dramatic decline in cases. Similar drops in incidence have been seen in
other countries or areas of countries, such as Israel, Italy, and Spain.
Currently, WHO recommends that the results of appropriate epidemiological and cost-
benefit studies should be weighed carefully before deciding on national policies on
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Part 2: Diseases and their vaccines
immunization against hepatitis A (72). In highly endemic countries, HAV infects virtually
all young children, without causing symptoms but effectively protecting the population
against symptomatic hepatitis A disease in later life. In such countries, large-scale hepatitis
A vaccination is not required. In countries of intermediate endemicity where a relatively
large proportion of the adult population is susceptible to HAV, and where hepatitis A
represents a significant public health burden, large-scale childhood vaccination may be
considered as a supplement to health education and improved sanitation. In regions of
low endemicity, vaccination against hepatitis A is indicated for individuals with increased
risk of contracting the infection.

Evidence from use of the vaccine in the United States and other countries, suggests that
universal hepatitis A vaccine introduction can reduce the disease to very low nationwide
incidence rates, raising the possibility of ultimately eliminating the disease.
Hepatitis B – the first vaccine against cancer
Of the many viruses known to cause hepatitis, the hepatitis B virus (HBV) inflicts the
heaviest public health burden. The infection spreads by exposure to blood or other body
fluids of an infected person, as in sexual contact, through a skin wound, or through use of
an infected needle or syringe, and, in the case of infants, from an infected mother during
childbirth. People infected with HBV are between 50 and 100 times more infectious (to
others) than those infected with HIV. Further, the HBV virus is capable of remaining viable
for over one week on contaminated environmental surfaces.
In most cases, the infection runs an acute course lasting from one to three months.
Symptoms include jaundice, malaise, loss of appetite, nausea and vomiting, fever,
muscle pain, and fatigue. They may be mild or, as in most infants and children, totally
absent.
The most feared effect of HBV is chronic or lifelong infection – feared because it can lead
to death from cirrhosis or cancer of the liver (1). More than 350 million people in the world
today have chronic hepatitis B infection, according to a WHO estimate (73). About 90% of
infants infected during the first year of life develop chronic infection, compared with 30%
of children infected between one and four years, and less than 5% of people infected as
adults (1). In 2002, an estimated 600 000 deaths occurred from chronic HBV infection.
In 1982, the first hepatitis B vaccine – the first vaccine against a human cancer – became
available. Over the next decade, studies showed that the vaccine could protect about
95% of recipients from HBV infection. In 1992, WHO called on all countries to use the
vaccine in their routine immunization programmes. Where transmission of the infection
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State of the world’s vaccines and immunization
during childbirth is common, as it is in several developing countries of WHO’s South-East
Asia Region, the first vaccine dose should be given to babies within 24 hours of birth.
WHO also urges countries to vaccinate adults at risk of infection, such as health-care
workers exposed to blood or other body fluids, dialysis patients, prison inmates, injecting
drug users, household and sexual contacts of chronically infected people, and those
with multiple sexual partners.
Adoption of the vaccine in routine immunization programmes was slow to take off. By
1997 – the WHO deadline for universal adoption of the vaccine in infant immunization
programmes – only 62 countries had adopted the vaccine and only 14% of children were
receiving the full three doses (41). Limited recognition of the burden of HBV infection
and lack of funds to deploy the vaccine were among the main obstacles to wider
introduction of the vaccine. Over subsequent years, WHO-sponsored research on the
disease burden in developing countries did much to raise awareness of the infection and
its consequences. The advent of the GAVI Alliance in 2000 helped to erode the financial
obstacles to introducing the vaccine, at least for the poorer countries of the world. By
the end of 2007, 171 of WHO’s 193 Member States were using the vaccine in their infant
immunization schedule.
The impact of vaccination on acute HBV infection is difficult to evaluate, since it requires
intense surveillance for acute disease and laboratory confirmation. On the contrary, the
impact on chronic HBV infection is easier to assess, thanks to blood (serological) tests
for hepatitis B infection markers. Several countries achieving high vaccine coverage rates
have seen a substantial reduction in the prevalence of chronic infection. Communities in
China, for example, that began reaching high vaccine coverage rates in the late 1990s,
showed a 90% drop by 2006 in the prevalence of chronic HBV infection in children under
five years old (74).
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Box 18
Hepatitis B control in China: reducing disparities
Every year, 280 000 people in China die from liver cancer or cirrhosis, accounting for
almost one third of all HBV-related deaths worldwide. Even within this alarming statistic
there are marked disparities between rich and poor provinces. Overall, approximately
60% of the population has a history of HBV infection. Almost 10%, or 120 million
people, are chronically infected with HBV and risk early death from liver disease.
In response, China has made major investments in improving delivery of the hepatitis
B vaccine. Hepatitis B vaccination for infants was introduced in 1992, with the
recommendation that the first dose be given within 24 hours of birth. The cost of
immunization, however, was a barrier to disadvantaged high-risk populations. In
2002, therefore, the Health Ministry made the vaccine universally available through the
national immunization programme. This was followed, in 2005, by a Ministry decision
to abolish all fees for recommended infant vaccinations. It is estimated that this
initiative – a five-year, US$ 76 million project co-funded equally by the Government
of China and the GAVI Alliance – has averted over 200 000 premature deaths due to
chronic HBV infection.
By 2010, China aims to reduce chronic HBV infection rates to less than 1% in children
under five years of age. To achieve this goal, women are encouraged to give birth in
hospitals, and every hospital must keep enough vaccine available for administration
of the birth dose. A high-profile nongovernmental organization, China Hepatitis
Prevention and Control, is raising public awareness of the need to have all infants
fully immunized with hepatitis B vaccine from birth and to avoid discriminating against
people already infected with HBV.
The outcome of these measures has been dramatic: a surge in national birth dose
coverage from 29% in 1997 to 82% in 2005, and a drop in the chronic infection rate
over the same period to less than 2% of children under five. Some western provinces
only attained around 70% of birth dose coverage by 2006, which may be due to the
higher proportion of home births in those areas. The disparity is declining, but more
work is needed for China to reach its national goals (74).
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Growing confidence in hepatitis B vaccination has prompted WHO’s Western Pacific
Region – where all countries use the vaccine – to set a HBV control goal, namely, the
reduction by 2012 of the average regional prevalence rate of chronic HBV infection to
less than 2% in children under five years old. In 2008, the WHO Strategic Advisory Group
of Experts (SAGE) strongly recommended that “all regions and associated countries
develop goals for hepatitis B control appropriate to their epidemiologic situations.”
The numbers of countries adopting the hepatitis B vaccine and the numbers of regions
setting disease reduction goals show encouraging trends. But there are still challenges
confronting HBV control efforts. Although close to 90% of the 193 WHO Member States
were using the vaccine by the end of 2007, only 65% of children were receiving it. In
countries whose national immunization schedule includes a hepatitis B vaccine dose at
birth, there could be areas where most childbirths take place at home: in such areas,
reaching babies with the “birth dose” of vaccine is problematic. Efforts are under way to
make mothers and immunization providers in such areas more aware of the importance
of protecting newborn infants with this initial vaccine dose. Moreover, in many countries,
health workers and other high-risk groups are not being vaccinated in sufficient
numbers. WHO is working with these countries to close this gap. A third problem is the
continuing risk of HBV transmission from unsafe injection practices and blood transfusion
procedures: efforts are under way to reduce this risk.
Human papillomavirus – a second cancer vaccine
It is estimated that, in 2002, there were 493 000 cases of cervical cancer and over
274 000 related deaths (18). More than 80% of these cases and deaths occurred in
developing countries. Worldwide, and in developing countries, cervical cancer is the
second most common cancer in women, after breast cancer (75). The highest incidence
rates are in sub-Saharan Africa and Latin America, and also in parts of Asia (India alone
accounts for nearly a quarter of cases occurring annually in the world) (76). In all cases,
the causative agent is human papillomavirus (HPV).
Widespread use of screening (Papanicolau) tests by industrialized countries in the 1960s
and 1970s brought incidence down by more than six-fold, to less than eight cases per
100 000 (77, 76) in industrialized countries. In most developing countries, however, the
relatively high cost of screening was prohibitive (78).
Up to about 20 years ago, HPV infection was generally considered a cause of relatively
harmless, if unsightly, warts on the skin and genital area, in both women and men. In
the mid-1980s, DNA analysis by German researchers revealed the presence of genes
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from the virus in cervical cancer cells taken from thousands of women. The virus was
clearly a “necessary cause” of cervical cancer, i.e. its presence is necessary for cervical
cancer to develop (it is not, however, a “sufficient cause”: its presence will not always
produce cancer). This evidence put to rest beliefs that over the centuries had invoked
such things as toads, witchcraft and male secretions (smegma) as causes of cervical
cancer. One cause, postulated by Italian physician Rigoni-Stern in 1842, was close to
the truth: observing that nuns never died of cervical cancer, he assumed that sexual
activity was to blame.
Today, HPV is known to be transmitted through sexual contact – not only penetrative
sexual intercourse, but also sexual skin-to-skin contact. Contributing to the risk of HPV
infection are factors such as early age of sexual activity, cigarette smoking, prolonged
use of oral contraceptives, and co-infection with HIV, chlamydia, or herpes simplex virus
(77). Most cases of HPV infection produce no symptoms. In more than 90% of cases,
the infection disappears spontaneously (1). In the remaining cases it persists, and in
10–12% of these cases, it progresses over the next 20 to 30 years to cancer (1).
Cervical cancer is not the only cancer attributable to HPV, although it is the most
common, accounting for about 90% of all HPV-related cancers. HPV also causes most
cases (about 90%) of anal cancer, many cases (40%) of vulvar and penile cancers, and a
small proportion (12%) of head and neck cancers (1).
There are probably more than 200 genetically distinct types (genotypes) of HPV virus (76).
About 106 are known to cause disease in humans, and of these, 13 genotypes account
for more than 95% of oncogenic HPV infections and have been labelled “high-risk” HPV
types (76). Within a few years of starting sexual activity, more than 50% of sexually active
women become infected with these high-risk types (76).The peak incidence of HPV
infection is in the 16–25 year age group (77, 78), although the peak incidence of the
HPV-related cancer is between 45 and 64 years (77).
The relative frequency of high-risk HPV genotypes (with types 16 and 18 causing about
70% of infections (78)) is fairly constant over all regions of the world (77). “Low-risk”
HPV genotypes – those rarely associated with anogenital cancer – include types 6 and
11, which cause 90% of anogenital warts and cause a relatively rare but potentially
life-threatening disease of the larynx – recurrent respiratory papillomatosis (RRP) – that
occurs mostly in children under five years old.
Work on developing a vaccine against HPV began in the 1980s. Initial experiments
using live attenuated or killed whole virus in animals gave promising results, but research
quickly came up against two stumbling blocks. First, getting the virus to grow in the
quantities needed to produce a vaccine proved difficult. Second, the whole virus contains
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genes (oncogenes) that cause cancer and could present a risk to vaccine recipients.
The solution to both problems lay in the structure of the HPV virus itself. Covering the
virus is an outer shell (capsid) consisting of about 360 proteins. When the shell is taken
apart and the proteins are put into an appropriate chemical solution, they automatically
arrange themselves to form a new empty shell that is an exact copy of the original. This
artificial shell, commonly known as a “virus-like particle” (VLP), contains no genes or
other potentially risky or infectious viral material, but produces as strong a protective
immune response in animals as the original whole virus. It can also be readily produced
in large quantities.
In 2006, an HPV vaccine – the second against a human cancer (the hepatitis B vaccine
was the first) – became available, followed a year later by another HPV vaccine. Both
vaccines are based on VLP technology. One, a two-antigen (bivalent) vaccine, has
VLPs carrying two HPV genotypes – 16 and 18 – which cause about 70% of cervical
cancer in most parts of the world (77). The other vaccine, a four-antigen (quadrivalent)
vaccine, has VLPs carrying the same HPV 16 and 18 genotypes but also 6 and 11,
which cause about 90% of genital warts in women and men (78). In large-scale clinical
trials in industrialized and developing country settings, both vaccines protected more
than 90% of recipients against HPV infection. By the end of 2008, the bivalent vaccine
was licensed in 90 countries and the quadrivalent in 109 countries.
In late 2008, the SAGE established global recommendations for HPV vaccination (79).
These recognize the importance of HPV disease burden worldwide and recommend
that HPV vaccination should be included in national immunization programmes
where: prevention of cervical cancer and/or other HPV-related diseases are a public
health priority; introduction of the vaccine is feasible; financing can be secured and is
sustainable; and the cost-effectiveness of vaccination strategies in the country or region
have been considered. The primary target population should be girls prior to initiation
of sexual activity, with specific age ranges based on local data on age of sexual debut
(most commonly 9 or 10 to 13 years). It is also recommended that in countries where it
is feasible and affordable, older adolescent girls should be considered as a secondary
target population, provided this is cost-effective and does not distract from the success
of vaccinating the primary target. Vaccination of men to prevent cervical cancer in women
is not recommended as this is unlikely to be cost-effective for cervical cancer prevention
if high coverage is achieved in the target population. The SAGE also recommends
that where possible, vaccine introduction should be in concert with a national cancer
prevention programme that includes education, screening, and diagnosis and treatment
of precancerous lesions. In April 2009, WHO issued a position paper based on these
recommendations (80).
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Influenza – keeping scientists guessing
Influenza, commonly called “flu”, is a respiratory illness caused by a virus (1). The name
is Italian for “influence”, the word used by 16
th
century Italians to denote several illnesses
believed to be caused by “the heavens” or “the stars”. Symptoms of influenza last about
a week on average, and include fever, sore throat, headache, aches and pains, chills,
loss of appetite, and fatigue. About 30–50% of infected people have few or no symptoms
(1). Children and elderly people are particularly vulnerable to infection and to the risk of
developing severe complications, which may require hospital care. In the United States,
up to 40 000 influenza-related deaths have been reported in severe influenza seasons
(1). Worldwide, influenza infections are responsible for between 250 000 and 500 000
deaths a year on average (81).
The influenza virus spreads via tiny droplets released into the air when an infected
person coughs or sneezes. The virus has a preference for the cold, dry air typical of the
winter season in temperate climes. Every year, about 5–10% of adults and 20–30% of
children come down with seasonal influenza (82). In tropical countries the illness occurs
with less or no seasonality.
Influenza also occurs in an often devastating, pandemic form. Pandemics have been
documented throughout the ages with the most recent pandemics occurring in 1918,
1957 and 1968. In 1918, the most devastating pandemic on record infected about half
the world’s population and killed an estimated 20–50 million people (82). Since pandemics
tend to occur every 40 years or so, public health experts have been monitoring the H5N1
strain during the past few years, fearing that a new pandemic might be imminent.
The two types of influenza virus that cause illness in humans were identified in the 1930s
and 1940s. Both types (A and B) are extremely efficient at evading the human immune
system. By constantly altering their surface molecules and thereby mutating into new
strains from one season to the next, they ensure that the immunity a population develops
against the infection in one season will not protect the population in the following season.
In other words, the influenza virus enjoys a constantly renewed pool of susceptible
people from one season to the next.
This so-called antigenic drift mechanism also gives vaccine researchers, using WHO’s
85-country Global Influenza Virus Surveillance Network, the task of predicting, several
months before the onset of the influenza season every year, which proteins (or antigens)
from the virus, should be included in an influenza vaccine so as to protect against the
probable new virus strain.
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The first commercial influenza vaccine – a relatively crude product consisting of an
inactivated (or killed) whole influenza virus – became available in 1945. Whole-virus
influenza vaccines are still used in some countries, but since the 1970s most countries
use vaccines that are purer and produce fewer, albeit minor, side-effects.
A live attenuated influenza vaccine has been available since 1967. This is administered
by nasal spray and is therefore easier to use in children, whereas the inactivated vaccine
is administered mainly by intramuscular or subcutaneous injection. The live attenuated
vaccine has also been found to stimulate a broader immune response against new viral
strains resulting from antigenic drift, than the inactivated vaccine (1).
Currently available influenza vaccines protect about 70–90% of recipients provided their
antigen composition closely matches that of the viruses circulating at the time (82, 83).
There is evidence that these vaccines are effective enough to reduce the number of
hospitalizations in a population by 25–39% and to reduce the number of deaths by
39–75% (82). About 75 countries, mostly industrialized, offer influenza vaccination to
high-risk population groups, such as elderly people.
In 2003, the World Health Assembly called on Member States that use influenza vaccines
to provide vaccination to at least 50% of their elderly population by 2006, and 75% by
2010. Firm data regarding progress in meeting the goal is difficult to obtain, especially
from countries where almost all of the influenza seasonal vaccinations are offered by
private health-care providers.
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In February 2009, new global capacity figures for the production of influenza vaccine
were published (84). These indicate that seasonal influenza vaccine capacity is expected
to increase considerably from 2009 to 2014. Likewise, production capacity for producing
H5N1 vaccine has increased, due to overall capacity expansion, antigen-sparing
techniques, and yield improvements. Despite this improvement, supply does not yet
meet global needs.
Meanwhile, seasonal vaccine production capacity is rising faster than annual demand –
which is currently less than 500 million doses per annum – and current stockpile demand.
If demand does not exist to utilize this excess capacity, however, manufacturers are likely
to rationalize some of it, creating further shortages at the time of a pandemic.
In view of this, some countries consider that it is a matter of health security for them
to acquire the technology to produce influenza vaccine domestically. This prompted
WHO to initiate in 2007 an influenza vaccine production technology transfer project. As
of the end of 2008, six vaccine manufacturers in developing countries had undertaken
development activities for influenza vaccines, and more projects are expected to begin
in 2009.
Box 19
Pandemic influenza – the H5N1 threat
Between 2003 and April 2009, fears of an influenza pandemic, or worldwide epidemic,
focused on influenza viruses belonging to the subtype H5N1, which continue to
circulate in birds but have also infected mammals, including people. Since 2003,
H5N1 influenza viruses have spread through Africa, Asia, Europe, and the Middle East,
causing the deaths or culling of tens of millions of birds in more than 27 countries. As
of May 2009, 429 people in 16 countries had been infected with the H5N1 avian
influenza virus according to reports of laboratory confirmed cases received by WHO
(19). What is particularly worrying about this virus is its capacity for rapid geographical
spread, its long-lasting persistence in birds, and its high pathogenicity (more than
60% of infected people have died from the infection).
Two H5N1 influenza vaccines have been developed. One was awarded a United
States licence in 2007 and was provided for a United States stockpile. Another was
licensed by the European Medicines Agency in 2008. Several countries, including
Finland, Mexico, Switzerland, and the United Kingdom, have begun stockpiling
H5N1 vaccine in preparedness for a pandemic and several multinational manufacturers
have pledged to contribute millions of doses of vaccine to a potential WHO
stockpile.
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Box 20
Pandemic influenza – the H1N1 threat
In April 2009, pandemic influenza concerns expanded from H5N1 to a novel strain of
influenza A (H1N1) virus. First circulating in North America, the virus has rapidly spread
across the world. By the end of May 2009, 13 398 laboratory-confirmed cases had
been reported in 48 countries (85).
Although disease caused by the H1N1 virus has generally been mild, severe illnesses
resulting in hospitalization and a total of 95 deaths have occurred in Canada, Costa
Rica, Mexico and the United States. Although too early to determine the impact of the
emergence of the virus, large community-wide outbreaks and school outbreaks have
been reported (86).
As soon as the first human cases of the H1N1 virus became known, WHO initiated
communication with the pharmaceutical and vaccine industry and discussions with
experts from other relevant fields began. In respect of vaccines, consultations focused
on review of the epidemiology of infections and associated disease burden, potential
vaccine options, the status of seasonal vaccine production and potential production
capacity for an H1N1 vaccine, and the timing of a potential recommendation to initiate
commercial scale production of an H1N1 vaccine. The WHO Collaborating Centers
and Essential Regulatory Laboratories began work to develop candidate vaccine
viruses.
At the time of writing, regular communication with all those involved in vaccine
production and regulation is ongoing in order to ensure appropriate and timely
decisions relating to protection against the H1N1 virus through vaccination are made.
The considerable work undertaken by WHO and partners in recent years to put in
place expedited processes for regulation and licensing in the event of a large-scale
epidemic or pandemic is already proving to have been a wise investment.
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Japanese encephalitis – a regional scourge, waning but still
present
Japanese encephalitis is a viral disease transmitted by mosquitoes of the Culex species,
which pick up the virus from animals – mainly wild water birds and pigs. As such, it is a
disease of rural areas. Virus circulation has been demonstrated in many Asian regions
within the tropical and temperate climate zones. At least 50 000 cases and 10 000
deaths are estimated to occur every year, mostly among children under ten years old
(87, 4). In temperate areas of Asia, the disease occurs in regular epidemics, whereas
in southern, tropical areas, such as parts of India, Nepal, Thailand, and Viet Nam, it is
present in an endemic, or more permanent form (88). Over the past years, surveillance
has intensified in many countries, but there is still a need to both better define the burden
of disease and to extend surveillance in order to define populations at risk.
Only about 1 in 250–500 of infected people develop clinical disease (87), which is fatal
in 10–30% of cases (89). Symptoms can be relatively mild, with fever, cough, nausea,
vomiting, and diarrhoea; or severe with inflammation of brain membranes or a polio-like
flaccid paralysis (90). Permanent sequelae, such as cognitive and language impairment
and motor deficits, account for much of the burden of the disease.
The first Japanese encephalitis vaccines were produced in the late 1930s in the Union
of Soviet Socialist Republics and Japan. They consisted of chemically inactivated virus
taken from the brains of infected mice. After World War II, research institutes in Japan
produced several refined versions of this mouse-brain vaccine, which were subsequently
manufactured and used in many Asian countries. Since its introduction in the mid-1950s
into Japan’s immunization programme, reported cases of Japanese encephalitis in
Japan have plummeted.
In the 1960s, an inactivated vaccine was developed in China based on virus grown,
not from mouse brain, but from cultured cells. This vaccine was used in China from
the 1970s to the 1990s and was subsequently replaced by a new, live vaccine using
the so-called SA14-14-2 strain, which is being used widely in routine programmes and
mass campaigns to immunize children from 1 to 15 years of age in several countries,
including China and India (91). In 2005, China incorporated the live vaccine into its
routine immunization programmes. The vaccine has turned into the most widely used
product against the disease, and benefits from a competitive price. It is not currently
WHO-prequalified, but plans have been established for a submission.
A number of new Japanese encephalitis vaccines are in development and some are
approaching licensure. One – a live, attenuated vaccine – consists of a genetically
engineered combination of the yellow fever vaccine with a fragment of the Japanese
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encephalitis virus strain SA14-14-2. If it fulfils its promise, this so-called “chimeric”
vaccine may produce long-term protection with a single dose, and allow concurrent
administration with the measles vaccine. Another – an inactivated vaccine, based again
on the SA14-14-2 strain, and produced in cell culture – is about to reach licensure,
promising a simplified immunization schedule as compared with the mouse-brain
vaccine. It is anticipated that several Japanese encephalitis vaccines should be on the
market soon for use in endemic countries, and WHO-prequalification of one or several
products is expected (92).
Immunization, together with higher standards of living and urbanization, has brought the
incidence of Japanese encephalitis down to a handful of cases per year in the more
developed Asian countries, such as Japan and the Republic of Korea (1). Experts warn,
however, that the virus is still circulating in the pig populations of many of these countries,
indicating that the risk of human infection and disease is still very much present, should
immunization programmes be discontinued (1).
WHO recommends that immunization against Japanese encephalitis be integrated into
national immunization programmes in all areas where the disease is a public health
problem. In countries where the disease is endemic and where Japanese encephalitis
vaccination is not yet incorporated into the national immunization programme, the
immunization strategy with the greatest potential impact on public health, according to
WHO, consists of a one-time mass campaign, followed by incorporation of the vaccine
into the routine immunization programme (87).
Measles – record progress but risk of resurgence is high
Measles is an extremely contagious viral disease, which – before the widespread use of
the measles vaccine – affected almost every child. High-risk groups for complications
from measles include infants, and people suffering from chronic diseases and impaired
immunity, or from severe malnutrition, including vitamin A deficiency (93).
Routine measles vaccination – giving one dose of vaccine to infants – began in developing
countries in the mid-1970s. Many industrialized and several developing countries have
since added a second dose given to children between one and seven years of age
(depending on the country). By 2000, 72% of the world’s children were receiving at least
one dose of measles vaccine (versus 16% in 1980); annual reported cases had dropped
by 80% (from 4.2 million in 1980 to 853 000); and annual estimated deaths had dropped
by 70% (from 2.5 million in 1980 to 750 000) (1). By 2002, WHO’s entire Americas Region
had eliminated measles (i.e. had no indigenous cases, as distinct from imported cases,
for more than 12 months) (94).
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Despite these results, in 2000, measles was still the leading cause of vaccine-
preventable deaths in children, and the fifth leading cause of death from any cause
in children under five years old (95). Responding to this situation, in 2001, the
American Red Cross, UNICEF, the United Nations Foundation, the CDC, and WHO
launched the Measles Initiative aimed at reducing the death rate from measles in
Africa, where nearly 60% of measles deaths were occurring (96). In 2007, major
financial support for the Initiative was provided on a one-time basis by the IFFIm through
the GAVI Alliance.
In 2004, the Initiative extended its mandate to other regions (notably Asia) where measles
was a significant burden and marked 47 high-burden countries for priority action. The
Initiative aimed to boost routine immunization coverage to more than 90% of children
under one year of age in every district of these countries and to maintain coverage
at over 90%. Supplementary mass immunization campaigns were to be conducted
periodically, targeting all children between nine months and 14 years of age, with “follow-
up” campaigns every two to four years targeting children between nine months and five
years of age. Increased emphasis was to be placed on laboratory-backed surveillance of
new measles cases and monitoring of vaccination coverage.
The Initiative’s efforts gained impetus when in 2003, the World Health Assembly called
on WHO Member States to halve measles deaths by the end of 2005, compared with
1999 estimates. In 2005, the World Health Assembly endorsed the even more ambitious
GIVS goal, namely, a 90% reduction, by 2010, of measles mortality, compared with 2000
estimates (see Chapter 1). By the end of 2006, the Measles Initiative had surpassed
the goal to halve measles deaths by 2005: end-of-year estimates for 2005 showed a 60%
drop in global measles deaths since 1999 (i.e. from 873 000 to 345 000 deaths) (96).
For many measles observers, the 2010 GIVS goal calling for a 90% reduction in measles
mortality compared with 2000 estimates can be achieved. Estimates for 2007 show a
record-breaking 82% global vaccination coverage rate, up from 72% in 2000, with most
of the increase coming from Africa’s surge in coverage to 74%, up from 56% (97). Most
significantly, estimated annual measles deaths had dropped by 74% from 2000–2007, to
197 000 globally. The Eastern Mediterranean and African Regions, with a 90% and 89%
fall in deaths respectively, accounted for most of the global decline, thereby reaching the
2010 mortality reduction goal three years ahead of schedule.
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State of the world’s vaccines and immunization
The road ahead, however, holds a number of hurdles to achieving measles mortality-
reduction goals:
• As of 2007, there were still 197 000 measles deaths occurring annually – 69% of
them in the WHO South-East Asia Region (97). The main reason is because mass
vaccination campaigns have not yet begun in India. In addition, while routine measles
vaccination coverage has risen from 61% in 2000 to 73% in 2007, it is the lowest
among all six WHO regions (97).
• An estimated 23 million children under one year of age were, in 2007, still not receiving
their first dose of measles vaccine through routine immunization: about 15 million
(65%) of these children are living in eight populous countries: India (8.5 million), Nigeria
(2 million), China (1 million), Ethiopia (1 million), Indonesia (0.9 million), Pakistan (0.8
million), Democratic Republic of the Congo (0.6 million), and Bangladesh (0.5 million).
• Sustaining the decline in measles deaths will call for all districts in all 47 high burden
countries to be vaccinating at least 90% of children before their first birthday, and
to be conducting follow-up supplementary immunization activities every two to four
years.
Figure 11
Estimated measles deaths 2000−2007
Source: (97)
1 000 000
High-low lines indicate
uncertainty bounds
800 000
600 000
400 000
200 000
-
M
e
a
s
l
e
s

d
e
a
t
h
s
Year
2000 2001 2006 2005 2004 2003 2002 2007
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• Looking to the future, as yet there is no global consensus on global elimination
or eradication of measles. Four of the six WHO regions have elimination goals –
the Americas (for 2010), Europe (2010), the Eastern Mediterranean (2010), and
the Western Pacific (2012). Meanwhile, reducing global measles mortality remains
the overriding concern.
Meningococcal disease – still a deadly menace across Africa
The meningococcus (Neisseria meningitidis), is a major cause of meningitis and is
permanently present (endemic) in every country in the world (98). It is also present, as
a colonizing bacterium, in the nose and throat tissues of about 10–25% of the world’s
population – the healthy carriers (1). For reasons that are not clear, in a small number of
these healthy carriers, the organism becomes invasive and, in most cases, the resulting
disease is meningitis. In 5% to 15% of cases, the clinical disease is pneumonia or, more
alarmingly, a severe blood infection (fulminant septicaemia) or joint infection (septic
arthritis) (1). Early symptoms of meningococcal disease include high fever, headache, stiff
neck, nausea and vomiting.
Before antibiotics became available, 70–80% of those infected died, usually within a day
or two. Treatment with antibiotics has reduced the death rate among infected people
to less than 15% (98), but about 20% of survivors have important sequelae, of which
the most severe include loss of a limb, epilepsy, mental retardation, and deafness.
WHO estimates that about 500 000 cases of meningococcal disease occur every year
worldwide (98) causing 50 000 deaths.
Other causes of meningitis are viruses and other bacteria, notably Hib and the
pneumococcus (Streptococcus pneumoniae). The meningococcus, however, is the only
bacterial cause of meningitis that causes epidemics. With the advent in the 1940s of
antibiotics, together with the availability of hospital-based intensive care units, large-scale
epidemics began to peter out in industrialized countries, although the disease remained
endemic, causing isolated cases, clusters of cases and, in some instances, epidemics.
On average, since the year 2000, more than 7000 cases have been reported in western
Europe and about 3000 in the United States (1).
In Africa, major epidemics have been occurring over the past 100 years (1, 98) – most
of them in the so-called “African meningitis belt” that spans sub-Saharan Africa from
Senegal in the west to Ethiopia in the east (99). In 1996 to 1997, the largest epidemic in
history swept across the belt, causing over 250 000 cases, an estimated 25 000 deaths,
and disability in 50 000 people. Large epidemics tend to recur in the meningitis belt
every 7–12 years, against a backdrop of smaller annual epidemics (100). Although the
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annual epidemics are smaller, they are still large enough to disrupt the health services
and damage the already fragile economies of the 25 countries in the belt, not to speak of
the social lives of its nearly 400 million inhabitants (100).
Work on a vaccine against the meningococcus began in the 1890s (1). The early
meningococcal vaccines, developed between 1900 and the 1940s, were effective
enough to elicit an immune response but not pure enough to avoid untoward reactions
in vaccine recipients.
Efforts to develop a vaccine need to take into account the distribution of different strains
of meningococci. Researchers have identified 13 different meningococcal groups, based
on the organism’s outer sugar capsule. Five groups – A, B, C, Y, and W-135 – are
associated with most cases of severe disease and epidemics. Broadly speaking, groups
A, B, and C, account for most cases and epidemics in the world. Group A is predominant
in Africa and Asia and is the main cause of epidemic meningitis in sub-Saharan Africa;
group B occurs in many regions; group C occurs mainly in North America, Europe, and
Australia; and group Y is gaining importance in the United States. Group W-135 has
only recently emerged as a cause of epidemics in Africa and the Middle East. A vaccine
against one group does not confer cross protection to another group.
By the mid-1970s the first modern “polysaccharide” vaccines were introduced, and
were based on the carbohydrate capsule (polysaccharides) surrounding the organism.
Between the late 1970s and the mid-1980s, several polysaccharide vaccines became
available, targeting one (A, C, Y, or W-135), two (A and C), or four (A, C, Y, and W-135)
meningococcal groups. However, as with the polysaccharide vaccines developed against
Hib and the pneumococcus, they gave little or no protection to children under two
years of age. Other age groups were protected but for only three to five years, and the
vaccines conferred no “herd” or community immunity, whereby even the unvaccinated
are protected. Despite their shortcomings, polysaccharide meningococcal vaccines were
used, with mixed results, either for routine preventive vaccination (in China and Egypt), or
for selected high-risk groups during epidemics.
Since 1999, four new-generation conjugate vaccines (see Chapter 2) have appeared,
targeting one (group C) or four groups (A, C, Y, W-135). At least five more candidate
conjugate vaccines are in the late stages of development.
To date, there are no licensed vaccines against the group B meningococcus, but several
vaccine manufacturers have products that are being evaluated clinically. For example,
group B vaccines that have been custom-made against specific epidemic strains have
been successfully used to control specific outbreaks in Brazil, Chile, Cuba, France, New
Zealand, and Norway.
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In industrialized countries, particularly in Canada and Australia, and countries in
Europe, the incidence of meningococcal meningitis was falling prior to the introduction
of conjugate vaccines, and their introduction has accelerated the decrease in disease
rates. This is not the case in developing countries, where high endemic disease rates still
occur, with the additional problem of periodic major epidemics. This situation is very likely
to improve – at least for the African meningitis belt, where a new, inexpensive group A
conjugate vaccine is in the late stages of development and is expected to be ready for
use in 2010 (see Box 21).
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Box 21
A new meningococcal vaccine to control meningitis in Africa
It was the year 2001. All the ingredients were in place: the conviction that it had to
be done and could be done; the knowledge needed to prepare a meningococcal
vaccine; and the international partnership to develop a vaccine. By 2010, a vaccine
against group A meningococcus is expected to be available for use in a huge swathe
of Africa, home to nearly half a billion people. Meningococcus A is believed to cause
some 85% of meningococcal meningitis cases in Africa.
In 2001, WHO and PATH – with funding from the Bill & Melinda Gates Foundation
– created the Meningitis Vaccine Project, with the single goal of developing a new,
affordable group A conjugate vaccine (101). A Dutch firm agreed to manufacture
vaccine-grade group A polysaccharide, and an Indian vaccine manufacturer
provided the carrier protein (tetanus toxoid) that would be linked (conjugated) to the
polysaccharide to create a new vaccine that would induce a strong, durable immune
response. Scientists from the FDA helped to overcome the administrative and legal
hurdles, and transferred a new conjugation technology to the Indian manufacturer,
who, with Project support, undertook the development, scale-up and production of
the vaccine.

This new group A conjugate vaccine will cost no more than US$ 0.50 a dose and
has been shown to be safe and highly immunogenic in clinical trials in the Gambia,
India, Mali, and Senegal (102, 103, 104, 105). Project officials hope it will be licensed
and ready for use before the end of 2009. Health officials in the 25 countries that
make up the African meningitis belt and that stand to benefit most from the new
vaccine are optimistic: at a September 2008 meeting in Cameroon, ministers from
all 25 countries pledged to start making plans to introduce the vaccine as soon as it
becomes available (106).
If all goes well, by 2015, nearly 300 million people will have been vaccinated in the 25
belt countries and, assuming vigorous herd immunity, more than 400 million people
will be protected against death and disability from the meningococcus.
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Mumps – not always mild, not yet conquered
Two of the features of mumps – swelling around the ears (parotitis, or inflammation
of the salivary glands) and painful swelling of one or both testes (orchitis, or testicular
inflammation) – were described in the fifth century BC by Hippocrates, the founder of
medicine. A second milestone was the detailed account of the course of the disease,
including its occasional involvement of the central nervous system, made in the late 18
th

