# Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies

> **NIH NIH P01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $2,654,146

## Abstract

UNAIDS has documented millions of new HIV-1 infections every year, thus a vaccine for HIV-1 is highly
desirable. To date, despite numerous efforts, no immunization regimen reproducibly elicits broadly neutralizing
antibodies (bNAbs) against HIV-1. Recently available native-like HIV-1 envelope spike (Env) trimers elicit
antibodies that neutralize autologous tier-2 viruses but these antibodies have only limited potency and breadth.
The observations that inferred germline (iGL) antibody precursors of bNAbs do not generally bind HIV-1 Env
proteins or neutralizing HIV-1 suggested that rationally designed iGL-targeting Env immunogens would be
required to initiate bNAb responses. Drs. Bjorkman and Nussenzweig propose a highly collaborative project
to apply this approach to target epitopes of two classes of HIV-1 bNAbs: a class related to PGT121 that binds
to the base of the V3 variable loop and interacts with the N332gp120 glycan (V3/N332 bNAbs), and IOMA-like
bNAbs, a new class of CD4-mimetic CD4 binding site (CD4bs) bNAbs derived from the VH1-2 germline gene
segment. The V3/N332 and IOMA classes were chosen because (i) V3/N332 Abs are among the most potent
of bNAbs and are commonly found in HIV-infected individuals who develop bNAbs, (ii) IOMA's relatively low
number of somatic hypermutations and its normal-length CDRL3 suggest it may be more easily elicited than
VRC01-class VH1-2–derived CD4bs bNAbs that are heavily somatically mutated and contain rare 5-residue
CDRL3s, and (iii) immunogen design will be facilitated the crystal structure of a natively-glycosylated Env
trimer bound to the V3/N332 bNAb 10-1074 and to IOMA. The Bjorkman lab will create immunogens to target
iGLs and shepherd bNAb maturation, while the Nussenzweig lab develops immunization schemes to elicit
bNAbs using the designed immunogens. The Nussenzweig lab specific aims are: (1) Develop and simplify
immunization protocols that elicit bNAbs to V3/N332 in iGL knock-in mice, (2) Adapt immunization protocols
developed for V3/N332 bNAbs in knock-in mice to wild type and AlivaMab mice that carry un-rearranged
human antibody loci, (3) Develop an immunization protocol to elicit IOMA-like antibodies, and (4) Determine
the frequency of IOMA and V3/N332 bNAb precursors in the naïve B cell repertoire of un-infected human
donors. The Bjorkman lab specific aims are: (1) Solve structures of iGL–immunogen complexes to aid in
structure-based immunogen design, (2) Use structure-based design and library screening to identify Env
trimers that bind V3/N332 iGLs with high affinity, (3) Use structural information to guide construction of a yeast
display library to find rare variants that bind IOMA iGL, (4) Combine results to create Env trimer immunogens
that bind iGLs of both bNAbs and work with Dr. Nussenzweig to evaluate double and single immunogens in
mice. These efforts will be supported by Core A (Automated cell/biochemical assays) and Core B (Protein
Expression). The proposed experiments will produ...

## Key facts

- **NIH application ID:** 10307758
- **Project number:** 5P01AI100148-09
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Pamela J Bjorkman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,654,146
- **Award type:** 5
- **Project period:** 2013-02-10 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307758

## Citation

> US National Institutes of Health, RePORTER application 10307758, Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies (5P01AI100148-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10307758. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*