Vaccines: The Week in Review 29 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 continues to issue weekly “updates” and briefing notes on the H1N1 pandemic at: Pandemic (H1N1) 2009 - update 93 Weekly update 26 March 2010 As of 21 March 2010, worldwide more than 213 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 16,931 deaths. WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and member states and through monitoring of multiple sources of information. Situation update: The most active areas of pandemic influenza virus transmission currently are in parts of Southeast Asia, West Africa, and in the tropical zone of the Americas… More at:

The GAVI Alliance announced that GlaxoSmithKline (GSK) and Pfizer became “the first two companies to make long-term commitments to supply new vaccines against pneumococcal disease” under the Advance Market Commitment (AMC) for pneumococcal disease. The AMC has been supported by the governments of Italy, the United Kingdom, Canada, Russia, Norway and the Bill & Melinda

Gates Foundation. GAVI CEO Julian Lob-Levyt said, "Today’s landmark announcement promises to make new vaccines available affordably, where they are urgently needed, and faster than ever before. Through this AMC, and thanks to the political will demonstrated by donors and least developed nations and the participation of the pharmaceutical companies, prevention against the world’s biggest childhood killer is now within reach.” GAVI estimates that the introduction of suitable and affordable vaccines against the disease could save approximately 900,000 lives by 2015 and up to seven million lives by 2030. Pfizer and GSK “have committed to supply 30 million doses each per year, for a 10 year period…(to be) made available at US$ 3.50 per dose to be paid by GAVI and the developing country governments that introduce the vaccines.” GAVI said that, for approximately 20% of the doses, companies will also receive an additional payment of US$3.50 for each dose they provide, which is paid with donor commitments (AMC funds). In total, this is a fraction of the current cost of pneumococcal vaccines in many industrialised countries, GAVI noted. ommitment.php

The FDA recommended that “healthcare practitioners temporarily suspend use of the Rotarix vaccine for rotavirus immunization in the United States while the agency learns more about components of an extraneous virus detected in the vaccine, noting that there is no evidence at this time that this finding poses a safety risk. Full text of the announcement follows: “The agency recently became aware that an independent U.S. academic research team, using a novel technique, has found DNA from porcine circovirus 1 (PCV1) in Rotarix, which is manufactured by GlaxoSmithKline. PCV1 is not known to cause illness in humans or other animals. In addition, Rotarix has been studied extensively, before and after approval, and found to have an excellent safety record. “Follow-up tests by GlaxoSmithKline and FDA scientists confirmed the academic team’s findings and confirmed that viral components have been present since the early stages of the vaccine’s development, including during clinical studies. Preliminary testing by both the academic researchers and FDA scientists of another licensed vaccine against rotavirus infection, RotaTeq, has not detected components of PCV1. “"We are making clinicians aware of information recently received by FDA about the Rotarix vaccine,” said Dr. Margaret A. Hamburg, Commissioner for Food and Drugs. “There is no evidence at this time that there is a safety concern. FDA is recommending that clinicians temporarily suspend use of Rotarix until we can learn more about the situation. We will keep the public and the clinical community updated on our findings…” “…In many countries, rotavirus causes so much severe illness and death that the known benefits of continued use of Rotarix far outweigh any theoretical risk of harm from the vaccine,” said Dr. Thomas Frieden, Director of the Centers for Disease Control and Prevention. “We anticipate that many

