2012 USPHS Scientific and Training Symposium

1. Strengthening Health Systems through the Nigerian Ministryof Defense—U.S. Department of Defense Walter Reed Program Nigeria Partnership Nelson L. Michael, M.D., Ph.D Colonel, Medical Corps, U.S. Army Director US Military HIV Research Program (MHRP) Walter Reed Army Institute of Research 2012 USPHS Scientific and Training Symposium The views expressed are those of the presenter and should not be construed to represent the positions of the U.S. Army or DoD

3. Towards a Globally Effective HIV Vaccine:The role for Nigeria

4. 4 MHRP’s Product Development Plan • MHRP’s vaccine development strategy emphasizes regional and global approaches. 1 BUILDING ON RV144 REGIONAL VACCINE STRATEGY Building on the RV144 outcome and lessons learned, conduct efficacy trials of the prime-boost concept in: Thai MSM populations High-risk populations in Southern Africa 2 DIVERSIFYING AND REFINING THE PORTFOLIO GLOBAL VACCINE STRATEGY Pursuing diverse platforms (e.g. vectors, multi-valent constructs or mosaic inserts) that build on the prime-boost concept and readily translate to multi-clade testing and a globally effective vaccine.

5. Pox-Protein

6. NEJM 361:2209 (03 Dec 09)

7. RV 144 demonstrated efficacyfor HIV acquisition C. Modified Intention-to-Treat Analysis* 1.0 0.9 Placebo 0.8 0.7 0.6 Probability of HIV Infection (%) 0.5 Vaccine 0.4 0.3 0.2 0.1 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years N=16,395 51 vaccine, 74 placebo HIV infected Est. VE = 31% 95% CI 1-51% (p=0.04) Rerks-Ngarm et al. (2009, NEJM)

8. What we have learned—RV 144 • Protection among low incidence heterosexual Thais, VE 31.2% at 42 months • No effect on post-infection viremia or CD4 count • Relatively monophyletic circulating variants CRF01_AE • Efficacy appears to be early and non-durable • Evoked binding Ab but not measurable, primary isolate Nab— BAb appeared early and decreased by > 10 fold over 6 months • CD4+ Env responses, but not CD8 responses • Correlate/surrogate studies limited by samples and endpoints

9. What we would want next • Extend the observation of early 60% efficacy by increasing the durability of such protection (additional boosts) • Heterosexual risk groups in Asia • Ensure that we can elucidate correlates/surrogates of protection with more appropriate sample collection. • Establish protection in higher incidence populations (additional boosts) • Heterosexuals in sub-Saharan Africa • MSM in Africa and Asia

10. NEJM 366:1275 (05 Apr 2012)

11. Comparison of Infection Rate and Vaccine Efficacy Between Vaccine and Placebo Recipients in the RV144 ALVAC-HIV, AIDSVAX B/E Trial V1V2 Antibodies High V1V2 Antibodies, Increased Vaccine Efficacy Low V1V2 Antibodies, Same Infection Rate as Placebos

12. Comparison of Infection Rate and Vaccine Efficacy Between Vaccinees and Placebo Recipients in the RV144 ALVAC-HIV, AIDSVAX B/E Trial IgA Magnitude and Breadth Antibodies High IgA Antibodies, No Efficacy, Same Infection Rate as Placebo—No Enhancement Low IgA, Increased Vaccine Efficacy

13. Sequence variation in position 169 Edlefsen, SCHARP

14. Sequence variation in position 181 Edlefsen, SCHARP

15. Summary • The case control correlates data suggest 2 hypotheses: • Binding to gp70:V1V2 correlates inversely with HIV infection rate? • A244 and MN V2 crown linear peptides show similar effects • Linear epitope microarray data suggest V2 effect • Anti-EnvIgA M-B correlates directly with HIV infection rate • Sieve analysis suggests a V2 effect

16. Planned studies are mutually reinforcing and will amplify public health impact and regional relevance. Focus on regional public health impact Precedent for vaccine efficacy Future amplification of global reach THAILAND High Risk MSM Mutually reinforcing studies strengthen and support public health benefit in target populations and the translation of the platform globally. US/EUROPE SOUTHEAST ASIA RV144 SOUTHERN AFRICA Republic of South Africa(RSA) High Risk Heterosexual • Strategy for achieving potential licensure in target markets and having the broadest public health impact. 16 May 2011

17. The pox-protein approach is regional • Will we have to tailor vaccines for multiple sub-epidemics? • What will be the inducement to industry to support such an approach? • There are significant public health challenges with regional vaccine approaches. • What about Nigeria, and the rest of West Africa, with a dominance of pure subtype G and A/G recombinant HIV infections? • Can we make a universal HIV vaccine?

