CBER Perspective

1. CBER Perspective VRBPAC Meeting, November 16, 2010

2. Implementation of the Animal Rule • To fulfill the fourth criterion of the Animal Rule, the combination of animal protection data and human immunogenicity data need to assure us that the vaccine dose given to humans is reasonably likely to provide clinical benefit • How should animal protection data be bridged to humans for the post-exposure prophylaxis indication?

3. Post-exposure Prophylaxis (PEP) Indication • For the prevention of disease caused by residual B. anthracis spores in exposed individuals who have received a full course of antibiotics

4. What immune marker should be used to link animal protection data to humans for PA-based anthrax vaccines?

5. Antibodies as a Correlate of Protection • Data from NIH and CDC studies have shown: • Antibody levels correlate with protection in animal studies • Antibodies alone, in the absence of other facets of the immune system, can protect • Therefore, CBER believes that antibodies would be an appropriate immune marker to link animal protection data to human efficacy

6. How should protective antibody levels be determined?

7. Animal Study Design • GUP (general use prophylaxis) design: • Immunize animals • Challenge animals • Determine protection afforded by the vaccine against B. anthracis • PEP (post-exposure prophylaxis) design: • Challenge animals • Initiate antibiotics and immunize animals • Terminate antibiotics after 7 days • Determine protection afforded by the vaccine in the face of exposure to B. anthracis • Passive immunization design: • Animals administered antitoxin antibodies • Challenge animals • Determine protection afforded by the antibodies

8. Animal Study Designs: Chronology of Vaccine Response and Exposure • GUP: Exposure to spores is delayed until the immune response to vaccine has developed • PEP: “Exposure” to vegetative bacteria is delayed until the immune response to vaccine has developed • Passive: Exposure to spores is delayed until antibody is present

9. Determining and Extrapolating Protective Antibody Levels • All three study designs provide useful information regarding vaccine protection and the role of antibodies in protection • For a post-exposure prophylaxis indication, which study design(s) should be used to estimate protective antibody levels? • Estimating protective levels using GUP data is relatively straightforward. Is infection in humans caused by spores that remain after a full course of antibiotics fundamentally a GUP scenario? • Complexities exist that limit the usefulness of the PEP and passive immunization study designs in estimating protective antibody levels and extrapolating those levels to humans

10. Bridging Using GUP Study Design • Immunize animals and measure immune response at relevant time points (e.g., peak titer, immediately before challenge) • Challenge animals with B. anthracis • Assess survival

11. Estimating Protective Antibody Levels: GUP studies • Determine the • relationship between • antibody levels and • survival

12. Extrapolating Protective Antibody Levels: GUP studies • Determine the population • distribution of antibody titers • in the human study • population

13. Extrapolating Protective Antibody Levels: GUP studies • Link data sets using an antibody • bridge • Extrapolate animal protection data • to humans • (Extrapolation should be made using antibody • levels assessed at relevant and comparable time • points in both animals and humans, e.g., • compare peak response of animals to peak • response of humans.) • Assess whether the vaccine is • reasonably likely to provide clinical • benefit

14. Design of Pivotal Clinical Studies using GUP Data • Immunogenicity endpoints in pivotal clinical trials • would be based on protective levels that might be • expressed either as: • Threshold value (e.g., the proportion of subjects achieving the antibody level that protected a certain percentage of animals) • “Predicted vaccine efficacy” f(x)=Prob (death|x) g(x)=Pr distrib of x where x=immune response Prob (death in pop.) = ∫f(x)g(x)dx = avg. prob death or p* If prob death in unvaccinated = 1.0 then VE= 100(1-p*) (from Kohberger, 2007)

15. PEP Study Design • Challenge animals • Treat with antibiotics and administer vaccine as appropriate • Group 1 antibiotics only • Group 2 antibiotics + vaccine • Group 3 no antibiotics, no vaccine • After minimal amount of time needed for the vaccine to elicit an immune response, antibiotic treatment is terminated • Assess protection afforded by the vaccine