century by Scottish physician Robert Hamilton. And the third was the discovery in the
1930s by United States pathologists that a virus was the causative agent. Two decades
later, the first mumps vaccine was undergoing tests in humans (1).
Historically, mumps has been generally regarded as a relatively benign, self-limiting illness
affecting mainly children aged five to nine years. Most cases involve little more than a
week or two of influenza-like symptoms with earache and soreness around the jaws.
About 20–40% of infections produce no symptoms at all. Nevertheless, the need for
vaccination is based on solid arguments. For one thing, in pre-vaccine days, the disease
was disabling enough to be a significant cause of absenteeism of young children from
school, of adolescents from higher educational institutions, and of soldiers from army
duty (1). For another, complications of the disease can be severe, and on rare occasions,
fatal: among the most feared complications of mumps are meningitis, encephalitis, and
pancreatitis. Deafness in one or both ears is among the most disabling. Yet another
argument is the sheer prevalence of the infection, which can spread throughout an entire
community and pose an ever-present risk of severe complications. This alone would
justify protection of the community by vaccination (107).
More than 13 mumps vaccines – all live, attenuated vaccines – exist today and can
protect about 80% of recipients (1). Each of these vaccines is based on a different
strain of the mumps virus. They are available as single (monovalent) vaccines, or as a
component of the bivalent measles-mumps or trivalent measles-mumps-rubella (MMR)
vaccine. Since the 1960s, mumps vaccination has been used primarily in industrialized
countries but increasingly also in countries in economic transition (108). Some countries
(13 at the end of 2007) administer only one dose, given at 12–24 months of age. Most
(101 at the end of 2007) give a second dose in later childhood, most often in the form of
the MMR vaccine. With the two-dose MMR schedule, mumps vaccination is highly cost-
effective, according to economic analyses published in 2004, particularly in countries
where direct and indirect costs are substantial. Direct costs include medical treatment
(mainly for hospitalization and treatment of meningitis and encephalitis), and indirect
“societal” costs related to reduced work productivity of patients and carers, and also
disrupted school attendance (107).
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WHO recommends routine mumps vaccination as a two-dose schedule for countries
that have efficient child vaccination programmes, countries that can sustain high vaccine
coverage rates, and those that regard mumps as a public health priority (108). The first
condition is based on the fact that in areas where routine mumps vaccination reaches less
than 80% of infants, there are still enough susceptible children to sustain transmission
of the infection and to infect non-immune (susceptible) adolescents and young adults
– a population group more likely than young children to develop severe complications.
Knowing whether mumps can be regarded as a public health priority is a problem for
many developing countries. Mumps, despite WHO urging, is not yet a notifiable disease
in most countries. Most cases run a generally mild course and thereby escape official
notice. The result is that reported case numbers are believed to reflect less than 10% of
the true incidence of the disease. Active surveillance efforts could to some extent solve
the problem, but many countries lack the motivation and resources to implement these
for a disease traditionally considered of marginal public health importance compared
with more visible scourges, such as malaria, pneumonia, and measles.
As of the end of 2007, 114 countries were administering mumps vaccine, compared
with 104 countries at the end of 2002. In virtually all countries where routine mumps
vaccination has been adopted, the incidence of mumps has plunged to negligible
levels (1). The effectiveness of vaccination has been so dramatic as to prompt several
countries, notably Finland, Sweden, and the United States, to set goals for eliminating
the disease. Several factors, however, suggest that vaccination has still some way to go
before elimination can be achieved and sustained.
• Outbreaks of mumps have continued to occur since the 1980s even in countries
achieving high coverage rates with routine vaccination. More recently, large outbreaks
occurred in the United Kingdom from 2004 to 2005 (107), in the United States in 2006
(109), and in the Republic of Moldova from 2007 to 2008 (110). All three outbreaks
involved adolescents or young adults. In two of the outbreaks, most of the cases
occurred in individuals who were believed to have received two doses of the MMR
vaccine. This may suggest that immunity to the vaccine, which was thought to protect
against mumps for at least 15 years, may start to wane much sooner. A first-line
response to mumps outbreaks is mass vaccination of the entire population at risk. A
second option under consideration by some countries using the two-dose schedule
is to add a third dose, at least to control mumps outbreaks. The question then is
whether mumps control would still be cost-effective. Developing a vaccine with a
more durable protective efficacy is another option but achievable only in the much
longer term.
• All of the mumps vaccines available internationally through the United Nations vaccine
procurement system occasionally cause parotitis (1–2% of recipients), and very
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occasionally, viral (aseptic) meningitis – a usually benign inflammation of the linings
of the brain (107). The risk of aseptic meningitis following mumps vaccination varies
widely according to vaccine strain, the manufacturer, the awareness and vigilance of
health practitioners, and the intensity of surveillance (range: 1:11 000 recipients to
fewer than 1:100 000 recipients (108)).
The future of global mumps control will thus hinge on how quickly and extensively the
true public health burden of mumps will emerge from epidemiological research; how
effectively the risk of mumps outbreaks and of vaccine-related side effects can be
reduced; and, consequently, how many countries will know enough and have enough
resources to consider routine mumps vaccination a worthwhile option.
Pertussis – too many children not being vaccinated, too many
uncounted deaths
Pertussis, or whooping cough, is a disease of the respiratory system caused by infection
with the bacterium Bordetella pertussis. The most characteristic symptom is a cough
that occurs typically in spasms ending in a classic inspiratory whoop. In young infants,
the only signs or symptoms may be cessation of breathing (apneoa) and blue colouring
of the skin (cyanosis).
Complications arise in 5–6% of cases – the most serious and often fatal of them
being bronchopneumonia and encephalopathy (111). Death from pertussis still occurs
in industrialized countries (less than 1 per 1000 cases (111)), but more rarely than in
developing countries (40 per 1000 infants, and 10 per 1000 in older children (111)). The
global burden of the disease is difficult to estimate, given the paucity of surveillance
data available. WHO’s latest estimates put the annual number of cases worldwide as of
2004 at nearly 18 million, with about 254 000 deaths, of which 90% are in developing
countries (111, 4).
The first pertussis vaccine used the killed whole bacterium (whole cell) as the immune-
stimulating antigen. It appeared in 1914 and became available in combination with
diphtheria and tetanus antigens (DTP) in 1948 (1). Today, there are many whole-
cell pertussis vaccines, some more effective and safer than others, and the variability
depending mainly on the method of production (111). Fifteen safe and effective
pertussis vaccines, usually in combination with tetanus and diphtheria vaccines, have
been prequalified by WHO for international distribution through the United Nations
procurement systems.
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Adverse reactions related to whole-cell pertussis vaccines are frequent but mostly minor
and self-limiting. In the mid-1970s, suspicions arose that whole-cell pertussis vaccines
could very rarely cause serious complications, such as encephalopathy (111). Although
no scientific studies have confirmed a link between whole-cell pertussis vaccines and
encephalopathy, these suspicions caused enough public concern to fuel a search for a
more purified, and presumably safer, vaccine.
The result was a non-whole-cell (acellular) pertussis vaccine, which first became
available in Japan and later in other industrialized countries. Several acellular pertussis
vaccines are currently available. Clinical trials suggest that the “best” whole-cell and
acellular vaccines protect about 85% of recipients. Both are safe, although the acellular
vaccine appears less reactogenic, i.e., less likely to produce fever or local reactions at
the site of the injection (particularly among older age groups), than the whole-cell
vaccine.
By the end of 2007, 46 of WHO’s Member States had switched from whole cell to
acellular vaccines (41). Most of these countries were in industrialized countries, where
public sensitivity to rumour and even to the mild reactions to the whole-cell vaccine has
been greater than in developing countries, and where the higher cost of the acellular
compared to the whole-cell vaccine is less of a problem. An additional constraint on
adoption of the acellular vaccines by developing countries is the fact that they have not
acquired WHO prequalification status (largely because up to mid-2008 no manufacturer
had the capacity to supply the developing country market). WHO expects a prequalified
acellular vaccine to be available in the near future. However, more widespread use in
developing countries will depend on country demand and secure financing.
In most countries, pertussis vaccination consists of three initial doses of the pertussis-
containing DTP (the primary series) given at least one month apart to infants between
six weeks and six months of age (111). In 1980, routine vaccination with three DTP
doses was reaching about 20% of the world’s infants (41). By the end of 2007, the
figure had risen to 81%. Determining the impact vaccination is making on the global
burden of pertussis is difficult. Certainly, following widespread vaccination during the
1950s and 1960s, the industrialized world saw a more than 90% drop in pertussis cases
and deaths (111). And certainly, numbers of cases reported annually to WHO dropped
by 92% from about 2 million in 1980 to 162 000 by the end of 2007 – a drop consistent
with the upward trend of vaccination coverage (111). But due to lack of adequate
surveillance, reported cases of pertussis are believed to reflect less than 1% of the true
incidence (1).
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There is little doubt, though, that pertussis vaccination is preventing pertussis cases
and deaths – nearly 38 million cases and 600 000 deaths in 2004, according to WHO
estimates (111). What is less sure is its impact on circulation of the causative B. pertussis
bacterium (111). High vaccine coverage rates in some industrialized countries are not
preventing periodic outbreaks among adolescents and adults who remain susceptible
to infection. Finland offers a striking example of this “epidemiological shift”: with vaccine
coverage reaching 98% of the infant population, the incidence of pertussis among
adolescents doubled in the four years between 1995 and 1999 (111). Other industrialized
countries are facing a similar trend. Compounding the problem is the likelihood of
adolescents and adults acting as a source of infection for infants who have not been
vaccinated by routine vaccination (1).
The primary purpose of pertussis vaccination is to prevent severe disease and death
among infants and young children. To achieve this, at least 90% of the infant population
should be receiving the primary three doses of DTP according to schedule. As of the end
of 2007, 78 (40%) of WHO’s 193 Member States had less than 90% coverage, and there
were an estimated 24 million partially vaccinated or unvaccinated children in the world.
WHO also recommends countries that have achieved a substantial reduction in pertussis
incidence through infant vaccination to give a booster dose to all children one to six
years after the primary series.
Future priorities for pertussis control include measures to improve disease surveillance
and the consequent reliability of case reporting, particularly in the most severely affected
(and often poorest) countries. Diagnosis of the disease is difficult and calls for laboratory
facilities and expertise often lacking in the most affected countries. Research is under
way to explore the possibility of developing diagnostic methods that could be used on
a far wider scale to provide more accurate case reporting than is at present possible.
Pneumococcal disease – many deaths from many strains,
many hopes from new vaccines
The bacterium Streptococcus pneumoniae, also known as the pneumococcus, is a
leading cause of severe disease and deaths in children under five years old. According
to unpublished WHO estimates, in 2000 there were 14.5 million episodes of severe
pneumococcal disease and more than 800 000 deaths (of which 88 000 were HIV-related)
among children in this age group. Children under five, people with depressed immune
systems, smokers, and elderly people are among the population groups at highest risk of
pneumococcal disease. The total number of annual deaths attributable to this bacterium,
including adults and children, is about 1.6 million, according to WHO estimates (112).
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In children, pneumonia accounts for about 95% of severe pneumococcal disease
episodes and close to 90% of deaths due to the pneumococcus (other major causes
of bacterial pneumonia include Haemophilus influenzae type b). Meningitis accounts for
less than 1% of cases of severe pneumococcal disease in children, but is responsible
for more than 7% of the deaths caused by pneumococcal infection. In addition, the
pneumococcus can also cause sepsis, and other invasive diseases such as peritonitis,
arthritis, and osteomyelitis.
The pneumococcus was first identified in the 1880s as the most common cause of
pneumonia (1). By 1911, researchers began human tests of a crude whole-cell vaccine,
made up of the whole pneumococcus, and by the mid-1940s, at least three vaccines
had appeared. However, within a few years these had been withdrawn from the market
for lack of commercial interest: physicians in industrialized countries favoured penicillin
treatment (1).
Over the next four decades, however, it became clear that antibiotics were not making
a large enough impact on reducing deaths from pneumococcal disease, and public
health interest in pneumococcal vaccination revived. The early 1960s saw the advent
of the first modern pneumococcal vaccines. These were “polysaccharide” vaccines, so-
called because they targeted the sugar molecules (polysaccharides) making up the outer
capsule, or coat, of the pneumococcus. At least 90 different types of the pneumococcus
exist, each with a different capsular polysaccharide configuration. Less than 30 of these
capsular types are commonly associated with human disease. In 1983, a polysaccharide
vaccine became available, which contained 23 capsular polysaccharides – responsible
for 85–90% of severe pneumococcal disease in industrialized countries (112). However,
the vaccine had several shortcomings, the most serious being its inability to induce
protective immunity in children under two years of age, the age group most affected by
the disease.
The need for a better vaccine was clear. Researchers turned to conjugation technology
(see Chapter 2). In the year 2000, a conjugate pneumococcal vaccine arrived on the
market, which protected against the seven capsular types of the bacterium responsible
for 65–80% of cases of severe disease in young children living in industrialized countries
(112). However, this “7-valent” vaccine did not contain all the important serotypes
responsible for severe pneumococcal disease in developing countries (1). Clinical
trials of candidate conjugate vaccines containing 9 or 11 of the serotypes prevalent in
developing countries conferred long-lasting protection in infants against invasive disease
and pneumonia. One trial in the Gambia showed, in addition, a 16% reduction in deaths
from all causes among children vaccinated with the “9-valent” vaccine. Although the
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respective manufacturers decided not to seek licensure for these two vaccines, other
formulations of the vaccine containing 10 and 13 serotypes are in the late stages of
clinical testing and are likely to be on the market by 2009-2010 (113). In addition, other
vaccine candidates, including conjugate vaccines as well as others based on protein
antigens and some developed by emerging manufacturers, are in earlier stages of
testing.
By mid-2008, the 7-valent conjugate vaccine was in use in more than 60 countries.
Introduction of this or the newer vaccine in the poorest countries is expected to begin
in 2009 through support from the GAVI Alliance. One analysis (112) has estimated that
at current rates of DTP coverage, pneumococcal vaccines could prevent about 262 000
deaths a year in the 72 countries eligible for GAVI Alliance funding.
A substantial reduction in invasive pneumococcal disease and pneumonia has been seen
in countries that have introduced conjugate vaccines. Within three years of conjugate
vaccine introduction in the United States, invasive pneumococcal disease due to the
pneumococcal serotypes in the vaccine had fallen by 94% in vaccinated children (114).
In addition, unexpectedly large reductions in disease were seen in the unvaccinated
population, including in elderly people, as a result of reduced transmission of the
infection – a phenomenon referred to as “herd immunity”. The total cases prevented in
older children and adults through herd immunity in the United States were estimated to
be twice as many as in the vaccinated age groups.
The mood in the vaccine community is decidedly optimistic over the potential for
conjugate vaccines to improve child survival and thereby contribute to achievement of
MDG 4.
With the availability of two effective vaccines that have great potential to control
pneumonia – one of the major causes of sickness and deaths among children under
five years old – there has been an increasing demand to scale up other interventions
for pneumonia control along with vaccination. In the early months of 2007, WHO and
UNICEF began laying the foundations for a Global Action Plan for Pneumonia Control
(GAPP). The plan includes the use of vaccines but also better case management and
the adoption of measures against indoor air pollution, malnutrition, and other factors that
contribute to the public health burden of pneumonia (115).
An upsurge in funding for pneumococcal vaccines also reflects the renewed concern
over pneumonia. Through an Advance Market Commitment (AMC) (see Chapter 4), in
February 2007, five industrialized countries and the Bill & Melinda Gates Foundation
pledged US$ 1.5 billion to accelerate the development and introduction of new
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pneumococcal conjugate vaccines. The keenly awaited 10-valent and 13-valent vaccines
should protect even more children against the infection, particularly in developing
countries where the additional bacterial types covered by these candidate vaccines are
prevalent. The outcome could be the saving of more than seven million children’s lives
between now and 2030.
Polio – a tough end-game
In 1988, polio was endemic in 125 countries and paralyzing an estimated 350 000
children every year (close to 1000 cases a day) (25). In that year, the World Health
Assembly (WHA) passed a resolution calling for global eradication of the disease by
2000. An international partnership, the Global Polio Eradication Initiative (GPEI), came
into existence to achieve that goal.
By the end of 2007, the disease had been eradicated in three of WHO’s six regions –
the Americas, Europe, and the Western Pacific – but not worldwide. At the end of June
2009, indigenous poliovirus remained endemic in only four countries, where 440 new
cases had been reported in 2009 – Afghanistan (10 cases), Pakistan (20 cases), India (89
cases), and Nigeria (321 cases).
There were several reasons for the missed deadline. The mass vaccination campaigns
necessary to stop polio transmission did not kick off in Asia and Africa until the mid-
1990s. Driving the infection from densely populated urban areas in Egypt and India
proved more difficult than had been anticipated. And vaccination was not reaching
enough children among population groups on the move between the Afghanistan and
Pakistan border.
More recently, in 2003, unfounded rumours that the oral polio vaccine (OPV) was
being used to sterilize young girls brought polio immunization to a halt for 12 months
in at least one northern Nigerian state, unleashing a nationwide polio epidemic and the
transcontinental reinfection of 20 previously polio-free countries in Africa, Asia and the
Middle East (116).
Among measures the GPEI took to deal with these setbacks was the introduction of
new, faster diagnostic tests capable of providing more rapid identification of the specific
poliovirus strain causing an outbreak or sustaining the endemic presence of polio
infection in a given area. At the same time, the GPEI exploited the elimination of type
2 wild poliovirus by developing “monovalent” polio vaccines, designed to more rapidly
provide protection against each of the two surviving poliovirus strains. Case control
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studies carried out in India, Nigeria and Pakistan, as well as clinical trials in Egypt and
India, demonstrated that the monovalent vaccines provided at least twice the protective
efficacy provided by the traditional trivalent OPV, dose for dose.
In early 2007, the GPEI stakeholders launched an intensified eradication effort in which
these diagnostic and vaccine tools – and tactics tailored to the specific challenges to
reaching children in each of the remaining infected areas – were paired with intense high-
level advocacy to ensure that children could be accessed in all remaining polio-infected
areas. At the end of 2008, two advisory bodies to the WHO, the Strategic Advisory Group
of Experts (SAGE) on immunization and the Advisory Committee on Polio Eradication
(ACPE), concluded that the intensified eradication effort had demonstrated that the
remaining technical, financial, and operational challenges to completing eradication
could be overcome.
In India’s Uttar Pradesh state, indigenous type 1 polio was interrupted for more than
12 months, and contingency plans were developed to address further the technical
challenge of compromised OPV efficacy in that setting. Direct oversight by sub-
national leaders in areas such as the Punjab in Pakistan, Bihar in India, and Jigawa in
northern Nigeria overcame the operational challenges to raising OPV coverage to the
levels needed to stop transmission in each of those settings. In addition, the application
of new international guidelines on polio outbreak response rapidly stopped 45 of the
49 importations into “non-endemic” countries in 2007 and 2008. Meanwhile, GPEI
donors and the affected countries demonstrated that the financial challenges could be
addressed, by fully funding the US$ 1.4 billion needed for the 2007–2008 intensified
eradication activities.
The 2008 World Health Assembly proved a turning point in polio eradication. Member
States called directly on polio-endemic countries to remove the remaining operational
barriers to reaching children in all areas. Underpinning the WHA’s resolution was
the recognition that eradicating polio is an essential step towards meeting the
MDGs. “Completing polio eradication,” said WHO Director-General Dr Margaret Chan,
“is essential to our credibility to deliver basic health interventions to over 80% of the
world’s children and to our capacity to achieve the MDGs.”
Despite this progress, as of early 2009, efforts to interrupt wild poliovirus transmission
globally faced considerable challenges. In Africa, a large outbreak of type 1 polio in
northern Nigeria, where about 20% of children were still not being reached by vaccination,
had spread to surrounding countries and threatened the entire region. In Angola, Chad,
and the Democratic Republic of the Congo, outbreaks that started between 2003 and
2007 lingered on, further endangering children across the African continent. As a result,
by the end of February 2009, an additional 11 countries were responding to importation-
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associated outbreaks in West Africa and the Horn of Africa. In Asia, the key state of
Uttar Pradesh in India was still struggling to stop a new type 1 outbreak following an
importation in mid-2008 from neighbouring Bihar state. In Afghanistan and Pakistan,
security was increasingly compromising access to children in parts of both countries,
while oversight and accountability remained weak in other parts of the countries.
The humanitarian and financial benefits of interrupting wild poliovirus transmission
globally, and then stopping the routine use of the oral poliovirus vaccines, are massive.
The rare but substantive risks associated with continued OPV use after wild virus
interruption account for the continuing occurrence of vaccine-associated paralytic polio
cases (VAPP), and of outbreaks due to circulating vaccine-derived polioviruses (cVDPVs).
The oral polio vaccine has itself caused polio outbreaks in nine countries due to cVDPVs,
including in six that were previously free from the disease.
The GPEI is implementing an extensive programme of work to manage the long-term
risks associated with continued use of OPV. The cornerstone of the risk management
strategies is the eventual cessation of the use of OPV in routine immunization. In 2008,
the WHA endorsed the concept of eventual OPV cessation and a strategy of bio-
containment, surveillance, stockpile development, and outbreak response to manage
the risks following eradication.
The WHA gave particular attention to the use of the inactivated polio vaccine (IPV). At
a minimum, IPV will be needed in all countries that store poliovirus stocks. For other
countries, which may perceive that the long-term polio risks warrant continued routine
immunization, IPV will be the only option with which to do this, as it is the only vaccine
which does not give rise to circulating vaccine-derived polioviruses and may be used
safely in a post-eradication world. The GPEI is studying a range of approaches to
establish “affordable” strategies for IPV use to achieve immunity at a cost similar to that
achieved through OPV.
Rabies – a terrible but vaccine-preventable death
In most cases, the first symptoms of rabies in humans resemble those of influenza.
Their onset, though, signals an almost inevitable, imminent death. As the virus begins
to infest the central nervous system, the symptoms, in most cases, are anything but
mild – anxiety, confusion, spasms, convulsions, agitation, delirium, and paralysis (1).
Within a few days, coma and death from cardiac and respiratory arrest bring relief.
Perhaps worst of all, the patient often remains conscious and aware of the body’s
relentless decline (1).
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The disease is caused by a bullet-shaped “lyssavirus.” In about two-thirds of cases (1),
rabies runs a so-called “furious” course, marked by violent agitated movements of the
body. A less dramatic form, “dumb” rabies, characterized by lethargy and paralysis,
occurs in about a third of cases (1). In both forms, the outcome is invariably fatal within
a few days although intensive medical care can delay, but not prevent, death (1). Only
a very small number of people with symptomatic rabies have been known to escape
death, and several of the survivors were left with neurological damage (1).
Worldwide, dogs are the main source of human infection. Transmission of the virus to
a person occurs mainly through the bite, scratch, or lick of an infected (rabid) animal
(transmission from human-to-human is rare). The virus in the animal’s saliva enters the
body and attaches to nerves close to the wound. Over an incubation period lasting
typically two months (117), the virus travels up through the peripheral nerves to the brain
(the closer the infective animal bite or scratch is to the head, the less distance the virus
has to travel, and the shorter the incubation period (1)). In the brain, the virus takes up
residence in nerve cells, out of sight of the person’s immune system, starts replicating,
and sets off the fatal sequence of symptoms.
During incubation of the disease, there is no test to indicate whether a person bitten
by a rabid animal has in fact been infected, nor a way to determine whether the biting
animal is rabid unless it is put to death and its brain examined in the laboratory. Nor is
there any effective treatment for rabies after the onset of symptoms. However, highly
effective vaccines exist, and when administered as soon as possible after exposure, the
rabies vaccine gives the patient an almost 100% chance of surviving. Post-exposure
treatment comprises – in addition to a series of vaccine shots – thorough cleansing
and disinfection of the bite wound and, in severe cases of exposure, administration of
anti-rabies immunoglobulins (a purified solution of anti-rabies antibodies taken from the
blood of vaccinated people or horses). Every year, post-exposure prophylaxis (mostly the
vaccine alone) is used in an estimated 10 million people (117), mostly in China and India
(117). It is estimated that current levels of post-exposure prophylaxis prevent more than
250 000 deaths each year, mainly in Asia and Africa.
About 3.3 billion people live in the 100 or so countries where dog rabies is endemic
(enzootic). A conservative estimate puts the annual number of rabies deaths occurring
in Asia and Africa at 55 000. More than 60% of the total annual rabies deaths occur
in Asia (the majority in India), and the rest occur mainly in Africa (118). Rabid dogs
account for more than 98% of the deaths in people. Children aged 9 to 15 are the
most common victims of dog bites. In industrialized countries and in most parts of
Latin America and some Asian countries (e.g. Thailand), widespread use of a veterinary
vaccine in domestic dogs, and measures to manage the dog population, have made
human rabies a rare occurrence (117). Holding rabies in check, however, in both
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industrialized and developing countries, is costing more than US$ 1 billion a year, at a
minimum (117).
The first rabies vaccine was developed more than a century ago by Louis Pasteur in
Paris (1). By 1910, Pasteur Institutes throughout the world were making this first, crude
rabies vaccine that consisted essentially of dried nerve tissue taken from rabies-infected
rabbits. Serious safety concerns over the vaccine, plus occasional failures, prompted a
search for better vaccines.
Up until the late 1950s (1), several vaccines were developed. All, however, were made
with rabies virus “grown” in animal nerve tissues. These nerve tissue vaccines, which
are still in use in a few developing countries, have a number of drawbacks (119). The
most serious is the fairly frequent occurrence of sometimes fatal neurological allergic
reactions. The most inconvenient is their limited potency and the consequent need for
a daily injection for up to 23 days (117). In the early 1960s, researchers succeeded
in making a third-generation vaccine using rabies virus grown in a culture of human
diploid cells (1, 117). A fourth generation of rabies vaccines cultivated on various
cell lines (e.g. primary chicken embryo fibroblasts, continuous cell lines such as vero
cells), have since been developed and are produced today in very large quantities
using fermentor technology. Modern cell culture vaccines are much more potent
than nerve tissue vaccines. Devoid of animal nerve tissue, they are also much safer
(120).
Cell culture vaccines have today replaced the older nerve-tissue vaccines in all
industrialized countries and in most developing countries. Although they are primarily
used for post-exposure prophylaxis, they are also recommended, at least in industrialized
countries, for “pre-exposure” immunization in high-risk groups, such as laboratory staff,
veterinarians, hunters, trappers, animal handlers, and travellers to areas with endemic
rabies (117). Since 1991, WHO has repeatedly, with growing insistence, called on all
countries to switch to the modern vaccines. Since then, 11 Asian countries, including
India, and many Latin American countries, have made the switch. But the high cost
of these vaccines (average US$ 50.00 for the five intramuscular doses needed), is an
obstacle both for governments in the poorest countries when vaccines are provided free
at rabies treatment centres, and also for individuals who have to pay for the vaccine
themselves.
Applying the recommended immunoglobulin component of the post-exposure regimen
is also an obstacle for many poorer countries because of its cost (average US$ 50.00 for
a purified horse derived product) and limited availability worldwide. Currently on average
only 1% of people infected or presumed to be infected with the rabies virus receive
immunoglobulin.
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To increase the supply of immunoglobulin, manufacturers in developing countries
are being encouraged to produce purified equine immunoglobulin. An alternative to
immunoglobulin is also being sought. One approach showing promise in animal studies
is the use of a “cocktail” of at least two monoclonal, or highly specific, antibodies that
can neutralize most commonly circulating rabies viruses.
One way of reducing the cost of the modern cell culture vaccines is by using the
intradermal, instead of the standard intramuscular, route of vaccine administration.
Intradermal injection is as effective and as fast-acting as intramuscular injection
and requires a much smaller volume of vaccine – up to 60% less than for vaccines
administered by the standard intramuscular route (117). This tactic is being successfully
used in India, the Philippines, Sri Lanka, and Thailand. In India, intradermal administration
has brought the cost of a full vaccination regimen down from US$ 81.00 to about
US$ 13.00 (1).
The use of routine preventive pre-exposure vaccination has been considered for children
living in countries where they have high risk of infection from rabid animals. Preliminary
clinical studies in Thailand and Viet Nam have shown that it produces a high immune
response in the vaccinated children. One economic analysis showed that use of pre-
exposure vaccines becomes cost-effective in areas where 20–30% of children are bitten
by dogs over a year (1).
Global eradication of rabies is not an option, given the large number of animal species
providing a large and diverse reservoir for the causative virus. Elimination of the human
disease caused by dog rabies has been widely achieved by eliminating rabies in dogs
through the use of effective veterinary vaccines. It takes vaccination coverage rates
of 75–80% to achieve this outcome. The Bill & Melinda Gates Foundation and WHO
are together supporting dog rabies control projects in some poorer countries, with
the aim of demonstrating the cost-effectiveness of dog rabies as a means to eliminate
human rabies and thereby drastically reduce the need for human post-exposure
prophylaxis.

Rotavirus – vaccines set to prevent half a million child deaths
a year
Discovered in 1973, rotaviruses are the most common cause of severe diarrhoeal
disease in young children throughout the world (1, 121). Virtually all children under three
years of age are infected in both industrialized and developing countries (1, 121). Most
disease episodes consist of a mild attack of watery diarrhoea, accompanied by fever
and vomiting (1). In about 1 in every 75 cases, however, the infection produces severe,
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State of the world’s vaccines and immunization
potentially fatal dehydration (1). Globally, more than two million children are hospitalized
for rotavirus infections every year (122). According to WHO 2004 estimates, 527 000
children under five years old die every year from rotavirus disease. Nearly two-thirds of
these deaths occur in just 11 countries, with most – 23% of total rotavirus deaths – in
India (121).
Work on developing a vaccine to prevent rotavirus disease began in the early 1980s and
culminated in August 1998 with the licensure in the United States of the first rotavirus
vaccine, Rotashield™. Nine months later, after more than 600 000 children had received
the vaccine, the manufacturer withdrew it from the market: several cases of bowel
intussusception (severe bowel blockage caused by the bowel telescoping into itself)
had occurred, supposedly associated with administration of the vaccine. The vaccine
community was dismayed. In 2000, voicing the opinion of many vaccinologists at the
time, Dr Ciro de Quadros, then Director of the Division of Vaccines and Immunization at
PAHO, believed “it would take at least a decade to get new rotavirus vaccines”. In fact,
it took only six years: by the end of 2006, two new-generation rotavirus vaccines, made
by multinational companies, had appeared on the market. Meanwhile, other vaccine
producers, including some in developing countries (notably, China, India, and Indonesia)
had been working on several vaccine candidates, of which at least six, as of mid-2008,
were in the advanced stages of the R&D pipeline.
Before receiving regulatory approval for human use, the two new vaccines had to
prove not only their efficacy but, more importantly given the fate of the first rotavirus
vaccine, their safety in much larger studies. In trials conducted in industrialized and
developing country settings, each involving more than 60 000 participants, the
new vaccines protected 85–98% of vaccinated infants from severe rotavirus disease
(123, 124, 125). Both vaccines were found to be safe and are now WHO-prequalified
(123, 124, 125).

Optimism over these new vaccines is, however, tempered by the need for further
large-scale trials – particularly in the poorest developing countries – before they can be
considered universally applicable. Both are live oral vaccines and may prove less effective
in developing countries with higher child mortality than in industrialized countries. This was
the case with other live oral vaccines, such as those against polio, cholera, and typhoid.
Several of these trials are being completed in 2009 and will provide the necessary data
for WHO to review its recommendations for introduction of these vaccines in Africa and
Asia.
Cost is another issue. In 2008, the new vaccines cost between US$ 16.00 and
US$ 17.00 per fully immunized child when bought by the PAHO Revolving Fund for use
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in Latin America – almost a tenth of the price on the private United States market but still
too expensive for the poorest countries with the highest rotavirus mortality rates in other
regions. One rotavirus vaccine that is manufactured, licensed, and has been in wide use
in China since 2000, sells for about US$ 16.00 a dose to the private sector in China (it
has not yet requested WHO prequalification status for international use). Of course, for
the 72 countries within the GAVI Alliance purview, cost may not be a major issue, at least
in the short term. In the longer term, the costs of sustaining rotavirus vaccination may
prove difficult for some countries.
Rubella – eliminating a threat to the unborn
Rubella, or German measles, was first noted in the mid-19
th
century as a mild disease
involving little more than a skin rash. However, its ability to cause congenital defects –
cataracts, heart disease, and deafness, to mention three – became evident in the 1940s.
And it was not until the early-1960s, during a rubella epidemic in the United States, that
the full range of congenital abnormalities making up the “congenital rubella syndrome”
(CRS) was revealed to the world.
The United States rubella epidemic caused 12.5 million cases of rubella, including
more than 2000 cases of brain inflammation (encephalitis) and 20 000 cases of CRS
in newborns. Of these newborns, more than 8000 were deaf, some 3600 were both
deaf and blind, and nearly 2000 were mentally retarded (1). There were more than 2000
deaths, as well as over 6000 spontaneous and 5000 induced abortions. The world
awoke to the dramatic reality of CRS, and the quest for a vaccine began.
By 1970, several rubella vaccines were available. Before the end of the decade, one
(using the so-called RA 27/3 rubella virus strain) emerged from the pack as offering
a high degree of safety and efficacy in protecting children against mild (or “acquired”)
rubella (1). Given to women of childbearing age, the vaccine gives 95–100% protection
for at least 15 years against the risk of having a baby with CRS (1, 126).
By 1996, 65 countries, accounting for 12% of babies born in that year, were using
the vaccine in their national immunization programmes (71). By the end of 2007, the
rubella vaccine was being used nationally in 125 countries, accounting for 31% of births
worldwide (71).
WHO recommends that all countries where CRS has been identified as a major public
health problem should use the vaccine. Moreover, where logistically feasible, they should
do so in conjunction with measles elimination activities (126). Linking up with the Measles
Initiative makes sense, given the availability of combined measles-rubella vaccines and
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State of the world’s vaccines and immunization
the compatibility of the two administration schedules. Indeed, most countries using the
rubella vaccine administer it as part of the MMR vaccine, given in two doses, the first at
12–18 months of age and the second later in childhood. However, in most developing
countries, rubella vaccine has not been included in the national immunization schedule
because of lack of information on the burden caused by rubella, increased cost, and the
concern that if high coverage (>80%) cannot be achieved and maintained, the risk of
CRS may increase due to a shift in rubella susceptibility to older age groups including
women of childbearing age.
Elimination of CRS, i.e. stopping indigenous (or endemic) transmission of the rubella
virus that causes the disease, is possible. It calls for a strategy to ensure high levels
of immunity through vaccination among children, adolescents, and young adults (both
women of childbearing age and men). For poorer countries, this strategy may not be
affordable, but on the other hand, caring for people with CRS is costly. Cost-benefit
studies in developed as well as developing countries have shown that where coverage
rates exceed 80% and rubella vaccination is combined with measles vaccination, the
benefits of rubella vaccination outweigh its cost (of US$ 0.60 a dose) (127).
Use of the rubella vaccine has eliminated CRS in a number of countries (e.g. Cuba, the
English-speaking Caribbean countries, Sweden, and the United States). Successful use
of the vaccine has also prompted the WHO Regions of the Americas and Europe – the
two WHO regions with the highest rubella vaccine coverage rates in young children – to
target rubella for elimination by 2010.
As for eradication, rubella, like measles, fulfils the biological criteria for an eradicable
disease: only humans maintain transmission of the virus, accurate diagnosis is possible,
and transmission has already been interrupted in large geographical areas (128). And if
eradicating two diseases with a single blow is the aim, the combined measles-rubella
vaccine is there to make the operation feasible. Two unanswered questions, though, point
to potential stumbling blocks: will there be sufficient political will to mount and maintain
a two-disease eradication effort ? And will it be possible to bring sustained vaccination
to communities lacking access to basic health services or isolated by conflict ? The end-
game struggles of the polio eradication initiative are instructive in this respect. Meanwhile,
country-by-country elimination of rubella and congenital rubella syndrome is surely a
worthwhile first step, and more and more countries are taking it.
Tetanus, neonatal and maternal – victory in sight
Tetanus is characterized by muscle rigidity and painful muscle contractions caused by
a toxin – one of the most potent ever identified – released by the bacterium Clostridium
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tetani. The spores of this bacterium are present throughout the world in soil. A person
is infected when the spores enter the body via dirt or soil through a scratch or open
wound. Neonatal tetanus, which is the most common form of the disease in developing
countries, is primarily caused by infection of the umbilical cord stump in babies delivered
in unhygienic conditions. It is most prevalent among the poorest, most neglected
population groups that have little or no access to medical care. In the late 1980s, tetanus
was estimated to be causing more than a million deaths a year, of which about 790 000
were newborn infants.
Prevention of tetanus is possible and inexpensive. The tetanus toxoid vaccine is one
of the most effective, safest, and least costly vaccines on the market. Its discovery,
subsequent development and initial use, at least in industrialized countries, date from
the first half of the 20
th
century.
In 1989, the public health community officially declared neonatal tetanus a target for
elimination, defined as an incidence of less than one case per 1000 live births in all
districts. At that time, 90 countries had not yet reached the elimination target (129).
Vaccination of women before or during pregnancy with at least two doses of the vaccine
was the main strategy to be used to reach the target. Antibodies produced by the
vaccine protect not only the mother but also the foetus and, for up to two months, the
newborn child. Vaccination was combined with efforts to increase the proportion of
births taking place in hygienic conditions and to reduce harmful traditional practices
at home births.
By 1995, 27 of the 90 countries had eliminated neonatal tetanus. In the 63 remaining
countries, most cases were occurring in poor, hard-to-reach communities. To accelerate
elimination efforts, a “high-risk approach” was adopted that aimed to reach out to these
“high-risk communities”. This new approach called for mass immunization campaigns,
delivering three sequential doses of vaccine to all women of childbearing age in the high-
risk communities. Education about providing hygienic conditions for births was also part
of the strategy.
The new approach paid off. By 2000, 135 countries had eliminated neonatal tetanus
(28) and annual deaths from the disease had fallen to an estimated 200 000 – a 75%
drop from the 790 000 deaths in 1988 (28). Ninety percent of these 200 000 deaths
were occurring in just 27 countries, mostly in South Asia and sub-Saharan Africa. WHO,
UNICEF, and the United Nations Population Fund (UNFPA) decided to launch a more
vigorous attack on tetanus, both neonatal and, in a new development, also maternal
tetanus. In fact, an estimated 15 000–30 000 women were dying every year from tetanus
contracted during or shortly after pregnancy. This maternal and neonatal tetanus (MNT)
elimination partnership also set a new deadline, 2005, for achieving elimination – a
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State of the world’s vaccines and immunization
deadline which, however, was to prove too optimistic. By the end of 2008, 12 of the 58
remaining countries with neonatal tetanus had achieved elimination in all districts (see Fig.
12).
The MNT elimination partnership estimates that – with sufficient funding – by the end
of 2010, only 10 countries will still be in the grip of the disease and that by 2012, all
countries will have reached the ultimate target. Their confidence is based on the impetus
that tetanus elimination efforts have been gathering since 2000, and also from the influx
of funds – US$ 160 million – the partnership has received since 2000, mostly through
UNICEF and the GAVI Alliance, to finance its activities.
Confidence is, however, tempered by hurdles still to be overcome. One is the need for
funding over the 2008–2012 period. A second is the lack of solid data on which to base
disease estimates: less than 10% of cases are being reported, according to survey
findings. Disease surveillance clearly needs a major boost.
As for the longer-term future, will the momentum created by elimination of neonatal
and maternal tetanus be sustained? Clostridium tetani is, and will always be present
in nature, and its spores are extremely resistant to destruction. If future generations are
to live without the threat of a catastrophic resurgence of the disease, tetanus experts
estimate that routine immunization coverage in all countries must reach and stay at 80%
of women of childbearing age in all districts and that at least 70% of births must take
place in hygienic conditions. If countries succeed in reaching most people with booster
doses in school-age, adolescence, and early adulthood, not only would MNT remain
eliminated, but protection against tetanus would be life-long (131). Several countries are
taking steps in that direction, by offering tetanus vaccines in school-based immunization
programmes and in activities such as mother and child health days or immunization
weeks.
148
Part 2: Diseases and their vaccines
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149
State of the world’s vaccines and immunization
Tuberculosis – waiting for a better vaccine
The first and only vaccine ever used to protect against tuberculosis is the Bacille
Calmette-Guérin (BCG) vaccine, developed at the Pasteur Institute in Paris and first used
in 1921. Since the 1950s, when routine BCG immunization against tuberculosis began in
many countries, more than four billion people are believed to have received the vaccine
worldwide (1). By 1990, 81% of the world’s newborn infants were receiving the vaccine.
By the end of 2007, BCG coverage had climbed to 89%. In Europe and North America,
several countries where the incidence of reported tuberculosis had dropped to below
25 cases per 100 000 have ceased routine BCG immunization.
That is the good news. The not-so-good news is that over the past two decades the
burden of tuberculosis has followed an upward curve that peaked in 2004 with 8.9 million
new cases (up from 8 million in 1997) and approximately 1.46 million deaths (4). The
advent of HIV/AIDS in the 1980s, with its ability to lower natural protection against latent
infections, including tuberculosis, has contributed to the escalation of tuberculosis cases:
globally, about 15% of tuberculosis cases occur in people with HIV/AIDS, but in some
countries with high HIV incidence rates, the proportion can be as high as 50–60%, as in
Mozambique, South Africa, and Zimbabwe (132).
By contrast, estimates of both incidence and mortality rates in 2007 (132) suggest that
the disease may be on the verge of a downswing. But despite worldwide use of BCG
over the past three or four decades, and despite the availability since the early 1990s of
an inexpensive highly effective treatment strategy (“DOTS”), tuberculosis is still a leading
cause of disease and death. The inability to control this disease has been called “a
colossal failure of public health” (1).
For the vaccine community, the mood is one of frustration over the lack of evidence that
BCG consistently protects against pulmonary tuberculosis. Some studies have found
a high degree of protection; others none at all. By contrast, evidence from several
trials has consistently shown that BCG gives strong protection against tuberculosis
in infants and young children (1). Tuberculous meningitis and disseminated (miliary)
tuberculosis – the two most common and most severe forms of extrapulmonary
tuberculosis – occur in about 25% of children with tuberculosis and are rapidly fatal
without treatment (1). BCG is protective against these forms of tuberculosis in 64–78%
of recipients (1).
However, there is no empirical evidence that high coverage of a population with BCG
vaccination lowers the incidence of these severe forms of tuberculosis in infants and
young children. The problem is that tuberculosis in children is very difficult to diagnose
and often remains undetected. The disease is so rapidly fatal, that diagnosis can only
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be attempted in the earliest stages of the disease. But at that stage, the symptoms are
not specific, x-rays show no evidence of disease, and tuberculin skin tests are negative
in about 40% of cases (1). Under-reporting and poor record-keeping compound the
difficulty of gathering incidence or mortality data.
Given this situation, many health officials wonder if vaccination with BCG at birth is
worth the effort and cost. A recent analysis (133) suggests that it is. BCG costs US$ 2–3
per dose. Given to more than 100 million infants in 194 countries in 2002, the vaccine
would have prevented more than 40 000 cases of tuberculous meningitis and miliary
tuberculosis in children under five years of age. The cost, worldwide, would have been
US$ 200 or less per healthy life year gained, using the disability-adjusted life year (DALY)
measure. In the WHO African Region, South-East Asia Region, and Western Pacific
Region, where the incidence of tuberculosis and BCG coverage are highest, the analysis
showed BCG to be a cost-effective intervention against severe childhood tuberculosis
– almost as cost-effective as short-course chemotherapy – costing US$ 50 per DALY
gained. In the few industrialized countries where BCG is still used routinely despite a
low risk of infection, the cost per DALY gained amounts to several thousand dollars.
Such countries, the research team speculates, may be better off replacing routine BCG
vaccination by vaccination of only high-risk population groups, such as health workers
and others at risk of exposure to the infection. This has, in fact, long been the strategy
adopted by several countries, including the United Kingdom and the Netherlands.
To most tuberculosis experts, it is clear that a new, more consistently effective vaccine
is needed that protects not only against the disease in childhood but against pulmonary
tuberculosis in adults. Several candidate vaccines are in early-stage clinical trials and are
being tested for safety, immunogenicity, and early indicators of efficacy (134, 135).
Typhoid fever – vaccines ready and waiting
Typhoid fever, also known as enteric fever, is caused by one of the most virulent
bacteria to attack the human gut. Commonly spread via contaminated water and food,
the causative bacterium, Salmonella typhi, thrives in unsanitary conditions, particularly
where clean water is lacking. Through the gut, the organism infects the bloodstream,
altering brain function in some cases, and often resulting in death. Before the advent of
antibiotics, the symptoms of typhoid fever – typically, persistent high fever, abdominal
pain, malaise, and headache – usually lasted several weeks and in many cases
culminated in death.
Today, in industrialized countries, typhoid fever has ceased to be a problem, thanks to
improved hygiene and a clean water supply. In developing countries, however, it is still
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State of the world’s vaccines and immunization
very much a problem. In 2004, WHO estimated the global typhoid fever disease burden
at 21 million cases annually, resulting in an estimated 216 000–600 000 deaths per year,
predominantly in children of school age or younger. The majority of this burden occurs
in Asia (136). In a comprehensive study relating to the incidence of typhoid fever in five
countries in Asia, it was reported that incidence in highly-endemic countries is similar in
children 2–5 years of age as in school-aged children 5–15 years of age and adolescents
(137).
Typhoid fever was discovered as a distinct disease entity in the 1880s. At that time, its
hold on industrialized countries had begun to slacken in the face of improved sanitation.
Cases still occurred though, often in outbreak situations, and among high-risk population
groups, such as migrant groups. The continued occurrence of the disease and the
fear engendered by its high mortality rate – 10–20% of infections resulted in death (1)
– combined to fuel the search for a cure and a means of prevention. A cure came in the
form of antimicrobial drugs; prevention in the form of vaccines.
Early research produced two vaccines made from the entire (whole-cell) bacterium.
One became available in the 1890s, the second in 1952. Both protected about 65% of
recipients. However, the frequency and severity of the adverse effects they caused dissuaded
many countries from using them. These shortcomings, combined with drug treatment
failures, which had escalated in previous years as a result of increasingly widespread
resistance to antibiotic therapy, intensified the quest for a more effective vaccine.
Before the end of the 20
th
century, two new-generation typhoid vaccines had entered the
scene. One, named “Ty21a” and first licensed in 1983, is given in three to four oral doses
(136) and consists of a live but genetically modified S. typhi strain (138). The second,
named “Vi” and licensed in 1994, is given by injection and consists of a sugar molecule
(polysaccharide) located on the surface of the bacterium (138). In clinical trials and early
field use, the duration of efficacy of both vaccines varied to some degree. Moreover,
no evidence of efficacy has been reported in children under two years of age. On a
positive note, both vaccines are licensed, internationally available, and safe, and both are
effective enough not only to reduce the incidence of typhoid fever in endemic areas but
also to control outbreaks.
Price was initially thought to be a barrier to adoption of the vaccines by developing
countries. However, several manufacturers in developing countries now quote prices
of about US$ 0.50 for the Vi vaccine in multi-dose vial presentations for use in public
health programmes, and the main producer of Ty21a is offering a discounted price for
the poorest countries. Moreover, typhoid vaccines have now been accepted by the GAVI
Alliance as a possible candidate for future financial support.
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In 2008, WHO reiterated its earlier recommendations that the new vaccines be used for
routine immunization – alongside active strategies to improve hygiene and sanitation – in
countries or areas (such as deprived urban areas) where typhoid fever is endemic. In
most of these countries, vaccination will be confined to high-risk population groups, such
as school-age and preschool-age children, particularly in areas where antibiotic-resistant
strains of S. typhi are prevalent. WHO also recommends use of the new vaccines for
the control of outbreaks (136). Which of the two vaccines a country chooses depends
on the capacity, logistics, and cultural context of its immunization programme. Very
few countries still use the whole-cell vaccine: those that do should, according to WHO,
switch to one of the new-generation vaccines (136).
Meanwhile, third-generation typhoid vaccines are in the pipeline. One is a Vi conjugate
vaccine that protects about 85% of recipients, according to late-stage clinical trials, and
appears to be effective in children under two years of age. A second candidate vaccine,
further back in the R&D pipeline, is, like Ty21a, a live attenuated vaccine but, unlike
Ty21a, can be given in a single oral dose.
Vaccine scientists point out, though, that these newer typhoid vaccines have still several
years to go before reaching the market. Action against the daily toll of disease and death
from typhoid fever in endemic populations is needed now and, although current new-
generation vaccines may not be perfect, they are available to meet that need.
Varicella and herpes zoster – a single virus that can linger for
a lifetime
Varicella, commonly known as chickenpox, is caused by the varicella-zoster virus (a
member of the herpesvirus family), which was first identified in 1952 (139). The same
virus, when reactivated from a latent state in nerve cells causes another disease –
herpes zoster, or shingles. In most populations, varicella is a disease of children, and
herpes zoster a disease of elderly people. However, the epidemiology of disease can
vary, especially in tropical countries where infection and varicella may occur more often
in older age groups. The hallmark symptom of varicella is an itchy rash, consisting of
blister-like vesicles. Seventeenth century medical documents describe chickenpox as a
mild form of smallpox (139) but in 1767 the English physician William Heberden showed
that the two diseases are distinct (1).
The varicella-zoster virus only infects humans. It spreads from person-to-person through
direct contact, or from the virus being sneezed or coughed into the air or released from
the vesicles on the skin. Generally, varicella is a mild disease. However, complications,
which can sometimes be severe, occur in about 10% of cases, mostly in adolescents
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State of the world’s vaccines and immunization
and adults (139) (who are 30–40 times more likely than children to die from severe
complications (139)). The most common, and sometimes life-threatening, complications
of varicella are bacterial infections of the skin, which can occasionally become severe
through spread to contiguous or distant parts of the body (1). Other bacterial infections
(pneumonia, or infection of the bones or bloodstream), neurological conditions
(uncontrollable muscle movement or brain inflammation), and inflammatory conditions
(of the liver, kidneys, heart, or testicles) are prominent on the list of complications from
varicella (139, 1). In pregnant women, the infection can cause congenital limb foetal
abnormalities, brain damage, and death. However, babies born to women who have
immunity to varicella receive their mother’s anti-varicella antibodies and are protected
against the infection for about a month after birth (139). Varicella infection itself induces
lifelong immunity to chickenpox in virtually everyone whose immune system is working
normally (139).
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Part 2: Diseases and their vaccines
Box 22
Herpes zoster – the same virus, a different disease
In 10–20% of children infected with varicella, the virus takes up residence in nerve
cells, where it lies dormant for several decades, until a lowering of the host’s immune
defences (as a result of ageing, disease, or immunosuppressive treatment) allows it to
awaken, begin replicating, and precipitate herpes zoster disease, or shingles as it is
commonly known (139). In the United States alone, 43 million people are believed to be
at risk of herpes zoster (1).
Herpes zoster is characterized by a painful blistering rash along the distribution of the
infected nerve cells (139). In many elderly people the rash and pain subside and resolve
completely in a few weeks. In about 15% of patients, though, pain and numbness in
the area of the rash can last for weeks or months. The pain can be severe and highly
disabling, both physically and mentally (1). Itching, which may fluctuate from mild to
intense, adds to the person’s discomfort (1).
In addition, 8–15% of people suffer permanent neurological damage, impaired vision, or
problems of bowel or bladder function (1, 139). Elderly people and immunocompromised
people run the highest risk of developing herpes zoster. Since the same virus causes
varicella, people with herpes zoster constitute a source of varicella outbreaks among
unvaccinated children and other non-immune population groups.
Treatment with antiviral drugs is effective if started soon after the onset of herpes zoster.
However, accurate diagnosis at that stage of the infection is difficult and in most cases
antiviral treatment is begun too late to be of optimal benefit (1).
In 2005, a vaccine against herpes zoster was licensed for use in people over 60 years
of age. It contains at least 14 times the amount of virus as the varicella vaccine (1). Its
protective efficacy, though, varies with the recipient’s age, falling from 64% in the 60–69
year age group to 41% in the 70–79 year age group, and 18% in the 80–89 year age
group (1). Some herpes zoster experts believe younger age groups – such as people in
their 50s, who account for almost 20% of herpes zoster cases – could benefit from the
vaccine (1). Two factors, though, militate against its widespread adoption by developing
countries: price (the vaccine currently costs about US$ 150 a dose in industrialized
countries), and the low public health priority of herpes zoster in relation to the many
other serious diseases that ravage these countries.
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State of the world’s vaccines and immunization
Little is known about the burden of varicella in developing countries (139). However, in
2006, an estimate based on the incidence of varicella in industrialized countries gave a
total worldwide estimate of 90 million cases a year (1).
Treatment for varicella consists of antiviral drugs, which are expensive and work only
when used early in the course of infection. It is generally reserved for people at risk
of severe disease. Vaccination is the only way to protect whole communities and
populations from varicella, and possibly from herpes zoster. A safe and effective vaccine
against varicella has been available in several formulations since the mid-1970s (139),
and in 2005, a combination measles-mumps-rubella-varicella vaccine also came on
to the market. The single-antigen (i.e. containing varicella virus only) vaccine has been
administered to millions of children, adolescents, and adults in many countries (1). In
children, a single dose produces anti-varicella antibodies in about 95% of recipients and
protects them against the disease (139). Furthermore, at least 90% of people given the
vaccine within three days of being exposed to the virus are protected against developing
the disease (139). In those who develop disease after vaccination, it is much milder than
in unvaccinated individuals.
The effectiveness and cost-effectiveness of the vaccine have prompted several
industrialized countries in Asia, Europe, and North America to adopt it in their routine child
immunization programmes (139). In 1995, the United States became the first country
to adopt the vaccine into its routine immunization programme (1) and by 2002 saw a
74–92% drop in child deaths from varicella and an 88% drop in hospitalizations due to
the disease (1). The use of the vaccine has also been shown to be cost-effective in the
United States (139). Some epidemiologists believe that widespread routine administration
of the varicella vaccine in children could eventually lead to the virtual disappearance of
the disease.
In general, most developing countries have other diseases associated with high disease
burden and deaths that need to be given higher priority than varicella. Where varicella
represents a sizeable public health and socioeconomic problem, countries may consider
routine varicella immunization. However, immunization programmes must reach at least
85–90% of children as lower coverage rates could theoretically shift the target of the
virus from young children to older children and adults.
156
Part 2: Diseases and their vaccines
Yellow fever – defusing a bomb waiting to explode
Yellow fever is a viral haemorrhagic fever caused by a virus transmitted to humans and
non-human primates by the bite of a mosquito. After a few days of being bitten by an
infected mosquito, sub-clinical infection, non-specific illness, or influenza-like symptoms
can develop. The latter can culminate in the vomiting of blackish blood, one of the two
hallmark symptoms of the disease (1). A few days later, in about 15% of cases, bleeding
occurs from several sites, accompanied by painful convulsions and failure of several
organ systems, notably the liver, kidneys, and heart (1). This stage is also marked by
jaundice – the second hallmark symptom – which colours the skin a deep yellow. About
20–50% of people with severe disease die from the disease. Children and elderly people
run the greatest risk of death from yellow fever.
Yellow fever was a major scourge in the 18
th
and 19
th
centuries in colonial settlements in
the Americas and West Africa. The discoveries (in 1900) that mosquitoes were responsible
for transmission and that the disease was preventable by vector control, as well as the
development of vaccines (in the 1930s), have reduced both the fear associated with
the disease and its medical impact. In 1940, mass vaccination of 25 million people in
French-speaking West and equatorial Africa led to the virtual disappearance of yellow
fever. However, inadequately immunized populations and urbanization set the stage for
the disease to re-emerge.
Today, yellow fever remains an endemic and epidemic disease affecting thousands of
people in tropical Africa (33 countries) and South America (11 countries and territories)
(140), and is a continued threat to people who travel to these regions without vaccination.
An estimated 200 000 cases and 30 000 deaths (141) occur every year worldwide. About
90% of cases and deaths occur in Africa (141), where more than 600 million people are
at risk of infection (141). In South America, about 60 million people live in endemic areas (1).
Outbreaks may affect urban populations, with the infection spreading by mosquitoes from
human-to-human. Yellow fever also occurs in jungles, where it exists as an animal (epizootic)
disease, spread by mosquitoes from monkey-to-monkey and, accidentally, to humans.
Travellers, too, are at risk of yellow fever. Every year, an estimated nine million people
travel from non-endemic to endemic areas and about three million of these travellers may
be going to places where outbreaks are raging (141). Only 10–30% of travellers to these
“danger zones” are vaccinated, according to one estimate (141). The International Health
Regulations require travellers to or from endemic countries, to carry a valid vaccination
certificate (1).
No specific treatment exists for yellow fever. Vector control targeting the mosquito
responsible for transmitting the disease, has its limits. Hence, vaccination is the single
157
State of the world’s vaccines and immunization
most effective means of obtaining protection against yellow fever. The 17D vaccine is
both highly effective and safe, conferring a high degree of protective immunity for at least
30–35 years (and probably for a lifetime). The vaccine is highly cost-effective as it confers
long-term immunity in an infant for an estimated US$ 0.01 a year.
In 1988, WHO and UNICEF proposed a two-pronged vaccination strategy that is still the
universally recommended approach to controlling yellow fever. It is designed to create a
high level of protective immunity in at-risk populations, to sustain that level from generation
to generation, and, ultimately, to eliminate yellow fever as a public health problem.
One prong of the strategy is the integration of the vaccine into the national childhood
immunization programmes of countries at risk of epidemics (141). The second prong is
the use of mass vaccination campaigns to protect susceptible older age groups (141)
and populations threatened by imminent or incipient outbreaks. In addition, the strategy
calls for vector control measures; for use of the vaccine to battle ongoing outbreaks;
and for strengthening disease surveillance which is critical for outbreak detection and
control, and for programme monitoring.
Implementing the strategy has been slow. Of the 33 endemic countries in Africa, 22 had
adopted the vaccine in their national immunization programmes by the end of 2007, up
from eight countries in 2000. The GAVI Alliance provided support to the poorest endemic
countries. However, according to data reported by WHO and UNICEF, the proportion of
children vaccinated with the yellow fever vaccine in the 33 African countries had reached
an average of only 50% by the end of 2007.
Poor disease surveillance, resulting in gross underestimation of the disease burden,
has been a key deterrent to the implementation of the WHO-recommended vaccination
strategies. One reason is that the signs and symptoms of yellow fever are similar to those
of other diseases, such as malaria, influenza, and typhoid fever (141). Surveillance must
therefore be backed up by a network of laboratories capable of accurate diagnosis (141).
Another deterrent is an “insecure” vaccine supply. Approximately 30 million doses a
year (1) are provided by manufacturers for the African market. Yet, to meet demand for
enough vaccine to implement the WHO-UNICEF strategy would require an estimated
40 million doses plus at least 6 million doses to respond to outbreaks.
At US$ 0.71 a dose (on the developing country market), the cost of the vaccine has been
an additional deterrent for many countries. However, the support of the GAVI Alliance
has made it possible for the GAVI-eligible countries to adopt the vaccine.
These three deterrents – surveillance, vaccine supply, and price – are likely to become
less critical, at least for the poorest countries at highest risk of yellow fever: the GAVI
Part 2: Diseases and their vaccines
158
Alliance has been supporting the introduction of yellow fever vaccine into routine infant
immunization since 2002. In addition, it has supported an emergency vaccine stockpile
since 2003. More recently, the GAVI Alliance has approved a request from WHO, UNICEF
and other members of the Yellow Fever Initiative to provide about US$ 100 million for
control of yellow fever in Africa. The money would be spent over five years mainly on
providing vaccines for preventive campaigns in 12 endemic African countries within the
GAVI Alliance mandate, and also for responding to outbreaks in any GAVI-eligible country
at risk in the event of outbreaks.
In South America, yellow fever vaccination has been ongoing for at least three decades.
Up to 1991, mass vaccination campaigns were carried out every five years in the endemic
countries of the region (1). Since 1998, integration of the yellow fever vaccine within
national child immunization programmes has become the norm (1). By the end of 2007,
the average reported vaccine coverage had reached 86% for these countries (1). One
concern in the region is the movement of unvaccinated people from coastal areas, where
vaccination is not carried out, to the more inland endemic areas. Another is resurgence
and spread of the urban form of the disease as a result of the recent re-invasion of the
continent by the urban-dwelling mosquito vector (1).
For Africa and South America, the ongoing circulation of the yellow fever virus remains
a time-bomb waiting to explode. The new funding being provided to endemic African
countries for yellow fever vaccines and vaccination, and the high levels of vigilance and
surveillance in South American countries, should keep the bomb from exploding. But it
is still ticking. With escalating international air travel providing a mechanical vector for the
mosquito and the virus, and with the lack of adequate immunity in many populations (a
single case of infection can cause a massive outbreak in the presence of the mosquito
responsible for transmitting the disease), the bomb could explode, disseminating the
virus well beyond its current hunting grounds.
State of the world’s vaccines and immunization
159
160
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168
Annex 1
Population data in thousand
1
2007 2006 2005 2004 2003 2000 1990 1980
Total population 6'659'040 6'580'921 6'502'983 6'425'275 6'347'724 6'113'437 5'279'007 4'439'786
Live births 135'590 134'985 134'397 133'865 133'418 132'820 136'793 123'711
Surviving infants 128'816 128'120 127'440 126'816 126'275 125'369 128'148 114'051
Pop. less
than 5 years
628'7210 625'407 622'797 620'980 619'905 620'422 629'747 545'390
Pop. less than
15 years
1'843'756 1'841'906 1'841'380 1'842'270 1'844'242 1'846'856 1'724'575 1'566'771
Female 15-49 years 1'718'802 1'698'386 1'677'375 1'655'843 1'633'781 1'564'554 1'314'119 1'058'498
Number of reported cases
Diphtheria 4'273 3'978 12'735 10'069 6'781 11'625 23'864 97'774
Measles 280'771 373'941 601'232 509'734 680'454 852'937 1'374'083 4'211'431
Mumps 407'787 643'078 619'062 654'216 334'063 544'093 - -
Pertussis 161'861 119'916 135'326 244'989 110'854 190'476 476'377 1'982'384
Polio 1'385 2'021 2'032 1'258 784 2'971 23'366 52'795
Rubella 196'506 252'340 267'366 308'219 321'180 671'286 - -
Rubella (CRS) 225 63 37 88 99 181 - -
Tetanus (neonatal) 6'086 8'376 9'918 9'318 9'028 16'943 25'293 13'005
Tetanus (total) 19'867 14'646 15'980 13'772 12'857 21'242 64'378 114'248
Yellow fever 265 356 588 1'344 672 684 4'336 144
Percentage of target population vaccinated by antigen
based on WHO-UNICEF estimates TT2plus and YFV are based on reported coverage
BCG 89 88 86 84 83 81 81 16
DTP1 90 89 88 87 85 85 88 30
DTP3 81 81 79 77 75 73 75 20
HepB3 65 60 56 50 46 32 1 -
Hib3 26 22 21 20 19 14 - -
MCV 82 81 79 77 75 72 72 16
Pol3 82 82 79 77 76 74 75 21
TT2plus 71 69 66 59 61 62 55 9
YFV
51 48 42 35 31 26 4 0
Annex 1. Global immunization profile
State of the world’s vaccines and immunization
169
Most countries have standard recommendations regarding which vaccines should be offered
and at what ages they should be given. In general, vaccines are recommended for the
youngest age group at risk of developing the disease whose members are known to respond
to the immunization without adverse effects.
Unless otherwise specified, data are provided by Member States through the WHO-UNICEF
Joint Reporting Form and WHO regional offices.
1)
Source: (6)
|3BN 97B 92 4 1563B6 4

Suggested citation: WHO, UNICEF, World Bank. State of the world’s vaccines and immunization, 3rd ed. Geneva, World Health Organization, 2009. This book is dedicated to all those individuals who work tirelessly to improve and save lives through vaccines and immunization.

