3
Resources and Infrastructure

Global resources and infrastructures for the development, production, and supply of vaccines are large, and their full documentation is beyond the scope of this study. In this chapter, the committee seeks to give the reader a perspective on the number and variety of participants in immunization activities, both in the United States and internationally.

RESOURCES IN THE UNITED STATES

The United States supports a large number of public agencies and programs involved in vaccine-related activities (National Vaccine Advisory Committee, 1992). Each year, the federal government spends hundreds of millions of dollars to conduct research for new and improved vaccines, ensure the safety of existing vaccines, purchase and distribute vaccines to the states, and conduct educational and other outreach activities to encourage vaccine use. The U.S. government does not currently produce vaccines on a large scale, that is the province of private industry. However, both Massachusetts and Michigan manufacture vaccines for their respective populations.

The bulk of federally supported vaccine research and development is funded by the National Institutes of Health (NIH), primarily through the National Institute of Allergy and Infectious Diseases (NIAID); the Centers for Disease Control and Prevention (CDC); the U.S. Agency for International Development (AID); the U.S. Department of Defense (DOD),



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The Children's Vaccine Initiative: Achieving the Vision 3 Resources and Infrastructure Global resources and infrastructures for the development, production, and supply of vaccines are large, and their full documentation is beyond the scope of this study. In this chapter, the committee seeks to give the reader a perspective on the number and variety of participants in immunization activities, both in the United States and internationally. RESOURCES IN THE UNITED STATES The United States supports a large number of public agencies and programs involved in vaccine-related activities (National Vaccine Advisory Committee, 1992). Each year, the federal government spends hundreds of millions of dollars to conduct research for new and improved vaccines, ensure the safety of existing vaccines, purchase and distribute vaccines to the states, and conduct educational and other outreach activities to encourage vaccine use. The U.S. government does not currently produce vaccines on a large scale, that is the province of private industry. However, both Massachusetts and Michigan manufacture vaccines for their respective populations. The bulk of federally supported vaccine research and development is funded by the National Institutes of Health (NIH), primarily through the National Institute of Allergy and Infectious Diseases (NIAID); the Centers for Disease Control and Prevention (CDC); the U.S. Agency for International Development (AID); the U.S. Department of Defense (DOD),

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The Children's Vaccine Initiative: Achieving the Vision largely through the Departments of the Army and Navy; and the U.S. Food and Drug Administration (FDA). DOD and CDC purchase vaccines at federally negotiated contract prices and distribute them to the military and civilian sectors, respectively. Regulatory oversight and licensure are performed by FDA's Center for Biologics Evaluation and Research (CBER). Demonstration projects, field testing, and postmarketing surveillance for vaccines are conducted or funded by AID, CDC, and FDA. The National Vaccine Program (NVP), which is part of the Office of the Assistant Secretary for Health of the U.S. Department of Health and Human Services, is authorized to coordinate and provide direction to the nation's various vaccine-related efforts; this mandate is carried out under the guidance of the National Vaccine Advisory Committee, which is composed of representatives of government agencies, public health experts, private industry, and citizens groups. U.S. Federal Agencies and Programs U.S. Agency for International Development The U.S. Agency for International Development participates in a wide range of immunization-related activities. On the domestic front, AID representatives participate as liaison members to the NVP's National Vaccine Advisory Committee (NVAC). In addition, they sit on the U.S. Department of Health and Human Services' NVP Interagency Group, whose membership comprises senior scientific and policy officials from AID, CDC, DOD, FDA, NIH, and NVP and is charged with overseeing implementation of the NVP. AID's vaccine-related initiatives are international in scope. The bulk of AID resources supports national EPI programs and is provided through bilateral agreements. Since 1986, AID has committed an estimated $246 million for immunization programs and vaccine-related research to more than 60 countries (U.S. Agency for International Development, 1992). In 1991, AID allocated over $15 million for the development and testing of vaccines (Institute of Medicine, 1991; U.S. Agency for International Development, 1992). AID funds also support the development, testing, and introduction of diagnostics and immunization-related technologies intended to simplify vaccine administration and improve the ''cold chain" (the system needed to keep vaccines refrigerated from manufacture to administration). AID has provided extensive support to strengthen the developing world's capacity for vaccine testing and delivery and for disease surveillance. The agency funds the development of epidemiological and research capacity in

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The Children's Vaccine Initiative: Achieving the Vision developing countries and provides grant support for epidemiology and field testing. In 1992, AID initiated a set of specific responses to the international Children's Vaccine Initiative (CVI) (U.S. Agency for International Development, 1992). These included a grant program to support research on CVI-related topics conducted jointly by scientists from the United States and less-developed countries. AID also has provided funding for the Vaccine Independence Initiative, sponsored by the United Nations Children's Fund (see International Resources, below). Center for Biologics Evaluation and Research, U.S. Food and Drug Administration The Center for Biologics Evaluation and Research at FDA is responsible for the scientific review of license applications for new biologics, including vaccines. CBER examines new biologics submitted by vaccine manufacturers for safety and efficacy, as well as process consistency and regulatory compliance. In addition to its role in licensing vaccines and facilities that manufacture vaccines, CBER has active laboratory research and postmarketing surveillance programs that complement and support its regulatory activities. CBER also works closely with scientific committees at the World Health Organization (WHO) and is working toward greater international harmonization of vaccine standards. In fiscal year 1992, CBER had a total of 641.3 full-time equivalent positions (FTEs) (Center for Biologics Evaluation and Research, Office of Management, 1993). The operating budget was $24,365,000, and the payroll, including salaries and benefits, was $36 million (Center for Biologics Evaluation and Research, Office of Management, 1993). The number of FDA FTEs engaged in vaccine activities was 223, and FDA allocated over $27 million to CBER's vaccine work (Center for Biologics and Evaluation Research, Office of Management, 1993), $14.9 million of which was directed toward research and development for children's vaccines (World Health Organization/Children's Vaccine Initiative, 1993). CBER has also received support from the National Vaccine Program Office (NVPO) (U.S. Department of Health and Human Services, 1992). In fiscal year 1991, the NVPO provided eight FTEs and almost $1.9 million to FDA, permitting the agency to enhance the development of a safer pertussis vaccine, establish a computer tracking system to analyze the lot-specific relationships of reports of adverse events, and work on projects associated with the CVI (Kessler, 1992; U.S. Department of Health and Human Services, 1992). FDA representatives actively participate on WHO technical and expert committees, which review and set international technical standards for

