VACCINE SHORTAGES: History, Impact, and Prospects for the Future

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1 Annu. Rev. Public Health : doi: /annurev.publhealth Copyright c 2006 by Annual Reviews. All rights reserved First published online as a Review in Advance on September 8, 2005 VACCINE SHORTAGES: History, Impact, and Prospects for the Future Alan R. Hinman, 1 Walter A. Orenstein, 2 Jeanne M. Santoli, 3 Lance E. Rodewald, 3 and Stephen L. Cochi 3 1 Task Force for Child Survival and Development, Decatur, Georgia 30030; ahinman@taskforce.org 2 Emory Vaccine Center, Emory University, Atlanta, Georgia 30322; worenst@emory.edu 3 National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia 30333; zmd4@cdc.gov, lar9@cdc.gov, slc1@cdc.gov Key Words immunization, health policy, liability, vaccine manufacture Abstract Vaccine shortages can result from higher-than-expected demand, interruptions in production/supply, or a lack of resources to purchase vaccines. Each of these factors has played a role in vaccine shortages in the United States during the past 20 years. Since 2000, the United States has experienced an unprecedented series of shortages of vaccines recommended for widespread use against 9 diseases, after more than 15 years without vaccine supply problems. In developing countries, the major cause of vaccine shortages is lack of resources to purchase them. Although there are several steps that could reduce the likelihood of future vaccine shortages, many would take several years to implement. Consequently, we will probably continue to see occasional shortages of vaccines in the United States in the next few years. INTRODUCTION Between 2000 and mid-2005, the United States experienced an unprecedented series of shortages of vaccines recommended for widespread use against 9 diseases, after more than 15 years without vaccine supply problems. Vaccine shortages have resulted from interruptions in supply (as might occur with production problems, failure to meet FDA regulations, or manufacturers unwillingness to continue production for economic reasons), higher-than-expected demand [as might occur with the introduction of a new vaccine recommended for use in all children such The U.S. Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper /06/ $

2 236 HINMAN ET AL. as pneumococcal conjugate vaccine (PCV7)], or from a lack of funds to purchase vaccines. This article describes vaccine development, financing, procurement and provision of vaccines in the USA; vaccine shortages; their impact; and measures that have been, or might be, taken to reduce the likelihood or impact of shortages in the future. VACCINE DEVELOPMENT Vaccine development is a long and costly process. It is preceded by substantial basic research (vaccine discovery) to identify causative pathogens, elucidation of the immune response needed to induce protection, development of candidate vaccines that induce those responses in animals, and subsequent testing in three formal phases of trials (40). Phase I trials are designed to assure basic safety of the product and to help determine doses and schedules needed for protection; they typically enroll 20 to 80 participants. Phase II trials can enroll from several hundred to 2000 or more participants. These trials more carefully define safety and immunogenicity; the larger trials may actually test efficacy, although the estimates of efficacy are usually too imprecise for licensure. Phase III trials can involve tens of thousands of participants and usually measure efficacy in randomized doubleblind controlled trials. They can also detect common adverse events. Phase III trials are usually the pivotal trials for licensure. The development process is heavily regulated and requires an Investigational New Drug (IND) permit to be obtained from the FDA, production of vaccines under good laboratory practices (GLP), movement of vaccine production from a research laboratory with limited production capacity to a plant that will make the final commercial product under Good Manufacturing Practices (GMP), conduct of clinical trials under Good Clinical Practices (GCP) standards, review and approval of protocols through Institutional Review Boards (IRBs), and much more. Estimates of costs to bring a new vaccine through the process into licensure have ranged, based on analogy from drug manufacturers, from $100 million to more than $800 million (46). The National Vaccine Advisory Committee (NVAC) recently reviewed vaccine development in the United States and noted the time lag from initial development to production was as much as 21 years (44). Further, vaccine development has been a risky business. In the past few years, Lyme vaccine developed by GlaxoSmithKline (GSK) was withdrawn after limited recommendations for use by public health authorities, limited uptake by the public, and substantial controversy about alleged though unproven safety concerns (21). A rhesus rotavirus vaccine, initially recommended for all infants, was withdrawn after postlicensure surveillance identified an attributable risk of intussusception on the order of 1 in 10,000 doses (45). As public health recommending bodies, such as the Advisory Committee on Immunization Practices (ACIP), rarely become involved in setting priorities for vaccine development, manufacturers generally develop vaccines at some risk hoping the final products will receive a recommendation for widespread use.

3 VACCINE SHORTAGES 237 THE MANUFACTURING BASE The number of commercial manufacturers that produce vaccines for universal vaccination of children has remained relatively constant over the past several decades even though the number of vaccine-preventable diseases of childhood has increased from 8 in 1985 to 13 in 2005 (Table 1). The vaccines administered to children have TABLE 1 U.S. vaccine manufacturers for routinely recommended childhood vaccines, 1985 and 2005 Vaccine 1985 Manufacturer Vaccine 2005 Manufacturer DTP Hepatitis B Lederle Connaught Massachusetts Public Health Biologics Laboratory Michigan Department of Public Health Not recommended for children universally DTaP Hepatitis B sanofi pasteur GlaxoSmithKline GSK Merck Hib polysaccharide Praxis Hib conjugate GSK sanofi pasteur Merck Influenza Not recommended for young children universally Influenza for children 6 23 months sanofi pasteur MCV4 Not licensed MCV4 sanofi pasteur MMR Merck MMR Merck Oral Polio Vaccine Lederle Inactivated Polio Vaccine sanofi pasteur (GSK, in combination DTaP-IPV-HepB) PCV7 Not licensed PCV7 Wyeth Td Lederle Connaught Massachusetts Public Health Biologics Laboratory Michigan Department of Public Health Td sanofi pasteur Massachusetts Public Health Biologics Laboratory Tdap Not licensed Tdap GSK sanofi pasteur Varicella Not licensed Varicella Merck Abbreviations: DTP/DTaP, diphtheria and tetanus toxoids and acellular pertussis vaccine, adsorbed; MCV4, meningococcal conjugate vaccine; MMR, measles, mumps, and rubella vaccine; PCV7, pneumococcal conjugate vaccine; Td, tetanus and diphtheria toxoids, adult formulation; Tdap, tetanus and diphtheria toxoids and adsorbed pertussis vaccine, adult formulation.

