Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial

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Abstract

The RV144 phase 3 vaccine trial in Thailand demonstrated that ALVAC-HIV (vCP1521) and AIDSVAX® B/E administration over six months resulted in a 31% efficacy in preventing HIV acquisition. In this trial, we assessed the immunologic impact of an additional vaccine boost to the RV144 regimen at varying intervals between the priming vaccine series and the boost. RV306 is a double-blind, placebo-controlled, randomized clinical trial conducted in three clinical sites in Thailand. HIV-uninfected volunteers aged 20–40 randomly received the primary RV144 vaccine series at months 0, 1, 3, and 6, with no additional boost (Group I), additional AIDSVAX® B/E and ALVAC-HIV (vcp1521) at month 12 (Group II), AIDSVAX® B/E alone at month 12 (Group III), AIDSVAX® B/E and ALVAC-HIV at month 15 or 18 (Groups IVa or IVb), or placebo and were followed for 24 months. A randomization schedule was centrally generated with fixed sized strata for RIHES Chiang Mai (n=60) and combined Bangkok clinics (n=300). Primary outcomes were to assess the safety and tolerability of these vaccination regimens and characterize and compare cellular and humoral immune responses between the RV144 series alone and late boosts at different timepoints. Safety and tolerability outcomes were assessed by evaluating local and systemic reactogenicity and adverse events in all participants. Primary immunogenicity outcomes were evaluated by comparing peak humoral responses (HIV-specific IgG and IgA ELISA) and cellular responses (HIV-specific intracellular cytokine staining and polyfunctionality) two weeks post final vaccination among per-protocol participants who completed all vaccinations. This trial is registered at ( ClinicalTrials.gov ( NCT01931358 ); clinical follow up is now complete. Between 28 October 2013 and 29 April 2014, 367 participants were enrolled, of whom 27 were assigned active vaccination in Group I, 102 in Group II, 101 in Group III, 52 in Group IVa, 51 in Group IVb, and 34 combined placebo across all groups. Late boosting did not induce vaccine-related serious adverse events. There were no significant differences in the occurrence or severity of local or systemic reactogenicity across active groups. Groups with late boosts (Groups II, III, IVa, and IVb) had increased peak plasma IgG binding antibody levels against gp70 V1V2 relative to Group I vaccine recipients with no late boost (gp70V1V2 92TH023 adjusted p < 0·02 for each; gp70V1V2 Case A2 adjusted p<0·0001 for each). Boosting at month 12 (Groups II and III) did not increase gp120 responses compared to the peak responses after the RV144 priming regimen at month 6; however, boosting at month 15 (Group IVa) improved responses to gp120 A244gD- D11 (p=0·0003), and boosting at month 18 (Group IVb) improved responses to both gp120 A244gD- D11 (p<0·0001) and gp120 MNgD- D11 (p=0·0016). Plasma IgG responses were significantly lower among vaccine recipients boosted at month 12 (pooled Groups II+III) than at month 15 (Group IVa; adjusted p < 0·0001 for each except for gp70 V1V2 CaseA2 p = 0·0142) and at month 18 (Group IVb; all adjusted p < 0·001). Boosting at month 18 versus month 15 resulted in a significantly higher plasma IgG response to gp120 antigens (all adjusted p < 0·01) but not gp70 V1V2 antigens. CD4+ functionality and polyfunctionality scores after stimulation with HIV-1 Env peptides (92TH023) increased with delayed boosting: month 18 (Group IVb) > month 15 (Group IVa) > month 12 (Groups II+III) > no late boost (Group I). Groups with late boosts had increased both functionality and polyfunctionality scores relative to vaccine recipients with no late boost (all adjusted p < 0·05, except for polyfunctionality score in Group I vs in Group IVb p < 0·01). Taken together, these results suggest that additional boosting of the RV144 regimen with longer intervals between the primary vaccination series and late boost improved immune responses and may improve the efficacy of preventing HIV acquisition. US National Institute of Allergy and Infectious Diseases (NIAID) and U.S. Department of the Army.

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HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.

Michael R Betts, Martha C Nason, Sadie M West … (2006)

Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.

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Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.

Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayaphan … (2009)

The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.) 2009 Massachusetts Medical Society

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

Barton Haynes, Peter Gilbert, M. Juliana McElrath … (2012)

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. 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. 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. 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.