# Determinants of HIV broadly-neutralizing antibody precursor induction in infants

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $1,518,131

## Abstract

ABSTRACT – OVERALL
The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is
considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target
the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor
yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of
bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated
omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma
bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be
detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less
somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms
of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with
BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the
induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that
observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes
compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2
infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb
development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many,
although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize
that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of
bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems
biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the
modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the
interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core).
The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and
fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune
responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505
GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2).
Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict
the development of bnAb precursors. The results of the Prog...

## Key facts

- **NIH application ID:** 10852977
- **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:** $1,518,131
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852977

## Citation

> US National Institutes of Health, RePORTER application 10852977, Determinants of HIV broadly-neutralizing antibody precursor induction in infants (5P01AI178377-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10852977. Licensed CC0.

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