Designing HIV-1 envelope immunogens to maximize neutralization breadth through use of multiple founder envelope antigens

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Project Summary/Abstract An HIV-1 (HIV) vaccine capable of eliciting broad and potent neutralizing antibody (Ab) response to HIV envelope (Env) remains elusive. HIV has a high mutation rate, Env is highly glycosylated as well as conformationally dynamic and, well-characterized broadly neutralizing responses reported to date have been generated after chronic HIV infection, rather than by candidate HIV vaccines. Recently, we reported that precursor broadly neutralizing antibodies (bNAbs) can develop during early HIV infection and neutralization breadth was more frequent when multiple HIV variants established infection in an individual, defined here as multiple-founder variant (MFV) infection. Furthermore, Env diversity during initial infection was higher in individuals who developed neutralization breadth. We concluded that Env-specific B cell development within one month of initial HIV infection can predict neutralization breadth years later; this phenomenon highlights the critical importance of these initial interactions, which prime B cells at the earliest stages of HIV infection. To determine the immunogenicity of an HIV vaccine design based on the MFV concept, we formulated a cocktail of five Env trimer proteins derived from MFV in acute infection. The Env sequences corresponded to 5 founder lineages in one participant. They were further optimized by stabilizing them in a closed conformation using the ’Repair and Stabilize’ strategy developed by Janssen Pharmaceuticals. The cocktail of minimally distant, stabilized Env proteins were formulated with the novel vaccine adjuvant, Army Liposome Formulation plus QS-21 (ALFQ). Preliminary immunogenicity data in rabbits demonstrated that this vaccine candidate elicited a greater breadth of neutralizing Ab responses than an equivalent total dose of a single stabilized Env trimer protein. These minimally distant immunogens also elicited a higher magnitude of IgM responses to HIV; a predictor of subsequent neutralization breadth in our studies of early infection. Therefore, we propose to select an optimal combination of minimally distant HIV Env immunogens that mimic the diversity and development of neutralizing Ab breadth seen in acute infections with MFV in vitro and in vivo. We will optimize the antigenicity of the HIV Env trimer immunogens by comparing native stabilized trimers with Env trimers that have shortened hypervariable (HV) loops and glycan modifications in an attempt to improve their antigenicity (Aim 1). We will optimize immunogen delivery and display strategies, including multivalent trimeric Envs delivered as messenger RNA (mRNA) and, multivalent immunogen display on self-assembling liposomal cobalt porphyrin phospholiposomes (CoPoP) that afford Env base shielding (Aim 2). We will utilize pre-specified Go/No-Go criteria to downselect the optimal vaccine regimen of optimized minimally distant HIV vaccine candidates, to evaluate protective immune responses in non-human primate SHIV challenge studies (Aim 3). Our long-term goal is to develop a multivalent HIV vaccine candidate that elicits protective broadly neutralizing Ab responses for subsequent manufacture and evaluation in human clinical trials.