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The Children's Vaccine Initiative: Achieving the Vision biologics. FDA staff also sit on several CVI task forces and product development groups. In addition, the FDA is actively involved in the International Conference on Harmonization, which includes the European Community, Japan, and the United States and addresses global standardization. For the most part, the International Conference on Harmonization has thus far addressed technical requirements for drugs. The FDA conducts bilateral activities with the European Community, Mexico, Canada, and the United Kingdom; these activities consist primarily of information sharing and discussion of broad regulatory policy issues. Finally, the FDA carries out bilateral activities with a number of countries, including Egypt, India, and Russia—activities that are largely funded by AID. Centers for Disease Control and Prevention The Centers for Disease Control and Prevention is charged with protecting the health of U.S. citizens. CDC's vaccine-related activities are carried out by its Division of Immunization. CDC purchases 50–60 percent of all public-sector doses of vaccine recommended for general use in the United States. Every year, CDC negotiates consolidated federal contracts with manufacturers for routinely recommended childhood vaccines. These public-sector rates are substantially lower than those charged the private sector (see Chapter 4). CDC makes grants to the states to purchase the vaccines at the contract price. In fiscal year 1992, CDC funded the purchase of $154 million worth of vaccines. An additional $18.7 million was awarded to the states to support immunization program operations, and another $12.8 million was targeted at efforts to manage follow-on activities related to the measles outbreak of 1989–1990 (Centers for Disease Control and Prevention, Division of Immunization, 1992). In addition to the purchase of vaccines, CDC helps states and localities determine their immunization needs and plan and implement immunization programs. Among other tasks, states must distribute and administer vaccines, develop and maintain systems that can be used to detect adverse events associated with vaccination, conduct disease surveillance, assess immunization levels, and provide professional educational materials about the importance of vaccination. CDC also has developed the national vaccine stockpile, currently having a 26-week reserve of most childhood vaccines, to manage any short-term interruption in supply. The agency, along with the FDA, monitors the Vaccine Adverse Events Reporting System, a surveillance network which receives reports of the adverse events that occur within specified time frames following vaccination. Although CDC's efforts are focused primarily on U.S. health needs, the agency does participate in immunization-related activities on a global level.

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The Children's Vaccine Initiative: Achieving the Vision TABLE 3-1 NCID Expenditures in Research, Development, and Clinical Trials for Selected Vaccines in Fiscal Year 1992 Vaccine Research and Development ($) Clinical Trials ($) Dengue 282,000   Haemophilus influenzae 25,000   type b     Hepatitis B   368,000 Malaria 143,000   Measles 25,000   Meningitis 130,000 140,000 Pertussis 247,000   Pneumococcus 272,000   Polio 154,000 130,000 Streptococcus (group a)   32,000 Streptococcus (group b) 25,000   Venezuelan equine 20,000   encephalitis     Total 1,459,000     SOURCE: Joseph McDade, Office of the Director, National Center for Infectious Diseases, Atlanta, Georgia, May 1993. The majority of research and training in the area of infectious diseases supported by the CDC is conducted by the National Center for Infectious Diseases (NCID) (Table 3-1). Although CDC does not sustain overseas laboratories, it does support overseas field stations that conduct research and training in infectious diseases as collaborative activities with the host country. The agency has approximately 50 employees based in foreign countries, many of whom are working on infectious disease activities. In fiscal year 1990, the agency responded to 25 international public health emergencies, 10 of which were related to infectious disease outbreaks (Institute of Medicine, 1992). CDC's Epidemic Intelligence Service provides training and field experience in epidemiology to health professionals. Epidemic Intelligence Service officers are assigned to CDC headquarters, CDC's domestic field stations, state and local health departments, or other federal agencies to carry out epidemiological research and investigations. This program is a model for the joint CDC/WHO Field Epidemiology Training Program. The programs are funded by the host country and countries with epidemiologists who can assist in the development and implementation of disease control and prevention programs (Institute of Medicine, 1992).

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The Children's Vaccine Initiative: Achieving the Vision TABLE 3-2 Amount of Vaccine Distributed to Army Installations by the Defense Logistics Agency in Calendar Year 1991 Vaccine No. of Doses Purchased Price/Dose ($) Total Cost ($) Measles-mumps-rubella 251,000 18.66 4,700,454 Diphtheria and tetanus toxoids and pertussis 253,950 8.15 2,069,693 Polio (oral) 474,100 2.44 1,156,804 Meningococcal 196,100 3.83 751,063 Plague 374,514 0.79 295,866 Rabies 8,576 49.79 426,999 Typhoid (parenteral) 31,220 0.55 17,171 Yellow fever 227,560 3.29 748,672 Hepatitis B 19,122 23.85 456,060 Adenovirus (type 7) 120,800 0.65 78,520 Adenovirus (type 4) 108,000 0.65 70,590 Total 2,066,442   10,769,892   SOURCE: Robert J. Lipnick, Disease Surveillance Officer, U.S. Army Medical Material Agency, Frederick Maryland, October 6, 1992. U.S. Department of Defense The U.S. Department of Defense is both a purchaser of vaccines and an active vaccine research and production entity. In calendar year 1991, DOD's procurement arm, the Defense Logistics Agency, bought some $10.7 million worth of vaccine at government-negotiated prices (Table 3-2). The total spent by DOD on vaccines is thought to be on the order of two to three times this amount, however, since many DOD units buy vaccine directly from the manufacturer. The vaccines, including at least three intended for use in the developing world (plague, typhoid, and yellow fever), are distributed to various Army installations by the Defense Logistics Agency. In fiscal year 1992, DOD spent a total of $76.7 million on vaccine-related research, $42 million of which supported work on vaccines against human immunodeficiency virus (HIV), the virus that causes AIDS (Table 3-3). As the lead agency for infectious disease research, the Army provides the U.S. Naval Medical Research Institute $10 million annually. However, DOD vaccine research is conducted mostly by the Division of Communicable Disease and Immunology at the Walter Reed Army Institute of Research, which employs approximately 220 people and spends roughly $15 million annually. Vaccine research and development is also conducted at the U.S. Army Institute of Infectious Diseases (USAMRIID) at Fort Detrick,

