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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 BOX 2 Possible Approaches to an Improved Neisseria menigitides Group B Vaccine Eliminate the class 4 OMP to avoid inducing blocking antibodies Employ multivalent vaccines strains that express multiple subtype determinants Use more effective adjuvants Alter the vaccine schedule to include three doses of vaccine Evaluate alternative vaccine approaches and antigens (LPS, iron-uptake proteins, B polysaccharide conjugates, etc.) Evaluate mucosal (intranasal) immunization with native antigens to mimic carriage SOURCE: Zollinger, 1994. be to focus on the conjugates.19 It may be that an A/C conjugate vaccine should be combined with Hib rather than with a group B meningococcal vaccine. Still, a single vaccine directed against A, B, and C meningococci would be potentially of great value, since together the three serogroups account for over 90 percent of all meningococcal-caused meningitis. Such a formulation might consist of group A and C polysaccharides, each conjugated to tetanus toxoid, combined with group B outer membrane vesicles from class 2 and class 3 expressing strains (which also contained class 1 and class 5 proteins). For maximum effect, a booster dose would need to be given 8 to 9 months after the primary series, and perhaps again 2 to 4 years later. PROVING VACCINE EFFICACY: THE CHALLENGE OF DEVELOPING-COUNTRY FIELD TRIALS20 Accurate diagnosis is essential for understanding the extent and basis of pneumonia infections. Yet, the three traditional methods for diagnosing bacterial pneumonia—utilizing blood culture, lung aspirates, and sputum culture—are far 19 Emil Gotschlich. 20 Unless otherwise noted, material in this section is based on presentations by Claire Broome, Helena Makela, and Myron Levine.
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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 from perfect. Although blood culture assays are highly specific, they are insensitive (even under ideal conditions, only about 20 percent of pneumococcal disease can be accurately detected, for example); methods that look at lung aspirates, while producing more sensitive results, are difficult to perform even in the research setting; and because of the problem of frequent carriage, sputum sampling gives relatively nonspecific (and insensitive) information. The availability of accurate diagnostics would make it possible to define the public health impact of pneumonia, characterize its epidemiology, and would facilitate studies of viral-bacterial interactions in ARI. Diagnostic capability also would give scientists a tool for estimating the potential impacts of conjugate vaccines, a critical factor in convincing developing-country health ministers to include ARI vaccines in their immunization programs. Finally, accurate diagnosis of pneumonia would have a direct, positive impact on the conduct of ARI vaccine studies (Box 3). BOX 3 Impact of Accurate Diagnosis of Bacterial Pneumonia on Vaccine Trials Increased ability to evaluate efficacy against nonbacteramic disease Improved ability to evaluate population-based impact Potentially reduced diagnostic bias in case-control studies Potentially improved information on vaccine formulation Decreased sample size for prospective randomized controlled trials SOURCE: Broome, 1994. A number of laboratories are exploring PCR (polymerase chain reaction) techniques to improve diagnostic accuracy. While some of their results look promising, PCR may not increase sensitivity beyond that achieved with blood culture. Diagnostic methods based on antigen detection were thought to show promise. Some tests using latex agglutination reagents—for example, to identify Hib infection—successfully flag 90 percent or more of bacteremic patients, based on antigens found in their serum or urine. Unfortunately, these sorts of studies have often failed to include a control group of healthy carriers. When that is done, antigen-detection assays frequently are found to misclassify as positive a significant proportion of individuals who are carriers. (Similarly misleading
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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 results have been seen in tests designed to detect neonatal sepsis.) Soluble antigens may be distributed systemically from carriage strains, allowing absorption of polysaccharides detectable in serum and urine, when in fact the underlying infection is viral.21 Accuracy may also vary when a diagnostic kit tested in a controlled setting, such as a hospital, is evaluated in a community setting where pneumonia incidence is relatively low but carriage is high. Finding a way to preserve and share epidemiologically and bacteriologically characterized specimens would aid efforts to evaluate newly developed diagnostics. Although saddled with less than perfect diagnostic tools, researchers nevertheless are evaluating in humans vaccines against a number of ARI pathogens, including S. pneumoniae and Hib. Unfortunately, the classic double-blind randomized placebo-controlled efficacy trial is not ideally suited to vaccine studies. For one thing, it may sometimes be difficult to include a placebo group in such a way that is acceptable to the participants. And while recordkeeping in controlled clinical trials is often problematic no matter what the setting, it frequently poses a much greater challenge in the developing world. Elaborate, large-scale clinical studies are also expensive and time consuming. While randomized clinical trials are central to evaluating vaccine efficacy, some information about vaccine effectiveness may be obtained via hospital-based surveillance of pneumonia in already-vaccinated populations. Using this approach, all children admitted to a hospital with severe pneumonia or other severe disease would have blood cultures taken. The type and number of pathogens identified during this process would be compared with their expected distributions, based on previous blood-culture studies. By looking specifically at the incidence of infection with the vaccine-type organism, one could begin to get a picture of vaccine efficacy, even in less than ideal circumstances (Box 4). A number of useful comparisons might be made, including between pre- and postvaccination disease rates. Because it does not require vaccination records to provide useful information, surveillance may prove more useful in the developing-world setting than the case-control paradigm. A recent postlicensure Hib trial in Chile illustrates another way developing or transitional countries can obtain useful information about vaccine effectiveness without investing in traditional double-blind, placebo-controlled studies. After epidemiologic research implicated Hib as the cause of meningitis outbreaks, Chilean health officials began to consider adding the vaccine to the group of vaccines administered under the Expanded Programme on Immunization (EPI). Before making a long-term commitment to purchase the conjugate, however, they wanted proof that the vaccine would reduce disease incidence. Since Hib had already been licensed, it was the public health impact (effectiveness) rather than the biological activity (efficacy) that was at issue. 21 Gerald Fischer.
