Modulation of the immune response to B cell lineage-based immunization by other immune interventions administered in infancy

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

ABSTRACT – PROJECT 2 Vaccines are one of the most effective tools in the prevention of infectious diseases; but despite decades of research, an HIV-1 vaccine has yet to be licensed. Recent results from preclinical studies and adult clinical trials demonstrating that vaccination with germline targeting immunogens can induce broadly neutralizing antibody (bnAb) B cell precursors have renewed hope that a protective vaccine is a reachable goal. One of the most studied germline-targeting (GT) immunogens is BG505 GT1.1 SOSIP trimer (GT1.1 SOSIP), which was designed to engage CD4 binding sites (CD4bs) and V2 apex bnAb precursor lineages. We recently observed that infant rhesus macaques immunized with the GT1.1 SOSIP vaccine can develop bnAb precursors at higher frequency than that of juveniles receiving the same vaccine regimen. Moreover, there is mounting evidence that the early life immune system may be particularly adept at developing bnAbs, as young children develop broad neutralization more frequently and over a much shorter time period than in adults. Importantly, initiation of HIV vaccination early in life could afford protection prior to sexual debut and contribute to prevent infections among adolescents and young adults, the only population in which the number of infections is growing worldwide. Young children receive vaccines against several other pathogens as part of the expanded program for immunization (EPI) and a subset of infants receiving the HIV-1 vaccine will likely be born to women living with HIV-1 and possess virus-specific maternally transferred antibodies. In addition, a HIV-1 vaccine initiated in infancy will likely be administered in the setting of passive immunization with bnAbs to ensure infant protection throughout the breastfeeding period. These natural and therapeutic immunizations will create a distinct immune environment that could impact the safety and immunogenicity of a HIV-1 vaccine-administered in infancy. The overall goal of this Project is to define how passive immunization with maternal antibodies or bnAbs and/or administration of EPI vaccines modulate the response to GT1.1 SOSIP immunization in infants. We hypothesize that infant vaccination with GT1.1 SOSIP in the setting of passive immunization and EPI vaccines is safe, but interactions between these distinct immune-based interventions modulate the response to the B cell lineage-based HIV-1 vaccine. We will use a non-human primate infant model to address the following aims: 1) Model the impact of maternally transferred HIV-specific antibodies on infant response to HIV-1 GT1.1 SOSIP vaccination; 2) Define the interactions between passive immunization with bnAbs and active immunization with HIV GT1.1 SOSIP in infants and 3) Evaluate the interactions between EPI and HIV GT1.1 SOSIP vaccines. Investigating potential interactions between a promising HIV vaccine candidate and other early life immunization strategies in a relevant, age-specific preclinical animal model will provide important insights that will inform, derisk and maximize the potential success of future pediatric HIV vaccine trials.