7
Development of Vaccines

Vaccination within 3 to 4 days of exposure to smallpox is an important control strategy that prevents the disease or modifies its severity In addition to adequate supplies of vaccine, a large-scale outbreak would necessitate well defined plans for their rapid distribution and inoculation of those exposed to or at risk of exposure to variola virus.

The administration of live vaccinia vaccine made possible the global eradication of smallpox in the 1970s The clinical experience with vaccinia vaccine is vast, involving millions of recipients who were immunized over a period of many decades in all geographic areas of the world, often at times and locations in which health conditions were far from optimal [1]. Given this broad experience, variola virus is not needed in the maintenance of vaccine prevention capabilities. However, the most important concern related to vaccine prevention of smallpox is that the available supplies of vaccinia vaccine are limited and may be deteriorating because of prolonged storage. This situation must be addressed if the reemergence of smallpox is considered to be a risk or if laboratory research using live variola virus is to be continued.

The vaccinia vaccines made from virus isolates that were used so widely against smallpox in the past are accepted as being relatively safe and highly effective, as long as proper standards for their manufacture, storage, and delivery are maintained. The testing of new lots of vaccinia vaccine made using standard methods, or of well-characterized strains of vaccinia grown in tissue culture cells, would not require live variola virus. Although not of overriding concern, retention of live variola virus stocks would, however, permit corroborating assessments of the probable efficacy of new tissue culture vaccines, using laboratory assays to measure immune inhibition of variola replication or testing



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--> 7 Development of Vaccines Vaccination within 3 to 4 days of exposure to smallpox is an important control strategy that prevents the disease or modifies its severity In addition to adequate supplies of vaccine, a large-scale outbreak would necessitate well defined plans for their rapid distribution and inoculation of those exposed to or at risk of exposure to variola virus. The administration of live vaccinia vaccine made possible the global eradication of smallpox in the 1970s The clinical experience with vaccinia vaccine is vast, involving millions of recipients who were immunized over a period of many decades in all geographic areas of the world, often at times and locations in which health conditions were far from optimal [1]. Given this broad experience, variola virus is not needed in the maintenance of vaccine prevention capabilities. However, the most important concern related to vaccine prevention of smallpox is that the available supplies of vaccinia vaccine are limited and may be deteriorating because of prolonged storage. This situation must be addressed if the reemergence of smallpox is considered to be a risk or if laboratory research using live variola virus is to be continued. The vaccinia vaccines made from virus isolates that were used so widely against smallpox in the past are accepted as being relatively safe and highly effective, as long as proper standards for their manufacture, storage, and delivery are maintained. The testing of new lots of vaccinia vaccine made using standard methods, or of well-characterized strains of vaccinia grown in tissue culture cells, would not require live variola virus. Although not of overriding concern, retention of live variola virus stocks would, however, permit corroborating assessments of the probable efficacy of new tissue culture vaccines, using laboratory assays to measure immune inhibition of variola replication or testing

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--> against variola challenge in animal models not yet available. Moreover, the development of novel smallpox vaccines not incorporating live vaccinia might be undertaken in order to provide vaccines safe for use with immunocompromised individuals (see the discussion below). Variola virus would have to be available for the later phases of evaluation of any such novel vaccines before their clinical use could be considered. Current Status of Vaccinia Vaccine Preparations The commercial smallpox vaccine currently approved for use in the United States is a lyophilized preparation of live vaccinia virus prepared from calf lymph. The vaccine is made by inoculating animals with seed virus derived from the New York City Board of Health (NYCBH) strain of vaccinia [32]. Vaccinia vaccine made using this traditional process in animals can be evaluated for potency by demonstrating reactogenicity or ''take," defined by formation of the characteristic lesion at the site of inoculation by skin abrasion. These vaccines exhibit high seroconversion rates and infrequent adverse events. For every I million individuals inoculated, 75 experienced medical complications from the vaccine [1]. Possible complications include generalized vaccinia, which in persons without underlying illness is characterized by a vesicular rash of varying extent that generally is self-limiting and requires little or no therapy. Postvaccinal encephalitis is the most serious complication in otherwise healthy individuals. It generally affects infants less than 1 year old, and is associated with a mortality rate of about 25 percent and a risk of permanent neurologic consequences in about 25 percent of its survivors. Persons with eczema or exfoliative skin conditions may experience a disseminated or systemic infection (eczema vaccinatum). Finally, progressive vaccinia is a severe, potentially fatal illness that occurs almost exclusively among persons with cellular immunodeficiency. The HIV epidemic and the new immune-modulating drugs and therapies currently used to treat cancers and allow successful transplantation of organs and bone marrow have placed many people worldwide at risk of this complication. The limited experience with vaccinia vaccines in those with HIV infection (two military personnel inoculated before being identified as HIVpositive) suggests that use of the vaccine with those individuals is likely to produce disseminated vaccinia infection [33, 34]. The largest problem is likely to be in countries with substantial prevalence of HIV infection. Vaccinia immune globulin (VIG) is the only product developed for the treatment of complications of vaccinia vaccination. VIG is effective for the treatment of eczema vaccinatum and some cases of progressive vaccinia; it is of no benefit in the treatment of postvaccinal encephalitis. Wyeth Laboratories, currently the only licensed producer of vaccinia vaccine in the United States, discontinued distribution of smallpox vaccine to civil-