countries will decide to continue vaccinating with Rotarix while more information becomes known.” “FDA will continue to gather more information about the PCV1 components in Rotarix, including whether intact virus, as opposed to DNA fragments, is present. The agency is assessing current vaccine testing methods. In four to six weeks, FDA will convene an expert advisory committee and make additional recommendations on the use of rotavirus vaccines. “FDA will provide updates to patients, providers, and the general public as more information becomes available. The agency will also continue to communicate with the World Health Organization and counterpart regulatory agencies in other countries. .htm WHO: Rotavirus vaccination - WHO does not recommend any change to use of Rotarix vaccine 22 March 2010 Following announcements today by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding use of the rotavirus vaccine, Rotarix, the World Health Organization (WHO) encourages all countries using the vaccine to carefully consider the significant benefits of continued use of the vaccine in any decisions about further use. The FDA and EMA statements follow the recent report to the vaccine manufacturer that DNA sequences originating from porcine circovirus 1 (PCV1) had been detected in two batches of the vaccine during a study undertaken in the United States of America (USA). WHO concurs with the views of the FDA and EMA that the findings do not present a threat to public health. Moreover, rotaviruses are the most common cause of severe diarrhoeal disease in young children throughout the world, with an estimated 527 000 deaths among children under five years old, most of whom live in low-income countries. Therefore, WHO does not recommend any change to use of the vaccine. The vaccine is prequalified by WHO, and the prequalification status remains unchanged. WHO will continue to work closely with the FDA , EMA and other regulatory agencies to evaluate further information that the manufacturer will be providing as a matter of urgency. ndex.html Statement of the Global Advisory Committee on Vaccine Safety on Rotarix On 25 March 2010, WHO’s Global Advisory Committee on Vaccine Safety (GACVS) met by teleconference to review new data on Rotarix, an oral vaccine for prevention of rotavirus gastroenteritis. Academic investigators recently reported to the vaccine manufacturer, GlaxoSmithKline, that the vaccine contains DNA from porcine circovirus type 1 (PCV1). PCV1 is not known to cause disease in animals or humans. Further analysis of the master cell bank and master viral seed used for vaccine production have demonstrated the presence of PCV1 DNA, which in retrospect has been in the vaccine throughout its clinical development, including the prelicensure clinical trials. There are studies underway both by the manufacturer and

others that will provide additional information to help more fully assess this new finding. The safety of Rotarix is supported by both large clinical trials prelicensure and an extensive (>60 million doses) postlicensure safety experience. GACVS reviewed the safety data from both clinical trials and spontaneous reports, both of which supported the continued safety of Rotarix. Rotavirus gastroenteritis is the most common cause of severe diarrheal disease in young children throughout the world, with an estimated 527 000 deaths annually among children under five years old. Given the extensive clinical data supporting the safety of Rotarix and the benefits of rotavirus vaccination for children, GACVS considers that the benefits of vaccination far outweigh any currently known risk associated with use of Rotarix. GACVS will continue to review data as it becomes available and will update this statement as we learn more. 2010/en/index.html

PATH and the International Enteric Vaccine Consortium (EntVac) announced a new partnership for early-stage research into a vaccine concept against enterotoxigenic E. coli (ETEC), described as one of the leading bacterial causes of diarrheal disease. PATH will fund EntVac, a consortium of universities anchored by the University of Maryland School of Medicine, to pursue preclinical proof of concept of a stable toxin (ST) toxoid vaccine. PATH said such a vaccine “offers the prospect of broad protection against ETEC, but requires additional research and evaluation.” PATH will provide funding of US$1.1 million over 2.5 years for the research effort. ETEC is responsible for up to 840 million infections and approximately 400,000 deaths worldwide each year, mostly in children in developing countries. The research will be conducted at the University of Maryland School of Medicine’s Center for Vaccine Development, the University of Bergen, the University of South Dakota, and Tulane University. The Research Council of Norway is also funding the EntVac consortium for this research project.

The Center for Strategic and International Studies (CSIS) Commission on Smart Global Health Policy launched its final report – A Healthier, Safer and More Prosperous World – “promoting a longterm, strategic US approach to global health.” The report advises U.S. policymakers in five major issue areas which “chart a course for US global health investment through 2025”: - Maintaining commitments to HIV/AIDS, tuberculosis, and malaria - Narrowing health gaps for women and children - Strengthening prevention and preparedness capabilities - Improving coordination and increasing capacity between implementers and policymakers - Making smart investments in multilateral institutions.

