power, it is unlikely that the study will be able to determine other potential risk factors for any differences in immune response to AVA. Larger numbers of participants would be needed to account simultaneously for age and other immune effectors such as illness or nutritional status. The role of immune memory in protection is not likely to be sufficiently addressed by the B-cell studies planned, which focus unnecessarily on cellular as opposed to humoral factors. Finally, the proposed studies will not fully answer the question of which components of AVA contribute most significantly to protection because there is no plan to evaluate individual components in AVA; the protective effects of AVA are known to be due primarily to an immune response to protective antigen (PA). 2

BOX 4-1 CDC Objectives for Research on the Efficacy of the Anthrax Vaccine

  1. Assess AVA efficacy in humans immunized with AVA by measuring immune responses identified as protective in efficacy objective B (animal studies). Immune markers of protection will be evaluated by varying the number of priming shots and the route of administration.

  2. Assess AVA efficacy in animals immunized with serial dilutions of AVA and challenged with live, inhaled anthrax spores.

  3. Use blood samples from the subjects in the clinical trial and in animal studies to identify immune correlates of protection and validate laboratory studies to measure them.

SOURCE: CDC, 2002e, p. 10.

BOX 4-2 Critical Research Questions Regarding the Efficacy of the Anthrax Vaccine, as Identified by CDC

  • What are the correlates for protection against inhalational anthrax?

  • When is protection achieved, and how long does it last?

  • Are enzyme-linked immunosorbent assay (ELISA) and toxin neutralizing antibody assay (TNA) the most appropriate measurements of immune response to AVA?

  • How does gender affect immune response to AVA?

  • What are important risk factors for lowered immune response to AVA?

  • How can we bridge from animal challenge data to predict likelihood of survival in AVA-vaccinated humans?

  • What is the role of circulating antibody in protection?

  • What is the role of immune memory in protection?

  • What is the antigenic make-up in the AVA lots used for CDC studies?

  • What is the quantity of PA [protective antigen] in the AVA lots used for CDC studies?

  • Which components of AVA contribute most significantly to protection against anthrax?

  • What is the basis, if any, for the current series and can that series be reduced to a more practical number?

  • Is the vaccine equally efficacious or immunogenic when administered intramuscularly?

  • What level of circulating antibody protects an unvaccinated macaque from anthrax?

SOURCE: CDC, 2002f.

2  

Efficacy studies in laboratory animals have indicated that PA must be present in a cell-free anthrax vaccine or produced by a live vaccine to achieve protection (Ivins et al., 1986, 1992, 1998; discussed in IOM 2002).



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