1. Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services For more information: 1-866-833-LIFE vrc.nih.gov VRCforLIFE@mail.nih.gov HVTN 505: Objectives and Timelines Barney S. Graham, MD, PhD XIX International AIDS Conference Workshop on Correlates of Immunity in Vaccine Research July 23, 2012

2. The Goals of Vaccination Individuals – To prevent infection – To prevent disease – To control or reduce disease Population – To prevent transmission to susceptible individuals – To control epidemic spread of infection Measures of Vaccine Efficacy (VE) VEs VEp VEi 2

3. Transmission Persistence or clearance Attachment Innate response Adaptive response Physical barriers or Pre-existing antibody Elements of host immunity Factors required to maintain an epidemic Population Individual Points where vaccination can influence an epidemic Susceptible host Invasion or resistance Exposure Viral Interaction with Individual Host and Population Evasion or abortive replication 3

4. R o =   c  D R o = reproductive rate of agent in a population  = transmission efficiency c = rate of partner change or new exposures D = duration of infectious period If R 0 < 1 epidemic will contract If R 0 >1 epidemic will expand Reduced exposure risk Vaccine-induced T cell response reduces virus load and shedding Vaccine-induced antibody reduces transmission efficiency  D c RoRo How can vaccines impact an epidemic? 4

5. What is an immunological correlate?  Correlate - An immune response (biomarker) that is statistically correlated with a clinical outcome  Correlate of risk (CoR) - Statistically correlated with the rate of HIV infection in the vaccine group (Qin et al., JID, 2007)  Correlate of protection (CoP) - Statistically correlated with vaccine efficacy in the vaccine and placebo groups (Plotkin and Gilbert, CID, 2012) nCoP: nonmechanistic CoP is an immune response indirectly associated with protection mCoP: mechanistic CoP is an immune response causally responsible for protection  Surrogate – an immune response that can be used as a substitute endpoint for clinical efficacy  Specific - Predictive of VE for a particular vaccine platform or study population  General - Predictive of VE in different settings (e.g., across vaccine platforms, study populations, viral populations, or species) 5

6. Trial Design New Trial Design Modifiy: Size Populations Primary outcome Randomization or allocation Outcome Real- Time Data Analysis Trial Design Randomization Data Analysis Could start with multiple study groups and continuously roll in additional groups Data Analysis Randomization Outcome Adaptive trial design Conventional trial progression Randomization Typically small number of study groups The key for adaptive vaccine trials to gain efficiency is to analyze study endpoints while accrual is ongoing. This is possible for vaccine studies using a surrogate endpoint based on the identification of an immune correlate, but not if the endpoint is infection since it is likely that sufficient data would not be available until accrual is completed. Data Analysis Why is it important to identify immune correlates? 6 Koup, Graham, Douek. Nature Reviews Immunology 2011; 11:65-70.

7. Antibody T cells +++ +/- +++- -- Virus-infected cell Latency or extracellular sequestration Isolated virion How do adaptive immune responses control virus infection?

8. Brief History of HIV Vaccines 878889909192939495969798990001020304050607080910111213 gp160/gp120 subunits Poxvirus vector + protein rAd5-gag/pol/nef DNA/rAd5-Env/gag/pol/nef Relative focus on vaccine effector mechanisms CD8 T cells Pivotal basic & clinical research discoveries 8 Antibody

9. HIV Vaccine Efficacy Trial Outcomes 0 1 2 3 6 Vaccine Placebo Rate of Infection (%) Efficacy 1st interim analysis 3Q2013 ? 5.7 5.8 0 0.6 0.9 ↓ 31.2% (p=.04) ++ RV144 7.3 5.0 ↑ 31.5% (NS) Step HVTN 505 VaxGen Schedule (months) 9

10. HVTN 505 01212 Months369 Env A Env B Env C gag B pol B nef B CMV-R promoter Env A Env B Env C gag/pol B rAd5 10

11. Phase 2b, Randomized, Placebo-Controlled Test-of Concept Trial to Evaluate the Safety and Efficacy of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a Multiclade Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female Transgender Persons Who Have Sex with Men Short Title: VRC DNA/rAd5 Multiclade, Multigene HIV-1 Vaccine Regimen in HIV(-) MSM Version 3.0 Principal Investigator - Scott M. Hammer, M.D. HVTN 505 11

12. HVTN 505: Vaccination Schedule PrimeBoost HVTN 505 GroupsNDay 0Wk 4Wk 8Wk 24 Group 1: Vaccine1100 DNA (4 mg) DNA (4 mg) DNA (4 mg) rAd5 (10 10 PU) Group 2: Placebo1100PBS FFB 80% power to detect 50% reduction in HIV-1 acquisition 93% power to detect 1 log 10 reduction in setpoint VL if VE=0; 84% power if VE=50% 12

13. HVTN 505: Primary Endpoints Week 28 (4 weeks post-boost) through Month 24 Post-infection diagnosis visit schedule VL setpoint = average of all values between week 10 and 20 after diagnosis study visit and prior to ART initiation Weeks 04122241068162014 Diagnosis of HIV Infection Acquisition (VE) endpoint VL endpoint 13

