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RCSI Royal College of Surgeons in Ireland Coliste Roga na Minle in irinn

Immunisations: past and future


Class
Course
Code
Title
Lecturer
Date

IC2
Tropical Medicine
TM
Immunisation: past and future
Prof. Samuel McConkey
10th September 2015

Objectives
To understand, through examples, the success
of vaccines
The concept of vaccines
History of vaccines
Future of vaccine development e.g. Ebola

The story of control of meningitis


Haemophilus influenzae b
Streptococcus pneumonia
Neisseria meningitidis subtype C

The story of neonatal tetanus


How to prevent cancer
Hepatitis B vaccine

Number of cases of invasive Haemophilus


influenzae subtype b per year in Ireland
120
Hib vaccine introduced

100
80
60
40
20

From Health Protection Surveillance Centre, Dublin Sept 2014

2011

2009

2007

2005

2003

2001

1999

1997

1995

1993

1991

1989

1987

From Centre for Disease Control, Atlanta, Georgia 2014

Men C Vaccine introduced

Figure. 1. Number of Meningococcal C events on CIDR by Year & Quarter, Q11999 to Q2-2014
From Health Protection Surveillance Centre, Dublin Sept 2014

Source, hpa. org.uk

Irish Medicines Exports 2002 from UNCTAD data On-line 2005


Credit to Worldmapper.org

UNCTAD 2012 report

World exports Irish

Medicine including veterinary

$332b

$25.1b

Organo-inorganic compounds

$ 87b

$23.6b

Pharmaceuticals excluding meds

$134b

$ 9.5b

Med device and appliances

$ 68b

$ 3.6b

Pfizer Ringaskiddy
Organic Synthesis Plant No 4

Neonatal tetanus

Source, Lancet, and Journal National Cancer Institute

How vaccines were made historically

Live attenuated vaccinia, BCG, polio (Sabin)


Killed Rabies (Pasteur),
Adjuvanted- alum,
Sub-units- Hepatitis B surface protein
Conjugated vaccines,
Hib, covalently linked to tetanus toxoid, Men B omp
pneumococcus CHO linked to CRM197 (diphtheria t)
Men C linked to tetanus

Future

DNA vaccines- work in mice


Vectored in vaccinia
Prime-boost
Polyvalent- 6 in 1, 23 valent PneumoVax
H1N1 influenza A vaccine AS03 & narcolepsy
Individualised APC primed against cancers

Ebola vaccine

How to make one.


Candidates
Pre-clinical trials
Clinical trials
Licensure
Marketing and distribution

Source: kenyon.edu

How to make a vaccine


Whole-cell killed XXX
Live attenuated XXX
Sub-unit
Conserved sequences : Glycoprotein
Immunogenic
Adjuvants antibodies or T cells

DNA plasmids
Vectored- Chimpanzee adenovirus

Judith M. White & Kathryn L.


Schornberg
Nature Reviews Microbiology 10,
317-322 (May 2012)

Correlates of protection
Use studies of partial protection
Antibodies correlation with survival
Neutralising Ab, how much? to which antigen?
Passive transfer experiments

CD8+ cytotoxic T cells


CD4+ helper T cells
Combination of above

Animal model

Mice
Guinea pig
Hamster
Non-human primates

cynomolgus
rhesus
baboons
African green

Subunits
Glycoprotein
Plasmid DNA
Works in Guinea pigs
Adenovirus 5
Has gone to Phase I study

Structure of ebolavirus and of ebolavirus vaccines protective in NHPs


Shown are schematic representations of ebolavirus (center) and VLP, rAd5,
rVSV and rHPIV3 vaccine particles, as well as of the recombinant virus
genomes for rAd5, rVSV and rHPIV3. Ebolavirus genes and proteins are
shown in color (blue: glycoprotein, yellow: matrix proteins, red: nucleocapsid
proteins), whereas genes and proteins of the vaccine vectors are shown in
gray. For the rAd5 genome deletions in the E1 and E3 regions are indicated.
Expert Opin Biol Ther. Hoenen et al. Jul 2012; 12(7): 859872.
Published online May 5, 2012. doi: 10.1517/14712598.2012.685152

Pre-clinical evaluationTested in animals


Stability temperature, time
Purity, toxins, contaminants, LPS,
Mice immunogenicity
Antibody levels
Neutralising antibodies
T cell responses

Toxicity and path in 2 species mice, rabbits


Distribution
Efficacy in animal models, incl. primates

Clinical trials
Phase I- immunogenicity in human, tolerability
Phase II- efficacy, likely no trials in humans
Deployment based on safety and
immunogenicity in humans and
efficacy in animal models
Licensing
Manufacturing and distribution