4 238 HINMAN ET AL. changed over time, with DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine) replacing DTP (diphtheria and tetanus toxoids and pertussis vaccine), IPV (inactivated poliovirus vaccine) replacing OPV (oral poliovirus vaccine), Hib (Haemophilus influenzae type b vaccine) conjugate replacing Hib polysaccharide, and new vaccines added to the schedule. Of the two major public manufacturers of vaccines in 1985, Massachusetts Public Health Biologics Laboratory now produces only limited quantities of Td (tetanus and diphtheria toxoids, adult formulation) and DT (diphtheria/tetanus toxoids) and the Michigan Department of Public Health no longer produces any vaccines. Since 1985, Wyeth has purchased Lederle and Praxis, Connaught became part of Aventis (now sanofi pasteur), and GlaxoSmithKline has entered the U.S. market. Merck has remained stable and has introduced several new vaccines. Chiron has taken over a British manufacturer, Powderject, and makes influenza vaccine for the U.S. market but does not have a license for children <4 years of age. Although the number of large commercial manufacturers has been limited, new products entering or presumed to be entering the US market in the near future have increased substantially in recent years. In 2005, a meningococcal conjugate vaccine (MCV4) was licensed and recommended for all adolescents (9). Two pertussis boosters (Tdap) were licensed for 11- to 18-year olds (or 11- to 64-year olds) and likely will also be recommended for adolescents (18,19). Phase III trials for new rotavirus vaccines have been completed, raising the potential for reintroduction of a rotavirus vaccine into the U.S. immunization schedule in the near future (23). An enhanced potency varicella-zoster vaccine for shingles has completed phase III trials in older adults (42). Human papillomavirus vaccines now undergoing Phase III trials have the potential to prevent as much as 70% of cervical cancer cases in women. Preliminary trials suggest that these vaccines will be very effective (22, 32). In addition, efforts are under way to develop many more vaccines including products to prevent AIDS, West Nile Virus, herpes simplex type 2, severe acute respiratory syndrome (SARS), staphylococcal disease, and many other infectious disease burdens. Whereas the major vaccines for children are produced by a limited number of large commercial manufacturers, a substantial number of smaller firms produce vaccines or are developing vaccines for smaller niche markets such as for the military for biodefense. For example, BioPort in Michigan is producing an adsorbed anthrax vaccine. VaxGen is developing a recombinant protein anthrax vaccine. Dynport is developing plague, botulinum toxoid, and Venezuelan equine encephalitis vaccines. Acambis is developing a smallpox vaccine and a West Nile Virus vaccine. A number of other vaccines are also under development by smaller biotech companies (34). In contrast to drugs, there are no manufacturers of generic vaccines. Vaccine manufacture is substantially more complicated than drug manufacture because production involves biologic systems instead of chemical systems and characterization of the final product is more difficult. Plotkin has listed a variety of impediments to vaccine development and entry into the US market, attributable to manufacturers, regulators, and public health

5 VACCINE SHORTAGES 239 authorities (46). Among the manufacturer barriers are competition with drug products (all of the large vaccine producers are also drug manufacturers), which are perceived to be more profitable with larger markets, limited capacity to take many new vaccines into trials simultaneously, potential incorrect estimates of vaccine market potential, technical manufacturing scale-up obstacles, and holding of critical intellectual property rights to the exclusion of other potential vaccine developers. Regulatory concerns included a risk-averse climate that puts a premium on safety even if theoretical safety concerns might be significantly outweighed by expected vaccine benefits. Finally, Plotkin mentions that lack of prioritization in vaccine development by public health vaccine recommending bodies may lead to limited markets after large-scale development investments, acting as a disincentive to further development. Danzon et al. note a dichotomy between research investments in new vaccines with the potential for monopoly and investment in ( me too ) vaccines for which another manufacturer already has the market (14). There seems to be more interest among companies in reaching new markets than in competing for existing markets of other companies. Thus the United States is vulnerable to single suppliers for the foreseeable future. Of the 13 vaccine-preventable diseases of childhood, there are single manufacturers producing vaccines against eight diseases for the USA (excluding Pediarix by GSK that includes IPV but only as part of a combination DTaP-IPV-Hep B, and Chiron and Medimmune, which do not have influenza vaccines that can be administered to young children) (5, 17, 40). IMMUNIZATIONS IN THE UNITED STATES OF AMERICA Child Immunization Until the mid-1950s, child immunization was fairly simple only smallpox and DTP were administered to all children. Most children received immunizations from private practitioners and their parents paid for the immunizations. The cost of the vaccines was minimal (<$1). Some children received free immunizations from local health departments, with costs borne by local/state taxes or coming from the Maternal and Child Health Block Grant (41). The introduction of IPV in 1955 stimulated major public interest in assuring that all children received the vaccine. Federal funds were appropriated in 1955 and 1956 to help states and local communities buy and administer IPV. In 1960 Congress made a one-time appropriation for a stockpile of OPV to be used in combating epidemics (28). Incomplete and unequal coverage with vaccines led to the passage in 1962 of the Vaccination Assistance Act (Section 317 of the Public Health Service Act). The central thrust of this legislation was to provide grants to state and local health departments to support immunization. The first grants were made to state and local health departments in June Section 317 allowed the federal government to provide vaccines and personnel (public health advisors and epidemiologists) to

6 240 HINMAN ET AL. health departments instead of cash (direct assistance). The federal government negotiated vaccine prices with manufacturers at significant savings compared with private sector cost (because of volume of sales, limited number of distribution points, a no-return policy, etc.). Section 317 has been continuously reauthorized since 1962 and has become a mainstay of public sector support for immunization in the United States. The cost of immunizations rose dramatically beginning in the 1990s, primarily as a result of the introduction of new vaccines (e.g., acellular pertussis vaccine, varicella vaccine). Newer vaccines, produced by technologically more sophisticated procedures, are substantially more expensive than the traditional vaccines. Table 2 depicts the public and private sector prices of vaccines recommended for universal use in children in 1987 compared with 2005 (exclusive of MCV4) (7, 28). In 2005, the cost to provide all vaccines recommended for children from birth through school entry was $ in the public sector ($ in the private sector) for vaccine alone, without including costs of administering the TABLE 2 Changes in vaccine costs for childhood immunization from birth through school entry in the United States, 1987 and 2005 Cost of vaccine series (cost/dose) ($US) Year, vaccine CDC price Catalog price OPV doses 5.72 (1.43) (8.67) 5 DTP doses (3.01) (11.22) 1 MMR dose Hib dose Td dose Total IPV doses (10.42) (21.80) 5 DTaP doses (12.75) (20.96) 2 MMR doses (16.67) (40.37) 3 Hib product doses (10.22) (22.77) 3 Hepatitis B doses (9.00) (21.37) 1 Td dose Varicella dose PCV 7 doses (54.12) (65.95) 3 Influenza doses (12.02) (13.00) Total Abbreviations: OPV, oral poliovirus vaccine; DTP, diphtheria and tetanus toxoids and cellular pertussis vaccine; MMR, measles, mumps, and rubella vaccine; Hib, Haemophilus influenzae type b vaccine; Td, tetanus and diphtheria toxoids, adult; IPV, inactivated poliovirus vaccine; DTaP, diphtheria and tetanus toxoids and pertussis vaccine, adsorbed; PCV7, pneumococcal conjugate vaccine. Source: References (7, 28).

