5
Vaccines and Global Health

Goal 5 in the draft National Vaccine Plan states: Increase global prevention of death and disease through safe and effective vaccination (HHS, 2008). The plan would likely benefit from a clear explanation of the relevance to the United States of global immunization as it may seem unusual that an American national vaccine plan would include objectives and strategies related to implementation and financing of vaccination programs in other countries.

Several developments justify the inclusion of global vaccine issues in the plan. The world is not as it was when smallpox was declared eradicated in 1980; air travel and global trade have grown exponentially, and the scientific and commercial entities that develop, manufacture, and market vaccines span the globe. The American infectious disease landscape includes emerging infections (e.g., severe acute respiratory syndrome), re-emerging infections (e.g., tuberculosis [TB]), and even the occurrence of vaccine-preventable childhood diseases through international travel (e.g., of un-vaccinated American children or unvaccinated foreign visitors). Infectious diseases, especially vaccine-preventable diarrheal and respiratory infections in children, are responsible for millions of deaths (one-fifth of global mortality) (Kieny and Girard, 2005). Pneumococcal disease and rotavirus diarrhea alone cause approximately 1.3 million deaths among infants and young children (WHO, 2006b).

Many diseases that are potentially preventable by vaccines cause considerable social burden including chronic disabilities (such as deafness and brain damage) in low- and middle-income countries. Improved health and resultant reduced morbidity and mortality in developing countries contrib-



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5 Vaccines and Global Health Goal 5 in the draft National Vaccine Plan states: Increase global pre- vention of death and disease through safe and effective vaccination (HHS, 2008). The plan would likely benefit from a clear explanation of the rel- evance to the United States of global immunization as it may seem unusual that an American national vaccine plan would include objectives and strat- egies related to implementation and financing of vaccination programs in other countries. Several developments justify the inclusion of global vaccine issues in the plan. The world is not as it was when smallpox was declared eradicated in 1980; air travel and global trade have grown exponentially, and the scientific and commercial entities that develop, manufacture, and market vaccines span the globe. The American infectious disease landscape includes emerging infections (e.g., severe acute respiratory syndrome), re-emerging infections (e.g., tuberculosis [TB]), and even the occurrence of vaccine- preventable childhood diseases through international travel (e.g., of un- vaccinated American children or unvaccinated foreign visitors). Infectious diseases, especially vaccine-preventable diarrheal and respiratory infections in children, are responsible for millions of deaths (one-fifth of global mortal- ity) (Kieny and Girard, 2005). Pneumococcal disease and rotavirus diarrhea alone cause approximately 1.3 million deaths among infants and young children (WHO, 2006b). Many diseases that are potentially preventable by vaccines cause con- siderable social burden including chronic disabilities (such as deafness and brain damage) in low- and middle-income countries. Improved health and resultant reduced morbidity and mortality in developing countries contrib- 

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN utes to economic development, reduction of poverty, and greater political stability. Reduction and eradication of infectious diseases overseas (e.g., polio, measles) also decreases the likelihood they will affect Americans traveling or working overseas and reduce the risk of importation into the United States by returning travelers, refugees, and immigrants. The U.S. interest in global health in general1 and in immunization in particular is motivated by many factors, including the interconnectedness of the world and a “humanitarian obligation to enable healthy individuals, families, and communities everywhere to live more productive and fulfilling lives” (IOM, 2009b:1). Since the completion of the 1994 plan (HHS, 1994), the landscape of global immunization has changed dramatically. Low- and middle-income country manufacturers have gained increased prominence in manufacturing and furnishing affordable vaccines in these countries. In fact, most of the world’s supply of certain vaccines is manufactured by these companies. Phil- anthropic organizations and the public-private partnerships (such as prod- uct development partnerships [PDPs]) they support have emerged as major actors in vaccine research and development specifically for the developing world. Global funding, from both private philanthropy and government aid, has markedly increased to support the purchase of newer and costlier vaccines, such as pneumococcal conjugate vaccines. The stakeholders for Goal 5 in the National Vaccine Plan include an array of public, private, and not-for-profit entities. The federal agencies with responsibilities for developing country vaccine issues (e.g., development, regulation, and use of vaccines for diseases not endemic to the United States) include the National Institutes of Health (NIH), the Food and Drug Admin- istration (FDA), the Centers for Disease Control and Prevention (CDC), the U.S. Agency for International Development (USAID) in the Department of State, and the Department of Defense. USAID represents the United States in most global organizations that provide governance, develop policy, or coordinate financing for immunization. USAID also supports the Immuni- zationBASICS program that supports lower income countries in policy de- velopment and aspects of capacity building. The United Nations Children’s Fund (UNICEF), the World Health Organization (WHO), the Pan American Health Organization (PAHO), and WHO’s expert committees play central roles in developing international vaccine policy and programs, and in advis- ing and supporting developing countries’ own immunization policies and activities. In the past decade, foundations such as the Bill and Melinda Gates Foundation have emerged as major contributors to financing and innovation in the realm of immunization for low- and middle-income countries. The Global Alliance for Vaccines and Immunisation (GAVI) is a relatively new 1 As exemplified in the Administration’s Global Health Initiative (White House, 2009).