WHO Library Cataloguing-in-Publication Data State of the world's vaccines and immunization. -- 3rd ed. 1.Immunization programs 2.Immunization 3.Vaccines 4.Biomedical research 5.Child 6.Infant 7.Interinstitutional relations 8.International cooperation 9.Developing countries I.World Health Organization. ISBN 978 92 4 156386 4 (NLM classification: WA 110)

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State of the world's vaccines and immunization. Third edition ISBN 978 92 4 156386 4
Please note the following:

Page 38: Innovative regulatory pathways Traditionally, when a national regulatory authority in a developing country considers whether to host clinical trials of a new vaccine produced in another country, or whether to adopt a new vaccine in its country’s immunization programme, it would be favourably influenced if the vaccine had been approved for human use by the European Medicines Agency or the FDA. However, in 2004 and 2007, respectively, both agencies decided to no longer accept vaccines for marketing approval where they are intended for use exclusively outside their geographical jurisdictions. This decision raised a fear that the supply of new life-saving vaccines to developing countries may be hindered or delayed for lack of authoritative marketing approval. In 2005, therefore, the European Medicines Agency introduced a mechanism, known as “Article 58”, whereby it issues a “scientific opinion” based on the customary Agency process but with the addition of an evaluation of the vaccine by WHO-appointed experts from countries where the vaccine is intended to be used. This mechanism, although stopping short of formally granting a licence, involves all the steps of a regular licensing procedure. It carries enough weight to allay fears that vaccines may be introduced without having been assessed for safety and quality. Moreover, the FDA and the European Medicines Agency have agreed to work with national regulatory authorities or with networks of regulators in the regions, to provide advice on vaccine safety and efficacy as well as on clinical trial protocols. Similar collaborative agreements are being forged in other parts of the world, notably in Asia.

1

should read: Innovative regulatory pathways Traditionally, when a national regulatory authority in a developing country considers whether to adopt a new vaccine in its country’s immunization programme, it would be favourably influenced if the vaccine had been approved for human use by the European Medicines Agency (EMEA) or the FDA. However, in 2004, the EMEA decided to no longer issue marketing authorization for vaccines intended exclusively for use outside the European Union. This decision raised a fear that the supply of new life-saving vaccines to developing countries may be hindered or delayed for lack of authoritative marketing approval. In 2005, therefore, the EMEA introduced a mechanism, known as “Article 58”, whereby it issues a “scientific opinion” based on the customary Agency process but with the added input of experts — proposed by WHO to the EMEA — from countries where the vaccine is intended for use. This mechanism, although stopping short of formally granting a licence, involves all the steps of a regular licensing procedure. It carries enough weight to allay fears that vaccines may be introduced without having been assessed for quality, safety and efficacy for the intended population. Moreover, the national regulatory authorities in Europe and the United States have agreed to work with global and regional networks of regulators. Collaborative agreements are being established to promote expert advice from the European and United States regulators to regulatory authorities of developing countries hosting clinical trials or reviewing registration dossiers of vaccines manufactured under the jurisdiction of the former.

Pages 49-50 By mid-2005, 53 countries, mostly in Africa and Asia, had begun implementing the RED strategy to varying degrees (see Fig. 6) (32). In 2005, an evaluation of five countries in Africa that had implemented RED found that the proportion of districts with over 80% of children fully immunized with DTP vaccine had more than doubled (33). More recently, a nine-country evaluation carried out by the CDC in 2007 found that the RED strategy had been adopted by 90% of all districts within these countries. However, few of the nine countries were implementing all five components of the strategy (see Box 11). The CDC evaluation noted that further studies would be needed over a longer period to assess the effectiveness and sustainability of the strategy. should read: By mid-2005, 53 countries, mostly in Africa and Asia, had begun implementing the RED strategy to varying degrees (see Fig. 6) (32). In 2005, an evaluation in five countries in Africa that had implemented RED carried out by staff from WHO's Regional Office for Africa, with the support of UNICEF, the IMMUNIZATIONbasics project, and the United States Centers for Disease Control and Prevention found that the proportion of districts with over 80% of children fully immunized with DTP vaccine had more than doubled (33). A nine-country in-depth evaluation carried out by the same groups in 2007 found that the RED strategy had been adopted by 90% of all districts within these countries. However, few of the nine countries were implementing all five components of the strategy (see Box 11). The in-depth evaluation noted that further studies would be needed over a longer period to assess the effectiveness and sustainability of the strategy. 2

Page 105 The search for a safer. cholerae linked to a genetically engineered (recombinant) fragment (B-subunit) of the cholera toxin. This vaccine. of which only one is available for widespread use today. of which only one is available for widespread use today. prompting WHO to recommend its inclusion in the routine immunization programmes of all countries where Hib was recognized as a public health burden and where the cost of the vaccine was not prohibitive (70). by 1997 only 29 countries were using it routinely. is made from the whole-cell V. more effective cholera vaccine produced three new-generation vaccines. more effective cholera vaccine produced three new-generation vaccines. should read: These observations have prompted countries where diphtheria is no longer endemic to extend vaccination protection beyond the primary three-dose series for infants by administering one booster dose every 10 years to adults through the diphtheria-tetanus (dT – low content of diphtheria) combination vaccine (67). should read: The search for a safer. Page 107 These observations have prompted countries where diphtheria is no longer endemic to extend vaccination protection beyond the primary three-dose series for infants by administering one. or sometimes two. This vaccine. should read: Notwithstanding clear evidence of the vaccine’s efficacy. is made from the whole-cell V. Page 108 Notwithstanding clear evidence of the vaccine’s efficacy. first licensed in Argentina in 1997 and codenamed WC/rBS. by 1997 only 26 countries were using it routinely. booster doses every 10 years to adults through the diphtheria-tetanus (dT – low content of diphtheria) combination vaccine (67). first licensed in Argentina in 1997 and codenamed WC/rBS. prompting WHO to recommend its inclusion in the routine immunization programmes of all countries where Hib was recognized as a public health burden and where the cost of the vaccine was not prohibitive (70). 3 . cholerae and a genetically engineered (recombinant) fragment (B-subunit) of the cholera toxin.

Should read: Death from pertussis still occurs in industrialized countries (less than 1 per 1000 cases (111)). and 10 per 1000 in older children (111)). 4 . For example. therefore. there are no compelling reasons for recommending a systematic booster dose.Page 111 At the present time. Cuba. Those vaccines that have been available during the past years were custom-made against specific epidemic strains and have been used to control outbreaks in Brazil. Cuba. and Norway. and 10 per 1000 cases in older children (111)). Chile. New Zealand. Chile. there are no compelling reasons for recommending a fourth dose of vaccine outside of the routine immunization programme. should read: At the present time. group B vaccines that have been custom-made against specific epidemic strains have been successfully used to control specific outbreaks in Brazil. and Norway. there are no licensed vaccines against the group B meningococcus. but more rarely than in developing countries (40 per 1000 cases in infants. should read: To date. therefore. there are few licensed vaccines against the group B meningococcus. New Zealand. France. Page 132 Death from pertussis still occurs in industrialized countries (less than 1 per 1000 cases (111)). but more rarely than in developing countries (40 per 1000 infants. Page 127 To date. France. but several vaccine manufacturers have products that are being evaluated clinically.

State of the world’s vaccines and immunization Third edition .

.

Bruce Aylward. Chris Elias. David Bloom. Reviewers Gratitude is extended to the many individuals who invested considerable time reviewing the document: Teresa Aguado. Uli Fruth. Madeline Beal. Philippe Duclos. Ruth Levine. Godwin Enwere. Rudi Eggers. Peter Folb. and Kevin Reilly provided invaluable advice in the early stages of drafting. Adwoa Bentsi-Enchill. Diana Chang-Blanc. Her assiduity in dealing with the comments of multiple reviewers. Marta Gacic-Dobo. Tony Dutson. Liliana Chocarro. Bjarne Bjorvatn. The secondary writer was Sheila Davey. Julian Bilous. Michel Greco (for section on vaccine industry in Chapter 2). Martin Friede. François III . Brent Burkholder. Maritel Costales. Laure Dumolard. Lahouari Belgharbi. Chris Dye. Logan Brenzel. John Clemens. Peter Carrasco. The main contributions of the Committee were provided during a two-day retreat in Switzerland. at tight deadlines. Alejandro Costa. Julie Buss. Linda Eckert. Editorial Committee An Editorial Committee composed of Amie Batson. Julian Bilous (hepatitis B control in China). Nora Dellepiane. Special thanks to John for his extensive research and writing and editing of many drafts of the document. Written comments on drafts were also provided. Thomas Cherian. who took over the writing during the last months of revisions. Mercy Ahun. Armin Fidler. Alya Dabbagh. Tatu Kamau. Sona Bari. Rob Breiman. Patrick Lydon (Chapter 4). is much appreciated. Logan Brenzel (Chapter 4).State of the world’s vaccines and immunization Acknowledgements Writers The principal writer of the 3rd edition of the State of the world’s vaccines and immunization was John Maurice. Contributors Contributions to the text were provided by Jeffrey Bates (for communications sections in Chapter 3). Rehan Hafiz. and Rob Matthews (on vaccine supply issues). Janice Bernat.

14 Corbis. p. IV . Miloud Kaddar. Edward Hoekstra. Mark Young. Steve Wiersma. Eileen Quinn. Melinda Henry. Craig Shapiro. Ivana Knezevic. Nina Schwalbe. Tracey Goodman.25 MVI/David Poland. Ahmed Magan. Simon Wreford-Howard. Lalitha Mendis. Alison Rowe. Marc LaForce. David Wood. Patience Kuruneri. Ministry of Public Health.allmeo. Editor Thanks are extended to Cathy Needham for her careful editing of final drafts. François-Xavier Meslin. Suresh Jadhav. Naroesha Jagessar. Thomas Sorensen.52 WHO/H.40 JeanMarc Giboux. p. p. Peter Salama. p. Julian Lob-Levyt. Gill Mayers. Orin Levine. www. Steve Jarrett. Bjorn Melgaard.2 Jean-Marc Giboux. Marie-Pierre Preziosi. Sarah Schmitt. p. p.Acknowledgements Gasse. Scott Wittet. Lois Privor-Dumm. Jeffrey Rowland. Judy Heck (graphics). p. p. Jennifer O’Brien.36 Department of Medical Sciences. Georges Peter.61 WHO/U. Carsten Mantel. Joachim Hombach. Marie-Paule Kieny. Graphic design Mise en oeuvre. Daniel Lavanchy. Patrick Lydon. Peter Smith. p. p. Duncan Steele. Pierre van Damme. Benny Kim. p. Photography Front cover: Marc-André Marmillod. Maya Vandenent. Eric Laurent. Rama Lakshiminarayana.9 Courtesy of the PneumoADIP. Oliver Rosenbauer. Julie Milstien. Daniel Tarantola. Ryoko Krause. Kartoglu. Umit Kartoglu.92 Amélie Coulombel. Maria Ieroianni. Robert Steinglass. Thailand. Haydar Nasser.72 Istockphoto. Switzerland. Alex Palacios. Roland Sutter. Christiana Toscana. photo by Adrian Books. Nicole King.64 WHO/H. Teresa Taube. Peter Strebel. Nikki Turner.com. p.Hasan. Bernard Ivanoff.Hasan.95 Jim Lin. Patrick Zuber. Eric Mast. Rob Matthews. Pankaj Mehta.

Jos Vandelaer. Anthony Measham.State of the world’s vaccines and immunization Steering Group Alison Brunier. Jean-Marie Okwo-Bele. and Michel Zaffran oversaw the production of the document from inception to publication. V . providing input and direction on content at all stages of drafting. Osman Mansoor.

not even antibiotics.Vaccines “With the exception of safe water. has had such a major effect on mortality reduction…” (1) . no other modality.

Immunization and human development 2. protecting Towards vaccines of assured quality Making and meeting standards of quality and safety Strengthening national regulatory authorities A regulators’ network for developing countries Harmonizing and standardizing vaccine regulation Innovative regulatory pathways XIV XVII 1 2 14 17 17 18 19 20 21 21 23 24 27 27 27 28 31 31 34 35 36 38 VII .State of the world’s vaccines and immunization Contents Foreword Executive summary PART 1: Progress and challenges in meeting global goals 1. producing. A new chapter in vaccine development A vaccine boom Explaining the new momentum Technology comes of age Reverse technology Conjugation technology Adjuvants Cell substrates New licensed vaccines Vaccines in the pipeline Supplying vaccines for a changing world A rapidly expanding market A concentrated industry Planning.

Investing in immunization What does immunization cost? Is the investment worth making? Who pays the bill and how? National governments Multilateral.Contents 3. and other donors The Global Polio Eradication Initiative The GAVI Alliance New financing mechanisms The International Finance Facility for Immunisation Advance Market Commitment A concluding conundrum 5. The view from the future 40 45 49 51 54 56 59 62 66 68 72 75 79 81 81 85 85 87 89 89 90 91 92 VIII . bilateral. Immunization: putting vaccines to good use The unfinished immunization agenda Extending the benefits of immunization equitably within countries Reaching more children through campaign strategies Greater awareness fuels demand Surveillance and monitoring: essential health system functions Optimizing the delivery of vaccines Linking interventions for greater impact Combating fear with knowledge and evidence Remarkable progress. huge challenges 4.

neonatal and maternal – victory in sight Tuberculosis – waiting for a better vaccine Typhoid fever – vaccines ready and waiting Varicella and herpes zoster – a single virus that can linger for a lifetime Yellow fever – defusing a bomb waiting to explode 103 104 106 108 111 112 115 118 122 123 126 130 132 134 137 139 142 144 145 149 150 152 156 IX . too many uncounted deaths Pneumococcal disease – many deaths from many strains.State of the world’s vaccines and immunization PART 2: Diseases and their vaccines Cholera – exploring the use of available vaccines Diphtheria – controlled by vaccines but waiting to resurface Haemophilus influenzae type b (Hib) – increased attention for this little known but lethal disease Hepatitis A – paradox and potential Hepatitis B – the first vaccine against cancer Human papillomavirus – a second cancer vaccine Influenza – keeping scientists guessing Japanese encephalitis – a regional scourge. many hopes from new vaccines Polio – a tough end-game Rabies – a terrible but vaccine-preventable death Rotavirus – vaccines set to prevent half a million child deaths a year Rubella – eliminating a threat to the unborn Tetanus. not yet conquered Pertussis – too many children not being vaccinated. waning but still present Measles – record progress but risk of resurgence is high Meningococcal disease – still a deadly menace across Africa Mumps – not always mild.

Global Immunization Vision and Strategy (GIVS) goals What’s so special about vaccines? AIDS and malaria defy science The role of industry in vaccine research and development Product development partnerships Vaccine security How good is a national regulatory authority? Prequalification – flagging vaccines fit for public purchase The impact of immunization 11 13 19 22 26 29 33 39 44 48 50 53 56 59 68 70 97 114 120 121 129 154 10. Herpes zoster – the same virus. 8. Strengthening post-marketing surveillance of newly licensed vaccines 17. Vaccine Safety Net for quality web sites 16. Hepatitis B control in China: reducing disparities 19. 7. Reaching Every District (RED) 12.Contents Boxes 1. 3. 6. 9. Pandemic influenza – the H1N1 threat 21. Reaching out to communities 14. The future of immunization 18. What it takes to run a successful national immunization programme 15. Mass mobilization to extend the reach of immunization 13. 4. 2. a different disease X . Strengthening health systems – the six building blocks 11. 5. A new meningococcal vaccine to control meningitis in Africa 22. Pandemic influenza – the H5N1 threat 20.

Status of elimination of maternal and neonatal tetanus XI . 7. 2004 Quantities of WHO-prequalified vaccines offered to UNICEF Global three-dose DTP coverage for 1980–2007 and goals for 2008–2010 Immunization coverage and density of health workers Countries implementing the RED strategy in 2005 More comprehensive health centres have better vaccination coverage Relation between the number of WHO Member States using hepatitis B vaccine and the UNICEF weighted average price for the monovalent vaccine 6 7 30 43 46 51 63 77 84 110 125 148 9. Trends in global mortality in children under five years old Leading causes of vaccine-preventable death in children under five years old. Government funding of vaccines for routine immunization. 5. Countries introducing Hib vaccine 1997 to 2008 11. Estimated measles deaths 2000–2007 12. 2007 10. 2. 6. 8.State of the world’s vaccines and immunization Figures 1. 4. 3.

Acronyms Acronyms AIDS AMC BCG CDC cMYP CRS cVDPV DALY DTP EPI FDA GIVS GMP GNI GPEI HAV HBV Hib HIV HPV IFFIm IPV MDG MDG 1 MDG 4 MMR MNT OPV PAHO R&D RED SAGE TAT UCI UNICEF VPPAG VLP WHA WHO Acquired immunodeficiency syndrome Advance Market Commitment Bacille Calmette-Guérin [vaccine] Centers for Disease Control and Prevention Comprehensive multi-year plan for immunization Congenital rubella syndrome Circulating vaccine-derived poliovirus Disability-adjusted life year Diphtheria-tetanus-pertussis [vaccine] Expanded Programme on Immunization United States Food and Drug Administration Global Immunization Vision and Strategy Good manufacturing practice Gross national income Global Polio Eradication Initiative Hepatitis A virus Hepatitis B virus Haemophilus influenzae type b Human immunodeficiency virus Human papillomavirus International Finance Facility for Immunisation Inactivated polio vaccine Millennium Development Goal The first Millennium Development Goal The fourth Millennium Development Goal Measles-mumps-rubella [vaccine] Maternal and neonatal tetanus Oral polio vaccine Pan American Health Organization Research and development Reaching Every District [strategy] WHO Strategic Advisory Group of Experts [on Immunization] Toxin-antitoxin Universal child immunization United Nations Children’s Fund Vaccine Presentation and Packaging Advisory Group Virus-like particle World Health Assembly World Health Organization XII .

State of the world’s vaccines and immunization XIII .

go to school. It prevents debilitating illness and disability. UNICEF Foreword Immunization is one of the most powerful and cost-effective of all health interventions. The World Bank Group Ann M. and improve their life prospects. and saves millions of lives every year.Foreword Margaret Chan Director-General. Veneman Executive Director. lives – giving children a chance to grow up healthy. The contribution of immunization is especially critical to achieving the goal to reduce deaths among children under five years old (MDG 4). provision of deworming medicine and bednets to prevent malaria – immunization becomes a major force for child survival. When vaccines are combined with other health interventions – such as vitamin A supplementation. WHO Graeme Wheeler Managing Director. Vaccines have the power not only to save. XIV . but also to transform. It is also key to achieving the Millennium Development Goals (MDGs) – commitments made by world leaders in 2000 to reduce poverty and improve human development.

more children are being immunized than ever before – over 100 million children a year in recent years. And more vaccines are increasingly being made available to protect adolescents and adults. prevent the leading causes of the two main child-killers – pneumonia and diarrhoea. Identifying and implementing strategies to overcome the barriers to access must be a top priority. Innovative funding mechanisms are being put in place to help developing countries increase immunization coverage and provide new vaccines that can save even more lives. Pneumococcal and rotavirus vaccines. Governments too have stepped up to the mark. efforts have been scaled up to meet the MDGs and the supporting goals of the Global Immunization Vision and Strategy (GIVS). These include vaccines that protect against life-threatening diseases such as influenza. Despite the progress. more must be done to target the 24 million children. With financial support from the GAVI Alliance and other partners. and cancers that occur in adulthood. Many governments are demonstrating strong and effective leadership and national ownership of their immunization programmes – a key requisite for ensuring the long-term sustainability of immunization investments. who are proving difficult to reach with vaccines. New and improved vaccines are urgently needed to prevent the unacceptable toll XV . given the right of every child to protection from preventable diseases. These are impressive achievements. Their introduction provides an opportunity to scale up the use of other interventions for the prevention and treatment of pneumonia and diarrhoea to achieve better overall disease control. At the same time. developed by WHO and UNICEF. now available to GAVI-eligible countries. But they need to be sustained and improved. access to vaccines and immunization is becoming more equitable. with increasing spending on vaccines and immunization since the year 2000.State of the world’s vaccines and immunization Since 2000. mainly in developing countries. meningitis.

and the development of new vaccines that could save millions of additional lives every year does not slow down. Veneman Executive Director. These are promises to be kept. This report is a call to action to governments and donors to sustain and increase funding for immunization in order to build upon the progress made so far in meeting the global goals. UNICEF XVI . Margaret Chan Director-General. Poverty. Continued investments are essential to ensure the breakthroughs needed in the research and development (R&D) of these next-generation vaccines. and AIDS. The World Bank Group Ann M. and premature deaths have not gone away. Major efforts will be needed in the coming months and years to ensure that. illness.Foreword of sickness and deaths from diseases such as malaria. a decline in international development assistance. an increase in poverty. hard-won gains in immunization are protected. Experience shows that economic crises can lead to government cuts in social sector spending. tuberculosis. The global goals have not changed. Equity and social justice are still to be achieved. The price of failure will be counted in children’s lives. This must not be allowed to happen again. and an upsurge in deaths among children under five years old. WHO Graeme Wheeler Managing Director. during the current global financial and economic crisis.

State of the world’s vaccines and immunization Executive summary XVII .

making this decade the most productive in the history of vaccine development. and the integrated delivery of essential health interventions. More money is available for immunization through innovative financing mechanisms. Yet despite extraordinary progress in immunizing more children over the past decade. meningitis. More vaccines have been developed and others are already in the late stages of clinical trials. more vaccines are available and more lives are being saved. knowledge. And more creative energy. and technical know-how is being put to use through the development of public-private partnerships – forged to help advance the immunization-related global goals. And the benefits of immunization are increasingly being extended to adolescents and adults – providing protection against life-threatening diseases such as influenza. in 2007. immunization has moved centre stage as one of the driving forces behind efforts to meet the Millennium Development Goals (MDGs) – in particular. XVIII . fragile states. deprived urban settings. 24 million children – almost 20% of the children born each year – did not get the complete routine immunizations scheduled for their first year of life.Executive summary Overview Since the Millennium Summit in 2000. and strife-torn regions – is essential if the MDGs are to be equitably met. Reaching these vulnerable children – typically in poorly-served remote rural areas. In developing countries. increased immunization coverage. the goal to reduce deaths among children under five years old (MDG 4). For the first time in documented history the number of children dying every year has fallen below 10 million – the result of improved access to clean water and sanitation. and cancers that occur in adulthood. More children than ever before are being reached with immunization: over 100 million children a year in 2005–2007.

tuberculosis. new initiatives have been launched to accelerate both the development and deployment of new life-saving vaccines. and if countries could raise vaccine coverage to a global average of 90%. by 2015 an additional two million deaths a year could be prevented among children under five years old. But even when the global goals have been met. success will be measured against an additional benchmark – whether the achievements are sustainable. The stakes are high. Solid building blocks are being put in place – strengthening of health systems and immunization programmes. WHO has estimated that if all the vaccines now available against childhood diseases were widely adopted. It would also greatly reduce the burden of illness and disability from vaccine-preventable diseases. new long-term global financing mechanisms. innovative and sustainable delivery strategies. Part 1 (Chapters 1–5) examines the impact of immunization on efforts to meet the MDGs. continued investments will be needed to accelerate the research and development of urgently needed vaccines against diseases such as malaria. especially the XIX . new public-private partnerships for vaccine development and immunization. This would have a major impact on meeting the global goal to reduce child deaths by two-thirds between 1990 and 2015 (MDG 4). mainly in developing countries. At the same time. In addition. and acquired immunodeficiency syndrome (AIDS). a major global push is under way to ensure that these difficult-to-reach children – most of them in Africa and Asia – are immunized.State of the world’s vaccines and immunization In response. and contribute to improving child health and welfare. This edition of the State of the world’s vaccines and immunization focuses on the major developments in vaccines and immunization since 2000. as well as reducing hospitalization costs. which together account for over four million deaths a year and a high burden of disease. and improved advocacy and communication strategies – to ensure that long-term progress is not sacrificed for short-term gains.

With an overriding focus on the need to ensure equity in access to vaccines and immunization. the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) published the Global Immunization Vision and Strategy (GIVS) for the decade 2006–2015. Part 2 focuses on over 20 vaccine-preventable diseases and reviews progress since 2000 in efforts to protect populations against these diseases through the use of vaccines. which committed the international community to eight development goals aimed at reducing poverty and improving human development. One of these goals calls for a massive reduction in deaths among children under five years old – a two-thirds drop in the under-five mortality rate between 1990 and 2015. it looks beyond 2015 to likely changes in the immunization landscape. It looks at the development and use of vaccines and at the safeguards that have been put in place to ensure their safety. leaders of more than 190 countries signed the United Nations Millennium Declaration.Executive summary goal to reduce deaths among children under five. In 2005. Finally. and quality. and efforts to ensure that the achievements are sustainable in the long term. and looks at the cost of scaling up immunization coverage to meet these goals. Immunization and human development Chapter 1 outlines the progress in vaccines and immunization over the past decade against the backdrop of a changing health and development landscape. In September 2000. It sets out the progress and challenges in meeting the immunization-related global goals. the strategy sets out the steps that the immunization community needs to take in order to contribute fully to the attainment XX . Most of the effort in achieving these goals is focused on developing countries. efficacy. which account for over 90% of deaths among children in this age group.

as far as possible. the global vaccine market has almost tripled – reaching over US$ 17 billion in global revenue by mid-2008. The first decade of this century has been the most productive in the history of vaccine development. integrating immunization with other components in the health system context. A new chapter in vaccine development Chapter 2 highlights the surge in vaccine development over the past decade and outlines the reasons for this. more costly vaccines. and making the vaccine industry one of the fastest growing sectors of industry. which account for more than half of the total value of vaccine sales worldwide. XXI . rotavirus diarrhoeal disease. The global goals have added a sense of urgency to vaccine-related activities and spurred renewed efforts to complete. more dynamic period. and cervical cancer caused by human papillomavirus (HPV). It documents the unprecedented growth in the volume of traditional childhood vaccines now being produced by manufacturers in developing countries. The chapters which follow chart the progress made so far in completing this agenda and in meeting the global goals. Implementing the strategy calls for four main approaches: protecting more people. introducing new vaccines and technologies. New life-saving vaccines have been developed for meningococcal meningitis. avian influenza caused by the H5N1 virus. Since the year 2000. and immunizing in the context of global interdependence. and effectiveness of vaccines. Most of this expansion comes from sales in industrialized countries of newer. pneumococcal disease. what the GIVS refers to as “the unfinished immunization agenda”. safety.State of the world’s vaccines and immunization of the MDG mortality reduction targets. The vaccine industry is experiencing a new. And it reports on progress in efforts to assure the quality.

and new funding resources and mechanisms (see Chapter 4). by post-marketing testing of vaccine batches for consistency of the production process. vaccine supply remains heavily reliant on a limited number of vaccine manufacturers and continued vigilance is needed. Making sure that vaccines are safe. after licensure.Executive summary The recent surge in new vaccine development is largely due to three key factors: the use of innovative manufacturing technology. growing support from public-private product development partnerships. the demand for these traditional vaccines has also grown since 2000. Since the early 1990s. the vaccine market has changed. usually in the laboratory. XXII . followed. UNICEF – which procures vaccines to reach more than half (55%) of the world’s children – established the Vaccine Security Strategy to ensure the uninterrupted and sustainable supply of vaccines that are both affordable and of assured quality. It continues with clinical testing for safety and efficacy in humans. It begins with the “infancy” of the vaccine. In response. as well as surveillance to identify any potential cases of vaccinerelated adverse events. there has been unprecedented growth in the capacity of manufacturers in developing countries to contribute to the supply of the traditional childhood vaccines. Overall. and a reduction in excess production capacity led to a vaccine supply crisis beginning in the late-1990s. a drop in the number of suppliers in industrialized countries. effective. where its components are tested for criteria such as purity and potency. and of good quality is a pivotal element of vaccine development and deployment. While the strategy succeeded in reversing the fall-off in the supply of vaccines to UNICEF. partly to meet the massive needs of the major initiatives put in place to eradicate polio. At the same time. Growing divergence between the vaccines used in developing and industrialized countries. and reduce the burden of measles and of neonatal and maternal tetanus.

State of the world’s vaccines and immunization

Licensure, or approval for human use, is the most crucial step in the process. The official body that grants the licence – the national regulatory authority – is the arbiter of whether established standards have been met to ensure that a vaccine is of assured quality. All industrialized countries have a reliable, properly functioning vaccine regulatory system, but only about one quarter of developing countries do. The international health community has launched a series of initiatives, spearheaded by WHO, to ensure that vaccines used in national immunization programmes are “vaccines of assured quality”. The initiatives include a prequalification system established by WHO to advise UN vaccine procurement agencies on the acceptability, in principle, of vaccines available for purchase, and efforts to ensure that every country has a reliable, properly functioning national regulatory authority.

Immunization: putting vaccines to good use
Chapter 3 highlights the achievements of immunization over the past decade and reports on progress and challenges in efforts to reach more people with more vaccines, to boost immunization coverage at the district level, and to target difficultto-reach children who have not been immunized. It also sets out some of the key elements of an effective immunization programme. Over the past decade, immunization programmes have added new and underused vaccines to the original six – diphtheria, tetanus, pertussis, measles, polio, and tuberculosis – given to young children. They include vaccines against hepatitis B, Haemophilus influenzae type b (Hib) disease, mumps, pneumococcal disease, rotavirus, rubella, and – in countries where needed – yellow fever and Japanese encephalitis.

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Executive summary

Immunization averts an estimated 2.5 million child deaths a year, but despite the successes, millions of children in developing countries – almost 20% of all children born every year – do not get the complete immunizations scheduled for their first year of life. Reaching these children will require overcoming a number of critical barriers that have slowed progress. A major barrier is the underlying weakness of the health system in many developing countries. Another is the difficulty in delivering vaccines through an infrastructure and logistical support system that is often overloaded. Yet another is a lack of understanding about the importance of vaccines – especially among the poorest populations – and a failure to actively demand access to immunization services. The threat posed by false or unsubstantiated rumours about vaccine safety is also a barrier to progress, as is the projected shortfall in funding needed to reach the global immunization-related goals (see Chapter 4). Efforts under way to overcome the barriers to expanded immunization include the use of immunization campaigns and “outreach” operations that seek out population groups not adequately covered by routine immunization programmes. In addition, special initiatives, such as the Optimize project, have been launched to help countries manage the growing complexity of immunization logistics (delivery and storage of vaccines, for example) underpinning immunization activities. The Reaching Every District (RED) strategy, launched in 2002, is designed to strengthen immunization delivery at the district level, by encouraging district-level immunization officials to adopt the principles of “good immunization practice”, such as the identification and resolution of local problems, the organization of regular outreach vaccine delivery services, and the involvement of communities in ensuring adequate functioning of immunization services. Another strategy aims to integrate immunization activities with other services provided by the health system. Any contact that a health worker has with a child or

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State of the world’s vaccines and immunization

mother at a health facility is also an opportunity to check immunization status and, if need be, to administer vaccines. Conversely, a mobile team offering immunization to a community can also distribute medicines, antimalarial bednets, and other health commodities or interventions. Community participation is a key factor in raising vaccine coverage. Creating awareness of, and public demand for, the benefits of immunization is an essential component of an active immunization programme. However, it is also important to ensure that demand can be reliably met. The availability of new vaccines against pneumococcal disease and rotavirus is expected to have a rapid and major impact in global efforts to reduce child deaths (MDG 4), prevent sickness, and, for pneumococcal disease, prevent disability. At the same time, vaccination against these diseases provides a key opportunity to actively promote the prevention and treatment of pneumonia and diarrhoea, which together account for over one third of all deaths among children under five years old. Surveillance and monitoring are the cornerstones of immunization programmes, playing a key role in programme planning, priority setting, and mobilization of resources, as well as in monitoring trends in disease burden, and assessing the impact of disease control programmes and progress towards global goals. Since 2000, the increase in data-driven immunization initiatives (such as the RED strategy) and the need for disease data to monitor the impact of new vaccines have highlighted the need to strengthen surveillance and monitoring at all levels. Disease surveillance systems are also expected to provide an early warning of impending or ongoing outbreaks of disease. The revised International Health Regulations, which entered into force in 2007, require WHO Member States to establish and maintain core capacities for surveillance at the local, intermediate, and national levels.

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Executive summary

Over the past decade, progress has been made in setting up or improving surveillance systems for vaccine-preventable diseases. An example of a high-performance surveillance system is the polio surveillance network, which enables rapid detection of polio cases worldwide, and has been expanded in some countries to include measles, neonatal tetanus, yellow fever, and other vaccine-preventable diseases. Meanwhile, as vaccine coverage has increased and the incidence of vaccinepreventable diseases has fallen – particularly in industrialized countries – there has been an increase in concern about the potential side-effects of vaccines. Making sure vaccines are made, used, and tested in accordance with internationally accepted standards is one part of the effort to reduce the likelihood of a vaccine producing an adverse event (see Chapter 2). The other part is having an efficient post-marketing surveillance and investigation system in place that will rapidly pick up and verify any rumours or reports of adverse events allegedly related to the use of a vaccine. Most industrialized countries have such a system, but many developing countries lack the resources or experience required. To address this, WHO has established a Global Advisory Committee on Vaccine Safety, made up of independent experts, to assess and respond to reports and rumours about vaccine safety. In addition, in 2009, WHO established a Global Network for Post-marketing Surveillance of Newly Prequalified Vaccines which have recently been introduced into national immunization programmes.

XXVI

and examines the response of both new and established sources of immunization funding. new and underused vaccines cost more than the traditional vaccines. Fourth.50–5.State of the world’s vaccines and immunization Investing in immunization Chapter 4 looks at the costs involved in scaling up immunization since 2000. and yellow fever. GAVI Alliance (formerly known as the "Global Alliance for Vaccines and Immunisation") support for immunization enabled many low-income countries to strengthen their routine vaccine delivery systems and introduce underused vaccines. A third is the “hidden” costs of introducing a new vaccine into a national immunization programme. Beyond 2010. such as the costs of staff training. For a start. public information. Immunization is among the most cost-effective health interventions. XXVII . total annual expenditure on immunization in developing countries averaged out at an estimated US$ 3. their costs should fall. There are several reasons for these rising costs. the figure had risen only slightly to about US$ 6. Hib. requiring expanded storage facilities and more frequent delivery of supplies. Not unexpectedly. the average cost of immunizing a child is projected to rise to about US$ 18.00 per live birth.00 per live birth. such as hepatitis B.00 per live birth. but what does it cost. By 2000.00 per live birth. By 2010. is the increased cost of providing immunization services for difficult-to-reach children. immunization expenditure began to rise again. scaling up vaccine coverage with new vaccines – such as pneumococcal and rotavirus vaccines – to meet the MDGs and the GIVS goals is likely to raise the cost above US$ 30. and is the investment worth making? In the 1980s. and expanded surveillance and monitoring. although as the market and demand expands. Since 2000. A second reason is that the increased quantities of vaccines place considerable pressure on the existing vaccine supply chain.

which cost US$ 100 million over a 10-year period up to 1977. the global eradication of smallpox.Executive summary Meeting the goals of the GIVS will mean protecting children against 14 diseases – diphtheria. meningococcal disease. tetanus. The classic example of prevention of serious disability has been the prevention of paralytic polio in hundreds of thousands of children since the advent of the Global Polio Eradication Initiative (GPEI). Among children who survive an episode of pneumococcal meningitis. and (where needed) Japanese encephalitis and yellow fever. vaccine-preventable diseases also constitute a major cause of illness and long-term disabilities among children both in industrialized and developing countries. For example. including US$ 35 billion for the 72 countries that have a gross national income (GNI) per capita below US$ 1000 (as of 2006). Of the new vaccines. pneumococcal disease. a large XXVIII . it is estimated that immunization could prevent an additional two million deaths a year in this age group – making a major contribution to the achievement of MDG 4. has resulted in savings of US$ 1. the pneumococcal vaccine has been shown to be associated with a 39% reduction in hospital admissions due to pneumonia from any cause. Hib. tuberculosis. Is the investment worth making? Data on the cost-effectiveness of immunization confirm that it is. rubella. polio.and lower-middle-income Member States between 2006 and 2015.3 billion a year in treatment and prevention costs ever since. If all countries immunize 90% of children under five years of age with these vaccines. measles. These countries are eligible for GAVI Alliance funding and have received support for introducing underused and new vaccines as well as support to strengthen their immunization systems. A WHO-UNICEF analysis published in 2008 estimated how much it would cost to attain the GIVS goals in 117 WHO low. The total bill came to US$ 76 billion. pertussis. hepatitis B. In addition to being a significant contributor to childhood deaths. rotavirus.

State of the world’s vaccines and immunization

proportion are left with long-term disabilities. Similarly, the rotavirus vaccine has been shown to reduce clinic visits and hospitalizations due to rotavirus diarrhoea by 95%. Thus, while the impact on child deaths alone would be sufficient justification for the use of vaccines in children in developing countries, the reduction of long-term disability among children and the savings from reductions in clinic visits and hospitalization more than justify their use in children everywhere. Immunization has other far-reaching benefits beyond the positive impact on individual and community health. A recent study by a Harvard School of Public Health team found that by keeping children healthy and in school, immunization helps extend life expectancy and the time spent on productive activity – thereby contributing to poverty reduction (MDG 1). Who pays the bill and how? In 2007, WHO’s 193 Member States were funding an average 71% of their vaccine costs (33% in low-income countries). Of these, 86% of countries reported having a separate line item for vaccines within their national budget – a measure associated with increased budget allocations to vaccines and immunization and with long-term political commitment to immunization. From the WHO-UNICEF costing analysis, it is estimated that 40% of the costs of immunization for the period 2006–2015 will be met by national governments. Since 2000, immunization funding from multilateral, bilateral, and other funding sources has increased by 13% (not adjusted for inflation). At the same time, there has been a shift both in the way funds are channeled and in the way they are used. At the global level, some bilateral donors have increasingly used the GAVI Alliance as a channel for funding. At a country level, there has been a move away from a project-based approach to the use of broad-based funding mechanisms to support the health sector as a whole.

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Executive summary

Health and immunization systems benefit substantially from targeted immunization efforts such as the GPEI. A substantial proportion of the investment in polio eradication has been spent on strengthening routine immunization and health systems, and on achieving the goals of the GIVS. In recent years, several innovative public-private partnerships and new financing mechanisms have been introduced to provide predictable and sustainable external financial support to help countries meet the immunization-related global goals. The GAVI Alliance is a public-private global health partnership that provides support to countries with a GNI per capita below US$ 1000, to strengthen their health systems and immunization programmes, increase routine immunization coverage, and introduce new and underused vaccines. As of the end of 2008, the Alliance had received a total of US$ 3.8 billion in cash and pledges from public and private sector donors, and disbursed US$ 2.7 billion to eligible countries. Over the period up to 2015, the Alliance has an estimated US$ 3 billion funding gap out of the estimated US$ 8.1 billion total funding needed. During its first phase (2000–2005), the GAVI Alliance focused on the introduction of new and underused vaccines (hepatitis B, Hib, and yellow fever). During the second phase (2006–2015) support is being expanded to new vaccines (rotavirus and pneumococcal vaccines). In addition, the GAVI Alliance Board has approved for possible future support a further package of vaccines to be offered to countries, including HPV, Japanese encephalitis, rubella, and typhoid. To meet concerns about financial sustainability, all GAVI-supported countries were required to prepare a comprehensive multi-year plan for immunization, or cMYP. In 2007, the Alliance introduced a new co-financing system, which requires countries to pay a gradually increasing share of the cost of their new vaccines, based on a country’s GNI per capita. By the end of 2008, 30 countries had begun using this system to pay for the introduction of the pentavalent vaccine (DTP-Hepatitis B-Hib), rotavirus vaccine, and pneumococcal vaccine.

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State of the world’s vaccines and immunization

A new, innovative source of funding is the International Finance Facility for Immunisation (IFFIm), which uses long-term legally binding commitments by donors to issue bonds on the international capital markets. The sale of these bonds provides cash that can be used by the GAVI Alliance to fund programmes. As of early 2008, the bonds had raised US$ 1.2 billion from investors worldwide. Another innovative financing mechanism is the Advance Market Commitment (AMC) – a new approach to public health funding designed to accelerate the development and manufacture of vaccines for developing countries. Conceived in 2005 by the Center for Global Development, a pilot AMC for pneumococcal vaccine was launched in 2007 by the Governments of Canada, Italy, Norway, the Russian Federation, and the United Kingdom of Great Britain and Northern Ireland; the Bill & Melinda Gates Foundation; the GAVI Alliance; and the World Bank; with an investment of US$ 1.5 billion. The good news is that more investment is being made in immunization and projected trends indicate growing financing in the future. Yet, without further growth, expected future funding from governments and donors will not be enough to sustain the gains already achieved towards GIVS goals and the MDGs. “The real challenge,” the WHOUNICEF 2008 analysis report concluded, “will hinge on how national governments, and the international community at large manage their roles and responsibilities in reaching and financing the goals of the GIVS until 2015.”

