Vaccines: The Week in Review 1 March 2010 Center for Vaccine Ethics & Policy

A program of - Center for Bioethics, University of Pennsylvania - The Wistar Institute Vaccine Center

- Children’s Hospital of Philadelphia, Vaccine Education Center

This weekly summary targets news and events in the global vaccines field gathered from key governmental, NGO and company announcements, key journals and events. This summary provides support for ongoing initiatives of the Center for Vaccine Ethics & Policy, and is not intended to be exhaustive in its coverage. Vaccines: The Week in Review is now also posted in a blog format at Each item is treated as an individual post on the blog, allowing for more effective retrospective searching. Given email system conventions and formats, you may find this alternative more effective. This blog also allows for RSS feeds, etc. Comments and suggestions should be directed to David Curry, Editor and Executive Director of the Center, at

The WHO Director-General issued a statement on 24 February 2010 following the seventh meeting of the Emergency Committee on 23 February 2010 in which the Committee's views on the determination of the pandemic status were assessed: “A detailed update was provided to the Committee on the global pandemic situation. After asking additional questions and reviewing the evidence and holding extensive discussion, the Committee was of the view that there was mixed evidence showing declining or low pandemic activity in many countries, but new community level transmission activity in West Africa. Moreover, they expressed concern that the winter months of the Southern Hemisphere had not yet started and there was uncertainty whether additional generalized waves of activity might occur and the need to not undermine preparations. “The Committee advised that it was premature to conclude that all parts of the world have experienced peak transmission of the H1N1 pandemic influenza and that additional time and information was needed to provide expert advice on the status of the pandemic. The Committee accordingly suggested that the Committee be re-convened in a few weeks to review intervening developments and related epidemiological information. “Having considered these views, the current epidemiological evidence and other relevant information, the Director-General determined that there had been no change in the pandemic phase, and decided to continue to monitor the situation and developments closely and to convene the Committee again within the next several weeks.

“The WHO Director-General asked the Committee for their views on continuance of the three current temporary IHR recommendations issued for the public health emergency of international concern. The consensus view of the Committee was in favor of continuation but to update the second recommendation by replacing "Intensify" with "Maintain" in recognition of the increased pandemic surveillance already implemented by countries and the need to maintain this activity. Having considered the views of the Emergency Committee, and the ongoing pandemic situation, the Director-General determined to continue the three temporary recommendations, as modified, namely: - countries should not close borders or restrict international traffic and trade; - maintain surveillance of unusual flu-like illness & severe pneumonia; - if ill, it is prudent to delay travel. The WHO continues to issue weekly “updates” and briefing notes on the H1N1 pandemic at: Pandemic (H1N1) 2009 - update 89 Weekly update 26 February 2010 As of 21 February 2010, worldwide more than 213 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 16226 deaths... Situation update: In the temperate zone of the northern hemisphere, pandemic influenza virus continues to be detected across many countries, however, overall influenza activity continues to wane in most places. The most active areas of transmission are currently in parts of south and southeast Asia and in limited areas of east and southeastern Europe. In Southeast Asia, pandemic influenza virus continued to circulate in areas, however, the overall intensity of respiratory diseases activity remained low and unchanged, except in a few countries. More at:

The U.S. Food and Drug Administration approved Prevnar 13, a pneumococcal 13-valent conjugate vaccine for infants and young children ages 6 weeks through 5 years. Prevnar 13 will be the successor to Prevnar, the pneumococcal 7-valent conjugate vaccine licensed by the FDA in 2000 to prevent invasive pneumococcal disease (IPD) and otitis media. The new vaccine extends the protection to six additional types of the disease causing bacteria. Prevnar 13 is approved for the prevention of invasive disease caused by 13 different serotypes of the bacterium Streptococcus pneumoniae. It also is approved for the prevention of otitis media caused by the seven serotypes shared with Prevnar. The bacterium can cause infections of the blood, middle ear, and the covering of the brain and spinal cord, as well as pneumonia. Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research, said, “Although the rates of invasive pneumococcal

disease have declined dramatically, there are still children in the United States who are suffering with this serious illness. The availability of Prevnar 13 will help prevent pneumococcal disease caused by the six additional serotypes.” The FDA said that safety was evaluated in 5,084 infants and young children who received Prevnar 13, compared with 2,760 who received Prevnar, the control vaccine. Common adverse reactions reported after administration of Prevnar 13 were pain, redness and swelling at the injection site, irritability, decreased appetite and fever. These reactions were similar to what has been observed with Prevnar, which has a good safety record in the United States. Post marketing studies will include continued monitoring for reduction in IPD and otitis media, as well as continued evaluation of safety. .htm

