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1 愛滋病毒疫苗中華民國防疫學會王任賢理事長

4 HIV Prevention Landscape Behavioral modification and proven interventions Drugs for prevention pmtct Treatment of discordant (+) partner Post-exposure prophylaxis (PEP) Pre-exposure prophylaxis (PrEP) Microbicides Male circumcision Treatment/prevention of genital ulcer disease Especially HSV-2 Vaccine

17 PAVE 100: VRC Candidate HIV Vaccine Months CMV-R promoter Env A Env B Env C gag B pol B nef B rad5 Env A Env B Env C gag/pol B

19 Differences in VRC and Merck Clinical Products VRC Months Only one constituent, rad5 Gag-Pol (no Nef), partially related to Merck product Merck Months

20 Distinctions Between VRC and Merck AIDS Vaccines Feature VRC Merck Delivery: DNA/DNA/DNA/rAd rad/rad/rad Immunogens: Env A, Env B, Env. C Gag, Pol, Nef Gag, Pol, Nef, Gag-Pol Related Components: 1/10 3/3 Homologous boost: DNA rad Heterologous boost: DNA/rAd none Study population: Primarily heterosexual Primarily MSM +MSM/IDU +heterosexual/idu Immune Function CD4 Increased diversity low CD4 CD8 Increased magnitude yes IgG High titer with boost minimal SIV Protection Model: Survival None

23 PAVE 100 Protocol Purpose To test the concept that the VRC multiclade, multigene DNA prime/rad5 vector boost preventive vaccine approach provides efficacy in preventing HIV acquisition or modulating viremia (and disease progression) once HIV infected Phase IIB, international, multicenter, randomized, blinded, placebo-controlled Event driven: 180 endpoints will provide 90% power for detecting VE of 0.42 for acquisition endpoint VE of 0.4 log 10 difference for viremic endpoint Hope to open study in North America in TBD- possibly JAN 08

24 PAVE 100: Study Population 8500 healthy, HIV-uninfected males and females, ages years, at risk for HIV-1 infection through sexual exposure, from three regions of the world with circulating A, B and C subtypes Region (Countries) (Partner Organizations) Americas (US, Haiti, Dom Republic, Jamaica, Brazil, Peru) (HTVN) Southern Africa (South Africa, Zambia) (HVTN, IAVI) Eastern Africa (Kenya, Rwanda, Tanzania, Uganda) (USMHRP, IAVI, CDC) Predominant Subtype in Region Planned Regional Accrual (Partner Org Accrual) Projected Incidence B % C A, C, D (varies locally) 2500 (2300, 200) 3000 (2100, 400, 500) 3.0% 2.0%

25 HIV Vaccine Efficacy Trials: Primary Endpoints Acquisition of HIV Viremia in those HIV-infected Safety

26 Potential Availability Of Efficacy Data From Current & Planned Trials* RV 144 Merck 023/HVTN 502 (STEP) HVTN 503 PAVE 100 Enrollment Follow-up STEP RV 144 HVTN 503 PAVE 100 Anticipated Data Availability *Assuming no early termination Courtesy, J Flores

27 Impact on Vaccine Efficacy Trial Design Baseline Target population Projected incidence Proportion of men circumcised Proportion HSV-2 positive On-study Risk behavior STI incidence Male circumcision Results of ongoing studies ACV prophylaxis PrEP Microbicides

28 Impact on Vaccine Efficacy Trial Design: Assuming Positive Results of Prevention Studies Current Design PAVE 100 Sample Sizes Under Various Scenarios % Men Circumsized % HSV-2 (+) s on ACV % on PrEP (TDF+FTC) % Women Using Microbicide Sample Size 40% ,500 Assumptions for Current Design: Will enroll 40% women and 60% men 40% of men enrolled will be circumcised

29 Challenges Pursuit of HIV vaccine efficacy trials, already a complex and expensive endeavor, will become only more so Need to complete current and planned trials as quickly as possible Need to design trials that offer maximal efficiency Current non-vaccine considerations include Provision of comprehensive prevention package Provision of information and referral services for male circumcision Determination of HSV-2 status at baseline and on-study Monitoring and treatment for STI s Continuum of risk-reduction counseling

30 Conclusions Vaccine trialists have an ethical obligation to offer proven prevention modalities to trial volunteers Can lead the way (as has been done for commitment to provide care, including ART, to HIV-infected study participants) Operational and resource challenges apparent but manageable Multi-modality HIV prevention (integrated with HIV care, including provision of ART) is the near- and mid-term prospect until a fully effective HIV vaccine is discovered, licensed and made universally available

34 Vaccine-induced antibody responses can be distinguished from infection-induced antibody responses by Western blot. Also, detection of HIVspecific nucleic acid by PCR will be negative in vaccinees, but positive in HIV-infected persons.

35 懇請賜教

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