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Executive summary

The view from the future
Chapter 5 looks forward over the next decade and considers how the immunization landscape may have changed by 2020. By the 2020s, the strategies put in place to reach the MDGs should have brought deaths among children under five years old to an all-time low. Polio should be eradicated, and measles eliminated in all countries. Neonatal and maternal tetanus should no longer be exerting such a heavy toll on babies and mothers, and today’s underused vaccines (against Hib disease, hepatitis B, and yellow fever) may have rid the world of the lethal burden of these diseases. The use of new vaccines against pneumococcal, rotavirus, meningococcal, and HPV disease may have inspired a new, more ambitious set of international health and development goals. Vaccines may have been developed that can turn the tide against malaria, tuberculosis, and AIDS. Over the next decade or so, an increasing number of developing countries will be using the new vaccines coming onto the market. Some of these (such as the HPV vaccine) will be given to adolescents; others (such as the influenza vaccine) will be given to adults. However, there is as yet little knowledge or experience of reaching older age groups in developing countries, except through special immunization campaigns. School-based immunization is one possible solution, especially since school attendance is increasing in many developing countries. New vaccine delivery systems are also anticipated. Devices that use needles may have been largely replaced with new approaches such as aerosol formulations sprayed in the nose (already available for an influenza vaccine) or lungs (currently being tested for several vaccines); adhesive skin patches; drops under the tongue; and oral pills.

XXXII

Despite this. But the world will face fresh challenges. public demand for vaccines and immunization is expected to rise. When supplied with a vaccine vial monitor to check exposure to heat. And over the next two decades.State of the world’s vaccines and immunization Another potential breakthrough is the development of an increasing number of vaccines that are heat-stable. energy. New public-private partnerships and product development groups are becoming important drivers of vaccine development and deployment. their contribution to global vaccine supply may be on a more equal footing with the industrialized countries – a development likely to increase competition. Moreover. Climate change looms large and is likely to alter the epidemiological landscape in which vaccines and immunization operate – bringing new health challenges. XXXIII . enthusiasm. which threaten to unravel hard-won gains. these vaccines should be available for use outside the cold chain – greatly relieving the pressure on the cold chain and logistics. and dedication. countries throughout the world are facing economic recession and financial turmoil. As it does so – and far into the future – there is every reason to believe that immunization will continue to be a mainstay of public health. Vaccines can make a major contribution to achieving the MDGs. Vaccine development is in a dynamic phase and more people are being reached with vaccines. the overall picture is one of cautious optimism. By 2020. manufacturers in developing countries may have acquired the capacity to make their own state-of-the-art vaccines tailored to meet their own specific needs. As of early 2009.

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State of the world’s vaccines and immunization Part 1: Progress and challenges in meeting global goals 1 .

Ch t Chapter Chapter 1. Immunization and human development ha n hu human development m n 2 .

State of the world’s va nes an imm zation State of the world’s vaccines and immunization ate t he orld’s vaccines and immunization s ac e mu a Chapter 1 Immunization and human development 3 .

and deaths among children under five years old. especially the goal to reduce deaths among children under five years old (MDG 4). disability. • Vaccines prevent more than 2. Immunization and human development Key messages • Immunization is key to achieving the Millennium Development Goals (MDGs). 4 . • The introduction of new vaccines against pneumococcal disease and rotavirus could have a rapid impact – within three to five years – on reducing the high toll of sickness. • Available vaccines could prevent an additional two million deaths a year among children under five years old.5 million child deaths a year. • Over 100 million children are immunized every year before their first birthday. • Around 24 million children under one year old – almost 20% of the children born every year – are not being reached with vaccines.Chapter 1.

such as the Global Fund to Fight AIDS. Too many problem areas. and the International Health Partnership. leaders of more than 190 countries signed the United Nations Millennium Declaration. Investment in health has taken off in earnest within the donor community – a trend reflected in the birth of several major global partnerships. One of the eight MDGs that emerged from the Millennium Declaration calls for a drastic reduction in deaths among children under five years of age. and premature death. specifically. Tuberculosis and Malaria. The year 2000 marked a turning point in the world’s reaction to these inequities. bringing the global average life expectancy at birth to 69 years for women and 65 years for men (2). tuberculosis. disease. which committed the international community to the task of removing the “abject and dehumanizing conditions” holding more than one billion of the world’s population in the grip of poverty. a 5 . In September of that year. Alleviating the inequity of that burden is part of the task. the GAVI Alliance. and diarrhoeal diseases account for over two million deaths (4). Inequalities and inequities still roam freely across the globe. And these are only a few examples. And every year more than half a million women – almost all (99%) in developing countries – die from pregnancy-related causes (5). disease and death among neglected population groups that is hidden beneath promising regional or national indicators of progress. Among all age groups. lower respiratory infections (mainly pneumonia) account for over four million deaths. several positive changes have occurred in the world of human development. and malaria kill more than four million people a year. are still waiting for change. the number of children under five years old dying every year has fallen below 10 million (3). Reducing the toll of deaths among children under five years old is another. AIDS. People are living longer. For the first time in documented history. though. About nine million children under five years old are still dying every year – most of them in developing countries.State of the world’s vaccines and immunization Since the turn of the century. Yet another is to seek out and remedy the preventable poverty. Undernutrition is an underlying factor in about one third of all deaths in children.

0 14.1 12. schooling. Immunization and human development two-thirds drop in the under-five mortality rate between 1990 and 2015 (MDG 4). 6 .3 1970 1980 1990 1995 2000 2005 2007 2015 Year Source: UNICEF Programme Division. Figure 1 Trends in global mortality in children under five years old 18 Number of deaths (millions) 16 14 12 10 8 6 4 2 0 17. where developing countries – with 85% of the world’s population – account for only 12% of global spending on health (6).5 9. and other essentials that are mostly taken for granted in the better-off parts of the world. antimalarial bednets.6 9. not only with vaccines. especially the goal to reduce deaths among children under five years old (MDG 4). sanitary living conditions. Most of the effort in achieving this goal focuses on developing countries.Chapter 1. clean water. Reducing these deaths means providing more children.8 11. which account for over 90% of child deaths.2 4. 2009 Immunization is key to achieving the MDGs. It also means addressing the global imbalance in spending on health.9 10. but also with life-saving drugs.

and poverty. 2004 estimates. the time is ripe for accelerating the role of life-saving 7 .State of the world’s vaccines and immunization Figure 2 Leading causes of vaccine-preventable death in children under five years old. Source: (4) One change. that could seriously imperil efforts to battle inequity. death. Pneumococcal diseases and Hib estimates are for the year 2000. Much will depend on the continued commitment of governments and the international community to sustain and build on their efforts to improve child survival and meet the MDGs. is the collapse of global financial markets in the last months of 2008. and the economic slowdown that has since swept over the world. preventable disease. With the renewed energy and enthusiasm that now pervades the vaccine landscape. Vaccines and Biologicals estimates based on Global Burden of Disease. United Nations Secretary-General Ban Ki-moon has expressed deep concern about the impact of the crisis “particularly on the poorest of the poor and the serious setback this is likely to have on efforts to meet major goals”. however. 2004 800 Number of deaths worldwide (thousands) 700 600 500 400 300 200 100 0 Pneumococcal Rotavirus* diseases* Measles Hib* Pertussis Tetanus (neonatal and non-neonatal) * WHO/Department of Immunization.

tetanus (including neonatal tetanus through immunization of mothers). to mention just three. These vaccines are preventing more than 2. Immunization and human development vaccines and other linked health interventions in global efforts to achieve the MDGs. 8 . Vaccines and Biologicals. 24 million children are not being reached with vaccines: in 2007. polio. pertussis. At the same time. compared with 2% in industrialized countries. Most of these 24 million unimmunized or incompletely immunized children live in the poorest countries. efforts are needed to ensure that the benefits of immunization are increasingly extended to adolescents and adults. which affect millions of people every year and contribute to increasing poverty. All countries have national immunization programmes. This estimate is based on assumptions of no immunization and current incidence and mortality rates in children not immunized (World Health Organization. and armed conflict. but have not given priority to. hepatitis B. Other unimmunized children live in countries that can afford. over 10% of children under one year old in developing countries were not receiving even one dose of DTP vaccine. Department of Immunization. measles. unpublished). and AIDS. to protect against diseases such as influenza. diphtheria.Chapter 1. and in most developing countries. and Hib. tuberculosis. However. ongoing vaccine research and development efforts must be intensified to accelerate the development of urgently needed vaccines against diseases such as malaria. children under five years old are immunized with the standard WHOrecommended vaccines that protect against eight diseases – tuberculosis. difficult geographical terrain. meningitis. acquiring or maintaining the infrastructure and human resources required to deliver immunization. In addition. and vaccine-preventable cancers that occur in adulthood.5 million child deaths each year. where many factors combine to thwart attempts to raise vaccine coverage rates – fragile or non-existent health service infrastructure. Today. over 100 million children under one year of age are immunized every year with the required three doses of diphtheria-tetanus-pertussis (DTP) vaccine.

as well as in major disease-defeating drives. Manufacturers based in industrialized countries are 9 . and yellow fever vaccines). Failure to reach these different groups of children with vaccines is jeopardizing the massive efforts and funding being invested in expanding the use of currently underused vaccines (such as the Hib. such as eradicating polio. Good news comes also from the vaccine development area. and eliminating maternal and neonatal tetanus. reducing child deaths from measles. beyond the reach of routine immunization. The good news is that strategies are being implemented to overcome these obstacles to immunization. Since 2000. Manufacturers in developing countries are emerging as a significant presence on the vaccine market. hepatitis B. Nurse Justina Munoz Gonzalez about to vaccinate four-month old Olga Damaris outside her home near the remote village of San Pablo near Murra in the Nueva Segovia state of Nicaragua. including immunization.State of the world’s vaccines and immunization And others are refugees or homeless children. with a perceptibly positive impact on the affordability of vaccines and the sustainability of vaccine supply. Some strategies aim at strengthening the ability of health systems to deliver health care. others use immunization campaigns and similar approaches to bring immunization to more people in districts where vaccine coverage is low. the global vaccine supply landscape has changed. for example.

WHO estimated that if all the vaccines currently available against childhood diseases are widely adopted. underpinning the new vaccine landscape is an influx of new financial resources and an array of new strategies and mechanisms for sustaining and managing these resources. and human papillomavirus (HPV). and if immunization programmes can raise vaccine coverage to a global average of 90%.Chapter 1. new vaccines have become available that protect against three organisms – the pneumococcus. the development of new vaccines. vaccines would prevent an additional two million deaths a year among children under five by 2015 – making a major contribution to MDG 4. Immunization and human development expanding their presence in developing countries and are working increasingly with international health organizations to make vaccines that are designed for use in developing countries and affordable by these countries. for pneumococcal disease. And. and assumptions of no immunization and current incidence and mortality rates in children not immunized. and other considerations. rotavirus. supply. most encouragingly.3 million deaths among children under five years old – 12% of all deaths among this age group – as well as high rates of sickness and. are receiving a substantial boost from more than a dozen new public-private partnerships created specifically for this purpose. sustainability. however. In addition. This projection is based on unpublished WHO estimates of the expected future cohort of children under five. For any country. staff training. The overall effect of these changes is to stimulate and revitalize all facets of the vaccine arena – demand. However. etc.). and efforts to put these vaccines into use in the poorer countries. immunization – even with the addition of the new. pneumococcal disease and rotavirus diarrhoea together account for 1. more costly vaccines – remains one of the most 10 . disability. and use. the decision to adopt a new vaccine cannot be taken lightly: there are issues of cost. Over the past decade. logistics (storage space and transportation. While HPV is a cause of premature deaths from cancers that occur in adulthood. In a recent analysis (7).

mortality due to measles will have been reduced by 90% compared to the 2000 level. Immunization with newly introduced vaccines will have been offered to the entire eligible population within five years of the introduction of these new vaccines in national programmes. Global childhood morbidity and mortality due to vaccine-preventable diseases will have been reduced by at least two thirds compared to 2000 levels. Box 1 Global Immunization Vision and Strategy (GIVS) goals By 2010 or earlier: • Increase coverage. Globally. • Reduce measles mortality. Every person eligible for immunization included in national programmes will have been offered vaccination with vaccines of assured quality according to established national schedules. in 2005. supported by laboratory confirmation where necessary. The challenge is to get vaccines into use in the countries where they are most needed. and to do so quickly. • Ensure capacity for surveillance and monitoring. Responding to this challenge.State of the world’s vaccines and immunization cost-effective health interventions. All countries will have developed the capacity at all levels to conduct case-based surveillance of vaccinepreventable diseases. The vaccination coverage goal reached in 2010 will have been sustained. 11 . • Reduce morbidity and mortality. • Ensure access to vaccines of assured quality. WHO and UNICEF published the Global Immunization Vision and Strategy (GIVS) for the decade 2006 to 2015 (8). in order to measure vaccine coverage accurately and use these data appropriately. • Introduce new vaccines. By 2015 or earlier: • Sustain coverage. Countries will reach at least 90% national vaccination coverage and at least 80% vaccination coverage in every district or equivalent administrative unit.

It is unlikely. All national immunization plans will have been formulated as an integral component of sector-wide plans for human resources. iii) integrating immunization with other components in the health systems context. If the optimism turns out to be justified. costed and implemented so as to ensure that human resources. Immunization and human development • Strengthen systems. 12 . and where “solidarity among the global community guarantees equitable access for all people to the vaccines they need”. The GIVS strategy foresees a world in which “every child. however. Source: (8) Equality and equity are central to the GIVS vision. Implementing the strategy calls for four main approaches: i) protecting more people. and despite the economic downturn. the vaccine community allows itself a degree of cautious optimism. that the unfinished agenda will ever be finished as new infections will undoubtedly emerge.Chapter 1. Nevertheless. new vaccines will continually be needed. vaccines and immunization will have a good chance of realizing their potential to help make the world a safer. All national immunization plans will have been formulated. • Assure sustainability. financing and logistics. and iv) immunizing in the context of a globally inter-linked. and new global crises – such as the financial crisis that has engulfed the world since the last months of 2008 – may threaten the sustainability of funding for vaccine-related activities. but also for future generations. place for all – not only for people alive today. ii) introducing new vaccines and technologies. what the GIVS calls the “unfinished immunization agenda”. funding and supplies are adequate. more equitable. new ways of overcoming obstacles to making use of new vaccines will have to be found. adolescent and adult has equal access to immunization”. interdependent health and development system. This report chronicles the efforts being made since 2000 to complete. as of early-2009. as far as possible.

and cost-saving.State of the world’s vaccines and immunization Box 2 What’s so special about vaccines? Vaccines are special. disability (from pneumococcal disease). Not surprisingly. it is estimated that new vaccines against pneumococcal disease and rotavirus could have a rapid impact – within three to five years – in reducing the high burden of sickness. Table: The ten most cost-effective solutions to major global challenges. and even entire populations (the eradication of smallpox is a case in point). Third. continues to be good value for money (see Chapter 4). Copenhagen Consensus 2008 Solution 1 2 3 4 5 6 7 8 9 10 Micronutrient supplements for children (vitamin A and zinc) The Doha development agenda Micronutrient fortification (iron and salt iodization) Expanded immunization coverage for children Biofortification Deworming and other nutrition programmes at school Lowering the price of schooling Increase and improve girls’ schooling Community-based nutrition promotion Provide support for women’s reproductive role Challenge Malnutrition Trade Malnutrition Diseases Malnutrition Malnutrition & Education Education Women and development Malnutrition Women and development Source: The Copenhagen Consensus 2008 (10) 13 . Second. Today. vaccines are both life. a panel of distinguished economists convened by the Copenhagen Consensus Center – an international think-tank that advises governments and philanthropists how best to spend aid and development money – put expanded immunization coverage for children in fourth place on a list of 30 costeffective ways of advancing global welfare (see Table). they help healthy people stay healthy and in doing so help to remove a major obstacle to human development. even with more expensive vaccines. for example. in 2008. they benefit not only individuals but also communities. Finally. Recent data show that immunization. their impact on communities and populations is more rapid than that of many other health interventions: between 2000 and 2007. global mortality from measles was reduced by 74% (from 750 000 to 197 000 (9)). Furthermore. and deaths among children under five years old. First. for most vaccines. unlike many other health interventions. the United States’ Centers for Disease Control and Prevention (CDC) put vaccination at the top of its list of ten great public health achievements of the 20th century.

Imm Chapter 1.Chapte Chapter 1. Immunization and human development p Immunization development evelopmen lopment o 14 4 .

State of the world’s vaccines and immunization Chapter 2 A new chapter in vaccine development 15 15 .

• Systems have been put in place to ensure the safety. 16 . and quality of all vaccines.Chapter 2. • Most low-cost traditional vaccines are now produced by vaccine manufacturers in developing countries. • New life-saving vaccines have been developed. and others will soon be available. tuberculosis. and AIDS. • New vaccines are urgently needed to reduce illness and deaths from high-burden diseases such as malaria. • Public-private partnerships are accelerating the availability of new vaccines. A new chapter in vaccine development Key messages • The first decade of the 21st century has been the most productive in the history of vaccine development. effectiveness.

about 30 of these candidates aim to protect against diseases for which there are no vaccines currently available (11). Another stimulus to vaccine development has come from public-private product development partnerships.State of the world’s vaccines and immunization A vaccine boom Since the turn of the century. the vaccine industry has put 25 new vaccine formulations on the market – several specifically designed for use in age groups (adolescents and elderly people. have played a substantial role in the current upswing in productivity of the global vaccine industry. of which half have appeared since the year 2000. Two diseases have been added to the list of vaccine-preventable diseases. that have in the past not been priority targets for vaccine developers. the mood in the vaccine community has been decidedly enthusiastic – and for good reason. an increase in the use of innovative vaccine technology by the R&D-based vaccine industry. the total number of vaccine “products” (all formulations combined) had reached a record of over 120. for example) and in populations (in developing countries. Explaining the new momentum Compared with the recent past. and a greater sharing of technology between manufacturers in industrialized countries and emerging market producers. according to recent unpublished data. In addition. The current surge in vaccine development is also the result of new funding resources and new funding mechanisms (see Chapter 4). Furthermore. for example). 17 . Enthusiasm also stems from the exceptionally large number of candidate vaccines in the late stages of research and development (R&D) – over 80 according to recent unpublished data. whose numbers have grown significantly over the past decade: there are now close to 30. making the first decade of this century the most productive in the history of vaccine development. By the end of 2008. bringing the total number to a record of over 30.

has been achieved in the face of several constraints.Chapter 2. Technology comes of age Vaccine industry executives attribute much of the surge in new vaccine development to the “maturing” of breakthroughs in biotechnology that occurred in the 1980s and 1990s. require the application of innovative research and manufacturing technologies that have only recently become available (see Box 3). The unparalleled growth in vaccine development. Vaccine manufacturers also face a high risk of failure: only one in four to five candidate vaccines ends up as a marketable vaccine (12). A recent analysis (13) points to a “technological revolution [which has] removed most of the technical barriers that formerly limited vaccine developers” and to the fact that “biotechnology in the current era of vaccine development has enabled totally unprecedented advancements in the development of vaccines”. some vaccines under development against particularly complex pathogens. such as the malaria parasite and the AIDS virus. The rising cost of producing a vaccine – upwards of US$ 500 million (1) – is also a constraining factor. 18 . A new chapter in vaccine development Their arrival on the scene reflects a new concern of the global health and development community over the unmet needs of developing countries for vaccines and immunization. due partly to increasingly stringent regulatory oversight and the resulting greater industry investment in more complex and more costly manufacturing technology. however. For example.

which are then screened for their ability to produce protective immune responses. it turns into a different biological life-stage. This antigenic variability occurs not only within a single person but also between different people. its transmissibility. To date. more than a dozen genetic HIV subtypes and up to 24 different recombinant forms have been reported. Reverse vaccinology The science of genomics has provided scientists with the complete genome sequences of more than 300 bacterial species – most of them responsible for human disease (14). As it passes through the different anatomical parts of its human and mosquito hosts. One of the most devastating properties of HIV is that it attacks its host’s immune system – the very system designed to protect the human host against infections.State of the world’s vaccines and immunization Box 3 AIDS and malaria defy science The plasmodium parasite that causes malaria and the human immunodeficiency virus (HIV) that causes AIDS are both adept at evading human immune defences. and different geographical locations. HIV strains can easily recombine giving birth to complex recombinant or mosaic viruses – called “circulating recombinant forms” or CRFs – some of which can play an important role in regional sub-epidemics. Researchers use an organism’s genome to pick out the genes most likely to correspond to conserved antigens that could be used in a vaccine. as well as vaccine development remains unclear and complicates significantly the development of broadly effective novel prevention tools. The malaria parasite also has an additional immunity-evading capability. presenting its host’s immune system each time with a different set of antigens. the genes can be combined and inserted into a different. This 19 . Both are able to alter the configuration of the immunity-stimulating molecules (antigens) they carry and that would otherwise signal their presence to their host’s immune system. different population groups. The impact of such enormous genetic variability on the biological properties of the virus. pathogenic properties. HIV is characterized by extremely high levels of genetic variability and rapid evolution. rapidly multiplying organism – such as yeast – to produce candidate antigens. Once identified.

some of which are currently in the late stages of clinical testing (for example. a candidate vaccine against group B meningococcus). and from which a limited number of antigens are isolated. conjugation allows scientists to link (conjugate) the sugar molecules on the outer envelopes of certain bacteria – such as the pneumococcus. the meningococcus. do protect young children. First used in the 1980s. unlike the older vaccines. In contrast. however. which is grown in the laboratory (a lengthy process made more complex by the fact that some pathogens cannot easily be grown in a laboratory). These are then tested for their ability to induce potentially protective immune responses. but usually failed to elicit protective immunity in children under two years of age. thereby producing a so-called “herd immunity” that protects even unvaccinated people from the pathogen. conjugate vaccines have even been shown to reduce the numbers of healthy carriers of the pathogen in a community. The new conjugate vaccines. Again. A case in point is the use of the 20 . Reverse vaccinology has not yet produced a licensed vaccine but researchers have used it to develop several candidate vaccines. and the Hib bacterium – to strongly immunogenic “carrier” proteins. In addition. Older vaccines of this type relied on the sugar molecules to stimulate immunity. Conjugation technology Conjugation technology has also spurred vaccine development. the new conjugate vaccines stimulate the type of immune cells needed to create a long-lasting memory of the pathogen: the immunity from those cells can thus be boosted by subsequent vaccine doses or by exposure to the pathogen itself. A new chapter in vaccine development approach is known as “reverse vaccinology”: it starts with a genetic blueprint of an organism and rapidly generates antigens of interest.Chapter 2. unlike the older vaccines. the more time-consuming conventional approach starts with the pathogenic organism itself.

The malaria candidate vaccine – RTS. only five of the 20 or so types of adjuvants under development have been licensed for use in vaccines administered to humans (16). measles. none of whom had ever received the vaccine (15). Recent advances in technology and research have led manufacturers 21 .State of the world’s vaccines and immunization pneumococcal conjugate vaccine in the United States of America: one year after its introduction. Adjuvants Adjuvant technology. Progress in understanding how the human immune system recognizes the molecules carried by pathogens has led to the development of a host of adjuvants. the incidence of invasive pneumococcal disease fell by 69% among vaccinated children under two years of age – but also by 32% in adults (aged 20–39 years) and by 18% among older age groups (aged over 65 years). Adjuvants are substances that help a vaccine to produce a strong protective response. too. and so on) are grown. have been used for over 50 years as “substrates” on which the viruses used to make vaccines against viral diseases (influenza. has also benefited from a 15-year research programme undertaken by its manufacturer to produce an innovative adjuvant system comprising three types of adjuvant. They can also reduce the time the body takes to mount a protective response and can make the immune response more broadly protective against several related pathogens. Several vaccine manufacturers have invested heavily in the search for safe and effective adjuvants. Up to now. notably for vaccines against pandemic influenza and HPV. Cell substrates Cells derived from humans and from animals (such as monkey kidney cells or chicken embryo cells). has evolved.S/AS01 – which is due to enter advanced (Phase 3) clinical trials in Africa in 2009.

industrialization. The ultimate aim is to find technologies that will produce greater yields of vaccine virus and facilitate their harvesting from these cell substrates. and the industrialization and commercialization of vaccines. cells from dogs. the largest Biotech companies that manage to make their way to the market are usually taken over and absorbed by Big Pharma. and are only minor players in the applied research area. As the recent case of Roche taking over Genentech in 2009 has demonstrated. rodents. They have strengthened their industrial capability and become credible players. Their main role is in vaccine evaluation. including the vaccine business. Biotechs concentrate on applied research. plants. even though their innovation potential is still limited by their regulatory environment and financial capacity. Sub-contractors are increasingly engaged in all sectors of the pharmaceutical industry.Chapter 2. Some companies have even contributed to the development of new products. Although these companies are expected to play an increasingly important role in vaccine R&D. but are increasingly outsourcing some of these functions. and clinical development up to Phase 2 clinical trials. Box 4 The role of industry in vaccine research and development The role of industry in vaccine R&D involves at least four groups of actors: Big Pharma – with regard to vaccine production – is a group of five major pharmaceutical companies. Producers in emerging markets and developing countries have in recent years become major suppliers of traditional children’s vaccines and of a few combination vaccines. insects. These firms do not invest in in-house basic research (which is conducted mainly by academic institutions). registration. This situation is likely to evolve. They constitute the main source of innovation and account for nearly 50% of Big Pharma’s financial investment in R&D. A new chapter in vaccine development to explore a broad array of new cell substrates that use. and human constraints. One major development is the emergence 22 . pre-clinical development. for example. and other living organisms. their ability to penetrate downstream functions such as Phase 3 clinical trials. financial. is often limited by structural. and marketing of vaccines. prompting Big Pharma to seek alliances and partnerships with them. Some of these substrates are “immortal” – continuous cell lines that avoid the ongoing use of animals. They are powerful engines for the development.

fundamental change will take time. according to WHO estimates of the year 2000. causes more than 14. as well as high rates of meningitisrelated disability among children who survive (including mental retardation. it is critical that non-industrial actors – while recognizing the unique role played by the vaccine industry – should be able to fully engage in dialogue and collaborate more effectively with the private sector. In the meantime. accounts annually for an estimated two million hospitalized cases of severe diarrhoeal disease in children (17) and kills an estimated 527 000 children a year.State of the world’s vaccines and immunization of large sub-contractors capable of large-scale production on behalf of Biotechs and even of Big Pharma. Although this situation is not static. and deafness). seizures. • two new vaccines against rotavirus (replacing a previous vaccine withdrawn from the market because of adverse events) – a virus which. These include: • the first conjugate vaccine against the pneumococcus. in particular in the context of public-private partnerships. Big Pharma is expected to remain a major and indispensable driver of innovation in the field of vaccines and immunization. Strategic restructuring may in the future enable some sub-contractor companies to become vaccine producers and suppliers in their own right. a bacterium which. New licensed vaccines Several new vaccines and new vaccine formulations have become available since the year 2000. This is because the companies in question have: • • • • the ability to rapidly mobilize large financial resources skilled technical and regulatory expertise in many domains a large workforce that is generally competent and well trained management tools which increase global competitiveness. 23 .5 million episodes of serious pneumococcal disease and more than 800 000 deaths annually among children under five years old. according to WHO 2004 estimates.

S/AS01 candidate vaccine against malaria go well. such as malaria and dengue. of whom more than 60% have died (19). and for over 400 reported cases among people in 16 countries as of May 2009. If Phase 3 trials of the RTS. are responsible for 70% of cervical cancer and also cause cancers of the vulva. responsible since 2003 for the deaths and culling of tens of millions of birds. a virus which causes cervical cancer. this vaccine could be licensed by 2012. According to recent unpublished data. If successful. vagina. • the first vaccines for human use against avian influenza caused by the H5N1 virus. including dengue haemorrhagic fever. head and neck. penis. and one candidate vaccine is currently being evaluated in a large-scale trial. There is no specific treatment for dengue fever – a severe influenza-like illness that can occur in more serious forms. Two candidate vaccines against dengue virus have been evaluated in children. These vaccines are not envisaged at the time of writing for use in large population groups.Chapter 2. According to GLOBOCAN estimates. another mosquito-borne disease of major public health concern. included in both vaccines. it would be the first vaccine against a parasite that causes disease in humans. The HPV genotypes 16 and 18. more than 80 candidate vaccines are in the late stages of clinical testing. A new chapter in vaccine development • the first two vaccines against HPV. there were 493 000 new cases of cervical cancer and 274 000 related deaths in 2002 (18). anus. Vaccines in the pipeline A large number of vaccine products are currently in the pipeline and are expected to become available by 2012. Several candidate vaccines are also under development against dengue. • the first DTP combination vaccines specifically formulated for adolescents and adults. A successful vaccine needs to confer 24 . About 30 of these candidate vaccines aim to protect against major diseases for which no licensed vaccines exist.

such as pneumococcal disease. 25 . However. and cholera: however. researchers are hopeful that dengue vaccines will become available in the coming years. more easily administered. Phase 3 malaria vaccine trial participants and their mothers (on bench) with Dr Salim Abdulla (standing left) and vaccination staff at the Bagamoyo Research and Training Centre of the Ifakara Health Institute in the United Republic of Tanzania. About 50 candidate vaccines target diseases for which vaccines already exist. hepatitis A. and evaluation of the vaccines is complex.State of the world’s vaccines and immunization immunity against all four circulating dengue viruses. Japanese encephalitis. and more affordable than the existing vaccines. these candidates hold the promise of being more effective.

Chapter 2. A new chapter in vaccine development

Box 5

Product development partnerships
Product development partnerships are typically not-for-profit entities mandated to accelerate the development and introduction of a product, such as a vaccine. They are funded by donors to promote research and development, often through links between developing country academic programmes, biotechnology companies, and vaccine manufacturers. Product development partnerships have encouraged investment in various aspects of vaccine development, including large-scale clinical trials of vaccines against diseases prevalent in the poorest countries of the world. Examples of product development partnerships concerned primarily with vaccine development are the: • • • • • International AIDS Vaccine Initiative (launched in 1996) Global HIV Vaccine Enterprise (launched in 2004) Aeras Global TB Vaccine Foundation (launched in 1997) European Malaria Vaccine Initiative (launched in 1998) PATH Malaria Vaccine Initiative (launched in 1999).

Product development partnerships that lean more towards vaccine introduction than development are the: • GAVI-funded Pneumococcal Accelerated Development and Introduction Plan (PneumoADIP) • Rotavirus Accelerated Development and Introduction Plan (RotaADIP) • Hib Initiative Each of these three partnerships is ending in 2009. The Meningitis Vaccine Project (launched in 2001) is involved in both vaccine development and introduction.

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State of the world’s vaccines and immunization

Supplying vaccines for a changing world

A rapidly expanding market
Over the first eight years of this century, the global vaccine market almost tripled, reaching over US$ 17 billion in global revenue by mid-2008, according to recent estimates (20). This increase represents a 16% annual growth rate, making the vaccine market one of the fastest-growing sectors of industry generally – more than twice as fast as that of the therapeutic drugs market. Most of the expansion comes from sales in industrialized countries of newer, relatively more expensive vaccines, which account for more than half of the total value of vaccine sales worldwide (20). These vaccines include the two second-generation rotavirus vaccines, two recombinant HPV vaccines, a varicella zoster (shingles) vaccine, and a conjugate pneumococcal vaccine (which alone totalled US$ 2 billion in sales between 2000 and 2007). The commercial success of these products, according to a recent vaccine market analysis (21), “is sparking renewed interest and investment in the vaccine industry, which had appeared moribund in the 1980s”.

A concentrated industry
The vaccine supply scene is dominated by a small number of multinational manufacturers based in industrialized countries. As of mid-2008, five major firms producing vaccines – all Big Pharma companies – account for more than 80% of global vaccine revenue. The remaining revenue is divided among more than 40 manufacturers in developing countries. By contrast, in terms of volume, only 14% of the vaccine required to meet global vaccine demand comes from suppliers in industrialized countries. The remaining 86% is met by suppliers based in developing countries. The striking disparity

27

Chapter 2. A new chapter in vaccine development

between revenue and volume reflects the large volume of low-cost, mainly traditional vaccines produced by these developing country suppliers, primarily for use in their own or in other low- and middle-income countries – a market that represents 84% of the world’s population. The growth in the manufacturing capacity of suppliers in developing countries is also a response to increasing demand from the two United Nations public-sector procurement entities – the Pan American Health Organization (PAHO) and UNICEF (which also buys vaccines on behalf of the GAVI Alliance). The purchases of these agencies account for about 5–10% of the value of all vaccine doses produced in the world. UNICEF alone bought 3.2 billion vaccine doses in 2007 at a value of US$ 617 million (22) – mainly the traditional vaccines intended for use in developing countries. In 2000, 39% of vaccine doses purchased by these agencies came from suppliers in developing countries. By 2007, that proportion had soared to 60%. A good part of the increase is due to the vaccine requirements of the initiatives mounted to eradicate polio, eliminate neonatal tetanus and maternal tetanus, and reduce deaths from measles.

Planning, producing, protecting
Up to the mid-to-late 1990s, manufacturers in industrialized countries were supplying UNICEF and PAHO with large volumes of vaccines at a low price for use in developing countries. Most of these vaccines were the traditional vaccines recommended by WHO’s Expanded Programme on Immunization (EPI) against the basic cluster of six childhood vaccine-preventable diseases – diphtheria, pertussis, tetanus, polio, measles, and tuberculosis. The manufacturers were able to supply these vaccines at a low price for at least three reasons. First, at that time, the richest and poorest countries were using much the same vaccines: by selling the same vaccines at higher prices to the richer countries and at lower prices to the poorer countries (i.e. via UNICEF and PAHO through a tiered, or differential, pricing arrangement), manufacturers were able to recoup their production

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State of the world’s vaccines and immunization

costs. Second, manufacturers tended to keep an excess production capacity for many of the traditional vaccines, which enabled them to supply vaccines at a low price to developing countries without having to invest in expanding production capacity. And third, up to the 1980s, there were enough vaccine suppliers to sustain competition among them, which kept vaccine prices low. The vaccine market has since changed. The three factors conducive to low vaccine prices have evaporated. No longer do industrialized and developing countries use the same vaccines. Industrialized countries increasingly favour secondgeneration vaccines such as the acellular pertussis vaccine; combination vaccines such as the measles-mumps-rubella combination; and new vaccines such as the pneumococcal conjugate or HPV vaccines. No longer do manufacturers maintain excess production capacity: supply must be equivalent to demand, since the newer vaccines are more costly to make, and too costly or too perishable to keep. And in the traditional markets, with the exception of hepatitis B, there is no longer enough competition among suppliers to keep prices down: there are now far fewer suppliers from industrialized countries than before and those that remain tend increasingly to protect their products from competition through a system of patents and royalties.

Box 6

Vaccine security
In the late 1990s, a vaccine supply crisis began, which highlighted the need for a new approach to ensure the uninterrupted and sustainable supply of vaccines of assured quality. In the run-up to this period, quantities of WHO-prequalified vaccines offered to UNICEF declined significantly, threatening immunization programmes in the 80– 100 countries supported by UNICEF procurement, including over 50% of the routine vaccine requirements for the poorest countries. With growing divergence between the vaccines used in developing and industrialized countries, some manufacturers stopped production of the traditional vaccines and supplies plummeted. A critical shortage of oral polio vaccine (OPV) for immunization campaigns signaled the need for a new approach to doing business with the vaccine manufacturers.

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Chapter 2. vaccine supply remains heavily reliant on a limited number of vaccine manufacturers and continued vigilance is needed. UNICEF procurement on behalf of GAVI increased by 76% to over US$ 230 million. with 2. The aim is to ensure the uninterrupted and sustainable supply of vaccines that are both affordable and of assured quality. Denmark. A new chapter in vaccine development In response. Figure 3 Quantities of WHO-prequalified vaccines offered to UNICEF 600 Vaccine doses (millions) 500 400 300 200 100 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year Measles Tetanus toxoid Diphtheria-tetanus-pertussis Bacille Calmette-Guérin Source: UNICEF Supply Division. But while the strategy succeeded in reversing the fall-off in the supply of vaccines to UNICEF. developed the Vaccine Security Strategy (23). 30 . providing a critical pooled procurement function securing vaccines for the world’s poorest children. 2009 Today. for example. UNICEF procures vaccines to reach more than half (55%) of the world’s children. Industry reacted positively to the changes and the trend of decreasing vaccine availability was reversed. Through its Supply Division based in Copenhagen. Procurement of OPV also remains very high. in consultation with vaccine manufacturers and partners. The Supply Division is also responsible for procuring vaccines on behalf of the GAVI Alliance. and appropriate contracts are in place. In 2007.3 billion doses of vaccine purchased for the Global Polio Eradication Initiative (GPEI) in 2007. UNICEF. UNICEF is the world’s largest vaccine buyer for developing countries. timely funding. The strategy includes a focus on developing a healthy vaccine market through implementing specific vaccine procurement strategies and ensuring that the key elements of accurate forecasting.

the system in use in all industrialized countries and in a growing number of developing countries covers three main testing phases: preclinical laboratory testing. immunity-stimulating capacity (immunogenicity). among many other things. genetic and biochemical stability. potency.State of the world’s vaccines and immunization Towards vaccines of assured quality Making and meeting standards of quality and safety An internationally accepted system of testing vaccines for their efficacy. were the first regulatory agencies created to ensure the safety of biological products. clinical trials in humans. characterization of its biochemical components. and safety has gradually developed over the past century.e. dose-ranging. purity. In Phase 1. During the preclinical laboratory phase. A regulatory authority will. A vaccine that has successfully completed the preclinical and clinical trial stages is ready to be submitted to a regulatory authority for licensure – or approval for human use. and efficacy in up to several hundred volunteers. a vaccine undergoes biochemical testing and evaluation in laboratory animals for. The regulators will also inspect the production site and make a detailed review of 31 . including vaccines. including animal tests. Phase 2 tests for safety. human) trial stage covers three phases. In the early 1900s. quality. The clinical (i. the United States Food and Drug Administration (FDA) in the United States. Phase 3 tests for efficacy and safety in several thousand volunteers. Today. and the PaulEhrlich Institute in Germany. and surveillance following regulatory approval for marketing. among other things. the vaccine is tested in a few volunteers for safety and efficacy (immunogenicity). and for an initial indication of the appropriate dose to be used (dose-ranging). and safety in animals. undertake a review of how the preclinical and clinical tests were conducted and what they found.

but only about one quarter of developing countries do. efficacy. and routine inspection of the manufacturing process to ensure continuing conformity to standards of good manufacturing practice (GMP). and quality. starting with the raw materials and ending with the finished product. WHO’s efforts to ensure the safety and quality of vaccines uses a system that first establishes international standards of vaccine efficacy. Vaccines that have successfully emerged from the six-function national regulatory authority oversight (see Box 7) with no “unresolved confirmed reports of quality-related problems” are regarded by WHO as “vaccines of assured quality”. post-marketing evaluation (Phase 4) involves surveillance for any adverse events. Following licensure. safety and quality. and will even check the qualifications of the manufacturer’s staff. Having an independent and functional national regulatory authority is a good start for a country wishing to ensure that the vaccines it uses meet internationally agreed standards of safety. These inspections can take place at any stage in a vaccine’s life-cycle. During the life cycle of a product. 32 . introduce variations to the production process. properly functioning vaccine regulatory system. Setting international standards is the role of WHO’s Expert Committee on Biological Standardization. A new chapter in vaccine development how the vaccine was produced. the variations are reported to the national regulatory authority for review and approval. a manufacturer may wish to. In 1981. or have to.Chapter 2. the Expert Committee on Biological Standardization called upon all countries to have a national regulatory authority. In 2008. All industrialized countries have a reliable. about 70% of vaccines met the WHO criteria for assured quality. In such cases. and then monitors the extent to which a given licensed vaccine meets those standards. The post-marketing stage also includes testing of vaccine batches for consistency of the production process. Monitoring how fully a vaccine made or used in a given country complies with these standards is the role of the country’s national regulatory authority.

State of the world’s vaccines and immunization Box 7 How good is a national regulatory authority? For a country using or making vaccines. simply having a national regulatory authority is not enough. Two additional core functions for countries that procure their vaccines directly in the domestic or international market are: (3) verifying consistency of the safety and quality of different batches of vaccine coming off the production line (lot release). The sixth function is also recommended for any countries that host clinical trials of vaccines: (5) inspecting vaccine manufacturing sites and distribution channels. it must have the legal basis that defines its mandate and enforcement power. (2) ensuring that post-marketing surveillance is carried out. with a focus on detecting. as needed. For countries that manufacture vaccines. WHO. 33 . The national regulatory authority must be able to work independently (of vaccine manufacturers and of the government. core functions of the national regulatory authorities are: (1) issuing a marketing authorization. (4) accessing. and licensing vaccine production facilities and vaccine distribution facilities. and it should perform between two and six core functions. a national control laboratory in order to test vaccine samples. for example). For countries that procure their vaccines through UN agencies (UNICEF. or PAHO). depending on how the country acquires its vaccines. (6) authorizing and monitoring clinical trials to be held in the country. two additional functions are required. investigating and responding to unexpected adverse events following immunization.

Re-assessing the national regulatory authority within two years to evaluate progress. fully functioning national regulatory authority. safe. Using benchmark indicators and other pertinent tools to assess the national regulatory system. To address this problem. 3. the know-how. the initiative undertakes a five-step capacitydevelopment process tailor-made to the requirements of each individual country. the 34 .e. the experience. A new chapter in vaccine development The problem. Defining and then regularly updating benchmarks and other tools used to assess whether a national regulatory system is capable of ensuring that the vaccines used and/or made in its country are of the required standards of quality. To achieve its objectives. and safety. When the initiative started in 1997. compliant with GMP. and effective). had a reliable. 2. however. 4. properly functioning national regulatory authority. Working with the country’s regulators and other health officials in drawing up an institutional development plan for dealing with any shortcomings in the country’s regulatory system and for building upon the existing regulatory strengths in the country. efficacy. 1. 5. Implementing the institutional development plan. which may involve technical support or staff training to perform regulatory functions. Strengthening national regulatory authorities The ultimate objective of WHO’s initiative to strengthen the regulatory capacity of countries is for all countries to have a reliable. WHO launched an initiative in 1997 to strengthen the capacity of national regulatory authorities. or the political backing – to assess and monitor whether a vaccine is of assured quality (i. is that in some countries the national regulatory authority lacks the capacity – the human and material resources. By the end of 2008.Chapter 2. only 37 (19%) of WHO’s 190 Member States.

therefore. of ethics. In 2004. By the end of 2008. WHO launched the Developing Countries Vaccine Regulators Network. The danger is that in countries with little or no regulatory capacity. These countries are increasingly being asked by vaccine manufacturers to host clinical trials of vaccines intended for use in developing countries. In 1997. A regulators’ network for developing countries The power of networking is being applied to the quest for stronger regulatory oversight in countries where regulation is lacking or inadequate. quality. where regulatory oversight is weak or altogether absent. Clearly. and efficacy. In 2006. The network allows members to share expertise and information – particularly information about problems of vaccine safety and efficacy that may have surfaced during a clinical trial. the trials may take place without due respect for international standards of good clinical practice. malaria. and is working in much the same way as the developing countries’ network – clinical trials on candidate vaccines against diseases including AIDS. and of vaccine safety. Network participants also inspect clinical trials for their adherence to good clinical practice. the African Vaccine Regulatory Forum was established. Priority countries for the initiative are those that have vaccine manufacturers and thus contribute to the world’s vaccine supply. the numbers had risen to 33 (69%) of 48 vaccine producing countries. functioning national regulatory authority. aimed at strengthening the regulatory capacity of developing countries to assess clinical trial proposals and to oversee ongoing clinical trials.State of the world’s vaccines and immunization number had risen to 58 (30%) of WHO’s 193 Member States. these vaccines must be tested for their safety and efficacy in the “real-life” conditions of these developing countries. 35 . 20 (38%) of the 52 vaccine producing countries had a reliable. and meningitis are under way in the 19 Forum countries.

It can also force manufacturers to obtain separate authorizations for each intended market – a long. 36 . to the standards of safety. Ministry of Public Health. Hence the need for regulatory harmonization. and quality they apply to vaccines. the diversity of regulatory standards from one country to another can seriously complicate international trade in vaccines. more importantly. Clearly. efficacy. At the end of 2008.Chapter 2. Thailand. A new chapter in vaccine development Harmonizing and standardizing vaccine regulation Strengthening regulatory capacity also means bringing some uniformity to the way regulatory oversight is practised in different countries and. costly. but not all were applying the same regulatory standards for vaccine licensure. The problem is that vaccine manufacturers – both in developing and in industrialized countries – are increasingly seeking a global market for their products. 58 countries possessed a reliable national regulatory authority. and uncertain process that runs counter to current endeavours to accelerate the introduction of new vaccines into countries’ immunization programmes. Vaccine quality testing by the Division of Biological Products at the Department of Medical Sciences.

