​Shaw: Germline targeted SOSIPs and SHIVs to elicit V2 apex bNAbs

OVERVIEW

This grant will test the hypothesis that a chimpanzee SIV or HIV-1 Env SOSIP trimer protein immunization followed by SHIV infection can prime, boost, and mature an immunofocused V2 apex-targeted antibody response in rhesus macaques (RMs), leading to accelerated development of neutralization breadth in a majority of animals. The overall goal of this project is to demonstrate proof-of-concept for the reproducible elicitation of V2 apex-targeted bNAbs in primates and to identify evolved Env ‘immunotypes’ that bind intermediate-stage immunoglobulin receptors on B cells (BCRs), leading to neutralization breadth. ‘Forward’ and ‘reverse’ vaccinology strategies will be pursued simultaneously. In the ‘forward’ approach, studies will focus on whether SOSIP Env trimers and corresponding SHIVs whose Envs have been shown to bind human germline V2 apex bNAb precursors can engage and expand rhesus B cell bNAb precursors and mature these cells through successive rounds of Env-Ab coevolution and affinity maturation to achieve neutralization breadth. In the ‘reverse’ approach, rhesus V2 apex bNAbs from existing SHIV-infected RMs will be isolated and their germline unmutated common ancestors (UCAs) inferred. Homology to human germline Ig genes will then be determined, and the HIV-1 Envs selected for rhesus immunizations will be assessed for how efficiently they bind the rhesus bNAb UCAs. The cloned rhesus UCA mAbs will be used to screen a panel of >200 primary HIV-1 Envs for preferential binding, and selected Envs will be used in next-generation SOSIP and SHIV designs. The goal of this research is to develop a SOSIP-SHIV immunization scheme that reproducibly elicits V2 apex bNAbs in RMs and to transition this scheme to a lineage-based SOSIP-only vaccination regimen for testing first in RMs, and then in humans. These studies will inform the ‘rules’ governing consistent, rapid elicitation of V2 apex bNAbs in RMs. This information could then be translated to HIV-1 vaccine designs for humans.

RESEARCH OBJECTIVES

The specific goals of this investment are:

1) To conduct a prospective preclinical trial in 32 RMs, evaluating the efficacy of three or four V2 apex germline-targeted SOSIP/SHIV combinations designed to elicit immunofocused V2 apex bNAb responses. The trial will involve an adaptive study design wherein four groups of four animals each will initially be assessed for both SOSIP immunogenicity and persistent SHIV replication as a “go, no-go” step prior to SOSIP vaccinations and infections of subsequent animals. This will allow for modification or down-selection in SOSIP-SHIV combinations and treatment groups, ensuring that sufficient numbers of evaluable animals are included in each treatment arm to obtain statistically robust comparisons of outcomes. The primary outcome measure that will define success is 50% neutralization breadth against a panel of 20 heterologous tier 2 virus strains at titers ≥1:40 in at least 50% of animals in one or more arms of the study at 18 months post-SHIV infection.
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2) To isolate V2 apex bNAbs from existing SHIV-infected RMs, infer their germline IgRs, determine their homology to human Ig genes, decipher Env-Ab coevolutionary patterns leading to neutralization breadth, and identify candidate Env ‘immunotypes’ that bind intermediate BCRs, leading to bNAb induction. The primary outcome measure that will define success is the elucidation of SHIV Env-Ab coevolution pathways leading to the elicitation of rhesus V2 apex bNAbs for subsequent translation into improved SOSIP immunogen designs.