Effect of HIV Envelope Vaccination on the Subsequent Antibody Response to HIV Infection

Abstract

Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial, n = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial, n = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial, n = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth.IMPORTANCE There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.

Keywords: DNA/MVA vaccines; HIV breakthrough infections; HIV vaccines; HIV-1 envelope; HIV-specific binding antibodies; binding antibody epitopes; broadly neutralizing antibodies; rAd5.

FIG 1

HIV-specific binding and neutralizing antibody responses elicited by the vaccines at peak immunogenicity. (A) Binding antibody responses against HIV-1 ConS gp140 were measured using BAMA for all 10 vaccine recipients (red) and 4 placebo recipients (blue) at 2 to 4 weeks after the last vaccination. The dashed line shows the cutoff for the assay. MFI, mean fluorescence intensity. (B) Historical data for tier 1A virus MW965.26 neutralization at the peak immunogenicity time point for the HVTN 073, HVTN 086, and HVTN 204 trials. Neutralizing antibody data were available for 7 of 10 HVTN 204 participants. Vaccine recipients are indicated in red, and placebo recipients are indicated in blue.

FIG 2

Binding antibody responses to HIV antigens pre- and post-HIV-1 infection. Serum samples from 10 vaccine recipients (Vacc; red) and 4 placebo recipients (Plac; blue) were tested for binding responses against the V2, V3, and MPER peptides and the gp41 ectodomain protein pre-HIV infection and at 1, 2, and 3 years after HIV infection. Open triangles, HVTN 073 participants; open boxes, HVTN 086 participants; closed circles, HVTN 204 participants; black circles, participants who were tested for MPER neutralization responses in the assay whose results are shown in Fig. 4.

FIG 3

MPER responses in HVTN 204 participants postinfection. Longitudinal serum samples from 2 HVTN 204 participants with MPER binding responses at 3, 4, 5, and 6 years post-HIV infection were tested against the HIV-2/HIV-1 chimeric constructs containing point mutations. Also shown are the sequences carried by the MPER of each engrafted HIV-2/HIV-1 chimeric construct. Amino acid differences between HIV-1 and HIV-2 are indicated in blue. Neutralization titers are shown as ID₅₀ and are color coded, as described in the key at the bottom right, with HIV-2 used as a negative control. 4E10 and Z13.e1 were used as positive controls.

FIG 4

Tier 1A virus-neutralizing responses in infected vaccine and placebo recipients. Serum samples from 10 vaccine (red) and 4 placebo (blue) HIV-infected recipients were assessed for neutralization activity against the MN.3, SF162, and MW965.26 tier 1A viruses. (Top) Data for HVTN 073/086 trial participants; (bottom) data for HVTN 204 trial participants. Time PI, time since the estimated date of infection. Titers of 1:40 are considered positive.

FIG 5

Tier 2 virus-neutralizing responses following HIV infection among vaccine and placebo recipients. Serum samples from 7 vaccine and 3 placebo recipients in the HVTN 204 trial who became HIV infected were assessed for neutralizing activity against 34 viruses from subtypes A, B, and C and circulating recombinant forms (CRFs) at 3 years postinfection. Data are shown as a heatmap, with the titers being color coded as shown in the key at the bottom right. Each column represents one participant, and the total number of viruses neutralized is indicated at the bottom.

FIG 6

Prior vaccination does not impact the neutralizing antibody responses induced by HIV infection. The pie charts show the tier 2 virus neutralization breadth for HVTN 404 and CAPRISA participants at 2 and 3 years post-HIV infection. A total of 131 CAPRISA participants and 13 HVTN 404 participants were assessed at 2 years postinfection, and 118 CAPRISA participants and 7 HVTN 404 participants were assessed at 3 years postinfection. Neutralization breadth was compared for 18 tier 2 isolates that were also evaluated in the CAPRISA cohort. Red indicates neutralization of >50% of the virus isolates, yellow indicates neutralization of 25 to 49% of the virus panel, indicates neutralization of 25% of the virus panel, and aqua indicates a lack of neutralization breadth (No neut).