# Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1

> **NIH NIH P01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $418,203

## Abstract

Project Summary/Abstract
 Broadly neutralizing antibodies (bNAbs) that bind to the HIV-1 Envelope glycoprotein (Env) are expected to
be an important component of the immune response elicited by an effective HIV-1 vaccine. However, efforts to
elicit bNAbs through vaccination with recombinant Env have not yet been successful. VRC01-class antibodies
are among the broadest and most potent bNAbs that have been isolated from infected individuals, and their
elicitation would be an ideal goal of a vaccine. VRC01-class antibodies have been isolated from multiple donors,
and they all interact with Env in a nearly identical manner; are derived from the same antibody heavy chain gene,
VH1-2*02; and have an unusually short third complimentary determining region (CDRL3) on the light chain.
 During the course of infection, VRC01-class antibodies acquired a number of mutations in their antibody
genes that allow them recognize and neutralize diverse HIV-1 viral isolates. Using sequence homology, one can
predict the sequence of the B-cell receptor (BCR) on the naive B cell that gave rise to each VRC01-class
antibody. Previous work from our group and others has demonstrated that these inferred-germline versions of
VRC01-class antibodies fail to recognize diverse recombinant Envs. Thus, conventional Env immunogens are
likely ineffective at binding to and activating naive B cells that can give rise to VRC01-class antibodies.
 The structural similarity and shared genetics of VRC01-class antibodies have led to the proposal that
immunogens designed to specifically to engage VRC01-class precursor B cells could, at the very least, start the
process of VRC01-class antibody production. Indeed we, and others, have designed Env-based immunogens
that can activate B cells expressing VRC01-class precursor BCRs in vitro and in vivo. However, these
immunogens also present off-target, potentially immunodominant epitopes that could ultimately frustrate the
development of VRC01-class antibodies in competitive germinal center reactions.
 As an alternative to Env-derived immunogens, we have produced and isolated anti-idiotypic antibodies that
are highly specific for the antigen binding site of VRC01-class precursor BCRs. Importantly, because they are
non-Env derived, they lack the off-target epitopes present on other germline-targeting immunogens. Our
overarching hypothesis is that if used as a vaccine prime, anti-idiotypic antibodies can selectively seek out and
expand rare VRC01-class B cells, such that the expanded pool will have a selective advantage over other B cells
that respond to off-target epitopes following a boost with germline-targeting Env. This hypothesis will be tested
in transgenic mouse models as part of this HIVRAD application, in collaboration with Drs. Stamatatos and
Nussenzweig. The focus of this project is to evaluate the ability of these novel immunogens to seek out rare
VRC01-class precursor B cells from human PBMC samples and from mice expressing a diverse hum...

## Key facts

- **NIH application ID:** 10062817
- **Project number:** 5P01AI138212-03
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Andrew McGuire
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,203
- **Award type:** 5
- **Project period:** 2018-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062817

## Citation

> US National Institutes of Health, RePORTER application 10062817, Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1 (5P01AI138212-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10062817. Licensed CC0.

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