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--> ians in 1983 [35]. Since then, CDC has been the only nonmilitary source of the Wyeth vaccine and the only distributor of VIG. CDC maintains the vaccinia under contract with Wyeth, while Baxter-Highland Laboratories maintains VIG for the U.S. Department of Defense. In the past, CDC has maintained a supply of several million doses of vaccinia vaccine and the requisite VIG for treating complications. However, these supplies are now 17 to 20 years old and exhibit signs of loss of potency. Recently, some of the stored vaccinia diluent vaccine was found to be unusable. Without assessing the entire supply, it is not possible to know exactly how many usable doses are currently available. Replacing these vaccine doses is problematic because the cost of undertaking the manufacture of new lots of vaccine and completing the applications required to obtain government approval of these preparations is high enough to discourage commercial enterprises from doing so. Moreover, manufacture of new vaccine to augment current stocks would have to meet current standards of vaccine production and standardization, which might require adjustments in the production process. In addition, no VIG is currently available. The license on the available VIG expired in October 1998, and the U.S. Food and Drug Administration (FDA) did not grant an extension. The status of the VIG stock is pending final review by FDA and Baxter-Highland Laboratories in early 1999.* As noted above, the evaluation of new lots of live vaccinia vaccine would not require laboratory testing involving the use of live variola virus. During the history of smallpox vaccination, many different vaccinia isolates and several different animal hosts were used to manufacture vaccine. These diverse vaccines were effective against epidemiologically distinct variola viruses responsible for smallpox outbreaks that were separated by distance as well as time. In practice, however, testing of the reactogenicity of new lots of vaccinia, even if performed under standard conditions, requires access to VIG. The availability of VIG, which is made by immunizing healthy human donors with vaccinia vaccine, would enable a therapeutic intervention in the unlikely event of an adverse response. Thus the lack of VIG is a further obstacle to replenishing the vaccinia vaccine supply. Evaluation of Vaccinia Vaccine Derived from Tissue Culture In replacing the existing supplies of vaccinia vaccine or planning for a potential situation in which widespread vaccination might be required, one could make the vaccine by infecting tissue culture cells, rather than by inoculating animals. The current approach to the manufacture of most other live attenuated vaccines is based on growth of the vaccine virus in tissue culture cells that have *   John Becker, Personal communication, December 1998.

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--> been certified for production of human vaccines. Some limited evaluation of the safety and immunogenicity, or potency to produce immunity, of vaccinia vaccine made in tissue culture has been carried out in susceptible individuals in Japan [1]. Similar vaccines have been produced in Germany and The Netherlands, but vaccine preparations of this type have not been approved for use in the United States. Vaccinia vaccines made in tissue culture cells are closely related to those made in animals because the same virus stocks, such as the NYCBH strain, can be used. As noted earlier, given the predicted similarities between new and traditional vaccinia vaccines, the validation of new vaccines derived from tissue culture would not require the use of variola virus. Comparisons of genomic stability could be made to confirm the relationship of vaccinia derived after replication in these cells to the input virus and to vaccinia preparations made by inoculating animals. Molecular analyses of vaccines produced in this manner could be used to document the preservation of the expected vaccinia genotype by comparison with existing vaccinia vaccine stocks. The potency of vaccinia vaccines made in tissue culture cells could be assessed in human volunteers using the protocols for testing of reactogenicity and seroconversion that are used for standard vaccinia vaccines. Vaccines made in this way would be closely related to existing vaccines and could be evaluated using "bridging" studies. In such studies, the new vaccine is compared with the existing vaccine in small numbers of healthy susceptible individuals, using assays for vaccine reactogenicity or "take" and seroconversion that have served as markers of effective vaccinia vaccines in the past. These measures of equivalence between vaccines derived from tissue culture and traditional vaccines made in animals would not, however, constitute definitive proof of protective efficacy, which would have to be defined by field testing under conditions of natural exposure. No specific immunologic correlates of protection for vaccinia vaccines were defined during the smallpox era. Licensure of vaccinia vaccines derived from tissue culture would therefore require a departure from the usual criteria for regulatory approval. Nevertheless, there would be a high degree of confidence in predictions of efficacy based on direct comparison of the vaccines thus derived and existing vaccine with regard to local reactogenicity and immunogenicity. This judgment is based on the fact that limited passage of vaccinia in tissue culture cells would not be likely to cause further attenuation, and preservation of the capacity of the vaccine strain to replicate in vivo could be documented by the expected lesion formation after abrasive inoculation. It should be noted that use of an alternative route of inoculation, such as subcutaneous injection, would eliminate the latter important correlate of potency and hamper the judgment of vaccine equivalence. As suggested above, although it is not an overriding concern, retention of live variola virus would permit complementary or corroborating assessments of the probable efficacy of new vaccines derived from tissue culture, using laboratory assays to measure immune inhibition of variola replication or

