# Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $242,474

## Abstract

Abstract – Project 2
Globally, 600,000 young adults become infected with HIV-1 each year. Therefore, there is an urgent need to
develop an early life vaccine strategy that protects young adults from HIV infection. This early life vaccine should
elicit protective broadly neutralizing antibodies (bNAbs), which have been shown to be effective against infection
in nonhuman primates and humans. Newer, rationally designed native-like HIV envelope trimer-based vaccines
that engage germline B cell receptors and drive evolution of bNAbs have been developed. These B cell lineage-
based vaccines induce bNAb precursors in 50–60% of infant and adult nonhuman primates, and early clinical
trial data suggests some humans also develop bNAbs. While these findings offer significant promise that the
long-standing goal of an effective HIV vaccine is on the horizon, there is a gap in our understanding of the
determinants of bNAb induction that results in only half of vaccinees developing a favorable response. It is now
clear that the microbiome is intricately intertwined with the development and modulation of the immune system,
and that these microbiome–immune interactions are critical for vaccine responses. Our preliminary data confirm
that the microbiome is a necessary and modifiable factor that influences vaccine responses, with specific
bacterial taxa positively associated with antibody titers resulting from immunization with HIV Env-based vaccines.
Thus, Project 2 proposes to define specific microbial features that can be harnessed as an endogenous adjuvant
to help—along with optimal exogenous adjuvants identified by Project 1—drive induction of HIV bNAb
precursors after vaccination with the BG505 GT1.1 SOSIP trimer immunogen. Specifically, Aim 1 of this project
will couple shotgun metagenomic data and microbe–phenotype triangulation, a novel microbiome discovery
platform we developed, to define microbial features that associate with the induction of HIV bNAb precursors.
Aim 2 will test the hypothesis that some commensal bacteria predispose towards beneficial vaccine responses
by helping induce vaccine-elicited antibodies that are cross-reactive with the microbiome. To enhance the
translational potential of our work, we will examine microbiome cross-reactive antibodies in both infant NHPs
and humans. Finally, Aim 3 will develop a gnotobiotic human B cell lineage knock-in mouse model to
experimentally define the role of the microbiome in bNAb precursor induction, including functionally validating
the bioinformatically identified microbial features. Taken together, the results of this Project will elucidate specific
microbes that modulate the immune landscape such that a greater percentage of B cell lineage-based vaccine
recipients develop bNAb precursors. Ultimately, these adjuvant-like microbes can be incorporated into future
vaccine strategies.

## Key facts

- **NIH application ID:** 10852992
- **Project number:** 5P01AI178377-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kristina De Paris
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $242,474
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852992

## Citation

> US National Institutes of Health, RePORTER application 10852992, Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants (5P01AI178377-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10852992. Licensed CC0.

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