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 VACCINES AND GLOBAL HEALTH global entity with a governing board that includes representatives of WHO, UNICEF, and various nations (such as USAID for the United States). GAVI has been a coordinating mechanism for a number of major immunization initiatives such as the Vaccine Fund, the International Financing Facility for Immunization (IFFIm), and Advanced Market Commitments (AMCs). Finally, there are several disease-specific vaccine initiatives, including the Meningitis Vaccine Project, the Malaria Vaccine Initiative, and the AERAS Global TB Vaccine Foundation. In June 2009 the committee held a meeting with stakeholders on Goal 5 in the National Vaccine Plan. Several themes surfaced during the meeting, reflecting areas of agreement about major challenges and opportunities in the field. These themes include the following: • Programmatic and infrastructure challenges, including most promi- nently surveillance and epidemiologic research to provide burden of disease data needed to inform vaccine research on and the development of new vaccines and to assess rates of vaccine-related adverse events, • The promise of PDPs and the U.S. government role, • Competing priorities: program-specific versus broader health infra- structure objectives and investment; periodic intensification of immuniza- tion (e.g., polio campaigns) versus routine immunization programs, and • Creating a viable market for vaccines using both innovative and well-established financing mechanisms (e.g., IFFIm, differential pricing). CHALLENGES AND OPPORTUNITIES IN A CHANGING LANDSCAPE In Chapter 1, the committee cites a 1997 paper prepared by the U.S. National Vaccine Advisory Committee on the “delicate fabric” of the public- private vaccine development enterprise (NVAC, 1997). A contemporary update of that paper would reflect greater complexity and a similar level of fragility. Also, it is no longer applicable to speak of the American enterprise without reference to the fact that it is part of a global network of national and international governmental, commercial, academic, and civil society actors. The makers of vaccines licensed for the United States are largely multinational corporations. There are multiple barriers to ensuring that developing countries can immunize against major vaccine-preventable diseases. These include market- related factors (lack of incentive to develop vaccines for neglected diseases that affect low- and middle-income countries), financing (for both vaccine development and purchase), operational problems (lack of immunization infrastructure, health care workforce), managerial expertise, scientific and technical issues (such as the challenges encountered in developing HIV and

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN malaria vaccines), and lack of political will (Mahmoud, 2005). Despite the array of challenges described above immunization is the most consistently delivered health service in most of the world, and coverage remains reason- ably good. Efforts by global partners to increase the availability of vaccines in low- and middle-income countries have led to significant increases in immunization rates and lower rates of disease in the past few decades. Nearly three-fourths of children around the world complete their series of DTP (diphtheria, tetanus, pertussis) vaccinations.2 Moreover, the uptake of additional vaccines (e.g., hepatitis B, Haemophilus influenzae b [Hib]) into the routine Expanded Program on Immunization in developing countries has greatly increased. By 2009, 61 of 72 countries eligible for GAVI funding were expected to have introduced Hib vaccine into their routine immuniza- tion programs (PneumoADIP, 2009). Vaccine manufacturers make products that have historically offered minimal or modest returns on investment in high-income countries in part due to uncertain demand and in part because vaccines are one-time or limited-use products (Milstien et al., 2006). Although the vaccine market in developed nations has experienced a kind of renaissance (Gapper, 2009), concerns about profitability remain strong in the context of the vaccine needs of lower income countries (Batson, 2005; Danzon et al., 2005). Consequently, the development of new vaccines for diseases that primarily affect poor counties has been slow. Innovative solutions have been devised to provide incentives for vaccine makers or to find alternate ways and part- ners to develop a needed vaccine. Manufacturers in developing countries supply an increasing proportion of vaccines purchased by or on behalf of developing countries. One concern is that as this segment of the global vaccine industry grows, its growing capacity for research and development paired with a potential shift from its current humanitarian focus could lead manufacturers away from a focus on traditional, low-cost childhood vac- cines (Frew et al., 2008). The story of meningococcal conjugate vaccine for Africa’s meningitis belt offers one case study of a novel kind of partnership to facilitate vaccine development for a market with limited financial potential. The collabora- tion has involved WHO, Program for Appropriate Technology in Health (PATH), U.S. government agencies, and a developing country manufacturer (Serum Institute of India, Limited) to develop a new vaccine against menin- gococcal meningitis with technological support from the public and non- profit sectors (see the meningitis vaccine timeline in Table 5-1). The areas of need in the field of global immunization include the following: 2 Tetanus, diphtheria, acellular pertussis vaccine is used in the United States, but diphtheria, tetanus, whole cell pertussis remains in use in most low- and middle-income countries.

