Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge

Abstract

Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4 env/rev, SIV239 gag and SIV239 nefΔ1–13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP activities were similar. The complex challenge outcomes may reflect differences in IgG subtypes, Fc glycosylation, Fc-R polymorphisms, and/or the microbiome, key areas for future studies. This first demonstration of a sex-difference in SIV vaccine-induced protection emphasizes the need for sex-balancing in vaccine trials. Our results highlight the importance of mucosal immunity and memory B cells at the SIV exposure site for protection.

Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

“…Vaccine approaches in many of these studies included priming with plasmid DNA encoding SIV/HIV immunogens followed by the administration of viral vectors (modified vaccinia virus Ankara, adenovirus type 5) (31,32,50) or priming with viral vectors followed by recombinant protein boosts (39,(51)(52)(53)(54)(55). Consistent with the findings of these studies, analysis of correlates of protection in our current study revealed that the magnitude of the Env-specific binding antibody titers at week 37 prechallenge correlated strongly with the protection induced by immunization with protein-NP (Fig.…”

Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

“…ADCP was measured by a modified form of a previously described method (23). Biotinylated gp120 (5 g) was incubated with 1 l streptavidin-fluorescent beads (FluoSpheres NeutrAvidin-labeled microspheres, 1.0 m, yellow-green fluorescent [505/515 nm], 1% solids; Invitrogen) that were diluted 100-fold for 25 min at room temperature in the dark.…”

HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis

“…Locally produced or passively administered mucosal IgA antibodies can block entry and spread of experimental SIV/SHIV infection as shown in various nonhuman primate models (38)(39)(40). The finding that oral PrEP use is associated with elevated mucosal HIV-1-neutralizing IgA responses warrants further study in humans and nonhuman primate models to elucidate whether induced mucosal immune responses could augment oral PrEP efficacy and overall protection from HIV-1 acquisition.…”