Background: The RV144 ALVAC-HIV/AIDSVAX® B/E/alum HIV vaccine trial conducted in Thailand demonstrated 31% vaccine efficacy at 3.5 years. Following RV144, vaccine components were modified to express HIV-1 antigens matched to circulating clade C strains, the adjuvant was changed to MF59 and a booster immunization was added. The vaccine regimen of clade C ALVAC-HIV (strains ZM96 and LAI), and bivalent subtype C gp120 (strains 1086.C and TV-1) /MF59 is being tested in a phase1/2 trial, HVTN100 in 6 South African clinical trial sites. Archived RV144 samples were contemporaneously compared to vaccine-induced immune responses in HVTN100 samples. Four pre-specified immune criteria associated with vaccine take; potency and correlates of risk in RV144 guided the decision about whether or not to proceed to a phase 2b efficacy trial.
Methods: 52 HIV-uninfected adults (43% female) were enrolled and randomly assigned to receive vaccine (n= 210) or placebo (n=42). Humoral and cellular responses were measured 2 weeks after the 6-month vaccination (ALVAC-HIV/Bivalent Subtype C gp120/MF59 boost) in HVTN100 (185 vaccine/ 37 placebo) and contemporaneously assayed RV144 (201 vaccine/ 24 placebo) samples from per-protocol participants. Twelve-month booster vaccinations are currently ongoing.
Results: No safety concerns were identified. 100% of HVTN100 vaccine-recipients developed IgG binding antibodies to all three clade C gp120 vaccine-matched envelope insert antigens with significantly higher titers (3.6-8.8 fold, P''s < 0.001) than in RV144 to the corresponding RV144 vaccine-matched antigens. CD4 T cell response rate to the ALVAC ZM96 envelope antigen in HVTN100 was 57.5% vs. 41.4% to 92TH023 in RV144 (P=0.002), with a significantly greater 5-function polyfunctionality score in HVTN100 (P < 0. 001). 80% (95%CI=74.0%-85.4%) of participants in HVTN100 demonstrated an IgG response to at least one of the three vaccine-matched V1V2 antigens, above the 63% threshold needed to predict 50% vaccine efficacy in a Phase 2b trial under a V1V2 correlate of protection model.
Conclusions: Cellular and humoral immune responses in HVTN100 met pre-specified criteria, supporting future evaluation in a phase 2b vaccine efficacy trial. This will also be critical for defining relevant correlates of protection of this regimen in Southern African.