# Guiding the maturation of anti-CD4-BS bnAbs through sequential heterologous Env immunization

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $349,040

## Abstract

PROJECT SUMMARY / ABSTRACT
An effective HIV-1 vaccine will be one that elicits diverse anti-viral immune responses, including broadly
neutralizing antibodies (bnAbs). Here, we focus on eliciting anti-CD4-binding site (CD4-BS) bnAbs, including
VRC01-class bnAbs, through a guided immunization approach with specifically designed Env-derived
immunogens. We previously reported on the design of a clade C Env-derived immunogen that activates naïve
B cells expressing the bnAb precursors of VRC01-class antibodies in vivo. We also reported on the design of a
second immunogen, derived from a clade B Env, that when administered as a 1st boost, increases the
maturation of the emerging VRC01 B cells. Our proposal is based on our recent identification of two additional
Env immunogens that complete the maturation of VRC01-class antibody responses towards their cross-
neutralizing forms. Thus, after 4 Env immunizations of knock-in mice expressing elements of human VRC01
BCRs, we isolate VRC01-class antibodies that neutralize ~33% of heterologous tier 2 viruses. Here, our efforts
focus on optimizing this immunization schema to improve the neutralizing breadth of the elicited VRC01-class
antibodies. An important aspect of our proposal is that we will not limit our work to well-controlled knock-in
mice, but transgenic mice that express diverse human VH/VL genes, as well. Because the B cell repertoire of
these mice better reflects that of humans, we expect that our optimized immunization schema will not only lead
to the generation of VRC01-class antibodies, as it does in the knock-in mice, but that additional classes of anti-
CD4-BS antibody responses will also be elicited. A second important aspect of our proposal is that we will
examine whether mRNA-based immunogen-delivery platforms accelerate the development of cross-
neutralizing CD4-BS antibody responses.

## Key facts

- **NIH application ID:** 10838276
- **Project number:** 1R01AI177095-01A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Leonidas Stamatatos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,040
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838276

## Citation

> US National Institutes of Health, RePORTER application 10838276, Guiding the maturation of anti-CD4-BS bnAbs through sequential heterologous Env immunization (1R01AI177095-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10838276. Licensed CC0.

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