RV 144: The Thai Phase III Trial and Development of a Globally-Effective, Multi-Clade HIV Vaccine HIV Vaccine: Quo Vadis AIDS July 2010 Dr. Merlin Robb Deputy Director, Clinical Research US Military HIV Research Program (MHRP) Walter Reed Army Institute of Research
Objectives Overview of RV144 outcomes Post-hoc hypothesis generating analyses Update on ongoing research efforts Correlates research Product development plans for a globally-effective HIV vaccine 7 June MHRP
6-month vaccination schedule 3 years of follow-up (every 6 mo.) ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24 AIDSVAX® B/E gp120 boosting at week 12, 24 (time in years) HIV test, risk assessment and counseling Vaccination and Follow-up Schedule RV 144
Vaccine Efficacy Appears Highest 6-12 months mITTPP monthEventsEfficacyEventsEfficacy 61654%n/a %2168% %4141% %5327% %6231% 12 months = 60% (Cox PH, 95% CI 22, 80) 3.5 years after first vaccination: Protective Efficacy = 31.2% P = % CI: 1.1 – 52.1% No effect on viral load RV 144
Anti-gp120 Reciprocal Mean Geometric Titers 1 VISIT 2 WEEKS POST VACCINE (V8) 24 WEEKS POST VACCINE (V9) AFRIMSVRC AFRIMSVRCAFRIMSVRC FOLD DECREASE (8:9 – A) FOLD DECREASE (8:9- V) ANTIGEN A MN Courtesy of Dr. Rick Koup, May 2010
Baseline Risk-stratified Treatment Effects (mITT) VaccinePlaceboTreatment Effect NEndpointsPY Rate %NEndpointsPY Rate %Efficacy95% CI Low3, , % -8.5, 67.2 Medium2, , % -6.0, 74.0 High1, , % -72.7, 46.3 VE for each risk category was statistically similar Caveats: Overall incidence was low Risk was primarily heterosexual in low prevalence setting 90% of infections subtype E RV 144
Baseline versus cumulative risk Risk AssessmentRisk : Treatment Interaction Baseline risk (pre-hoc analysis)p = 0.21 “Ever” high / not ever highp = This may reflect the transient protective effect of the vaccine regimen rather than imply protection only in “lower risk” individuals RV 144
RV 144 lessons Protection from infection possible No or minimal primary neutralizing antibody Limited CD8 T cell immunity Other immune effectors play a role Protection seems greatest early and in low risk participants Boosting may improve overall efficacy Studies must consider risk variable Mode of transmission Frequency of exposure Dose per exposure 8 7 June 2010 RV 144
Ongoing RV 144 Research November 2009 Immunogenicity studies HIV virus characterization May 2010: Correlates Pilot Studies begin Collaboration with 30 US and international researchers Using RV144 samples Humoral and Innate Immunity T-cell immunity Host Genetics Animal Models 9 7 June 2010 RV 144
Goal: Globally Effective HIV Vaccine 10 Effective in high-risk populations Multi-clade protection against acquisition Durable, safe and effective Globally accessible GLOBALLY EFFECTIVE HIV VACCINE Corollary: Efficacy trials are the only way to determine a correlate of immunity and establish a rational basis for HIV vaccine development. MHRP
Vaccine Strategy: Guiding Principles Reasonable concepts Distinct from those previously tested, and Best represent the concept Evaluate these in efficient efficacy trials Leverage a diversity of approaches Build incrementally on past successes Minimize risk 11 7 June 2010 MHRP
Product Development Plan Parallel product development pathways toward a globally effective HIV vaccine. REGIONAL VACCINE STRATEGY Building on the RV144 regimen Phase IIb efficacy trial with extended ALVAC/protein boosts, shorter follow-up: a)MSM Thai population b)High-risk heterosexuals in RSA APPROACH BUILDING ON RV144 1 Multi-clade populations for study Increase CD8 potency Improve humoral response Add primary neutralizing AB APPROACH 7 June 2010 DIVERSIFYING AND REFINING THE PORTFOLIO GLOBAL VACCINE STRATEGY Pursuing diverse approaches toward a globally effective vaccine. 2 MHRP
Vaccine Downselection A known correlate (unlikely) would guide downselection In the absence of a correlate: If products generate similar immune responses, strongest response will be selected If products generate distinct immune response, both concepts should be considered Practical considerations inform selection: Availability, complexity, and cost 13 7 June 2010 MHRP
A Balanced Strategy 14 7 June 2010 BUILDING ON RV144: A Regional Vaccine Strategy 1 DIVERSIFYING AND REFINING THE PORTFOLIO: A Global Vaccine Strategy Objective: minimize risk and maximize the likelihood of achieving an effective HIV vaccine. MHRP 2