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 VACCINES AND GLOBAL HEALTH • Development of novel vaccines against diseases and strains not targeted by currently licensed vaccines, • Infrastructure and capacity, • Financing vaccine development and purchase, and • Surveillance infrastructure and operational or programmatic capacity. TABLE 5-1 Developing Meningococcal Conjugate Vaccine for Africa’s Meningitis Belt Date Event 1986 Polysaccharide vaccines available in developed countries show limited duration of protection in Africa (Reingold et al., 1985). Vaccine protects individuals for a short time, but does not prevent spread to others, so useful primarily to control epidemics. 1996 Epidemic of meningococcal meningitis in sub-Saharan meningitis belt results in 250,000 cases and 25,000 deaths; generally, 10% of those infected die within days, and 10-20% of survivors suffer neurological sequelae (WHO, 2006a). 1990s WHO decides that a conjugate vaccine for Africa is a high priority; Pasteur Merieux develops conjugate vaccines against meningitis that contain both serotypes A and C; WHO supports evaluation in Niger (Campagne et al., 2000). 2001 Gates Foundation awards WHO and the non-governmental organization PATH $70 million for the Meningitis Vaccine Project (PATH, 2009). 2003 CDC and a British public health laboratory are selected to implement serologic studies. Serum Institute of India is selected to develop the vaccine (PATH, 2009). Meningitis Vaccine Project contracts with a European research group to develop the conjugation technology to be transferred to the Serum Institute of India and used in making the new vaccine (Roberts, 2008). 2003-2004 The European research group refuses to transfer the new technology to the Serum Institute so FDA transfers its recently developed conjugation technology to the Serum Institute (Roberts, 2008). 2009 An epidemic in the meningitis belt causes more than 25,000 cases and more than 1,500 deaths (WHO, 2009a). In the 2008-2009 epidemic season 73,398 cases and 3,869 deaths are reported (UNICEF, 2009). 2010 The new vaccine is expected to be introduced starting 2009-2010 in Burkina Faso and will be phased into an additional 24 countries between 2010 and 2015, with GAVI support (LaForce and Perea, 2008).

