money provided by the government that supports basic research at universities and private research institutions. To some degree, agencies themselves can help focus this research on areas of particular relevance to vaccine development. The National Institutes of Health (NIH) is providing additional push through its new Clinical and Regulatory Affairs Branch (part of the National Institute of Allergy and Infectious Diseases). Branch staff are a source of information on regulatory matters for university-based scientists working on products of potential interest to industry. The NIH also can make pilot lots of vaccine suitable for early-phase clinical testing and, through its Vaccine and Treatment Evaluation Units, can support a limited number of vaccine trials. An IOM panel suggested recently the need for a National Vaccine Authority, which among other tasks would take on early-stage development of certain vaccines destined for developing-world use.28

The public sector may exert its strongest influence by establishing policies that reduce the number of risks industry must take in developing vaccines. In the United States, two independent groups—the Advisory Committee on Immunization Practices and the American Academy of Pediatrics ’ Red Book Committee—exert an especially strong pull by setting national immunization standards. These standards have the effect of creating a market where none may have existed before. The uncertainty of developing a vaccine might be further reduced if the two advisory groups established criteria for adding a vaccine to the set of recommended immunizations before the product is licensed.29

INTRODUCING AN EFFECTIVE VACCINE30

As newer, more expensive vaccines, including conjugates, come on the market, cost will figure increasingly in decisions about whether or not these products are used in a developing-country setting. Cost-effectiveness analysis provides useful information for policymakers charged with making these decisions. The CDC, as part of a larger effort coordinated by WHO and the London School of Hygiene and Tropical Medicine to look at pneumonia prevention, has developed global cost-effectiveness estimates for H. influenzae and pneumococcal vaccines.

According to CDC, there are some 8.8 million cases of H. influenzae pneumonia, and 464,000 H. influenzae-caused pneumonia deaths worldwide in

28  

The Children’s Vaccine Initiative: Achieving the Vision. National Academy Press, 1993.

29  

Donald Shepard.

30  

Unless otherwise noted, the material in this section is based on presentations by Benjamin Schwartz, Maria Costales, Otavio Oliva, George Siber, and Ciro de Quadros.



