Mechanisms of Early-life Immunity Associated with HIV-1 Vaccine-induced Neutralizing Antibody Responses

Abstract At the end of 2021, an estimated 1.7 million children were living with HIV-1, including 160,000 children who were newly infected (UNAIDS), thus pediatric HIV-1 remains a global health concern. However, there is a gap in our knowledge of B cell development in early-life that prevents us from implementing the full potential of pediatric HIV-1 vaccines. Understanding the mechanisms of early-life immunity that can establish and maintain vaccine-induced responses to HIV-1 immunogens in pediatric populations will contribute to this knowledge gap. A primary goal of a prophylactic HIV-1 vaccine is induction of broadly neutralizing antibodies (bNAbs) that target the envelope (Env) surface protein and prevent infection of different circulating HIV-1 strains. Infants and children living with HIV-1 develop HIV-1 Env-reactive bNAbs, and often develop bNAbs more rapidly than adults. Young rhesus macaques (RMs) that were simian-HIV (SHIV)-infected as infants generated heterologous HIV-1 NAbs with bNAb characteristics in association with enhanced germinal center (GC) activity, including elevated antigen (Ag)-specific GC B cells—a mechanism for bNAb induction in humans. Natural killer (NK) cells have also been postulated to act as rheostats regulating GC-dependent anti-viral B cell responses. However, the permissive immunological environment for vaccine-induced HIV-1 Env-reactive bNAb development in early-life are vastly understudied. In this proposal, we will immunize infant RMs with an innovative pediatric vaccine regimen of bNAb lineage-inducing HIV-1 Env immunogens and a clinically- approved Hepatitis (Hep) B childhood vaccine known to elicit durable memory B cell responses. We will perform immunologic studies with cells from different B cell compartments (peripheral blood (PBMCs), lymph node (LN), and bone marrow (BM)) in neonatal RMs immunized with the multicomponent cocktail HIV-1 and clinically-approved childhood vaccines in an innovative study design to establish the mechanisms of early-life HIV-1 Env immunity that elicit NAbs, a subset of which has the capacity to develop breadth. The specific aims for this proposal are as follows: Aim 1. Define the B cell repertoires elicited by a cocktail pediatric immunization strategy in infant RMs Aim 2: Define the dynamics and functions of vaccine-induced GC B and T cell subsets in LN, and plasma cells in BM, of infant RMs Aim 3. Define the mechanisms of NK cell immunoregulation on the quality of vaccine-induced memory B cells in infant RMs