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN DEVELOPING NOVEL VACCINES In Chapter 1 of this report, the committee discussed the first goal in the National Vaccine Plan, which pertains to developing new and improved vaccines. As noted above, the United States is part of an increasingly global vaccine enterprise (i.e., vaccines for the U.S. market are largely produced by multinational companies) thus, the discussion in Chapter 1 also applies to vaccines for so-called neglected diseases that disproportionately affect developing countries. In Chapter 1, the committee recommended two priority actions pertain- ing to the development of new and improved vaccines for both domestic and global use. The first action would be to prioritize new and improved vaccine candidates, and the committee has recommended that separate but similar information-gathering and decision-making processes be undertaken to set vaccine priorities for domestic and global health objectives. Storability and ease of delivery are related issues of crucial importance to vaccines for the developing world. Vaccines that do not need refrigeration and vaccines that may be administered orally or intranasally could dramatically transform the immunization landscape, removing or considerably lessening the logistical challenges, training requirements, and potential safety challenges related to vaccine management and administration. The committee recognizes that prioritization of new and improved vac- cines described in Chapter 1 would have no effect unless it is paired with a coordinated, outcome-focused process for facilitating action to implement the priorities. The domestic and global challenges in this area differ some- what, but there are lessons that may be shared. For example, the PDP model, although insufficiently evaluated to determine its overall effectiveness and specific aspects most likely to contribute to effectiveness, represents an in- novative tool that could be adapted to accelerate vaccine development for U.S. use as well as for global purposes. Effective surveillance systems can monitor the impact of vaccine use and inform research and development. The basis of priority setting for new and improved vaccines for global health can be strengthened when information is available on diseases to target based on (1) the burden of disease, and (2) which strains, serotypes, or antigens to include in vaccines developed for low- and middle-income countries (e.g., rotavirus, Neisseria meningiditis). Ascertaining the impact of vaccine use can inform governments, health care workers, and funders of successes of and gaps in the immunization infra- structure (WHO, 2009b). Four models of vaccine research and development have been defined (Wilson, 2007). These include (1) predominantly private sector develop- ment; (2) public sector vaccine design, and transfer to the private sector for clinical trials and production; (3) predominantly public sector development; and (4) coordination by a non-profit entity. The model still common in the

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 VACCINES AND GLOBAL HEALTH United States is the second: government-supported academic research at the early stage of discovery and design, followed by transfer to industry for product development (IAVI, 2009). The model used to develop vaccines for low- and middle-income countries is an increasingly hybrid model, or rather, an array of hybrid arrangements. A main example is the PDP, a public- private entity designed to manage the entire process, from discovery through selection of the most viable candidates, clinical trials, and production. Other novel mechanisms intended to spur innovation have emerged in recent years. As an example, a recent Institute of Medicine (IOM) work- shop summary on Drug Development for Rare and Neglected Diseases and Individualized Therapies (IOM, 2009a) described the approach of the Collaboration for AIDS Vaccine Discovery (CAVD), a program of the Bill and Melinda Gates Foundation consisting of a network of centers and con- sortia. The network adopted a process for exchanging “essential research materials and information to accelerate research” that includes participant agreement and compliance with “certain principles for the sharing of ma- terials and data, as well as to use a master MTA [material transfer agree- ment] and a confidential disclosure agreement for exchanges of materials and information among the various CAVD awardees and collaborators” (IOM, 2009a). INFRASTRUCTURE AND CAPACITY TO PROVIDE IMMUNIZATION Low- and middle-income countries have limited health care infra- structures that are unable or only partially able to support the delivery of needed vaccines, although each country’s needs and circumstances may differ. Infrastructure limitations include obstacles in obtaining and main- taining cold-chain equipment, lack of sufficient and appropriately trained health care personnel to administer vaccines safely and manage all aspects of immunization programs, and lack of systems to monitor vaccine use and potential adverse events (in addition to disease surveillance). Without strengthened infrastructure, funding for vaccines alone will not get vaccines to those who need them. The efforts of low-income countries to recruit and retain health care workers have been complicated by structural adjustment programs, recruitment of health care workers by program-specific activi- ties such as HIV treatment and research, and by emigration to developed countries. Furthermore, developing nations are facing increases in chronic diseases, such as diabetes, and this may place additional requirements on the limited health care funds available. In both developed and developing nations, immunization may be an indicator of health care delivery system status and its contemporary challenges. For example, in low- and middle- income countries, a high vaccination rate in children may be indicative of