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The Children's Vaccine Initiative: Achieving the Vision TABLE 3-3 Infectious Disease Vaccine Research by the U.S. Defense Department in Fiscal Year 1992 Area of Vaccine Research Fiscal Year Cost (in millions of $) Viral diseases 14.1 Bacterial diseases 8.1 Malaria vaccine research 7.9 Nonenteric bacteria 4.6 HIV/AIDS 42.0 Total 76.7   SOURCE: COL William Bancroft, Director, Military Diseases Hazards Research Program, U.S. Army Medical Research and Development Command, U.S. Department of Defense, October 1992. Maryland. The U.S. Army Medical Material Development Activity (USAMMDA), with a yearly operating budget of $15 million to $20 million, is DOD's product development unit. USAMMDA supports a clinical testing facility at the University of Maryland, Baltimore, and manufactures pilot lots of vaccines, including those for Q fever, Rift Valley fever, and Venezuelan equine encephalitis, through a contract with the Salk Institute in Swiftwater, Pennsylvania. DOD completed modernization of its own pilot vaccine manufacturing facility in 1992 at Forest Glen, Maryland, at an estimated cost of $5 million. This $25 million facility, expected to be fully validated and functional in October 1993, will be capable of producing up to 1 million doses of vaccine for clinical trials annually by using traditional or modern molecular biology techniques (Jerald C. Sadoff, Walter Reed Army Institute of Research, personal communication, 1993). DOD also supports a number of overseas field laboratories that have the capacity to conduct vaccine-related research on a variety of tropical diseases. The laboratories are based in Thailand, Kenya, Brazil, Peru, Indonesia, and Egypt. National Institutes of Health The National Institutes of Health supports an active program in vaccine research, implemented through intramural research projects and extramural contracts, cooperative research and development agreements, and grants. Although the research is conducted through a number of institutes, including the National Cancer Institute and the National Institute of Child Health and

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The Children's Vaccine Initiative: Achieving the Vision Human Development (NICHD), the vast majority of vaccine research is concentrated at the National Institute of Allergy and Infectious Diseases (NIAID). In 1981, NIAID founded its Program for Accelerated Development of Vaccines to focus and enhance research activities leading to new vaccines for important diseases. Over the next decade, the program grew, addressing vaccine priorities with the assistance of previous Institute of Medicine studies (Institute of Medicine, 1986a,b). The 1991 NIH Strategic Plan identified vaccines and immunology as a trans-NIH critical area of technology and provided a framework for strengthening nontraditional targets. The goals of the CVI provide an additional focus for vaccine research and development that combines the goal of prevention with goals that incorporate the availability of vaccines that are more effective and efficient in preventing infectious diseases, both in the United States and abroad. In 1992, NIAID created the Task Force on Microbiology and Infectious Disease, which provided NIAID with guidance for future research directions in six areas, including the accelerated development of vaccines (National Institute of Allergy and Infectious Diseases, 1992a). Recommendations of the task force included the following: applied vaccine research, including studies on the most effective bacterial or viral carriers, increased temperature stability, improved efficacy and safety of adjuvants, and the development of preparations allowing for the controlled release of immunogens for single-dose vaccines; development of more effective, safer, and preferably, oral vaccines; and production of experimental vaccines on a pilot plant scale and under acceptable conditions for subsequent use in clinical trials (National Institute of Allergy and Infectious Diseases, 1992a). In addition to traditional grants and contracts, there are several key elements of NIAID's vaccine research program. Extensive portfolios of investigator-initiated research projects in infectious diseases, microbiology, and immunology are complemented by intramural laboratories, collaborations with industry, and research groups that focus, at least in part, on key areas of vaccinology. NIAID supports seven Vaccine and Treatment Evaluation Units (VTEUs), one Mucosal Immunization Group, one Maternal Immunization Group, seven International Collaborations in Infectious Disease Research, three Tropical Medicine Research Centers, five Centers for Sexually Transmitted Diseases, and four Tropical Disease Research Units. Established in the early 1960s to evaluate the safety and immunogenicity of candidate vaccines in human trials, the network of VTEUs is based at university-affiliated medical research facilities in the United States. In addition, NIAID supports (to a more limited extent) the preclinical evaluation of vaccines in animal models and primates as well as the development of reagents and reference serologic assays. NIAID has a

