Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys

Abstract

The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:

Figure 1. Vaccine-Elicited Humoral Immune Responses

(A) Env-specific ELISAs using a diversity of Envs from multiple clades, including 92UG037 (UG37; clade A), UG92/29 (UG92; clade A), CN54 (clade C), ZA/97/003 (ZA97; clade C), 92UG021 (UG21; clade D), 93BR029 (BR29; clade F), and mosaic (Mos1; clade M) at weeks 0, 4, 16, and 32. Mean log endpoint ELISA titers +/− s.e.m. are shown. (B) V2-specific binding assays by surface plasmon resonance using cyclic V2 peptides from multiple clades, including 92TH023 (TH23; clade AE), MN (clade B), ConC (clade C), Mos1 (clade M), and Mos2 (clade M) at weeks 0, 4, 16, and 24. V2-specific binding assays were not run with the TH23 and MN cyclic V2 peptides at week 24. Mean response units +/− s.e.m. are shown. (C) HIV-1 tier 1 TZM-bl neutralization assays against DJ263 (clade A), SF162 (clade B), and MW965 (clade C) at weeks 0, 4, 16, and 32. Mean ID50 titers +/− s.e.m. are shown. (D) HIV-1 tier 2 A3R5 neutralization assays against SC22 (clade B), 1086 (clade C), and DU422 (clade C) at weeks 0 and 16. Mean ID50 titers +/− s.e.m. are shown. (E) HIV-1 tier 2 TZM-bl neutralization assays against the SHIV-SF162P3 challenge stock at weeks 0, 16, and 32. Mean ID50 titers are shown. (F) Antibody-dependent complement deposition (ADCD) assays with YU2 (clade B) and SF162 (clade B) Env gp120. Mean % C3b deposition responses +/− s.e.m. are shown. (G) Antibody-dependent cellular phagocytosis (ADCP) assays with SF162 (clade B) Env gp120. Mean phagocytic score responses +/− s.e.m. are shown.

Figure 2. Vaccine-Elicited Cellular Immune Responses

(A) IFN-γ ELISPOT assays using global PTE peptide pools at weeks 0, 4, and 16. Mean spot-forming cells (SFC) per 10⁶ PBMC +/− s.e.m. are shown. (B) Numbers of reactive subpools of 10–16 peptides using PTE and mosaic peptide sets. Mean subpools +/− s.e.m. are shown. (C) Numbers of mapped individual CD8+ and CD4+ T lymphocyte epitopes. Mean epitopes +/− s.e.m. are shown. (D) Individual CD8+ and CD4+ epitope-specific immune responses mapped with heterologous PTE and vaccine-matched mosaic peptide sets. 83 responses were detected by both PTE and mosaic peptides, 58 by only mosaic peptides, and 27 by only PTE peptides. Box-and-whisker plots are shown. See also Supplementary Figure S1, Supplementary Table S1, and Supplementary Data S2.

Figure 3. Protective Efficacy Against SHIV-SF162P3 Challenges

(A) Number of challenges required for acquisition of infection in each vaccine group. (B) Statistical analyses include hazard ratios with 95% confidence intervals (CI), the per-exposure reduction in acquisition risk, and the absolute percentage of uninfected animals in each group after 1, 3, and 6 challenges. P-values reflect Cox proportional hazard model. (C) Log peak SIV RNA copies/ml are depicted for each group. P-values represent Wilcoxon rank-sum tests. Box-and-whisker plots are shown. (D) Log setpoint SIV RNA copies/ml are depicted for each group at day 70. Box-and-whisker plots are shown. (E) Clinical survival curve. (F) Statistical analyses of survival at 250 days following challenge. P-values reflect Fisher's exact tests comparing the vaccinated groups to the control group.

Figure 4. Immunologic Correlates of Protection

(A) Correlation of log Mos1 ELISA titers at peak immunogenicity with the number of challenges required to establish infection. (B) Correlation of log SF162 NAb titers at peak immunogenicity with the number of challenges required to establish infection. (C) Correlation of SF162 ADCP phagocytic score at peak immunogenicity with the number of challenges required to establish infection. (D) Correlation of SF162 ADCD % C3b deposition at peak immunogenicity with the number of challenges required to establish infection. For all panels, correlates analyses included only the vaccinated monkeys that became infected and did not include the sham controls. P-values reflect uncorrected Spearman rank-correlation tests. See also Supplementary Figures S2 and S3 and Supplementary Table S2.