# Expediting elicitation of HIV-1 bnAbs with membrane Env vaccines

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $726,229

## Abstract

Project Summary / Abstract
A primary goal in HIV/AIDS vaccine development is to elicit broadly neutralizing antibodies (bnAbs) against the HIV-1
envelope glycoprotein spike that is anchored in the membrane (m-Env). To date, experimental vaccines have elicited mostly
narrow, weak or non-neutralizing antibodies, typically using soluble Env (s-Env) molecules. Here, we will use membrane
Env liposome (MEL) vaccines that incorporate well-ordered and stabilized m-Env trimers into liposomes via the
transmembrane domain. MELs thus present a relevant conformation of Env in a multivalent manner and contain important
epitopes of the membrane proximal external region (MPER) that are missing from s-Env vaccines. The creation of MELs
has been made feasible by recent improvements to m-Env production by creation of high Env producer cells. Meanwhile,
B cell anergy is common among HIV-1 bnAb lineages but is not well addressed by traditional vaccines. Preliminary data
show initial promise of MELs in eliciting nAb responses in human CD4BS bnAb CH103 UCA heterozygous dKI (HC+LC
KI) mice in which ‘on-target’ anergy prone B cells had responded poorly to s-Env vaccines. In Aim 1, we will build on
these findings by using consensus Env MELs, and mixed Env MELs, combined with selective removal of N-glycan at
position 197 to increase accessibility to the CD4 binding site in order to expedite elicitation of cross-neutralizing antibodies
in the prime. This will be followed by sequential boosting with MELs. The ‘Booster MELs’ will be consensus Envs, or
those selected in part based on specific binding by antecedent serum antibodies from prior immunization, with the intent to
drive affinity maturation of B cells against conserved elements of the target site. In an effort to further broaden nAb
responses, we will use an approach described recently that elicits bnAbs to the fusion peptide (FP) in multiple species
including mice. In this approach, a prime-boost regimen in CH103 UCA het dKI mice consisting of an FP-KLH prime and
MEL boosts is designed to “co-elicit” CD4BS bnAbs and FP bnAbs. In Aim 2, we will test a similar sequential MEL
immunization strategy designed to elicit MPER-directed bnAbs in 2F5 KI mice, whose B-cells are also under more
significant anergy controls. Hence, we will use strong universal T helper cell epitopes as a strategy to further help break B
cell anergy to maximize bnAb responses. This will involve “pre-priming” with universal Th epitopes using a lentiviral
vaccine vector (LVV). Finally, in Aim 3, down-selected m-Env vaccine candidates eliciting the best nAb responses, and
ideally comprising practical regimens that elicit nAbs to CD4BS, FP and MPER with the least boosts, will be used to
immunize in fully polyclonal systems, i.e. rabbits and humanized Ig locus KI (Trianni) mice. The creation of m-Env-based
vaccine schemes able to elicit cross-neutralizing antibodies against key vaccine targets, particularly in humanized polyclonal
Ig KI mice, should have...

## Key facts

- **NIH application ID:** 9997723
- **Project number:** 1R01AI152523-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** MICHAEL B ZWICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $726,229
- **Award type:** 1
- **Project period:** 2020-03-09 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997723

## Citation

> US National Institutes of Health, RePORTER application 9997723, Expediting elicitation of HIV-1 bnAbs with membrane Env vaccines (1R01AI152523-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997723. Licensed CC0.

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