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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 money provided by the government that supports basic research at universities and private research institutions. To some degree, agencies themselves can help focus this research on areas of particular relevance to vaccine development. The National Institutes of Health (NIH) is providing additional push through its new Clinical and Regulatory Affairs Branch (part of the National Institute of Allergy and Infectious Diseases). Branch staff are a source of information on regulatory matters for university-based scientists working on products of potential interest to industry. The NIH also can make pilot lots of vaccine suitable for early-phase clinical testing and, through its Vaccine and Treatment Evaluation Units, can support a limited number of vaccine trials. An IOM panel suggested recently the need for a National Vaccine Authority, which among other tasks would take on early-stage development of certain vaccines destined for developing-world use.28 The public sector may exert its strongest influence by establishing policies that reduce the number of risks industry must take in developing vaccines. In the United States, two independent groups—the Advisory Committee on Immunization Practices and the American Academy of Pediatrics ’ Red Book Committee—exert an especially strong pull by setting national immunization standards. These standards have the effect of creating a market where none may have existed before. The uncertainty of developing a vaccine might be further reduced if the two advisory groups established criteria for adding a vaccine to the set of recommended immunizations before the product is licensed.29 INTRODUCING AN EFFECTIVE VACCINE30 As newer, more expensive vaccines, including conjugates, come on the market, cost will figure increasingly in decisions about whether or not these products are used in a developing-country setting. Cost-effectiveness analysis provides useful information for policymakers charged with making these decisions. The CDC, as part of a larger effort coordinated by WHO and the London School of Hygiene and Tropical Medicine to look at pneumonia prevention, has developed global cost-effectiveness estimates for H. influenzae and pneumococcal vaccines. According to CDC, there are some 8.8 million cases of H. influenzae pneumonia, and 464,000 H. influenzae-caused pneumonia deaths worldwide in 28   The Children’s Vaccine Initiative: Achieving the Vision. National Academy Press, 1993. 29   Donald Shepard. 30   Unless otherwise noted, the material in this section is based on presentations by Benjamin Schwartz, Maria Costales, Otavio Oliva, George Siber, and Ciro de Quadros.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 young children each year. The agency estimates that about 60 percent of these deaths are caused by infection with Hib. An additional 25,000 deaths in this age group result from Hib-related meningitis. Assuming that the Hib vaccine is administered with DTP and that vaccine coverage averages about 70 percent for each of three doses, as many as 167,000 deaths, or roughly half of those expected, could be averted. If herd immunity were established, 90 percent of expected deaths could be prevented. Based on a cohort of 127 million children, a vaccine cost of $1, and vaccine wastage of 50 percent, it would cost $276 million (for a two-dose vaccine) or $413 million (for a three-dose vaccine) to achieve these results. There would be no additional expense associated with delivering the vaccine, since it would be mixed in a vial with DTP. Adding the costs of side effects (between $2.3 and $3.5 million) and subtracting treatment expenses that were not incurred (about $3 million), CDC calculated the costs per death averted, with no herd immunity, at between $1,640 and $2,881 (Table 3). Hib cost-effectiveness is highly dependent on vaccine pricing. The current U.S. public-sector price for Merck’s Hib conjugate is $5.50 per dose; using this figure in the calculation yields a per-death-averted cost of $9,020. TABLE 3 Cost-Effectiveness of Immunization with Hib Conjugate   Cost per Death Averted Cost per Case Averted HbOC (Connaught) $2,628–$2,881 $462–$506 PRP-OMP (Merck) 1,640–2,331 288–410 PRP-OMP with herd immunity 994 140 NOTE: It is assumed that all vaccines are administered with DTP. SOURCE: CDC, 1994. Brazil recently undertook a cost-effectiveness analysis of Hib vaccine, focusing on the vaccine’s role in preventing meningitis rather than pneumonia.31 Based on data from 1992, public health officials there estimated the country experiences 1,547 cases of Hib-caused meningitis each year in children under age 31   It should be noted that this analysis did not attempt to calculate the value of lives saved or of disability averted through the use of Hib vaccine.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 2. The costs of treating these cases, 7 percent of which could be expected to result in severe neurological problems, would run to $24 million. Assuming the price of vaccine is $9, 32 it would cost almost $137 million to completely immunize Brazil’s under-age-2 cohort, a group of some 6.5 million. This is considerably more than the $54 million the country spent in 1994 to purchase all of its other vaccines. Without a significant drop in the price of the Hib conjugate—perhaps through bulk importation and local filling, or local production (involving technology transfer)—Brazil will probably not add this vaccine to its immunization armamentarium. In the Philippines, some health officials expect that the Hib vaccine will be the next vaccine introduced into that nation’s immunization program. Hib vaccine is a high priority in the country, since pneumonia is the leading cause of death among all Filipinos and is the second most common cause of death among Philippine infants. The Philippines, along with a number of other developing nations, is taking part in the Vaccine Independence Initiative (VII), established by UNICEF and USAID. The VII is a revolving fund that allows countries to purchase vaccine with their own currency and to pay upon receipt of vaccine. There is concern, at least among health officials in some of the participating countries, that the VII will not be sufficiently capitalized with hard currency to allow the purchase of expensive, new vaccines. While the potential cost and cost-effectiveness of Hib immunization are daunting, programmatic and technologic improvements could be made that would reduce these outlays. By decreasing the age of immunization, for instance, more deaths and cases could be prevented. Increasing vaccine coverage, ideally to the point at which herd immunity takes hold, could similarly save more lives. Cutting vaccine wastage in half would lower the cost per death averted by 17 percent. Decreasing the number of vaccine doses required, improving vaccine efficacy, and lowering vaccine production costs all would improve cost-effectiveness. In the case of S. pneumoniae, CDC estimates that there are 1.127 million pneumococcal deaths each year around the world. (The agency notes that the assumptions and models used to generate this mortality figure are subject to revision.) Based on serotype data from the developing world, Merck’s seven-valent pneumococcal vaccine would cover about 60 percent of cases, while Lederle-Praxis’ formulation would cover about 68 percent. The vaccines would annually prevent between a quarter and nearly one-third of all pneumococcal deaths. Herd immunity would boost this to 650,000 deaths prevented, or nearly 32   That the price quote for Hib was higher than the U.S. public-sector price probably reflects the fact that the number of doses to be purchased was relatively small and the supply contract was short term. Both factors would drive up the cost of vaccine (Otavio Oliva; personal communication, 1995).