Their aim is to harmonize technical guidelines and licensing requirements for pharmaceutical products. progress towards harmonization of standards is slow but steady. including vaccines. through a mutual recognition agreement. and efficacy of these products. In 1989. Generally speaking. a regional regulatory authority. harmonization is a major objective of the European Medicines Agency. A year later. the WHO International Conference of Drug Regulatory Authorities laid plans for an international harmonization initiative run jointly by regulatory authorities together with pharmaceutical industry input. which. Topics chosen for harmonization relate to criteria for assessing the safety.State of the world’s vaccines and immunization In the Americas. including vaccines. by all other European Union states. Japan. quality. and the United States. The Conference. since 1980. In Europe. vaccines for use in the European Union are regulated either by the European Medicines Agency itself or by a European Union Member State. 37 . held every two years. brings together the regulatory authorities and pharmaceutical industry experts of Europe. An encouraging sign is that the recommendations of the WHO Expert Committee on Biological Standardization on regulatory standards for pneumococcal conjugate vaccines and vaccines against pandemic influenza – published in 2005 and 2008. the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was born. in which case the licensure of the vaccine is recognized. a Vaccines Working Group of the Pan American Network on Drug Regulatory Harmonization was set up in 2005 to work with regulatory officials from PAHO Member countries in establishing guidelines on regulatory standards for licensure of vaccines to be used in the region. At present. Another entity whose objectives include greater regulatory harmonization is the WHO International Conference of Drug Regulatory Authorities. The Conference is credited with achieving substantial progress in harmonizing technical guidelines and applications for licensing. has provided regulatory authorities of WHO Member States with a forum for discussion and collaboration on the regulation of medicinal products.

involves all the steps of a regular licensing procedure. notably in Asia. known as “Article 58”. It carries enough weight to allay fears that vaccines may be introduced without having been assessed for safety and quality. although stopping short of formally granting a licence. it would be favourably influenced if the vaccine had been approved for human use by the European Medicines Agency or the FDA. This mechanism. Similar collaborative agreements are being forged in other parts of the world. to provide advice on vaccine safety and efficacy as well as on clinical trial protocols. respectively. A new chapter in vaccine development respectively – are being applied by virtually all national regulatory authorities in the world. in 2004 and 2007. However. both agencies decided to no longer accept vaccines for marketing approval where they are intended for use exclusively outside their geographical jurisdictions. Moreover. the FDA and the European Medicines Agency have agreed to work with national regulatory authorities or with networks of regulators in the regions. 38 .Chapter 2. when a national regulatory authority in a developing country considers whether to host clinical trials of a new vaccine produced in another country. Innovative regulatory pathways Traditionally. the European Medicines Agency introduced a mechanism. This decision raised a fear that the supply of new life-saving vaccines to developing countries may be hindered or delayed for lack of authoritative marketing approval. In 2005. or whether to adopt a new vaccine in its country’s immunization programme. whereby it issues a “scientific opinion” based on the customary Agency process but with the addition of an evaluation of the vaccine by WHO-appointed experts from countries where the vaccine is intended to be used. therefore.

Not surprisingly. all five major multinational companies of the Big Pharma marketed products that had passed a prequalification assessment.State of the world’s vaccines and immunization Box 8 Prequalification – flagging vaccines fit for public purchase In 1987. By 2008. manufacturers in industrialized countries were supplying all the vaccines purchased through United Nations agencies. In the early 1990s. but also from those in industrialized countries. in principle. fully functioning national regulatory authority in the country where the vaccine is manufactured. such as Brazil. As of mid-2008. applications for prequalification evaluation have escalated in recent years. In addition. They are coming not only from manufacturers in developing countries. after which the vaccine is reassessed to determine if it – and the manufacturer – still meet the standards required to retain prequalification status. and Senegal. 39 . Cuba. a vaccine must. of vaccines available for purchase by these agencies. The prequalification process. also determines how well the national regulatory authority of the country where the vaccine is made is fulfilling its regulatory role in enforcing manufacturers’ compliance with WHO recommended standards. inter alia. more than half were coming from manufacturers in developing countries. Prequalification status normally lasts for two years. many countries that do not use these procuring agencies but buy vaccines directly from manufacturers also use the WHO list to select vaccines for purchase. The prequalification system is widely credited with contributing to the growing number and proportion of quality vaccines being supplied by manufacturers in developing countries. In order to be included in the list of WHO prequalified vaccines (24). The United Nations procuring agencies invite tenders only for vaccines on WHO’s list of prequalified vaccines. India. in addition to assessing individual vaccines. for example. be licensed and be under continuous regulatory oversight by an independent. Indonesia. a prequalification system was established by WHO to advise United Nations vaccine procuring agencies on the acceptability.

Immunization putting vacc n Chapter 3.Chapter 3. Immunization: putting v cines to good use ap e Immunization: tting vaccines good use mm atio o nes oo 40 40 .

Stat State of the world’s vaccines an immunization State of the worlld’s vacciines and immunization tat he orld’s acc ne and mmunization d’s cci un Chapter 3 Immunization : putting vaccines to good use 41 41 .

• Strong and effective leadership. • Disease surveillance and monitoring programmes need to be strengthened at all levels. • Weak health systems are a major constraint on the effectiveness of immunization programmes. • Polio has been eradicated in three of WHO’s six regions and is today endemic in only four countries – down from 125 countries in 1988. • False or unsubstantiated rumours about vaccine safety can undermine immunization programmes and cost lives. Immunization: putting vaccines to good use Key messages • From 2000 to 2007. • Integrating immunization with the delivery of other health interventions can boost immunization coverage and accelerate the achievement of MDG 4. 42 42 . • Targeted immunization strategies for difficult-to-reach populations increase equity in access to vaccines. • There is a need to foster increased public demand for vaccines.Chapter 3. intensified vaccination campaigns resulted in a 74% reduction in measles deaths globally. are key components of a successful national immunization programme. and national ownership of immunization programmes.

and more recently. tetanus (including tetanus in mothers and newborns). In addition. elderly people (for pneumonia. immunization programmes are increasingly reaching out to other population groups – older children and adolescents (for meningococcal disease and HPV disease). measles. though. and tuberculosis. rotavirus diarrhoea. Increasingly. shingles. hepatitis B. and cancers due to HPV. and influenza). rubella. immunization programmes the world over have been administering vaccines to young children to protect them against a cluster of common childhood diseases – diphtheria. Hib disease. of national immunization programmes and of the EPI. and people exposed to locally prevalent diseases (for yellow fever and Japanese encephalitis). The main focus. pneumococcal and meningococcal disease. mumps. They include hepatitis A.State of the world’s vaccines and immunization Year after year. polio. which WHO created in 1974 to establish and coordinate the work of these Figure 4 Global three-dose DTP coverage for 1980−2007 and goals for 2008−2010 100 80 Coverage (%) 60 40 20 Source: (31) 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 0 Year 43 . pertussis. with the development of new and improved vaccines (see Chapter 2) more diseases are being added to this traditional childhood cluster of vaccine-preventable diseases.

from an estimated 750 000 to an estimated 197 000 children (9). 4). The numbers of new cases reported for these four countries in 2009 as at end June were: Afghanistan: 10. • Between 2000 and 2007. which serves as a measure of how well immunization programmes are functioning (see Fig. the number of children dying from measles dropped by 74% worldwide. annual deaths from neonatal tetanus had fallen to an estimated 128 000. As of 2007. including measles-related deafness. Immunization: putting vaccines to good use programmes. India. India: 89. is still on infants. down from 790 000 deaths in 1988 (28. Box 9 The impact of immunization The selected data below testify to the impact of immunization in achieving its main objective: to reduce the number of children dying. 44 . polio was endemic in 125 countries and paralyzing an estimated 350 000 children every year (close to 1000 cases a day) (25). In addition. • In 1988. The life-saving impact of national immunization programmes is impressive (see Box 9). blindness. Nigeria and Pakistan. polio had been eradicated in three of WHO’s six regions – the Region of the Americas. 4). Nigeria: 321. the European Region. • Every year immunization averts an estimated 2. or being disabled as a result of diseases that can be prevented by vaccines. In mid 2009. 135 countries had eliminated neonatal tetanus (25) and by 2004. the number of reported cases of rubella declined by 98% between 1998 and 2006 (27). falling ill. indigenous poliovirus remained endemic in only four countries: Afghanistan. and Pakistan: 20 (26). about 80% of children under one year old were receiving the full three-dose schedule of the DTP vaccine. By the end of 2007.5 million deaths among children under five years old. and mental disability. • Following implementation of the rubella elimination strategy in the Americas. immunization prevents sickness as well as lifelong disability.Chapter 3. • By 2000. and the Western Pacific Region.

poor management skills.30) have warned that countries experiencing the greatest difficulties in meeting the MDGs – mainly in sub-Saharan Africa – face absolute shortfalls in their workforce. and the loss of health workers to higher-paid jobs overseas. Those targets call. Achieving these targets will not be easy. Many health workers that remain are often poorly distributed across the country. where AIDS and worker migration have depleted the health workforce. and weak monitoring and information systems. for all countries to be immunizing by 2010 at least 90% of their total child population under five years old. unmotivated. badly paid. Of the 57 countries worst affected by extreme shortages of health workers. This is compounded by a severe shortage of health workers. Recent reports by WHO (29. inadequately trained and unsupervised. and often have skills that are ill-matched to the work they have been assigned to do. The ability of health systems to deliver services such as immunization is often constrained by a lack of political and financial commitment. One critical barrier is the underlying weakness of the health systems in many developing countries. due to high rates of sickness and deaths. among other things. But a lot remains to be done in order to achieve the targets of the GIVS set by WHO and UNICEF (see Chapter 1). Countries in Africa account for 24% of the global disease burden but have only 3% of the world’s health workers. 36 are in Africa. Figure 5 illustrates how immunization coverage is affected by the density of health workers. 45 . and at least 80% of children under five in every district throughout the country.State of the world’s vaccines and immunization The unfinished immunization agenda Remarkable progress has been made in reducing disease incidence and deaths from vaccine-preventable diseases.

Many of the unimmunized children live in isolated rural areas without easy access to health facilities. There are unreached populations and immunization failures in every country but 73% of the children currently unreached with three doses of DTP immunization live in just 10 countries – all in Asia and Africa (31). religion. or the many children whose births go unregistered – may not even officially “exist”. 46 . Immunization: putting vaccines to good use Figure 5 Immunization coverage and density of health workers 100 90 80 Coverage (%) 70 60 50 40 30 20 10 0 1 10 100 1000 Human resources for health Doctors Nurses Density (per 100 000) Source: (29) In a poorly functioning health system it is difficult to ensure equity in access to immunization. and as a result. Some – like the children of “illegal” immigrants in urban areas. or among displaced populations that are on the move and especially difficult to reach. including gender. recent studies have also highlighted a number of social factors that may inhibit mothers from seeking immunization. densely populated urban areas and informal settlements. In India. and social status (caste).Chapter 3. Others live in poor. there may be a high degree of variability in immunization coverage. Some live in fragile states where public services are weak or non-existent and where access to health facilities may be severely restricted due to ongoing conflict. Additional operational research is needed in other regions to confirm these findings.

and high wastage. children may be vaccinated once but fail to return for the required follow-up doses. is the difficulty of delivering vaccines – especially the newer vaccines – through an infrastructure and logistical support system that in many developing countries is characterized by poor vaccine stock management. In some communities. A third barrier – especially among the poorest populations – is a lack of information and understanding about the importance of vaccines and immunization. Against this backdrop. sparking outbreaks of disease and untold deaths. fanned by reports of adverse events that are rumoured or suspected of being related to vaccines. A fifth barrier. well-targeted information and social mobilization campaigns are needed to transform a community’s “passive acceptance” of immunization into a well-informed demand for vaccines that can protect their children against lifethreatening diseases. is the need to secure additional financing to meet a projected shortfall in funding needed to achieve the global immunization 47 . single dose in pre-filled glass syringes as opposed to multi-dose vials – require new vaccine management strategies and increased storage capacity. putting a huge strain on an already weak supply chain.e.State of the world’s vaccines and immunization In addition to a weak health system. A fourth barrier relates to the fear of immunization. the value of an intervention that “helps healthy people to stay healthy” may suffer in comparison with medicines that can visibly heal the sick. another barrier to achieving the GIVS targets. some with non-standard characteristics – i. addressed in Chapter 4. poor vaccine handling and storage. With everincreasing access to Internet-based information. To counter these and other misconceptions. an unsubstantiated rumour about vaccines can rapidly circle the globe and undermine immunization services. And where parents lack a basic understanding of how vaccines work. people need to know how safe a vaccine is and how it can reduce disease and deaths. Since fear of vaccines and immunization often stems from a lack of information. the introduction of new vaccines. also rooted in the overall health system.

Immunization: putting vaccines to good use goals. coalition-building. fairly distributed. safety. there are sufficient staff.Chapter 3. 48 . responsive and productive). • A well-functioning health system ensures equitable access to essential medical products. attention to system-design and accountability. and their scientifically sound and cost-effective use. Box 10 Strengthening health systems – the six building blocks In an effort to promote a common understanding of what a health system is. regulation. efficacy and cost-effectiveness. and are protected from financial catastrophe or impoverishment associated with having to pay for them. WHO has defined six “building blocks” that make up a health system (30). The following sections outline the steps being taken to overcome the barriers to achieving global immunization goals. vaccines and technologies of assured quality. • Leadership and governance involves ensuring strategic policy frameworks exist and are combined with effective oversight. quality personal and non-personal health interventions to those who need them. • Good health services are those which deliver effective. This comes amid growing concern that the current global financial and economic crisis may have an adverse effect on the funds available for development assistance. • A well-performing health workforce is one that works in ways that are responsive. with minimum waste of resources. health system performance and health status. • A good health financing system raises adequate funds for health. analysis. It provides incentives for providers and users to be efficient. dissemination and use of reliable and timely information on health determinants. including for immunization. fair and efficient to achieve the best health outcomes possible. when and where needed. in ways that ensure people can use needed services. they are competent.e. safe. • A well-functioning health information system is one that ensures the production. given available resources and circumstances (i. The aim is to clarify the essential functions of a health system and set out what a health system should have the capacity to do.

though. The strategy provides support – including training – to ensure that district-level immunization managers apply the principles of “good immunization practice”. 49 . while ensuring that vaccines are delivered regularly in all districts. knowledge. and involvement of communities in the planning and delivery of immunization services. supply. In 2005. working in close collaboration with national immunization programmes and key partners. More recently. These principles call for district health officials to identify local immunization-related problems and oversee remedial action. and other partners devised the Reaching Every District (RED) strategy. a nine-country evaluation carried out by the CDC in 2007 found that the RED strategy had been adopted by 90% of all districts within these countries. The RED strategy also calls for timely collection of data on vaccine coverage and other vaccine-related activities (logistics. A closer look. mostly in Africa and Asia. therefore. an evaluation of five countries in Africa that had implemented RED found that the proportion of districts with over 80% of children fully immunized with DTP vaccine had more than doubled (33). there were districts where fewer than 50% of the children were receiving the full three doses of this vaccine.State of the world’s vaccines and immunization Extending the benefits of immunization equitably within countries In 2002. proper supervision of immunization health workers. “Outreach” staff take vaccines to hard-to-reach villages and make sure that all the children are vaccinated. and human resources of the GPEI were used to plan and implement the RED approach in many countries. The expertise. WHO. had begun implementing the RED strategy to varying degrees (see Fig. 6) (32). By mid-2005. which takes the district as its primary focus and aims to improve equity in access to immunization by targeting difficult-to-reach populations. found that in some of these countries. In 2002. notably the GAVI Alliance. 53 countries. UNICEF. and surveillance). 135 of WHO’s Member States were reaching a national average of more than 80% of children under one year old with the full three doses of the DTP vaccine.

and social mobilization and communication during immunization contacts. supportive supervision and on-site training. and supplies for programme implementation in every district. • provide timely funding. monitoring and use of data for action. defaulter tracing. It involves: • • • • • re-establishment of regular outreach services. Special measures are needed to ensure that difficult-to-reach populations are reached with vaccines and other health interventions. • strengthen the managerial skills of national and district immunization providers and managers. • reduce the number of immunization drop-outs (incomplete vaccination) through improved management. and develop and update supervisory mechanisms and tools. socially. These include efforts to: • map (geographically. few of the nine countries were implementing all five components of the strategy (see Box 11). 50 . and by avoiding missed opportunities to vaccinate. Immunization: putting vaccines to good use However. and culturally) the entire population – through microplanning at the district or local level – in order to identify and reach the target populations at least four times a year. logistics support.Chapter 3. better planning and management of human and financial resources. community links with service delivery. The CDC evaluation noted that further studies would be needed over a longer period to assess the effectiveness and sustainability of the strategy. Box 11 Reaching Every District (RED) The Reaching Every District (RED) strategy aims to improve equity in access to immunization by targeting difficult-to-reach populations.

or in the case of pregnant women. 51 . It is mostly during contacts in health centres that such vaccines are given. access may only be possible during certain periods of the year.State of the world’s vaccines and immunization Figure 6 Countries implementing the RED strategy in 2005 Source: (32) Reaching more children through campaign strategies Immunization is mostly delivered by health workers as a pre-defined series of vaccines. provided through outreach services. where access to health centres is very limited. in order to prevent maternal and neonatal tetanus. tetanus toxoid vaccine is also provided to pregnant women. In some very isolated villages. or entirely. In many countries. administered in a given schedule to children of a given age. during antenatal care visits. and mobile teams are needed to deliver vaccines and other essential health interventions. immunization may be partly. In remote areas.

or to stem outbreaks. For example. and epidemic meningococcal meningitis. during which all individuals receive a certain vaccine. However. Efforts to eradicate polio. 52 . A health worker marks a child's finger to show that measles vaccine has been administered — during measles vaccination campaign in Côte d'Ivoire in November 2008. to achieve some of the global elimination or eradication goals. In these scenarios. Immunization: putting vaccines to good use In countries with well-functioning health systems and where the populations have good access to the system. measles “catch-up” campaigns are used to reach children who may have missed out on measles immunization during their first year of life and children who may not have developed a protective immune response when immunized the first time round. eliminate measles.Chapter 3. often regardless of prior immunization. diphtheria. and eliminate maternal and neonatal tetanus all rely on this approach – in addition to routine immunization – either nationwide or targeted at selected high-risk areas only. yellow fever. routine immunization contacts may be sufficient to control vaccine-preventable diseases. a mass-mobilization campaign-style approach is adopted. Campaigns have also been used to control outbreaks of measles. so-called “supplementary immunization activities” may be needed to improve protection at population levels – for example.

deworming tablets.State of the world’s vaccines and immunization A campaign has the potential to rapidly reach more children. supported by adapted communications and monitoring mechanisms. growth monitoring. the campaign-style approach to immunization often manages to reach more people than can be reached through the regular immunization contacts. The “immunization weeks” in many American and European countries. and the “child health days” in numerous African countries. Immunization weeks in the Americas have proved particularly effective in reaching difficult-to-reach people. Box 12 Mass-mobilization to extend the reach of immunization Through mass-mobilization. In Europe. from micro-planning logistics to well-trained health workers. over 52 countries conducted child health days. And they tend to cover more equitably all socioeconomic sections of the target population. Uptake of measles vaccine in a campaign in Kenya showed equal uptake of over 90% in all wealth quintiles. especially those missed by routine immunization. These are very much the same components that are the basis of any health care system or any other public health programme. All this requires a strong support system. compared to routine immunization that reached less – only 60% – of the poorest wealth quintile (34). 53 . The child health days were originally introduced by UNICEF to deliver vitamin A supplementation. exhibitions. and insecticide-treated bednets. but now offer an integrated package of preventive services that can include. depending on local needs. have been using massmobilization techniques to ensure universal coverage as much as possible. training sessions. immunization weeks in the Americas are now organized in 45 countries – up from 19 in 2003. and tripled in west and central Africa from 5 to 16. Debates. workshops. the number of countries conducting child health days in east and southern Africa almost doubled from 10 to 18. vitamin A. and media events are among the activities on the agendas of these weekly campaigns. compared with 28 countries in 2005. Over the same period. immunization. such as those living in isolated border communities where immunization coverage is limited. immunization weeks have mainly had a social mobilization function. Immunization weeks are now organized in 30 countries in Europe – up from 9 in 2003. They are usually conducted twice a year and target a large proportion of the population. During 2008.

especially in areas where there is high illiteracy and poor access to the media. Parents in particular need to understand why they should seek immunization. is only one side of the coin. for example – is one way of building up trust. but they may lack awareness of the need for follow-up doses to complete the schedule. policy-makers. and health workers understand the vital importance of immunization for both children and adults. and ensuring that the community is motivated to demand immunization and is fully engaged as a partner. In some cases mothers may understand why their children need to be immunized. Countries need to ensure that innovative methods are used to reach these communities – for example. not just a recipient of vaccines. and village volunteers. This is critical in maintaining support for national immunization programmes and in providing information about the introduction of new vaccines and technologies to a national immunization schedule. The active involvement of community members to assist health workers – by informing the community about an upcoming immunization session. though. or a break in the cold chain. Others may refuse immunization for social or cultural reasons. inadequate supplies. The health system – particularly the health workers who vaccinate community members – must also be able to reliably meet that demand. 54 . helping to track children who are due for their next dose of vaccine. Weak immunization performance and a failure to deliver services due to transport problems. Immunization: putting vaccines to good use Greater awareness fuels demand Renewed efforts are needed to ensure that the public. can lead to a loss of confidence and fall-off in demand for immunization. through engaging a network of community leaders such as religious leaders. Creating demand in communities. and helping to identify newborns or pregnant women. There is a need for grass-roots mobilization for immunization at community level. staff shortages. women’s associations.Chapter 3.

perceived inconvenience or difficulty in accessing services. zinc supplementation. and control of environmental risk factors such as water and sanitation (for diarrhoea) and indoor air pollution (for pneumonia). Low demand persists because of poor understanding about the benefits of vaccines. The basic message so far has been relatively simple: Diseases are a threat. and low prioritization of immunization – especially among people who are barely surviving. hand-washing with soap. because not all causes of diarrhoea and pneumonia are vaccine-preventable. access to community case management. particularly UNICEF. But for some of the newer vaccines the situation is more complex. This includes early and exclusive breastfeeding. misconceptions about vaccine safety. will only prevent a proportion of all cases of diarrhoea and pneumonia respectively. for example. But even though the message is not so simple. to create awareness of and demand for vaccination among community members. Take the vaccine and prevent the disease. many communities still do not actively seek immunization.State of the world’s vaccines and immunization Despite longstanding efforts by the international community. 55 . Rotavirus and pneumococcal vaccines. immunization against these diseases creates an opportunity to actively promote the prevention and treatment of diarrhoea and pneumonia. which together account for over 36% of deaths among children under five. reduction of malnutrition.

Surveillance and monitoring: essential health system functions In addition to its key role in programme planning and monitoring. priority setting. • Improve the quality of vaccine delivery services before trying to convince community members of the need to use them. • Adapt immunization services to the local culture so that community members can come to trust them.Chapter 3. • Engage marginalized or underserved communities. It provides the information needed to monitor trends in disease burden 56 . UNICEF has identified some fundamental communication approaches to help health workers and local public health officials provide information about vaccines. who usually have high credibility and a large following among community members. especially traditional and religious leaders. and trust in immunization services. Immunization: putting vaccines to good use Box 13 Reaching out to communities In an effort to increase demand for immunization among community members. which often suffer greater disease burdens than other segments of society. • Engage local leaders as spokespersons for immunization. • Emphasize that the disease constitutes a threat but a threat that can be reduced by vaccination. • Identify strategies for reaching women: they are the primary caretakers of young children but usually have less access to mass media and often face obstacles to accessing health services. an effective disease surveillance system provides the critical intelligence that is needed to guide an immunization programme. and mobilization and allocation of resources. • Explain how to access local immunization services. • Evaluate the impact of the communications strategy on vaccine coverage rates and on efforts to improve knowledge of. as well as by key behaviours such as breastfeeding.

and yellow fever. 57 . high-performance surveillance system is the global polio surveillance network. Over the past decade. and conducting post-marketing surveillance to ensure the safety of all newly introduced vaccines. Effective surveillance systems are indispensable in guiding the decisionmaking process for the introduction of new vaccines. national. polio surveillance systems have been expanded to include reporting on other vaccine-preventable diseases such as measles. including influenza.State of the world’s vaccines and immunization and the impact of disease control programmes. The GIVS goal to vaccinate 90% of children at the national level and 80% in each district by 2010 (see Chapter 1). have highlighted the need to strengthen routine surveillance and monitoring at all levels. and global systems for the surveillance of vaccine-preventable diseases. surveillance systems need to be strengthened for other vaccine-preventable diseases. meningococcal disease. as well as the data needed to guide public health policy and to monitor progress towards global goals. that rely heavily on the use of data to drive strategic interventions. An example of an outstanding. In addition to the need to improve case-based surveillance and outbreak response for diseases such as measles and polio. progress has been made in setting up or improving regional. Disease surveillance and monitoring systems are also expected to give an early warning of impending or ongoing disease outbreaks – providing a first line of defence against the threat of emerging or pandemic diseases. In many developing countries where disease surveillance systems are weak. such as the RED strategy. pneumococcal disease. especially in developing countries. The availability of new vaccines to combat diseases such as Hib. neonatal tetanus. which enables rapid detection of polio cases throughout the world. and related approaches. monitoring the impact of these new vaccines on disease patterns. and rotavirus diarrhoea provides the potential to significantly reduce childhood illness and deaths.

and national levels. This framework calls for: alleviating health system barriers to surveillance. This intelligence provides a platform for high-level advocacy for surveillance support within countries. provide notification of. 58 . and health facility levels as well as in sentinel sites. and a new opportunity to build on synergies between different existing surveillance systems. Efforts to strengthen immunization surveillance. require Member States to establish and maintain core capacities for surveillance at the local. intermediate. which entered into force in mid-2007.Chapter 3. through providing better data to improve health system management. building capacity for surveillance at national. For example. immunization surveillance data on coverage and drop-out rates can be used as an indicator of the equity of health system performance – a measure of its ability to continue to provide health services to difficult-to-reach populations (35). assuring quality data. monitoring. district. The regulations stipulate that countries should be able to detect. where appropriate. In 2007. the WHO Strategic Advisory Group of Experts on Immunization (SAGE) endorsed a new Global Framework for Immunization Monitoring and Surveillance. regional. and linking surveillance of vaccine-preventable diseases and immunization monitoring with other national surveillance systems. Immunization: putting vaccines to good use The revised International Health Regulations. and evaluation can also help alleviate “system-wide” barriers. and take initial steps to control outbreaks of diseases of global health importance.

• Cold-chain facilities and logistics. and responding to adverse events following immunization. • Sound decision-making on which vaccines to schedule. • A motivated. monitoring.State of the world’s vaccines and immunization Box 14 What it takes to run a successful national immunization programme • Political motivation. and well supervised staff. as well as knowledge of available international funding mechanisms. • A surveillance system for detecting. well trained. • A well-functioning national regulatory authority. planning. • The capacity for efficient financial planning. • A well-functioning health system that facilitates the delivery of immunization to all communities. • Use of routine surveillance data (immunization coverage. vaccine use and wastage. • Strong and effective leadership and national ownership of immunization programmes. • Country-driven policies. investigating. and reporting. based on local. • An effective National Immunization Technical Advisory Committee to help facilitate evidence-based decision-making at country level. and incidence of diseases) for programme management. Optimizing the delivery of vaccines As new vaccines come on the scene (see Chapter 2) and as more vaccine doses are needed to immunize more people in more age groups. regional. and global data. including multi-year planning and a budget line for immunization in the national health budget. the logistics and infrastructure needed to transport vaccines safely and efficiently from the manufacturer to the 59 .

reduce wastage. In addition. In addition. the increased volume of packaging used for a new vaccine exceeds the cold storage space available at the country level. a plane had to be chartered to deliver the vaccine to Rwanda. accurately forecast vaccine demand. means that managers must be able to maintain lower levels of vaccine stocks. and prevent break-downs in cold-chain equipment. PATH. For example. But the shipping volume was even higher at 370 cubic metres. coupled with the rising cost of vaccines. For 30 years. In 2007. with the support of the Bill & Melinda Gates Foundation. In some regions. and the need for training and supportive supervision. pre-filled glass syringes.Chapter 3. Optimize aims to make use of technological and scientific advances to help guide the development of new products and ensure maximum efficiency and safety in the field. In some cases. there are major implications for the cost and logistics of international transport. the first shipment of pneumococcal conjugate vaccine (679 500 doses) to Rwanda in March 2009. waste disposal. the packaging and presentation of these new vaccine products – often single-dose presentation. launched Optimize – a global effort to help countries manage the growing complexity of immunization logistics. which can interrupt the supply of vaccines and entail major financial losses. cold storage facilities are inadequate to cope with the massive increase in the volume of vaccine being shipped. countries have relied on the same system to store and transport vaccines safely from manufacturers to recipients – the cold chain – which keeps vaccines at controlled temperatures throughout. WHO and a non-profit organization. required over 40 cubic metres of storage space in the national cold storage. As long as vaccines could be 60 . which is now greatly inflated by the high-volume packaging of the new vaccines. Immunization: putting vaccines to good use end user – without jeopardizing their potency – have in many countries become increasingly complex. and bulky packaging – have implications not only for storage but for service delivery strategies. As a result. This logistical challenge.

and the addition of the vaccine vial monitor – a small sticker that indicates exposure to heat – may mean that these vaccines can move out of the cold chain altogether. In addition. and could help reduce costs. These carts use no electricity as they are charged with well-insulated plates that have been prerefrigerated or frozen and that maintain consistently cool temperatures for long periods of time. One possible solution could be to use the passively cooled carts used to deliver fruit and vegetables to European supermarkets. putting even more pressure on the system. Optimize is working directly with manufacturers and countries to identify problems and test solutions that could have a global application. the landscape is changing. this system worked. Today. there is relief in other areas: some of the vaccines that currently pass through the system are now heat-stable. Tetanus toxoid vaccines. despite high wastage rates (more than 50% for some vaccines) and high maintenance costs. to transport vaccines within developing countries. more costly vaccines arrive on the market. as new. However. being packed at a vaccine manufacturing facility in Bandung. with vaccine vial monitors attached. technology innovations that protect these vaccines and reduce waste – such as single-dose vials and prefilled syringes – require significantly more space on trucks and in refrigerators.State of the world’s vaccines and immunization acquired at low cost and in large quantities. They are also are capable of carrying a significantly higher volume than traditional vaccine cold boxes. Indonesia. 61 .

and cost-effective way to organize the development of health systems. 62 . in response to the high energy costs and unreliable power supply in developing countries. is well-placed to benefit from this increased visibility. Immunization. There is clear evidence.Chapter 3. for example. experts involved in public sector delivery of vaccines. fair. Immunization: putting vaccines to good use Elsewhere. as well as to develop a more generic presentation and packaging guideline to address the range of potential new vaccines in the development pipeline. and industry representatives – both the International Federation of Pharmaceutical Manufacturers Association (IFPMA) and the Developing Country Vaccine Manufacturer’s Network (DCVMN) – to discuss vaccine presentation and packaging issues in order to support the development of products tailored for use in developing country settings. WHO took over the role of convening VPPAG. VPPAG was established in 2007 by the GAVI Alliance to respond to industry requests in relation to the packaging and presentation of the pneumococcal conjugate vaccine and rotavirus vaccine. as one of many components of a country’s health system. This is because in many countries. that where health centres offer a range of services. The Vaccine Presentation and Packaging Advisory Group (VPPAG) provides a forum for representatives of UN agencies. Linking interventions for greater impact The primary health care approach. and the work of the group was broadened to look at presentation and packaging formats for the HPV vaccine. as an efficient. Another initiative is the establishment of an inter-agency advisory group to recommend vaccine presentations and packaging for use by developing countries. is back on centre stage. vaccine coverage rates tend to be higher. immunization has always been an integral part of the health system and has benefited from the health system’s synergistic potential. In 2008. Optimize is examining the use of battery-free solar refrigerators as a possible means of improving the reliability and efficiency of refrigeration systems at health centres and clinics.

c Includes vaccination of children not belonging to target population. 2004) Madagascar (534 health centres.b DTP3 vaccination coverage (%) Democratic Republic of the Congo (380 health centres. immunization can benefit the delivery of other health interventions. Source: (36) b For years. Vaccination coverage was not included in the assessment of overall health-centre performance across a range of services. 2006) Weighted average of coverage in each country quintile Rwanda (313 health centres. 1999) 120 DTP three-dose vaccination coverage (%) c 100 80 60 40 20 0 20% health centres Quintile 2 with lowest overall performance Quintile 3 Quintile 4 20% health centres with highest overall performance Facility performance score a Total 1227 health centres. Conversely. For people with limited access to health centres. immunization programme managers have urged health workers to use any and every contact with a child in a health centre to check the child’s (and mother’s) immunization status and to vaccinate if needed. covering a population of 16 million people.State of the world’s vaccines and immunization Figure 7 More comprehensive health centres have better vaccination coveragea. an immunization outreach or mobile team may offer the only contact they have with the health system: providing more health commodities (such 63 .

bring together large numbers of children and their parents into a limited place over a limited time. supply. The provision of a range of preventive and curative services may result in increased trust in the health system by the community. and can offer interventions to many people that they have previously missed out on. Immunization: putting vaccines to good use as medicines. joint training. human resources are adequate. Child collecting an insecticide treated net to protect against malaria during measles vaccination campaign in Côte d'Ivoire in November 2008. and there is good monitoring and evaluation.Chapter 3. and nutritional supplements) or health services (such as checking children’s growth and giving antenatal advice) to these people. as more of their demands are met. can have a positive health impact. and delivery. experience has shown that platforms offering multiple interventions can have a negative impact on coverage unless the interventions are well-targeted. 64 . However. improved management. there are other advantages in combining targeted health interventions. Meanwhile. bednets. well-planned linkages between interventions may involve the pooling of human and financial resources. who are often among the least served by the health services. and a reduction in costs through shared transport and distribution mechanisms. too. good logistics systems are in place to ensure accurate forecasting. Immunization campaigns. In addition to the direct health benefits.

while targeting hard-to-reach people with additional interventions capable of reducing mortality in children under five years old. substantially reduce malaria). A 2008 evaluation found that rapid impact on mortality rates could be achieved through the package of interventions – especially through the distribution of vitamin A and bednets. 65 . Distributing these interventions as part of measles immunization campaigns can serve to rapidly increase demand for measles immunization. 30 million doses of deworming medicine. • The GPEI calculated that by the end of 2006.State of the world’s vaccines and immunization Examples of linked interventions include the following. • In 2008. routine and supplementary polio and measles immunization activities have been used to deliver insecticide-treated bednets (which. when used properly. integrated supplementary immunization activities against measles resulted in the distribution of over 35 million doses of vitamin A.6 million insecticide-treated bednets (37).25 million deaths worldwide (38). • Since 2001. and more than 5. using its OPV immunization activities to deliver vitamin A tablets had helped to avert 1. • The Accelerated Child Survival and Development programme – set up in 2002 and managed with support from UNICEF and the Canadian International Development Agency (CIDA) – was established to help increase the delivery of a package of key health interventions in districts of 11 African countries with high under-five mortality rates.

and the general public. where in 2002–2003 rumours that the OPV was being used to lower the fertility of young girls brought polio immunization to a halt for 12 months in several states: the result was a nationwide polio epidemic that ultimately spread to 20 previously polio-free countries in Africa. with potentially disastrous consequences. parents. but widely publicized 1999 British study (39) linking the measles-mumpsrubella (MMR) combination vaccine to autism. Part of that system should provide for communication of the findings to health workers. Another well-known case in point concerns Nigeria. Communication has to be truthful without fanning fears that could compromise future vaccination activities and diminish their benefits.Chapter 3. loss of public confidence in a vaccine due to real or spurious links to adverse events can curtail or even halt immunization activities. Immunization: putting vaccines to good use Combating fear with knowledge and evidence As vaccine coverage has increased and the incidence of vaccine-preventable diseases has fallen – particularly in industrialized countries – immunization has become a victim of its own success. concern about the potential sideeffects of vaccines has increased. has fuelled continuing anxieties among parents about the safety of the vaccine and has caused a decline in vaccine coverage in many countries: ten years later. including Austria. Israel. and the Middle East. Most industrialized countries have such a post-marketing surveillance and 66 . health officials. The CDC reported record numbers of measles cases in the United States for the first seven months of 2008 – many in children whose parents had refused vaccination. Dealing with such rumours and with adverse events following immunization requires an efficient post-marketing surveillance and investigation system that can assess whether these events are truly caused by vaccines. For example. measles is making a comeback in several industrialized countries. and the United Kingdom. a scientifically flawed. Switzerland. In both developing and industrialized countries. Asia. Italy. As the diseases prevented by immunization have become less frequent and less visible.

made up of independent experts. and autism in children (“no evidence of toxicity in children or adults exposed to thiomersal in vaccines”). though. Developing countries are. There are still many countries. In 1999.State of the world’s vaccines and immunization investigation system. to respond promptly. a vaccine preservative (known as thimerosal in some countries). Recent topics dealt with by the Committee include: • alleged links between the hepatitis B vaccine and multiple sclerosis (“no evidence found of such a link”. • a higher than normal risk of Bacille Calmette-Guérin (BCG)-related disease in HIVpositive children vaccinated with BCG (“evidence suggests a higher risk and that BCG vaccine should not be used in HIV-positive children”). to rumours and reports related to vaccine safety. that do not have the experience or resources needed to investigate rumours or reports of adverse events following immunization and to restore public confidence. making progress in detecting and dealing with reports of adverse events. efficiently. the Committee observed). and with scientific rigour. 67 . • alleged links between thiomersal. • the risk of administration of multiple vaccines overloading a child’s immune system (“no evidence to support any risk of immune overload”). on the whole. • the safety of newly licensed rotavirus vaccines (“pre-licensing safety profiles reassuring but careful post-marketing surveillance required at country level”). WHO set up a Global Advisory Committee on Vaccine Safety.

Immunization: putting vaccines to good use Box 15 Vaccine Safety Net for quality web sites “Is this new rotavirus vaccine likely to produce side-effects in my baby?” “Can a pregnant woman be vaccinated against tetanus without risking health problems for herself and her unborn baby ?” “How safe is the new vaccine against the human papillomavirus?” To find answers to such questions. and health practitioners may well turn to the Internet. The web sites they find are as likely to present inaccurate. members of the general public. WHO. the Vaccine Safety Net listed 29 web sites (40). In 2003. the GIVS goal to reach 90% immunization coverage nationally and at least 80% in each district by 2010 – see Chapter 1). It will also require the use of operational research to help identify innovative approaches and solutions that are tailored to local needs. huge challenges The immunization achievements are immense but so too are the challenges that lie ahead in meeting the immunization-related MDGs and those of the GIVS (in particular. Remarkable progress. misleading. health officials. prompted by its Global Advisory Committee on Vaccine Safety and other members of the health and development community.Chapter 3. among other requirements. web sites must. as well as their sources of information and their data protection policy. disclose their ownership and their sponsors. 68 . Reaching the 24 million children a year who remain unvaccinated will not be easy. which lists web sites that contain vaccine safety information and that a WHO team has approved as being sound and credible. As of March 2009. unbalanced. or unjustifiably alarming information as they are reliable information. Success will depend on better use of surveillance and monitoring data at the local level to identify and target these difficult-to-reach children. To meet the required standards. began a “Vaccine Safety Net” service. to tip the balance in favour of reliable information.

and more responsive information and communication strategies – should help to ensure that long-term progress has not been sacrificed for shortterm gains. technical know-how. the difficulty of delivering vaccines. These barriers include the constraints in some countries of weak health systems. dynamic global health alliances and public-private partnerships. and problem-solving ingenuity needed to get the job done. 69 . the failure of many governments to mobilize populations and establish a wellinformed demand for vaccines. The solid building blocks that are being put in place – health system and immunization programme strengthening.State of the world’s vaccines and immunization Efforts to reach the global goals have focused on overcoming some of the main barriers to increasing immunization coverage. But even when the global goals have been met. New global alliances have been forged to help address these and other challenges – attracting new financing for immunization and bringing together people from the public and private sector and civil society with the collective knowledge. and the projected shortfalls in funding. new long-term global financing mechanisms for immunization (see Chapter 4). success will be measured against an additional benchmark – ensuring that the achievements are sustainable. experience. the global threat posed by false or unsubstantiated rumours about the safety of vaccines.

Mexico. Member countries will submit data on adverse events to a common database housed at the Uppsala Monitoring Centre – a WHO Collaborating Centre – in Sweden. on a wider scale. In 2006. data will be shared with other countries. PAHO set up a surveillance network comprising five member countries – Argentina. and United Nations vaccine supply agencies. and will forge strong links between their national immunization programmes. 70 . vaccine manufacturers. concern has been growing over the possibility that the investigation of an adverse event following the routine use of a newly licensed vaccine may not be undertaken as rapidly or reliably in the sometimes difficult conditions of developing countries as it is in industrialized countries. Immunization: putting vaccines to good use Box 16 Strengthening post-marketing surveillance of newly licensed vaccines In recent years. The Network will share safety data among member countries and. and national pharmacovigilance centres. This concern prompted WHO to set up in 2009 a Global Network for Post-marketing Surveillance of Newly Prequalified Vaccines.Chapter 3. through a harmonized approach. Brazil. Panama and the Bolivarian Republic of Venezuela – that operates on much the same lines as the global network. regulatory authorities. This Network brings together selected developing countries to share information about adverse events following immunization. They will share among themselves information about adverse events following immunization.

State of the world’s vaccines and immunization 71 .

Investing n immunization Chapter 4.Chap er Ch pte Chapter 4. Investing iin immuniizatiion vesti g mmun zat on st on 72 2 .

Sta State o the world’s vaccines a immunization State of the world vaccine and immunization rld’s ccin and mm niz on nes n Chapter 4 Investing in immunization 73 .

predictable funding for immunization. immunization helps extend life expectancy and the time spent on productive activity. government spending on vaccines and immunization has been increasing. • New sources of funding and innovative funding mechanisms are providing long-term. • By keeping children healthy. even with newer. the level of development assistance for immunization has increased by about 13%. • Since 2005. • Since 2000. 74 74 . more expensive vaccines. thereby contributing to poverty reduction (MDG 1). Investing in immunization Key messages • Immunization remains one of the most cost-effective health interventions. • There remain funding shortfalls to be addressed if global goals are to be reached.Chapter 4. • Since the year 2000. bilateral donors are making use of broadbased funding mechanisms and partnerships to support the health sector as a whole.

though. Throughout this sequence.00 per live birth. on a global scale. came the EPI – set up to establish and coordinate. which began in that year.50–5. By the early 1990s. but not routinely in a systematic organized manner. the figure had risen only slightly to about US$ 6. tetanus. and other partners. questions have arisen about the economics of immunization. Support for immunization from the GAVI Alliance. Then. and tuberculosis). the military. page 2). but what does it cost? Is it cost-effective? And who pays for it? These questions are being asked with growing insistence as new vaccines are becoming available. and to this day. are calling for large reductions in child and maternal mortality. pertussis. the drive for universal child immunization (UCI) launched by UNICEF. Immunization is clearly effective. and as new goals. What does immunization cost? In the 1980s. had helped raise immunization coverage to a global average of about 80%. starting in the mid1970s. In the mid-1980s. protect millions of children from disease and death (41). the systematic use of vaccines by national immunization programmes and thereby to protect as many children as possible in the world against six infectious diseases (diphtheria.State of the world’s vaccines and immunization First came the vaccines: by the early 1970s. polio. measles. such as the MDGs and the GIVS goals (see Chapter 1. came the evidence that these immunization programmes could. By 2000.00 per live birth. vaccines against about 20 diseases had become available. or for occasional mass campaigns. and so on). total annual expenditure on immunization for low-income countries averaged US$ 3. in a matter of a few years. and in most countries were being used for high-risk population groups (travellers. WHO. as new funding sources and resources are materializing. and thereby stepping up the pressure to maximize the life-saving potential of immunization. allowed many of the poorest countries of the world to 75 .

There are several reasons for the rising costs of immunization. the rotavirus vaccine. scaling up vaccine coverage with newer vaccines to the levels needed to meet the MDGs and the GIVS goals is likely to exceed US$ 30. such as those against yellow fever. and the HPV vaccine. compared with only about 15% for the costs of vaccines. The price of the hepatitis B vaccine. immunization expenditure began to rise again. human resources and operational costs accounted for the bulk of immunization costs. as the market and demand for these vaccines expands. By 2010. Not unexpectedly.Chapter 4. efforts to accelerate the adoption by developing countries of the most recently developed vaccines (the pneumococcal conjugate vaccine. hepatitis B. for example) could bring the share of the vaccine component to 60% of the total costs. the price of new and underused vaccines is higher than the older vaccines – the prices of these new and underused vaccines are in the dollars per dose compared with a few cents per dose for the traditional ones. First.00 per live birth. In the 1980s. has fallen steeply over the past decade or so (see Fig. the vaccine costs should fall as these newer vaccines become more widely used. Vaccines (and injection equipment) have now replaced human resources and operational costs as the most expensive component of immunization. 76 . for example. However. and as multiple suppliers (including manufacturers from developing countries) enter the market. as vaccine production methods become more efficient. Investing in immunization 4: strengthen their routine vaccine delivery systems and to introduce underused vaccines. 8). Today. and Hib into their immunization programmes. the cost per live birth for immunization with the traditional vaccines plus the hepatitis B and Hib vaccines is likely to reach US$ 18. Beyond 2010.00 per live birth.

State of the world’s vaccines and immunization Figure 8 Relation between the number of WHO Member States using hepatitis B vaccine and the UNICEF weighted average price for the monovalent vaccine 180 2.5 2 Year Number of WHO Member States using hepatitis B vaccine UNICEF weighted average price of monovalent hepatitis B vaccine in US$ Source: WHO: based on programme data received from WHO Member States and UNICEF weighted average price for monovalent hepatitis B vaccine Second. stored. The increased quantities of vaccines need to be managed. rotavirus vaccine. and informing communities about the benefits of the vaccines.5 80 1 60 40 20 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 0 0. US $ 100 77 . and transported. and will place considerable pressure on existing national vaccine supply chains. and costs associated with expanding surveillance and monitoring activities to cover the added disease or diseases.5 Number of WHO Member States 160 140 120 1. introducing underused and new vaccines come with additional costs of training staff to safely administer and dispose of the waste. and HPV vaccine). the expansion of immunization schedules with underused and new vaccines (particularly the pneumococcal conjugate vaccine. will increase the quantities of vaccines that need to be stored in the cold chain. because vaccines are temperature sensitive. costs of updating and printing new vaccination cards. Third. the immunization system will require additional investments to cope. As such.

civil strife. many people live on less than US$ 2 per day and require support from national authorities and the international community to meet their basic needs. many countries need to rely on outreach services and supplementary immunization activities. prioritization. including about 30 million children. including immunization. The remaining 45 countries are those whose GNI per capita classify them as lowermiddle-income countries according to the World Bank classification (42).and lower-middle-income Member States between 2006 and 2015. as well as support to strengthen their immunization systems. a WHO and UNICEF analysis. identification of new financing opportunities. and vaccine quality assurance. enhanced participation of the private health sector in provision of immunization services. In addition. In some of these countries.Chapter 4. The total population in these lower-middle-income countries is nearly two billion. These strategies require increasing investments in immunization. are eligible for GAVI Alliance funding and have received support for introducing underused and new vaccines. reaching the 20% hard-to-reach children who are not receiving the full threedose schedule of the DTP vaccine is increasingly difficult and costly. such as mass vaccination campaigns and child health days. and decision-making. These countries however. as many of them are hard to reach for reasons of geography. Thirty-five of these countries are unable to benefit from GAVI Alliance funding and face increasing difficulties in financing the introduction of underused and new vaccines. The total bill came to US$ 76 billion. the bill came to US$ 35 billion – enabling them to protect more than 70 million children. calculated how much it would cost to attain the GIVS goals in 117 WHO low. and inter-country collaboration to address the challenge of vaccine procurement. including technical assistance in disease surveillance. For the 72 poorest countries. or lack of sufficient health service resources (see Chapter 3). to reach more children with vaccines. manufacturing. Investing in immunization Fourth. There are a number of strategies that could help to assist the lower-middle-income countries to access new and underused vaccines. published in 2008 (7). evaluation. 78 . To put a price tag to these rising costs for immunization.