16. Survival Data from Three NIAID Rabbit PEP studies (pooled data)

17. Estimating Protective Antibody Levels: PEP Studies Ideal situation: Estimate protective antibody levels in animals Compare these levels to those achieved by humans receiving vaccine administered on the schedule intended for post-exposure prophylaxis Assess whether the vaccine is reasonably likely to provide clinical benefit However, estimation of protective antibody levels from the PEP model is more complex than with the GUP model

18. Complexities in Estimating Protective Levels: PEP Studies • PEP model is a dynamic situation in which antibody levels are rapidly increasing rapidly during the time period that deaths • occur • What is the appropriate time point to estimate protective antibody levels in animals? Day 7? (i.e., day that antibiotics discontinued) • Likely to underestimate protective levels • At peak or on day of last death in antibiotics-only control group (day 28)? • May significantly overestimate protective levels

19. Complexities in Estimating Protective Levels: PEP Studies • 2. Technical limitations require that the animals receive antibiotics and vaccine on schedules that differ substantially from the human schedules • What would be the relevant and comparable time point to assess antibody levels in humans?

20. Complexities in Estimating Protective Levels: PEP Studies • Estimates for protective levels are influence by the method used to impute missing antibody levels (e.g., those for animals that • died previous to the day protective levels are estimated) Adds uncertainty to protective level estimates

21. Complexities in Estimating Protective Levels: PEP Studies • 4. Antibody response may be influenced by infection • Evidence from studies using PEP design indicates that the antibody concentrations can be higher in animals that receive vaccine and challenge than those that receive vaccine only • May result in overestimation of protective antibody levels

22. Estimation of Protective Antibody Levels • Estimation of protective antibody levels using data from PEP studies would be associated with a high degree of uncertainty (may either significantly underestimate or overestimate)

23. Passive Immunization Studies • Data in the literature indicate that anti-PA antibodies can protect animals (rabbits and guinea pigs) against challenge with B. anthracis suggesting that antibodies play a role in protection • NIH and CDC studies demonstrate that human antitoxin antibodies provide protection against exposure to B. anthracis • Ideal situation: Use passive immunization study design to directly assess human antibody levels that protect animals from challenge

24. Passive Immunization to Estimate Protective Antibody Levels: Complexities Passive immunization study design represents a dynamic situation with antibody levels declining rapidly during the critical time period between challenge (day 1) and day the last death occurred (day 7) What is the appropriate time point to estimate protective antibody levels in animals?

25. Passive Immunization to Estimate Protective Antibody Levels: Complexities Circulating antibody levels at the time of challenge do not appear to be the sole mechanism of protection afforded by active immunization

26. Passive Immunization to Estimate Protective Antibody Levels: Complexities Circulating antibody levels at the time of challenge do not appear to be the sole mechanism of protection afforded by active immunization; the anamnestic response of vaccinated animals upon exposure may contribute to protection. Passive immunization studies may significantly overestimate antibody levels needed for protection after active vaccination

27. Proposed Strategy for Bridging Animal Protection Data to Humans for PA-Based Anthrax Vaccines for a PEP Indication • Conduct appropriately designed GUP studies. Data from these studies would be used to: • Estimate protective antibody levels in animals • Extrapolate animal protection to humans via an antibody bridge • Used as a basis for defining clinical immunogenicity endpoints • Animal PEP studies would serve as a proof-of-concept that the vaccine can protect in a post-exposure setting in which an individual has been exposed. These studies would be considered supportive, but would not be used to estimate protective antibody levels • Passive immunization studies serve as a proof-of-concept that antibodies generated by PA-based vaccines provide protection against exposure. These studies would be considered supportive, but would not be used to estimate protective antibody levels

28. Discussion Point • Please discuss whether CBER’s proposed strategy • would adequately bridge animal protection data to • humans to support a post-exposure prophylaxis • indication for a PA-based anthrax vaccine. Post-exposure prophylaxis indication: For the prevention of disease caused by residual B. anthracis spores in exposed individuals who have received a full course of antibiotics