14. HVTN 505 Enrollment through July 7, 2012 14 Average enrollment over past 40 weeks (since Oct 1,2011) = 14.6 ppts/wk

15. Non-Efficacy Stopping Boundary: VE(24) Non- Efficacy Interim Analysis No. Week 28+ Infections w/ 20 weeks of Post-Dx Follow-up Expected No. Week 28+ Infections if VE(24)= 0% Est. VE(24)% Stopping Boundary No. Vaccine : No. Placebo Week 28+ Infections 130439.1%21:22 2486117.4%28:33 3667721.8%34:43 15 Note that a final analysis point estimate of VE(24)=36% (31:46 vaccinee:placebo distribution of infections) would have P<0.05. Peter Gilbert

16. What will we learn from HVTN 505? Is the rate of HIV acquisition reduced by >50%? Is mean VL reduced by >1 log 10 genome copy/ml? Is there a sieve effect or selective escape from vaccine- induced antibody or T cell responses in breakthrough viruses? Is there an immune correlate of protection? 16

17. HVTN 505 Timeline Final analysis Interim analysis 17 CDC 4370 TDF/FTC PrEP in IVDU – Thailand iPrEx TDF/FTC PrEP – Americas – 44% efficacy MSM CAPRISA 004 TDF microbicide gel 39% efficacy Partners PrEP TDF/FTC – East Africa - 62-73% efficacy HPTN 052 – Treatment of discordant couples – global - 96% efficacy CDC 4940 TDF/FTC PrEP in heterosexuals – Botswana - 63% efficacy VOICE – TDF oral &TDF gel microbicide – South & East Africa – stopped early FEM-PrEP TDF/FTC – Africa – stopped early – no efficacy Future trials will compete with other preventive approaches

18. Considerations in Choosing Endpoints for the Correlates Analysis Strength of association between the immune response and the rate of HIV infection in vaccinees Dynamic range of the immune response in vaccinees Precision of assay for measuring functionally relevant response Number of Week 28+ infected vaccinees –The correlates analysis is based on comparing infected vaccinees with control vaccinees who are not infected 18

19. HVTN 505: Scientific Planning Preparation for correlates analysi s Marker Working Group established to direct and prioritize activities (Scott Hammer and Peter Gilbert co-Chairs) Pilot studies to down-select assays for immune correlates not used in RV144 Confirm specificity and sensitivity, background levels, controls of assays to be used Real-time analysis Sequencing of breakthrough viral isolates Selected humoral and cellular immune studies TDF/FTC levels Mucosal studies have been added to last 1/3 of subjects Optional rectal secretion and semen sampling for antibody and cytokine analysis 19

20. V1V2 gp70 His 6 Pinter A, et al. Vaccine 16:1903, 1998 Scaffold: Murine leukemia Virus gp70 HIV-1 V1V2 Scaffolded gp70-V1V2 Protein V1 V2 alpha4,beta7 interaction motif 20

21. membrane proximal domain + lipid V3/glycan (aa332N) CD4 binding site (aa368D) V1V2/glycan (aa160N-165I) gp120 inner domain gp120 outer domain bridging sheet McLellan, Ofek, Zhou, Zhu, Kwong Prototypic Antibodies for Broad Neutralization of HIV-1 21

22. Transmission bottleneck is point of greatest vulnerability Blood or mucosal exposure Regional spread 18-72 hours Systemic Dissemination between 4 and 12 days Latency Infection of immunoprivileged sites & sequestration 22

23. Study population is important Weak physical barrier, many target cells Strong physical barrier, sparse target cells No physical barrier, abundant target cells Rectal mucosa Cervical/vaginal mucosa Blood Thai general population IVDU MSM 23

24. HVTN 505 Protocol Team Chair: Scott Hammer Co-Chairs: Magdalena Sobieszczyk & Michael Yin Protocol Team Leader: Shelly Karuna Biostatisticians: Peter Gilbert, Holly Janes, Doug Grove & Amy Krambrink DAIDS Medical Officers: Chuka Anude & Elizabeth Adams VRC Developer Representatives: Barney Graham & Mary Enama VRC Immunologist: Richard Koup Core Medical Monitor: Shelly Karuna HVTN Laboratory Program: John Hural & Julie McElrath Clinical Trials Manager: Shelly Mahilum Protocol Development Coordinator: Carter Bentley SDMC Senior Project Manager: Drienna Holman SDMC Project Manager: Diana Lynn SDMC Clinical Affairs: Pat Farrell DAIDS Pharmacist: Ana Martinez DAIDS Regulatory Affairs: Michelle Conan-Cibotti HVTN Regulatory Affairs : Renee Holt HVTN Pharmacist: Jan Johannessen Community Ed Unit Representative: Gail Broder Communications: Jim Maynard Community Engagement: Steve Wakefield Community Educators/Recruiters: Coco Alinsug & Jason Roberts CAB Members: Rick Church & Rich Trevino Clinic Coordinator: Steven Chang Clinical Trials Manager HVTN Investigators: Susan Buchbinder, Mike Keefer, Beryl Koblin, & Mark Mulligan Technical Editor: Adi Ferrara 24

25. Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health 1-866-833-LIFE www.vrc.nih.gov vaccines@nih.gov