In addition to being a significant contributor to child deaths. or from vast areas of the world. making a major contribution to meeting MDG 4. rotavirus diarrhoea. 47. measles was the leading cause of 79 . as in the case of smallpox. rubella. recent data show that immunization. has since been saving the world about US$ 1. This would represent a major reduction (60–70%) since 2000 in the number of under-five deaths from vaccine-preventable diseases. pneumococcal disease. That investment. 45. tuberculosis. The classic example of vaccines preventing serious disability has been the prevention of paralytic polio in hundreds of thousands of children since the advent of the GPEI. meningococcal disease. tetanus. In addition. Meeting the GIVS goals (see Chapter 1. is the investment worth making? If all countries manage to reach 90% of children under five years old with these vaccines. prior to the widespread use of the measles vaccine. 44. 49). would mean protecting children against 14 diseases – diphtheria.3 billion a year in treatment and prevention costs. according to one estimate (50). 48. and (in certain areas) Japanese encephalitis and yellow fever. 46. the GIVS goals are necessary stepping stones to achieving MDG 4.State of the world’s vaccines and immunization Is the investment worth making ? The investments in immunization continue to increase. page 2). and efforts to meet internationally accepted goals will add substantially to the cost of immunization. continues to be good value for money and a proven cost-effective health intervention (43. polio. Eradicating smallpox cost US$ 100 million over a 10-year period up to 1977. For WHO and UNICEF. then by 2015 immunization could prevent an additional two million deaths a year in this age group. An extreme example is its ability to remove a disease altogether from the world’s public health landscape. even with more expensive vaccines. Yet. vaccine-preventable diseases also constitute a major cause of illness and disabilities among children both in industrialized and developing countries. pertussis. measles. as in the case of polio. hepatitis B. In addition. Hib.

can be prevented through immunization. In a large clinical trial conducted in 11 countries in North America and Europe. A large proportion of children who survive an episode of pneumococcal meningitis are left with long-term disabilities: a recent study in Bangladesh showed that close to half the children had either a neurological deficit. blindness. Congenital rubella also. accounting for an estimated 15 000– 60 000 cases of blindness every year (51). rotavirus diarrhoea is a common cause of clinic visits or hospitalization among children in both industrialized and developing countries. while the impact on child deaths alone would be sufficient justification for the use of vaccines in developing countries. Similarly. and severe mental retardation. Thus. however. the pneumococcal vaccine has been shown to reduce severe acute otitis media – one of the commonest childhood illnesses that requires medical attention in industrialized countries. immunization lengthens life expectancy and the time 80 . should take into account more than its positive impact on individual and community health. Among the newer vaccines. By keeping children healthy. More recently. In Africa. use of the rotavirus vaccine was shown to reduce clinic visits and hospitalizations due to rotavirus diarrhoea by 95% (54). or a developmental deficit (53). the reduction of long-term disability among children and the cost savings from reduction in clinic visits and hospitalization more than justify their use in children everywhere. Other complications of measles that result in severe neurological disabilities are the post-infectious encephalitis and the subacute sclerosing panencephalitis (SSPE). rotavirus vaccine prevented three cases of severe rotavirus diarrhoea that required hospitalization (55). which is associated with deafness.Chapter 4. Investing in immunization blindness in children in developing countries. The cost-effectiveness equation for immunization. use of the pneumococcal vaccine was shown to be associated with a 39% reduction in hospital admissions due to pneumonia from any cause (52). such as hearing or visual loss. for every 100 vaccinees.

an estimated funding flow of US$ 25 billion to support immunization is expected to become available from government. In order to get a clearer understanding of who pays the immunization bill. For the 72 poorest countries. Who pays the bill and how? The WHO and UNICEF analysis to calculate how much it would cost to attain the GIVS goals (7).State of the world’s vaccines and immunization spent on productive activity. As a Harvard School of Public Health team recently found in a study on the economics of immunization in countries receiving GAVI Alliance support. “Healthy children perform better at school. Against a total immunization bill of US$ 35 billion in these countries. Hence. and healthy adults are both more productive at work and better able to tend to the health and education of their children. it is useful to look at each funding source separately. not only estimated the total price tag. multilateral. resources spent on them go further. Healthy families are also more likely to save for the future. this leaves an unfunded mandate and funding gap of US$ 10 billion. and thereby contributes to a reduction in poverty (the first Millennium Development Goal. since they tend to have fewer children. thereby improving their life prospects” (56). and other sources (including the GAVI Alliance). MDG 1). but also matched this against estimated future funding. about a US$ 1 billion shortfall needs to be financed every year if the GIVS goals and MDG 4 are to be achieved. and calculated the estimated shortfalls between 2006 and 2015. National governments Since the launch of the EPI in 1974. the financing of vaccines and immunization in developing countries has largely been made possible through support from the global international health community – primarily from multilateral and bilateral 81 .

many governments of developing countries became complacent about the need to use their own domestic resources to pay for their basic vaccines and immunization. the majority of countries in the Americas are today almost entirely self-sufficient in the financing of vaccines and immunization – with over 90% of immunization costs paid for out of national government resources. Budget line items also facilitate resource tracking and allow for greater accountability of expenditures. with most of the funding for vaccines and immunization focused toward disease control and eradication initiatives. Investing in immunization sources and from international development banks. At the same time. using local currencies. including important investments in equipment and infrastructure. The presence of this separate budget line within a country’s national health budget contributed significantly to increasing government financing of vaccines and routine immunization in the Americas. after 1990. huge investments were made to reach the 1990 goal of universal child immunization (UCI). donor funding to sustain routine immunization services began to dwindle. which already had access to a regional funding mechanism for vaccines. with payment not due until up to 60 days after delivery. Notable exceptions to this were the countries in the Americas. The pooled fund is able to secure low vaccine prices through large volume contracts with manufacturers. As a result. most 82 . As a result. immunization performance suffered and vaccination coverage stagnated throughout the 1990s.Chapter 4. And. PAHO established a revolving fund to help all countries in the region become more self-sufficient in the purchase of vaccines for routine immunization. In 1979. Another part of the success of the PAHO model for financing immunization was the requirement that countries create a specific budget line item in the national budget for the purchasing of vaccines. However. the reason being that budget line items give visibility to immunization as a permanent presence within the national planning and budgeting process. The mechanism enables participating countries to buy vaccines. In the 1970s and 1980s.

From the 2008 WHO-UNICEF costing analysis (7). it is estimated that 40% of the costs of immunization for the period 2006–2015 will be met by national governments. Other studies have shown that since the year 2000. A WHO analysis of immunization financing indicators from 185 countries collected through a joint WHO and UNICEF monitoring system. Of these. 83 .and lower-middle-income countries). WHO’s 193 Member States were funding an average 71% of their vaccine costs (33% in low. In 2007. 86% of countries reported having a line item for vaccines within their national health budgets (75% of the 117 low. they signal a long-term political commitment that could protect budget allocations for immunization during economic downturns.and lower-middle-income countries).State of the world’s vaccines and immunization importantly. governments’ spending on vaccines and immunization has been increasing at a steady rate. confirmed that breaking out vaccine purchases as a line item in the national health budget is indeed associated with increased governmental budget allocations to vaccines and routine immunization (57).

84 0% (25 countries or 13%) >0% & <50% (33 countries or 17%) >50% & <100% (20 countries or 10%) 100% (115 countries or 60%) Source: (57. 2007 . Investing in immunization Government funding of vaccines for routine immunization.71) Figure 9 Chapter 4.

At a country level. international development assistance. bilateral.State of the world’s vaccines and immunization Multilateral. and other donors If the 2015 Millennium Development Goals are to have any chance of being achieved. the donor funding environment began to change. immunization alone will require an additional US$ 1 billion a year over the decade 2006–2015. Many donor governments have pledged to raise their development assistance to 0. according to a widely quoted estimate (58). Starting in 2005. needs to double from the current US$ 50 billion per year. bilateral. but few have fulfilled that pledge. remaining more or less at its baseline level. in order to help meet the MDGs. The Global Polio Eradication Initiative In addition to the broader immunization financing mechanisms. and were making increasing use of broad-based funding mechanisms. a number of publicprivate partnerships have been established to deliver targeted immunization goals. bilateral donors began to increasingly use the GAVI Alliance as a channel for funding.0 per infant.7 per infant between 2005 and 2010. however. bilateral.6 per infant to US$ 3. Since the start of GAVI support in 2000. from an average of US$ 2. or partnerships. to support the health sector as a whole. funding for immunization from multilateral. Such targeted efforts offer substantial benefits for broader immunization objectives – 85 . and other funding sources increased by 13% (not adjusted for inflation). Moreover. At a global level. As mentioned above. and other external donor sources is projected to average US$ 2. they started moving away from providing direct support to individual projects or interventions. Overall financing from multilateral.7% of their gross domestic product. it should be spent primarily on the poorest countries.

Chapter 4. A striking example of this is the wideranging impact of the worldwide investment in the Global Polio Eradication Initiative (GPEI). About 50% of the annual GPEI budget is spent on polio supplementary immunization activities such as the purchase of polio vaccine and transport of vaccinators. the remaining 50% is used for training of health staff. more than US$ 6 billion in international resources has been invested in the GPEI. a one-time contribution in 2007 from the International Finance Facility for Immunisation (IFFIm). in addition to an estimated equal amount in the form of in-kind contributions at the national level. Rotary International. However. refurbishment of vaccine cold-chain systems. Since 1988. such mechanisms include innovative funding partnerships between Rotary International and the Bill & Melinda Gates Foundation. Bill & Melinda Gates Foundation. and UNICEF. Rotary International. district-level micro-planning. When the recipient country’s polio eradication programme has been completed. A substantial proportion of this amount has been allocated to the strengthening of routine immunization and health systems. and the UN Foundation. In addition to ongoing support through traditional donor engagement. and for scaling up the technical capacity of networks for surveillance and monitoring of vaccine-preventable diseases. and a budget allocation from the G8 Group of countries. Another funding mechanism is the Investment Partnership for Polio. This involves the use of long-term “soft loans” issued by the International Development Association (IDA) – the concessionary lending arm of the World Bank – to enable countries to buy oral polio vaccine. launched in 2003 by the World Bank. the Investment Partnership for Polio will then “buy down” the loans – effectively turning them into grants – through the use of a trust fund established by the 86 . which includes not only development aid but also domestic resources. the CDC. a public-private partnership launched in 1988 and spearheaded by WHO. Investing in immunization a contribution which often goes unrecognized. The GPEI is increasingly funded through innovative financing mechanisms. and towards meeting the GIVS goals (see Chapter 1).

and public health and research institutions. and to ensure the safety of immunization. Up to 2005. 87 . In 2003. 75 countries were eligible for GAVI Alliance support. The GAVI Alliance The GAVI Alliance is a public-private global health partnership that includes governments in industrialized and developing countries. the Alliance has an estimated funding gap of US$ 3 billion out of the estimated US$ 8. To be eligible for GAVI Alliance support. countries must have a GNI per capita of less than US$ 1000. due to changes in GNI per capita.State of the world’s vaccines and immunization Bill & Melinda Gates Foundation. vaccine manufacturers from industrialized and developing countries. and the World Bank). As of early 2009. international organizations (UNICEF.1 billion total funding needed.7 billion to eligible countries. As of the end of 2008. the Bill & Melinda Gates Foundation). WHO. but also to strengthen health systems and the work of civil society organizations. Over the period up to 2015. primarily for vaccines and immunization. civil society. foundations (notably. the GAVI Alliance had received a cumulative total of US$ 3. The GAVI Alliance offers all eligible countries support. All the partners have signed the Alliance’s declared mission “to save children’s lives and protect people’s health by increasing access to immunization in poor countries”. and had disbursed US$ 2.2 billion from the sale of IFFIm bonds). They must also have a costed comprehensive multi-year plan for immunization (cMYP). two countries – Nigeria and Pakistan – are making use of this funding mechanism.8 billion in cash and pledges from public and private sector donors (including US$ 1. and the UN Foundation. Rotary International. the number of countries dropped to 72. non-governmental organizations.

as part of its second phase. Investing in immunization During its first phase. During the Alliance’s second phase. from 2000 to 2005. In the third year. they receive a bonus of US$ 20 per additional child vaccinated compared with the previous year. whereby countries eligible for support are required to pay a gradually 88 . and 35.6 million against yellow fever. An analysis of 50 of the financial sustainability plans reveals an upward trend since 2000 in both national and external sources of funding for routine immunization. had previously remained largely unavailable to poor countries. GAVI Alliance support for these underused vaccines and for vaccination against diphtheria. Under the GAVI Alliance’s “immunization services support” programme. the GAVI Alliance focused on vaccines against hepatitis B and Hib – especially those used in combination with the DTP vaccine. the GAVI Alliance introduced a co-financing system. and known to have significant public health benefits. and pertussis had. which are recommended by WHO because they are safe. thanks to GAVI Alliance support. tetanus. The Alliance also focused on yellow fever vaccine in areas at risk for this disease. To meet concerns about financial sustainability. averted 3. nearly 42 million against Hib disease. all GAVI-supported countries were required to prepare a financial sustainability plan (now replaced by a cMYP). which runs from 2006 to 2015. The GAVI-supported vaccines. the focus of financial support has expanded to include rotavirus and pneumococcal vaccines.4 million children had been immunized with the full three doses of DTP vaccine – children who would not have immunized without the Alliance’s immunization support programme.Chapter 4. countries receive funds over a two-year period – the so-called “investment phase”. according to GAVI Alliance and WHO estimates. An evaluation exercise conducted by the Alliance in 2007 estimated that about 2. it is estimated that over 192 million children had been immunized against hepatitis B. By the end of 2008. cost-effective.4 million premature deaths. In 2007. launched in 2000.

State of the world’s vaccines and immunization increasing share of the cost of the vaccines provided through the Alliance. Sweden. seven countries – France. Spain. The aim is not only to assist countries on the path to greater financial sustainability.3 billion over a 20-year period. and the affordability and likely cost-effectiveness of using the vaccine. New financing mechanisms The International Finance Facility for Immunisation The International Finance Facility for Immunisation (IFFIm) is a multilateral development institution created to accelerate the availability of predictable. South Africa. The sale of these bonds provides cash that the IFFIm gives to the GAVI Alliance and that can be used immediately to fund the Alliance’s programmes. The IFFIm uses these commitments to issue bonds on the international capital markets. The World Bank acts as financial adviser and treasury manager to the project. The 89 . and the United Kingdom – had made commitments totalling US$ 5. IFFIm was created as a development financing tool to help the international community achieve the MDGs. based on their GNI per capita. Donors contribute to the IFFIm by making long-term legally binding commitments or grants to support immunization activities in poor countries. Launched in 2006 as a pilot project of the International Finance Facility (IFF). but also to encourage them to base their decisions about vaccine introduction on solid evidence about the burden of disease targeted by a vaccine. and pneumococcal vaccine. As of the end of 2008. rotavirus vaccine. longterm funds for health and immunization programmes through the GAVI Alliance in 70 of the poorest countries in the world. and promoted by the United Kingdom Government. Norway. Italy. 30 countries were using the co-financing system to pay for the introduction of the pentavalent (DTP-Hepatitis B-Hib) vaccine. By the end of 2008.

in November 2006. the Russian Federation.Chapter 4. Advance Market Commitment Conceived in 2005 by the Center for Global Development. Italy. together with the Bill & Melinda Gates Foundation. governments of developing countries are able to plan and budget for their immunization programmes – with the assurance that vaccines will be available in sufficient quantity. the Advance Market Commitment (AMC) is a new approach to public health funding. As a result. These commitments provide vaccine makers with the incentive to invest the considerable sums required to conduct research and build manufacturing capacity.5 billion to a pilot AMC targeting pneumococcal disease. and developing countries request them. raised US$ 1 billion from institutional investors worldwide. Companies that participate in an AMC make legally binding commitments to supply the vaccines at lower and sustainable prices after the donor funds made available for the initial fixed price are spent. and the World Bank. and carried forward by five bilateral donor governments. in March 2008. Norway. thus creating the potential for a viable future market. the GAVI Alliance. for the long term. However. donor funds are not provided until after the proposed vaccines have met stringent. 90 . A second offering. The Governments of Canada. and the United Kingdom. raised US$ 223 million from private investors in Japan. have committed US$ 1. It is estimated that pneumococcal vaccines – if made widely available in developing countries – could save over seven million lives by 2030. Investing in immunization IFFIm’s first bond offering. the Bill & Melinda Gates Foundation. Through an AMC. pre-agreed technical criteria. donors commit money to guarantee the price of vaccines once they have been developed. Its aim is to stimulate the development and manufacture of vaccines specially suited to developing countries. at a price they can afford.

Today. when possible. Vaccines will not prevent all diseases or all child deaths. expected future funding from governments and donors will not be enough to sustain the gains already achieved towards GIVS goals and the MDGs. governments have an unprecedented number of partners willing to help pay for vaccines and immunization. “will hinge on how national governments.” 91 . it will be important for governments to sustain and. Yet. some 40% of all funding for routine immunization is estimated to come from national government funds. For a government faced with competing priorities. As the current economic downturn unfolds. Between 2006 and 2015. increase these investments in immunization. and using vaccines. as never before. as it surely does: then why are children still dying from diseases that vaccines can prevent? The answer to this conundrum lies perhaps in the difficulty of choosing between conflicting priorities. buying. “The real challenge. The choices are made primarily by governments. and the future projections indicate increasing financing.State of the world’s vaccines and immunization A concluding conundrum If children’s lives are worth saving – and who would doubt that they are. But vaccines can prevent much of the needless suffering caused by infectious diseases – enough to help create a space where families can busy themselves with things other than sheer survival. if vaccines save lives – and the evidence is clear that they do. and if the world has the means of making. and the international community at large manage their roles and responsibilities in reaching and financing the goals of the GIVS until 2015.” the WHO-UNICEF analysis report (7) concluded. The good news is that more investment is being made in immunization. choosing is not easy.

The view from the future ter he view m he uture e 92 .Chapte Chapter 5. The vie from the future Chapter 5.

Sa State o State of the world’s vaccines and immunization world’s vaccines and immunization or d s cines n mmunizat e nization Chapter 5 The view from the future 93 3 .

tuberculosis. and HPV are expected to have inspired new health and development goals. meningococcal disease. 94 94 . and other diseases. The view from the future Key messages By the 2020s: • child deaths from infectious diseases are expected to be at an all-time low.Chapter 5. and measles eliminated in all countries. • today’s new vaccines against pneumococcal disease. • hopes remain high that new vaccines will be available to combat malaria. AIDS. rotavirus. • polio should be eradicated.

energy. and dedication. Some of these activities are well on the way to achieving their objectives. vaccines and immunization can make a major contribution to achieving the MDGs and thereby reduce the gross inequities that create an ever wider gap between the haves and have-nots (Chapter 1). more vaccine producers in developing countries. especially mass campaigns. Vaccine development presents a dynamic picture (Chapter 2) – safer and more effective vaccines coming off an exceptionally rich pipeline. too. enthusiasm. Clearly. But the overall picture is one of cautious optimism. The vaccine world. innovative regulatory mechanisms. more efficient ways of making vaccines. Others are stalling. has set a number of goals: its GIVS identifies the targets to be reached if immunization is to lend its full potential to achieving the MDGs. 95 .State of the world’s vaccines and immunization This report paints a picture of where the many and diverse activities relating to vaccines and immunization stand today. more efficient ways of ensuring maximum vaccine safety and efficacy. and more partnerships harnessing the combined strengths of the public and private sectors to spur development of even better vaccines. Administration of measles vaccine through the aerosol route could facilitate measles immunization efforts. for one reason or another.

are the achievements of major thrusts to remove the burden of three diseases: polio is close to being eradicated. A groundswell of activities and projects – some new and some newly revitalized – are working to achieve this goal (Chapter 3). and maternal and neonatal tetanus is well on the way to being eliminated (see Box 17). Funding to pay for all these activities is clearly on a more solid footing than it was a decade ago (Chapter 4). where the main focus has been on infants and young children. including groups – such as adolescents. Governments – even of some of the poorest countries – are spending more on vaccines and immunization. disease-preventing power of vaccines. Innovative mechanisms for mobilizing and channeling donor funds have created new incentives among almost all players on the vaccine and immunization stage. And less recent. women outside child-bearing age – and members of hard-to-reach communities – who have been neglected to some degree by traditional immunization policies. for example – immunization becomes a driving force for child survival and for meeting MDG 4. from the vaccine industry to the health ministry. diarrhoea. To some extent. elderly people. A new. More people are being reached with vaccines. The view from the future To meet the goals of the GIVS. more people need to benefit from the life-saving. deaths from measles have plunged to record lows. ambitious plan to create a global network for the surveillance and monitoring of vaccine-preventable diseases is also taking shape. When linked with other health interventions – to prevent and treat childhood pneumonia. New strategies have also been put in place to accelerate the integration of immunization programmes within the health systems of countries. and malaria. Donors – both multilateral and bilateral – have increased their generosity and are currently financing about a fifth of immunization costs worldwide.Chapter 5. but no less exciting. and to expand the use of these programmes to deliver other health interventions. the entire field of vaccines and immunization is buoyed by an 96 .

vaccines against yellow fever and Japanese encephalitis – are being used in a growing number of countries. pertussis. Another potential breakthrough is the development of an increasing number of vaccines that are heat-stable. delivering vaccines into the human body may. and oral pills. have done away with devices that use needles. The problem is that. measles. Over the next decade or so. Some of these vaccines (such as the HPV vaccine) will be given to adolescents. adolescents. others (such as the influenza vaccine) to adults. rubella. especially as school attendance is growing in many developing countries. pneumococcal disease. Over the next decade. will be given to older children. and rotavirus – and. or lungs (currently being tested in humans with a measles vaccine. Some needle-free approaches are already appearing. and pertussis. these vaccines should be available for use outside the cold chain – greatly relieving the pressure on the cold chain and logistics. and tuberculosis. In many countries. adhesive skin patches. increasing numbers of developing countries should be using the new vaccines coming onto the market. and in monkeys with an HIV or HPV vaccine). such as those against tetanus. and will need to be integrated into the immunization schedules of developing countries (as they are today in industrialized countries). with the exception of special immunization campaigns. in areas where they are needed. second doses of the measles vaccine will be offered through routine immunization programmes to children beyond their first birthday. to a large extent. routine immunization schedules have gone beyond the six traditional childhood vaccines – diphtheria. Moreover. polio. booster doses of some of the traditional vaccines. and others are still in the experimental phase. When supplied with a vaccine vial monitor to check exposure to heat. Hib. School-based immunization is a possibility. diphtheria. there is little knowledge or experience about how to reach older age groups in developing countries. in most developing countries.State of the world’s vaccines and immunization Box 17 The future of immunization How will immunization change over coming decades? Today. and adults. drops under the tongue. They include vaccines in aerosol formulations that are sprayed into the nose (already available for an influenza vaccine). Vaccines against hepatitis B. 97 . tetanus.

is facing a massive financial and economic crisis. The world. with the financial world in turmoil. UNICEF. health aid has doubled. Views differ about the potential impact of the economic downturn on future donor health funding. However rough the path into the future may be in some places. sustainable funding. and international health and development organizations (WHO. today’s vaccines and immunization scene clearly bears the mark of progress. Its partners span almost the entire spectrum of vaccine and immunization activities: private foundations and governments of industrialized countries. Current efforts. Optimists remain hopeful that the MDGs will exert a strong enough “pull” on the donor community to provide predictable. are being made to assist these governments in making decisions about vaccines and 98 . The view from the future unprecedented influx of new wealth. cash is scarce. that the current momentum within the vaccine community and the current soaring trends in the life-saving achievements of vaccines will motivate the donor community to keep immunization high on their priority lists. which raises the question: How long can the dynamo that drives progress in the vaccine arena continue to function? A look at the forces driving the dynamo may hold some clues. in both developing and industrialized countries. More funds from more sources are clearly a driving force for all areas of work on vaccines and immunization.Chapter 5. according to one report (59). that should bear fruit in the future. industry. Increasingly. as it enters the final years of this decade. partnerships are becoming important drivers of vaccine development and deployment. As of early 2009. and that it will encourage donors to sustain and even increase financial support well beyond the 2015 deadline for achieving the MDGs. The GAVI Alliance – a public-private global health partnership – is a prime example of this trend. Since 2000. The effects of these funds have rarely been so visible. the World Bank. Perhaps the most crucial partners are the developing countries. and others). civil society organizations. whose governments are responsible for choosing and using the vaccines that are available.

In the long term. government ownership of national immunization programmes. But growing awareness of the benefits of vaccines is also likely to increase concerns over their safety. and vaccine advocates will feel the need to offset rumours and doubts with even more timely. strategies. the MDGs should have brought child deaths from infectious diseases to an all-time low. accurate information than they provide today. Polio 99 . the vaccine supply landscape is likely to have changed by 2020. adapting. Public demand in developing countries is likely in the future to be as strong as it is today in industrialized countries. As for vaccine development. For another. And their contribution to global vaccine supply may well be on a much more equal footing with industrialized countries than it is today – a development likely to increase competition.State of the world’s vaccines and immunization immunization – decisions that should be made on the strength of sound evidence. one driving factor is the progress being made in devising. Over the next two decades that demand should rise. Another force likely to drive future vaccine development and expand immunization coverage is public demand for vaccines and immunization services. Their claim to a share of these benefits is likely to become bolder. Judging from current trends. thereby boosting the popularity of immunization. should ensure the sustainability of today’s investments in immunization. Vaccine producers and regulators will no doubt feel increasing pressure to ensure that vaccines are safe. monitoring. developing countries may well have acquired the capacity to make their own state-of-the-art vaccines that meet their own specific needs. Certainly. Will those advances continue? And will they justify the setting of new goals for combating vaccine-preventable diseases and deaths? Looking into the 2020s. and reporting. more vaccines are likely to become available against more diseases. For one thing. more people are likely to have access to more education and to have a greater awareness of the benefits of immunization. and using advances in vaccine science and technology. including country-driven policies.

there is no question. AIDS and other diseases that seem. rotavirus. 100 . of course. It has worked in the past. especially when it’s about the future”. there is every reason to believe that immunization will continue far into the future to be a mainstay of human health.Chapter 5. “The business of predicting. But. Immunization works. hepatitis B. It is working in the present. unconquerable.” as Nobel laureate Niels Bohr is often quoted as saying. Which is another way of saying: the future holds more questions than answers. The view from the future should be a thing of the past. and yellow fever – may well have rid the world of the lethal burden of these diseases. Today’s underused vaccines – against Hib disease. Surely today’s new vaccines – against pneumococcal. tuberculosis. though. and HPV disease – will have inspired tomorrow’s new goals for going beyond the life-saving achievements of the current international health and development goals. Climate change is already a major challenge and is likely. Neonatal and maternal tetanus should no longer be exerting such a heavy toll on babies and their mothers. vaccine science and industrial inventiveness will have produced high-performance vaccines capable of turning the tide against malaria. About one thing. The world is currently facing the challenges of economic recession and financial turmoil. meningococcal. And short of a radical change in human biology. and measles eliminated in all countries. today. “is very difficult. over coming decades. to alter the epidemiological landscape in which vaccines and immunization operate. new goals will likely face new challenges. And surely.

State of the world’s vaccines and immunization 101 .

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State of the world’s vaccines and immunization Part 2: Diseases and their vaccines 103 .

such as inconsistency in the case definition and a lack of a standard vocabulary (61). and inadequate sanitation. the disease spread eastwards throughout Europe and Asia. in 1884 by the German microbiologist Robert Koch. a total of 236 896 cases were notified to WHO from 52 countries: 31 out of 46 African countries experienced an outbreak of cholera and reported a total number of 202 407 cases with 5259 deaths (62). Today. rapidly followed by dehydration. V. About 80% of cholera episodes are of mild-to-moderate severity. The causative agent of cholera was first discovered in 1854 by the Italian scientist Filippo Pasini. varying from 100 000 to 300 000 cases per year. In 2006. the actual number of cholera cases is known to be much higher. and finally reached Latin America early in 1991 (60). The seventh pandemic. cholerae is transmitted by contaminated water and food and. It consisted of the killed whole cholera bacterium and was administered by injection. like typhoid fever. with Africa accounting for more than 94% of the total. poor hygiene. The number of cholera cases reported to WHO annually has remained relatively constant since 1995. several injectable whole-cell cholera 104 . in the International Health Regulations (IHR) that replaces compulsory public notification of cholera with a more discreet outbreak response arrangement between affected countries and WHO. began in 1961 in Indonesia. Africa. Over subsequent years. in the absence of treatment. Today. limitations of surveillance systems. The problem may be less acute following the change. no country requires proof of cholera vaccination as a condition for entry. renal failure and death (1). where outbreaks have occurred since the early 1800s. up to 50% of infected people died from the disease. Globally. which is still ongoing. the discrepancy is the result of underreporting due to fear of unjustified travel and trade-related sanctions. In that year. Vibrio cholerae. and. is associated with poverty.Part 2: Diseases and their vaccines Cholera – exploring the use of available vaccines Often referred to as one of humankind’s “most devastating diseases”. and westwards to the Americas. In the past. seemingly independently. cholera was for centuries a permanent feature of life in the slums and poverty-stricken villages of India. and “re-discovered”. on a global average (61). then spread through Asia and Africa. Cholera usually responds to prompt administration of oral rehydration salts to replace lost fluids. the risk of death is less than 3%. and Asia (60). Europe. From there. and this perhaps represents 10-20% of all cases (63). before the advent of fluid replacement therapy. Ships sailing from the Bay of Bengal during an 1817 epidemic are believed to have brought the disease to Europe in bilge water contaminated with the causative organism. there have been seven major cholera pandemics in areas of South America. the first cholera vaccine was made and began to be used in Spain. in 2005. Since 1817. The disease typically begins with an acute attack of diarrhoea and copious vomiting.

and has since been implicated in a growing number of outbreaks in Asia. despite its shortcomings. cholerae after oral administration of a single dose. the WC/rBS vaccine. it was successfully deployed in mass campaigns carried out in Indonesia. the vaccine R&D pipeline holds the promise of several new vaccines which. Field trials in Bangladesh. The year 1959 saw licensure of the first cholera vaccine to benefit from modern manufacturing technology. such as urban slums. its protective capability takes about three weeks to develop after administration of the first dose. and the first to be submitted to reliable scientific scrutiny. in the first instance. cholerae strain (serogroup): until recently. cholerae linked to a genetically engineered (recombinant) fragment (B-subunit) of the cholera toxin. From a public health standpoint. Over the period 2003–2006. Second. 0139. Guided by its Global Task Force on Cholera Control. including India and Russia. Since 2006. Meanwhile. 105 . several well-designed studies in Asia found that the vaccine possessed only limited efficacy and caused a significant number of side-effects. it is effective only against the 01 V. WHO is weighing how best vaccines might be used to supplement these basic measures. first licensed in Argentina in 1997 and code-named WC/rBS. It does have shortcomings.State of the world’s vaccines and immunization vaccines made their appearance and were used in millions of people in several countries. where these measures are particularly difficult to apply. Protection is highest during the first six months after vaccination but lasts for up to three years (64). particularly in areas. would be affordable by developing countries. was identified as the cause of epidemics in Bangladesh and India. WHO’s cholera control policy (61) calls. if they fulfil their promise. Reported efficacy of these early vaccines varied widely. of which only one is available for widespread use today. though. The search for a safer. this strain was the most frequent cause of epidemics but in 1992 a second serogroup. more effective cholera vaccine produced three new-generation vaccines. particularly in epidemics. 65). As of mid-2008. is the only new-generation cholera vaccine recommended for use by travellers to choleraendemic areas. it requires two doses given one week apart and taken with liquid (a buffer solution to neutralize stomach acid) – two factors that complicate its use. Mozambique. However. the use of cholera vaccine should be considered by governments in the context of other public health priorities (61. and the only one to have been used in mass vaccination campaigns. and the Sudan. WHO has recommended that in complex emergencies. First. is made from the whole-cell V. This vaccine. or in conditions. for the improvement of basic sanitary conditions and hygiene. Mozambique. Third. such as epidemics. and would not require or overload current cold-chain facilities. would confer long-lasting immunity against all predominant strains of V. and Peru found the vaccine to be effective and safe.

Diphtheria is highly contagious. The rationale was that the toxin would stimulate immunity and the antitoxin (antibodies) would counteract the toxicity of the toxin and prevent it from causing disease in the recipient (1). in 1883. a major epidemic occurred in Europe and spread to the United States. mostly in infants and young children. devastating epidemics have made diphtheria one of the most feared childhood diseases (67). killing about 50% of infected people. the disease is fatal (66). The hallmark of diphtheria is a greyish-white membrane (a pseudomembrane) that forms on throat tissue. in 1907. it can cause death by suffocation.Part 2: Diseases and their vaccines Diphtheria – controlled by vaccines but waiting to resurface Diphtheria is a disease of the upper respiratory tract caused by the bacterium Corynebacterium diphtheriae. and when the toxin travels in the blood or lymph system. When this membrane spreads downwards into the larynx. Two millennia later. gave the name “diphtheria” to the disease (from the Greek word for “leather”) (1). and trachea. Diphtheria epidemics continued to ravage Europe over subsequent decades: in 1943. Thanks to this prophylaxis. diphtheria swept across Europe in the 17th century. including the heart (resulting in myocarditis) and nervous system (resulting in polyneuritis) (1). Starting in 1910. and a similar number of cases and deaths were believed to be occurring every year in developing countries at the time (67). about one million cases and 50 000 deaths occurred. The organism spreads through direct physical contact or air-borne droplets. Towards the end of the following century. In more than 10% of cases. it can attack just about any organ in the body. Corynebacterium diphtheriae was identified in a German laboratory as the causative agent. 106 . Corynebacterium diphtheriae also causes a cutaneous infection that is a further source of transmission. however. experiments had begun on using a toxin–antitoxin (TAT) solution to induce protective immunity. Meanwhile. However. French physician Pierre Bretonneau. who in 1825 performed the first successful tracheotomy to save the life of a patient threatened by suffocation from the leathery membrane. larynx. The latest WHO estimates for 2004 put the number of deaths worldwide at 5000. Most cases run a mild course with only sore throat and fever. Throughout history. The organism. and Greek writings (1). of which 4000 are in children under five (4). and may confer some protection against the respiratory disease. several cities in Europe and the United States set up immunization programmes to administer the TAT complex. and often no symptoms at all. secretes a toxin that can cause inflammation of the pharynx. Known as “the strangler” in Spain and “the gullet disease” in Italy. By the beginning of the 20th century. the disease was causing about 150 000 cases and 13 000 deaths annually in the United States. Egyptian. the average death rate among infected people declined from about 50% to under 15%. the earliest detailed descriptions of the disease date from ancient Syrian.

and high vaccine coverage rates in most countries have mostly eliminated the risk of epidemics. Over the same period. The paradox is still the subject of debate. Re-vaccination of health-care workers and using the dT combination vaccine (rather than the tetanus toxoid alone). the Middle East. Another observation fuelling debate is the high percentage of adult cases in these epidemics. 107 . In the 1990s. without depriving it of its immunestimulating (immunogenic) properties. The resulting product was a safer vaccine. from 97 774 to 4273 (41) (reported case numbers rarely reflect true numbers but the trend certainly shows a convincing inverse relationship to vaccination coverage). 81% of all infants worldwide were protected with three doses of DTP (41). By 1980. In 1974. the standard diphtheria vaccine and one of the safest and effective in the immunological arsenal. These observations have prompted countries where diphtheria is no longer endemic to extend vaccination protection beyond the primary three-dose series for infants by administering one. and South America (41). researchers discovered that they could attenuate the diphtheria toxin by exposing it to certain chemicals or to heat. Some countries with high infant vaccination coverage rates are giving booster doses of diphtheria toxoid to older children to compensate for the loss of natural immunity that they would have acquired from exposure to the bacterium had it still been circulating. Diphtheria is no longer endemic. in countries with low (<50%) routine immunization coverage the risk of epidemics is still high. with only minor modifications. If nothing else. booster doses every 10 years to adults through the diphtheria-tetanus (dT – low content of diphtheria) combination vaccine (67). Paradoxically. or sometimes two. reported cases worldwide fell by more than 95%. 20% of the infant population was receiving the full three-dose series of DTP (41). diphtheria outbreaks have also occurred in Africa. less likely to cause allergic reactions than the TAT complex. some of the affected countries had relatively high reported vaccination coverage rates (67). for prophylaxis against tetanus following injury are additional safeguards some countries are adopting to lower the risk of a diphtheria outbreak (67). even where infant vaccination coverage was high and adults were receiving booster vaccine doses. this outbreak served as an object lesson in the risk countries face when they lower their vaccination guard. However. national routine immunization programmes working with WHO’s newly created EPI. By the end of 2007. Asia. a particularly alarming epidemic broke out in countries of the former Union of Soviet Socialist Republics following a drop in vaccination coverage. Since 1990. To this day the toxoid has remained. began using the diphtheria toxoid as one of the components of the DTP combination vaccine.State of the world’s vaccines and immunization In the early 1920s.

an additional 8000 deaths are estimated to occur in HIV-infected children. WHO estimates of the year 2000 attribute to this bacterium an annual toll among the under-fives of nearly 8.1 million cases of invasive disease and pneumonia of which 363 0001 are fatal (68). researchers used conjugation technology to develop several vaccine products that were highly immunogenic and conferred protection on all age groups. or Hib. however. Following the WHO global recommendation. has been known by epidemiologists to cause meningitis. thereby masking the role of Hib. prompting WHO to recommend its inclusion in the routine immunization programmes of all countries where Hib was recognized as a public health burden and where the cost of the vaccine was not prohibitive (70). showed a drop in pneumonia incidence of just over 20% in Gambian children (69). in particular. especially in developing countries. large-scale studies in Africa and Latin America. and trachea. 108 . bones. Yet. and with growing demand for the vaccine together with increasing supply. Haemophilus influenzae type b. Since the early 1980s. and more recently also in Asia. found a substantial reduction in the burden of pneumonia and meningitis in countries that had used the vaccine widely. Wide use of this Hib “conjugate” vaccine enabled several countries – both industrialized and developing – to virtually wipe out Hib disease. by 1997 only 29 countries were using it routinely. the cost of the three doses of the single-antigen Hib vaccine had fallen to approximately US$ 10. Over the next few years. Notwithstanding clear evidence of the vaccine’s efficacy. mouth. beyond the epidemiologists and public health analysts of the vaccine community. One reason is the difficulty in detecting this bacterium as a common cause of pneumonia and meningitis cases.Part 2: Diseases and their vaccines Haemophilus influenzae type b (Hib) – increased attention for this little known but lethal disease Since the mid-20th century. the burden of Hib disease is still not widely appreciated. both these conditions were to prove deterrents to Hib introduction for many countries. blood. and is now beginning to see even more 1 reflects only deaths in HIV-negative children. joints. heart. The problem is complicated by the fact that in many parts of the world. pneumonia. Moreover. One African trial. clinicians have treated these diseases with antibiotics. Hib also causes potentially severe inflammatory infections of the face. epiglottis. peritoneum. and other serious infections in infants and young children.

10) and a further 25 countries are expected to do so before the end of 2009. those with a per capita gross national income of less than US$ 1000). the GAVI Alliance began offering financial support for procurement of the vaccine to its then-75 eligible countries (i. the London School of Hygiene and Tropical Medicine. In 2000. 109 . 135 countries had adopted the vaccine in their routine immunization programmes (Fig. The year 2005 also saw the birth of the Hib Initiative.e. that was set up. and the CDC). bringing the total to 160 countries. a consortium of four public health entities (WHO. with GAVI Alliance support. Johns Hopkins Bloomberg School of Public Health. or 83% of all 193 WHO Member States (71).State of the world’s vaccines and immunization significant declines. By late 2008. to speed up the adoption of Hib vaccine (70).

110 Figure 10 Countries introducing Hib vaccine 1997 to 2008 1997 26 countries introduced Part 2: Diseases and their vaccines 2008 133 countries introduced 2 countries partially introduced Source: (71) .

but the risk of death increases with age. where their use led to a dramatic decline in cases. with the symptoms related to age. Similar drops in incidence have been seen in other countries or areas of countries. Prompt detection of a resurgence of Hib disease could enable an appropriate vaccination response to be made. Most people recover after a few weeks. the infant vaccination schedule with Hib conjugate vaccines is usually followed by one further dose during the second year of life. anorexia. dark urine. fever. and case fatality may range from zero in children under 5 years old to 1. therefore. and abdominal discomfort. and 70% of children under six years of age may have no symptoms. WHO recommends that the results of appropriate epidemiological and costbenefit studies should be weighed carefully before deciding on national policies on 111 . older children and adults who do not have immunity. Recent data from Latin America and Africa suggest that Hib disease can be eliminated with a three-dose regimen. young children may not be infected. in countries where its incidence is lower. hepatitis A becomes more visible and controlling the disease through vaccination becomes a possibility.State of the world’s vaccines and immunization Hib vaccines are administered at the same time as DTP. HAV infects more than 80% of the population before adolescence. In industrialized countries. the Hib vaccine is only used for younger infants. Severe complications are rare. In most other countries.5% in people aged over 60. often in combination vaccines that also include the DTP and hepatitis B antigens. such as Israel. with the result that the disease is the most commonly reported of vaccine-preventable diseases in these countries. The paradox of hepatitis A is that the very countries in which the disease is most prevalent are those where it has least visibility. Infection with HAV does not become chronic. in industrialized countries with better sanitation. and Spain. outbreaks of the disease are very evident. At the present time. Currently. but during outbreaks. In developing countries. may be ill with jaundice for up to two months. But this paradox also defines the potential: when countries improve their socioeconomic conditions. there are no compelling reasons for recommending a fourth dose of vaccine outside of the routine immunization programme. Inactivated hepatitis A vaccines were licensed in the United States in 1996. Hepatitis A – paradox and potential Hepatitis A is an acute illness caused by a virus (HAV) transmitted through the faecaloral route. However. Italy. To help dispel such doubts. it is not yet known whether the protection conferred by the primary three doses will last a lifetime or if susceptibility to Hib infection could appear later in life. In contrast. It is characterized by jaundice. countries using Hib vaccines need to sustain surveillance for bacterial meningitis.

