Multipurpose prevention technologies and their potential interaction with vaccines. Robin Shattock

Transcription

1 Multipurpose prevention technologies and their potential interaction with vaccines Robin Shattock

2 Opportunities for biomedical interventions YEARS HOURS 72 HOURS YEARS Prior to exposure Exposure (pre-coital/coital) Exposure (pre-coital/coital) After infection Male circumcision Oral pre exposure prophylaxis (daily PrEP) Topical PrEP (daily gels or intra-vaginal rings (microbicides) Preventive HIV Vaccines Preventative STD vaccines Oral pre exposure prophylaxis (intermittent PrEP) Coitally dependent topical PrEP (microbicides) Oral post exposure prophylaxis (PEP) Anti-retroviral therapy Immediate treatment of positive partners in discordant couples Treatment for prevention in all who test positive for HIV (T4P)

3 Time to consider a combination approach to biomedical interventions Possible biomedical prevention combinations: Combined use of oral PREP and microbicides for intermittent dosing optimal systemic and local drug levels (steady state and bolus) PrEP (oral, topical) for women combined with circumcision + oral PrEP for men T4P combined with ARV PrEP (microbicide or oral for women, oral for MSM) for the HIV-negative partner. HIV vaccines plus ARV PrEP specific considerations HIV vaccines plus T4P specific considerations HIV vaccines plus other STD vaccines

4 Lessons might be learned from the Thai RV144 vaccine trial The vaccine appeared most effective (60% reduction) at 1 year post vaccination Infection may be reflective of suboptimal immune responses (correlates analysis) or exposure to a higher and/or more frequent infectious challenge Revaccination (annual/biannual) likely required to have a significant impact on incidence (Hontelez et al Vaccine June 2011) Co-implementation of PrEP (oral, microbicides) might provide conditions that could significantly increase vaccine efficacy This hypothesis could be explored future ALVAC-protein primeboost trials.

5 How might (VaccPrEP) deliver better protection? Providing protection during the immunization period Reducing infectious challenge and primary foci of infection Increase eclipse phase prior to systemic viral dissemination providing an extended opportunity for adaptive immunity to respond Boosting local immunity (virus/antigen) Converting high risk challenge to low risk challenge (RV144) Coverage between potential re-vaccination campaigns as immunity wanes Providing better virological control in combination with immediate ART with potential for reduction/elimination of reservoirs

6 Can vaccine candidates be coformulated with microbicides?

7 Can VaccPrEP provide better protection than vaccine or PrEP alone 1% tenofovir gel A B D = IN (intranasal) immunization = IM (intramuscular) immunization = Challenge in presence of 1% tenofovir gel = Challenge in the absence of microbicide = Assess systemic and local immunity

8 Can biomedical combinations be tested in clinical trials? Design 1, PrEP (oral or microbicide) assumed not to be in general use. (closing window of opportunity for use of placebo PrEP) A 4 arm study: 1. Placebo (placebo vaccine + placebo PrEP) 2. PrEP (placebo vaccine + PrEP), 3. Vaccine (vaccine + placebo PrEP), 4. VaccPrEp (vaccine+ PrEP) Requires infection to demonstrate direct benefit of vaccination with or without PrEP (fewer infections needed when synergy is present). Potential for adaptive design: assess relative ranking of active arms test for superiority among active arms test for interaction (synergy) of the combination eliminate regimes not better than placebo introduce vaccine boost if needed.

9 Can biomedical combinations be tested in clinical trials? Design 2: PrEP reduces risk of HIV acquisition (oral 44-73%, microbicide 39%) assumes PrEP is available to all participants? Two-arm study: PrEP alone Vaccine + PrEP (VaccPrEP) Requires 30 to 60 incident infections to assess the additional benefit of vaccination on risk of infection and setpoint viral load. Main challenge, PrEP as active control arm will reduce incidence and increase trial size Superiority of VaccPREP does not imply vaccine alone is efficacious Lack of superiority does not imply vaccine alone is ineffective (potential antagonism). Excler JL, et al AIDS Res Hum Retroviruses Dec 16.

10 Potential challenges to combination trials Increased sample size, trial complexity and cost Additional visits for safety, HIV testing etc Risk compensation and adherence may vary according to perceived efficacy of the individual components of any combination Issue of informed choice become more complex Open-label trials may be the best way to assess concerns about risk compensation while learning about implementation.

11 Co-implementation of other STD vaccine Similar target groups Similar routes of transmission Significant shortfall in funding STD vaccines Technological advantages in HIV vaccine development could provide significant gains for development of other STD vaccines No vaccines Chlamydia (C. trachomatis)* Chancroid (Haemophilus ducreyi)* Gonorrhea (Neisseria gonorrhoeae)* Syphilis (Treponema pallidum)* Trichomoniasis (Trichomonas vaginalis)* Hepatits C Virus Herpes Simplex virus* Existing Vaccines Human Papilloma Virus Hepatits B Virus * Associated with increased risk of HIV acquisition Potential complications Antigenic competition and immuno-dominance Increased activation or recruitment of CD4 cells to mucosal surfaces might enhance HIV acquisition Negative impact on HIV vaccine efficacy

12 Summary Can vaccine candidates be co-formulated with microbicides: Yes Can mucosal exposure to virus in the context of PrEP lead to immune response: indicated in animals Does vaginal vaccination modify mucosal immunity to HIV: indicated in animals, yet to be tested in humans Will VaccPrEP provide better protection than PrEP alone?: indicated in animal models Can combination prevention be tested in human trials: Yes

13 Conclusions A limited window may exist for placebo (PrEP) controlled trials ARV PrEP combined with vaccines may create lower-risk conditions making a partially efficacious vaccine a viable option Additive or synergistic effects will stimulate incremental reductions in HIV incidence This in turn will raise the bar of evidence required for new approaches (cost-effectiveness and population impact) in RCT Decreasing incidence will necessitate larger and more costly trials with an increased emphasis on adaptive design Placing an intrinsic value on high incidence cohorts and predictors of vaccine efficacy.

14 Pathway to reversing the epidemic Seeing prevention research/funding as a continuum Circumcision Treatment 4 prevention ARV PrEP (oral, microbicide) Partially effective HIV vaccine STD vaccines A combined research strategy for biomedical interventions is likely to provide the fastest, most tangible impact on HIV transmission HIV incidence highly effective HIV vaccine Behavioral and structural interventions Science. 2011;333:42-3