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HIV Vaccine: Quo Vadis AIDS 2010 20 July 2010

Dr. Merlin Robb Deputy Director, Clinical Research US Military HIV Research Program (MHRP) Walter Reed Army Institute of Research. RV 144: The Thai Phase III Trial and Development of a Globally-Effective, Multi- Clade HIV Vaccine. HIV Vaccine: Quo Vadis AIDS 2010 20 July 2010. Objectives.

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HIV Vaccine: Quo Vadis AIDS 2010 20 July 2010

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  1. Dr. Merlin Robb Deputy Director, Clinical Research US Military HIV Research Program (MHRP) Walter Reed Army Institute of Research RV 144: The Thai Phase III TrialandDevelopment of a Globally-Effective,Multi-Clade HIV Vaccine HIV Vaccine: Quo Vadis AIDS 2010 20 July 2010

  2. Objectives MHRP 2 • 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

  3. Vaccination and Follow-up Schedule RV 144 HIV test, risk assessment and counseling 0.5 1 2 3 (time in years) 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

  4. Vaccine Efficacy Appears Highest 6-12 months RV 144 3.5 years after first vaccination: Protective Efficacy = 31.2% P = 0.04 95% CI: 1.1 – 52.1% No effect on viral load VE @ 12 months = 60% (Cox PH, 95% CI 22, 80)

  5. Anti-gp120 Reciprocal Mean Geometric Titers1 1Courtesy of Dr. Rick Koup, May 2010

  6. Baseline Risk-stratified Treatment Effects (mITT) RV 144 • Caveats: • Overall incidence was low • Risk was primarily heterosexual in low prevalence setting • 90% of infections subtype E VE for each risk category was statistically similar

  7. Baseline versus cumulative risk RV 144 This may reflect the transient protective effect of the vaccine regimen rather than imply protection only in “lower risk” individuals

  8. RV 144 lessons RV 144 8 • 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

  9. Ongoing RV 144 Research RV 144 9 • 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

  10. Goal: Globally Effective HIV Vaccine MHRP Corollary: Efficacy trials are the only way to determine a correlate of immunity and establish a rational basis for HIV vaccine development. 10

  11. Vaccine Strategy: Guiding Principles MHRP 11 • 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

  12. Product Development Plan MHRP Parallel product development pathways toward a globally effective HIV vaccine. APPROACH 1 BUILDING ON RV144 • Phase IIb efficacy trial with extended ALVAC/protein boosts, shorter follow-up: • MSM Thai population • High-risk heterosexuals in RSA REGIONAL VACCINE STRATEGY Building on the RV144 regimen APPROACH 2 DIVERSIFYING AND REFINING THE PORTFOLIO • Multi-clade populations for study • Increase CD8 potency • Improve humoral response • Add primary neutralizing AB GLOBAL VACCINE STRATEGY Pursuing diverse approaches toward a globally effective vaccine.

  13. Vaccine Downselection MHRP 13 • 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

  14. A Balanced Strategy MHRP BUILDING ON RV144: A Regional Vaccine Strategy 1 2 Objective: minimize risk and maximize the likelihood of achieving an effective HIV vaccine. DIVERSIFYING AND REFINING THE PORTFOLIO: A Global Vaccine Strategy 14

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