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, 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

Abstract

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.

Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
HVTN 100 trial profile and prespecified immunological criteria scoring Env=envelope. GMT=geometric mean titre. V1V2=variable loops 1 and 2. *Prespecified immunological criterion passed.
Figure 2
Figure 2
Binding antibody responses to env gp120 vaccine-insert antigens among vaccine recipients at month 6·5 Boxplots show (A) IgG and (B) IgG3 responses and are based on positive responders only (shown as coloured circles); negative responders are shown as grey triangles and positive response rates are indicated above the boxes. p values compare response rates (prate) and magnitudes (pmag) among positive responders between HVTN 100 and RV144 vaccine recipients. env=envelope glycoprotein. MFI=mean fluorescence intensity.
Figure 3
Figure 3
Binding antibody response rates to V1V2 antigens among vaccine recipients at month 6·5 Boxplots show (A and B) IgG and (C) IgG3 responses to vaccine-matched antigens and are based on positive responders only (shown as coloured circles); negative responders are shown as grey triangles and positive response rates are indicated above the boxes. p values compare response rates (prate) and magnitudes (pmag) among positive responders between HVTN 100 and RV144 vaccine recipients. (D) Plot shows the magnitude–breadth of IgG binding antibody responses to subtype C env V1V2 antigens among vaccine recipients in the per-protocol cohorts of HVTN 100 and RV144 2 weeks after the month 6 vaccination. Solid curves are average breadth across individuals for HVTN 100 and RV144 vaccine recipients. Breadth is defined as the proportion of antigens in the panel with log10 (MFI – blank) greater than the threshold on the x axis. AUC=area under the curve. env=envelope glycoprotein. MFI=mean fluorescence intensity. V1V2=variable loops 1 and 2.
Figure 4
Figure 4
CD4+ T-cell responses to vaccine-matched env antigens among vaccine recipients at month 6·5 (A) Boxplots show expression of interleukin-2, interferon-γ, or CD40L by CD4+ T cells and are based on positive responders only (shown as coloured circles); negative responders are shown as grey triangles and positive response rates are indicated above the boxes. p values compare response rates (prate) and magnitudes (pmag) among positive responders between HVTN 100 and RV144 vaccine recipients. One participant had a positive response to env.TV1.C gp120 greater than 2%. (B and C) Heatmaps of COMPASS posterior probabilities for CD4+ T-cell subsets to env antigens. Columns correspond to the different cell subsets, identified by the blue, green, and pink grid that indicates 19 of 32 possible subsets with env-specific responses detectable in more than five cells and in more than two participants in HVTN 100. Purple and white colour-coding indicates the expression of cytokines (white indicates the subset is not expressed, purple shading indicates it is expressed), ordered by degree of functionality from one function on the left (light blue) to five functions on the right (pink). Rows correspond to participants, ordered by treatment group (placebo or vaccine), and by functionality score within each group. Each cell of the heatmap shows the probability that the corresponding cell-subset (column) shows an antigen-specific response in the corresponding participant (row), where the probability is colour-coded from white (zero) to purple (one). (D) Functionality and polyfunctionality scores of CD4+ T-cell subsets recognising env antigens. COMPASS=combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. env=envelope glycoprotein. IFN=interferon. IL=interleukin.

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