Analysis of the HIV Vaccine Trials Network 702 Phase 2b–3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk

Abstract

Background The ALVAC/gp120 + MF59 vaccines in the HVTN 702 efficacy trial did not prevent HIV-1 acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. Methods Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative non-cases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks post-fourth and fifth immunizations. Cox proportional hazards models assessed pre-specified responses as predictors of HIV-1 acquisition. Results The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs. 40%, P = 0.03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs. 100%, P< 0.001; Pmag< 0.001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P<=0.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). Conclusions HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T-cells with HIV-1 acquisition.

WITHDRAWN: Immunogenicity of a cold-chain friendly and long-term stable HIV multi-epitope protease cleavage sites (MEPCS)-mRNA-LNP vaccine.

“…Nevertheless, the only HIV vaccine clinical trial demonstrating modestly efficacious is "The RV144 Thai trial", with 31.2% protection 7 . However, the efficacy of the clinical trial of "The HVTN-702", conducted as an extension of the RV144 trial 8,9 , was ineffective 10,11 . Further, recently the clinical efficacy trials of the "Imbokodo study" (HVTN 705/HPX2008) and "the Mosaico" (HVTN 706/ HPX3002 Mosaico) were pre-maturely discontinued due to the lack of efficacies 12 .…”

A rabies virus-vectored vaccine expressing two copies of the Marburg virus glycoprotein gene induced neutralizing antibodies against Marburg virus in humanized mice

“…Squalene is easily metabolized by the body, and numerous studies have shown that squalene-based oil-in-water nano adjuvants can induce both good humoral and cellular immune responses [ 41–43 ]. Moreover, the squalene adjuvant MF59 has been approved for influenza vaccines [ 44 ]. Therefore, we used AddaVax adjuvant, similar in composition to MF59, to evaluate the immunogenicity of inactivated rS-MARV.…”

Needle-Free Devices and CpG-Adjuvanted DNA Improve Anti-HIV Antibody Responses of Both DNA and Modified Vaccinia Ankara-Vectored Candidate Vaccines

“…HIV is still a major problem in the world and particularly in South Africa, where it is estimated that 7.9 million people are living with HIV—which translates to 14% of the population [ 1 ]. One of the means of controlling the ongoing HIV pandemic is by prophylactic vaccination; unfortunately, only one trial has shown modest efficacy [ 2 ] with a number of recent vaccine trials being unsuccessful [ 3 , 4 ]. Trials of infused monoclonal antibodies demonstrated the broadly neutralizing monoclonal antibody, VRC01, was able to prevent infection by viruses that were sensitive to neutralization by this antibody [ 5 ].…”

“…In the RV144 trial, the correlate of protection was described as high V1V2 Ab reactivity in plasma and low Env-specific IgA in plasma [ 16 ]. However, clinical trials based on the same concept as RV144 have not been successful [ 3 ]. In addition, while a lot of emphasis is placed on testing HIV vaccines in non-human primates, the correlates of protection that have been predicted from non-human primate studies as well as various clinical trials are not consistent [ 17 ].…”