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HVTN 702 Confidential – Do Not Distribute.

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Presentation on theme: "HVTN 702 Confidential – Do Not Distribute."— Presentation transcript:

1 HVTN 702 Confidential – Do Not Distribute

2 HVTN 702 Protocol Team Confidential – Do Not Distribute

3 3 Novel Strategies for Efficacy
Efficacy Studies P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702) Multi-clade approach using rAd26/MVA/gp140 trimer (Crucell/Janssen) Neutralizing antibody approach using VRC01 (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085)

4 P5 strategy based on the Thai Trial (RV144) Primary Results
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.9 0.8 0.7 0.6 0.4 0.3 0.2 0.1 Years Probability of HIV Infection (%) Placebo Vaccine Modified Intention-to-Treat Analysis*

5 Construction of the P5 Clade C Vaccine Regimen: Rationale for HVTN 702
Construct Bivalent Subtype C gp120/MF59 Add Booster at 12 and now 18 months Construct ALVAC-HIV-C (vCP2438) Optimize regimen for regional relevance, increased potency, and durability

6 1ST EFFICACY SIGNAL IN AN HIV VACCINE TRIAL
AIDSVAX (GP120) B/E + ALVAC + ALUM RV144 2009 RV144 REGIMEN HAS GOOD SAFETY PROFILE + SLIGHTLY BETTER IMMUNOGENICITY IN SA COMPARED TO THAILAND HVTN097 2014 PHASE 1-2a: SAFETY + IMMUNOGENICITY CLADE C PRODUCTS: ALVAC-C, gp120-C, MF59® FOLLOW UP HVTN100 2015- PHASE 2b-3 EFFICACY CLADE C PRODUCTS HVTN702 2016 Adapted from: Gray GE, Laher F, Lazarus E, Ensoli B, Corey L. Approaches to preventative and therapeutic HIV vaccines. Curr Opin Virol.

7 P5 Vaccine Program: HVTN 100 & HVTN 702 Dosing Schedule
Dose 1 ALVAC Dose 3 ALVAC, gp120/MF59 Dose 2 ALVAC Dose 4 Booster 1 6 12 3 HVTN 100 HVTN 702 MONTH RV144 Dose 1 ALVAC Dose 3 ALVAC, AIDSVAX gp120 Dose 2 ALVAC Dose 4 ALVAC, AIDSVAX gp120 1 6 3 MONTH

8 Criteria required to move into efficacy testing
Criterion 1: Prevalence of antibodies to gp120 vaccine antigens to be ≥ 75% 100% of HVTN 100 subjects developed Env binding antibodies to the Clade C strain in the ALVAC vector, as well as the two Clade C strains in the bivalent gp120 protein boost. Criterion 2: Magnitude of Env antibody response to be ≥ 50% of that seen in RV144 HVTN 100 binding antibody responses were 3.6 to 8.8 fold higher than in RV144. Criterion 3: CD4 T cell response to Env will be at least equal to that seen in RV144 HVTN 100 Env specific CD4 T cell responses exceeded those in RV144 (58% vs. 41%, respectively) and showed considerably higher polyfunctionality than in RV144. (3B. The polyfunctionality score was shown to be an independent correlate of VE in RV144.) Criterion 4: Prevalence of IgG antibodies to the V1V2 loop to be ≥ 63% Prevalence of IgG V1V2 to the 1086 Clade C strain in the vaccine was 71% The cumulative prevalence of IgG antibodies to the V1V2 loop was 80%; this level exceeds the threshold predicted for a VE=50% based upon RV144 Confidential – Do Not Distribute

9 HVTN 100 go no go criteria provided the green light to proceed to HVTN 702
Confidential – Do Not Distribute

10 HVTN 702 A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59 in preventing HIV-1 infection in adults in South Africa Started in Nov 2016 in RSA Glenda Gray, Chair Co-Chairs: Linda Gail Bekker, Fatima Laher, Mookh Malaheha Womandla!

11 Study Schema: HVTN 702 Open for 39 weeks: 997 participants enrolled, averaging 25.6/week N (total 5400) Primary Vaccine Regimen Booster Month 0 Month 1 Month 3 Month 6 Month 12 2700 ALVAC-HIV (vCP2438) ALVAC-HIV (vCP2438) ALVAC-HIV+ Bivalent Subtype C gp120/MF59® ALVAC-HIV+ Bivalent Subtype C gp120/MF59® Placebo Placebo + Placebo Estimated Total Study duration 72 months: Stage 1: 60 months-18 months for enrolment, 24 months of follow-up for HIV-1 uninfected individuals, 18 months follow up for HIV-1 infected individuals) Stage 2: an additional 12 months of follow up for uninfected individuals

12 Power to reject null: VE (0-24) ≤ 25%
Study Design Features Evaluates Stage 1 vaccine efficacy (VE) to 24 months after 1st vaccination If evidence of positive VE, evaluates VE durability to 36 months after 1st vaccination Continuous monitoring for harm Sequential monitoring for non-efficacy non-efficacy/efficacy futility Monitoring for high efficacy 90% power to detect VE of 50% (enrollment through 24 months) = 90% power to reject null hypothesis (VE ≤ 25%) True Average VE (0-24) Power to reject null: VE (0-24) ≤ 25% 30% 7 40% 45 50% 90 60% 100 70% 80%

13 HVTN 702 timeline You Are Here * First DSMB
*Approximate date: Timing of the first interim futility analysis is endpoint drive. Confidential – Do Not Distribute

14 HVTN 100 data to support 18 month boost
Confidential – Do Not Distribute

15 Month 18 booster HVTN 702 designed, in part, to test hypothesis that Correlates of Risk (CoR) identified in RV144 are, in fact, Correlates of vaccine Protection (CoP) Specifically, IgG antibodies to V1V2 epitopes in Env Ab titers drop rapidly from peak after vaccination 11/16/2018 Confidential – Do Not Distribute