7 VACCINE SHORTAGES 241 vaccines. This should be compared to 1987 vaccine costs of $33.70 and $115.99, respectively. One consequence of the increasing cost of the vaccine schedule during the 1980s and early 1990s was that many families were unable to pay for them and increasingly went to health departments for free immunizations. Many private providers referred their lower-income patients to public facilities to receive immunizations (50, 56, 62). Although this allowed the children to receive needed vaccines, it fragmented their care and led to missed opportunities to vaccinate (54, 55). A resurgence of measles in the United States from 1989 to 1991 underscored the fact that many preschoolage children had not received vaccine (35). To ensure that vulnerable children have access to vaccines, the Vaccines for Children (VFC) Act was passed in 1993 (48). The Act provides an entitlement to free vaccines for children who are uninsured, on Medicaid, or who are American Indians/Alaska Natives. It also provides free vaccines at Federally Qualified Health Centers (FQHC) for children who have insurance that does not cover immunization ( underinsured ). Vaccines are provided through a network of more than 120,000 public and private providers who receive vaccines without having to pay up-front purchase costs ( replacement model ). Funding under Section 317 was also increased. CDC (unpublished data) estimates that in 2005 the private sector purchased 45% of childhood vaccines used in the United States, VFC 40%, Section 317 8%, and state/local governments 7%. The combination of additional funding for Section 317 and VFC has played an important role in enabling the United States to achieve its highest immunization levels ever in young children (3, 6). The National Immunization Survey, which assesses immunization in children 19 to 35 months old, for several years has shown that coverage with most vaccines is 90%, the goal established in Healthy People However, series-complete levels are lower and have remained relatively static over the past few years. Racial/ethnic and income disparities in immunization coverage levels in young children have markedly diminished at the national level, although local variations continue (39, 49, 54). A recent national analysis by Chu et al. shows an increasing disparity in the receipt of the complete series of recommended vaccines among preschool children in the United States (11). The Section 317 program has been subject to marked swings in appropriations with consequent impact on public sector delivery of immunizations. As an entitlement, the VFC program is not subject to fluctuations. A 2000 Institute of Medicine (IOM) study on immunization finance policies and practices recommended, among other things, increased federal funding through Section 317, increased funding of immunizations by the states, and conversion of the 317 program from a discretionary to a formula basis (to enhance predictability for state planning) (30). A later section describes progress in this area. Public purchase has been raised as a serious impediment to vaccine development by some manufacturers. The allegations are that the federal government, with its large-scale control of the market, has the power to effectively bargain for minimal

8 242 HINMAN ET AL. prices, thereby reducing profits. However, the large-scale recent development of vaccines for children and adolescents and the ability of public purchase to speed implementation of certain vaccines and set the standard for vaccine financing in the private sector argues against a negative role of federal purchase. Further, since the VFC has been enacted, large-scale development of new vaccines for children and adolescents has continued. Large-scale government purchase could be a disincentive for new companies to enter an existing market but does not appear to have been a disincentive for bringing new vaccines to market (12, 13, 38). Adult Immunization Unlike childhood immunization, where there has been extensive public-private collaboration for 40 years, adult immunization has been left to the private sector until relatively recently. Vaccines currently recommended for universal use in adults are periodic tetanus-diphtheria boosters (all adults, every 10 years), annual influenza immunization (persons 50 years of age), and one-time pneumococcal vaccination (persons 65 years of age). A number of vaccines, including hepatitis A and B, influenza, pneumococcal, and rabies vaccines, are recommended for those at increased risk of infection/complication as a result of medical condition, occupation, lifestyle, etc. (4, 47). Regular preventive care visits comparable to well-child visits are not as ingrained in adult medicine as in pediatrics. There is no adult counterpart to VFC. The adult model is one of fee for service in which the provider purchases vaccines up front and is reimbursed after administering them ( reimbursement model ). Medicare, which insures virtually all Americans 65 years of age, specifically excluded coverage for preventive services until 1981, when reimbursement was permitted for pneumococcal vaccine and a limited number of other preventive services. In 1993, reimbursement for influenza vaccine was authorized. Hepatitis B vaccination has long been a covered service for beneficiaries at increased risk of acquiring hepatitis B disease, primarily through Medicare s end-stage renal disease program. However, the vast majority of adults at high risk of hepatitis B are either younger than 65 years of age or without end-stage renal disease and, hence, are not covered by Medicare. Vaccination coverage levels for adults are substantially below rates among young children. The National Health Interview Survey (NHIS) is used to track vaccination coverage levels among adults. The NHIS shows that among individuals 65 years of age, influenza vaccination coverage for the season was 69.9% and pneumococcal coverage was 64.2% (2). Annual coverage levels of influenza vaccination are more than double the 30% level in 1988, before Medicare s coverage of influenza vaccination. Medicare reimbursement for administration of influenza vaccine has been felt inadequate by many practitioners; it has recently been increased (10). In contrast to childhood vaccination, there are marked racial/ethnic disparities in coverage among adults for each vaccine (59).

