Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.
Linda-Gail Bekker, Zoe Moodie, Nicole Grunenberg, Fatima Laher, Georgia D Tomaras, Kristen W Cohen, Mary Allen, Mookho Malahleha, Kathryn Mngadi, Brodie Daniels, Craig Innes, Carter Bentley, Nicole Frahm, Daryl E Morris, Lynn Morris, Nonhlanhla N Mkhize, David C Montefiori, Marcella Sarzotti-Kelsoe, Shannon Grant, Chenchen Yu, Vijay L Mehra, Michael N Pensiero, Sanjay Phogat, Carlos A DiazGranados, Susan W Barnett, Niranjan Kanesa-Thasan, Marguerite Koutsoukos, Nelson L Michael, Merlin L Robb, James G Kublin, Peter B Gilbert, Lawrence Corey, Glenda E Gray, M Juliana McElrath, HVTN 100 Protocol Team
Author Information
Linda-Gail Bekker: The Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa. Electronic address: linda-gail.bekker@hiv-research.org.za.
Zoe Moodie: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Nicole Grunenberg: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Fatima Laher: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Georgia D Tomaras: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Kristen W Cohen: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Mary Allen: Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Mookho Malahleha: Setshaba Research Centre, Soshanguve, Pretoria, South Africa.
Kathryn Mngadi: Centre for the Programme of Aids Research in South Africa (CAPRISA), Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
Brodie Daniels: South African Medical Research Council, Durban, South Africa.
Craig Innes: The Aurum Institute, Klerksdorp Research Centre, Klerksdorp, South Africa.
Carter Bentley: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Nicole Frahm: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Daryl E Morris: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lynn Morris: National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
Nonhlanhla N Mkhize: National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
David C Montefiori: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Marcella Sarzotti-Kelsoe: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Shannon Grant: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Chenchen Yu: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Vijay L Mehra: Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Michael N Pensiero: Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Sanjay Phogat: Sanofi Pasteur, Swiftwater, PA, USA.
Carlos A DiazGranados: Sanofi Pasteur, Swiftwater, PA, USA.
Susan W Barnett: GSK Vaccines, Cambridge, MA, USA; Bill & Melinda Gates Foundation, Seattle, WA, USA.
Nelson L Michael: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Merlin L Robb: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
James G Kublin: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Peter B Gilbert: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Lawrence Corey: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Glenda E Gray: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; South African Medical Research Council, Cape Town, South Africa.
M Juliana McElrath: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
BACKGROUND: Modest efficacy was reported for the HIV vaccine tested in the RV144 trial, which comprised a canarypox vector (ALVAC) and envelope (env) glycoprotein (gp120). These vaccine components were adapted to express HIV-1 antigens from strains circulating in South Africa, and the adjuvant was changed to increase immunogenicity. Furthermore, 12-month immunisation was added to improve durability. In the HIV Vaccine Trials Network (HVTN) 100 trial, we aimed to assess this new regionally adapted regimen for advancement to efficacy testing. METHODS: HVTN 100 is a phase 1/2, randomised controlled, double-blind trial at six community research sites in South Africa. We randomly allocated adults (aged 18-40 years) without HIV infection and at low risk of HIV infection to either the vaccine regimen (intramuscular injection of ALVAC-HIV vector [vCP2438] at 0, 1, 3, 6, and 12 months plus bivalent subtype C gp120 and MF59 adjuvant at 3, 6, and 12 months) or placebo, in a 5:1 ratio. Randomisation was done by computer-generated list. Participants, investigators, and those assessing outcomes were masked to random assignments. Primary outcomes included safety and immune responses associated with correlates of HIV risk in RV144, 2 weeks after vaccination at 6 months (month 6·5). We compared per-protocol participants (ie, those who completed the first four vaccinations and provided samples at month 6·5) from HVTN 100 with stored RV144 samples assayed contemporaneously. This trial is registered with the South African National Clinical Trials Registry (DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311). FINDINGS: Between Feb 9, 2015, and May 26, 2015, 252 participants were enrolled, of whom 210 were assigned vaccine and 42 placebo. 222 participants were included in the per-protocol analysis (185 vaccine and 37 placebo). 185 (100%) vaccine recipients developed IgG binding antibodies to all three vaccine-matched gp120 antigens with significantly higher titres (3·6-8·8 fold; all p<0·0001) than the corresponding vaccine-matched responses of RV144. The CD4+ T-cell response to the ZM96.C env protein in HVTN 100 was 56·4% (n=102 responders), compared with a response of 41·4% (n=79 responders) to 92TH023.AE in RV144 (p=0·0050). The IgG response to the 1086.C variable loops 1 and 2 (V1V2) env antigen in HVTN 100 was 70·5% (95% CI 63·5-76·6; n=129 responders), lower than the response to V1V2 in RV144 (99·0%, 95% CI 96·4-99·7; n=199 responders). INTERPRETATION: Although the IgG response to the HVTN 100 vaccine was lower than that reported in RV144, it exceeded the predicted 63% threshold needed for 50% vaccine efficacy using a V1V2 correlate of protection model. Thus, the subtype C HIV vaccine regimen qualified for phase 2b/3 efficacy testing, a critical next step of vaccine development. FUNDING: US National Institute of Allergy and Infectious Diseases (NIAID), and Bill & Melinda Gates Foundation.