CDC’s Advisory Committee on Immunization Practices (ACIP) voted on 24 February to expand the recommendation for annual influenza vaccination to include all people aged 6 months and older. The expanded recommendation is to take effect in the 2010 – 2011 influenza season. The new recommendation “seeks to remove barriers to influenza immunization and signals the importance of preventing influenza across the entire population.” Prior to the action, ACIP recommendations for seasonal influenza vaccination – which focused on vaccination of higher risk persons, children 6 months through 18 years of age and close contacts of higher risk persons – already applied to about 85 percent of the U.S. population. CDC said that discussion at the ACIP meeting “focused on the value of protecting all people 19 to 49 years of age, who have been hard hit by the 2009 H1N1 pandemic virus, which is likely to continue circulating into next season and beyond. Another reason cited in favor of a universal recommendation for vaccination is that many people in currently recommended “higher risk” groups are unaware of their risk factor or that they are recommended for vaccination. The ACIP discussion also recognized the practicality and value of issuing a simple and clear message regarding the importance of influenza vaccination in the hopes that this would remove impediments to vaccination and expand coverage. Finally, new data collected over the course of the 2009 H1N1 pandemic indicates that some people who do not currently have a specific recommendation for vaccination may also be at higher risk of serious flu-related complications, including those people who are obese, post-partum women and people in certain racial/ethnic groups”

The Weekly Epidemiological Record (WER) for 26 February 2010, vol. 85, 9 (pp 69–80) includes: Global tuberculosis control: key findings from the December 2009 WHO report.

Journal Watch

[Editor’s Note] Vaccines: The Week in Review continues its weekly scanning of key journals to identify and cite articles, commentary and editorials, books reviews and other content supporting our focus on vaccine ethics and policy. Journal Watch is not intended to be exhaustive, but indicative of themes and issues the Center is actively tracking. We selectively provide full text of some editorial and comment articles that are specifically relevant to our work. Successful access to some of the links provided may require subscription or other access arrangement unique to the publisher. Our initial scan list includes the journals below. If you would like to suggest other titles, please write to David Curry at JAMA Vol. 303 No. 8, pp. 693-804, February 24, 2010 [No relevant content] Journal of Infectious Diseases 15 March 2010 Volume 201, Number 6 [No relevant content] The Lancet Feb 27, 2010 Volume 375 Number 9716 Pages 697 - 776 Comment Time for fair trade in research data Elizabeth Pisani, James Whitworth, Basia Zaba, Carla Abou-Zahr Extract Geneticists, astrophysicists, and molecular biologists routinely share research data with colleagues and rivals alike. The reason is that scientists and their funders know we will understand complex issues sooner if people build on one another's work.1,2 Yet scientists in the complex area of public health have been left behind in the data-sharing revolution. The Lancet Infectious Disease Mar 2010 Volume 10 Number 3 Pages 139 - 212 Editorial Gates Foundation's decade of vaccines Original Text The Lancet Infectious Diseases

The GAVI Alliance celebrated the tenth anniversary of its foundation on Jan 29 this year. During its 10 years GAVI has overseen the delivery of vaccines to around 250 million children in the world's poorest countries, a programme that has probably averted around 5 million deaths. To mark GAVI's birthday, the Bill and Melinda Gates Foundation announced that it will commit US$10 billion over the next 10 years to a so-called decade of vaccines—ie, research and development and delivery of vaccines to the world's poorest. As an agency whose role is vaccine delivery, rather than research and development, it is not clear how much of the Gates billions will be coming to GAVI. However, GAVI is already the foundation's largest grantee, having received $1·5 billion in its 10 year history. Other major GAVI donors are national governments, of which 16 have contributed to the alliance plus the European Commission. Countries that have donated the most to GAVI's core funding include Canada, the Netherlands, Norway, the UK, and the USA. Although the direct donation made by Gates far outstrip those made by any national government, France and the UK have committed billions of dollars to a funding mechanism called the International Finance Facility for Immunisation and other governments have promised substantial amounts to this scheme. GAVI currently disburses around $1 billion per year among the 65 countries in which it supports vaccination programmes. The alliance focuses its activities on delivery of a childhood pentavalent vaccine that protects against diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b. However, to roll out this vaccine to all 65 countries by 2015, plus achieve its goal of adding pneumococcal and rotavirus vaccines to the immunisation schedule, will require an additional $3 billion. A lot more than just wishful thinking has gone into Gates' decision to donate $10 billion. A model developed at the Johns Hopkins Bloomberg School of Public Health (Baltimore, MD, USA), indicated that 90% vaccine coverage—including the rotavirus and pneumococcal vaccines—would prevent the deaths of 7·6 million children younger than 5 years between now and 2020. Adding the malaria vaccine, which is undergoing clinical trials, from 2014 could save an additional 1·1 million lives. The Gates Foundation will certainly not be funding this expansion in vaccine coverage on its own, but its financial commitment should act as an incentive for donor governments to provide the additional funds to achieve 90% coverage with childhood vaccines in developing countries within the next 10 years. In addition to the diseases already mentioned, vaccination against measles will likely be targeted for some of the Gates' billions. Progress in preventing deaths from measles has been remarkable, with around 82% of those eligible worldwide now receiving vaccine and the number of measles-related deaths falling from around 750 000 in 2000 to 164 000 in 2008. GAVI does not currently fund measles vaccination programmes; rather, another international collaboration, the Measles Initiative, provides technical and financial support for national vaccination programmes in developing countries. Other areas that might benefit include the provision of autodisposable syringes that cannot be reused, funding for new vaccines against group A meningococcal meningitis and against tuberculosis, and perhaps even a final push to eliminate polio.