9 VACCINE SHORTAGES 243 VACCINE SHORTAGES Setting the Stage: Pandemic Influenza Alarm about shortages of vaccines was first raised around influenza pandemics, real or anticipated, particularly because production of vaccine requires several months after identification of a new strain of influenza virus. In the 1957 Asian flu pandemic, there was a several-month lag between recognition of the new influenza strain and its widespread circulation in the United States. This lag allowed time to manufacture a significant quantity of vaccine. Because there was not a preexisting recommendation for routine vaccination of the elderly or the chronically ill, it was difficult to project how much vaccine would be needed. Additionally, the federal government was not in the position of purchasing influenza vaccine. By the time the epidemic peaked in November 1957, 49 million doses of vaccine had been released, but not many people had effectively developed immunity by that time. A large surplus of vaccine remained after the epidemic had subsided (33). By the time of the Hong Kong flu pandemic, it was recommended that the elderly and the chronically ill receive annual influenza immunization, but there was no federal involvement in routine purchase or distribution of influenza vaccine. No recommendations were developed for mass vaccination of the population, and the usual market forces determined purchase and distribution. Only 15 million doses had been released by the time the epidemic peaked in January 1969 and, as in 1957, a large amount of vaccine went unused (33). In January 1976, identification of a new influenza virus strain in New Jersey associated with the death of an otherwise-healthy U.S. Army recruit led to a recommendation for mass vaccination of the U.S. population against swine flu and a commitment by the federal government to purchase and distribute the vaccine. Vaccine manufacturers were apprehensive about their liability exposure in the setting of mass vaccination campaigns because adverse events were likely to occur in some individuals following vaccination even if the vaccine played no role in causing the adverse event. They refused to manufacture vaccine until indemnified by the government. This action resulted in delays in production and in the date for initiating immunization, a form of shortage. Once indemnified, vaccine production and distribution proceeded as planned (other than the delay in initiation) until suspension of the program later in the year as the result of the occurrence of Guillain-Barré syndrome in some recipients (16). Shortages of Childhood Vaccines MEASLES When rubella vaccine was licensed in 1969, the language of Section 317 was changed to authorize purchase of rubella vaccine. Unfortunately, the changed wording precluded use of Section 317 funds for purchase of measles vaccine. Consequently, there was a shortage of measles vaccine in the public sector in several states (e.g., New York) that had relied heavily on federal support for its

10 244 HINMAN ET AL. purchase. This was reflected in a resurgence of measles in some states until the authorizing language was amended to again allow purchase of measles vaccine (25). In contrast to subsequent shortages, in this case the shortage resulted from decreased ability to purchase vaccines. Production was adequate. POLIO The 1972 decision in Reyes v Wyeth, subsequently upheld on appeal, established that manufacturers could be held liable for an adverse event occurring following an immunization if there had not been an individualized medical judgment that the benefits of vaccination outweighed the risks. Because many vaccines in the public sector are administered by nurses based on standing orders, in 1976 the manufacturer refused to sell OPV to the federal government unless the government assumed the duty of warning recipients of the risks and benefits of vaccination. Negotiations over this issue resulted in temporary scattered shortages of OPV (1a). DTP During the 1970s and early 1980s several manufacturers of childhood vaccines left the U.S. market, because of mergers, liability concerns, tightened standards on manufacturing practices, and low profit margins. It is impossible to determine the relative importance of these factors. In the early 1980s, there was an explosion of litigation around manufacturers of whole-cell DTP (26). In 1984, there were three commercial companies, Lederle, Wyeth, and Connaught. As a result of the major increase in liability exposure, Wyeth dropped out of the market, ceding its supply to Lederle. Connaught dropped out temporarily, although it eventually self-insured against liability claims related to DTP and re-entered the marketplace. During the shortage in 1985 a recommendation was made to postpone the fourth and fifth doses of DTP until adequate supplies became available. Infants still received the initial three doses, which provided partial protection. The rationing lasted only a few months, and there was no detectable increase in incidence of pertussis resulting from the rationing (58). MULTIPLE VACCINES Between 1985 and 2000 there were no significant shortages of childhood vaccines. However, between 2000 and mid-2005, shortages occurred for vaccines protecting against 9 of the 13 diseases for which all children are immunized: diphtheria, influenza, measles, mumps, pertussis, pneumococcal disease, rubella, tetanus, and varicella (36). The vaccines, approximate dates of shortage, and immediate factors contributing to the shortage are shown in Table 3. In response to the shortages, the ACIP recommended deferring selected doses (endof-primary series doses or boosters) of each of the vaccines to ensure that infants received initial protection. A survey of managers of state and urban area immunization programs found that more than 85% of immunization programs changed the way they distributed PCV7 (pneumococcal conjugate vaccine), DTaP, and Td. Changes included limiting the amount of vaccine that could be ordered or distributing partial orders (60).

11 VACCINE SHORTAGES 245 TABLE 3 Childhood vaccine shortages Vaccine Approximate dates Immediate precipitating factors Td 11/2000 6/2002 Decreased production in 2000 by both major US manufacturers (Wyeth, Aventis Pasteur) Decision of one manufacturer (Wyeth) to cease production 11-month period required for production led to a lag before increased supplies became available from remaining major manufacturer DTaP 3/2001 7/2002 Recommendation to eliminate/decrease use of thimerosal-containing vaccines Decision of one manufacturer (Wyeth) to cease production PCV 9/2001 5/2003 Unanticipated initial demand Several sporadic manufacturing problems at the sole manufacturer (Wyeth) MMR 10/2001 7/2002 Voluntary renovations at a vaccine filling suite, which affected multiple vaccines (Merck) Varicella 10/2001 8/2002 Voluntary renovations at a vaccine filling suite, which affected multiple vaccines (Merck) Influenza 10/2004 4/2005 One of two manufacturers (Chiron) dropped out because of bacterial contamination Abbreviations: Td, tetanus and diphtheria toxoids, adult; DTaP, diphtheria and tetanus toxoids and acellular pertussis vaccines, adsorbed; PCV, pneumococcal conjugate vaccine; MMR, measles, mumps, and rubella vaccine. Source: References (5, 36). PCV7 presented a particularly complex problem, with unanticipated demand, production problems, and inadequate funds to purchase the vaccine contributing to shortages. The vaccine was licensed in February In October 2000, the ACIP recommended routine use of the vaccine for infants and toddlers. Initially, the manufacturer faced an unanticipated demand. In addition, there were also problems in vaccine production (53). Compounding the problem was the fact that the cost for the four-dose series essentially doubled the public sector cost of vaccines for children (and increased private sector costs by approximately 50%). Because PCV7 was included in the VFC program, it was automatically available to VFC-eligible children. In many states, however, Section 317 and state funding was not adequate to cover PCV7 for underinsured children. Consequently, 19 states adopted a two-tiered approach in public health department clinics: VFC-eligible children could receive PCV7 but other children could not. Many private physicians developed similar two-tiered approaches. In addition, five states that traditionally provided all childhood vaccines free to private providers ( universal purchase states) adopted a selective policy in which all recommended vaccines for children except for PCV7 were provided to all immunization providers (28).

