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Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

ABSTRACT: BACKGROUND:In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk. METHODS:In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Assays were performed on samples from 41 vaccinees who became infected and 205 uninfected vaccinees, obtained 2 weeks after final immunization, to evaluate whether immune-response variables predicted HIV-1 infection through 42 months of follow-up. RESULTS:Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P=0.02; q=0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P=0.03; q=0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies. CONCLUSIONS:This immune-correlates study generated the hypotheses that V1V2 antibodies may have contributed to protection against HIV-1 infection, whereas high levels of Env-specific IgA antibodies may have mitigated the effects of protective antibodies. Vaccines that are designed to induce higher levels of V1V2 antibodies and lower levels of Env-specific IgA antibodies than are induced by the RV144 vaccine may have improved efficacy against HIV-1 infection.

SUBMITTER: Haynes BF

PROVIDER: S-EPMC3371689 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

Haynes Barton F BF Gilbert Peter B PB McElrath M Juliana MJ Zolla-Pazner Susan S Tomaras Georgia D GD Alam S Munir SM Evans David T DT Montefiori David C DC Karnasuta Chitraporn C Sutthent Ruengpueng R Liao Hua-Xin HX DeVico Anthony L AL Lewis George K GK Williams Constance C Pinter Abraham A Fong Youyi Y Janes Holly H DeCamp Allan A Huang Yunda Y Rao Mangala M Billings Erik E Karasavvas Nicos N Robb Merlin L ML Ngauy Viseth V de Souza Mark S MS Paris Robert R Ferrari Guido G Bailer Robert T RT Soderberg Kelly A KA Andrews Charla C Berman Phillip W PW Frahm Nicole N De Rosa Stephen C SC Alpert Michael D MD Yates Nicole L NL Shen Xiaoying X Koup Richard A RA Pitisuttithum Punnee P Kaewkungwal Jaranit J Nitayaphan Sorachai S Rerks-Ngarm Supachai S Michael Nelson L NL Kim Jerome H JH

The New England journal of medicine 20120401 14

<h4>Background</h4>In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case-control analysis to identify antibody and cellular immune correlates of infection risk.<h4>Methods</h4>In pilot studies conducted with RV144 blood samples, 17 antibody or cellular assays met prespecified criteria, of which 6 were chosen for primary analysis to determine the roles of T-cell, IgG antibody, and IgA antibody responses i ...[more]

PMID: 22475592

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Project description:BackgroundIn the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection.MethodsThrough case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors.ResultsDay 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.42 (0.27, 0.65; p<0.001); 0.35 (0.20, 0.61; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%).ConclusionsBinding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19.Trial registration numberCOVE ClinicalTrials.gov number, NCT04470427.

Project description:BackgroundElevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.MethodsWe examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4(+) and CD8(+) T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-log(e) increase of the immune responses.FindingsWe found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-log(e) increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4(+) or CD8(+) T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).ConclusionsThe proportion of cells, likely CD4(+) T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study.

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Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

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Immune-correlates analysis of an HIV-1 vaccine efficacy trial.

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