Although the life-saving benefits of vaccination are beyond question, no immunisation programme is without an element of controversy. As pointed out in Newsdesk, GAVI is optimistic about rolling out pneumococcal vaccine on a large scale to developing countries, because it believes the cost of the vaccine can be reduced by 90%; however, little research has been done on the public health effect of widespread pneumococcal vaccine use in the targeted countries—might there, for example, be replacement of the vaccine pneumococcal serotypes with other serotypes, thus making the vaccine only temporarily effective? Given the present influenza pandemic, some of the Gates money could be spent on researching the effect of influenza in developing countries and, if necessary, developing vaccines against influenza that are cheap enough for widespread use in these countries. These caveats are, of course, minor compared with the beneficial effect on global health that the commitment made by the Gates Foundation is likely to have. The foundation does need to set out a clear plan for how it intends to disburse its money over the decade of vaccines. Nevertheless, many more national governments than are currently backing global vaccine coverage should be inspired to follow the lead taken by the foundation. Reflection and Reaction Vaccine safety: misinformed about the misinformed Jonathan E Suk Preview Concern about the antivaccination movement is clearly warranted.1 It is also correct that most concerns about vaccine safety can, in theory, be allayed by logic and reason, and that the role of vaccines in improving public health should never be understated. The accumulation of more evidence and clearer communication about the differences between causation and correlation, would also help. Newsdesk Polio eradication within 5 years now a real possibility Kathryn Senior Last year was a significant one for polio eradication. Real progress was made simultaneously in northern Nigeria, on the Afghanistan–Pakistan border, and in the remaining pockets in Bihar and Uttar Pradesh in India, cutting the number of cases worldwide to 1597 (correct as of Feb 2, 2010). The new bivalent oral polio vaccine (bOPV), which targets type 1 and type 3 polioviruses, was licensed in late 2009 and has been in use since December. Starting in February, March, and April, 2010, multiple mass immunisations are planned in all four remaining countries where polio is endemic, at the start of a 3-year intensive effort to finally halt polio transmission worldwide. Personal View Reducing empiricism in malaria vaccine design Vasee S Moorthy, Marie Paule Kieny Preview Gains in the control of malaria and the promising progress of a malaria vaccine that is partly efficacious do not reduce the need for a high-efficacy vaccine in the longer term. Evidence supports the feasibility of developing a highly efficacious malaria vaccine. However, design of candidate malaria vaccines remains empirical and is necessarily based on many unproven assumptions because much of the knowledge needed to design vaccines and

to predict efficacy is not available. Data to inform key questions of vaccine science might allow the design of vaccines to progress to a less empirical stage, for example through availability of assay results associated with vaccine efficacy. Review Tuberculosis and air travel: a systematic review and analysis of policy Ibrahim Abubakar Preview WHO international guidelines for the control of tuberculosis in relation to air travel require—after a risk assessment—tracing of passengers who sat for longer than 8 h in rows adjacent to people with pulmonary tuberculosis who are smear positive or smear negative. A further recommendation is that all commercial air travel should be prohibited until the person has two consecutive negative sputum smears for drug-susceptible tuberculosis or two consecutive cultures for multidrug-resistant tuberculosis. Nature Volume 463 Number 7284 pp999-1112 25 February 2010 [No relevant content] New England Journal of Medicine Volume 362 — February 25, 2010 — Number 8 [No relevant content] Pediatrics February 2010 / VOLUME 125 / ISSUE 2 [Reviewed earlier] PLoS Medicine (Accessed 1 March 2010) &limit=10&document_count=1533&ct=1&SESSID=aac96924d41874935d8e1 c2a2501181c#results [No relevant content] Science 26 February 2010 Vol 327, Issue 5969, Pages 1043-1162 News of the Week Drug Safety: New Network to Track Drugs and Vaccines in Pregnancy