12 246 HINMAN ET AL. Shortages of Influenza Vaccine Influenza vaccine is different from other vaccines in that it is reformulated each year. Thus, absent a guaranteed purchase agreement, any doses manufactured but not sold/used in a given year must be discarded and the manufacturer takes a loss on the costs of production. Absence of an infrastructure for influenza immunization and of contracts for purchase of large quantities of vaccine (as occur with childhood vaccines) makes it difficult for manufacturers to plan their annual production. In consequence, manufacturers base their production plans for a given year on their experience the preceding year. In 2000, there were four U.S. licensed manufacturers of inactivated influenza vaccine: Aventis (now sanofi pasteur), Wyeth, Parkdale, and Evans (now Chiron). The FDA found both Parkdale and Wyeth were in violation of cgmp. Parkdale stopped producing; Wyeth paid more than $30 million in fines, retooled their plant but produced late in 2000, 2001, and 2002, but left the market after 2002 with millions of doses in unsold vaccine (14). Influenza vaccine production and distribution from 2000 to 2004 is summarized in Table 4 (52). Although there was manufacturer dropout or delay, there was a gradual increase in the amount of influenza vaccine distributed during the period , possibly related to growing public education about the importance of influenza immunization for the elderly and the chronically ill. However, the increase in distribution did not keep pace with the growth in production, with manufacturers experiencing a growing excess over the period, from 7.5 million doses in 2000 to 12 million doses in Because of the dropout of Wyeth, the number of doses produced by the two remaining manufacturers in 2003 was lower than the quantity produced in 2002 but higher than the net doses distributed in prior years. In 2003, however, publicity over the occurrence of influenza-related deaths in children during an unusually early influenza season (which peaked during traditional months for vaccination) led to a surge in late demand for vaccine that could not be met in many parts of the country (24). TABLE 4 Influenza vaccine doses produced and distributed for the U.S. market Year Doses produced (millions) Doses distributed (millions) a 58 a Nearly 50 million doses were produced by one manufacturer (Chiron) whose license was suspended; so none of its vaccine was distributed. Source: Presentation by E. Wilder to National Vaccine Advisory Committee, October 4, 2004.

13 VACCINE SHORTAGES 247 As a result of the 2003 experience, production for 2004 was increased to a projected total of approximately 100 million doses. Although the population for which annual influenza vaccination is recommended totals approximately 190 million persons in the United States, this amount should have been enough to meet usual demand. Slightly more than half of the vaccine was expected to come from sanofi pasteur and most of the remainder from Chiron. In addition, 1 2 million doses of the recently licensed live attenuated influenza vaccine (recommended for use in persons aged 5 to 49) were expected to be produced by Medimmune. Note that 2004 was the first year in which universal immunization of children 6 23 months of age was recommended (with two doses for first-time vaccinees): All of this vaccine was to come from sanofi pasteur. In early October 2004, British health authorities announced that they had suspended the production license of Chiron, whose production facility was located in England. This decision created an immediate unanticipated shortage, with reduction in anticipated supply by about one half. The problem was made even more dramatic because many large purchasers (health plans, states) had contracts with only one manufacturer and therefore were in an all-or-none situation with respect to vaccine supply. In addition, sanofi pasteur had already distributed just over half (33 million doses) of its 2004 production. Two major steps were taken to deal with the shortage. First, the ACIP reassessed and revised the recommended vaccination priorities to focus on the 85 million high-risk individuals ( 65 years of age or with specified chronic conditions), approximately 7 million health care workers, and an estimated 6 million household contacts of children aged 6 months of age. Second, although the federal government has no official role in overseeing distribution of influenza vaccine, sanofi pasteur agreed to make available its undistributed vaccine for sale/distribution in accordance with government recommendations. State health departments assessed the amount and distribution of vaccine within their states and cooperated in redistributing vaccine within their states and sharing with other states. In a few states, rules were enacted establishing priorities for vaccine receipt and penalties announced for those who violated the rules. Extensive media coverage and announcements from health departments urged persons who were not in the priority categories to forgo vaccination. A few instances of price gouging were reported, and some people went to Canada (where supply was adequate) to receive influenza vaccine. Negotiations were undertaken to import vaccine from other countries for use in the United States under Investigational New Drug (IND) conditions and 1.5 million doses were purchased and imported, but none were used (20). The measures were seemingly effective, and a report on vaccine coverage in January 2005 indicated that 62.7% of persons 65 years of age had received influenza vaccine between September 1, 2004 and January 31, 2005, not far below the reported 65.5% who had received vaccine in the season. Only 16.5% of healthy persons years of age, who are usually recommended to receive vaccine (but were not in a priority group during the shortage), did so, compared

14 248 HINMAN ET AL. with 38% in the season (2, 8). Among health care workers with patient contact, 35.7% reported having received influenza vaccine, compared with 40.1% in the season. Of children aged 6 23 months, 48.4% received at least one dose of influenza vaccine 2004 was the first year in which there was a recommendation for universal vaccination of this age group. MEASURES TAKEN Stockpiles (Strategic Reserves) of Childhood Vaccines The limited number of manufacturers of childhood vaccines led CDC in 1982 to request funds from Congress to establish a stockpile (or strategic reserve ) of vaccines equivalent to a six-month supply of vaccines routinely recommended for children (at that time DTP, OPV, and MMR). As new vaccines have been added to the schedule for universal immunization, they have been included in the stockpile. Table 5 shows the target number of doses of vaccines to be included in the stockpile and the status of the stockpile as of April 1, 2005 (E. Wilder, personal communication). The stockpile can best be thought of as a bulge in the supply line. CDC contracts with the manufacturers for a quantity of vaccine to be stored in the stockpile. Manufacturers increase their production to accommodate this amount and store the vaccine in finished form. The actual vials of vaccine in the stockpile are rotated to ensure that stockpile vaccine always has adequate shelf-life. In effect, newly produced doses of vaccine are added to the stockpile and older doses are shipped to customers. TABLE 5 Childhood vaccine stockpile Vaccine Target doses ( 000) In stockpile ( 000) Purchased a ( 000) DTaP 10, Hepatitis A b Hepatitis B Hib IPV MMR PCV Varicella a Purchased but not yet delivered. b Hepatitis A, based on 35% of birth cohort at risk. Abbreviations: DTaP, diphtheria and tetanus toxoids and acellular pertussis vaccine; Hib, Haemophilus influenzae type b conjugate vaccine; IPV, inactivated poliovirus vaccine; MMR, measles, mumps, and rubella vaccine; PCV, pneumococcal conjugate vaccine. Source: E. Wilder (personal communication).

