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.
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.