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