The US NIAID-supported HIV Vaccine Clinical Trials Network HVTN

1. The US NIAID-supported HIV Vaccine Clinical Trials Network (HVTN)

2. Global partners in HIV vaccine clinical research US NIH / NIAID / DAIDS HIV Vaccine Trials Network (HVTN) US Military HIV Research Program (USMHRP) Uganda, Kenya, Tanzania, Cameroon, Nigeria, Thailand, Viet Nam NIAID Vaccine Research Center (VRC) Center for HIV/AIDS Vaccine Immunology (CHAVI) US Centers for Disease Control and Prevention (CDC) International AIDS Vaccine Initiative (IAVI) Europe, Kenya, Uganda, Rwanda, Tanzania, South Africa, NYC, Rochester European Union EuroVacc AIDS Vaccine Integrated Program (AVIP) South African AIDS Vaccine Initiative (SAAVI) African AIDS Vaccine Programme (AAVP) Pharmaceutical industry: Merck Vaccines, Wyeth Vaccines

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4. HVTN Organization

5. HVTN Clinical Research Sites

6. HVTN Laboratory Program:oversight for ~81 HVTN-affiliated labs

7. Validated T-cell Immunogenicity assays IFN-? ELISpot Intracellular Cytokine Staining (ICS) for IFN-? and IL-2 TNF-a & others pending validation Global PTE (Potential T cell Epitope): A panel of 15-mer peptides whose sequences span all possible 10 a.a. T cell epitopes in HIV that occur at a frequency of >15%. This includes all the circulating strains annotated in the Los Alamos Database (~100-150 per subtype) Env, Gag and Pol require multiple pools in order to limit the total number of peptides in any one pool (160 peptides per pool, 9 pools) E.g., Env1, Env2, and Env3 Can be viewed as a reflection of circulating HIV-1 strains (tracks well with �transmitted strains� in the database) PBMC Cryopreservation: all within 8 hours of venipuncture on-site

8. Clinical Trials ofPreventive HIV Vaccines, 1988-2005*

9. HVTN Activity in 2006-2007 18 protocols in progress; > 3,400 participants enrolled 7 trials opened for enrollment DNA + MVA (HVTN 067) DNA + Ad5 or Ad35 (HVTN 069, 072*) DNA with IL-12, IL-15 (HVTN 070) Ad5 alone (HVTN 071*, 503* Phambili) 8 completed enrollment MVA + FPV (HVTN�055) DNA + MVA (HVTN 065) DNA with IL-12, IL-15 (HVTN 060, 063) DNA + Ad5 (HVTN 068, 204) DNA + rT-help polypeptide (HVTN 064) Ad5 alone (HVTN 502 Step Study) * 3 halted enrollment after Step Study results

11. HVTN 502 (STEP Study): MRKAd5 trivalent clade B HIV vaccine Gag, Pol, and Nef are major targets of the T cell response in HIV-1-infected patients Highly conserved across clades at the amino acid level 80-85% gag 80-85% nef >90% pol Gag, pol, nef are major targets of T cell response in HIV+ Highly conserved across clades at aa level: gag 80-85%, nef 80-85%, pol >90%Gag, Pol, and Nef are major targets of the T cell response in HIV-1-infected patients Highly conserved across clades at the amino acid level 80-85% gag 80-85% nef >90% pol Gag, pol, nef are major targets of T cell response in HIV+ Highly conserved across clades at aa level: gag 80-85%, nef 80-85%, pol >90%

12. HVTN 502: STEP Study design MRK Ad5-HIV (gag, pol and nef) at 1010 PU administered IM at 0, 1 and 6 months Half received vaccine and half received placebo (salt water) Initial trial design: 1500 HIV-seroneg ppts with low (<200) Ad5 titers Trial modified in July 2005 to add 1500 individuals with high (>200) Ad5 titers Enrollment stratified by Ad5 titer; <18, 18-200, 201-1000, >1000 Study volunteers counseled regularly to avoid HIV infection and tested for HIV every 6 months Primary study objectives: Among study participants with low Ad5 titers, vaccinees will have a lower likelihood of acquiring HIV infection, and/or Among study participants with low Ad5 titers who become HIV infected, vaccinees will have a smaller average viral load set point. Among study participants with low Ad5 titers, vaccine will be safe and well tolerated.