15 VACCINE SHORTAGES 249 There have been 12 withdrawals from the stockpile since it was established. Seven of these have occurred at the manufacturers request as a result of problems in production. The circumstances of each withdrawal are shown in Table 6 (E. Wilder, personal communication). Use of the stockpiles has recently been complicated due to accounting guidance from the Securities and Exchange Commission (SEC). In response to a series of financial misrepresentations of revenue during the late 1990s that had nothing to do with vaccines or pharmaceuticals, in 1999 the SEC published guidance for what represents revenue from a sale (57). This guidance defines certain criteria that must be met in order for any manufacturer to recognize revenue for certain types of transactions, including those in which the product is not physically delivered to the end customer (also called bill and hold transactions). Vaccine stockpiles, which are storage and rotation arrangements, are considered bill and hold transactions, and, therefore, must adhere to SEC guidance. Despite the fact that CDC pays the manufacturers for the doses in the stockpile, certain necessary elements of the transaction (especially the requirement to rotate the product to maintain efficacy) prevent the manufacturer from claiming the proceeds from this transaction as revenue for purposes of reporting earnings. This has resulted in several manufacturers stopping their participation until the issue is resolved. Resolution may require changes in legislation, which have not yet been introduced. Other Measures CHILDHOOD VACCINES A variety of factors other than the immediate factors shown in Table 3 contributed to the shortages of childhood vaccines, including the following (36). 1. The shift in focus of FDA inspections related to GMP to include more emphasis on quality systems, in-process testing, and facility and process validation. This required significant physical changes in many plants; some facilities that previously had passed inspections were now failing. 2. The fact that vaccines are undervalued compared with therapeutic measures, which is reflected in attitudes toward pricing of vaccines. 3. High cost and complexity of vaccine development, testing/licensure, manufacture, and distribution. 4. Lack of continued investment in some vaccine manufacturing facilities. 5. Barriers to communication, including intellectual property rights and confidentiality requirements. 6. The relatively small number of vaccine manufacturers. In 2000, an IOM report examined the infrastructure and financing of the immunization system in the United States and recommended a substantial increase in the federal immunization grant program as well as increases in state support to

16 250 HINMAN ET AL. TABLE 6 Year Stockpile usage history Vaccine/ Manufacturer Reason Production-related reasons for withdrawals from the vaccine stockpile 1984 OPV/Lederle Filling and packaging lines disrupted. Loaned entire supply of 3420,000 (a 10-week national supply); replaced in MMR/Merck Delayed delivery to stockpile and drew down 1,129,500 doses of MMR because of fire-damaged lyophilization cabinets and filling area (a 13-week national supply); replaced in DTP/Connaught Permission to withdraw 990,000 from stockpile because of continued production delays (a 2 3-week national supply); replaced in DTP/Lederle Permission to withdraw 1,609,995 doses (a 4-week national supply). This was a short-term loan to correct a filling line problem. An alternate filling location was arranged and DTP was replaced in IPV/Connaught Release difficulties; permission to withdraw entire stockpile of 19,150 doses (less than a 4-week supply); replaced in DTP/Connaught FDA release delays; permission to withdraw 2.4 M doses. Vaccine replaced in MMR/Merck Permission to withdraw 700,000 doses of MMR vaccine because of delay in release procedure. There is insufficient vaccine available to meet national needs. Merck replaced the vaccine in late Other reasons for withdrawals from the vaccine stockpile 1995 DT/Connaught & Lederle CDC terminated portions of the Connaught DT contract and the entire Lederle contract when CDC was unable to obtain bids for the additional years of storage. CDC had the DT vaccine delivered to various state immunization 1995 Td/Connaught & Lederle DTP/Connaught & Lederle 1998 Td/Connaught & Lederle programs to meet vaccine order needs in 1995 and CDC reduced Td stockpiles to ease a shortage of product in the market. This vaccine was distributed to state immunization programs. The reduced usage of DTP after the introduction of DtaP resulted in a series of partial withdrawals initiated at the request of the manufacturers because of an inability to rotate sufficient amounts of DTP stock. Final termination completed by Final distribution of Td vaccine completed from stockpiles. Companies refused to bid on standard purchase contracts and the remaining Td vaccine was distributed to state immunization programs to allow them to transition to the negotiation of individual state purchase contracts. (Continued)

17 VACCINE SHORTAGES 251 TABLE 6 Year (Continued) Vaccine/ Manufacturer Reason Other reasons for withdrawals from the vaccine stockpile 2003 MMR/Merck CDC had to withdraw 46,000 doses of MMR from the national stockpile due to a measles outbreak. Considerations for additional withdrawals will be made based on forthcoming information regarding the outbreak. CDC purchased additional MMR vaccine in 2003 to replenish the stockpile to the 6-month supply level. Source: E. Wilder (personal communication). strengthen the infrastructure (30). There have been some increases in the federal grant program but state support has remained substantially unchanged. To strengthen the supply of routinely recommended vaccines, NVAC recommended a number of strategies (36): Expanding vaccine stockpiles; Increasing support for regulatory agencies; Maintaining and strengthening liability protections; Improving communication among stakeholders; Increasing availability of public information; A campaign emphasizing benefits of vaccination; Evaluating appropriate financial incentives for manufacturers; and Streamlining the regulatory process without compromising safety or efficacy. In 2002, the National Immunization Program of the Centers for Disease Control and Prevention (CDC/NIP) asked IOM to carry out a study (31) to identify financial strategies designed to achieve an appropriate balance of roles and responsibilities in the public and private health sectors, integrate federal and state roles in supporting the purchase and administration of recommended vaccines for vulnerable populations, and develop a framework for identifying pricing strategies that can contribute to achieving current and future national immunization goals for children and adults. After considering the alternatives, the IOM Committee recommended the implementation of a new insurance mandate (requiring all health insurance policies to cover immunizations) combined with a government subsidy and voucher plan for vaccines recommended by the ACIP. This recommendation reflected the IOM s concern regarding the large and growing government share of the vaccine market and the belief that this is a disincentive for investment in vaccine manufacturing by industry. The subsidy/price of a vaccine would be set in advance of its development based on its estimated societal value. This approach was

