# Preclinical Evaluation of Envelope Immunogens Optimized to Elicit VRCOI-class An

> **NIH NIH U19** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $202,713

## Abstract

The overall goal of this IPCAVD proposal is the development and clinical testing of an Envelope immunogen 
optimized to elicit broadly neutralizing anti-HIV-1 antibodies. The goal of Project 2 is the preclinical 
evaluation of HIV-1 Envelope vaccine immunogens that have been optimized to engage the predicted 
germline precursor B cell receptors of neutralizing antibodies that target the CD4 receptor binding site and 
begin the process of their development. We hypothesize that one key reason for the failure of previous 
generations of Envelope immunogens to elicit such antibodies is that these immunogens do not engage 
germline B cell receptors, the key precursors to broadly neutralizing 'VRCOI '-class antibodies. Thus, 
previous immunogens did not efficiently initiate and drive the process of 'VRCOI'-class bNAb antibody 
maturation. In this project we will evaluate germline optimized Env immunogens for their ability to effectively 
initiate the development of broadly neutralizing anti-CD4-binding site antibodies of the 'VRCOI'-class, and 
will optimize the vaccine strategies that will be deployed in human clinical trials in Project 4. Utilizing four 
complementary animal model systems: lentigenic mice, transgenic mice , humanized Veloclmmune mice, 
and non-human primates, we will evaluate the ability of our immunogens to stimulate germline VH genes 
known to be the progenitors of 'VRCOr class broadly neutralizing antibodies, trace their maturation over the 
course of vaccination, and evaluate their ability to block HIV-1 infection. Ultimately, we will determine which 
optimized Envelope immunogen, and which vaccine modality is the most appropriate for deployment into 
human clinical trials. A second goal of this Project 2 is to confirm that similar engagement and maturation of 
germline BCRs that give rise to 'VRC01' class antibodies also takes place in humans immunized with our 
immunogens. Our studies will provide invaluable information on how well such broadly neutralizing 
antibodies can be stimulated by germline-optimized Envelope immunogens and how far we are able to drive 
antibody maturation by vaccination. Such a detailed analysis of vaccine-elicited anti-HIV-1 responses will 
provide valuable insight for future immunogen and vaccine regimen design efforts.

## Key facts

- **NIH application ID:** 9886179
- **Project number:** 5U19AI109632-08
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Leonidas Stamatatos
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,713
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886179

## Citation

> US National Institutes of Health, RePORTER application 9886179, Preclinical Evaluation of Envelope Immunogens Optimized to Elicit VRCOI-class An (5U19AI109632-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9886179. Licensed CC0.

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