HIV Vaccine Trials Network Developing a Safe and Effective Vaccine for Prevention of HIV Infections Globally State of Vaccine Research in Zimbabwe Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number UM1A1068614. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Overview HIV Vaccine Science HVTN/Janssen collaboration HIV Vaccine Trials Network HIV Vaccine Research Trials in Zimbabwe HVTN 107 HVTN 120 HVTN/Janssen collaboration Background HVTN 705/HPX2008

HIV Vaccine Trials Network HIV Vaccine Science HIV Vaccine Trials Network

Why an HIV vaccine? February 6, 2014 “Ultimately, we believe, the only guarantee of a sustained end of the AIDS pandemic lies in a combination of non-vaccine prevention methods and the development of a safe and effective HIV vaccine” 11/6/2018

HIV Vaccine Trials Network Established in 1999 to integrate the US and international efforts in testing HIV vaccines Operant principle – public non-commercial funding was needed to effectively test candidate HIV vaccines Global public health programs are the greatest beneficiary of an effective HIV vaccine Main funding is by the NIH of the US government Bill and Melinda Gates Foundation (BMGF) collaboration added in 2012. BMGF funds 50% of the clinical trial costs of HVTN efficacy trials

HVTN Mission To fully characterize the safety, immunogenicity, and efficacy of HIV vaccine candidates with the goal of developing a safe, effective vaccine as rapidly as possible for prevention of HIV infections globally

Achieving HVTN’s Mission to Develop a Vaccine for the Prevention of HIV Over 35 sites on 5 continents All phases of clinical trials Evaluating experimental vaccines for safety and immunogenicity Testing vaccine efficacy Over 65 clinical trials since 1999 11/6/2018

HIV Vaccine Science RV144 – thai trial success

Thai Trial (RV144) Primary Results Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand Supachai Rerks-Ngarm, M.D., Punnee Pitisuttithum, M.D., D.T.M.H., Sorachai Nitayaphan, M.D., Ph.D., Jaranit Kaewkungwal, Ph.D., Joseph Chiu, M.D., Robert paris, M.D., Nakorn Premsri, M.D., Chawetsan Namwat, M.D., Mark de Souza, Ph.D., Elizabeth Adams, M.D., Michael Bebenson, M.D., Sanjay Gurunathan, M.D., Jim Tartaglia, Ph.D., John G. McNeil, M.D., Donald P. Francis, M.D., D.Sc., Donald Stablein, Ph.D., Deborah L. Birx, M.D., Supamit Chunsuttiwat, M.D., Chirasak Khamboonruang, M.D., Prasert Thongcharoen, M.D., Ph.D., Merlin L. Robb, M.D., Nelson L. Michael, M.D., Ph.D., Prayara Kunasol, M.D., and Jerome Kim, M.D., for the MOPH-TAVEG Investigators* An HIV vaccine that prevents acquisition is possible What about in Africa? 0.5 1.0 1.5 3.5 0.9 0.8 0.7 0.6 0.4 0.3 0.2 0.1 0.0 Years Probability of HIV Infection (%) 2.0 2.5 3.0 Placebo Vaccine Modified Intention-to-Treat Analysis* Vaccine regimen had 60% efficacy at 12 months, but came down to 31.2% efficacy at 3 years after vaccination

Questions for Africa Will the same vaccine used in RV144 work just as well in the African population? Will a vaccine engineered for subtype C work well? Can we improve how well it works by adding adjuvants and changing the dosing regimen? HVTN 100 HVTN 702 HVTN 107 HVTN 120

Preventive Vaccine Development Well HIV-uninfected adults randomized Primary Objective Assess Vaccine Efficacy to prevent pathogen-specific disease (does it work?) Secondary Objective Assess vaccine-induced immune responses as “correlates of protection” (what is it that makes it work?) Vaccine Placebo Receive inoculations Measure immune response Follow for new HIV infection

2 HIV vaccine efficacy trials in 2017 Building on RV 144: ALVAC & gp120/MF59 South Africa HVTN 702 Efficacy Studies Multi-clade approach: Ad26 Mosaic & Clade C gp140 South Africa, Malawi, Mozambique, Zambia, Zimbabwe HVTN 705

2 HIV correlates of protection trials in 2017 Adjuvants: ALVAC & gp120/MF59 vs Alum Mozambique, South Africa, Zimbabwe (28/132) HVTN 107 Correlates Studies Adjuvants and dose: ALVAC & gp120/MF59 vs ASO1B South Africa, Tanzania, Zambia, Zimbabwe (28/320) HVTN 120

Janssen Vaccines and Prevention – HIV Vaccine Program background

Pre-clinical and clinical experience The vaccine candidates are very effective in preventing HIV infection in NHP models Protection was confirmed in several studies Protection was correlated with antibodies to HIV envelope as well as with the T-cell responses to the vaccines Phase I (clinical) studies showed that humans can make the same type and levels of antibodies achieved by NHP

Safety studies have been performed in about 650 participants HVTN 705/HPX2008 products Safety studies have been performed in about 650 participants Product # of vacinees Ad26.Mos.HIV (very similar to Ad26.Mos4.HIV) ~350 Ad26.Mos4.HIV ~115 (~235 by the time HVTN 705 will start) Clade C gp140 ~450 (~575 by the time HVTN 705 will start) In multiple studies, these vaccines have been well tolerated and have not raised any safety concerns

Go/No Go criteria met for HVTN 705 Endpoint Target (LL of 95% CI) Phase I Wk28 results Humoral IgG binding responses on clade C Env ADCP responses to Clade C Env Cellular ELISpot responses to at least one ENV peptide pool Env boost IgG to clade C Env of Ad/Ad+Env over Ad/Ad Magnitude >2.15 log10 cPTE Env ELISpot OR >3.8 log10 C97 ELISA Subjects should be above BOTH response thresholds Confidential – Do not disclose

Clade C gp140 (250 mcg + adjuvant) Schema Group N Month 0 Month 3 Month 6 Month 12 1 1300 Ad26.Mos4.HIV + Clade C gp140 (250 mcg + adjuvant) 2 Placebo Total: 2600 female participants Anticipated enrollment: 14 months Anticipated total study duration: 50 months (includes enrollment and follow-up)

Standard of prevention All participants will be offered comprehensive prevention methods: Risk reduction counselling Condom provision PrEP referral where available PEP access Couple counselling STI treatment provision Contraception The trial will compare the vaccine + Standard of Care vs. Standard of Care alone

Summary Test of Concept Trial: Trial to see if the vaccine can work in the most vulnerable subjects of people at risk – women in sub-Saharan Africa If this trial shows that the vaccine is efficacious, future trials including men in all of the world will follow Trial is co-funded by the US National Institutes of Health and the Bill and Melinda Gates Foundation

Thank You!