Leveraging antigenic seniority for maternal vaccination to prevent mother-to-child transmission of HIV-1

Abstract

The development of a maternal HIV vaccine to synergize with current antiretroviral drug prophylaxis can overcome implementation challenges and further reduce mother-to-child transmission (MTCT) of HIV. Both the epitope-specificity and autologous neutralization capacity of maternal HIV envelope (Env)-specific antibodies have been implicated in decreased risk of MTCT of HIV. Our goal was to determine if heterologous HIV Env immunization of SHIV.C.CH505-infected, ART-suppressed female rhesus macaques (RMs) could boost autologous Env-specific antibodies. SHIV.C.CH505-infected female RMs (n = 12), began a daily ART regimen at 12 weeks post-infection (wpi), which was continued for 12 weeks. Starting 2 weeks after ART initiation, RMs received 3 monthly immunizations with HIV b.63521/1086.C gp120 or placebo (n = 6/group) vaccine with adjuvant STR8S-C. Compared to the placebo-immunized animals, Env-vaccinated, SHIV-infected RMs exhibited enhanced IgG binding, avidity, and ADCC responses against the vaccine immunogens and the autologous SHIV.C.CH505 Env. Notably, the Env-specific memory B cells elicited by heterologous vaccination were dominated by cells that recognized the SHIV.C.CH505 Env, the antigen of primary exposure. Thus, vaccination of SHIV-infected, ART-suppressed RMs with heterologous HIV Envs can augment multiple components of the antibody response against the Env antigen of primary exposure, suggesting antigenic seniority. Our results suggest that a universal maternal HIV vaccination regimen can be developed to leverage antigenic seniority in targeting the maternal autologous virus pool.

Fig. 1. Infection, treatment, and immunization schedule for study of vaccine-elicited responses in SHIV-infected, ART-treated female monkeys to reduce MTCT.

a Study design schematic. Twelve female RMs were infected with SHIV.C.CH505 (brown arrow), started on a daily ART regimen at 12 wpi (yellow box). Six RMs received either a placebo vaccine (blue syringes) or a HIV Env combined clade B/C gp120 vaccine (red syringes). ART was discontinued at 24 wpi, and RMs were monitored for an additional 8 weeks. Plasma viral RNA kinetics through 32 wpi for placebo vaccinated (b) and HIV Env Clade B/C gp120 (c) vaccinated RMs. Plasma vRNA load at 12 wpi, prior to ART start, in placebo (blue) and HIV Env (red) vaccinated RMs (d). Medians are represented by the horizontal lines.

Fig. 2. Plasma gp120-specifc IgG antibody binding kinetics, avidity, and breadth.

Plasma gp120 IgG binding responses to vaccine antigens 1086.C (a) and b.63521 (b), and challenge virus antigen, CH505 (c) in placebo (blue) and Env vaccinated (red) macaques. Bold lines represent the median, and the range is depicted by the shaded area; black arrows indicate time points at which immunizations were administered (14, 18, and 22 wpi). Antibody avidity was assessed against vaccine and challenge antigens at week 12, pre-ART/immunization, and at week 20 when IgG gp120 binding peaked in the Env vaccinated group (d–f). Dot plots represent avidity score, each dot represents one animal, and medians are represented by horizontal lines (d–f). Statistical analysis was performed using Wilcoxon rank-sum tests with exact p-values to compare gp120-specifc IgG binding (Supplementary Table 3) and avidity (Supplementary Table 4) responses between vaccinated and placebo RMs, followed by FDR adjustments for multiple comparisons. **unadjusted p < 0.01. FDR adjusted p-values are reported in the dot plots. See Supplementary Table 3 and 4 for both unadjusted p and FDR_p for all comparisons. g Comparison of gp120 and gp140 IgG binding breadth at pre-ART/immunization, week 12, and at peak IgG binding post-immunization, week 20. Data shown are median MFI for each antigen for placebo (left panel) and HIV Env vaccinated (right panel) RMs.

Fig. 3. Epitope specificity of Env-specific IgG responses.

Plasma IgG specificity to a panel of HIV Env linear and conformational epitopes at pre-ART/immunization, week 12, and at peak IgG binding, week 20 post-infection (a). Data shown are median MFI for each antigen. Level of V3-specific IgG binding against vaccine (b, c), and challenge virus antigen (d) measured by quantitative ELISA. Bold lines represent the median, and the range is depicted by the shaded area. Black arrows indicate time points at which immunizations were administered (14, 18, and 22 wpi). Statistical analyses were performed using Wilcoxon rank-sum tests with exact p-values to compare V3-specifc IgG responses between vaccinated and placebo RMs, followed by FDR adjustments for multiple comparisons. **unadjusted p < 0.01. e Plasma blocking of soluble CD4-1086.C gp120 interactions. Each dot represents one animal, and medians are represented by horizontal lines.

Fig. 4. Functional antibody responses elicited in vaccinated and placebo recipient SHIV-infected, ART-treated rhesus monkeys.

Plasma neutralizing activity against tier 1 viruses, MW965 (a) and CH505 w4.3 (b) and the autologous CH505 (c) virus. Medians are indicated as horizontal lines, vertical dotted line indicates ART stop. Levels of infected cell binding expressed as Mean Fluorescent Intensity to a panel of HIV-1 1086.C or CH505.TF IMC-infected cells over time for each animal are shown (d, e). Maximum granzyme B activity (f, g) and the plasma dilution endpoint ADCC antibody titers (h, i) against 1086.C and CH505 gp120-coated target cells over time for each animal are shown. Statistical analyses were performed using Wilcoxon rank-sum tests with exact p-values to compare plasma IgG neutralization (a–c) and ADCC antibody titers (h, i) between vaccinated and placebo RMs, followed by FDR adjustments for multiple comparisons. *unadjusted p < 0.05, **unadjusted p < 0.01. FDR adjusted p-values are reported in the dot plots. See Supplementary Table 3 for both unadjusted p and FDR_p for all comparisons.

Fig. 5. Heterologous Env vaccination boosts pre-existing autologous Env-specific B cell responses compared to vaccine-specific responses among vaccinated RMs- evidence for antigenic seniority.

IgG binding responses specific for vaccine and challenge virus antigens were compared among Env vaccinated RMs (a). To evaluate changes in IgG binding responses among the vaccinated cohort across all three antigens, the fold change (b) from week 12 (pre-ART/immunization) were compared for each antigen at 16, 20, and 24 wpi (2 weeks post each immunization). Antibody avidity, measured by SPR, across all three antigens were also compared among vaccinees (c). Frequency of CH505 and 1086.C gp120-specific memory B cells at week 24 post-infection in HIV Env vaccinated and placebo recipient RMs (d). Each data point represents one animal, and medians are indicated as horizontal lines. Statistical analyses were performed using Wilcoxon signed-rank tests with exact p-values to compare Env vaccinated RMs’ plasma CH505 gp120 IgG binding and avidity responses, and Env vaccinated RMs’ CH505 gp120-specific memory B cells to 1086.C and b.63521-specific responses, followed by FDR adjustments for multiple comparisons. See Supplementary Table 5 for unadjusted p and FDR_p for all comparisons.