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--> testing against variola challenge in animal models (assuming suitable animal models became available). Evaluation of Novel Vaccines As noted earlier, clinical experience with vaccinia vaccines demonstrates that assessment of the level of viral attenuation measured in animals is not sufficient to prevent the occurrence of disseminated vaccinia in some individuals with compromised immune responses [32]. Thus novel vaccines might be developed to provide safe vaccination of these populations. Manufacturing the vaccine in tissue culture would not be expected to alter the risks of vaccinating immunocompromised individuals. To ensure safety, it would be necessary to develop vaccines that contained no live vaccinia virus or were made from vaccinia strains that had been changed genetically to block their ability to spread after inoculation. Options include subunit protein vaccines, DNA vaccines, synthesis of noninfectious particles, and others. Laboratory and animal testing in yet-to-be-devised systems would also be necessary. Scientifically, the task of developing novel vaccines that would be safe and effective against smallpox in immunocompromised patients would not be straightforward. A priori, it can be predicted to be an extremely costly effort, requiring years to accomplish. In fact, development of such vaccines may not be feasible because the varied immune deficiencies of different patients at risk may prevent an adequate response to any generic candidate vaccine. During the smallpox era, several highly attenuated strains of vaccinia virus were obtained by passage in tissue culture, and it is known that repeatedly growing vaccinia in minced chick embryo cells reduces the virulence of the virus in subsequent generations [1]. However, the genetic basis for this attenuation of virulence is not known, and whether these strains are safe or effective as vaccines for individuals who have abnormal immune systems is uncertain. The efficacy of any vaccine that was substantially changed in design could not be established by direct comparison with traditional vaccinia vaccines without more complete understanding of protection against variola immunopathogenesis. Confidence in the efficacy of different preparations of live vaccinia vaccines is based on the fact that these vaccines contain the complete virus, and the virus causes a limited infection in the vaccinated person. As a result, the immune system becomes sensitized to many viral proteins, and many memory B cells and T cells that can recognize cognate smallpox virus antigens are generated. Novel vaccines that departed from this design could not be judged for potency based on the criterion of reactogenicity at the inoculation site or by genetic comparison with vaccinia, and there are no known specific immunologic correlates of protection against smallpox. Much of the initial work toward developing new smallpox vaccines could be done without the use of variola virus. For example, persons given candidate

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--> novel vaccines could be evaluated using assays demonstrating the induction of immunity. Variola proteins expressed from plasmids or in other vectors could be used to detect variola-specific immunity, such as neutralizing antibodies or other viral proteins, or recognition of variola proteins by T cells that mediate cytotoxicity and antigen-specific cytokine release. Nevertheless, confirmatory assessment of the induction of functional protective immunity would require testing using variola virus, and the margin of confidence in the probable efficacy of such vaccines would be enhanced by studies of challenge by variola virus in animal models yet to be developed. Despite the major obstacles involved, the design of novel vaccines is scientifically feasible, and may constitute a rationale for preserving variola stocks for future use in such an endeavor. From a public health perspective, however, circumstances that would require vaccination of immunocompromised persons might never arise. If an early, limited outbreak were to be detected, it should be possible to protect these individuals and keep them from becoming new source cases by vaccinating a large enough portion of the population to prevent spread of the infection to those who could not be immunized safely. Should a very large-scale, contemporaneous exposure occur, protective isolation would be the only alternative to vaccination. If large numbers of people were placed at risk, protective isolation would not be a practical strategy, and a noninfectious vaccine would be valuable. On the other hand, one can envision an exposure situation evolving so rapidly that immunocompromised patients within the population at large could not be identified and excluded from the vaccine campaign in a timely manner. It is important to recognize that under these conditions, the availability of a novel vaccine safe for high-risk patients would have limited practical benefit.