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The Children's Vaccine Initiative: Achieving the Vision TABLE 3-4 NIAID Vaccine-Related Research   Amount Spent (in thousands of $) in Fiscal Year:a Research Area 1991 1992 1993 (estimated) AIDS 36,026 (33.94) 43,084 (34.13) 45,140 (34.38) Tropical diseases 6,452 (6.08) 6,745 (5.34) 6,987 (5.32) R&D on children's diseases 39,003 (36.74) 49,674 (3935) 51,462 (39.20) Other 24,670 (23.24) 26,730 (21.12) 27,693 (21.09) Total 106,151 (100.00) 126,233 (100.00) 131,282 (100.00) a Values in parentheses are the percentage of the total. SOURCE: S. Berkowitz, National Institute of Allergy and Infectious Diseases, 1992. limited capacity for production of pilot lots of vaccine under contract. Finally, the clinical evaluation of vaccines is supplemented by a regulatory support infrastructure which the NIAID has developed over the past decades. In fiscal year 1993, NIAID will spend an estimated $131 million on research related to vaccines—more than any other federal entity (Table 3-4). Of that amount, roughly one-third ($45 million) will go toward work on a vaccine against HIV. Vaccines immunizing against a total of 33 other specific viral, bacterial, or parasitic agents will be targeted in the research, including six (filariae, leishmania, leprosy, malaria, schistosomes, and trypanosomes) investigated as part of the United Nations Development Program/World Bank/WHO Special Program for Research and Training in Tropical Diseases. In fiscal year 1993, an additional $5.3 million was earmarked for research on CVI-related vaccines. NIAID has no in-house capacity to produce pilot lots of vaccine, but it does have a limited capacity to contract out pilot vaccine production. However, the NICHD does have a very small pilot vaccine production facility at the NIH campus in Bethesda, Maryland. NICHD currently spends approximately $8 million to $9 million on pediatric vaccine-related activities. National Vaccine Program Organized efforts to develop a vaccine policy for the United States began during World War II, when the Armed Forces Epidemiology Board planned the vaccine strategies for the war effort. The Office of the Assistant Secretary for Health made efforts to develop a national immunization policy

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The Children's Vaccine Initiative: Achieving the Vision that would ensure progress in vaccine-based disease prevention as early as 1976, following the anticipated swine flu epidemic (Institute of Medicine, 1985). Between 1979 and 1985, the congressional Office of Technology Assessment and the Institute of Medicine both worked to formulate approaches for creating a national vaccine policy (Institute of Medicine, 1985; Office of Technology Assessment, 1979). These efforts were motivated by a recognition that, despite the resources available for vaccine development and immunization, without a strategic plan and management structure, U.S. immunization efforts would continue to fall short of their potential. The National Vaccine Program (NVP) was created in 1986 by the same law (P.L 99-660) that authorized the Vaccine Injury Compensation Program (see Appendix F for authorizing legislation). NVP's goal was to achieve optimal protection from infectious diseases in the United States through the use of immunization. The NVP was assigned two functions: to develop a National Vaccine Plan annually and to provide special funds (intended to reach $30 million per year) to federal agencies to complete critical portions of the plan. In addition, an independent National Vaccine Advisory Committee was to be appointed in consultation with the Institute of Medicine. The National Vaccine Plan was supposed to outline the activities needed to advance vaccines from the research and development stage through to field trials, licensing, production, use, and finally, surveillance of adverse effects. The congressional committee that drafted the legislation believed that a National Vaccine Plan would provide the strongest argument for an infusion of new funds into vaccine and immunization programs. However, the Reagan Administration opposed the National Vaccine Program. No full-time administrator was appointed, and no appropriation was requested for the NVP during its first 3 years (Budget of the U.S. Government, 1987, 1988, 1989; Freeman, 1991; Medicine and Health, 1990). The administration believed that the Department of Health and Human Services could conduct of all the planning envisioned by the legislation with no new statutory authority. No National Vaccine Plan, required annually since January 1, 1987, has been submitted to the U.S. Congress. In the absence of a National Vaccine Plan, appropriations committees in the U.S. Congress have been reluctant to appropriate the funds whose use was to be guided by the plan. The measles epidemic of 1989–1990 underscored the need, however, to plan vaccine and immunization activities in the United States (National Vaccine Advisory Committee, 1991). By fiscal year 1991, the NVP had a staffing level of 23 FTEs and an operating budget of $9.5 million, most of which was distributed to other federal agencies (U.S. Department of Health and Human Services, 1992). In fiscal year 1991, the largest share of NVPO funds went to the CDC. ($3.3

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The Children's Vaccine Initiative: Achieving the Vision million), including nearly $1.3 million for research activities (U.S. Department of Health and Human Services, 1992). NIH received $2.7 million, almost all of which supported an ongoing trial of an acellular pertussis vaccine. The allocation to FDA totaled $1.9 million, $1 million of which supported research activities. The NVP itself received $1.4 million in fiscal year 1991 for operational expenses, primarily salaries and overhead (U.S. Department of Health and Human Services, 1992). In fiscal year 1992, NVPO funding fell to $7.9 million, and in fiscal year 1993, the appropriation dropped to $2.8 million. The committee is disturbed by the lack of support for the NVP because it believes that the concept of planning, organizing, and managing existing immunization resources under an accountable government mandate is vital to the development and use of vaccines. There is no doubt that the NVP's planning function and coordination of public-sector activities must be continued into the future. The NVP does not, however, as currently authorized, possess the programmatic nor operational capability to manage the development of new vaccines. Other Federal Programs Not all federal investments in immunization go toward purchasing vaccines or research. There are a number of ongoing efforts that have a positive but indirect impact on immunization services. These include initiatives designed to ensure access to immunization services, educate the public about the value of vaccination, and promote the appropriate use of childhood vaccines. For example, one important goal of Medicaid, the state-administered health program overseen by the Health Care Financing Administration, is to provide regular immunizations for those under age 21. Two programs (the Community and Migrant Health Centers and Maternal and Child Health Block Grant) run by the Health Resources and Services Administration have as a central mandate the provision of immunizations to particularly needy populations. Funds in the Maternal and Child Health Block Grant program are used by the states' local health departments to improve vaccine delivery services. All children participating in Head Start, a program of the Administration for Children and Families, are entitled to receive a comprehensive set of health services, including immunizations (National Vaccine Advisory Committee, 1992). In cooperation with the CDC, the U.S. Department of Agriculture has mounted an effort to increase immunization coverage among children who receive food under the Supplemental Food Program for Women, Infants, and Children. The U.S. Department of Education is working with federal

