Randomized, Double-Blind Evaluation of Late Boost Strategies for HIV-Uninfected Vaccine Recipients in the RV144 HIV Vaccine Efficacy Trial

Abstract

Background: The RV144 ALVAC-HIV prime, AIDSVAX B/E boost afforded 60% efficacy against human immunodeficiency virus (HIV) acquisition at 1 year, waning to 31.2% after 3.5 years. We hypothesized that additional vaccinations might augment immune correlates of protection.

Methods: In a randomized placebo-controlled double-blind study of 162 HIV-negative RV144 vaccine recipients, we evaluated 2 additional boosts, given 6-8 years since RV144 vaccination, for safety and immunogenicity, at weeks 0 and 24. Study groups 1-3 received ALVAC-HIV+AIDSVAX B/E, AIDSVAX B/E, and ALVAC-HIV, respectively, or placebo.

Results: Vaccines were well tolerated. For groups 1 and 2, plasma immunoglobulin (Ig) G, IgA, and neutralizing antibody responses at week 2 were all significantly higher than 2 weeks after the last RV144 vaccination. IgG titers against glycoprotein (gp) 70V1V2 92TH023 increased 14-fold compared with 2 weeks after the last RV144 vaccination (14069 vs 999; P < .001). Groups 1 and 2 did not differ significantly from each other, whereas group 3 was similar to placebo recipients. Responses in groups 1 and 2 declined by week 24 but were boosted by the second vaccination, albeit at lower magnitude than for week 2.

Conclusions: In RV144 vaccinees, AIDSVAX B/E with or without ALVAC-HIV 6-8 years after initial vaccination generated higher humoral responses than after RV144, but these responses were short-lived, and their magnitude did not increase with subsequent boost.

Clinical trials registration: NCT01435135.

Keywords: HIV; RV144; prime-boost.; vaccine.

Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Figures

Figure 1.

RV305 study design. Left, RV144 study vaccinations. Each RV305 participant received ALVAC-HIV (abbreviated ALVAC) and AIDSVAX B/E (abbreviated AIDSVAX) at the indicated time points, followed by a 6–8-year interval before RV305 enrollment. Participants were randomized to 1 of 3 groups and received inoculations at weeks 0 and 24. Group 1 received both ALVAC and AIDSVAX, group 2 received AIDSVAX alone, and group 3 received ALVAC alone. Participants were randomized within each group to receive either active vaccine product or corresponding placebo injections in a 5:1 ratio, and followed up for 12 months after the last injection.

Figure 2.

Immunoglobulin (Ig) G binding antibody responses against gp120 and scaffolded variable regions 1 and 2 (V1V2) antigens. Reciprocal titers against gp120 (A244 gD (A), gp70 V1V2 (92TH023) (B), and gp70 V1V2 (case A2) (C) are shown. Each panel graphically depicts titers for RV305 on the right, and for these same individuals in RV144 on the left, as along with numeric depiction of geometric mean titers, color coded where red represents ALVAC-HIV/AIDSVAX B/E; green, AIDSVAX B/E; blue, ALVAC-HIV; and purple, RV144. Error bars depict 95% confidence intervals. RV305 vaccine administration timing is indicated by black arrows. By study design, all volunteers were RV144 active product recipients, completing the 4 vaccination series on RV144 study week 24 (vaccinations not shown). Statistical significance was assessed using the Mann–Whitney U test. P values are color coded for pairwise within-group comparisons between time points indicated by black bars. Only comparisons reaching statistical significance at the level of P < .05 are shown. Results from RV305 volunteers randomized to receive placebo did not differ significantly from those from the ALVAC-HIV group (data not shown). *P < .05 to .001; †P < .001.

Figure 3.

Neutralizing antibody (Nab) activity against tier 1A envelope (Env)–pseudotyped viruses assayed in TZM-bl cells. Neutralization was assessed before the first boost (week 0 [W0]), 2 weeks after the first boost (W2), and 2 weeks after the second boost (W26). Assays were performed with 2 of the vaccine strains (MN.3, protein boost; TH023, vCP1521 prime) and 2 heterologous tier 1A viruses (MW965.26, clade C; SF162.LS, clade B). RV305 placebo recipients are designated as “no late boost” volunteers to emphasize that although they received placebo during RV305, they are not vaccine naive owing to previous receipt of RV144 vaccines. Medians are shown with 95% confidence interval with median, and boxes represent interquartile ranges. ID50, 50% inhibitory dose.

Figure 4.

Immunoglobulin A antibody responses to human immunodeficiency virus (HIV) type 1 envelopes induced in RV144 and RV305. Binding antibody multiplex assay responses to A1.con gp140 (A), B.MN gp120 (B), A/E.A244 gp120 (C), and A/E.92TH023 gp120 (D). The sample sizes were 12, 8, and 12 for groups 1, 2, and 3, respectively. Medians and ranges are shown. The threshold for positivity is shown by a dashed line and is calculated for each envelope protein separately, as the mean + 3 standard deviations (after removing outliers >5 times the interquartile range) of the mean fluorescent intensity (MFI) from ≥30 RV144 baseline plasma samples assayed at 1:40 dilution, or a minimum of 100.

Figure 5.

CD4+ T-cell responses. A, B, Percentage of vaccine responders as measured by interferon (IFN) γ (A), or interleukin-2 (IL-2) (B) production at study weeks shown on the x-axis for each study group; group 1 (ALVAC-HIV + AIDSVAX B/E) is shown in red, group 2 (AIDSVAX B/E) in green, group 3 (ALVAC-HIV) in blue, and volunteers (who did not receive active vaccine during this late boost study) in black. RV305 placebo recipients are designated as “no late boost” volunteers to emphasize that although they received placebo during RV305, they are not vaccine naive owing to previous receipt of RV144 vaccines. C, COMPASS (Combinatorial Polyfunctionality Analysis of Single Cells) functionality score by treatment group and visit for T cells stimulated with human immunodeficiency virus (HIV) type 1 envelope protein (92TH023), based on the 6 cytokines measured (154, 107, IL-2, interleukin 4 [IL-4], IFN-γ, and tumor necrosis factor [TNF] α). Points show the observed functionality score, and box plots show the median and interquartile range. Whiskers extend out to the most extreme data point that is ≤1.5 times the interquartile range from the upper or lower quartile. Functionality scores were compared between active treatment groups and the pooled RV305 placebo recipients at weeks 2 and 26, using a Wald test as described in Methods. Significant P values with a corresponding multiplicity adjusted Q value ≤ 0.2 (method of Benjamini and Hochberg) are shown above the corresponding box plot. The median and range of the mean fluorescence intensity are plotted by RV305 vaccine regimen (G1 ALVAC-HIV/AIDSVAX B/E in red, G2 AIDSVAX B/E in green, and G3 ALVAC-HIV in blue), for the 4 antigens A1.con gp140, B.MN gp120, A/E.A244 gp120, and A/E.92TH023 gp120, by week tested (bold font below x-axis). Medians from adjacent weeks are connected by lines.