18. Ad26-MVA +/- proteinBarouch et al Nature 482:89-93 02 Feb 2012

19. Nature 482, 89–93 (02 February 2012) 100 80 DNA/MVA 60 MVA/MVA % Uninfected Ad26/MVA 40 MVA/Ad26 20 Sham 0 0 2 4 6 8 Number of IR Challenges

20. MVA/Ad26 and Ad26/MVA Regimens Lower Early Setpoint Viral Loads Following SIVmac251 Infection Sham MVA/MVA DNA/MVA 6.09 5.75 Log SIV RNA 5.47 Days Following Infection Days Following Infection Days Following Infection Ad26/MVA 3x resistance to infection 4/8 : viremia blunted 1 log 3/8 : rapid virologic control 1/8 : persistently uninfected MVA/Ad26 Log SIV RNA 4.55 3.83 Days Following Infection Days Following Infection

21. Protection Against Acquisition of IR SIVmac251 by Ad35/Ad26-SIVsmE543GagPolEnv Vaccine

22. Ad26-MVA correlates analysis • Acquisition endpoint. • envelope binding antibody r= .79 p<.0001. • neutralization antibody r=.50 p=.0034 • ADCC r=.38 p=.034 • set point viral load endpoint, Many correlates (N=27); • prechallenge gag elispot count and gag elispot breadth were both correlated (r=-.50 p=.006 and r=-.64 p=.0002, respectively) with the endpoint. • peak envelope binding antibody r=-.70 followed by prechallenge neutralizing antibodyr=.67.

23. Increment 2: Pathway to a Global HIV Vaccine Multi-clade (A/C/E) or mosaic (M1/M2) inserts Phase I: Safety and immunogenicity Trials are prime-boost regimens with additional protein boost based on RV144 data Phase IIa: DNA/MVA vs Ad26/MVA (Ad35) for epitope and clade breadth and magnitude of immune response 2- or 3-arm efficacy trial with common placebo group Phase IIb Efficacy#: A successful outcome will yield a mosaic or multi-clade vaccine effective in high-risk populations. Commercial partners have yet to be identified and may restrict development and access to products. . 23

24. How to prepare Nigeria for HIV vaccine studies?

25. Preparing Nigeria for HIV Vaccine Development • Recognize a public health gap—Feb 2004 • Take risk—July 2004 • Recognize that you are in someone else’s country and never forget it—Jan 2005 (Bolingo) • Develop durable and inclusive frameworks (steering committees, EPIC) • Deliver prevention, care and treatment first (PEPFAR)

26. Preparing Nigeria for HIV Vaccine Development—2 • Find champions (Drs. Orits, Njoku, Idoko) • Give the champions protegees—Jide, Ayemoba, Umar • Build a laboratory that serves service delivery, then research (Mogadishu) • Assess risk, prevalence and subtypes (RV 230) • Community engagement from the inception (GPP version 2.0)

27. Preparing Nigeria for HIV Vaccine Development—3 • Work with partners (IHV, Harvard, Pop Council, Heartland Alliance, CDC, USAID, etc) • Focus on key populations—MSM, CSW (high incidence) • Engage with major stake holders (NIH, Gates) but do not vex them….let them see you take risk • Advocate…UNAIDS, AVAC, AAVP • South-south partnerships within MHRP

29. Acknowledgements Supported by: Collaboration for AIDS Vaccine Discovery Grant From the Bill and Melinda Gates Foundation HVTN, DAIDS, NIAID With Collaborations with the MHRP and Thai Ministry of Public Health • National Institute of Allergy and Infectious Diseases (NIAID) • National Institutes of Health (NIH) • Division of AIDS (DAIDS) • U.S. Department of Health and Human Services (HHS) Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-06 HVTN