Dr. Christopher Elias, president and CEO of PATH and a member of the CSIS commission, said, “The report from the CSIS Commission on Smart Global Health Policy highlights how crucial research and innovation for new global health products are to overall US global health efforts. It also illustrates how innovative financing mechanisms play vital roles in spurring the development of new vaccines, drugs, and other tools that save lives worldwide. US policymakers should implement these recommendations to maximize the country's efforts to improve health around the world.” The report and additional information available at:

The Weekly Epidemiological Record (WER) 26 March 2010, vol. 85, 13 (pp 117–128) includes: Cholera vaccines: WHO position paper

The MMWR Weekly for March 26, 2010 / Vol. 59 / No. 11 includes: 2009 Pandemic Influenza A (H1N1) in Pregnant Women Requiring Intensive Care — New York City, 2009 To characterize the severity of 2009 H1N1 virus infection in pregnant women, the New York City Department of Health and Mental Hygiene conducted surveillance for cases in pregnant women requiring intensive care. The findings indicated that, during 2009, 16 pregnant women and one who was postpartum were admitted to intensive-care units. Two women died. Of the 17 women, 12 had no risk factors for severe influenza complications other than pregnancy, and only one woman received antiviral treatment within 2 days of symptom onset.

PPD, Inc. announced the launch of PPD Vaccines & Biologics Center of Excellence, described as “a first-in-kind comprehensive network of integrated, world-class laboratory services focused specifically on vaccine and biologic drug development.” PPD said the Center significantly expands vaccine testing services PPD acquired from Merck in 2009. “With the industry’s largest collection of commercial vaccine assays and strong immunochemistry, cell culture and cGMP lab operations, PPD is the first CRO to offer the type of laboratory support that has the potential to bring significant efficiencies to the development of vaccines and biologics,” the company said. Christine Dingivan, M.D., chief medical officer, PPD, commented, “With the industry’s largest collection of commercial vaccine assays and strong immunochemistry, cell culture and cGMP lab operations, PPD is the first CRO to offer the type of laboratory support that has the potential to bring significant efficiencies to the development of vaccines and biologics. The Vaccines & Biologics Center of Excellence provides the high quality scientific

support our clients are seeking in a way that allows them to bypass costly capital and resource investments necessary to develop and maintain these capabilities internally.” ndmViewId=news_view&newsId=20100323007191&newsLang=en

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 Clinical Infectious Diseases 15 April 2010 Volume 50, Number 8 [Reviewed last week] Emerging Infectious Diseases Volume 16, Number 4–April 2010 Possible Transmission of Pandemic (HIN1) 2009 Virus with Oseltamivir Resistance M. Mandelboim et al. Human Vaccines Volume 6, Issue 3 March 2010 [Reviewed earlier] JAMA Vol. 303 No. 12, pp. 1119-1216, March 24/31, 2010 [No relevant content]

Journal of Infectious Diseases 15 April 2010 Volume 201, Number 8 [Reviewed last week] The Lancet Mar 27, 2010 Volume 375 Number 9720 Pages 1053 - 1134 Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study Elizabeth Miller, Katja Hoschler, Pia Hardelid, Elaine Stanford, Nick Andrews, Maria Zambon Summary Background Knowledge of the age-specific prevalence of immunity from, and incidence of infection with, 2009 pandemic influenza A H1N1 virus is essential for modelling the future burden of disease and the effectiveness of interventions such as vaccination. Methods In this cross-sectional serological survey, we obtained 1403 serum samples taken in 2008 (before the first wave of H1N1 infection) and 1954 serum samples taken in August and September, 2009 (after the first wave of infection) as part of the annual collection for the Health Protection Agency seroepidemiology programme from patients accessing health care in England. Antibody titres were measured by use of haemagglutination inhibition and microneutralisation assays. We calculated the proportion of samples with antibodies to pandemic H1N1 virus in 2008 by age group and compared the proportion of samples with haemagglutination inhibition titre 1:32 or more (deemed a protective response) before the first wave of infection with the proportion after the first wave. Findings In the baseline serum samples from 2008, haemagglutination inhibition and microneutralisation antibody titres increased significantly with age (F test p<0·0001). The proportion of samples with haemagglutination inhibition titre 1:32 or more ranged from 1·8% (three of 171; 95% CI 0·6—5·0) in children aged 0—4 years to 31·3% (52 of 166; 24·8—38·7) in adults aged 80 years or older. In London and the West Midlands, the difference in the proportion of samples with haemagglutination inhibition titre equal to or above 1:32 between baseline and September, 2009, was 21·3% (95% CI 8·8—40·3) for children younger than 5 years of age, 42·0% (26·3—58·2) for 5—14-year-olds, and 20·6% (1·6—42·4) for 15—24-year-olds, with no difference between baseline and September in older age groups. In other regions, only children younger than 15 years showed a significant increase from baseline (6·3%, 1·8 —12·9). Interpretation Around one child in every three was infected with 2009 pandemic H1N1 in the first wave of infection in regions with a high incidence, ten times more than estimated from clinical surveillance. Pre-existing antibody in older age