Jennifer Couzin-Frankel Both doctors and patients are jittery about whether to continue or drop potentially risky treatments during pregnancy. A new effort to bring risks into focus is being launched this week with $12.5 million from two U.S. agencies. It will start by examining asthma medications called short-acting beta agonists, as well as flu vaccines and antivirals for influenza. Called VAMPSS (the Vaccines and Medications in Pregnancy Surveillance System), the program will be funded for 5 years by the Agency for Healthcare Research and Quality and for 2 years by the Biomedical Advanced Research and Development Authority and coordinated by the American Academy of Allergy, Asthma, and Immunology. An advisory committee that includes members from pediatric and obstetric groups, and the Centers for Disease Control and Prevention, will guide VAMPSS's research. Policy Forum Intellectual Property: Fixing the Legal Framework for Pharmaceutical Research Sherry M. Knowles The cost of drug research and development (R&D) has increased from $230 million per drug in the early 1980s to $1.2 billion today, with R&D currently requiring about 10 to 15 years per drug (1–4). This investment of time and money cannot be sustained without a legal system that provides sufficient time to recoup the investment and to secure a reasonable return, as well as the ability to make important business decisions that remain correct over a long period of time. Pharmaceutical companies have historically relied on two kinds of market protection: (i) the exclusive ownership of their own clinical research and (ii) patents. However, the U.S. Hatch-Waxman Act (5), which is designed to strike a balance between innovative pharmaceutical research and access to generic drugs, is flawed. Further, U.S. courts sometimes retroactively change standards for patent protection long after large R&D efforts have been initiated, which increases the risk to defend and rely on patent protection. Chief Patent Counsel, GlaxoSmithKline, King of Prussia, PA 19406, USA. Science Translational Medicine 17 February 2010 vol 2, issue 19 Research Articles Vaccines Long-Term Thermostabilization of Live Poxviral and Adenoviral Vaccine Vectors at Supraphysiological Temperatures in Carbohydrate Glass Robert Alcock, Matthew G. Cottingham, Christine S. Rollier, Julie Furze, Samodh D. De Costa, Marian Hanlon, Alexandra J. Spencer, Jared D. Honeycutt, David H. Wyllie, Sarah C. Gilbert, Migena Bregu, and Adrian V. S. Hill 17 February 2010:19ra12 Abstract [Bolding by Week in Review] Live recombinant viral vectors based on adenoviruses and poxviruses are among the most promising platforms for development of new vaccines

against diseases such as malaria, tuberculosis, and HIV-AIDS. Vaccines based on live viruses must remain infectious to be effective, so therefore need continuous refrigeration to maintain stability and viability, a requirement that can be costly and difficult, especially in developing countries. The sugars sucrose and trehalose are commonly used as stabilizing agents and cryoprotectants for biological products. Here, we have exploited the ability of these sugars to vitrify on desiccation to develop a thermostabilization technique for live viral vaccine vectors. By slowly drying vaccines suspended in solutions of these disaccharide stabilizers onto a filter-like support membrane at ambient temperature, an ultrathin glass is deposited on the fibers of the inert matrix. Immobilization of two recombinant vaccine vectors —E1/E3-deleted human adenovirus type 5 and modified vaccinia virus Ankara —in this glass on the membranes enabled complete recovery of viral titer and immunogenicity after storage at up to 45°C for 6 months and even longer with minimal losses. Furthermore, the membrane carrying the stabilized vaccine can be incorporated into a holder attached to a syringe for almost simultaneous reconstitution and injection at point of use. The technology may potentially be developed for the deployment of viral vector–based biopharmaceuticals in resource-poor settings. Vaccine Volume 28, Issue 7, Pages 1661-1892 (17 February 2010) Conference Report The second Geneva Consensus: Recommendations for novel live TB vaccines Pages 2259-2270 K.B. Walker, M.J. Brennan, M.M. Ho, J. Eskola, G. Thiry, J. Sadoff, R. Dobbelaer, L. Grode, M.A. Liu, U. Fruth, P.H. Lambert Abstract Infection with Mycobacterium tuberculosis continues to be a major public health burden in most developing parts of the world and efforts to develop effective strategies for containing the disease remain a priority. It has long been evident that effective mass vaccination programmes are a cost effective and efficient approach to controlling communicable diseases in a public health setting and tuberculosis (TB) continues to be a major target. One approach with increasing acceptance is based upon on live mycobacterial vaccines, either as recombinant BCG or rationally attenuated M. tuberculosis, thus generating a new live TB vaccine. The Geneva Consensus published in March 2005 set out the opinion on priorities and requirements for developing live mycobacterial vaccines for Phase I trials. In the intervening period much progress has been made in both preclinical and clinical development of new TB vaccines and has provided the impetus for organising the second Geneva Consensus (held at WHO headquarters, April 2009) to discuss issues, including: i. Explore the regulatory requirements for live TB vaccines to enter Phase I trials, in particular those based on attenuated M. tuberculosis. Particular attention was paid to the characterisation and safety package likely to be

