# Development of prime-boost immunization schemes to elicit VRC01-class bNAbs in polyclonal human BCR backgrounds

> **NIH NIH P01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $410,413

## Abstract

ABSTRACT
 VRC01-class broadly neutralizing antibodies (bNAbs) recognize a conserved epitope within the CD4-
binding site of HIV-1 Env. They are among the most potent bNAbs known and protect animals from
experimental S/HIV infection, making them a highly attractive type of antibody to elicit by vaccination. They
have been isolated from multiple HIV-1-infected subjects, but are all derived from the same VH1-2 allele (*02)
and a small number of light chains, all of which express a 5 amino-acid CDRL3. In contrast to the mature, fully
mutated forms of VRC01-class antibodies, their inferred germline forms do not recognize Env and do not
neutralize HIV-1. This led to the hypothesis that previous recombinant Env immunogens were ineffective in
activating naïve B cells expressing germline VRC01-class B cell receptors (BCRs), which may, in part, explain
why such immunogens have not elicited VRC01-like antibody responses in vaccine studies. We reported on
the design of a clade C-derived Env protein (426c Core) that binds germline VRC01-class antibodies and
initiates the expansion of naïve B cells expressing the corresponding BCRs in vivo, but is insufficient to induce
the maturation of these BCRs towards their neutralizing forms. A major hurdle to overcome in order to elicit any
bNAbs through immunization is due to steric restrictions imposed by glycans present at the conserved
glycosylation site N276 in Loop D of Env. These glycans limit access to the epitope recognized by germline
VRC01-class antibodies, but as the antibodies undergo somatic hypermutation and affinity-based selection
they ‘learn’ how to bypass this steric block. The success of our immunization strategies to elicit VRC01-class
bNAbs will therefore depend on our ability to guide the evolution of germline VRC01-class antibodies along
particular maturation pathways to bypass the N276 glycan-imposed restrictions. In this Project we propose to
use concepts and reagents, not tested previously, in an effort to overcome these major obstacles preventing
the generation of VRC01-class antibodies by immunization. Specifically, we propose to use anti-idiotypic
monoclonal antibodies (aiMAbs) against the germline VRC01-class antibodies to specifically increase the
frequency of VRC01-expressing B cells prior to immunization with the germline-binding’ 426c Core
immunogen, followed by booster immunizations with Env-based reagents that select for VRC01-class B cells
that can bypass the restrictions imposed by the N276 glycans. Our studies will be performed in an iterative
fashion in diverse animal models that express VRC01-class BCRs, including mice engineered to express a
polyclonal human BCR repertoire.

## Key facts

- **NIH application ID:** 10062816
- **Project number:** 5P01AI138212-03
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Leonidas Stamatatos
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,413
- **Award type:** 5
- **Project period:** 2018-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062816

## Citation

> US National Institutes of Health, RePORTER application 10062816, Development of prime-boost immunization schemes to elicit VRC01-class bNAbs in polyclonal human BCR backgrounds (5P01AI138212-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062816. Licensed CC0.

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