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Principal Investigator: Pamela J Bjorkman
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $4,197,323
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies (bNAbs). During
the previous funding period, the Bjorkman lab used novel design strategies to develop HIV-1 envelope (Env)
trimer-based immunogens to elicit bNAbs against single and multiple epitopes, including the V3 glycan patch,
CD4 binding site (CD4bs), and triple V3/CD4bs/V1V2 targets. In publications among the 32 supported by the
current HIVRAD, the Bjorkman and Nussenzweig labs were the first to show that sequential immunizations
with multimerized immunogens on protein nanoparticles elicited heterologous neutralizing antibodies (Abs) in
inferred germline (iGL) mice, and more impressively, in wildtype (wt) animals with polyclonal Ab repertoires
[mice, rabbits, and rhesus macaques (RMs)]. However, the elicited cross-neutralizing Abs did not confer
protection from heterologous viral challenge, due at least in part to increasing off-target responses following
multiple boosts and the failure of the cross-neutralizing Abs to affinity mature to achieve high potency, breadth,
and durability. This led to the discovery by Nussenzweig of Ab feedback and epitope masking, which attenuate
focused B cell responses, a concept now becoming entrenched in the HIV-1 vaccine field. The goal of this
renewal application is to build on these fundamental discoveries and design more strategic and effective priming
and boosting immunogens. To accomplish this, we added a third collaborating research team
(Hahn/Shaw/Weissman) that brings expertise in the SHIV model of bNAb induction and mRNA immunogen
design. We will gain unique synergies from these highly collaborative research teams as follows: Project 1
(Bjorkman) will design next-generation prime and boost immunogens based on structural and biophysical
analyses of GL-targeted and lineage-based Env-Ab recognition from Project 2; Project 2
(Hahn/Shaw/Weissman) will decipher molecular pathways of Env-Ab coevolution shared among different SHIV-
infected RMs that develop neutralization breadth as a “molecular guide” for novel lineage-based immunogen
design in Project 1 and will test these new protein nanoparticle and mRNA vaccine platforms for immunogenicity
and protection in RMs; and Project 3 (Nussenzweig) will delineate the impacts of Ab feedback, epitope masking,
and T follicular helper (Tfh) cell repertoire on enhancing or attenuating on-target B cell responses. These projects
will be enabled by a Protein Expression and Automated Assays Core A (Vielmetter) and an Administrative
Core B (Bjorkman). Our hypothesis is that by incorporating lineage-based Env “immunotypes” that elicited
bNAbs in SHIV infected RMs in novel nanoparticle and mRNA-LNP vaccine designs (Projects 1 and 2) and by
modulating epitope masking and Tfh responses in germinal centers (Projects 1 and 3), we can develop new
prime and boost immunogens that lead to neutralization breadth, potency, and durability in wt animals. Achieving
this goal would represent a major scientific advance directly translatable to vaccine efforts in humans.
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