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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 BOX 4 Surveillance Gives Information About Impact (Effectiveness) When: Vaccination coverage is less than 100 percent; Vaccination misses important risk groups; Infants are not vaccinated at the ideal age; Many may receive only 1 or 2 doses; Vaccine quality may not be ideal; and Serotypes vary. SOURCE: Makela, 1994. Participants in the study were drawn from 71 urban health centers in metropolitan Santiago. Children using 36 randomly selected centers received Hib vaccine with DTP; children in the other 35 centers received DTP only. Nearly 100,000 people were enrolled in the study. Using standardized bacteriologic methods, investigators at the centers gathered routine diagnostic surveillance data for 20 months. The vaccine proved to be 89 percent effective. Based on these results, the Chilean government plans to incorporate Hib into the country ’s EPI schedule sometime in 1996. Despite the availability of alternative strategies, there continues to be considerable debate about whether, or at what point, these other approaches should take the place of randomized controlled trials for evaluating vaccines in the developing world. In the case of pneumococcal vaccines, a group of experts convened by the World Health Organization in 1993 agreed that a phase III randomized controlled trial was essential for a manufacturer to get usable efficacy data on a pneumococcal vaccine, while developing countries had a legitimate interest in conducting phase IV studies to obtain information on effectiveness.22 Still, many feel there is no substitute for a randomized controlled trial to determine whether a pneumococcal vaccine reduces both mortality and the proportion of individuals hospitalized with pneumonia (and perhaps ALRI). In addition, a randomized trial can reveal a vaccine ’s impact on the incidence of severe pneumonia, which may be crucial for convincing countries of the vaccine’s benefits. This is true even in the absence of specific diagnosis of nonbacteremic pneumococcal pneumonia, since the large sample size of such a study would probably allow documentation of a reduction in the incidence of 22 See footnote 12.
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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 severe disease. Furthermore, if the vaccine is highly efficacious, a randomized trial may provide useful information about the proportion of severe pneumonia caused by the vaccine-type pneumococci. This information is impossible to get in a postlicensure study, since those who get vaccine in an uncontrolled setting usually have very different risk factors for disease and different likely access to diagnostic testing (i.e. blood culture).23 Vaccine makers themselves may push for more than one randomized study to obtain pivotal trial-quality data.24 Indeed, there may be some benefit in conducting identically designed efficacy trials in many parts of the world at once, as was done with typhoid vaccine in the 1960s.25 The Public-/Private-Sector Interface26 The interface between the public and private sectors is different at each point along the vaccine R&D pipeline. Similarly, the sources of funding, the forces driving the system, accountability, and risks associated with R&D vary according to the perspective of the participant (Table 2). During the early phases of research, when there is undefined potential and significant risk, industry may directly fund projects in public-sector labs or it may work collaboratively with the public sector. Later stages of vaccine development, which require major resources and long-term facility use, tend to be unique to industry, however. Clinical research presents a number of opportunities for useful interactions between industry and others in both the developed and developing world. It is desirable, particularly for vaccines for the developing world, that these contacts be made as early as possible in the clinical-testing process. Manufacturing is capital intensive, and transferring to the developing world the ability to make vaccine is an extremely complex process. Even so-called turn-key operations, in which a modern plant is built from the ground up and staffed with trained personnel, can be plagued with problems related to product consistency and process validation. From industry’s point of view, one major downside of interacting with the public sector is potential loss of control of the research process. This may happen, for instance, when a clinical trial being conducted by the government with vaccine supplied by industry goes awry, producing data that may not be 23 Claire Broome. 24 George Curlin. 25 Myron Levine. 26 Unless otherwise noted, the material in this section is based on presentations by Frank Malinoski, Dale Spriggs, and George Curlin.
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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 TABLE 2 The Public-/Private-Sector Interface Government Academia Nonprofit Institute Industry Resources Taxes Government or industry support Donations Shareholders Driving forces Epidemiology and politics Resource constraints Competition and profit Accountability Congress Board of directors Board of directors Board of directors and regulatory authorities Risks Minimal Minimal Minimal Litigation SOURCE: Malinoski, 1994. acceptable to regulators. Although not directly responsible for these results, the firm may nevertheless have to answer to its shareholders for them. Industry is concerned also about who owns the rights to products developed with public-sector collaboration and what role government should play in setting the prices for those products. Having access to intellectual property and an exclusive license on a technology is a tremendous incentive for industry to invest in vaccine development. However, the high price of the resulting products may limit their availability in most parts of the developing world. One fundamental difference between industry and the public sector is the former’s need to define and penetrate a market. The vaccine industry, particularly biotechnology companies dependent on venture-capital funding, is very sensitive to the availability of commercial opportunity. In the case of human vaccines, three-quarters of current revenues come from just two regions of the world: Europe and the United States. 27 Much of the remaining money now made from vaccine sales is sheltered in several large markets—like those of Japan and China—that are virtually closed to the outside world. Vaccine purchased by the Pan American Health Organization and UNICEF accounts for roughly 5 percent of worldwide vaccine revenues. Presently, a relatively small share of the world’s vaccines is sold to developing-world nations. The public sector can provide both “push” and “pull” to enhance the productivity of vaccine research and production. A major push factor is the 27 World Human Vaccine Markets—Over 60 Products: Which Competitors Are Attacking Viruses? Frost & Sullivan, Inc., 1993.
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