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN the overall strength or quality of the health care infrastructure (German et al., 2001). In the United States, the fact that some populations do not have access to immunization services is reflective of the health care system’s chal- lenges in the area of access and payment. Strategies for introducing human papilloma virus (HPV) vaccine, not currently supported by any of the global vaccine purchasing arrangements (UNICEF, PAHO), are under consideration by GAVI and others. HPV vac- cine provides a forward-looking example of the utility of disease burden information to determine the cost-effectiveness of a vaccine in the global context. The introduction of HPV vaccines offers an opportunity to address a cause of substantial mortality, because women in developing countries typically do not have access to screening, detection, and treatment and could potentially benefit enormously from a vaccine that prevents the majority of cervical cancers. However, this will require a new immunization infra- structure targeting adolescents, which will make demands on the systems and capacity. Recommendation 5-1: The National Vaccine Plan should call for the engagement of U.S. federal agencies and partners to support immunization capacity-building to implement new vaccines in low- to middle-income countries through the provision of exper- tise and financial resources necessary to incorporate new vaccines, strengthen immunization infrastructure, and achieve higher levels of vaccination. One infrastructure component requiring specific attention is the development and implementation of surveillance systems for vaccination, disease burden, and vaccine safety that are innovative and appropriate for developing countries. FINANCING VACCINE DEVELOPMENT AND PURCHASE Vaccines are a cost-effective global public health strategy, and they are a good and in some cases excellent investment. For example, the World Bank’s 1993 World Development Report described interventions costing less than $100 per disability-adjusted life year (DALY) as “highly cost ef- fective.” Glennerster and Kremer (2000) calculated the savings made pos- sible by a malaria vaccine and found that over a 10-year horizon, $13 per DALY would be saved, including the cost of vaccine administration and of the U.S. tax incentive. Despite their cost-effectiveness, investment in the development of vaccines for low-to-moderate income countries is limited (WHO, 2003). Just 10 percent of global investment in biomedical research and devel- opment targets the needs of the world’s poorest 90 percent—the so-called 10/90 gap, and this also applies to vaccine research and development (Flory

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 VACCINES AND GLOBAL HEALTH and Kitcher, 2004; Oxfam, 2008). The vaccine industry may not have suf- ficient incentives, such as an ability to recoup high research and development costs and a reasonable return on investment, to develop vaccines solely for low-income countries (Batson and Milstien, 2008). A consequence of these factors for the global immunization enterprise has been an enormous lag in the development of vaccines needed to combat malaria, tuberculosis, and other diseases responsible for the great burden of illness and death in low- income countries. Funding for vaccine research and development for low- and middle- income countries has utilized two types of approaches called “push” and “pull” strategies.3 The former refers to direct support for technological and scientific research that turns an idea into a product, such as through tax credits and funding for investigator-initiated research (Grabowski, 2005). The latter refers to enhancing the demand or creating a market for a given vaccine, for example, through an AMC—a recent example is the U.S. government’s purchases (through Project Bioshield) of vaccines needed to meet biodefense or pandemic preparedness goals (Milstien et al., 2006). Partnerships between foundations and the public sector are support- ing some progress (Lieu et al., 2005). Changing this situation requires a creative blend of “push” and “pull” strategies, and over the past decade, novel partnerships between foundations, governments, and international organizations have led to some progress in addressing vaccine gaps for developing world needs. Several financing mechanisms have emerged. Advance-purchase agreements (also known as AMCs) have been proposed to increase incentives for the development and production of needed vac- cines. The first pilot AMC to accelerate the development, production, and introduction of pneumococcal vaccines was developed by GAVI and became operational in June 2009 (Frew et al., 2008; GAVI, 2007; World Bank and GAVI, 2006). In such agreements purchasers commit in advance of product development to the purchase of specific vaccines meeting appropriate crite- ria for low-income countries, at a fixed price specified in advance (Berndt and Hurvitz, 2005). Such arrangements are intended to reduce uncertainty about return on investment for pharmaceutical companies and give investors confidence (Berndt and Hurvitz, 2005). Another policy model that has been used successfully in the United States is the 1983 Orphan Drug Act that provides tax credits for research 3 As noted in Chapter 1, the terms “push” and “pull” refer to strategies to spur vaccine research and development from the supply side and from the demand side, respectively. “Push” mechanisms include tax credits for research and development, as well as the traditional strategy of funding investigator-initiated research. “Pull” mechanisms include mandates and incentives such as the AMCs for diseases in the developing world and Biomedical Advance Research and Development Authority requests for proposals for bioterrorism countermeasures (Grabowski, 2005).

