# Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination

> **NIH NIH R01** · SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE · 2022 · $1,309,318

## Abstract

Although leading HIV-1 vaccines now routinely elicit potent NAbs, 2 problems are 1) NAbs usually target strain-
specific "glycan holes", limiting breadth, 2) NAbs are inconsistent among vaccinees. Regarding the latter point,
we have found that eliminating glycan head group clashes reveals consistent tier 2 NAbs in all vaccinated
animals, suggesting that NAbs often fail to navigate glycans. In stark contrast, broad NAbs (bNAbs) from HIV-
1+ donors frequently contact glycans rather than avoid them. Therefore, we hypothesize that, by promoting
NAb-glycan contacts, we might improve vaccine breadth & consistency. Here, we propose sequential
heterologous prime-boost (SHPB) immunizations to try to elicit bNAbs to 2 conserved protein/glycan epitopes
(V2 & fusion peptide; FP). Both sites accommodate multiple NAb binding modes, facilitating epitope focused
approaches. In Aim 1, we will identify a panel of 5 diverse, multi-V2 bNAb-sensitive, well-expressed trimers.
Although high trimer expression is essential, such Envs are uncommon. 2 ways to obtain useful trimers will be:
1) to test various V2-sensitive "special" strains & 2) KI V2-sensitivity into high-expressing strains. Selected Envs
will be modified to: 1) Plug glycan holes, 2) KI the common FP variant 1 (FP8var1) sequence/KO the N611
glycan (regulates FP exposure). In Aim 2, we will try to improve vaccine NAbs, using virus-like particles (VLPs)
expressing trimers from Aim 1. CH01 HC KI BL6 mice express the UCA of the CH01 NAb heavy chain (HC) amid
a mouse HC repertoire that can combine with diverse mouse LCs. These mice can potentially generate NAbs to
additional targets like FP. Since early events shape NAb responses, following initial KLH-FP8v1 priming a variety
of concepts will be tested in 3 subsequent VLP shots, including glycosidase-digested VLPs to minimize clashes
or immunogenic foreign glycans to promote early NAb-glycan contacts. Later VLP shots will be kept consistent
to expand NAbs arising from earlier shots. 5 mice will be sacrificed at an intermediate timepoint & the rest after
the final shot, allowing us to study NAb ontogeny. The best priming regimen will be determined primarily from
neutralization kinetics, potency, breadth & consistency, & from molecular genetics criteria. This regimen will be
re-tested in mice where CH01 precursors are reduced to physiologic frequency by adoptive transfer & in CH01
HC x Balb/c F1 mice that also exhibit reduced CH01 HC frequency & a more robust genetic background to
potentiate NAb development. Having identified effective priming shots, assembled SHPB regimens will be tested
in the same F1 mice to try to improve breadth. Variables will include overlapping or non-overlapping sequential
shots, increasing strain diversity, & increasing epitope stringency. Finally, we will test leading regimens in Trianni
mice expressing polyclonal human IgG. Serum neutralization of vaccine & non-vaccine strains will be monitored.
MAbs will be rescued using VLP probes &...

## Key facts

- **NIH application ID:** 10406231
- **Project number:** 5R01AI093278-13
- **Recipient organization:** SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** JAMES M BINLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,309,318
- **Award type:** 5
- **Project period:** 2011-03-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406231

## Citation

> US National Institutes of Health, RePORTER application 10406231, Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination (5R01AI093278-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406231. Licensed CC0.

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