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The Children's Vaccine Initiative: Achieving the Vision TABLE 3-5 Pubic-Sector Expenditures for Vaccine Research and Development in the United States Entity 1992 Expenditure (in millions of $) Funds or Conducts R&D AID 15.0a Funds CBER/FDA 14.9 Conducts DOD 76.7 Conducts Massachusetts 1.5 Conducts Michigan 1.5 Conducts NCID/CDC 2.1b Conducts NIAID/NIH 126.2 Funds/Conducts NICHD/NIH 8.0 Funds/Conducts NVP 7.9 Funds Total 253.8   a This figure represents 1991 funding. b This figure represents pediatric vaccines only. Despite the substantial number of U.S. government agencies, private firms, and other organizations involved in vaccine-related activities, and despite specific legislation mandating a National Vaccine Plan, there has been no overall strategy guiding the research, production, procurement, and distribution of childhood vaccines in the United States. As noted in a recent Institute of Medicine report, ". . . the overall process of vaccine development, manufacturing, and use in the United States is fragmented. There is no direct connection between research and development on the one hand and use of vaccines on the other. The various decision makers do not work together; in fact, they respond to different pressures" (Institute of Medicine, 1992, p. 157). As a result, the system of vaccine development and supply lacks a certain degree of cohesion. For example, in the current system, costly research and development performed in the private sector are not always done in conjunction with what the public sector might identify as the greatest public health needs. Similarly and with specific regard to the CVI, U.S. government agencies interact with the global CVI virtually independently of each other. INTERNATIONAL RESOURCES Numerous multilateral and bilateral organizations support aspects of vaccine research, development, manufacture, procurement, or distribution. The following sections focus primarily on multilateral organizations.

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The Children's Vaccine Initiative: Achieving the Vision Multilateral Organizations Pan American Health Organization The Pan American Health Organization (PAHO) is a public health agency that serves as a regional office of WHO. PAHO raises money to assist its 38 member countries in carrying out health programs, disseminates scientific and technical information throughout the inter-American region, trains health-care workers and strengthens national training institutions, and hires scientific and technical experts to address priority health issues in Latin America and the Caribbean (Pan American Health Organization, undated). PAHO Revolving Fund During the 1970s, countries in the Americas faced considerable difficulties raising hard currency to purchase needed pediatric vaccines for their Expanded Program on Immunization programs. In response to this problem, in 1979 PAHO established a revolving fund for the purchase of vaccines and related supplies for EPI in the Americas. The revolving fund has a working capital of $5.5 million. Member countries pay local currency equivalents for vaccine purchases, and PAHO pays for the vaccine using hard currency from the fund. Local currency is channeled back into a variety of operations and programs in the country (Ciro de Quadros, Pan American Health Organization, personal communication, 1993). SIREVA Project The Regional System for Vaccines in the Americas (SIREVA) was established in 1991 as a possible model for collaboration among developing countries for vaccine research and production activities. SIREVA is a multinational system designed to generate epidemiological knowledge related to vaccine development and identify, develop, and evaluate candidate vaccines of importance to the region. SIREVA's first vaccine research and development projects are targeted against three diseases of prevalence in the Americas: pneumococcal disease in children, typhoid fever, and meningitis due to Haemophilus influenzae type b organisms. Whenever possible, the data and technologies acquired through SIREVA will remain in the public domain. It is hoped that SIREVA will eventually become an administratively and financially independent operation (Pan American Health Organization, 1991). United Nations Development Program The United Nations Development Program (UNDP) is the largest multilateral grant assistance organization in the world. It plays a key

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The Children's Vaccine Initiative: Achieving the Vision coordinating role for development activities undertaken by the United Nations. UNDP focuses its efforts in six priority areas: poverty alleviation and grass roots development, environment and natural resources, management development, technical cooperation, technology transfer, and women in development. Among other initiatives, UNDP actively supports the CVI, EPI, the Global Program on AIDS, the WHO/UNDP Program for Vaccine Development (described below), and the UNDP/World Bank/WHO Special Program for Research and Development in Tropical Diseases. Financed by voluntary contributions from governments, $1.4 billion was pledged to UNDP from member nations in 1991 (United Nations Development Program, 1992). UNDP is currently exploring the possibility of setting up an international vaccine institute in East Asia to facilitate improvements in vaccine quality and to promote technology transfer. United Nations Children's Fund UNICEF plays a critical role in enhancing immunization activities throughout the world through its purchases of vaccine, provision of cold-chain equipment and other supplies, training of health-care workers, and provision of resources to assist with social mobilization efforts. UNICEF currently buys about half of the vaccine used in EPI programs and has spent over $500 million on immunization since 1982, including approximately $177 million on vaccine purchases (UNICEF, 1991). In 1992, UNICEF procured $65 million worth of vaccine. In addition to its core activities, UNICEF plays a strong advocacy role promoting immunization programs around the world. In the next 5 years, over 5.5 billion doses of vaccine costing $363 million will be needed to maintain EPI programs around the world (UNICEF, 1991). About 10 countries have requested UNICEF assistance in procuring hepatitis B vaccine (John Gilmartin, UNICEF, personal communication, 1993). Given this level of need and current resources, there is likely to be a significant shortfall in the amount of vaccine available for EPI activities (UNICEF, 1991; World Health Organization/Children's Vaccine Initiative, 1992b). Vaccine Independence Initiative The Vaccine Independence Initiative was launched in early 1992 in an effort to help countries become self-sufficient purchasers of vaccine (UNICEF, 1991). Under the initiative, which is modeled after the PAHO revolving fund, UNICEF buys vaccine for the country and the country pays UNICEF the local currency equivalent for the vaccine. UNICEF then uses the local currency to administer UNICEF

