Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap

Abstract

A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 10(9) PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4(+) T-cell and CD8(+) T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4(+) T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4(+) T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.).

Copyright © 2016 Gray et al.

Figures

FIG 1

Injection site and systemic reactogenicity. The severity of reactogenicity symptoms is shown for the DNA/MVA prime-boost study (panels A and B) and for the study extension with the protein vaccine or placebo control (panels C and D). Panels A and C indicate local injection site symptoms; panels B and D indicate systemic symptoms. The percentage of participants who experienced no, mild, moderate, or severe symptoms following each administration of placebo (labeled C), DNA (labeled D), MVA (labeled M), or protein (labeled P) is shown by treatment group for each part of the study.

FIG 2

Intracellular cytokine staining assay for vaccine-induced T-cell responses after MVA or placebo vaccinations. The percentages of CD4+ T cells (upper panel) and CD8+ T cells (lower panel) expressing IL-2 or IFN-γ in response to global PTE peptide pools representing the HIV antigens specifically indicated on the x axis or showing a response to any one of these antigens (ANY) are shown. HIV-1-specific CD4+ and CD8+ T-cell responses were measured using a validated ICS assay. Results are from 2 weeks after the first MVA vaccination (M1) and 2 weeks after the second MVA vaccination (M2). Results from the placebo control group are combined from time points 2 weeks after the fourth and fifth placebo injections (far left). Responder data are shown as red dots, and nonresponder data are shown as blue triangles. Box plots show the distribution of the magnitude of response in positive responders only. The box indicates the median and interquartile range (IQR); whiskers extend to the furthest point within 1.5 times the IQR from the upper or lower quartile. Numbers at the top of each panel show the percentage and number of responders from each group among the evaluable participants.

FIG 3

Intracellular cytokine staining assay in study extension participants. The percentages of CD4+ T cells (upper panel) and CD8+ T cells (lower panel) expressing IL-2 or IFN-γ in response to any antigen represented in the global PTE peptide pools (PTEG) as measured using a validated ICS assay are indicated. Results from study extension participants who had received the DNA/MVA regimen are shown over time, from 2 weeks after the first MVA vaccination (M1), 2 weeks after the second MVA vaccination (M2), at extension baseline (B) prior to injection with gp140 or placebo, 2 weeks after each study extension injection, and 6 months after the final injection. Participants received either placebo (DDDMMCC group) or protein (DDDMMPP). Responder data are shown as red dots, and nonresponder data are shown as blue triangles. Box plots show the distribution of the magnitude of response in positive responders only. The box indicates the median and interquartile range (IQR); whiskers extend to the furthest point within 1.5 times the IQR from the upper or lower quartile. Numbers at the top of each panel show the percentage and number of responders from each group among the evaluable participants.

FIG 4

The frequency and magnitude of IgG antibody binding by HIV-1 binding antibody multiplex assay (BAMA). Responses to ConS gp140 CFI (upper panel) and gp140ΔV2.TV1 (lower panel) are shown. The MFI-minus-blank response data summarize the magnitudes at a given time point. Results from study extension participants who had received the DNA/MVA regimen are shown over time, from samples obtained 2 weeks after the first MVA vaccination (M1), 2 weeks after the second MVA vaccination (M2), at extension baseline (B) prior to injection with gp140 or placebo, 2 weeks after each study extension injection, and 6 months after the final injection. Participants received either placebo (DDDMMCC group) or protein (DDDMMPP). Numbers at the top of each panel show the percentage and number of responders from each group among the evaluable participants. Plots include data from responders in red and nonresponders in blue. Box plots show the distribution of the magnitude of response in positive responders only; the midline denotes the median, and the ends of the box denote the 25th and 75th percentiles. Whiskers extend to the most extreme data points within 1.5 times the interquartile range.

FIG 5

Linear epitope-specific response measured by peptide microarray. (A) Proportions of linear binding responses to each epitope region. The peptide region for each epitope is listed as the peptide numbers in the array library in parentheses next to the name of the epitope. Sequences of all peptides in the microarray library have been published previously (15). For each subject, the percentage values for each epitope are calculated as follows: maximum binding to the epitope/sum of maximum binding to all epitopes. Each pie slice represents the average value for all subjects (n = 12) mapped in the study. (B) Clade/strain preferences of the two dominant specificities (V3 and C5). Magnitudes of binding (maximum binding intensities) to V3 and C5 peptides of each clade/strain are plotted. Each bar represents the average value of the results for all 12 subjects mapped.

FIG 6

Neutralization 50% tissue culture infective dose (ID50) titers in the TZM-bl cell assay against the MW965.26 HIV-1C virus. The titer distributions for each treatment group are shown by time point, from samples obtained 2 weeks after the first MVA vaccination (M1), 2 weeks after the second MVA vaccination (M2), at extension baseline (B) prior to the first injection with gp140 or placebo, 2 weeks after each study extension injection, and 6 months after the final injection. Participants received either placebo (DDDMMCC group) or protein (DDDMMPP). Numbers at the top of each panel show the percentage and number of responders from each group among the evaluable participants. Plots include data from responders in red and nonresponders in blue. Box plots show the distribution of the magnitude of response in positive responders only; the midline denotes the median, and the ends of the box denote the 25th and 75th percentiles. Whiskers extend to the most extreme data points within 1.5 times the interquartile range.