# Project-001

> **NIH NIH P01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $236,999

## Abstract

The elicitation of cross-neutralizing or broadly neutralizing Abs (bNAbs) to diverse HIV strains by Env vaccination 
remains a high priority for a broadly efficacious vaccine. The elicitation of bNAbs against conserved Env 
determinants remains elusive; however, the recent isolation of bNAbs to the fusion peptide and other sites of 
vulnerability demark promising leads in this process. Using N-glycan deleted NFL trimer-liposome priming and 
heterologous boosting/restoration, cross-neutralizing responses in rabbits were elicited with isolation of a CD4 
binding site (CD4bs)-directed bNAb, E70, and 1C2 (87% breadth) directed toward the gp120:gp41 interface, as 
delineated by high resolution cryoEM (Dubrovskaya et al., Immunity 2019). More recently, we have also elicited 
cross-neutralizing responses in guinea pigs using this approach with novel, full length stabilized “MIF” trimers as 
well as autologous tier 2 neutralizing responses in wild type mice following mRNA lipid nanoparticle (LNP) 
vaccination. Accordingly, the major objective of Project 1 will be to leverage these initial promising small animal 
results to elicit bNAbs in non-human primates (NHPs) using an “epitope-targeted” approach against the CD4bs 
and the gp120:gp41 trimer interface. As both sites are conserved Env protein determinants ringed by glycans, 
the N-glycan deletion priming and restoration regimen will be further optimized. The NFL trimers will be modified 
to enhance presentation of the targeted sites, while improving trimer stability and homogeneity by tail-anchoring 
on covalently coupled trimer-liposomes, the cell surface from mRNA, or with a heterologous trimer motif (MIF). 
The three presentation platforms will be cross-compared for effectiveness and translatability. Further, based on 
studies indicating human infants and adolescents more readily develop bNAbs compared to HIV-infected adults, 
immunization responses will be compared between juvenile and adult macaques. As a secondary objective, the 
same regimens will be tested in guinea pigs to cross-validate the animal models. Guided approaches monitoring 
“real-time” serum IgG responses by EM polyclonal epitope mapping (EMPEM; Core C) as well as rapid 
monoclonal Ab (mAb) isolation (Project 2/VRC) will be utilized to inform boosting from a select, diverse panel of 
structure-based, stabilized and homogeneous NFLs, iterative redesign and subsequent experiments. All NFL 
trimers will be produced in Project 1 for the entire P01, validated by biophysical methods, including DSC, EM 
and crystallography (Core C). Following elicitation of Env serum responses, isolated mAbs will be screened to 
confirm elicitation and neutralization specificity. By these integrated processes and comprehensive analysis, we 
will elicit and preferentially drive neutralizing antibodies to cross-neutralizing sites in primates in anticipation of 
human testing in the clinic.

## Key facts

- **NIH application ID:** 11159098
- **Project number:** 3P01AI157299-04S1
- **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:** $236,999
- **Award type:** 3
- **Project period:** 2021-02-04 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11159098

## Citation

> US National Institutes of Health, RePORTER application 11159098, Project-001 (3P01AI157299-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11159098. Licensed CC0.

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