13. Estimated Relative Risk of HIV Infection Vaccine : Placebo(95% CI)

14. STEP Study Summary Test of concept provided definitive results 33 months after first participant enrolled Vaccine neither prevented infection nor lowered viral setpoint Greater number of infections in vaccine than placebo recipients This trend appeared to be concentrated in Ad5 seropositive strata (randomization w/i strata)

15. Summary (cont.) Multivariate analyses reaffirm the trend toward an overall increase in HIV infection risk in vaccine vs. placebo recipients [estimated hazard ratio (HR) 1.6 to 2.0] Increased risk of HIV infection is most evident in uncircumcised men with pre-existing Ad5 immunity [estimated vaccine HRs 4.2 to 4.8]. In contrast, no evidence of an increased risk in circumcised men without pre-existing Ad5 immunity [estimated vaccine HRs 0.6 to 0.8]. Uncertainty about whether there is increased risk if either/or Ad5 seropositive or uncircumcised (one but not both risk factors) Updated information was presented on Tues Feb 5th at CROI 2008 in Boston see webcast at www.retroconference.org/2008 follow ongoing information as it becomes available at www.hvtn.org

16. Future directions and hypotheses Awaiting data on HSV-2 status, HLA typing, sexual network clustering, and possibility of unblinding Additional multivariate analyses will be performed Possible mechanisms for potential increased HIV acquisition is being explored in laboratory studies Studies in vaccine recipients and non-human primates Data being considered in developing protocols with other Ad5 vectored approaches

17. Timeline for the development of an effective HIV-1 vaccine highlighting the process and noting the key times for the next series of Phase III efficacy trials This work is highly leveraged through CRADAs and our relationship with the NIH The essential milestones are noted with each product noting the critical immunologic milestones required to move forward with full advanced development. Safety is also necessary as we progress forward The key Thai trial is noted in the green box and will be launched next month You could then mention the 3rd and 4th generation products underdevelopment The VRC DNA prime and adeno virus boost vaccine for which we are preparing sites in Africa 4th generation products are being designed by the program and endorsed by NIH to include MVA (modified vaccinia vectored vaccines and new strategies using the modified lethal factor of anthrax to induce cellular and humoral immunity to the HIV-1 structure proteins. Ie the LF is being used as a unique adjuvantTimeline for the development of an effective HIV-1 vaccine highlighting the process and noting the key times for the next series of Phase III efficacy trials This work is highly leveraged through CRADAs and our relationship with the NIH The essential milestones are noted with each product noting the critical immunologic milestones required to move forward with full advanced development. Safety is also necessary as we progress forward The key Thai trial is noted in the green box and will be launched next month You could then mention the 3rd and 4th generation products underdevelopment The VRC DNA prime and adeno virus boost vaccine for which we are preparing sites in Africa 4th generation products are being designed by the program and endorsed by NIH to include MVA (modified vaccinia vectored vaccines and new strategies using the modified lethal factor of anthrax to induce cellular and humoral immunity to the HIV-1 structure proteins. Ie the LF is being used as a unique adjuvant

19. Conclusions The preventive HIV vaccine field is at a cross-roads. Clinical research has much to offer through an iterative approach coordinated with work in animal models. Discovery of better immunogens (especially those that can induce broadly neutralizing antibody to transmitted isolates) and a better understanding of the precise events of HIV transmission is essential. NIH �HIV Vaccine Summit� will take place on Tuesday March 25, 2008 in Rockville, MD HVTN is committed to continue to conduct collaborative clinical research in the spirit of the Global HIV Vaccine Enterprise

21. Points to consider: CHVI clinical trials program development Establish a balance between early phase research (phase I/IIA) and efficacy trial capabilities (phase IIB/III) Relationship between non-human primate research program and the clinical research program Challenge of working with mucosal specimens Community engagement/acceptance is critical and requires considerable attention