groups protects against infection. Children have an important role in transmission of influenza and would be a key target group for vaccination both for their protection and for the protection of others through herd immunity. Funding National Institute for Health Research Health Technology Assessment Programme. The Lancet Infectious Disease Apr 2010 Volume 10 Number 4 Pages 213 - 288 [No relevant content] Nature Volume 464 Number 7288 pp465-640 25 March 2010 [No relevant content] New England Journal of Medicine Volume 362 — March 25, 2010 — Number 12 Perspective Global Climate Change and Infectious Diseases E. K. Shuman [Initial article language per NEJM convention] The 2009 United Nations Climate Change Conference in Copenhagen ended on December 18 without passage of a binding resolution for tackling global climate change. With the debate over U.S. health care reform raging, this event went largely unnoticed by the U.S. health care community. However, climate change will have enormous implications for human health, especially for the burden of vectorborne and waterborne infectious diseases… The Pediatric Infectious Disease Journal April 2010 - Volume 29 - Issue 4 Original Studies Universal Mass Vaccination Against Rotavirus Gastroenteritis: Impact on Hospitalization Rates in Austrian Children Paulke-Korinek, Maria; Rendi-Wagner, Pamela; Kundi, Michael; Kronik, Renate; Kollaritsch, Herwig Abstract Background: Since July 2007, rotavirus vaccinations have been subsidized in Austria for all children from the seventh week up to the sixth month of life. Vaccination coverage over the whole period was 72% with an increase to 87% in 2008.

Methods: In a sentinel network including 11 pediatric hospital wards in Austria, data of children up to 15 years of age and hospitalized due to rotavirus gastroenteritis between January 2001 and December 2008 have been collected. Results: The hospitalization rates of children up to 12 months of age with rotavirus gastroenteritis were 2066 x 10-5 between 2001 and 2006 and decreased to 631 x 10-5 in 2008. For children between 12 and 24 months of age the hospitalization rate decreased from 1822 x 10-5 (2001-2006) to 1456 x 10-5 in 2008. In children aged 2 to less than 5 years, incidence rates were 436 x10-5 (2001-2006) and 461 x 10-5 in 2008. In older children, the hospitalization rates remained unchanged. In the target population for the RV-vaccine, a decrease of hospitalization rates due to rotavirus gastroenteritis of 74% was observed compared to the era before the introduction of the vaccine. The field effectiveness of the vaccine was estimated between 61% and 98%, depending on assumptions about the vaccination status. Conclusions: Within 18 months, the universal mass vaccination program against rotavirus led to a substantial decrease in the hospitalization rates of the target cohort of the immunization program in Austria. (C) 2010 Lippincott Williams & Wilkins, Inc. Pediatrics March 2010 / VOLUME 125 / ISSUE 3 [Reviewed earlier] PLoS Medicine (Accessed 28 March 2010) &limit=10&document_count=1533&ct=1&SESSID=aac96924d41874935d8e1 c2a2501181c#results [No relevant content] Science 26 March 2010 Vol 327, Issue 5973, Pages 1543-1678 News of the Week Swine Flu Pandemic: What's Old Is New: 1918 Virus Matches 2009 H1N1 Strain Jon Cohen The "novel" H1N1 swine influenza virus that last year caused the first human pandemic in 4 decades has one feature that is hardly novel: Its surface protein, hemagglutinin (HA)—which spikes cells and starts an infection— closely matches the HA in the H1N1 virus responsible for the 1918 pandemic. Separated by 91 years, the two strains of the highly mutable virus ought to be vastly different. This newfound similarity answers many mysteries about the 2009 pandemic, including why it largely spared the elderly. The new

