# Eliciting Broadly Neutralizing Antibody Responses against HIV-1 Fusion Peptide Epitope by AB Toxin B Subunit-Based Immunogens

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $859,597

## Abstract

Developing a vaccine that can elicit broadly neutralizing antibodies (bnAbs) against HIV remains a significant
challenge in the fight against HIV/AIDS. One major vulnerable site on the envelope protein that bnAbs
recognize is the fusion peptide (FP) on the Env. Although considerable efforts and progress have been made
to induce bnAb responses targeting this site by chemically conjugating FP with carrier proteins such as KLH,
which is difficult to use in human trials, broad and potent neutralization has not yet been achieved. In a recent
rabbit pilot study, we demonstrated that a recombinant FP-cholera toxin subunit B (FP-CTB) fusion
immunogen, in combination with a heterologous Env trimer boost, elicited tier 2 neutralizing antibody
responses against a standard global panel of viruses with unprecedented breadth and potency. CTB is the B
subunit of the AB toxin from the pathogen Vibrio cholerae and belongs to the well-known AB toxins with
pentameric B subunits. There are four main families of AB toxins: Cholera Toxin (CT), Pertussis Toxin (PT),
Shiga toxin (ST), and Subtilase cytotoxin (SU), each with different immunomodulatory properties. CTB is
particularly known for its mucosal adjuvant properties. We have previously used the pentameric B subunits to
carry gp120 V3 and V1V2 domains and demonstrated their strong capacity for immunofocusing and induction
of durable epitope-specific Ab responses. Furthermore, recombinant CTB has already been used in human
vaccines, making FP-CTB a promising vaccine candidate. Our central hypothesis is that fusing the flexible FP
onto a highly immunogenic toxin B subunit can help focus immune responses on the FP epitope, and these
responses can be guided to develop neutralization breadth by heterologous boosting using native Env trimers.
Building upon our exciting and promising preliminary results, we propose to advance the development of the
FP and toxin B subunit-based immunogens to improve the potency and breadth of bnAb responses. Our team
has the necessary expertise and resources to achieve this goal, and we have three aims, including Aim 1: Lay
the groundwork for a novel AB toxin B subunit-based FP vaccine, Aim 2: Improve the Breadth and Potency of
Neutralizing Antibody Responses, and Aim 3: Test the immunogenicity of refined FP immunogens in NHPs.
Upon completion of this project, our panel of novel FP immunogens will be fully developed and characterized
for structure, antigenicity, and immunogenicity, and selected immunogens can then be moved forward in the
pipeline for NHP challenge studies.

## Key facts

- **NIH application ID:** 11009295
- **Project number:** 1R01AI181676-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** XIANGPENG KONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $859,597
- **Award type:** 1
- **Project period:** 2024-08-02 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009295

## Citation

> US National Institutes of Health, RePORTER application 11009295, Eliciting Broadly Neutralizing Antibody Responses against HIV-1 Fusion Peptide Epitope by AB Toxin B Subunit-Based Immunogens (1R01AI181676-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11009295. Licensed CC0.

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