Hepatitis B – the first vaccine against cancer Of the many viruses known to cause hepatitis. The most feared effect of HBV is chronic or lifelong infection – feared because it can lead to death from cirrhosis or cancer of the liver (1). the first hepatitis B vaccine – the first vaccine against a human cancer – became available. fever. Where transmission of the infection 112 . In 1992. More than 350 million people in the world today have chronic hepatitis B infection. as in most infants and children. Over the next decade. People infected with HBV are between 50 and 100 times more infectious (to others) than those infected with HIV. totally absent. according to a WHO estimate (73). They may be mild or. In countries of intermediate endemicity where a relatively large proportion of the adult population is susceptible to HAV. suggests that universal hepatitis A vaccine introduction can reduce the disease to very low nationwide incidence rates. through a skin wound. malaise. vaccination against hepatitis A is indicated for individuals with increased risk of contracting the infection. the HBV virus is capable of remaining viable for over one week on contaminated environmental surfaces. the infection runs an acute course lasting from one to three months. In highly endemic countries. In 2002. nausea and vomiting. In regions of low endemicity. Evidence from use of the vaccine in the United States and other countries. or through use of an infected needle or syringe. large-scale childhood vaccination may be considered as a supplement to health education and improved sanitation. In such countries. WHO called on all countries to use the vaccine in their routine immunization programmes. and fatigue. Further. raising the possibility of ultimately eliminating the disease. from an infected mother during childbirth. The infection spreads by exposure to blood or other body fluids of an infected person. an estimated 600 000 deaths occurred from chronic HBV infection. compared with 30% of children infected between one and four years. In 1982. Symptoms include jaundice. and less than 5% of people infected as adults (1). and where hepatitis A represents a significant public health burden. large-scale hepatitis A vaccination is not required. and.Part 2: Diseases and their vaccines immunization against hepatitis A (72). without causing symptoms but effectively protecting the population against symptomatic hepatitis A disease in later life. studies showed that the vaccine could protect about 95% of recipients from HBV infection. HAV infects virtually all young children. the hepatitis B virus (HBV) inflicts the heaviest public health burden. loss of appetite. About 90% of infants infected during the first year of life develop chronic infection. in the case of infants. muscle pain. as in sexual contact. In most cases.

for example. at least for the poorer countries of the world. 171 of WHO’s 193 Member States were using the vaccine in their infant immunization schedule. that began reaching high vaccine coverage rates in the late 1990s. thanks to blood (serological) tests for hepatitis B infection markers. Over subsequent years. By 1997 – the WHO deadline for universal adoption of the vaccine in infant immunization programmes – only 62 countries had adopted the vaccine and only 14% of children were receiving the full three doses (41). Limited recognition of the burden of HBV infection and lack of funds to deploy the vaccine were among the main obstacles to wider introduction of the vaccine. and those with multiple sexual partners. Adoption of the vaccine in routine immunization programmes was slow to take off. On the contrary.State of the world’s vaccines and immunization during childbirth is common. The advent of the GAVI Alliance in 2000 helped to erode the financial obstacles to introducing the vaccine. injecting drug users. 113 . the impact on chronic HBV infection is easier to assess. the first vaccine dose should be given to babies within 24 hours of birth. showed a 90% drop by 2006 in the prevalence of chronic HBV infection in children under five years old (74). such as health-care workers exposed to blood or other body fluids. Communities in China. By the end of 2007. prison inmates. Several countries achieving high vaccine coverage rates have seen a substantial reduction in the prevalence of chronic infection. WHO-sponsored research on the disease burden in developing countries did much to raise awareness of the infection and its consequences. as it is in several developing countries of WHO’s South-East Asia Region. since it requires intense surveillance for acute disease and laboratory confirmation. dialysis patients. household and sexual contacts of chronically infected people. WHO also urges countries to vaccinate adults at risk of infection. The impact of vaccination on acute HBV infection is difficult to evaluate.

the Health Ministry made the vaccine universally available through the national immunization programme. The disparity is declining. by a Ministry decision to abolish all fees for recommended infant vaccinations. US$ 76 million project co-funded equally by the Government of China and the GAVI Alliance – has averted over 200 000 premature deaths due to chronic HBV infection. Almost 10%. It is estimated that this initiative – a five-year. and every hospital must keep enough vaccine available for administration of the birth dose. Overall. is raising public awareness of the need to have all infants fully immunized with hepatitis B vaccine from birth and to avoid discriminating against people already infected with HBV. was a barrier to disadvantaged high-risk populations. however. China aims to reduce chronic HBV infection rates to less than 1% in children under five years of age. in 2005. and a drop in the chronic infection rate over the same period to less than 2% of children under five. To achieve this goal. In response. approximately 60% of the population has a history of HBV infection. women are encouraged to give birth in hospitals. This was followed. China Hepatitis Prevention and Control. 280 000 people in China die from liver cancer or cirrhosis.Part 2: Diseases and their vaccines Box 18 Hepatitis B control in China: reducing disparities Every year. Even within this alarming statistic there are marked disparities between rich and poor provinces. By 2010. China has made major investments in improving delivery of the hepatitis B vaccine. or 120 million people. A high-profile nongovernmental organization. Some western provinces only attained around 70% of birth dose coverage by 2006. but more work is needed for China to reach its national goals (74). with the recommendation that the first dose be given within 24 hours of birth. which may be due to the higher proportion of home births in those areas. are chronically infected with HBV and risk early death from liver disease. The cost of immunization. The outcome of these measures has been dramatic: a surge in national birth dose coverage from 29% in 1997 to 82% in 2005. 114 . accounting for almost one third of all HBV-related deaths worldwide. In 2002. Hepatitis B vaccination for infants was introduced in 1992. therefore.

to less than eight cases per 100 000 (77. the reduction by 2012 of the average regional prevalence rate of chronic HBV infection to less than 2% in children under five years old. in many countries. reaching babies with the “birth dose” of vaccine is problematic. In countries whose national immunization schedule includes a hepatitis B vaccine dose at birth. Moreover. warts on the skin and genital area. 76) in industrialized countries. there could be areas where most childbirths take place at home: in such areas. the causative agent is human papillomavirus (HPV). More than 80% of these cases and deaths occurred in developing countries. In all cases. In most developing countries. Human papillomavirus – a second cancer vaccine It is estimated that. Widespread use of screening (Papanicolau) tests by industrialized countries in the 1960s and 1970s brought incidence down by more than six-fold. The highest incidence rates are in sub-Saharan Africa and Latin America. however. In 2008. WHO is working with these countries to close this gap. In the mid-1980s. namely. if unsightly. only 65% of children were receiving it.State of the world’s vaccines and immunization Growing confidence in hepatitis B vaccination has prompted WHO’s Western Pacific Region – where all countries use the vaccine – to set a HBV control goal. and also in parts of Asia (India alone accounts for nearly a quarter of cases occurring annually in the world) (76). the WHO Strategic Advisory Group of Experts (SAGE) strongly recommended that “all regions and associated countries develop goals for hepatitis B control appropriate to their epidemiologic situations. Worldwide. DNA analysis by German researchers revealed the presence of genes 115 . Up to about 20 years ago. health workers and other high-risk groups are not being vaccinated in sufficient numbers. cervical cancer is the second most common cancer in women. and in developing countries. But there are still challenges confronting HBV control efforts. A third problem is the continuing risk of HBV transmission from unsafe injection practices and blood transfusion procedures: efforts are under way to reduce this risk. in both women and men. in 2002. there were 493 000 cases of cervical cancer and over 274 000 related deaths (18). the relatively high cost of screening was prohibitive (78). Although close to 90% of the 193 WHO Member States were using the vaccine by the end of 2007.” The numbers of countries adopting the hepatitis B vaccine and the numbers of regions setting disease reduction goals show encouraging trends. Efforts are under way to make mothers and immunization providers in such areas more aware of the importance of protecting newborn infants with this initial vaccine dose. after breast cancer (75). HPV infection was generally considered a cause of relatively harmless.

many cases (40%) of vulvar and penile cancers. and co-infection with HIV. postulated by Italian physician Rigoni-Stern in 1842. Today. but research quickly came up against two stumbling blocks.The peak incidence of HPV infection is in the 16–25 year age group (77. The virus was clearly a “necessary cause” of cervical cancer. the infection disappears spontaneously (1). although the peak incidence of the HPV-related cancer is between 45 and 64 years (77). prolonged use of oral contraceptives. Contributing to the risk of HPV infection are factors such as early age of sexual activity. Cervical cancer is not the only cancer attributable to HPV.Part 2: Diseases and their vaccines from the virus in cervical cancer cells taken from thousands of women. This evidence put to rest beliefs that over the centuries had invoked such things as toads. cigarette smoking. HPV is known to be transmitted through sexual contact – not only penetrative sexual intercourse. 13 genotypes account for more than 95% of oncogenic HPV infections and have been labelled “high-risk” HPV types (76). although it is the most common. and of these. the whole virus contains 116 . or herpes simplex virus (77). and in 10–12% of these cases. About 106 are known to cause disease in humans. Work on developing a vaccine against HPV began in the 1980s. The relative frequency of high-risk HPV genotypes (with types 16 and 18 causing about 70% of infections (78)) is fairly constant over all regions of the world (77). i. 78). was close to the truth: observing that nuns never died of cervical cancer. it progresses over the next 20 to 30 years to cancer (1). Most cases of HPV infection produce no symptoms. he assumed that sexual activity was to blame. getting the virus to grow in the quantities needed to produce a vaccine proved difficult. chlamydia. “Low-risk” HPV genotypes – those rarely associated with anogenital cancer – include types 6 and 11. a “sufficient cause”: its presence will not always produce cancer). There are probably more than 200 genetically distinct types (genotypes) of HPV virus (76). Second. In the remaining cases it persists. witchcraft and male secretions (smegma) as causes of cervical cancer. its presence is necessary for cervical cancer to develop (it is not. HPV also causes most cases (about 90%) of anal cancer. however. which cause 90% of anogenital warts and cause a relatively rare but potentially life-threatening disease of the larynx – recurrent respiratory papillomatosis (RRP) – that occurs mostly in children under five years old.e. In more than 90% of cases. accounting for about 90% of all HPV-related cancers. Within a few years of starting sexual activity. First. and a small proportion (12%) of head and neck cancers (1). but also sexual skin-to-skin contact. One cause. Initial experiments using live attenuated or killed whole virus in animals gave promising results. more than 50% of sexually active women become infected with these high-risk types (76).

The other vaccine. introduction of the vaccine is feasible. Both vaccines are based on VLP technology. has VLPs carrying two HPV genotypes – 16 and 18 – which cause about 70% of cervical cancer in most parts of the world (77). In large-scale clinical trials in industrialized and developing country settings. the bivalent vaccine was licensed in 90 countries and the quadrivalent in 109 countries. but produces as strong a protective immune response in animals as the original whole virus. older adolescent girls should be considered as a secondary target population. contains no genes or other potentially risky or infectious viral material. It is also recommended that in countries where it is feasible and affordable. 117 . financing can be secured and is sustainable. screening. and the cost-effectiveness of vaccination strategies in the country or region have been considered. with specific age ranges based on local data on age of sexual debut (most commonly 9 or 10 to 13 years). commonly known as a “virus-like particle” (VLP). a two-antigen (bivalent) vaccine. WHO issued a position paper based on these recommendations (80). In 2006. This artificial shell. The primary target population should be girls prior to initiation of sexual activity. both vaccines protected more than 90% of recipients against HPV infection. Covering the virus is an outer shell (capsid) consisting of about 360 proteins. By the end of 2008. provided this is cost-effective and does not distract from the success of vaccinating the primary target. The SAGE also recommends that where possible. and diagnosis and treatment of precancerous lesions. the SAGE established global recommendations for HPV vaccination (79). they automatically arrange themselves to form a new empty shell that is an exact copy of the original. vaccine introduction should be in concert with a national cancer prevention programme that includes education. These recognize the importance of HPV disease burden worldwide and recommend that HPV vaccination should be included in national immunization programmes where: prevention of cervical cancer and/or other HPV-related diseases are a public health priority. followed a year later by another HPV vaccine. The solution to both problems lay in the structure of the HPV virus itself. When the shell is taken apart and the proteins are put into an appropriate chemical solution. an HPV vaccine – the second against a human cancer (the hepatitis B vaccine was the first) – became available. In late 2008. One. which cause about 90% of genital warts in women and men (78). Vaccination of men to prevent cervical cancer in women is not recommended as this is unlikely to be cost-effective for cervical cancer prevention if high coverage is achieved in the target population.State of the world’s vaccines and immunization genes (oncogenes) that cause cancer and could present a risk to vaccine recipients. a four-antigen (quadrivalent) vaccine. In April 2009. It can also be readily produced in large quantities. has VLPs carrying the same HPV 16 and 18 genotypes but also 6 and 11.

The two types of influenza virus that cause illness in humans were identified in the 1930s and 1940s. the task of predicting. public health experts have been monitoring the H5N1 strain during the past few years. which proteins (or antigens) from the virus. loss of appetite. This so-called antigenic drift mechanism also gives vaccine researchers. Children and elderly people are particularly vulnerable to infection and to the risk of developing severe complications. should be included in an influenza vaccine so as to protect against the probable new virus strain. Influenza also occurs in an often devastating. the most devastating pandemic on record infected about half the world’s population and killed an estimated 20–50 million people (82). Every year. the influenza virus enjoys a constantly renewed pool of susceptible people from one season to the next. Both types (A and B) are extremely efficient at evading the human immune system. is a respiratory illness caused by a virus (1). pandemic form. and include fever. 1957 and 1968.Part 2: Diseases and their vaccines Influenza – keeping scientists guessing Influenza. Since pandemics tend to occur every 40 years or so. and fatigue. The influenza virus spreads via tiny droplets released into the air when an infected person coughs or sneezes. In the United States. they ensure that the immunity a population develops against the infection in one season will not protect the population in the following season. In 1918. which may require hospital care. influenza infections are responsible for between 250 000 and 500 000 deaths a year on average (81). Symptoms of influenza last about a week on average. In tropical countries the illness occurs with less or no seasonality. aches and pains. By constantly altering their surface molecules and thereby mutating into new strains from one season to the next. The name is Italian for “influence”. using WHO’s 85-country Global Influenza Virus Surveillance Network. dry air typical of the winter season in temperate climes. About 30–50% of infected people have few or no symptoms (1). Pandemics have been documented throughout the ages with the most recent pandemics occurring in 1918. sore throat. about 5–10% of adults and 20–30% of children come down with seasonal influenza (82). The virus has a preference for the cold. 118 . headache. commonly called “flu”. Worldwide. chills. fearing that a new pandemic might be imminent. up to 40 000 influenza-related deaths have been reported in severe influenza seasons (1). the word used by 16th century Italians to denote several illnesses believed to be caused by “the heavens” or “the stars”. In other words. several months before the onset of the influenza season every year.

State of the world’s vaccines and immunization The first commercial influenza vaccine – a relatively crude product consisting of an inactivated (or killed) whole influenza virus – became available in 1945. 83). albeit minor. About 75 countries. A live attenuated influenza vaccine has been available since 1967. In 2003. whereas the inactivated vaccine is administered mainly by intramuscular or subcutaneous injection. but since the 1970s most countries use vaccines that are purer and produce fewer. Currently available influenza vaccines protect about 70–90% of recipients provided their antigen composition closely matches that of the viruses circulating at the time (82. mostly industrialized. This is administered by nasal spray and is therefore easier to use in children. offer influenza vaccination to high-risk population groups. There is evidence that these vaccines are effective enough to reduce the number of hospitalizations in a population by 25–39% and to reduce the number of deaths by 39–75% (82). the World Health Assembly called on Member States that use influenza vaccines to provide vaccination to at least 50% of their elderly population by 2006. Whole-virus influenza vaccines are still used in some countries. 119 . The live attenuated vaccine has also been found to stimulate a broader immune response against new viral strains resulting from antigenic drift. and 75% by 2010. side-effects. than the inactivated vaccine (1). such as elderly people. especially from countries where almost all of the influenza seasonal vaccinations are offered by private health-care providers. Firm data regarding progress in meeting the goal is difficult to obtain.

which continue to circulate in birds but have also infected mammals. and its high pathogenicity (more than 60% of infected people have died from the infection). In February 2009. creating further shortages at the time of a pandemic. its long-lasting persistence in birds. and more projects are expected to begin in 2009. If demand does not exist to utilize this excess capacity. some countries consider that it is a matter of health security for them to acquire the technology to produce influenza vaccine domestically. As of May 2009. Likewise. due to overall capacity expansion. fears of an influenza pandemic. however. have begun stockpiling H5N1 vaccine in preparedness for a pandemic and several multinational manufacturers have pledged to contribute millions of doses of vaccine to a potential WHO stockpile. Asia. manufacturers are likely to rationalize some of it. Mexico. Since 2003. H5N1 influenza viruses have spread through Africa. seasonal vaccine production capacity is rising faster than annual demand – which is currently less than 500 million doses per annum – and current stockpile demand. or worldwide epidemic. Switzerland. In view of this. supply does not yet meet global needs. Several countries. including Finland. including people. 429 people in 16 countries had been infected with the H5N1 avian influenza virus according to reports of laboratory confirmed cases received by WHO (19). One was awarded a United States licence in 2007 and was provided for a United States stockpile. causing the deaths or culling of tens of millions of birds in more than 27 countries. and the Middle East. new global capacity figures for the production of influenza vaccine were published (84). This prompted WHO to initiate in 2007 an influenza vaccine production technology transfer project. 120 . Two H5N1 influenza vaccines have been developed. As of the end of 2008. and the United Kingdom. Despite this improvement. Europe. These indicate that seasonal influenza vaccine capacity is expected to increase considerably from 2009 to 2014. and yield improvements. six vaccine manufacturers in developing countries had undertaken development activities for influenza vaccines. Another was licensed by the European Medicines Agency in 2008. production capacity for producing H5N1 vaccine has increased. focused on influenza viruses belonging to the subtype H5N1. antigen-sparing techniques.Part 2: Diseases and their vaccines Box 19 Pandemic influenza – the H5N1 threat Between 2003 and April 2009. What is particularly worrying about this virus is its capacity for rapid geographical spread. Meanwhile.

By the end of May 2009. As soon as the first human cases of the H1N1 virus became known. pandemic influenza concerns expanded from H5N1 to a novel strain of influenza A (H1N1) virus. Although disease caused by the H1N1 virus has generally been mild. WHO initiated communication with the pharmaceutical and vaccine industry and discussions with experts from other relevant fields began. the status of seasonal vaccine production and potential production capacity for an H1N1 vaccine. First circulating in North America. 121 . In respect of vaccines. Mexico and the United States. severe illnesses resulting in hospitalization and a total of 95 deaths have occurred in Canada. The considerable work undertaken by WHO and partners in recent years to put in place expedited processes for regulation and licensing in the event of a large-scale epidemic or pandemic is already proving to have been a wise investment. and the timing of a potential recommendation to initiate commercial scale production of an H1N1 vaccine. potential vaccine options. the virus has rapidly spread across the world.State of the world’s vaccines and immunization Box 20 Pandemic influenza – the H1N1 threat In April 2009. The WHO Collaborating Centers and Essential Regulatory Laboratories began work to develop candidate vaccine viruses. Costa Rica. At the time of writing. 13 398 laboratory-confirmed cases had been reported in 48 countries (85). Although too early to determine the impact of the emergence of the virus. large community-wide outbreaks and school outbreaks have been reported (86). consultations focused on review of the epidemiology of infections and associated disease burden. regular communication with all those involved in vaccine production and regulation is ongoing in order to ensure appropriate and timely decisions relating to protection against the H1N1 virus through vaccination are made.

but plans have been established for a submission. reported cases of Japanese encephalitis in Japan have plummeted. Thailand. waning but still present Japanese encephalitis is a viral disease transmitted by mosquitoes of the Culex species. which is fatal in 10–30% of cases (89). such as parts of India. nausea. the disease occurs in regular epidemics. and benefits from a competitive price. with fever. it is a disease of rural areas. mostly among children under ten years old (87. This vaccine was used in China from the 1970s to the 1990s and was subsequently replaced by a new. A number of new Japanese encephalitis vaccines are in development and some are approaching licensure. it is present in an endemic. Only about 1 in 250–500 of infected people develop clinical disease (87). China incorporated the live vaccine into its routine immunization programmes. In the 1960s. attenuated vaccine – consists of a genetically engineered combination of the yellow fever vaccine with a fragment of the Japanese 122 . and diarrhoea. Permanent sequelae. In temperate areas of Asia. but from cultured cells. As such. Virus circulation has been demonstrated in many Asian regions within the tropical and temperate climate zones. which were subsequently manufactured and used in many Asian countries. cough. which is being used widely in routine programmes and mass campaigns to immunize children from 1 to 15 years of age in several countries. It is not currently WHO-prequalified. account for much of the burden of the disease. research institutes in Japan produced several refined versions of this mouse-brain vaccine. including China and India (91). One – a live.Part 2: Diseases and their vaccines Japanese encephalitis – a regional scourge. After World War II. Nepal. live vaccine using the so-called SA14-14-2 strain. They consisted of chemically inactivated virus taken from the brains of infected mice. whereas in southern. and Viet Nam. Symptoms can be relatively mild. such as cognitive and language impairment and motor deficits. not from mouse brain. vomiting. tropical areas. or severe with inflammation of brain membranes or a polio-like flaccid paralysis (90). The first Japanese encephalitis vaccines were produced in the late 1930s in the Union of Soviet Socialist Republics and Japan. Since its introduction in the mid-1950s into Japan’s immunization programme. The vaccine has turned into the most widely used product against the disease. In 2005. At least 50 000 cases and 10 000 deaths are estimated to occur every year. surveillance has intensified in many countries. but there is still a need to both better define the burden of disease and to extend surveillance in order to define populations at risk. an inactivated vaccine was developed in China based on virus grown. which pick up the virus from animals – mainly wild water birds and pigs. 4). Over the past years. or more permanent form (88).

e. based again on the SA14-14-2 strain. according to WHO.2 million in 1980 to 853 000). and produced in cell culture – is about to reach licensure. It is anticipated that several Japanese encephalitis vaccines should be on the market soon for use in endemic countries. for more than 12 months) (94). By 2002. or from severe malnutrition. and people suffering from chronic diseases and impaired immunity. consists of a one-time mass campaign. as distinct from imported cases. should immunization programmes be discontinued (1). Immunization. this so-called “chimeric” vaccine may produce long-term protection with a single dose. including vitamin A deficiency (93). such as Japan and the Republic of Korea (1).5 million in 1980 to 750 000) (1). WHO recommends that immunization against Japanese encephalitis be integrated into national immunization programmes in all areas where the disease is a public health problem. 123 . and WHO-prequalification of one or several products is expected (92). 72% of the world’s children were receiving at least one dose of measles vaccine (versus 16% in 1980). High-risk groups for complications from measles include infants. Measles – record progress but risk of resurgence is high Measles is an extremely contagious viral disease. promising a simplified immunization schedule as compared with the mouse-brain vaccine. Another – an inactivated vaccine. however. Routine measles vaccination – giving one dose of vaccine to infants – began in developing countries in the mid-1970s. and allow concurrent administration with the measles vaccine. that the virus is still circulating in the pig populations of many of these countries. has brought the incidence of Japanese encephalitis down to a handful of cases per year in the more developed Asian countries. the immunization strategy with the greatest potential impact on public health. followed by incorporation of the vaccine into the routine immunization programme (87). By 2000. together with higher standards of living and urbanization. annual reported cases had dropped by 80% (from 4. Experts warn.State of the world’s vaccines and immunization encephalitis virus strain SA14-14-2. WHO’s entire Americas Region had eliminated measles (i. had no indigenous cases. which – before the widespread use of the measles vaccine – affected almost every child. and annual estimated deaths had dropped by 70% (from 2. Many industrialized and several developing countries have since added a second dose given to children between one and seven years of age (depending on the country). In countries where the disease is endemic and where Japanese encephalitis vaccination is not yet incorporated into the national immunization programme. indicating that the risk of human infection and disease is still very much present. If it fulfils its promise.

In 2005. a 90% reduction. with a 90% and 89% fall in deaths respectively.Part 2: Diseases and their vaccines Despite these results. in 2000. accounted for most of the global decline. of measles mortality. the 2010 GIVS goal calling for a 90% reduction in measles mortality compared with 2000 estimates can be achieved. the American Red Cross. with most of the increase coming from Africa’s surge in coverage to 74%. estimated annual measles deaths had dropped by 74% from 2000–2007. the United Nations Foundation. The Eastern Mediterranean and African Regions. compared with 1999 estimates. to 197 000 globally. in 2001. up from 72% in 2000. Estimates for 2007 show a record-breaking 82% global vaccination coverage rate. from 873 000 to 345 000 deaths) (96). compared with 2000 estimates (see Chapter 1). namely. Supplementary mass immunization campaigns were to be conducted periodically. UNICEF. by 2010. Most significantly. Responding to this situation. measles was still the leading cause of vaccinepreventable deaths in children. Increased emphasis was to be placed on laboratory-backed surveillance of new measles cases and monitoring of vaccination coverage. where nearly 60% of measles deaths were occurring (96). up from 56% (97). In 2007. the Initiative extended its mandate to other regions (notably Asia) where measles was a significant burden and marked 47 high-burden countries for priority action. and the fifth leading cause of death from any cause in children under five years old (95). By the end of 2006.e. For many measles observers. 124 . with “followup” campaigns every two to four years targeting children between nine months and five years of age. The Initiative aimed to boost routine immunization coverage to more than 90% of children under one year of age in every district of these countries and to maintain coverage at over 90%. the World Health Assembly called on WHO Member States to halve measles deaths by the end of 2005. targeting all children between nine months and 14 years of age. The Initiative’s efforts gained impetus when in 2003. major financial support for the Initiative was provided on a one-time basis by the IFFIm through the GAVI Alliance. In 2004. and WHO launched the Measles Initiative aimed at reducing the death rate from measles in Africa. thereby reaching the 2010 mortality reduction goal three years ahead of schedule. the CDC. the Measles Initiative had surpassed the goal to halve measles deaths by 2005: end-of-year estimates for 2005 showed a 60% drop in global measles deaths since 1999 (i. the World Health Assembly endorsed the even more ambitious GIVS goal.

Ethiopia (1 million). In addition. • Sustaining the decline in measles deaths will call for all districts in all 47 high burden countries to be vaccinating at least 90% of children before their first birthday.8 million). there were still 197 000 measles deaths occurring annually – 69% of them in the WHO South-East Asia Region (97). Nigeria (2 million). Pakistan (0.6 million). and Bangladesh (0. • An estimated 23 million children under one year of age were. it is the lowest among all six WHO regions (97). however. 125 . in 2007. holds a number of hurdles to achieving measles mortalityreduction goals: • As of 2007. China (1 million). The main reason is because mass vaccination campaigns have not yet begun in India.5 million). still not receiving their first dose of measles vaccine through routine immunization: about 15 million (65%) of these children are living in eight populous countries: India (8. Democratic Republic of the Congo (0. Indonesia (0.5 million). and to be conducting follow-up supplementary immunization activities every two to four years. while routine measles vaccination coverage has risen from 61% in 2000 to 73% in 2007.9 million).State of the world’s vaccines and immunization Figure 11 Estimated measles deaths 2000−2007 1 000 000 High-low lines indicate uncertainty bounds 800 000 Measles deaths 600 000 400 000 200 000 2000 2001 2002 2003 2004 2005 2006 2007 Year Source: (97) The road ahead.

Before antibiotics became available. 70–80% of those infected died. is the only bacterial cause of meningitis that causes epidemics. in some instances. notably Hib and the pneumococcus (Streptococcus pneumoniae). headache. stiff neck. of which the most severe include loss of a limb. Early symptoms of meningococcal disease include high fever. Europe (2010). in the nose and throat tissues of about 10–25% of the world’s population – the healthy carriers (1). together with the availability of hospital-based intensive care units. causing isolated cases. the Eastern Mediterranean (2010). and deafness. but about 20% of survivors have important sequelae. Four of the six WHO regions have elimination goals – the Americas (for 2010). Meanwhile. nausea and vomiting. major epidemics have been occurring over the past 100 years (1. In Africa. reducing global measles mortality remains the overriding concern. against a backdrop of smaller annual epidemics (100). in a small number of these healthy carriers. mental retardation. as yet there is no global consensus on global elimination or eradication of measles. In 5% to 15% of cases. usually within a day or two. Treatment with antibiotics has reduced the death rate among infected people to less than 15% (98). since the year 2000. Meningococcal disease – still a deadly menace across Africa The meningococcus (Neisseria meningitidis). the resulting disease is meningitis. although the disease remained endemic. more alarmingly. Although the 126 . is a major cause of meningitis and is permanently present (endemic) in every country in the world (98). and the Western Pacific (2012). The meningococcus. and disability in 50 000 people.Part 2: Diseases and their vaccines • Looking to the future. the largest epidemic in history swept across the belt. WHO estimates that about 500 000 cases of meningococcal disease occur every year worldwide (98) causing 50 000 deaths. an estimated 25 000 deaths. as a colonizing bacterium. however. the organism becomes invasive and. It is also present. Large epidemics tend to recur in the meningitis belt every 7–12 years. Other causes of meningitis are viruses and other bacteria. For reasons that are not clear. in most cases. epidemics. epilepsy. causing over 250 000 cases. In 1996 to 1997. a severe blood infection (fulminant septicaemia) or joint infection (septic arthritis) (1). With the advent in the 1940s of antibiotics. more than 7000 cases have been reported in western Europe and about 3000 in the United States (1). large-scale epidemics began to peter out in industrialized countries. On average. 98) – most of them in the so-called “African meningitis belt” that spans sub-Saharan Africa from Senegal in the west to Ethiopia in the east (99). the clinical disease is pneumonia or. clusters of cases and.

or for selected high-risk groups during epidemics. A vaccine against one group does not confer cross protection to another group. B. they gave little or no protection to children under two years of age. The early meningococcal vaccines. but several vaccine manufacturers have products that are being evaluated clinically. based on the organism’s outer sugar capsule. there are no licensed vaccines against the group B meningococcus. group B occurs in many regions. Work on a vaccine against the meningococcus began in the 1890s (1). groups A. four new-generation conjugate vaccines (see Chapter 2) have appeared. C. group B vaccines that have been custom-made against specific epidemic strains have been successfully used to control specific outbreaks in Brazil. B. targeting one (group C) or four groups (A. Chile. Group A is predominant in Africa and Asia and is the main cause of epidemic meningitis in sub-Saharan Africa. W-135). C. and C. not to speak of the social lives of its nearly 400 million inhabitants (100). Despite their shortcomings. developed between 1900 and the 1940s. To date. At least five more candidate conjugate vaccines are in the late stages of development. were effective enough to elicit an immune response but not pure enough to avoid untoward reactions in vaccine recipients. and group Y is gaining importance in the United States. Other age groups were protected but for only three to five years. and W-135) meningococcal groups. they are still large enough to disrupt the health services and damage the already fragile economies of the 25 countries in the belt. Group W-135 has only recently emerged as a cause of epidemics in Africa and the Middle East. Cuba. However. France. 127 . Y. Broadly speaking. Between the late 1970s and the mid-1980s. account for most cases and epidemics in the world. group C occurs mainly in North America. several polysaccharide vaccines became available. polysaccharide meningococcal vaccines were used. Y. New Zealand. and were based on the carbohydrate capsule (polysaccharides) surrounding the organism. two (A and C). Since 1999. Y. Europe. By the mid-1970s the first modern “polysaccharide” vaccines were introduced. Five groups – A. and W-135 – are associated with most cases of severe disease and epidemics. C. Researchers have identified 13 different meningococcal groups. and the vaccines conferred no “herd” or community immunity. For example. with mixed results. C. or W-135). either for routine preventive vaccination (in China and Egypt). and Norway. targeting one (A. whereby even the unvaccinated are protected.State of the world’s vaccines and immunization annual epidemics are smaller. Y. Efforts to develop a vaccine need to take into account the distribution of different strains of meningococci. as with the polysaccharide vaccines developed against Hib and the pneumococcus. or four (A. and Australia.

This situation is very likely to improve – at least for the African meningitis belt. and countries in Europe. where high endemic disease rates still occur.Part 2: Diseases and their vaccines In industrialized countries. particularly in Canada and Australia. with the additional problem of periodic major epidemics. where a new. the incidence of meningococcal meningitis was falling prior to the introduction of conjugate vaccines. and their introduction has accelerated the decrease in disease rates. 128 . inexpensive group A conjugate vaccine is in the late stages of development and is expected to be ready for use in 2010 (see Box 21). This is not the case in developing countries.

A Dutch firm agreed to manufacture vaccine-grade group A polysaccharide. and transferred a new conjugation technology to the Indian manufacturer.State of the world’s vaccines and immunization Box 21 A new meningococcal vaccine to control meningitis in Africa It was the year 2001. affordable group A conjugate vaccine (101). 103. Mali. and Senegal (102. a vaccine against group A meningococcus is expected to be available for use in a huge swathe of Africa. by 2015. 104. undertook the development. If all goes well. Health officials in the 25 countries that make up the African meningitis belt and that stand to benefit most from the new vaccine are optimistic: at a September 2008 meeting in Cameroon. more than 400 million people will be protected against death and disability from the meningococcus. with the single goal of developing a new. Meningococcus A is believed to cause some 85% of meningococcal meningitis cases in Africa. ministers from all 25 countries pledged to start making plans to introduce the vaccine as soon as it becomes available (106). All the ingredients were in place: the conviction that it had to be done and could be done. the knowledge needed to prepare a meningococcal vaccine. and the international partnership to develop a vaccine. nearly 300 million people will have been vaccinated in the 25 belt countries and. India. This new group A conjugate vaccine will cost no more than US$ 0. durable immune response. who. scale-up and production of the vaccine. 105). and an Indian vaccine manufacturer provided the carrier protein (tetanus toxoid) that would be linked (conjugated) to the polysaccharide to create a new vaccine that would induce a strong. home to nearly half a billion people. assuming vigorous herd immunity. with Project support. By 2010. Scientists from the FDA helped to overcome the administrative and legal hurdles. In 2001. Project officials hope it will be licensed and ready for use before the end of 2009.50 a dose and has been shown to be safe and highly immunogenic in clinical trials in the Gambia. WHO and PATH – with funding from the Bill & Melinda Gates Foundation – created the Meningitis Vaccine Project. 129 .

the need for vaccination is based on solid arguments. self-limiting illness affecting mainly children aged five to nine years. Most (101 at the end of 2007) give a second dose in later childhood. not yet conquered Two of the features of mumps – swelling around the ears (parotitis. mumps vaccination has been used primarily in industrialized countries but increasingly also in countries in economic transition (108). fatal: among the most feared complications of mumps are meningitis. encephalitis. This alone would justify protection of the community by vaccination (107). 130 . Some countries (13 at the end of 2007) administer only one dose. Each of these vaccines is based on a different strain of the mumps virus. Direct costs include medical treatment (mainly for hospitalization and treatment of meningitis and encephalitis). in pre-vaccine days. Two decades later. A second milestone was the detailed account of the course of the disease. Most cases involve little more than a week or two of influenza-like symptoms with earache and soreness around the jaws. Deafness in one or both ears is among the most disabling. Since the 1960s. most often in the form of the MMR vaccine. and indirect “societal” costs related to reduced work productivity of patients and carers. and pancreatitis. attenuated vaccines – exist today and can protect about 80% of recipients (1). the first mumps vaccine was undergoing tests in humans (1). which can spread throughout an entire community and pose an ever-present risk of severe complications. according to economic analyses published in 2004. and of soldiers from army duty (1). mumps has been generally regarded as a relatively benign. of adolescents from higher educational institutions. including its occasional involvement of the central nervous system. complications of the disease can be severe. and on rare occasions. mumps vaccination is highly costeffective. Yet another argument is the sheer prevalence of the infection. the founder of medicine. given at 12–24 months of age. and also disrupted school attendance (107). or testicular inflammation) – were described in the fifth century BC by Hippocrates. And the third was the discovery in the 1930s by United States pathologists that a virus was the causative agent. particularly in countries where direct and indirect costs are substantial. About 20–40% of infections produce no symptoms at all. or inflammation of the salivary glands) and painful swelling of one or both testes (orchitis. or as a component of the bivalent measles-mumps or trivalent measles-mumps-rubella (MMR) vaccine. Nevertheless. Historically. More than 13 mumps vaccines – all live. For one thing. With the two-dose MMR schedule.Part 2: Diseases and their vaccines Mumps – not always mild. They are available as single (monovalent) vaccines. the disease was disabling enough to be a significant cause of absenteeism of young children from school. made in the late 18th century by Scottish physician Robert Hamilton. For another.

and measles. Most cases run a generally mild course and thereby escape official notice. In two of the outbreaks. The first condition is based on the fact that in areas where routine mumps vaccination reaches less than 80% of infants. In virtually all countries where routine mumps vaccination has been adopted. there are still enough susceptible children to sustain transmission of the infection and to infect non-immune (susceptible) adolescents and young adults – a population group more likely than young children to develop severe complications. The effectiveness of vaccination has been so dramatic as to prompt several countries. large outbreaks occurred in the United Kingdom from 2004 to 2005 (107). Developing a vaccine with a more durable protective efficacy is another option but achievable only in the much longer term. pneumonia.State of the world’s vaccines and immunization WHO recommends routine mumps vaccination as a two-dose schedule for countries that have efficient child vaccination programmes. to set goals for eliminating the disease. A second option under consideration by some countries using the two-dose schedule is to add a third dose. notably Finland. is not yet a notifiable disease in most countries. suggest that vaccination has still some way to go before elimination can be achieved and sustained. countries that can sustain high vaccine coverage rates. the incidence of mumps has plunged to negligible levels (1). • All of the mumps vaccines available internationally through the United Nations vaccine procurement system occasionally cause parotitis (1–2% of recipients). and those that regard mumps as a public health priority (108). More recently. • Outbreaks of mumps have continued to occur since the 1980s even in countries achieving high coverage rates with routine vaccination. As of the end of 2007. 114 countries were administering mumps vaccine. All three outbreaks involved adolescents or young adults. Sweden. in the United States in 2006 (109). but many countries lack the motivation and resources to implement these for a disease traditionally considered of marginal public health importance compared with more visible scourges. most of the cases occurred in individuals who were believed to have received two doses of the MMR vaccine. Mumps. and in the Republic of Moldova from 2007 to 2008 (110). however. Active surveillance efforts could to some extent solve the problem. such as malaria. which was thought to protect against mumps for at least 15 years. may start to wane much sooner. Several factors. despite WHO urging. The question then is whether mumps control would still be cost-effective. at least to control mumps outbreaks. Knowing whether mumps can be regarded as a public health priority is a problem for many developing countries. and very 131 . and the United States. This may suggest that immunity to the vaccine. The result is that reported case numbers are believed to reflect less than 10% of the true incidence of the disease. compared with 104 countries at the end of 2002. A first-line response to mumps outbreaks is mass vaccination of the entire population at risk.

how many countries will know enough and have enough resources to consider routine mumps vaccination a worthwhile option. some more effective and safer than others. The risk of aseptic meningitis following mumps vaccination varies widely according to vaccine strain. viral (aseptic) meningitis – a usually benign inflammation of the linings of the brain (107). and the intensity of surveillance (range: 1:11 000 recipients to fewer than 1:100 000 recipients (108)). and 10 per 1000 in older children (111)). The future of global mumps control will thus hinge on how quickly and extensively the true public health burden of mumps will emerge from epidemiological research. with about 254 000 deaths. The first pertussis vaccine used the killed whole bacterium (whole cell) as the immunestimulating antigen. there are many wholecell pertussis vaccines. the only signs or symptoms may be cessation of breathing (apneoa) and blue colouring of the skin (cyanosis). and. Complications arise in 5–6% of cases – the most serious and often fatal of them being bronchopneumonia and encephalopathy (111). Fifteen safe and effective pertussis vaccines.Part 2: Diseases and their vaccines occasionally. too many uncounted deaths Pertussis. of which 90% are in developing countries (111. but more rarely than in developing countries (40 per 1000 infants. The most characteristic symptom is a cough that occurs typically in spasms ending in a classic inspiratory whoop. is a disease of the respiratory system caused by infection with the bacterium Bordetella pertussis. how effectively the risk of mumps outbreaks and of vaccine-related side effects can be reduced. 132 . 4). The global burden of the disease is difficult to estimate. usually in combination with tetanus and diphtheria vaccines. have been prequalified by WHO for international distribution through the United Nations procurement systems. Pertussis – too many children not being vaccinated. given the paucity of surveillance data available. Death from pertussis still occurs in industrialized countries (less than 1 per 1000 cases (111)). WHO’s latest estimates put the annual number of cases worldwide as of 2004 at nearly 18 million. consequently. the manufacturer. the awareness and vigilance of health practitioners. or whooping cough. In young infants. and the variability depending mainly on the method of production (111). Today. It appeared in 1914 and became available in combination with diphtheria and tetanus antigens (DTP) in 1948 (1).

routine vaccination with three DTP doses was reaching about 20% of the world’s infants (41). Several acellular pertussis vaccines are currently available. the figure had risen to 81%. Both are safe. Most of these countries were in industrialized countries. which first became available in Japan and later in other industrialized countries. Determining the impact vaccination is making on the global burden of pertussis is difficult. However. and presumably safer. suspicions arose that whole-cell pertussis vaccines could very rarely cause serious complications. following widespread vaccination during the 1950s and 1960s. An additional constraint on adoption of the acellular vaccines by developing countries is the fact that they have not acquired WHO prequalification status (largely because up to mid-2008 no manufacturer had the capacity to supply the developing country market). 133 . WHO expects a prequalified acellular vaccine to be available in the near future. By the end of 2007. less likely to produce fever or local reactions at the site of the injection (particularly among older age groups). Although no scientific studies have confirmed a link between whole-cell pertussis vaccines and encephalopathy. these suspicions caused enough public concern to fuel a search for a more purified. more widespread use in developing countries will depend on country demand and secure financing. reported cases of pertussis are believed to reflect less than 1% of the true incidence (1). such as encephalopathy (111)..State of the world’s vaccines and immunization Adverse reactions related to whole-cell pertussis vaccines are frequent but mostly minor and self-limiting. In 1980. The result was a non-whole-cell (acellular) pertussis vaccine. i. numbers of cases reported annually to WHO dropped by 92% from about 2 million in 1980 to 162 000 by the end of 2007 – a drop consistent with the upward trend of vaccination coverage (111). where public sensitivity to rumour and even to the mild reactions to the whole-cell vaccine has been greater than in developing countries. pertussis vaccination consists of three initial doses of the pertussiscontaining DTP (the primary series) given at least one month apart to infants between six weeks and six months of age (111). although the acellular vaccine appears less reactogenic. But due to lack of adequate surveillance.e. than the whole-cell vaccine. And certainly. Clinical trials suggest that the “best” whole-cell and acellular vaccines protect about 85% of recipients. and where the higher cost of the acellular compared to the whole-cell vaccine is less of a problem. In the mid-1970s. In most countries. By the end of 2007. vaccine. the industrialized world saw a more than 90% drop in pertussis cases and deaths (111). Certainly. 46 of WHO’s Member States had switched from whole cell to acellular vaccines (41).

The primary purpose of pertussis vaccination is to prevent severe disease and death among infants and young children. To achieve this. Diagnosis of the disease is difficult and calls for laboratory facilities and expertise often lacking in the most affected countries. The total number of annual deaths attributable to this bacterium. according to WHO estimates (112). 134 . 78 (40%) of WHO’s 193 Member States had less than 90% coverage. including adults and children. According to unpublished WHO estimates. smokers. WHO also recommends countries that have achieved a substantial reduction in pertussis incidence through infant vaccination to give a booster dose to all children one to six years after the primary series. Finland offers a striking example of this “epidemiological shift”: with vaccine coverage reaching 98% of the infant population. and there were an estimated 24 million partially vaccinated or unvaccinated children in the world. Future priorities for pertussis control include measures to improve disease surveillance and the consequent reliability of case reporting.5 million episodes of severe pneumococcal disease and more than 800 000 deaths (of which 88 000 were HIV-related) among children in this age group. What is less sure is its impact on circulation of the causative B. also known as the pneumococcus. Other industrialized countries are facing a similar trend. the incidence of pertussis among adolescents doubled in the four years between 1995 and 1999 (111). in 2000 there were 14. many hopes from new vaccines The bacterium Streptococcus pneumoniae. at least 90% of the infant population should be receiving the primary three doses of DTP according to schedule.6 million. people with depressed immune systems. As of the end of 2007. according to WHO estimates (111). is a leading cause of severe disease and deaths in children under five years old. particularly in the most severely affected (and often poorest) countries.Part 2: Diseases and their vaccines There is little doubt. Children under five. is about 1. Compounding the problem is the likelihood of adolescents and adults acting as a source of infection for infants who have not been vaccinated by routine vaccination (1). Research is under way to explore the possibility of developing diagnostic methods that could be used on a far wider scale to provide more accurate case reporting than is at present possible. Pneumococcal disease – many deaths from many strains. and elderly people are among the population groups at highest risk of pneumococcal disease. pertussis bacterium (111). that pertussis vaccination is preventing pertussis cases and deaths – nearly 38 million cases and 600 000 deaths in 2004. High vaccine coverage rates in some industrialized countries are not preventing periodic outbreaks among adolescents and adults who remain susceptible to infection. though.

made up of the whole pneumococcus. In 1983. These were “polysaccharide” vaccines. arthritis. Less than 30 of these capsular types are commonly associated with human disease. Meningitis accounts for less than 1% of cases of severe pneumococcal disease in children. it became clear that antibiotics were not making a large enough impact on reducing deaths from pneumococcal disease. a polysaccharide vaccine became available. however. In the year 2000. or coat. However. Over the next four decades. this “7-valent” vaccine did not contain all the important serotypes responsible for severe pneumococcal disease in developing countries (1). the most serious being its inability to induce protective immunity in children under two years of age. Although the 135 . However. and by the mid-1940s. each with a different capsular polysaccharide configuration. the pneumococcus can also cause sepsis. in addition. and public health interest in pneumococcal vaccination revived. Researchers turned to conjugation technology (see Chapter 2). but is responsible for more than 7% of the deaths caused by pneumococcal infection. researchers began human tests of a crude whole-cell vaccine. and osteomyelitis. One trial in the Gambia showed. a 16% reduction in deaths from all causes among children vaccinated with the “9-valent” vaccine. However. Clinical trials of candidate conjugate vaccines containing 9 or 11 of the serotypes prevalent in developing countries conferred long-lasting protection in infants against invasive disease and pneumonia. The need for a better vaccine was clear. socalled because they targeted the sugar molecules (polysaccharides) making up the outer capsule. of the pneumococcus. pneumonia accounts for about 95% of severe pneumococcal disease episodes and close to 90% of deaths due to the pneumococcus (other major causes of bacterial pneumonia include Haemophilus influenzae type b). which contained 23 capsular polysaccharides – responsible for 85–90% of severe pneumococcal disease in industrialized countries (112). By 1911. At least 90 different types of the pneumococcus exist. In addition. a conjugate pneumococcal vaccine arrived on the market. the vaccine had several shortcomings. which protected against the seven capsular types of the bacterium responsible for 65–80% of cases of severe disease in young children living in industrialized countries (112). at least three vaccines had appeared. within a few years these had been withdrawn from the market for lack of commercial interest: physicians in industrialized countries favoured penicillin treatment (1). and other invasive diseases such as peritonitis.State of the world’s vaccines and immunization In children. The early 1960s saw the advent of the first modern pneumococcal vaccines. the age group most affected by the disease. The pneumococcus was first identified in the 1880s as the most common cause of pneumonia (1).

WHO and UNICEF began laying the foundations for a Global Action Plan for Pneumonia Control (GAPP). An upsurge in funding for pneumococcal vaccines also reflects the renewed concern over pneumonia. invasive pneumococcal disease due to the pneumococcal serotypes in the vaccine had fallen by 94% in vaccinated children (114). The plan includes the use of vaccines but also better case management and the adoption of measures against indoor air pollution. other vaccine candidates. In addition.5 billion to accelerate the development and introduction of new 136 . pneumococcal vaccines could prevent about 262 000 deaths a year in the 72 countries eligible for GAVI Alliance funding. A substantial reduction in invasive pneumococcal disease and pneumonia has been seen in countries that have introduced conjugate vaccines. One analysis (112) has estimated that at current rates of DTP coverage. Through an Advance Market Commitment (AMC) (see Chapter 4). malnutrition. including conjugate vaccines as well as others based on protein antigens and some developed by emerging manufacturers. The mood in the vaccine community is decidedly optimistic over the potential for conjugate vaccines to improve child survival and thereby contribute to achievement of MDG 4. Introduction of this or the newer vaccine in the poorest countries is expected to begin in 2009 through support from the GAVI Alliance. as a result of reduced transmission of the infection – a phenomenon referred to as “herd immunity”. five industrialized countries and the Bill & Melinda Gates Foundation pledged US$ 1. By mid-2008.Part 2: Diseases and their vaccines respective manufacturers decided not to seek licensure for these two vaccines. In the early months of 2007. the 7-valent conjugate vaccine was in use in more than 60 countries. other formulations of the vaccine containing 10 and 13 serotypes are in the late stages of clinical testing and are likely to be on the market by 2009-2010 (113). and other factors that contribute to the public health burden of pneumonia (115). In addition. in February 2007. The total cases prevented in older children and adults through herd immunity in the United States were estimated to be twice as many as in the vaccinated age groups. With the availability of two effective vaccines that have great potential to control pneumonia – one of the major causes of sickness and deaths among children under five years old – there has been an increasing demand to scale up other interventions for pneumonia control along with vaccination. unexpectedly large reductions in disease were seen in the unvaccinated population. including in elderly people. are in earlier stages of testing. Within three years of conjugate vaccine introduction in the United States.