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0 PRIORITIES FOR THE NATIONAL VACCINE PLAN and development of products for neglected diseases as well as priority review and a “guaranteed seven-year market exclusivity that runs concurrently with any patent-exclusivity terms” (Grabowski, 2005). This strategy was further strengthened by the 2007 FDA Amendments Act that offered sponsors of a New Drug Application (NDA) or Biological License Application (BLA) for a product targeting a tropical disease a priority review voucher4 could be redeemed on a subsequent NDA or BLA or could be transferred and sold to another sponsor, generating income for the sponsor of an “orphan” vac- cine (IOM, 2009a). PDPs are another mechanism to spur research and development (first initiated by the Bill & Melinda Gates Foundation and The Rockefeller Foun- dation). PDPs have emerged specifically to address neglected diseases that affect low-income countries and novel “social technology” that has the po- tential to transform research and development to meet global health needs. PDPs bring together foundations, pharmaceutical companies, academia, and the public sector to support research and development of drugs and vac- cines for neglected diseases, while reducing the risk and uncertainty inherent in pharmaceutical product development (Freire, 2007; Frew et al., 2008; IAVI, 2009; Oxfam, 2008; Sorenson, 2009). While AMCs are intended to pay only for successful vaccine development, PDPs pay at every step of the development process. PDPs have been substantially funded by foundations with generally modest support from governments (IOM, 2009c; Oxfam, 2008). However, some PDP products are nearing the end of the pipeline and would benefit from an influx of funding to support them through the costly Phase III clinical trial and regulatory processes (Batson and Milstien, 2008). The unique operational strength of the PDP approach is that it generally entails building a portfolio of products against a single disease. This has the following advantages: vaccine design occurs across a variety of technologies using standard methods to compare them, there is an inherent incentive to terminate projects that are not promising and simply redirect resources, and PDPs can more easily mix and match technologies. The crucial decisions for PDPs include: how early to start along the development pipeline (earlier projects may carry more risk but also greater promise), what minimum standards a product must meet before it can be included in the portfolio, what the target product profile is, and finally, how to structure and manage the portfolio (how many projects, at which stages, what criteria to use in advancing projects between stages).5 One of GAVI’s objectives has been to support countries’ move toward sustainability of their vaccine needs. From 2000 to 2005, the GAVI Financ- ing Task Force helped 50 countries examine their key financial concerns 4 The voucher ensures review and action by the agency within six months of submission of that application. 5 Personal communication, M. Moree, Global Health Services, September 2009.

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 VACCINES AND GLOBAL HEALTH with regard to immunization and to develop financial sustainability plans. Although GAVI found some signs of success, “huge funding gaps remain for these countries due to the initial underlying assumptions of the GAVI and financial sustainability plan model” (Kamara et al., 2008). Given current economic pressure on national health budgets, the fiscal sustainability of immunization will remain a great challenge (Lydon et al., 2007). Many vaccines are used in both high- and low-income countries. His- torically, once vaccines are developed, they become available in high-income countries first and in low-income countries much later, at lower prices. Dur- ing this lag, mortality and morbidity from certain diseases continue to grow (Batson and Milstien, 2008). Thus, the challenge has been to find a way to facilitate timely access to new vaccines at a price low-income countries can afford. Differential pricing strategies involve charging different prices for the same vaccines, whereby “prices in affluent (and, to a lesser extent, middle income countries) exceed the marginal cost of production and dis- tribution in these countries by enough, in aggregate, to cover the joint costs of R&D, while prices in [developing countries] cover only their marginal cost” (Danzon and Towse, 2003). Bulk procurement systems, such as those used by UNICEF and PAHO (the Revolving Fund) set the greatly reduced prices they will pay for speci- fied member countries. A uniform price would bar low-income countries from having access to a vaccine. Differential pricing serves as an incentive to multinational manufacturers to develop and continue to produce needed vaccines, it enables producers to expand revenues and profits by having a larger market for their product, and it also makes possible slightly lower prices for higher income countries (Plahte, 2005). Differential pricing is important to facilitate ongoing availability and use of the vaccines at af- fordable prices (often paid for out of U.S. assistance funds) for the lowest income countries (i.e., GAVI-eligible). The committee finds that ways vaccines are priced have the potential to simultaneously achieve two different objectives: increase affordability of vaccines in lower income countries and increase incentives for manu- facturers to innovate. The committee also finds that vaccine pricing is not always congruent with a country’s ability to pay. There is a difference be- tween what a high-income country and a low-income country can afford, and pricing is generally consistent with that difference. However, certain international pricing mechanisms set the same price for low- and middle- income countries. This may keep certain vaccine prices unnecessarily low and thus limit the manufacturer’s ability to recoup research and develop- ment costs for vaccines for diseases endemic to low- and middle-income countries.