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The Children's Vaccine Initiative: Achieving the Vision programs in the country. Among its other goals, the initiative is designed to help countries forecast vaccine budgets and coordinate the immunization activities of various national ministries. Initial capital support for the Vaccine Independence Initiative has been provided by the U.S. Agency for International Development. In June 1992, the Kingdom of Morocco became the first country to participate in the Vaccine Independence Initiative (World Health Organization/Children's Vaccine Initiative, 1992b). World Bank The World Bank, officially known as the International Bank for Reconstruction and Development, was established in 1945 to help rebuild countries that were devastated during World War II. Owned by 160 governments, the principal purpose of the World Bank today is to raise the standard of living in developing countries by using resources from industrialized countries. In its early years, the World Bank primarily supported infrastructure projects such as road building and the construction of power-generating plants and telecommunications networks (World Bank, 1992). Since 1973, in an effort to benefit the citizens of developing countries more directly, World Bank lending is now targeted toward agricultural and rural development, education, health, nutrition, family planning, housing and urban services, water resources development, and electrification. The Bank is founding member of the UNDP/World Bank/WHO Special Program for Research and Training on Tropical Diseases, as well as a founding but nonpaying member of the CVI. It is currently financing a project in the People's Republic of China to build new vaccine manufacturing facilities for DTP, oral polio vaccine, and measles vaccine. World Health Organization Created in 1948, WHO is an intergovernmental organization within the United Nations system that is responsible for coordinating and directing international public health matters. The WHO executes its work through three principal bodies: the World Health Assembly, an annual meeting to discuss WHO's program plan and attended by delegates from the 166 member states; the Executive Board, comprising 31 individuals designated by member states; and the Secretariat, which is staffed by some 4,500 health experts under the leadership of a Director-General and which is responsible for overseeing the day-to-day operations of WHO. There are six WHO regional offices worldwide. The 1992–1993 operating budget of the WHO

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The Children's Vaccine Initiative: Achieving the Vision totaled approximately $1.7 billion, an increase of .3 billion from the 1990–1991 budget (Budget Office, World Health Organization, Washington, D.C., personal communication, 1993). Expanded Program on Immunization EPI was established by the World Health Assembly in May 1974 to assist national immunization programs in the developing world. To date, the EPI has been enormously successful in increasing immunization coverage among children in the developing world (see Chapter 2). In order to advance the long-term goal of universal childhood immunization, EPI supports a number of different activities related to vaccine delivery and utilization. These include the production of training and educational materials; assistance in planning and evaluating national immunization programs; surveillance of global, regional, and national immunization coverage and disease data; and promotion of the research and development necessary to solve operational problems. Although they may receive assistance from the EPI, national governments are ultimately responsible for coordinating and implementing their respective immunization programs. The EPI's operating budget for 1992–1993 totaled $30,325,600, falling from its 1990–1991 level of $46,019,700. Approximately $11 million of the 1992–1993 budget was allocated directly overseas, while roughly $19 million was appropriated to global and interregional funds to be disbursed by the Geneva headquarters (Budget Office, World Health Organization, Washington, DC, personal communication, 1993). Program for Vaccine Development The Program for Vaccine Development (PVD), which was initiated by the Director-General of WHO in 1984, coordinates international vaccine development with academic institutions and other scientific groups and encourages the participation and training of scientists from developing countries. Since its founding, PVD has trained over 500 scientists from 87 countries. PVD activities are guided by the Scientific Advisory Group of Experts, an international group of vaccine specialists. In 1990, PVD became a partnership between WHO and UNDP. By the end of 1991, PVD had received nearly $22 million in outside contributions from such groups as the Rockefeller Foundation, the Glenmede Trust, UNDP, and the governments of Australia, France, Italy, Japan, Norway, Sweden, and Switzerland. In 1991, the PVD budget was $5.9 million and the organization supported a total of 94 vaccine development projects in 22 countries (World Health Organization, 1991). In 1992, however, the budget fell to $4.9 million (World Health Organization/Children's Vaccine Initiative, 1993).

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The Children's Vaccine Initiative: Achieving the Vision Children's Vaccine Initiative The CVI, both a concept and an organization, is an international effort to accelerate the application of modern science and technology to the development of new and better childhood vaccines. The ultimate goal of the CVI, which was established following the 1990 World Summit for Children in New York City, is to develop a means of immunizing children at birth against all important childhood diseases. The desirable features of CVI vaccines are that they be given in a single dose, administered near birth, combined in novel ways, heat stable, effective against a variety of diseases, and affordable. The activities of CVI are carried out primarily through product development groups and task forces (see Chapter 2). The CVI is cosponsored by five organizations: UNICEF, UNDP, the Rockefeller Foundation, the World Bank, and WHO. The CVI is financed from voluntary contributions from governments, foundations, and international organizations. In 1992, the CVI budget stood at $3.8 million. The estimated budget for 1993 is $6.5 million (World Health Organization/Children's Vaccine Initiative, 1992a). Public-Sector Resources Many countries maintain public-sector institutes or support facilities that manufacture vaccines. Most often, the primary goal of such efforts is to meet the vaccine needs of the citizens of the respective country. Some countries manufacture all of their childhood vaccines, others import components for the manufacture of vaccines, and yet others purchase and import bulk vaccine for subsequent finishing and processing. The National Institute of Public Health and Environmental Protection (Rijksinstituut voor Volksgezondheid en Milieuhygiene) in The Netherlands manufactures DTP, inactivated polio vaccine, and MMR (see the box on RIVM in The Netherlands). State Bacteriological Laboratories in Sweden and the State Serum Institute of Denmark also import or produce vaccines that are deemed necessary for their respective national immunization programs. In eastern Europe, Czechoslovakia (now the Czech Republic and Slovakia) and Hungary manufacture a limited number of primarily bacterial vaccines. The Oswaldo Cruz Foundation in Brazil produces a number of different vaccines, including tetanus toxoid, DTP, and measles vaccine for the Brazilian population. Taiwan, India, Indonesia, and the People's Republic of China also produce some of the vaccines required by their respective populations. Not all of the countries that produce vaccines are self-sufficient in all or even one of the vaccines required by that country, however. Indeed, many countries, particularly those in the developing world, do not have the