Driving the infection from densely populated urban areas in Egypt and India proved more difficult than had been anticipated. unleashing a nationwide polio epidemic and the transcontinental reinfection of 20 previously polio-free countries in Africa. By the end of 2007. where 440 new cases had been reported in 2009 – Afghanistan (10 cases). At the end of June 2009. in 2003.State of the world’s vaccines and immunization pneumococcal conjugate vaccines. the Global Polio Eradication Initiative (GPEI). the GPEI exploited the elimination of type 2 wild poliovirus by developing “monovalent” polio vaccines. designed to more rapidly provide protection against each of the two surviving poliovirus strains. An international partnership. The mass vaccination campaigns necessary to stop polio transmission did not kick off in Asia and Africa until the mid1990s. the disease had been eradicated in three of WHO’s six regions – the Americas. Among measures the GPEI took to deal with these setbacks was the introduction of new. indigenous poliovirus remained endemic in only four countries. Europe. the World Health Assembly (WHA) passed a resolution calling for global eradication of the disease by 2000. polio was endemic in 125 countries and paralyzing an estimated 350 000 children every year (close to 1000 cases a day) (25). More recently. particularly in developing countries where the additional bacterial types covered by these candidate vaccines are prevalent. The outcome could be the saving of more than seven million children’s lives between now and 2030. In that year. India (89 cases). Pakistan (20 cases). faster diagnostic tests capable of providing more rapid identification of the specific poliovirus strain causing an outbreak or sustaining the endemic presence of polio infection in a given area. And vaccination was not reaching enough children among population groups on the move between the Afghanistan and Pakistan border. unfounded rumours that the oral polio vaccine (OPV) was being used to sterilize young girls brought polio immunization to a halt for 12 months in at least one northern Nigerian state. Asia and the Middle East (116). came into existence to achieve that goal. At the same time. and Nigeria (321 cases). The keenly awaited 10-valent and 13-valent vaccines should protect even more children against the infection. There were several reasons for the missed deadline. and the Western Pacific – but not worldwide. Polio – a tough end-game In 1988. Case control 137 .

GPEI donors and the affected countries demonstrated that the financial challenges could be addressed.Part 2: Diseases and their vaccines studies carried out in India. the GPEI stakeholders launched an intensified eradication effort in which these diagnostic and vaccine tools – and tactics tailored to the specific challenges to reaching children in each of the remaining infected areas – were paired with intense highlevel advocacy to ensure that children could be accessed in all remaining polio-infected areas. outbreaks that started between 2003 and 2007 lingered on. indigenous type 1 polio was interrupted for more than 12 months. concluded that the intensified eradication effort had demonstrated that the remaining technical.4 billion needed for the 2007–2008 intensified eradication activities. and contingency plans were developed to address further the technical challenge of compromised OPV efficacy in that setting. two advisory bodies to the WHO. In Angola. by fully funding the US$ 1. as well as clinical trials in Egypt and India.” said WHO Director-General Dr Margaret Chan.” Despite this progress. The 2008 World Health Assembly proved a turning point in polio eradication. Direct oversight by subnational leaders in areas such as the Punjab in Pakistan. In addition. In Africa. financial. had spread to surrounding countries and threatened the entire region. “is essential to our credibility to deliver basic health interventions to over 80% of the world’s children and to our capacity to achieve the MDGs. by the end of February 2009. and Jigawa in northern Nigeria overcame the operational challenges to raising OPV coverage to the levels needed to stop transmission in each of those settings. a large outbreak of type 1 polio in northern Nigeria. dose for dose. demonstrated that the monovalent vaccines provided at least twice the protective efficacy provided by the traditional trivalent OPV. As a result. the application of new international guidelines on polio outbreak response rapidly stopped 45 of the 49 importations into “non-endemic” countries in 2007 and 2008. further endangering children across the African continent. “Completing polio eradication. Meanwhile. Member States called directly on polio-endemic countries to remove the remaining operational barriers to reaching children in all areas. an additional 11 countries were responding to importation- 138 . and the Democratic Republic of the Congo. as of early 2009. In India’s Uttar Pradesh state. and operational challenges to completing eradication could be overcome. Underpinning the WHA’s resolution was the recognition that eradicating polio is an essential step towards meeting the MDGs. Nigeria and Pakistan. At the end of 2008. In early 2007. Chad. Bihar in India. the Strategic Advisory Group of Experts (SAGE) on immunization and the Advisory Committee on Polio Eradication (ACPE). efforts to interrupt wild poliovirus transmission globally faced considerable challenges. where about 20% of children were still not being reached by vaccination.

The cornerstone of the risk management strategies is the eventual cessation of the use of OPV in routine immunization. while oversight and accountability remained weak in other parts of the countries. imminent death.State of the world’s vaccines and immunization associated outbreaks in West Africa and the Horn of Africa. IPV will be the only option with which to do this. and paralysis (1). As the virus begins to infest the central nervous system. The oral polio vaccine has itself caused polio outbreaks in nine countries due to cVDPVs. agitation. The humanitarian and financial benefits of interrupting wild poliovirus transmission globally. The GPEI is implementing an extensive programme of work to manage the long-term risks associated with continued use of OPV. signals an almost inevitable. IPV will be needed in all countries that store poliovirus stocks. The rare but substantive risks associated with continued OPV use after wild virus interruption account for the continuing occurrence of vaccine-associated paralytic polio cases (VAPP). the WHA endorsed the concept of eventual OPV cessation and a strategy of biocontainment. and of outbreaks due to circulating vaccine-derived polioviruses (cVDPVs). Within a few days. spasms. Perhaps worst of all. the patient often remains conscious and aware of the body’s relentless decline (1). In Asia. and then stopping the routine use of the oral poliovirus vaccines. the first symptoms of rabies in humans resemble those of influenza. Their onset. 139 . confusion. delirium. and outbreak response to manage the risks following eradication. are anything but mild – anxiety. In 2008. surveillance. including in six that were previously free from the disease. Rabies – a terrible but vaccine-preventable death In most cases. security was increasingly compromising access to children in parts of both countries. are massive. The GPEI is studying a range of approaches to establish “affordable” strategies for IPV use to achieve immunity at a cost similar to that achieved through OPV. though. The WHA gave particular attention to the use of the inactivated polio vaccine (IPV). as it is the only vaccine which does not give rise to circulating vaccine-derived polioviruses and may be used safely in a post-eradication world. coma and death from cardiac and respiratory arrest bring relief. convulsions. which may perceive that the long-term polio risks warrant continued routine immunization. the symptoms. the key state of Uttar Pradesh in India was still struggling to stop a new type 1 outbreak following an importation in mid-2008 from neighbouring Bihar state. In Afghanistan and Pakistan. stockpile development. For other countries. At a minimum. in most cases.

and the rest occur mainly in Africa (118). widespread use of a veterinary vaccine in domestic dogs. post-exposure prophylaxis (mostly the vaccine alone) is used in an estimated 10 million people (117). Holding rabies in check. the virus travels up through the peripheral nerves to the brain (the closer the infective animal bite or scratch is to the head. During incubation of the disease. mostly in China and India (117). A less dramatic form. and when administered as soon as possible after exposure. and the shorter the incubation period (1)). and measures to manage the dog population. Rabid dogs account for more than 98% of the deaths in people. Worldwide. The virus in the animal’s saliva enters the body and attaches to nerves close to the wound. Over an incubation period lasting typically two months (117). A conservative estimate puts the annual number of rabies deaths occurring in Asia and Africa at 55 000. Thailand). “dumb” rabies. and several of the survivors were left with neurological damage (1). In the brain. marked by violent agitated movements of the body. however. there is no test to indicate whether a person bitten by a rabid animal has in fact been infected.Part 2: Diseases and their vaccines The disease is caused by a bullet-shaped “lyssavirus. the rabies vaccine gives the patient an almost 100% chance of surviving. and sets off the fatal sequence of symptoms. scratch. Children aged 9 to 15 are the most common victims of dog bites. out of sight of the person’s immune system. in both 140 . in severe cases of exposure. rabies runs a so-called “furious” course. have made human rabies a rare occurrence (117). In both forms. In industrialized countries and in most parts of Latin America and some Asian countries (e. starts replicating. the outcome is invariably fatal within a few days although intensive medical care can delay. About 3. highly effective vaccines exist. Nor is there any effective treatment for rabies after the onset of symptoms. Post-exposure treatment comprises – in addition to a series of vaccine shots – thorough cleansing and disinfection of the bite wound and. characterized by lethargy and paralysis. dogs are the main source of human infection. the less distance the virus has to travel. death (1). or lick of an infected (rabid) animal (transmission from human-to-human is rare). Transmission of the virus to a person occurs mainly through the bite.g.3 billion people live in the 100 or so countries where dog rabies is endemic (enzootic). mainly in Asia and Africa. nor a way to determine whether the biting animal is rabid unless it is put to death and its brain examined in the laboratory. Every year. but not prevent.” In about two-thirds of cases (1). the virus takes up residence in nerve cells. administration of anti-rabies immunoglobulins (a purified solution of anti-rabies antibodies taken from the blood of vaccinated people or horses). More than 60% of the total annual rabies deaths occur in Asia (the majority in India). occurs in about a third of cases (1). It is estimated that current levels of post-exposure prophylaxis prevent more than 250 000 deaths each year. Only a very small number of people with symptomatic rabies have been known to escape death. However.

Modern cell culture vaccines are much more potent than nerve tissue vaccines. 11 Asian countries.00 for a purified horse derived product) and limited availability worldwide. 141 . and also for individuals who have to pay for the vaccine themselves. several vaccines were developed. The first rabies vaccine was developed more than a century ago by Louis Pasteur in Paris (1). crude rabies vaccine that consisted essentially of dried nerve tissue taken from rabies-infected rabbits. researchers succeeded in making a third-generation vaccine using rabies virus grown in a culture of human diploid cells (1. with growing insistence.State of the world’s vaccines and immunization industrialized and developing countries. which are still in use in a few developing countries. All. WHO has repeatedly. veterinarians. called on all countries to switch to the modern vaccines. trappers. Serious safety concerns over the vaccine. animal handlers. prompted a search for better vaccines. continuous cell lines such as vero cells). have since been developed and are produced today in very large quantities using fermentor technology. Up until the late 1950s (1). These nerve tissue vaccines. and many Latin American countries. Since then. A fourth generation of rabies vaccines cultivated on various cell lines (e. such as laboratory staff. Cell culture vaccines have today replaced the older nerve-tissue vaccines in all industrialized countries and in most developing countries. Devoid of animal nerve tissue. The most inconvenient is their limited potency and the consequent need for a daily injection for up to 23 days (117). Although they are primarily used for post-exposure prophylaxis. including India. plus occasional failures. The most serious is the fairly frequent occurrence of sometimes fatal neurological allergic reactions. is costing more than US$ 1 billion a year. for “pre-exposure” immunization in high-risk groups. Currently on average only 1% of people infected or presumed to be infected with the rabies virus receive immunoglobulin. have made the switch. were made with rabies virus “grown” in animal nerve tissues. is an obstacle both for governments in the poorest countries when vaccines are provided free at rabies treatment centres. Applying the recommended immunoglobulin component of the post-exposure regimen is also an obstacle for many poorer countries because of its cost (average US$ 50. they are also recommended. primary chicken embryo fibroblasts. Pasteur Institutes throughout the world were making this first. In the early 1960s. 117).g. they are also much safer (120). By 1910. Since 1991. and travellers to areas with endemic rabies (117).00 for the five intramuscular doses needed). at a minimum (117). have a number of drawbacks (119). however. at least in industrialized countries. But the high cost of these vaccines (average US$ 50. hunters.

Preliminary clinical studies in Thailand and Viet Nam have shown that it produces a high immune response in the vaccinated children. An alternative to immunoglobulin is also being sought. In India. given the large number of animal species providing a large and diverse reservoir for the causative virus. This tactic is being successfully used in India.00 (1). In about 1 in every 75 cases. Global eradication of rabies is not an option. One approach showing promise in animal studies is the use of a “cocktail” of at least two monoclonal. Sri Lanka. 142 . Virtually all children under three years of age are infected in both industrialized and developing countries (1. It takes vaccination coverage rates of 75–80% to achieve this outcome. Most disease episodes consist of a mild attack of watery diarrhoea. with the aim of demonstrating the cost-effectiveness of dog rabies as a means to eliminate human rabies and thereby drastically reduce the need for human post-exposure prophylaxis. route of vaccine administration. the Philippines. 121). rotaviruses are the most common cause of severe diarrhoeal disease in young children throughout the world (1. manufacturers in developing countries are being encouraged to produce purified equine immunoglobulin. The use of routine preventive pre-exposure vaccination has been considered for children living in countries where they have high risk of infection from rabid animals. intradermal administration has brought the cost of a full vaccination regimen down from US$ 81. One way of reducing the cost of the modern cell culture vaccines is by using the intradermal. the infection produces severe. antibodies that can neutralize most commonly circulating rabies viruses. Rotavirus – vaccines set to prevent half a million child deaths a year Discovered in 1973.Part 2: Diseases and their vaccines To increase the supply of immunoglobulin. The Bill & Melinda Gates Foundation and WHO are together supporting dog rabies control projects in some poorer countries. 121). One economic analysis showed that use of preexposure vaccines becomes cost-effective in areas where 20–30% of children are bitten by dogs over a year (1). instead of the standard intramuscular. or highly specific.00 to about US$ 13. accompanied by fever and vomiting (1). and Thailand. Elimination of the human disease caused by dog rabies has been widely achieved by eliminating rabies in dogs through the use of effective veterinary vaccines. however. Intradermal injection is as effective and as fast-acting as intramuscular injection and requires a much smaller volume of vaccine – up to 60% less than for vaccines administered by the standard intramuscular route (117).

were in the advanced stages of the R&D pipeline. Both are live oral vaccines and may prove less effective in developing countries with higher child mortality than in industrialized countries. Globally. This was the case with other live oral vaccines. and Indonesia) had been working on several vaccine candidates. the new vaccines cost between US$ 16. The vaccine community was dismayed. with most – 23% of total rotavirus deaths – in India (121). the two new vaccines had to prove not only their efficacy but. Several of these trials are being completed in 2009 and will provide the necessary data for WHO to review its recommendations for introduction of these vaccines in Africa and Asia. as of mid-2008. however. Nearly two-thirds of these deaths occur in just 11 countries. In 2000. Cost is another issue. 125). Meanwhile. In fact. then Director of the Division of Vaccines and Immunization at PAHO. 124. two new-generation rotavirus vaccines. According to WHO 2004 estimates. including some in developing countries (notably. In trials conducted in industrialized and developing country settings. believed “it would take at least a decade to get new rotavirus vaccines”. more importantly given the fate of the first rotavirus vaccine. In 2008. such as those against polio. tempered by the need for further large-scale trials – particularly in the poorest developing countries – before they can be considered universally applicable. Rotashield™. Dr Ciro de Quadros. made by multinational companies. 124. 527 000 children under five years old die every year from rotavirus disease. China. of which at least six. other vaccine producers. supposedly associated with administration of the vaccine.State of the world’s vaccines and immunization potentially fatal dehydration (1).00 per fully immunized child when bought by the PAHO Revolving Fund for use 143 . more than two million children are hospitalized for rotavirus infections every year (122). the manufacturer withdrew it from the market: several cases of bowel intussusception (severe bowel blockage caused by the bowel telescoping into itself) had occurred. Before receiving regulatory approval for human use. 125).00 and US$ 17. the new vaccines protected 85–98% of vaccinated infants from severe rotavirus disease (123. it took only six years: by the end of 2006. voicing the opinion of many vaccinologists at the time. Work on developing a vaccine to prevent rotavirus disease began in the early 1980s and culminated in August 1998 with the licensure in the United States of the first rotavirus vaccine. Nine months later. after more than 600 000 children had received the vaccine. their safety in much larger studies. cholera. India. and typhoid. had appeared on the market. Optimism over these new vaccines is. each involving more than 60 000 participants. Both vaccines were found to be safe and are now WHO-prequalified (123.

Linking up with the Measles Initiative makes sense. and has been in wide use in China since 2000. WHO recommends that all countries where CRS has been identified as a major public health problem should use the vaccine. for the 72 countries within the GAVI Alliance purview. was first noted in the mid-19th century as a mild disease involving little more than a skin rash. By 1970. Rubella – eliminating a threat to the unborn Rubella. some 3600 were both deaf and blind. and the quest for a vaccine began. licensed. as well as over 6000 spontaneous and 5000 induced abortions.00 a dose to the private sector in China (it has not yet requested WHO prequalification status for international use). Of these newborns. In the longer term. during a rubella epidemic in the United States.5 million cases of rubella. given the availability of combined measles-rubella vaccines and 144 . that the full range of congenital abnormalities making up the “congenital rubella syndrome” (CRS) was revealed to the world. the rubella vaccine was being used nationally in 125 countries. accounting for 12% of babies born in that year. And it was not until the early-1960s. However. or German measles. several rubella vaccines were available. sells for about US$ 16. were using the vaccine in their national immunization programmes (71). The United States rubella epidemic caused 12. Moreover. they should do so in conjunction with measles elimination activities (126). One rotavirus vaccine that is manufactured. The world awoke to the dramatic reality of CRS. the costs of sustaining rotavirus vaccination may prove difficult for some countries. heart disease. its ability to cause congenital defects – cataracts. There were more than 2000 deaths. Of course. one (using the so-called RA 27/3 rubella virus strain) emerged from the pack as offering a high degree of safety and efficacy in protecting children against mild (or “acquired”) rubella (1). and nearly 2000 were mentally retarded (1). By 1996. 126). Given to women of childbearing age. and deafness. more than 8000 were deaf. Before the end of the decade. accounting for 31% of births worldwide (71). the vaccine gives 95–100% protection for at least 15 years against the risk of having a baby with CRS (1. 65 countries. including more than 2000 cases of brain inflammation (encephalitis) and 20 000 cases of CRS in newborns. at least in the short term.Part 2: Diseases and their vaccines in Latin America – almost a tenth of the price on the private United States market but still too expensive for the poorest countries with the highest rotavirus mortality rates in other regions. cost may not be a major issue. By the end of 2007. where logistically feasible. to mention three – became evident in the 1940s.

and the concern that if high coverage (>80%) cannot be achieved and maintained. Two unanswered questions. caring for people with CRS is costly. Meanwhile. and the United States). Tetanus. neonatal and maternal – victory in sight Tetanus is characterized by muscle rigidity and painful muscle contractions caused by a toxin – one of the most potent ever identified – released by the bacterium Clostridium 145 . increased cost. And if eradicating two diseases with a single blow is the aim. rubella vaccine has not been included in the national immunization schedule because of lack of information on the burden caused by rubella. Elimination of CRS. and more and more countries are taking it. the benefits of rubella vaccination outweigh its cost (of US$ 0. stopping indigenous (or endemic) transmission of the rubella virus that causes the disease. Sweden. in most developing countries. the risk of CRS may increase due to a shift in rubella susceptibility to older age groups including women of childbearing age.e. Use of the rubella vaccine has eliminated CRS in a number of countries (e. the first at 12–18 months of age and the second later in childhood. country-by-country elimination of rubella and congenital rubella syndrome is surely a worthwhile first step. Cost-benefit studies in developed as well as developing countries have shown that where coverage rates exceed 80% and rubella vaccination is combined with measles vaccination. the English-speaking Caribbean countries. and young adults (both women of childbearing age and men). the combined measles-rubella vaccine is there to make the operation feasible. Indeed. rubella. However. fulfils the biological criteria for an eradicable disease: only humans maintain transmission of the virus.State of the world’s vaccines and immunization the compatibility of the two administration schedules. like measles. Successful use of the vaccine has also prompted the WHO Regions of the Americas and Europe – the two WHO regions with the highest rubella vaccine coverage rates in young children – to target rubella for elimination by 2010. i.g. point to potential stumbling blocks: will there be sufficient political will to mount and maintain a two-disease eradication effort ? And will it be possible to bring sustained vaccination to communities lacking access to basic health services or isolated by conflict? The endgame struggles of the polio eradication initiative are instructive in this respect. but on the other hand. Cuba.60 a dose) (127). It calls for a strategy to ensure high levels of immunity through vaccination among children. For poorer countries. and transmission has already been interrupted in large geographical areas (128). adolescents. this strategy may not be affordable. most countries using the rubella vaccine administer it as part of the MMR vaccine. given in two doses. is possible. As for eradication. accurate diagnosis is possible. though.

At that time. Education about providing hygienic conditions for births was also part of the strategy. In the late 1980s. most neglected population groups that have little or no access to medical care. delivering three sequential doses of vaccine to all women of childbearing age in the highrisk communities. Vaccination of women before or during pregnancy with at least two doses of the vaccine was the main strategy to be used to reach the target. 2005. This new approach called for mass immunization campaigns. Prevention of tetanus is possible and inexpensive. By 1995. 27 of the 90 countries had eliminated neonatal tetanus. which is the most common form of the disease in developing countries. The tetanus toxoid vaccine is one of the most effective. subsequent development and initial use. for achieving elimination – a 146 . in a new development. In the 63 remaining countries. hard-to-reach communities. and the United Nations Population Fund (UNFPA) decided to launch a more vigorous attack on tetanus. UNICEF. By 2000. WHO. It is most prevalent among the poorest. the public health community officially declared neonatal tetanus a target for elimination. a “high-risk approach” was adopted that aimed to reach out to these “high-risk communities”. also maternal tetanus. A person is infected when the spores enter the body via dirt or soil through a scratch or open wound. To accelerate elimination efforts.Part 2: Diseases and their vaccines tetani. and least costly vaccines on the market. an estimated 15 000–30 000 women were dying every year from tetanus contracted during or shortly after pregnancy. for up to two months. This maternal and neonatal tetanus (MNT) elimination partnership also set a new deadline. In fact. 90 countries had not yet reached the elimination target (129). The new approach paid off. at least in industrialized countries. the newborn child. defined as an incidence of less than one case per 1000 live births in all districts. both neonatal and. safest. 135 countries had eliminated neonatal tetanus (28) and annual deaths from the disease had fallen to an estimated 200 000 – a 75% drop from the 790 000 deaths in 1988 (28). is primarily caused by infection of the umbilical cord stump in babies delivered in unhygienic conditions. Ninety percent of these 200 000 deaths were occurring in just 27 countries. Neonatal tetanus. tetanus was estimated to be causing more than a million deaths a year. The spores of this bacterium are present throughout the world in soil. Vaccination was combined with efforts to increase the proportion of births taking place in hygienic conditions and to reduce harmful traditional practices at home births. of which about 790 000 were newborn infants. mostly in South Asia and sub-Saharan Africa. date from the first half of the 20th century. most cases were occurring in poor. Its discovery. Antibodies produced by the vaccine protect not only the mother but also the foetus and. In 1989.

not only would MNT remain eliminated. 147 . and will always be present in nature. One is the need for funding over the 2008–2012 period. according to survey findings. By the end of 2008. and its spores are extremely resistant to destruction. If countries succeed in reaching most people with booster doses in school-age. however. and early adulthood. A second is the lack of solid data on which to base disease estimates: less than 10% of cases are being reported. Several countries are taking steps in that direction. 12). mostly through UNICEF and the GAVI Alliance. by offering tetanus vaccines in school-based immunization programmes and in activities such as mother and child health days or immunization weeks. all countries will have reached the ultimate target. Confidence is. Their confidence is based on the impetus that tetanus elimination efforts have been gathering since 2000. The MNT elimination partnership estimates that – with sufficient funding – by the end of 2010. adolescence. was to prove too optimistic. however. will the momentum created by elimination of neonatal and maternal tetanus be sustained ? Clostridium tetani is. Disease surveillance clearly needs a major boost. but protection against tetanus would be life-long (131). to finance its activities. If future generations are to live without the threat of a catastrophic resurgence of the disease. 12 of the 58 remaining countries with neonatal tetanus had achieved elimination in all districts (see Fig. tempered by hurdles still to be overcome. and also from the influx of funds – US$ 160 million – the partnership has received since 2000.State of the world’s vaccines and immunization deadline which. As for the longer-term future. tetanus experts estimate that routine immunization coverage in all countries must reach and stay at 80% of women of childbearing age in all districts and that at least 70% of births must take place in hygienic conditions. only 10 countries will still be in the grip of the disease and that by 2012.

Maharashtra. Tamil Nadu and West Bengal) *India is the only country with sub-national validation of MNT elimination . Gujarat. Pondicherry. Goa. Karnataka. Kerala. Sikkim. Himachal Pradesh. Punjab. Chandigarh.148 Nepal Bangladesh Viet Nam Egypt Eritrea Rwanda Togo Namibia South Africa Malawi Zambia Zimbabwe Source: (130) Figure 12 Part 2: Diseases and their vaccines Status of elimination of maternal and neonatal tetanus MNT eliminated prior to 1999 MNT not eliminated (46 countries) MNT eliminated during 2001-2008 (12 countries and 15 states in India*: Andhra Pradesh. Haryana. Lakshadweep.

The problem is that tuberculosis in children is very difficult to diagnose and often remains undetected. including tuberculosis. evidence from several trials has consistently shown that BCG gives strong protection against tuberculosis in infants and young children (1).46 million deaths (4). BCG is protective against these forms of tuberculosis in 64–78% of recipients (1). Some studies have found a high degree of protection. others none at all. as in Mozambique. developed at the Pasteur Institute in Paris and first used in 1921. estimates of both incidence and mortality rates in 2007 (132) suggest that the disease may be on the verge of a downswing. that diagnosis can only 149 . The not-so-good news is that over the past two decades the burden of tuberculosis has followed an upward curve that peaked in 2004 with 8. That is the good news. South Africa. By 1990. tuberculosis is still a leading cause of disease and death. 81% of the world’s newborn infants were receiving the vaccine. By contrast. but in some countries with high HIV incidence rates.9 million new cases (up from 8 million in 1997) and approximately 1. about 15% of tuberculosis cases occur in people with HIV/AIDS. there is no empirical evidence that high coverage of a population with BCG vaccination lowers the incidence of these severe forms of tuberculosis in infants and young children. has contributed to the escalation of tuberculosis cases: globally. In Europe and North America. But despite worldwide use of BCG over the past three or four decades. However. when routine BCG immunization against tuberculosis began in many countries. and despite the availability since the early 1990s of an inexpensive highly effective treatment strategy (“DOTS”). By the end of 2007. the proportion can be as high as 50–60%. The inability to control this disease has been called “a colossal failure of public health” (1). The advent of HIV/AIDS in the 1980s. the mood is one of frustration over the lack of evidence that BCG consistently protects against pulmonary tuberculosis.State of the world’s vaccines and immunization Tuberculosis – waiting for a better vaccine The first and only vaccine ever used to protect against tuberculosis is the Bacille Calmette-Guérin (BCG) vaccine. By contrast. and Zimbabwe (132). more than four billion people are believed to have received the vaccine worldwide (1). BCG coverage had climbed to 89%. Since the 1950s. Tuberculous meningitis and disseminated (miliary) tuberculosis – the two most common and most severe forms of extrapulmonary tuberculosis – occur in about 25% of children with tuberculosis and are rapidly fatal without treatment (1). several countries where the incidence of reported tuberculosis had dropped to below 25 cases per 100 000 have ceased routine BCG immunization. with its ability to lower natural protection against latent infections. For the vaccine community. The disease is so rapidly fatal.

may be better off replacing routine BCG vaccination by vaccination of only high-risk population groups. BCG costs US$ 2–3 per dose. in industrialized countries. however. A recent analysis (133) suggests that it is. it is still 150 . the cost per DALY gained amounts to several thousand dollars. To most tuberculosis experts. South-East Asia Region. and often resulting in death. malaise. and tuberculin skin tests are negative in about 40% of cases (1). This has. thrives in unsanitary conditions. it is clear that a new. Today. the causative bacterium. would have been US$ 200 or less per healthy life year gained. abdominal pain. the organism infects the bloodstream. and headache – usually lasted several weeks and in many cases culminated in death.Part 2: Diseases and their vaccines be attempted in the earliest stages of the disease. Salmonella typhi. Given this situation. and Western Pacific Region. many health officials wonder if vaccination with BCG at birth is worth the effort and cost. Through the gut. In the few industrialized countries where BCG is still used routinely despite a low risk of infection. the analysis showed BCG to be a cost-effective intervention against severe childhood tuberculosis – almost as cost-effective as short-course chemotherapy – costing US$ 50 per DALY gained. particularly where clean water is lacking. typhoid fever has ceased to be a problem. where the incidence of tuberculosis and BCG coverage are highest. in fact. such as health workers and others at risk of exposure to the infection. including the United Kingdom and the Netherlands. immunogenicity. also known as enteric fever. Commonly spread via contaminated water and food. the research team speculates. Several candidate vaccines are in early-stage clinical trials and are being tested for safety. more consistently effective vaccine is needed that protects not only against the disease in childhood but against pulmonary tuberculosis in adults. 135). x-rays show no evidence of disease. But at that stage. Typhoid fever – vaccines ready and waiting Typhoid fever. Such countries. and early indicators of efficacy (134. worldwide. altering brain function in some cases. thanks to improved hygiene and a clean water supply. Under-reporting and poor record-keeping compound the difficulty of gathering incidence or mortality data. Given to more than 100 million infants in 194 countries in 2002. In developing countries. the vaccine would have prevented more than 40 000 cases of tuberculous meningitis and miliary tuberculosis in children under five years of age. the symptoms of typhoid fever – typically. The cost. is caused by one of the most virulent bacteria to attack the human gut. long been the strategy adopted by several countries. persistent high fever. the symptoms are not specific. using the disability-adjusted life year (DALY) measure. Before the advent of antibiotics. In the WHO African Region.

named “Ty21a” and first licensed in 1983. A cure came in the form of antimicrobial drugs. two new-generation typhoid vaccines had entered the scene. However. the duration of efficacy of both vaccines varied to some degree.State of the world’s vaccines and immunization very much a problem. named “Vi” and licensed in 1994. The majority of this burden occurs in Asia (136). Moreover. prevention in the form of vaccines. it was reported that incidence in highly-endemic countries is similar in children 2–5 years of age as in school-aged children 5–15 years of age and adolescents (137). is given by injection and consists of a sugar molecule (polysaccharide) located on the surface of the bacterium (138). However. At that time. Price was initially thought to be a barrier to adoption of the vaccines by developing countries. the frequency and severity of the adverse effects they caused dissuaded many countries from using them. In a comprehensive study relating to the incidence of typhoid fever in five countries in Asia. Typhoid fever was discovered as a distinct disease entity in the 1880s. typhoid vaccines have now been accepted by the GAVI Alliance as a possible candidate for future financial support. These shortcomings. Cases still occurred though.50 for the Vi vaccine in multi-dose vial presentations for use in public health programmes. both vaccines are licensed. its hold on industrialized countries had begun to slacken in the face of improved sanitation. Moreover. In clinical trials and early field use. no evidence of efficacy has been reported in children under two years of age. typhi strain (138). 151 . predominantly in children of school age or younger. Both protected about 65% of recipients. internationally available. the second in 1952. often in outbreak situations. and the main producer of Ty21a is offering a discounted price for the poorest countries. One. WHO estimated the global typhoid fever disease burden at 21 million cases annually. such as migrant groups. which had escalated in previous years as a result of increasingly widespread resistance to antibiotic therapy. The continued occurrence of the disease and the fear engendered by its high mortality rate – 10–20% of infections resulted in death (1) – combined to fuel the search for a cure and a means of prevention. Before the end of the 20th century. The second. and both are effective enough not only to reduce the incidence of typhoid fever in endemic areas but also to control outbreaks. resulting in an estimated 216 000–600 000 deaths per year. is given in three to four oral doses (136) and consists of a live but genetically modified S. Early research produced two vaccines made from the entire (whole-cell) bacterium. combined with drug treatment failures. and safe. several manufacturers in developing countries now quote prices of about US$ 0. intensified the quest for a more effective vaccine. and among high-risk population groups. One became available in the 1890s. On a positive note. In 2004.

third-generation typhoid vaccines are in the pipeline. In most populations. consisting of blister-like vesicles. However. although current newgeneration vaccines may not be perfect.Part 2: Diseases and their vaccines In 2008. Which of the two vaccines a country chooses depends on the capacity. typhi are prevalent. Seventeenth century medical documents describe chickenpox as a mild form of smallpox (139) but in 1767 the English physician William Heberden showed that the two diseases are distinct (1). commonly known as chickenpox. The same virus. or shingles. is caused by the varicella-zoster virus (a member of the herpesvirus family). or from the virus being sneezed or coughed into the air or released from the vesicles on the skin. A second candidate vaccine. can be given in a single oral dose. according to late-stage clinical trials. Meanwhile. varicella is a disease of children. unlike Ty21a. and cultural context of its immunization programme. though. the epidemiology of disease can vary. particularly in areas where antibiotic-resistant strains of S. The varicella-zoster virus only infects humans. Varicella and herpes zoster – a single virus that can linger for a lifetime Varicella. It spreads from person-to-person through direct contact. and herpes zoster a disease of elderly people. complications. Very few countries still use the whole-cell vaccine: those that do should. Vaccine scientists point out. when reactivated from a latent state in nerve cells causes another disease – herpes zoster. occur in about 10% of cases. switch to one of the new-generation vaccines (136). is. like Ty21a. vaccination will be confined to high-risk population groups. Action against the daily toll of disease and death from typhoid fever in endemic populations is needed now and. especially in tropical countries where infection and varicella may occur more often in older age groups. varicella is a mild disease. which can sometimes be severe. Generally. and appears to be effective in children under two years of age. mostly in adolescents 152 . logistics. according to WHO. such as school-age and preschool-age children. WHO also recommends use of the new vaccines for the control of outbreaks (136). they are available to meet that need. a live attenuated vaccine but. In most of these countries. which was first identified in 1952 (139). WHO reiterated its earlier recommendations that the new vaccines be used for routine immunization – alongside active strategies to improve hygiene and sanitation – in countries or areas (such as deprived urban areas) where typhoid fever is endemic. that these newer typhoid vaccines have still several years to go before reaching the market. further back in the R&D pipeline. The hallmark symptom of varicella is an itchy rash. However. One is a Vi conjugate vaccine that protects about 85% of recipients.

kidneys. or infection of the bones or bloodstream). babies born to women who have immunity to varicella receive their mother’s anti-varicella antibodies and are protected against the infection for about a month after birth (139). 1). heart. or testicles) are prominent on the list of complications from varicella (139. and death. 153 . which can occasionally become severe through spread to contiguous or distant parts of the body (1). and sometimes life-threatening. However. Other bacterial infections (pneumonia. and inflammatory conditions (of the liver.State of the world’s vaccines and immunization and adults (139) (who are 30–40 times more likely than children to die from severe complications (139)). Varicella infection itself induces lifelong immunity to chickenpox in virtually everyone whose immune system is working normally (139). complications of varicella are bacterial infections of the skin. neurological conditions (uncontrollable muscle movement or brain inflammation). brain damage. In pregnant women. The most common. the infection can cause congenital limb foetal abnormalities.

both physically and mentally (1). Elderly people and immunocompromised people run the highest risk of developing herpes zoster. Treatment with antiviral drugs is effective if started soon after the onset of herpes zoster. In many elderly people the rash and pain subside and resolve completely in a few weeks. who account for almost 20% of herpes zoster cases – could benefit from the vaccine (1). accurate diagnosis at that stage of the infection is difficult and in most cases antiviral treatment is begun too late to be of optimal benefit (1). and the low public health priority of herpes zoster in relation to the many other serious diseases that ravage these countries. or immunosuppressive treatment) allows it to awaken. It contains at least 14 times the amount of virus as the varicella vaccine (1).Part 2: Diseases and their vaccines Box 22 Herpes zoster – the same virus. varies with the recipient’s age. militate against its widespread adoption by developing countries: price (the vaccine currently costs about US$ 150 a dose in industrialized countries). disease. The pain can be severe and highly disabling. impaired vision. Its protective efficacy. Two factors. Itching. begin replicating. 139). 154 . which may fluctuate from mild to intense. In addition. pain and numbness in the area of the rash can last for weeks or months. However. In 2005. until a lowering of the host’s immune defences (as a result of ageing. Since the same virus causes varicella. though. adds to the person’s discomfort (1). though. Some herpes zoster experts believe younger age groups – such as people in their 50s. falling from 64% in the 60–69 year age group to 41% in the 70–79 year age group. where it lies dormant for several decades. the virus takes up residence in nerve cells. Herpes zoster is characterized by a painful blistering rash along the distribution of the infected nerve cells (139). or shingles as it is commonly known (139). In about 15% of patients. In the United States alone. 8–15% of people suffer permanent neurological damage. people with herpes zoster constitute a source of varicella outbreaks among unvaccinated children and other non-immune population groups. 43 million people are believed to be at risk of herpes zoster (1). a different disease In 10–20% of children infected with varicella. and 18% in the 80–89 year age group (1). or problems of bowel or bladder function (1. and precipitate herpes zoster disease. a vaccine against herpes zoster was licensed for use in people over 60 years of age. though.

State of the world’s vaccines and immunization

Little is known about the burden of varicella in developing countries (139). However, in 2006, an estimate based on the incidence of varicella in industrialized countries gave a total worldwide estimate of 90 million cases a year (1). Treatment for varicella consists of antiviral drugs, which are expensive and work only when used early in the course of infection. It is generally reserved for people at risk of severe disease. Vaccination is the only way to protect whole communities and populations from varicella, and possibly from herpes zoster. A safe and effective vaccine against varicella has been available in several formulations since the mid-1970s (139), and in 2005, a combination measles-mumps-rubella-varicella vaccine also came on to the market. The single-antigen (i.e. containing varicella virus only) vaccine has been administered to millions of children, adolescents, and adults in many countries (1). In children, a single dose produces anti-varicella antibodies in about 95% of recipients and protects them against the disease (139). Furthermore, at least 90% of people given the vaccine within three days of being exposed to the virus are protected against developing the disease (139). In those who develop disease after vaccination, it is much milder than in unvaccinated individuals. The effectiveness and cost-effectiveness of the vaccine have prompted several industrialized countries in Asia, Europe, and North America to adopt it in their routine child immunization programmes (139). In 1995, the United States became the first country to adopt the vaccine into its routine immunization programme (1) and by 2002 saw a 74–92% drop in child deaths from varicella and an 88% drop in hospitalizations due to the disease (1). The use of the vaccine has also been shown to be cost-effective in the United States (139). Some epidemiologists believe that widespread routine administration of the varicella vaccine in children could eventually lead to the virtual disappearance of the disease. In general, most developing countries have other diseases associated with high disease burden and deaths that need to be given higher priority than varicella. Where varicella represents a sizeable public health and socioeconomic problem, countries may consider routine varicella immunization. However, immunization programmes must reach at least 85–90% of children as lower coverage rates could theoretically shift the target of the virus from young children to older children and adults.

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Yellow fever – defusing a bomb waiting to explode
Yellow fever is a viral haemorrhagic fever caused by a virus transmitted to humans and non-human primates by the bite of a mosquito. After a few days of being bitten by an infected mosquito, sub-clinical infection, non-specific illness, or influenza-like symptoms can develop. The latter can culminate in the vomiting of blackish blood, one of the two hallmark symptoms of the disease (1). A few days later, in about 15% of cases, bleeding occurs from several sites, accompanied by painful convulsions and failure of several organ systems, notably the liver, kidneys, and heart (1). This stage is also marked by jaundice – the second hallmark symptom – which colours the skin a deep yellow. About 20–50% of people with severe disease die from the disease. Children and elderly people run the greatest risk of death from yellow fever. Yellow fever was a major scourge in the 18th and 19th centuries in colonial settlements in the Americas and West Africa. The discoveries (in 1900) that mosquitoes were responsible for transmission and that the disease was preventable by vector control, as well as the development of vaccines (in the 1930s), have reduced both the fear associated with the disease and its medical impact. In 1940, mass vaccination of 25 million people in French-speaking West and equatorial Africa led to the virtual disappearance of yellow fever. However, inadequately immunized populations and urbanization set the stage for the disease to re-emerge. Today, yellow fever remains an endemic and epidemic disease affecting thousands of people in tropical Africa (33 countries) and South America (11 countries and territories) (140), and is a continued threat to people who travel to these regions without vaccination. An estimated 200 000 cases and 30 000 deaths (141) occur every year worldwide. About 90% of cases and deaths occur in Africa (141), where more than 600 million people are at risk of infection (141). In South America, about 60 million people live in endemic areas (1). Outbreaks may affect urban populations, with the infection spreading by mosquitoes from human-to-human. Yellow fever also occurs in jungles, where it exists as an animal (epizootic) disease, spread by mosquitoes from monkey-to-monkey and, accidentally, to humans. Travellers, too, are at risk of yellow fever. Every year, an estimated nine million people travel from non-endemic to endemic areas and about three million of these travellers may be going to places where outbreaks are raging (141). Only 10–30% of travellers to these “danger zones” are vaccinated, according to one estimate (141). The International Health Regulations require travellers to or from endemic countries, to carry a valid vaccination certificate (1). No specific treatment exists for yellow fever. Vector control targeting the mosquito responsible for transmitting the disease, has its limits. Hence, vaccination is the single

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most effective means of obtaining protection against yellow fever. The 17D vaccine is both highly effective and safe, conferring a high degree of protective immunity for at least 30–35 years (and probably for a lifetime). The vaccine is highly cost-effective as it confers long-term immunity in an infant for an estimated US$ 0.01 a year. In 1988, WHO and UNICEF proposed a two-pronged vaccination strategy that is still the universally recommended approach to controlling yellow fever. It is designed to create a high level of protective immunity in at-risk populations, to sustain that level from generation to generation, and, ultimately, to eliminate yellow fever as a public health problem. One prong of the strategy is the integration of the vaccine into the national childhood immunization programmes of countries at risk of epidemics (141). The second prong is the use of mass vaccination campaigns to protect susceptible older age groups (141) and populations threatened by imminent or incipient outbreaks. In addition, the strategy calls for vector control measures; for use of the vaccine to battle ongoing outbreaks; and for strengthening disease surveillance which is critical for outbreak detection and control, and for programme monitoring. Implementing the strategy has been slow. Of the 33 endemic countries in Africa, 22 had adopted the vaccine in their national immunization programmes by the end of 2007, up from eight countries in 2000. The GAVI Alliance provided support to the poorest endemic countries. However, according to data reported by WHO and UNICEF, the proportion of children vaccinated with the yellow fever vaccine in the 33 African countries had reached an average of only 50% by the end of 2007. Poor disease surveillance, resulting in gross underestimation of the disease burden, has been a key deterrent to the implementation of the WHO-recommended vaccination strategies. One reason is that the signs and symptoms of yellow fever are similar to those of other diseases, such as malaria, influenza, and typhoid fever (141). Surveillance must therefore be backed up by a network of laboratories capable of accurate diagnosis (141). Another deterrent is an “insecure” vaccine supply. Approximately 30 million doses a year (1) are provided by manufacturers for the African market. Yet, to meet demand for enough vaccine to implement the WHO-UNICEF strategy would require an estimated 40 million doses plus at least 6 million doses to respond to outbreaks. At US$ 0.71 a dose (on the developing country market), the cost of the vaccine has been an additional deterrent for many countries. However, the support of the GAVI Alliance has made it possible for the GAVI-eligible countries to adopt the vaccine. These three deterrents – surveillance, vaccine supply, and price – are likely to become less critical, at least for the poorest countries at highest risk of yellow fever: the GAVI

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Alliance has been supporting the introduction of yellow fever vaccine into routine infant immunization since 2002. In addition, it has supported an emergency vaccine stockpile since 2003. More recently, the GAVI Alliance has approved a request from WHO, UNICEF and other members of the Yellow Fever Initiative to provide about US$ 100 million for control of yellow fever in Africa. The money would be spent over five years mainly on providing vaccines for preventive campaigns in 12 endemic African countries within the GAVI Alliance mandate, and also for responding to outbreaks in any GAVI-eligible country at risk in the event of outbreaks. In South America, yellow fever vaccination has been ongoing for at least three decades. Up to 1991, mass vaccination campaigns were carried out every five years in the endemic countries of the region (1). Since 1998, integration of the yellow fever vaccine within national child immunization programmes has become the norm (1). By the end of 2007, the average reported vaccine coverage had reached 86% for these countries (1). One concern in the region is the movement of unvaccinated people from coastal areas, where vaccination is not carried out, to the more inland endemic areas. Another is resurgence and spread of the urban form of the disease as a result of the recent re-invasion of the continent by the urban-dwelling mosquito vector (1). For Africa and South America, the ongoing circulation of the yellow fever virus remains a time-bomb waiting to explode. The new funding being provided to endemic African countries for yellow fever vaccines and vaccination, and the high levels of vigilance and surveillance in South American countries, should keep the bomb from exploding. But it is still ticking. With escalating international air travel providing a mechanical vector for the mosquito and the virus, and with the lack of adequate immunity in many populations (a single case of infection can cause a massive outbreak in the presence of the mosquito responsible for transmitting the disease), the bomb could explode, disseminating the virus well beyond its current hunting grounds.

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State of the world’s vaccines and immunization 159 .

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less than 15 years 2006 2005 2004 2003 2000 1990 1980 6'659'040 6'580'921 6'502'983 6'425'275 6'347'724 6'113'437 5'279'007 4'439'786 135'590 128'816 628'7210 134'985 128'120 625'407 134'397 127'440 622'797 133'865 126'816 620'980 133'418 126'275 619'905 132'820 125'369 620'422 136'793 128'148 629'747 123'711 114'051 545'390 1'843'756 1'841'906 1'841'380 1'842'270 1'844'242 1'846'856 1'724'575 1'566'771 Female 15-49 years 1'718'802 1'698'386 1'677'375 1'655'843 1'633'781 1'564'554 1'314'119 1'058'498 Number of reported cases Diphtheria Measles Mumps Pertussis Polio Rubella Rubella (CRS) Tetanus (neonatal) Tetanus (total) Yellow fever 4'273 280'771 407'787 161'861 1'385 196'506 225 6'086 19'867 265 3'978 373'941 643'078 119'916 2'021 252'340 63 8'376 14'646 356 12'735 601'232 619'062 135'326 2'032 267'366 37 9'918 15'980 588 10'069 509'734 654'216 244'989 1'258 308'219 88 9'318 13'772 1'344 6'781 680'454 334'063 110'854 784 321'180 99 9'028 12'857 672 11'625 23'864 97'774 852'937 1'374'083 4'211'431 544'093 190'476 2'971 671'286 181 16'943 21'242 684 - 476'377 1'982'384 23'366 25'293 64'378 4'336 52'795 13'005 114'248 144 Percentage of target population vaccinated by antigen based on WHO-UNICEF estimates TT2plus and YFV are based on reported coverage BCG DTP1 DTP3 HepB3 Hib3 MCV Pol3 TT2plus YFV 89 90 81 65 26 82 82 71 51 88 89 81 60 22 81 82 69 48 86 88 79 56 21 79 79 66 42 84 87 77 50 20 77 77 59 35 83 85 75 46 19 75 76 61 31 81 85 73 32 14 72 74 62 26 81 88 75 1 72 75 55 4 16 30 20 16 21 9 0 168 .Annex 1 Annex 1. less than 5 years Pop. Global immunization profile Population data in thousand1 2007 Total population Live births Surviving infants Pop.

In general.State of the world’s vaccines and immunization Most countries have standard recommendations regarding which vaccines should be offered and at what ages they should be given. vaccines are recommended for the youngest age group at risk of developing the disease whose members are known to respond to the immunization without adverse effects. Unless otherwise specified. data are provided by Member States through the WHO-UNICEF Joint Reporting Form and WHO regional offices. 1) Source: (6) 169 .

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