18 252 HINMAN ET AL. thought to provide an incentive to develop vaccines with the highest public health priority. NVAC adopted an official response to the IOM report (27). NVAC agreed with many of the observations made, particularly that society undervalues vaccines, that actions are necessary to assure easy access to vaccines in a variety of settings by all for whom they are recommended (particularly adolescents and adults), and that actions are necessary to stabilize the vaccine market and make it attractive for manufacturers to remain in, or enter, the field. While NVAC agreed there is a need for strong legislative measures and additional funding to implement needed changes to the system, NVAC differed with the specifics of the IOM recommendations for action. NVAC did not feel it advisable to adopt the IOM recommendation to replace the current system with an insurance mandate and system of subsidies and vouchers, an approach that effectively eliminates the Section 317 program and the VFC program. NVAC did not believe that this approach reflects the peculiarities of research, development, and manufacture of biological agents. Furthermore, the IOM recommendations did not sufficiently acknowledge the progress made under the current system, the potential feasibility and impact of incremental changes, and the growth in the vaccine market that has occurred since the inception of VFC. NVAC was not convinced that the recommended approaches would have the desired effects of increasing vaccine research, development, and production capacity; reducing provider burden; and maintaining existing community and provider relationships. In addition, bringing about the legislative changes needed would be extremely complicated and difficult to achieve. NVAC believed that enhancement of the current system would go a long way towards stabilizing the financing of immunizations in the United States. Therefore, NVAC recommended the following: Expanded and stable funding through Section 317 for immunization program infrastructure and operations, as well as for vaccine purchase, within existing guidelines; Expanded funding through Section 317 to support adolescent and adult immunization programs including vaccine purchase; Rapid appropriation of new funds through Section 317 when new vaccines are recommended for universal use; Expansion of VFC to include underinsured children (as currently defined) in all public health clinics, removing price caps, and giving all providers and clinics a choice of vaccines; Regulatory harmonization to facilitate introduction into the United States of vaccines licensed in other countries that are in compliance with FDAapproved harmonized standards; Further exploration of regulatory and other factors impeding vaccine research and development to alleviate barriers;

19 VACCINE SHORTAGES 253 Increased communication between industry and FDA throughout the process of vaccine research and development; Promotion of first dollar insurance coverage for immunization and promoting prompt coverage and recalculation of capitation rates when new vaccines are recommended; Assurance of adequate reimbursement for administration of vaccines; and Expanded discussion about the need, desirability, and feasibility of a variety of approaches (e.g., Vaccines for Adults or Vaccines for All program) to ensure that adults have access to vaccines, even if they don t have insurance. In January 2005, NVAC held a second workshop on strengthening the supply of vaccines in the United States. Preliminary recommendations from that meeting addressed: increased financial incentives for research, development, production and administration of vaccines; modified regulatory processes; utilization of vaccine stockpiles; and resolving lingering liability issues (37). INFLUENZA VACCINE The major focus for improving the supply of influenza vaccine is to decrease manufacturer risk and to increase the predictability, demand, and hence the size of the market. Because influenza vaccine generally must be used in October and November of a given season and then usually is discarded, a back-end guarantee or buy back program for unused doses would reduce the financial risk for manufacturers. To enhance demand and achieve greater coverage among the approximately 190 million Americans for whom vaccine is recommended annually, several steps have been recommended by the Partnership for Prevention (43) and supported by leading medical and health organizations: Establish a multiyear pilot program in four states for the purchase and distribution of influenza vaccine for uninsured adults aged years included in the current recommendations of the ACIP. Require the Federal Employee Health Benefit Program (FEHBP) to stipulate that participating health plans provide first dollar coverage for influenza and pneumococcal vaccines for adults included in the current recommendations of the ACIP. Earmark additional funding in the Section 317 program of the Public Health Service Act specifically for adult immunization activities. Earmark $2 3 million per year over a five-year period for DHHS to conduct an educational campaign on the importance of adult immunizations among the general public, segments of the population with particularly low immunization rates, as well as providers, insurers and employers. Direct the Centers for Medicare & Medicaid Services (CMS) to expand its quality initiatives and make measuring and reporting vaccination rates among adult patients and health care workers a priority. Earmark $1 million for the Agency for Healthcare Research and Quality (AHRQ) to assess CMS efforts

20 254 HINMAN ET AL. and those of private organizations to identify the most effective approaches to measure and reward quality. Direct CMS to reach agreement with the Joint Commission on Accreditation of Healthcare Organizations to include immunization of health care workers as one of the standards that must be met for accreditation of hospitals, nursing homes, home health agencies, and other regulated facilities. The National Vaccine Advisory Committee has recommended development of an infrastructure and vaccine purchase program under Section 317 to support adult immunization. Such a program would help stabilize the influenza vaccine market and should help alleviate future shortages in interpandemic periods (27). Widespread acknowledgment of the high probability of another influenza pandemic has led the Department of Health and Human Services (DHHS) to develop a pandemic influenza preparedness plan (15) that describes overall goals for pandemic preparedness (minimizing severe morbidity and mortality from influenza and minimizing the social and economic disruption) as well as approaches to achieve the goals. The plan recognizes that there will almost certainly be shortages of vaccine (at least in the initial phases of the pandemic). The National Vaccine Advisory Committee (NVAC) is working with the Advisory Committee on Immunization Practices (ACIP) to develop a proposed list of priority populations to receive initial supplies of vaccine. These recommendations are to be completed before the end of OTHER COUNTRIES This paper has focused on vaccine shortages in the USA, but there are also concerns about adequacy of vaccine supply in other countries. In the developing world, concerns center around countries lack of resources to purchase vaccines, particularly newer, more expensive vaccines. In partial response to this problem, the Global Alliance for Vaccines and Immunization (GAVI) has established a Vaccine Fund, which provides assistance to the lowest-income countries in strengthening childhood immunization infrastructure and purchasing vaccines. There is also concern about the shortage (nonexistence) of vaccines to address health problems of poor countries (e.g., malaria). Vaccine research and development is so expensive (with unpredictable results) that manufacturers may not have great interest in investing the money required to bring forth a vaccine that will not be used in developed countries, where they can obtain an attractive profit margin. A variety of mechanisms has been proposed to support research and development of these vaccines, including advance purchase agreements, public-private partnerships, etc. A series of articles in a recent issue of Health Affairs addressed many of these issues (29). In 2002, the Sabin Vaccine Institute convened a meeting on the global vaccine shortage. The pathways to vaccine supply solutions that emerged from the colloquium included emphasizing the value of vaccines, exploring inventory management, enhancing production capacity, promoting innovations in financing,

