Coadministration of CH31 Broadly Neutralizing Antibody Does Not Affect Development of Vaccine-Induced Anti-HIV-1 Envelope Antibody Responses in Infant Rhesus Macaques

Abstract

Prevention of mother-to-child transmission (MTCT) is an indispensable component in combatting the global AIDS epidemic. A combination of passive broadly neutralizing antibody (bnAb) infusion and active vaccination promises to provide protection of infants against MTCT from birth through the breastfeeding period and could prime the immune system for lifelong immunity. In this study, we investigate the impact of a single infusion of CD4 binding site (CD4bs) bnAb administered at birth on de novo antibody responses elicited by concurrent active HIV envelope vaccination. Four groups of infant macaques received active immunizations with subunit Env protein or modified vaccinia Ankara (MVA)-vectored Env and subunit Env protein, with or without a single intravenous coadministration of CH31 bnAb at birth. Vaccinated animals were monitored to evaluate binding and functional antibody responses elicited by the active vaccinations. Despite achieving plasma concentrations that were able to neutralize tier 2 viruses, coadministration of CH31 did not have a large impact on the kinetics, magnitude, specificity, or avidity of vaccine-elicited binding or functional antibody responses, including epitope specificity, the development of CD4bs antibodies, neutralization, binding to infected cells, or antibody-dependent cell-mediated cytotoxicity (ADCC). We conclude that infusion of CD4bs bnAb CH31 at birth does not interfere with de novo antibody responses to active vaccination and that a combination of passive bnAb infusion and active HIV-1 Env vaccination is a viable strategy for immediate and prolonged protection against MTCT. IMPORTANCE Our study is the first to evaluate the impact of passive infusion of a broadly neutralizing antibody in newborns on the de novo development of antibody responses following active vaccinations in infancy. We demonstrated the safety and the feasibility of bnAb administration to achieve biologically relevant levels of the antibody and showed that the passive infusion did not impair the de novo antibody production following HIV-1 Env vaccination. Our study paves the way for further investigations of the combination strategy using passive plus active immunization to provide protection of infants born to HIV-1-positive mothers over the entire period of risk for mother-to-child transmission.

HIV Env-Specific IgG Antibodies Induced by Vaccination of Neonatal Rhesus Macaques Persist and Can Be Augmented by a Late Booster Immunization in Infancy

“…Consistent with the data from early human pediatric vaccine trials (10), we also observed persistence of Env-specific antibody responses after vaccination in early life (12). In addition, we recently reported that passive administration of an HIV Env-specific broadly neutralizing monoclonal antibody at birth does not interfere with the induction of Env-specific antibody responses by vaccination in infant macaques (15).…”

“…CH31 was administered to provide passive immunity during the time antibody responses were developing in response to vaccination. The vaccine-induced antibody responses up to week 14, 2 weeks after the 3rd boost, were previously reported (15). The goal of the earlier study was to document that passive administration of a bNAb at the time of the vaccine prime does not interfere with the induction of vaccine-induced antibody responses in infants.…”

Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

“…Type D retrovirus-, SIV- and STLV-1 free Indian rhesus macaques (RM) ( Macaca mulatta ) were maintained in the colony of California National Primate Research Center (CNPRC, Davis, CA), as previously described (47). Six infant RMs were orally challenged with SHIV.CH505.375H.dCT (22) as described in (26).…”

“…The positivity cut off for the assay was defined as the optical density (OD) of the lowest-concentration rhesus IgG standard that was greater than three times the average OD of blank wells. CD4 blocking ELISAs were done as described in (47).…”

“…The ADCC-GTL assay was used to measure plasma ADCC activity as previously described (47, 54). CEM.NKR CCR5 target cells were coated with recombinant CH505 gp120.…”