# Project-002

> **NIH NIH P01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $674,912

## Abstract

Summary 
Circulating (tier 2) HIV-1 variants are highly resistant to antibody-mediated neutralization, making broadly 
effective vaccine design a major challenge. Encouragingly, work in our previous HIVRAD program 
demonstrated that Ab responses capable of cross-neutralizing multiple heterologous tier 2 viruses were 
elicited by targeted N-glycan deletion priming and heterologous glycan restorative Env trimer-liposome 
boosting. The isolation of two monoclonal antibodies with broadly neutralizing activity from these studies 
and high-resolution structures in complex with native-like trimers revealed that one mAb targeted the 
conserved CD4 binding site (CD4bs) and the other targeted the gp41:gp120 interface region, 
substantiated this result. In the current application, we will build on these efforts by evaluating responses 
elicited by well-ordered, novel, trimer-based immunogens inoculated into Indian origin rhesus macaques. 
In addition to the use pf protein-based trimers, we will test trimer platforms based on administration of 
mRNA lipid nanoparticles as described in Project 1. 
In Project 2, we will characterize B cell responses elicited by vaccine regimens evaluated in Indian origin 
rhesus macaques in Core B by rapid, high-throughput monoclonal antibody (mAb) isolation to 
define the targeted epitopes and guide both the choice of boosting immunogens and, if needed, trimer 
redesign by eliminating or masking unwanted non-neutralizing immunodominant responses for 
subsequent immunization studies. We will interact with the investigators in Core C, who also will generate 
information about immunodominant Ab responses through their negative stain electron microscopy 
(nsEM)-based method for evaluation of vaccine-induced serum responses. Using the Env-specific mAbs, 
we will further determine how Env-specific antibody lineages evolve over time using Next Generation 
Sequencing (NGS) and IgDiscover, a computational tool optimized for use in rhesus macaques. We will 
generate individualized databases of macaque germline VDJ alleles for precise gene assignments, which 
is necessary for correct conclusions about Ab affinity maturation and SHM levels. We will further use 
the IgDiscover results and the new haplotype module to investigate if certain alleles, or combinations of 
alleles, predispose to elicitation of neutralizing Ab responses in either adult of juvenile macaques. We 
will investigate the level of expansion of neutralizing and non-neutralizing Ab lineages over time and 
ask if vaccine-induced neutralizing Ab lineages persist in long-lived immune compartments such 
as memory B cells and plasma cells, which are critical for the long-term protective effects of vaccines.

## Key facts

- **NIH application ID:** 11010180
- **Project number:** 5P01AI157299-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Richard Thomas Wyatt
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $674,912
- **Award type:** 5
- **Project period:** 2021-02-04 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11010180

## Citation

> US National Institutes of Health, RePORTER application 11010180, Project-002 (5P01AI157299-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11010180. Licensed CC0.

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