Synergizing neutralization and non-neutralization antibody targets at the HIV/SIV viral spike apex

Project Summary
An HIV vaccine remains a critical and as yet unrealized asset in the 40-year fight against the HIV/AIDS
pandemic. New insights towards achieving vaccine protection from HIV acquisition may be gained by a
comparative case study of COVID-19 vaccines, which achieved nearly 100% efficacy against a similarly
enveloped, RNA virus with a similarly architected, trimeric, Class I fusion viral spike mechanism. Neutralization
B-cell epitopes exposed at the apex of the SARS-CoV-2 trimeric viral spike correlated clearly and strongly with
protection from viral acquisition, both in humans in the real world/circulating virus setting and in non-human
primate (NHP) preclinical models. We hypothesized that vaccine immunogens could be improved by focusing
antibody responses to two equivalent B-cell epitopes at the HIV/SIV viral spike apex, one an epitope targeted
by neutralizing antibodies (V2b) and one a purely non-neutralization epitope (V2c). In preliminary results, we
showed that removal of the viral spike apical V1 loop segment (DV1-Env) masking the V2c epitope enhanced
protection against viral challenge in both a highly stringent SIV and matched SHIV challenge model, achieving
>90% vaccine efficacy. In further preliminary results, we designed an immunogen displaying only this V2c
epitope in isolation and proved that it was highly immunogenic as an isolated epitope and indeed elicited purely
non-neutralizing antibodies in vivo. The study revealed that V2c contributed to, but was not sufficient on its
own, for protection. In this exploratory study, we pursue the new hypothesis that the combination of the two
HIV, viral-spike apical, B-cell epitopes in a single vaccine can reconstitute an increased level of protection as
observed with COVID-19 vaccines, by synergizing V2c with the V2b neutralization epitope. We will 1) design
and validate a V2b-focused immunogen, and 2) test the precise combination of neutralizing, vaccine-elicited
anti-V2b antibodies with non-neutralizing, cytotoxic, vaccine-elicited V2c antibodies, along with coordinated
cellular immune responses in vivo for their ability to delay viral acquisition as compared to the V2c epitope
alone. Successful results in these two aims could justify a research project on the design and translational
development of a novel, viral-spike-apex-focused, efficacious HIV vaccine.

Grant Number: 5R21AI181677-02
NIH Institute/Center: NIH
Principal Investigator: TIMOTHY CARDOZO