1. Avian and Pandemic Influenza Vaccine Development John Treanor Professor of Medicine University of Rochester Medical Center Rochester, NY

2. Options for Pandemic Vaccines Inactivated vaccine resembling currently licensed inactivated vaccine Live vaccine resembling currently licensed live vaccine Inactivated vaccines with experimental adjuvants/route of administration Experimental approaches

3. Inactivated Vaccine Approach Proven technology –Used successfully in 1957 and 1968 –Efficacy data exist for both pandemic and interpandemic years –Large experience with clinical use Largest existing manufacturing capacity Licensing would be relatively straight-forward

4. Inactivated Vaccine Approach Unlikely to induce mucosal immunity Protection may be strain specific Requires multiple doses Manufacturing capacity limited by availability of eggs and capacity for expansion limited

5. Evaluation of Unadjuvanted Inactivated H5 Influenza Vaccines Avoid cleavage –Duck Singapore/97 (H5N3) –Recombinant, baculovirus-expressed HA of A/Hong Kong/156/97 (rH5) –Subvirion rgA/Vietnam/1203/04 vaccine (H5N1)

6. Egg-grown Duck/Singapore Nicholson, et al. Lancet. 2001;357:1937. Study day H5N3 Neutralization GMT

7. Recombinant rHA H5 Vaccine Insect cell expressing rHA RBCs Purified rHA H5 SDS-PAGE

8. Neutralization Titers Against A/Hong Kong/156/97 Log2 titer Treanor. Vaccine. 2001;19:1732. Vaccine administered at visit S1 and S3

9. Response Rates Following One or Two Doses of rHA H5 Vaccine Percent responding* *4-fold or greater increase to a titter of 1:80 with positive WB. Treanor. Vaccine. 2001;19:1732.

10. Evaluation of rgA/Vietnam/1203/04 (H5N1) Subvirion Vaccine (DMID 04-063) Subjects: Healthy adults ages 18 to 64 Design: Prospective, randomized, double blind Interventions: Two IM doses H5 vaccine separated by 28 days –Placebo, 7.5 mcg, 15 mcg, 45 mcg, 90 mcg –1:2:2:2:2 randomization Endpoints –Safety: solicited and unsolicited AEs –Immunogenicity: neutralizing titer of 1:40

11. DMID 04-063: Preliminary Results Vaccine was well tolerated at all doses Dose related local pain and tenderness Some neutralizing responses seen at all doses Best responses seen at highest doses – only 45 mcg and 90 mcg gave “acceptable” responses Results are very consistent with previous evaluation of rHA H5 vaccine

12. Strategies to Overcome Poor Responsiveness Booster strategies – include vaccine in annual vaccination, prime population Adjuvant strategies – add adjuvants with dose sparing potential Alternative routes of administration strategies

13. Strategies to Overcome Poor Responsiveness Booster strategies – include vaccine in annual vaccination, prime population Adjuvant strategies – add adjuvants with dose sparing potential Alternative routes of administration strategies

14. Age had a Dramatic Effect on the Serum HAI Response to Whole Viron (WV) or Subunit (SU) H9N2 Vaccines Age < 35 yr Age> 35 yr WVSU Stephenson. Lancet. 2003;362:1959.

15. H1N1 H2N2 H3N2 Effect of H2N2 Exposure on H9N2 Neutralizing Antibody Year of birth Stephenson. Lancet. 2003;362:1959. Pre-vaccine MN antibody titer

16. Reimmunization with Duck/Singapore Microneutralization GMT Stephenson et al. Vaccine. 2003;21:1687.

17. Booster Strategies DMID 05-043: Boosting of subjects who have previously received rH5 with rgA/VN/1203/04 DMID 05-090: Boosting subjects in 04-063 with a third dose at 6 months Proposed: interaction studies with TIV

18. Strategies to Overcome Poor Responsiveness Booster strategies – include vaccine in annual vaccination, prime population Adjuvant strategies – add adjuvants with dose sparing potential Alternative routes of administration strategies

19. Evaluation of Whole Virus H2N2 Vaccine with Alum Study Day GMT HAI Antibody Hehme. et al. Med Microbiol Immunol. 2002;191:203. Virus Res. 2004;103:163.

20. Evaluation of Whole Virus H9N2 Vaccine with Alum Study Day GMT HAI Antibody Hehme et al. Med Microbiol Immunol. 2002;191:203. Virus Res. 2004;103:163.

21. Significant Enhancement of the Response to H5N3 Virus with MF59 Nicholson et al. Lancet. 2001;357:1937. No adjuvant MF59 adjuvant Study day H5N3 Neutralization GMT 7.5 ug HA 15 ug HA 30 ug HA

22. Adjuvant Strategies Alum –H5 formulation – 30 mcg dose met EMEA criteria –H1, H3 vaccines – little enhancement seen in either pandemic or non-pandemic setting –Study – DMID 05-0127 dose ranging H5 on constant alum in healthy adults MF59 –Modest enhancement with TIV –Promising results with H5 vaccines, no obvious dose-response relationship, ? Stochiometry –DMID 04-019: significant enhancement of H9 response –Issues: availablility, intellectual property Others: MPL, CPG

23. Strategies to Overcome Poor Responsiveness Booster strategies – include vaccine in annual vaccination, prime population Adjuvant strategies – add adjuvants with dose sparing potential Alternative routes of administration strategies

24. Intradermal Vaccination: Post Vaccination GMT and Response Rate (%) GMT post vaccination HI antibody 18-60 yo> 60 433233354327261839162618 % response 15 mcg IM vs 6 mcg ID

25. Evaluation of Live Attenuated Vaccines (CAIV) H9 and H5 candidates generated, in clinical trials Highly immunogenic in susceptible populations –Critical need to define correlates of immunity Potential use of low doses –Studies should evaluate full range Induction of mucosal immunity might reduce transmission –Development of challenge models

26. Evaluation of Live Attenuated Vaccines (CAIV) Potential cross protection –Evaluate responses to range of antigenic variants Not licensed in all populations –Critical need to expand safety database –Define correlates of immunity that could be extended to elderly Concerns regarding transmission and reassortment –Clearly define conditions of deployment, expected shedding patterns, and biologic behavior of reassortants

27. Experimental Approaches Nasal inactivated vaccines Cross protective peptides/epitopes Virus-like particles Alternative live vaccines Vectored approaches DNA Vaccines

28. Considerations for Alternate Approaches Validation in clinical studies Extensive safety evaluation Specific markers of efficacy Individualized development strategy Need for early determination of potential advantages against conventional approaches

29. Critical Issues Is the H5 HA intrinsically less immunogenic? –Mechanism unclear Can cross-protective immune responses be generated? –M2 based immunity –Cross protective epitopes –CTL approaches