16 HVTN 100 Clade C V1V2 Panel Data
Confidential – Do Not Distribute

17 Predicted Average Immune Response Profiles: Clade C V1V2 AUC-MB
Scaled AUC is calculated using trapezoidal rule as the area under the mean log10 MFI curve, divided by 17.5 Confidential – Do Not Distribute

18 Predicted Average Immune Response Profiles: gp70_B.CaseA_V1_V2
With Month 18 boost, VE(6.5-24) is predicted to be 14% higher* * Based on RV144, each log10 net MFI increase is predicted to yield a 45% VE(6.5-24) increment Scaled AUC is calculated using trapezoidal rule as the area under the mean log10 MFI curve, divided by 17.5 Confidential – Do Not Distribute

19 18 month boost Adding a Month 18 boost to HVTN 702 is predicted to generate a higher average immune response over Months higher expected log MFI V1V2 response over Month , due to higher responses Month 18-24 18% and 14% higher predicted VE(6.5-24) based on C.1086C_V1_V2 Tags and gp70_B.CaseA_V1_V2 antigens Confidential – Do Not Distribute

20 Summary Using human clinical trials with intense evaluation of the Correlates of Protection is in the end - true “rational vaccine design”. For the first time, the basic science agenda in HIV vaccine development will be based on human clinical trials.

21 Partially efficacious vaccine can have impact!

22 HVTN 702 Protocol Team Acknowledgments
Chair Glenda Gray, PHRU Cochair Fatima Laher, PHRU Linda-Gail Bekker, Univ of Cape Town Mookho Malahleha, Setshaba Research Center PTL / CMM Nicole Grunenberg, HVTN Lab Lead John Hural, HVTN Statistician Holly Janes, SCHARP Yunda Huang, SCHARP Zoe Moodie, SCHARP Medical Officer Mary Allen, DAIDS, NIAID Community Engagement Unit RCSL Nandi Luthuli, HVTN Keitumetse Diphoko, HCRISA CSS REG Megan Jones, HVTN Elizabeth Briesemeister, HVTN CTM RML Shelly Ramirez, HVTN Simba Takuva, HCRISA Developer SCDM Carlos DiazGranados, Sanofi Gina Escamilla, SCHARP Corinne Lecomte, GSK Social Scientist Marguerite Koutsoukos, GSK Michele Andrasik, HVTN Olivier Van Der Meeren, GSK Millicent Atujuna, Univ of Cape Town Sanjay Phogat, Sanofi SRA Lab Brittany Sanchez, SCHARP On Ho, HVTN Doug Grove, SCHARP Lead Clinic Coordinator CAB Rep Katlego Mapetla, Setshaba Bulelwa Zono, Cape Town-Emavundleni PDM Kagiso Mothwa, Setshaba Carter Bentley, HVTN Themboko Maduna, PHRU-Soweto Pharmacist CER Rep Bijal Patel, DAIDS, NIAID Phumla Madi, PHRU - Kliptown Irene Rwakazina, DAIDS, NIAID Technical Editor Project Officer Erik Schwab, HVTN Michael Pensiero, DAIDS, NIAID Vijay Mehra, DAIDS, NIAID 11/16/2018

23 HVTN 702 - Acknowledgements
Funders & Other Collaborators NIAID/DAIDS BMGF South African Medical Research Council (SAMRC) GSK (formerly Novartis) Sanofi Pasteur Stats Brittany Sanchez, SCHARP Doug Grove, SCHARP Holly Janes, SCHARP Tahereh Nourbakhsh, SCHARP Yunda Huang, SCHARP Zoe Moodie, SCHARP Data Management Gina Escamilla, SCHARP Hannah Leingang, SCHARP 11/16/2018

24 Thank you to all the study participants, site investigators, clinic coordinators, CER teams, and site pharmacists. HVTN 702 Sites: Cape Town - Khayelitsha Mthatha Durban - eThekwini Rustenburg Durban - Isipingo Soshanguve Durban - Verulam Soweto - Bara Klerksdorp Soweto - Kliptown Ladysmith Tembisa Medunsa 11/16/2018

25 Clinical Research Site staff Community Stakeholders
Acknowledgements NIH, NIAID, DAIDS Anthony Fauci Carl Dieffenbach Mary Marovich Dale Hu Mary Allen Mary Ann Luzar Bijal Patel Michael Pensiero BMGF Emilio Emini Nina Russell Peggy Johnston Pervin Anklesaria Silvija Staprans Participants Clinical Research Site staff CAB members Community Stakeholders GSK Marguerite Koutsoukos Olivier Van-der-Meeren SANOFI PASTEUR Sanjay Gurunathan Jim Tartaglia Sanjay Phogat Carlos DiazGranados HVTN CORE Larry Corey Jim Kublin Nicole Grunenberg Carter Bentley Shelly Ramirez Niles Eaton Megan Jones Simba Takuva Nandi Luthuli Emilder Chihota Michelle Nebergall Kate Hopkins Liz Briesemeister Rachel McClennan Jim Maynard Bert LeRoux Co-Chairs Linda-Gail Bekkker Mookho Malahleha Fatima Laher SCHARP Holly Janes Zoe Moodie Yunda Huang Doug Grove Shannon Grant April Randhawa Jessica Andriesen Gina Escamilla Peter Gilbert Protocol CAB Kagiso Mothwa Thembeka Maduna Clinic coordinator Katlego Mapetla CER Phumla Madi Social scientists Michele Peake-Andrasik Millicent Atujuna HVTN LAB Julie McElrath John Hural On Ho Mike Stirewalt Andries Engelbrecht MRC (SA)

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