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN TABLE 5-2 The Complexity of Financing Global Vaccines and Immunization On the One Hand On the Other Hand Investment in vaccine financing is Investment in vaccine financing is enabling humanitarian aid nations to stand on their own feet Investment in vaccine financing is an Investment in vaccine financing is an investment in targeting help where it investment in sustainable infrastructure is needed most now (putting out fires) (helping to prevent fires) Vaccines are about improving health Vaccines are about economic development It is critical to use the vaccines that exist It is critical to develop the better vaccines that today may be used tomorrow Need to leverage the risk management Need to leverage the innovation and efficiency benefits of long-term partnerships benefits of competition Differential pricing: expanded access, Differential pricing: anti-efficiency, hard to justice enforce, unfair to middle-income nations Recommendation 5-2: The National Vaccine Plan should endorse active U.S. engagement in the development of global policy frame- works to further global adherence to differential pricing in order to ensure access to needed vaccines in all countries. Table 5-2 illustrates the extraordinary balancing act required of the global vaccine enterprise and the myriad governmental, multilateral and bilateral, industry, and non-governmental actors that are involved. SURVEILLANCE Surveillance systems in industrialized and developing countries suffer from a number of common constraints, including a lack of human and material resources, weak infrastructure, poor coordination, and uncertain linkages be- tween surveillance and response. However, these constraints are more pro- nounced in developing countries, which bear the greatest burden of disease and are where new pathogens are more likely to emerge, old ones to reemerge, and drug-resistant strains to propagate. (GAO, 2001:16) CDC defines public health surveillance as “the ongoing, systematic collection, analysis, interpretation, and dissemination of data about a health-related event for use in public health action to reduce morbidity and mortality and to improve health” (German et al., 2001). Establishing and maintaining effective surveillance for diseases and vaccine adverse events in low-resource environments presents considerable challenges. (Disease surveillance at or across international borders is particularly challenging.) Like the delivery of immunization services in general, surveillance relies on the existence of an adequate public health and health care infrastructure, the political will to support it, and many other resources. Many developing

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 VACCINES AND GLOBAL HEALTH countries have limited capacity to conduct surveillance of any kind, includ- ing the surveillance of basic health indicators such as death rates, causes of death, or general burden of disease, let alone surveillance for specific dis- eases and vaccine adverse events (GAO, 2004; IOM, 2007; WHO, 2009b). The World Health Organization operates an adverse event database—the Program for International Drug Monitoring—but reporting by most low- and middle-income countries has been extremely limited and in many cases non-existent (Letourneau et al., 2008). Traditionally, surveillance consists of a chain of reporting that begins at the level of an “astute clinician” who detects an adverse event or disease and ends at the level of national public health authorities. In settings where health care providers may be limited in number and overburdened by the volume of patients to be seen, disease surveillance may not be a high prior- ity, and the very first link in the chain may be missing. For this and other reasons, surveillance in developing countries requires creative uses of ap- propriate technology and cannot necessarily rely on the methods and tools used to conduct surveillance in developed countries. One example may be found in the use of cell phones to report adverse events by individuals who receive a modest amount of training. Cell phones are a modern technology widely available in some of the farthest reaches of developing countries (IOM, 2007). (Box 5-1 describes the purpose of Vaccine Adverse Event Surveillance.) CDC supports two programs intended to strengthen surveillance in developing countries: the International Emerging Infection Program and the Field Epidemiology Training Program/Field Epidemiology and Laboratory Training Program (FE[L]TP) (CDC, 2009a,b; GAO, 2004). CDC also has described several important criteria for decision making when develop- ing surveillance systems: usefulness, flexibility, acceptability, portability, Box 5-1 Purpose of Vaccine Adverse Event Surveillance Adverse event surveillance serves several different purposes that are of vary- ing importance to immunization programs. These include “(1) detection, correction and prevention of programmatic errors; (2) identification of problems with a specific vaccine lot or brand; (3) prevention of false blame from coincidental events; (4) maintenance of confidence by properly responding to parent/community concerns while increasing awareness; (5) generate new hypothesis (signal generation); (6) estimation of rates of adverse events following immunization (AEFI) in local populations; and (7) adjust informed consent, contraindications and benefit/risk analysis” (Duclos, 2004).

