PROJECT SUMMARY
Developing a vaccine that elicits HIV broadly neutralizing antibodies (bnAbs) remains a top priority in HIV
vaccine design. However, typically HIV bnAbs originate from rare B-cell germline precursors (‘UCAs’) and
require improbable somatic hypermutations (SHM) in HIV+ human repertoires. To reproducibly activate such
B-cells, ‘Germline Targeting’ (GT) vaccine priming strategies appear to be useful for activating specific bnAb
UCAs particularly in polyclonal systems including rhesus macaques, a key preclinical animal model. We
recently developed a novel membrane (m)Env liposome (MEL) platform using mEnvs that contain GT
mutations. One novel GT-MEL regimen targets a ‘CDRH3 dominated’ nAb response to the CD4-binding site
(CD4bs) and reproducibly elicited tier 2 serum neutralization in CH103 UCA knockin (KI) mice after only two
boosts. This GT-MEL regimen offers an alternative to the more commonly studied VH restricted CD4BS cluster
often targeted by soluble (s)Env immunogens. Meanwhile, we have generated GT-MELs based on described
GT-sEnvs that have been reported previously to elicit VH-restricted CD4BS HIV nAbs, i.e., activation of CH235
bnAb UCA in KI mice and possible CH235 homologs in macaques. The overall objective of this proposal is use
novel GT-MELs to elicit HCDR3-dominated and VH restricted CD4BS responses in rhesus macaques, in
addition to responses targeting HIV’s Fusion Peptide (FP). We will test a hypothesis that a CD4BS CDRH3-
dominated plus VH-restricted CD4BS GT-MEL prime-boost regimen tested in macaques will elicit serum
neutralization against tier 2 HIV (SA1). In SA2, we will use a fusion peptide nanoparticle (FP-NP) ‘pre-prime’
strategy followed by BG505 variant MEL boosting regimen designed to elicit tier 2 serum neutralization based
in part on a prior report by others using a sEnv immunization protocol that elicited tier 2 serum neutralization
and FP bnAbs. In Phase 2 of this ‘Innovation’ grant proposal, we will use the results of the above studies to
integrate the CD4BS (CH505) MEL and FP (BG505) vaccine approaches into one regimen meant to elicit HIV
nAbs to both the CD4BS and the FP supersites. These studies, will reveal the serum HIV nAb breadth that can
be elicited by the MEL vaccine platform in rhesus macaques against multiple overlapping targets on the
CD4BS and FP, and may inform the development of an HIV vaccine for humans.
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