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 70 percent of the expected total mortality. A common-antigen vaccine, theoretically covering all pneumococcal serotypes, would avert some 510,000 deaths each year. If the price of the conjugate vaccine were $5 per dose and three doses were given, the cost per death averted would be between $6,000 and $7,000; the cost per death avoided with the common-antigen vaccine (also three doses, priced at $1 per dose) would be less than $800 (Table 4). As with Hib, these calculations take into account the projected additional expense resulting from side effects and the expected savings from reduced treatment costs. TABLE 4 Cost-Effectiveness of Immunization with Pneumococcal Conjugate   Cost per Death Averted Cost per Case Averted Merck $6,823 $389 Lederle-Praxis 5,948 340 Lederle-Praxis with herd immunity 3,155 168 Common antigen 759 43 NOTE:It is assumed that all vaccines are administered with DTP. SOURCE: CDC, 1994. Although direct purchase of conjugate Hib, pneumococcal, and meningococcal vaccines may be an option for some developing countries, for many those costs will be insurmountable. Other options will need to be explored. The purchase of bulk conjugate vaccine for combination with locally produced DTP is one such option. But for many poor nations, even the expense of bulk vaccine will be prohibitive. Another alternative is to transfer conjugate vaccine production technology to the developing world. Indeed, given the potential size of the vaccine market in developing nations, it is highly unlikely that developed-country manufacturers alone could meet that need. Ultimately, indigenous production may be the only way poorer regions of the world will be able to afford to immunize their children.33 To produce these vaccines, developing countries must develop the 33   William Hubbard.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 capability to perform and control technically complex manufacturing processes—not an easy undertaking. This will require a variety of collaborative ventures between and among developed- and developing-country vaccine makers. Public-sector manufacturers in the developed world could play a useful role by facilitating these interactions. The International Vaccine Institute, recently established in Seoul, Korea, has as one of its goals the promotion of public-/ private-sector collaboration in vaccine development, with a focus on the needs of developing countries in Asia. According to one proposal, the elements of a successful vaccine technology transfer effort will need to address strategic, scientific, training, and licensing issues (Table 5). The strategy of combining conjugate vaccines with DTP is now seen as the best approach by those involved in the CVI. Having highly purified D, T, and P may allow these components to serve as carriers in the conjugate vaccines, and simplifying the conjugation process will increase yields and reduce costs. Vaccine staff in developing countries will need training in practical subjects (good manufacturing processes, quality assurance and quality control, production methods, animal testing, serology, computerized record keeping) as well as theoretical topics (polysaccharide and protein chemistry, microbiology, and biostatistics). Such training might involve partnerships between public- or private-sector vaccine manufacturers in the United States and other industrialized countries and university or government laboratories in the developing world. Bilateral manufacturing agreements, allowing access to vaccine production knowhow and patented technology, would be essential. TABLE 5 Vaccine Technology Transfer to the Developing World: Elements of a Solution Strategic (CVI) Combination vaccines with DTP Scientific (manufacturers and universities) Use highly purified diphtheria, tetanus, and pertussis components Simplify and increase yields of polysaccharide-protein conjugation Maximize immunogenicity of both pertussis and protein in conjugates Training (manufacturers and universities) Good manufacturing practices State-of-the-art production methods Clinical investigation Licensing/technology transfer (manufacturers) Bilateral agreements SOURCE: Siber, 1994.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 Historically, inefficiencies in production have limited the availability of newer vaccines outside of the developed world. For instance, acellular pertussis, while less likely to cause adverse reactions than its whole-cell counterpart, is also considerably more expensive because so much of the vaccine is lost during the manufacturing process. Yet, acellular pertussis may be a key element of successful technology transfer based on the DTP platform. There now are technologies available (involving pertussis toxin CRM), however, that can increase acellular yields threefold. The complexity and inefficiency of conjugation have similarly kept that technology out of the hands of developing-country vaccine makers. However, some manufacturers’ yields have jumped considerably over the past 2 years, and additional improvements are possible. Technology transfer, bulk purchase, participation in revolving funds, and other approaches for getting vaccine to children in the developing world will have little impact unless these countries want to take these steps. Indeed, national commitment may be one of the most important, albeit least tangible, requisites for improving childhood immunization. The successful polio eradication experience in the Americas revealed the importance of high-level political consensus about the importance of childhood immunization. This political commitment was backed up by a financial one: Over the program’s lifetime, participating nations spent more than $500 million of their own money on eradication efforts. Conversely, political instability can have dramatic negative effects on public health initiatives. Such was the case recently in Nigeria, where measles immunization coverage rates for those under age 2 fell from a reported 80 percent to as low as 25 percent in some regions during a period of political unrest.34 Perhaps equally important to political commitment is popular demand. It is often only when there is grass-roots support for vaccination that barriers such as cost can be overcome. Public awareness of the need for vaccination sometimes can be misguided, however. This may have been the case in Brazil, which has recently purchased large amounts of group B meningococcal vaccine to battle endemic meningococcal disease but has opted not to buy Hib vaccine, which might have greater benefits over the long term.35 In the Americas, coordination was crucial to polio eradication, and similar cooperation between developing-world nations may be important as vaccine technology transfer moves ahead in other parts of the world. A revolving fund for vaccine purchase established by PAHO removed many hard-currency concerns during the fight against polio. The infusion of some $200 million from Rotary International also played a key role. In addition, during the eradication program, countries in the region developed close working relationships with 34   Catherine Oyejide. 35   Donald Shepard.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 vaccine manufacturers. This not only allowed the efficient procurement of vaccine, it also facilitated cooperative problem solving around a variety of technical concerns.