required, including issues of attenuation, the presence of antibiotic resistance markers in live vaccines and the nature of any attenuated vaccine phenotype. ii. To identify the general criteria for further clinical development from Phase I through to Phase III. iii. Obtain a perspective of the regulatory landscape of developing countries where Phase II and III trials are to be held. iv. Review manufacturing considerations for live TB vaccines and relevance of the WHO and European Pharmacopeia guidelines and requirements for BCG vaccine. v. Consider requirements and associated issues related to the use of these new vaccines within an existing BCG vaccination programme. Cost-effectiveness of the CRM-based 7-valent pneumococcal conjugated vaccine (PCV7) in Argentina Pages 2302-2310 Norberto D. Giglio, Alejandro D. Cane, Paula Micone, Angela Gentile Abstract Due to the region's own conditions, universal vaccination with pneumococcal conjugate heptavalent vaccine (PCV-7) in Latin American countries is still controversial. Objective To compare projected economic costs and health benefits associated with pneumococcal conjugate heptavalent vaccine as a routine immunization in healthy children in Argentina. Design A decision analytic model of Markov simulated lifetime evolution of a birth cohort (n 696,451) was developed and compared costs and health benefits of pneumococcal disease in the presence and absence of vaccination. Main outcome measures Cost per life year (LY) gained, reduce in diseases burden and costs of vaccination. Results From the society's perspective, the incremental cost per LY gained was US$ 5599.42 and the purchase of the 4 doses of vaccine for the entire cohort with a cost of US$ 26.5 dose requires an investment of US$ 73,823,806.00. The model estimated that vaccination reduce the number of death by 159 cases of meningitis, 756 cases of bacteriemias 4594 cases of pneumonias about 84,769 cases of otitis media and 20 meningitis sequelae. The value of the cost per LY gained was considerably modified by the variation in the cost of the vaccine dose, efficacy/effectiveness of the vaccine for pneumonia the mortality from pneumonia and herd immunity. Conclusions Our analysis predicted that routine vaccination of healthy infants <2 years could prevent an important number of pneumococcal infectious and reduce related mortality and morbidity. This strategic could be highly cost-effective in Argentina. Meningococcal conjugate vaccination among adolescents aged 13–17 years, United States, 2007 Pages 2350-2355 Peng-jun Lu, Nidhi Jain, Amanda C. Cohn

Abstract Background An estimated 1000–2000 cases of invasive meningococcal diseases occur annually in the United States. In 2005, a new quadrivalent meningococcal conjugate vaccine (MCV4) was approved and, because of supply constraints, was recommended for routine vaccination of some groups of adolescents. In August 2007, vaccination recommendations were expanded for all adolescents 11–18 years. Methods We analyzed data from the 2007 National Immunization Survey-Teen (NISTeen), a nationally representative random digit dialed telephone survey. Estimates of MCV4 coverage were assessed from provider-reported vaccination histories. A multivariable logistic regression analysis and predictive marginal model were performed to identify factors independently associated with MCV4 vaccination. Results Provider-reported vaccination histories were available for 2947 adolescents aged 13–17 years with a response rate of 55.9%. Overall, MCV4 coverage was 32.4% (95% confidence interval (CI) = 30.2–34.7%) in 2007. Vaccination coverage was similar among adolescents aged 13–14 years compared to those aged 15–17 years (32.1% vs. 32.6%, respectively). Coverage was 30.6% for non-Hispanic whites, 35.9% for non-Hispanic blacks, and 36.1% for Hispanics; however, these variations were not statistically significant. Characteristics independently associated with a higher likelihood of MCV4 vaccination included having ≥2 physician contacts in the past year, having a well child visit at age 11–12 years, and ever having a doctor recommendation for meningitis vaccination of the adolescent. Conclusions In 2007, MCV4 coverage among 13–17 years old increased 20.7 percentage points from 2006. Achieving high vaccination coverage among adolescents will be challenging. Targeting adolescents with no health insurance and no recent healthcare provider visits may be important to increase coverage.

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