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Vaccines, Blood & Biologics

Regulatory Requirements for Historical and New Smallpox Vaccines

Regulatory Requirements for Historical and New Smallpox Vaccines
G7+ Workshop, Langen, Germany, September 5-6, 2002
Karen Midthun, M.D.
Director, Office of Vaccines Research and Review
Center for Biologics Research and Review
U.S. Food and Drug Administration

The historical smallpox vaccines used in the global eradication of smallpox were for the most part prepared on the skin of calves or other animals or in chicken eggs. Although these vaccines were not evaluated for efficacy in well-controlled trials, they were highly effective, as evidenced by the successful global eradication of smallpox (1). The U.S. regulatory requirements for these vaccines addressed the characterization of the seed virus, the production process in calves or embryonated chicken eggs, and the testing process (e.g., potency, bioburden, preservative, etc.). At present, the only smallpox vaccine licensed in the U.S. is a so-called historical vaccine, Wyeth's Dryvax. It was derived from the New York City Board of Health (NYCBH) strain of vaccinia, prepared on calf skin, and stored as a lyophilized product. Dryvax is no longer being manufactured, and remaining supplies are limited.

Second generation smallpox vaccines currently under development also are derived from the NYCBH strain, but are produced in cell substrates (e.g., MRC-5, VERO). Characterization and qualification of the master and working cell banks (e.g., adventitious agent testing, tumorigenicity) and of the master and working viral seeds (e.g., adventitious agent testing, comparability to licensed vaccine, including animal studies) are essential requirements, together with other common principles of production and quality control, such as detailed manufacturing procedures that ensure consistency of manufacture, defined compatible components, product characterization and specifications, source of materials, and stability (2). The standards for licensure of new smallpox vaccines are the same as for any product and require the demonstration of safety, purity, potency, efficacy, manufacturing reproducibility, and compliance with current good manufacturing practice.

The means whereby efficacy of new smallpox vaccines will be demonstrated requires careful consideration, because in the absence of disease, field trials cannot be conducted; also human challenge studies cannot be conducted ethically. However, numerous epidemiological studies have shown that protection against smallpox was correlated with the presence of a vaccination scar (3-8), which resulted from the classic Jennerian vesicle or so-called "vaccine take" induced by historical smallpox vaccines (e.g., Wyeth's Dryvax) used in the smallpox eradication efforts. Thus, for second-generation smallpox vaccines derived from the NYCBH strain or other strains that have been demonstrated to have field efficacy, efficacy will be based on clinical studies in which the new vaccine is compared with DryvaxÒ with regard to "take" rates and immunologic responses such as neutralizing antibody (9). Stringent animal models of efficacy will not be required for these types of vaccines. Human safety data will have to be collected and evaluated to support licensure.

Because second generation vaccines may cause serious adverse reactions similar to historical vaccines, there is a desire to develop safer vaccines that may be targeted toward populations for whom the second-generation vaccines are contraindicated or present an increased risk of adverse reactions. However, evaluation of third generation vaccines derived from strains with no previous demonstration of efficacy (e.g., Modified Vaccinia Ankara) is complex and will likely depend on a new final rule that allows the use of animal efficacy data in lieu of human efficacy data when scientifically appropriate (10). This rule specifically pertains to drugs and biologicals intended to reduce or prevent serious or life-threatening conditions caused by lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances and where human efficacy trials are not feasible or ethical. In these circumstances, efficacy can be based on adequate and well-controlled animal trials if the results establish that the product is reasonably likely to provide clinical benefit to humans. Safety and pharmacokinetic data in humans are also necessary. The rule further notes that animal studies can be used to support efficacy in humans when the pathophysiological mechanism for toxicity and its prevention by the product are well understood; the effect is demonstrated in more than one animal species that is expected to react with a response predictive for humans (single species acceptable in certain circumstances); the animal endpoint is clearly related to desired benefit in humans; and the data on pharmacokinetics and pharmacodynamics of the product in animals and humans are sufficiently well understood to allow selection of an effective dose in humans.

With regard to the clinical evaluation of smallpox vaccines derived from strains with no previous demonstration of field efficacy, the following factors should be considered. There is no well-established non-human primate model with variola, in that the challenge model of variola in monkeys requires high doses of variola and results in an accelerated infection not similar to smallpox in humans. However, a monkeypox challenge in non-human primates, in conjunction with a second animal model, and supporting in vitro studies (e.g., neutralization of variola with sera from vaccinated humans) may provide the basis for efficacy. The case will have to be made that animal models using non-variola orthopox challenges are relevant to efficacy of the vaccine against smallpox in humans. Human immune response data will be important, and human safety data will also be needed.

In conclusion, historical smallpox vaccines (e.g., grown on calf skin) are no longer manufactured in the U.S. To date, new smallpox vaccines intended for U.S. licensure are cell-substrate based. The efficacy of new vaccines derived from strains with demonstrated efficacy in the field (so-called second generation vaccines) will be based on comparison of take rates and immune responses with the licensed historical smallpox vaccine (Dryvax) in randomized, blinded clinical studies. The efficacy of new vaccines derived from strains without demonstrated efficacy in the field can be based on animal efficacy data, if scientifically appropriate, in addition to comparative human immune response data. As for any biologic, licensure of new smallpox vaccines requires demonstration of safety, efficacy, and quality and consistency of manufacture.


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  2. FDA Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information for a Vaccine or Related Product, 1999.
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  8. C.C.A. de Quadros, L. Morris, E. Azeredo da Costa, N. Arnt, C.H. Tigre. Epidemiology of variola minor in Brazil based on a study of 33 outbreaks. Bulletin of the World Health Organization 1972; 46:165-171.
  9. S.R. Rosenthal, M. Merchlinsky, C. Kleppinger, K.L. Goldenthal. Developing new smallpox vaccines. Emerging Infectious Diseases 2001; 7:920-926.
  10. New drug and biological products; evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible. Federal Register 2002; 67:37988-37998

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