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The Children's Vaccine Initiative: Achieving the Vision capacity to meet local demand and so must import vaccine either directly from the manufacturer or through such mechanisms as the PAHO revolving fund or UNICEF. For example, although Egypt's vaccine production institute, Vaccsera, makes tetanus toxoid, DTP, and BCG and imports bulk oral polio vaccine and hepatitis B vaccine for further finishing and packaging, Egypt is unable to produce enough of any single vaccine to meet national demand and obtains the remainder through UNICEF. Unlike private-sector companies, most public-sector operations have neither the budget nor the capacity to conduct extensive research and development and must acquire vaccine-related technology elsewhere. One of the critical problems for many national institutes in both industrialized and developing countries is obtaining the seed stock and the necessary production technology to manufacture a given vaccine (Homma, 1992). For those countries that possess basic vaccine production equipment, upgrading and improving that technology has proven to be an equally great problem. In 1980, for example, Brazil received second-generation measles vaccine production technology from Japan. The measles vaccine has improved significantly and is now in its fourth generation, yet Brazil has been unable to gain access to this improved vaccine production technology (Homma and Knouss, 1992). Private-Sector Resources As of 1992, seven private European vaccine manufacturers produced the majority of vaccines used by Europe and much of the rest of the world. These are Behringwerke (Germany), Immuno (Austria), Medeva-Evans (United Kingdom), Pasteur Mérieux Sérums et Vaccins (France), Sclavo (Italy), SmithKline Beecham (United Kingdom), and Swiss Serum and Vaccine Institute (Switzerland). In 1991, these seven companies formed the European Vaccine Manufacturers, a special group within the European Federation of Pharmaceutical Industries Association. In March 1992, they organized the First European Conference on Vaccinology, in Annecy, France (Baudrihaye, 1992). Pasteur Mérieux Sérums et Vaccins and SmithKline Beecham are the two largest international suppliers of vaccine, as well as the largest suppliers of vaccine to UNICEF. Pasteur Mérieux Sérums et Vaccins is wholly dedicated to the development of vaccines and biologics. On a much smaller scale is the Swiss Serum and Vaccine Institute, a privately held company that manufactures vaccines for Switzerland and UNICEF. There has been considerable movement in the pharmaceutical industry in Europe and Asia over the past several years, characterized by a number

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The Children's Vaccine Initiative: Achieving the Vision National Institute of Public Health and Environmental Protection (RIVM), The Netherlands RIVM is a Directorate-General of The Netherlands Ministry of Public Health. The primary objective of RIVM's vaccine department is to develop and produce vaccines for the population of The Netherlands; therefore, research, development, and manufacture are generally confined to diseases relevant to The Netherlands' public health and production needs. Development of new vaccines for the developing world and technology transfer have until now been identified as priority tasks of the RIVM, although so far all activities in this respect must be externally funded. RIVM has pilot facilities for both bacterial and viral vaccines. In 1991, production levels were as follows: DTP, 3 million doses; inactivated polio vaccine, 5 million doses; and MMR, 400,000 doses. Although RIVM does have the capability and capacity to regularly manufacture approximately 18 different vaccines, present policy is to gradually halt production of vaccines that are not relevant to the Netherlands Immunization Program. Technology transfer activities and capacities are devoted largely to the China Vaccine Project (funded by the World Bank and Rotary International), which is attempting to establish a large scale production capacity for DTP, tetanus toxoids, oral polio vaccine, and measles vaccine in the People's Republic of China through joint development, training, and technology transfer. Another ongoing project involves the upgrading and modernization of DTP production and quality control in Indonesia (this activity is supported by a loan from the Dutch government). In addition, at the request of WHO, RIVM organizes regular quality control courses (mostly focused on polio vaccine) in various countries. Finally, on October 25, 1990, a letter of intent was signed between the National Public Health Institutes of The Netherlands (RIVM), Sweden, Denmark, Norway, and Finland to jointly develop vaccines and transfer vaccine technology to developing countries. The development of a pneumococcal vaccine was selected as a first priority under this Dutch-Nordic Consortium.   Source: A. R. Bergen, Head, Bureau for International Cooperation, RIVM, personal communication, 1992.

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The Children's Vaccine Initiative: Achieving the Vision of mergers, acquisitions, and joint ventures. Ciba-Geigy, an established pharmaceutical firm based in Switzerland, joined with the U.S. biotechnology company Chiron to form Biocine, which subsequently acquired Sclavo, a medium-sized Italian vaccine manufacturer and supplier of vaccines to UNICEF. Pasteur Mérieux Sérums et Vaccins acquired Connaught Laboratories Ltd., of Canada in 1990. Medeva plc, based in the United Kingdom, bought the vaccine business of Wellcome plc of the United Kingdom in 1991. Medeva is currently the principal vaccine supplier to the National Health Service in the United Kingdom. Nongovernmental Organizations Finally, several international nongovernmental organizations support key aspects of immunization programs around the world. Task Force for Child Survival and Development Formed in 1984, the Task Force for Child Survival and Development is supported by the World Health Organization, UNICEF, the World Bank, the United Nations Development Program, and the Rockefeller Foundation. The initial mission was to assist in accelerating global childhood immunization. The goals that came out of the 1990 World Summit for Children led to the extension of the task force's mission to address problems concerning nutrition, respiratory infections, diarrheal diseases, breast-feeding, and the Safe Motherhood Initiative, in addition to immunization. Current projects being carried out by the task force include vaccine evaluation efforts in Mexico and Senegal, a surveillance improvement project in Uganda, collaborative neonatal tetanus immunization activities in Bangladesh and Pakistan, and consultation with several countries to help implement effective child survival programs. Barriers to vaccination for children and mothers in developing countries are among the areas of applied research on which the task force is focusing (Task Force for Child Survival and Development, undated). Save the Children Fund Founded in 1919, the Save the Children Fund reaches over 50 developing countries as well as the United Kingdom. It has been a strong supporter of the EPI since its inception and has provided vaccines, cold-