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN stability, and cost. The same criteria apply to surveillance in developing countries, although some criteria may require additional consideration in that context (Buehler et al., 2004). At the committee’s June 2009 meeting with stakeholders for Goal 5 in the draft National Vaccine Plan, the com- mittee heard that when surveillance data are not used, or findings are not communicated to the workers who gather and report data, the willingness to conduct surveillance may be adversely affected. This remark echoed comments at a past IOM (2007) workshop that when pathways for use of surveillance data are unclear, there is a decreased likelihood that countries will be willing to collect such data in the future because they cannot see a return on their investment. The best mix of surveillance interventions will vary from community to com- munity. A challenge now is to do the operations research to adapt academic surveillance concepts to unique community circumstances. This is important not only in communities with strong health systems, but also in developing countries, where nontraditional approaches may be more essential and afford- able than in places with a relative abundance of astute clinicians, laboratories, and hospitals, such as the United States. (IOM, 2007:50) The capacity for surveillance (of disease, vaccine use, and adverse events) in low- and middle-income countries is variable, depending on the perceived importance of surveillance, available resources, infrastructure, regulation, and available expertise. Both in the 2007 IOM workshop and at the committee’s information-gathering meeting there was agreement that the U.S. government could contribute valuable expertise to countries devel- oping innovative and appropriate surveillance systems to meet local needs. This may mean employing currently available techniques or may require innovative techniques (Curioso et al., 2005, 2007). Laboratory capacity is also a critical component of effective vaccine- preventable disease surveillance. For example, laboratory diagnosis of yel- low fever is invaluable because the clinical presentation can be non-specific and confused with other conditions. Also, determining the serogroup and type of an appropriate sample of meningococci has been useful for assess- ing the potential and actual impact of vaccines. Improved and rapid agent- specific laboratory and field diagnostics to support surveillance objectives could be useful tools. Whatever the type of surveillance and new technolo- gies employed, they need to be used in a thoughtful, well-planned manner that does not burden the system. The history of global polio immunization programs raises some impor- tant questions about the future of immunization infrastructure and capacity, including surveillance, in a polio-free world. Polio eradication programs have served as a model for other programs, such as measles, and have led to the creation and mobilization of a variety of resources, including expertise. U.S. plans for technical assistance and resources to support capacity building

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 VACCINES AND GLOBAL HEALTH need to consider the transition away from polio to other diseases once polio is eradicated. This would help to ensure that the decades of good work on polio eradication serve as a foundation for more widespread strengthening of all components of the immunization and public health infrastructure in developing countries. There are several interesting case studies in global disease surveillance. One comes from GAVI’s Pneumococcal Vaccines Accelerated Development and Introduction Plan surveillance initiative, which aimed to “strengthen and expand surveillance of bacterial meningitis and pneumonia in develop- ing countries” (Levine et al., 2009). The initiative included approximately 90 sites in 15 countries, and a March 2009 supplement to the journal Clinical Infectious Diseases included overviews of some of these activities (Levine et al., 2009). The initiative conducted surveillance through networks of sites that were created and sustained through annual meetings for shar- ing of data, best practices, and experiences. The initiative was primarily a collection of specifically-funded applied research studies, but it facilitated collaborations between national government decision makers and research- ers, and may provide some interesting lessons that could be applied to more routine surveillance systems. Global surveillance for avian influenza (H5N1) provides another case study of surveillance needs. The Wildlife Conservation Society has worked with individual governments to conduct surveillance of avian flu in wild birds (basic epidemiology and viral sample collection and characterization) in Mongolia. That surveillance program provided a candidate virus for the development of a human H5N1 influenza vaccine. These efforts have recent- ly been integrated and combined with the global avian influenza network for surveillance to expand international surveillance for influenza in wild birds and promote the dissemination of surveillance information to govern- ments, international organizations, and the private and public sectors. A key strategy has been training individuals and organizations to collect samples for analysis, and results are provided in an open access database. Although surveillance of adverse events following immunization in low- and middle-income countries is extremely limited and the underlying infrastructure is also limited, some targeted efforts have shown that adverse event surveillance is possible, especially in areas that have a basic public health infrastructure, such as health districts and personnel who can take reports and, in turn, convey them to central authorities. REFERENCES Batson, A. 2005. The problems and promise of vaccine markets in developing countries. Health Aff 24(3):690-693. Batson, A., and J.B. Milstien. 2008. The GO license: Only part of the solution. Health Aff 27(1):140-142.

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