# Project 1: Development of Nucleoside-Modified mRNAs Encoding Sequential HIV-1 Envelopes for Initiation of V3-glycan Neutralizing Antibody Lineages

> **NIH NIH U19** · DUKE UNIVERSITY · 2020 · $871,042

## Abstract

Project 1: Development of Nucleoside-Modified mRNAs Encoding Sequential HIV-1 Envelopes for
Initiation of V3-glycan Neutralizing Antibody Lineages
A major goal of HIV-1 vaccine development is to induce broadly neutralizing antibodies (bnAbs). This IPCAVD
team has immunogens that can trigger unmutated common ancestors (UCAs) of bnAb B cell lineages, a key
approach for an HIV vaccine. One such sequential Env immunogen termed, EnvSeq-3, is derived from the
study of the CH848 HIV-1-infected individual who made the DH270 HIV V3-glycan-targeted bnAb. We
hypothesize that use of priming immunogens that bind to the UCA of the DH270 B cell lineage followed
by sequential modified mRNA gp160 or gp140 trimer-based immunogens will result in the initiation of
V3-glycan bnAb B cell lineages in humans.
 • Specific Aim 1. Design and formulate sequential nucleoside-modified mRNAs encoding two
 gp160s or soluble chimeric, stabilized trimers that bind to intermediate antibodies of the DH270
 B cell lineage. Nucleoside-modified mRNA encoding the first 2 trimeric lineage immunogens after the
 V3-glycopeptide will be optimized for high level expression using established techniques.
 • Specific Aim 2. Determine if synthetic UCA-binding glycopeptides combined with GLA/SE
 adjuvant will prime DH270 UCA B cells for boosting with Env trimer-encoding mRNAs in DH270
 UCA VH and VL knock-in mice. Glycopeptide and mRNA immunogens will be analyzed including
 combinations to confirm in DH270 UCA VH + VL knock-in (KI) mice their induction of Tfh cells and
 selection of antibodies that target the V3-glycan bnAb site. The two selected mRNAs will be produced
 CGMP in Project 2.
 • Specific Aim 3. Test sequential immunogens in outbred rhesus macaques to optimize
 immunization schemes for use in a phase I clinical trial in year 5.
We believe that modified mRNA-LNPs encoding V3-glycan lineage immunogens will generate potent CD4+ Tfh
and antibody responses, and will initiate V3-glycan bnAb lineages in bnAb KI mice and in humans. This
project will use a promising sequential immunogen design in the form of nucleoside-modified mRNAs to
overcome barriers to bnAb development. If successful, the use of nucleoside-modified mRNAs will transform
HIV-1 vaccine development.

## Key facts

- **NIH application ID:** 9868262
- **Project number:** 5U19AI135902-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Barton F. Haynes
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $871,042
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868262

## Citation

> US National Institutes of Health, RePORTER application 9868262, Project 1: Development of Nucleoside-Modified mRNAs Encoding Sequential HIV-1 Envelopes for Initiation of V3-glycan Neutralizing Antibody Lineages (5U19AI135902-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868262. Licensed CC0.

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