findings, reported online this week in Science and Science Translational Medicine, also suggest intriguing explanations for how the 1918 influenza virus has evolved since it swept across the globe in several waves, killing more than 50 million people by the winter of 1919. And the investigators are proposing provocative—some say far-fetched—vaccination strategies to preempt future pandemics. Science Express Index Published Online March 25, 2010 Reports Structural Basis of Preexisting Immunity to the 2009 H1N1 Pandemic Influenza Virus Rui Xu,1, Damian C. Ekiert, Jens C. Krause, Rong Hai, James E. Crowe, Jr., Ian A. Wilson The 2009 H1N1 swine flu is the first influenza pandemic in decades. The crystal structure of the hemagglutinin from the A/California/04/2009 H1N1 virus shows that its antigenic structure, particularly within the Sa antigenic site, is extremely similar to human H1N1 viruses circulating early in the 20th century. The co-crystal structure of the 1918 HA with 2D1, an antibody from a survivor of the 1918 Spanish flu that neutralizes both 1918 and 2009 H1N1 viruses, reveals an epitope that is conserved in both pandemic viruses. Thus, antigenic similarity between the 2009 and 1918-like viruses provides an explanation for the age-related immunity to the current influenza pandemic. Science Translational Medicine 24 March 2010 vol 2, issue 24 Research Articles Influenza Cross-Neutralization of 1918 and 2009 Influenza Viruses: Role of Glycans in Viral Evolution and Vaccine Design Chih-Jen Wei, Jeffrey C. Boyington, Kaifan Dai, Katherine V. Houser, Melissa B. Pearce, Wing-Pui Kong, Zhi-yong Yang, Terrence M. Tumpey, and Gary J. Nabel Editor’s Abstract New strains of H1N1 influenza virus have emerged episodically over the last century to cause human pandemics, notably in 1918 and recently in 2009. Pandemic viruses typically evolve into seasonal forms that develop resistance to antibody neutralization, and cross-protection between strains separated by more than 3 years is uncommon. Here, we define the structural basis for cross-neutralization between two temporally distant pandemic influenza viruses—from 1918 and 2009. Vaccination of mice with the 1918 strain protected against subsequent lethal infection by 2009 virus. Both were resistant to antibodies directed against a seasonal influenza, A/New Caledonia/20/1999 (1999 NC), which was insensitive to antisera to the pandemic strains. Pandemic strain–neutralizing antibodies were directed against a subregion of the hemagglutinin (HA) receptor binding domain that is highly conserved between the 1918 and the 2009 viruses. In seasonal strains, this region undergoes amino acid diversification but is shielded from antibody neutralization by two highly conserved glycosylation sites absent in the pandemic strains. Pandemic HA trimers modified by glycosylation at

these positions were resistant to neutralizing antibodies to wild-type HA. Yet, antisera generated against the glycosylated HA mutant neutralized it, suggesting that the focus of the immune response can be selectively changed with this modification. Collectively, these findings define critical determinants of H1N1 viral evolution and have implications for vaccine design. Immunization directed to conserved receptor binding domain subregions of pandemic viruses could potentially protect against similar future pandemic viruses, and vaccination with glycosylated 2009 pandemic virus may limit its further spread and transformation into a seasonal influenza. Vaccine Volume 28, Issue 18, Pages 3071-3264 (19 April 2010) Regular Papers Modelling the seasonality of rotavirus disease and the impact of vaccination in England and Wales Pages 3118-3126 Christina Atchison, Ben Lopman, William John Edmunds Abstract Two rotavirus vaccines are currently recommended for inclusion in routine childhood immunization programmes. We developed a deterministic agestructured model of rotavirus transmission and disease to investigate the population-level effects of vaccination in England and Wales. The model explicitly captures the natural history of infection and uses realistic population mixing patterns. The model accurately reproduces the strong seasonal pattern and age distribution of rotavirus disease observed in England and Wales. We predict vaccination will provide both direct and indirect protection within the population. If coverage levels comparable to other childhood vaccines are achieved, we predict that vaccination will reduce rotavirus disease incidence by 61% resulting in a potential fall in burden on health-care services. Volume 28, Issue 17, Pages 2917-3070 (9 April 2010) Regular Papers Criteria for inclusion of vaccinations in public programmes Pages 2924-2931 Hans Houweling, Marcel Verweij, E. Joost Ruitenberg and on behalf of the National Immunisation Programme Review Committee of the Health Council of the Netherlands Abstract As more and more new vaccines are developed and brought to the market, governments have to make decisions about which vaccinations to include in public programmes. This paper describes the experience in the Netherlands in developing a framework for assessing whether a vaccination should be included in the National Immunization Programme (NIP). Bearing in mind the public nature, the factors that determine a vaccine's suitability for inclusion in a communal vaccination programme have been translated into seven selection criteria, grouped under five thematic headings: seriousness and