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The Children's Vaccine Initiative: Achieving the Vision chain equipment, training materials, technical advisers, and operations research support, as well as conferences and sponsorships. The Save the Children Fund has recently extended its goal to the establishment of sustainable delivery systems for a broad range of basic health services, which includes vaccines (Poore, 1992). Medicines sans Frontieres (Doctors without Borders, France) and the Task Force on Hepatitis B Immunization (based in the United States) are other examples of nongovernmental organizations that continue to influence immunization programs worldwide. REFERENCES American Home Products. 1991. Annual Report. Madison, New Jersey. Baudrihaye N. 1992. European vaccine manufacturers: Present status and future trends. Vaccine 10:893–895. Budget of the U.S. Government. 1987. Washington, D.C.: U.S. Government Printing Office. Budget of the U.S. Government. 1988. Washington, D.C: U.S. Government Printing Office. Budget of the U.S. Government. 1989. Washington, D.C: U.S. Government Printing Office. Center for Biologics Evaluation and Research, Office of Management. 1993. Data regarding CBER FTEs and budget. Provided in response to Institute of Medicine request. Rockville, Maryland. Centers for Disease Control and Prevention, Division of Immunization. 1992. Data regarding CDC budget. Provided in response to Institute of Medicine request. Atlanta. Children's Defense Fund. Undated. General information. Washington, D.C. Cohen J. 1993. Childhood vaccines: The R&D factor. Science 239:1528–1529. Freeman P. 1991. Memo to Friends of the National Vaccine Program. The Vaccine Project. March 15. Law Center, University of Massachusetts at Boston. Homma A. 1992. Technology transfer. Paper presented to the CVI Task Force on Priority Setting and Strategic Plans. Geneva: Children's Vaccine Initiative, Geneva. Homma A Knouss RF. 1992. Transfer of vaccine technology to developing countries: The Latin American experience. Paper presented at the NIAID Conference on Vaccines and Public Health: Assessing Technologies and Global Policies for the Children's Vaccine initiative. November 5–6, 1992, Bethesda, Maryland. Hoover G, Campbell A, Spain PJ, eds. 1991. Hoover's Handbook of American Business 1992. Emeryville, California: The Reference Press. Institute of Medicine. 1985. Vaccine Supply and Innovation. Washington, D.C.: National Academy Press. Institute of Medicine. 1986a. New Vaccine Development, Establishing Priorities. Volume 1. Diseases of Importance in the United States. Washington, D.C.: National Academy Press. Institute of Medicine. 1986b. New Vaccine Development, Establishing Priorities. Volume II. Diseases of Importance in the Developing World. Washington. D.C.: National Academy Press. Institute of Medicine. 1991. Malaria: Obstacles and Opportunities. Washington, D.C.: National Academy Press. Institute of Medicine. 1992. Emerging Infections. Washington, D.C.: National Academy Press. Kessler DA. 1992. Testimony before Senate Subcommittee on Labor, Health and Human Services, Committee on Appropriations. Childhood Vaccine Research and Development Issues. April. Washington, D.C: U.S. Congress, Senate. March of Dimes Birth Defects Foundation. 1991. Annual Report. Washington, D.C.

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The Children's Vaccine Initiative: Achieving the Vision Medicine and Health. 1990. A shot in the arm for vaccine advocates. Perspectives. July 30. Washington, D.C. MedImmune, Inc. 1991. Annual Report. Gaithersburg, Maryland. Merck & Co., Inc. 1991a. Annual Report. Rahway, New Jersey. Merck & Co., Inc. 1991b. Form 10-K. Washington, D.C.: Securities and Exchange Commission. National Institute of Allergy and Infectious Diseases. 1992a. Report of the Task Force on Microbiology and Infectious Disease. April. Bethesda, Maryland. National Institute of Allergy and Infectious Diseases 1992b. The Jordan Report. Bethesda, Maryland. National Vaccine Advisory Committee. 1992. Access to Childhood Immunizations: Recommendations and Strategies for Action. April. Rockville Maryland. North American Vaccine. 1991. Annual Report. Beltsville, Maryland. Office of Technology Assessment. 1979. A Review of Selected Federal Vaccine and Immunization Policies. September. Washington, D.C. Pan American Health Organization. Undated. General information. Washington, D.C. Pan American Health Organization. 1991. Regional System for Vaccines (SIREVA) Feasibility Study. Washington, D.C. Pharmaceutical Manufacturers Association. 1990. New Medicines in Development for Children. Fall. Washington, D.C. Poore P. 1992. Availability of quality vaccines: Policies of a nongovernmental organization. Vaccine 10:958–960. Rockefeller Foundation. 1991. Annual Report. New York, New York. Rotary Foundation of Rotary International. Undated. Polio Plus Evanston, Illinois. SmithKline Beecham. 1991. Annual Report. Philadelphia. Task Force for Child Survival and Development. Undated. General information. Atlanta. UNICEF. 1991. Executive Board Action Item: Establishment of a Vaccine Independence Initiative. March 12. New York, New York. UNICEF. 1992. Vaccine Independence Initiative. Project Proposal for Funding by Interested Donors. July 13. New York, New York. United Nations Development Program. 1992. New York, New York. UNIVAX Biologics, Inc. 1992. Common Stock Prospectus. February 4. Rockville, Maryland. U.S. Agency for International Development. 1992. Overview of Activities Supportive of the Children's Vaccine Initiative. Washington, D.C. U.S. Department of Defense. Army. Office of the Surgeon General. Health Measures and Immunizations, Preventive Medicine in World War 11. Washington, D.C. U.S. Department of Health and Human Services. 1992. Report on NVPO Expenditures for Acellular Pertussis Vaccine Research and other Activities. January. Washington, D.C. World Bank. 1992. Annual Report. Washington, D.C. World Health Organization. 1991. Programme for Vaccine Development: a WHO/UNDP Partnership. December. Geneva. World Health Organization. 1992. EPI for the 1990s. Geneva. World Health Organization/Children's Vaccine Initiative. 1993. Global Investment in Children's Vaccine Research and Development: Results of a Survey. April. Geneva. World Health Organization/Children's Vaccine Initiative. 1992a. Core Budget and Programme of Work for 1992 and 1993. October. Geneva. World Health Organization/Children's Vaccine Initiative. 1992b. Report of the Task Force on Situation Analysis. November. Geneva.