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

> **NIH NIH P01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $850,000

## Abstract

Project Summary/Abstract: Project 1
An effective HIV-1 vaccine likely requires induction of Abs against HIV-1 Env that neutralize across the majority
of circulating viral strains (i.e., broadly neutralizing antibodies; bNAbs). Because administered bNAbs are
protective against HIV-1 infection in animal models, it is widely believed that a vaccine that elicits bNAbs would
prevent infection. HIV-1 vaccine candidates generally target a single bNAb precursor lineage or epitope.
However, a protective HIV-1 vaccine likely requires inducing multiple bNAb lineages and/or bNAbs targeting
multiple epitopes on HIV-1 Env. We engineered three immunogens based on soluble native-like Env trimers
multimerized on protein nanoparticles, which together allow us to make priming immunogens to induce multiple
bNAb lineages against three epitopes: (1) RC1, targeting the V3-glycan patch; (2) IGT2, to elicit two classes of
CD4bs bNAbs; and (3) 3nv.2, a triple immunogen targeting the V3, CD4bs, and V1V2 epitopes. In our current
HIVRAD, the Bjorkman and Nussenzweig labs showed that these immunogens target intended epitopes and
elicit heterologously neutralizing Ab responses in both inferred germline (iGL) transgenic mice and wildtype (wt)
animals with polyclonal Ab repertoires. In addition, we demonstrated a boosting regimen using 3nv.2 as a prime
elicits more broad and potent Ab responses compared to a counterpart single epitope immunogen. Although
epitope mapping studies demonstrated Ab targeting of desired epitopes after a priming immunization, successive
boosting immunizations resulted in increasing elicitation of off-target Abs. This work provides a scaffold upon
which to improve GL targeting of bNAb precursor lineages and epitopes (Aim 1) and boosting regimens (Aims
2-4). We will improve Ab responses by applying boosting regimens designed through understanding viral
evolution from elicited Ab pressures are required to shepherd primed Ab responses to mature into potent bNAbs.
To design boosting regimens, we will use Env sequence information from two approaches in Aims 2 & 3: Aim 2
(with Drs. Hahn and Shaw): Immunogen immunized and then SHIV-infected rhesus macaques (RMs); Aim 3:
In vitro evolution assays. In addition, in Aim 4 (with Dr. Nussenzweig), we will design immunization regimens
using information from their studies aimed at mitigating impaired boosting from epitope-blocking Abs elicited by
a germline (GL)-targeting immunogen. In summary, the specific aims for Project 1 are: (Aim 1) Improve our V3,
CD4bs, and V3/CD4bs/V1V2 priming immunogens, (Aim 2) Improve boosting immunogens using viral evolution
data from RMs infected with GL-targeted and lineage-maturing SHIVs, (Aim 3) Use in vitro selection results to
engineer boosting immunogens to mimic Env evolution during infection, and (Aim 4) Investigate the effects of
epitope-targeting Abs to block a desired epitope during boosting.

## Key facts

- **NIH application ID:** 10810305
- **Project number:** 2P01AI100148-11
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Pamela J Bjorkman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $850,000
- **Award type:** 2
- **Project period:** 2013-02-10 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810305

## Citation

> US National Institutes of Health, RePORTER application 10810305, Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies (2P01AI100148-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10810305. Licensed CC0.

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