21 VACCINE SHORTAGES 255 harmonizing regulatory processes and vaccine schedules, examining product divergence trends, building mechanisms for stronger communication, assuring a fair rate of return on investment, regulating the vaccines in supply, maintaining a robust supply of vaccines, and sustaining vaccines high profile (61). Salisbury described the key elements of the vaccine purchasing policy of the Department of Health of the United Kingdom, which he felt have been effective in preventing or minimizing the effects of vaccine shortages. They are as follows: avoidance of dependence on single suppliers (when possible), forecasting of needs up to 12 months in advance, use of strategic reserves of vaccine to smooth out ebb and flow of supplies, and the ability to switch from unrestricted ordering of vaccines to managed allocation of supplies to physicians. The United Kingdom has avoided shortages despite the fact that public sector purchases through large contracts account for almost all vaccines delivered there (51). PROSPECTS FOR THE FUTURE Given the fact that there is only a single manufacturer for several childhood vaccines, vaccine stockpiles remain the best protection against interruptions in supply or increases in demand for these vaccines in the short to medium term. However, to be fully useful, the issue surrounding the SEC ruling on vaccine manufacturers realization of income must be resolved and there must be adequate appropriations to complete purchasing vaccine for the stockpiles. Expanding and improving the National Vaccine Injury Compensation Program would mitigate one of the factors that manufacturers take into account when deciding whether to enter (or remain in) the market. Attracting additional manufacturers for existing vaccines is another step that could help minimize the likelihood of shortages. Whether the market is large enough to be enticing is unclear. However, regulatory harmonization would make it easier to import vaccines licensed in other countries and to meet regulatory requirements that are equivalent to those in the United States. Assuring adequate funding to purchase needed supplies of vaccine would avoid shortages based on inadequate resources. In the developing world, this is probably the most important step needed. As demonstrated by the experience with PCV7, financing can also be a constraint in developed countries, although this was not a key factor in the recent shortages of PCV7. GAVI is leading efforts to enhance resource availability for developing countries. For influenza vaccines in the interpandemic period, probably the most important step to take to avert future shortages would be to establish contracts for guaranteed purchase of vaccine [or for government purchase of unsold vaccine (at a discount) at the end of the season]. This would markedly reduce the financial risk to manufacturers. Establishing an adult immunization program infrastructure and vaccine purchase program under Section 317, combined with an education campaign to increase demand, could help increase the market and stimulate other manufacturers to enter it.

22 256 HINMAN ET AL. For pandemic influenza vaccines, the most important steps are to develop methods of vaccine development/production that take less time than the current eggbased methods and to establish clearly what the government s role will be in purchase and distribution of pandemic influenza vaccine. Even if these steps are taken, shortages of the pandemic influenza vaccine are highly likely in the early phases of the pandemic. However, the delay between identification of a pandemic strain and availability of vaccine could be shortened considerably and the capacity of industry to rapidly scale up vaccine production could be enhanced. Some steps could be taken to alleviate the total shortages resulting from absence of a vaccine to protect against diseases that are important in the developing world. These include increased governmental support for research and development, enhanced private-public partnerships, and advance purchase agreements. CONCLUSION Vaccine shortages can result from higher-than-expected demand, interruptions in production/supply, or a lack of resources to purchase vaccines. Each of these factors has played a role in vaccine shortages in the United States during the past 20 years. In developing countries, the major cause of vaccine shortages is the lack of resources to purchase them. Although there are several steps that could reduce the likelihood of future vaccine shortages, many would take several years to implement. Consequently, it seems likely we will continue to see occasional shortages of vaccines in the United States in the next few years. ACKNOWLEDGMENTS Eddie Wilder of the National Immunization Program, Centers for Disease Control and Prevention, provided valuable information about vaccine stockpiles and influenza vaccine purchases. DISCLOSURE STATEMENT W.O. received grant funding from Chiron Foundation for influenza vaccine research and received clinical trials funding from Merck for HIV vaccines and from Medimmune for influenza vaccines. The Annual Review of Public Health is online at LITERATURE CITED 1a. Auerbach S States low in polio vaccine. Washington Post. Sept. 14, pp. A1, A8 1. Cent. Dis. Control Prev Influenza vaccination coverage among adults aged 50 years and pneumococcal vaccination coverage among adults aged 65 years United States, MMWR 52:987 92

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26 Annual Review of Public Health Volume 27, 2006 CONTENTS EPIDEMIOLOGY AND BIOSTATISTICS Effective Recruitment and Retention of Minority Research Participants, Antronette K. Yancey, Alexander N. Ortega, and Shiriki K. Kumanyika 1 Measuring Population Health: A Review of Indicators, Vera Etches, John Frank, Erica Di Ruggiero, and Doug Manuel 29 On Time Series Analysis of Public Health and Biomedical Data, Scott L. Zeger, Rafael Irizarry, and Roger D. Peng 57 The Promise and Pitfalls of Systematic Reviews, Patricia Dolan Mullen and Gilbert Ramírez 81 Hypertension: Trends in Prevalence, Incidence, and Control, Ihab Hajjar, Jane Morley Kotchen, and Theodore A. Kotchen 465 ENVIRONMENTAL AND OCCUPATIONAL HEALTH Environmental Justice: Human Health and Environmental Inequalities, Robert J. Brulle and David N. Pellow 103 Speed, Road Injury, and Public Health, Elihu D. Richter, Tamar Berman, Lee Friedman, and Gerald Ben-David 125 The Big Bang? An Eventful Year in Workers Compensation, Tee L. Guidotti 153 Shaping the Context of Health: A Review of Environmental and Policy Approaches in the Prevention of Chronic Diseases, Ross C. Brownson, Debra Haire-Joshu, and Douglas A. Luke 341 PUBLIC HEALTH PRACTICE Health Disparities and Health Equity: Concepts and Measurement, Paula Braveman 167 The Politics of Public Health Policy, Thomas R. Oliver 195 Vaccine Shortages: History, Impact, and Prospects for the Future, Alan R. Hinman, Walter A. Orenstein, Jeanne M. Santoli, Lance E. Rodewald, and Stephen L. Cochi 235 What Works, and What Remains to Be Done, in HIV Prevention in the United States, David R. Holtgrave and James W. Curran 261 vii