extent of the disease burden, effectiveness and safety of the vaccination, acceptability of the vaccination, efficiency of the vaccination, and priority of the vaccination. The seven criteria and the explanation of them provide a framework for the systematic examination of arguments for and against the inclusion and prioritisation of particular vaccinations. As an illustration, the vaccinations currently provided in the Netherlands through public programmes as well as 23 ‘candidate’ vaccinations are assessed against the seven criteria. The proposed assessment framework including the selection criteria can take full account of the values and specificities as they may differ between situations and countries; the transparency of the approach may help to clarify which elements of the assessment are pivotal in specific situations. Using the criteria furthers a trustworthy, transparent and accountable process of decision-making about inclusion of new vaccinations in public vaccination programmes and may help to retain public confidence. “All manner of ills”: The features of serious diseases attributed to vaccination Pages 3066-3070 Julie Leask, Simon Chapman, Spring Chenoa Cooper Robbins Abstract Anti-vaccination writings have linked vaccines with a wide range of negative outcomes. The majority of evidence negates such connections raising the question of what makes these attributions attractive. This research identified diseases and conditions which are claimed to have been caused by vaccines and identified their shared societal features. They shared an idiopathic origin; apparent rise in incidence; face-value biological plausibility of a link to vaccines; dreaded outcomes; and their onset having close proximity to immunisation. Any attempt to re-frame erroneous claims about vaccination first requires an identification of the deeper anxieties in which they are located. Volume 28, Issue 16, Pages 2799-2916 (1 April 2010) Editorial Improving the public health: The U.S. recommendation for universal influenza immunization Pages 2799-2800 Gregory A. Poland, Dale Morse Short Communication Constructing target product profiles (TPPs) to help vaccines overcome post-approval obstacles Pages 2806-2809 Bruce Y. Lee, Donald S. Burke Abstract As history has demonstrated, post-approval obstacles can impede a vaccine's use and potentially lead to its withdrawal. Addressing these potential obstacles when changes in a vaccine's technology can still be easily made may improve a vaccine's chances of success. Augmented vaccine target product profiles (TPPs) can help vaccine scientists better understand and anticipate these obstacles and galvanize conversations among various vaccine stakeholders (e.g., scientists, marketers, business development

managers, policy makers, public health officials, health care workers, third party payors, etc.) earlier in a vaccine's development. Regular Papers A comparison of the use of economics in vaccine expert reviews Pages 2841-2845 Philip Jacobs, Arto Ohinmaa Abstract We reviewed how health economics has been included in the vaccine expert review processes in a sample of countries. We identified two kinds of review processes – those in which vaccines and drugs are assessed using a common process, and those in which vaccines are assessed within the infectious disease framework. In either process, the countries recommend that their national pharmaco-economic (i.e., guidelines developed for drugs) guidelines be used to conduct the studies, although the guidelines themselves differ between countries. As a result of these factors, the decision process and the study outcomes can differ between countries, but because the vaccine adoption process includes other criteria as well, economic factors will not necessarily alter the outcome.

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