Abstract
In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008–0.05; estimated odds ratios of 0.53–0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection.Trial RegistrationClinicalTrials.gov NCT00223080
Highlights
The RV144 HIV-1 clinical vaccine trial using ALVAC-HIV and AIDSVAX gp120 B/E resulted in an estimated vaccine efficacy of 31.2% measured 36 months after the six month vaccination series [1]
Scaffolds that would include reagents with various immunologic characteristics, 19 V1V2-scaffolds and gp70WT.AP were tested by enzyme-linked immunosorbent assay (ELISA) in an initial ‘‘Phase 1’’ study (Table 1) using a set of plasma specimens drawn before immunization (Week 0) and two weeks after the last immunization (Week 26) from eight placebo and 32 vaccine recipients
There was a significant inverse correlate of risk (CoR) provided by Ab reactivity with two antigens carrying V1V2 regions from subtype C: gp70.C(97ZA012)-V1V2 and tags.C(1086)-V1V2 derived from a transmitted/founder virus
Summary
The RV144 HIV-1 clinical vaccine trial using ALVAC-HIV and AIDSVAX gp120 B/E resulted in an estimated vaccine efficacy of 31.2% measured 36 months after the six month vaccination series [1]. The level of IgG antibodies (Abs) binding to a fusion protein consisting of the first and second variable regions (V1V2) of an HIV-1 gp120 envelope glycoprotein and the gp of murine leukemia virus [2] was identified as a statistically significant inverse correlate of risk (CoR) of HIV-1 infection [3,4]. The identification of an inverse CoR with Ab reactivity to a variable region of the HIV-1 gp120 envelope protein provided. Phase 1+ Phase 2` Case-Control ELISA* BAMA**.
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