# Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens

> **NIH NIH R37** · UNIVERSITY OF PENNSYLVANIA · 2024 · $879,161

## Abstract

PROJECT SUMMARY (See instructions):
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies 
(bNAbs). Here, we leverage three recent discoveries from our groups to generate more effective V2 apex 
immunogens. Having found that unshielded regions (“glycan holes”) in Env are negatively associated with 
bNAb development, we have created bioinformatic tools to identify and mask these unwanted epitopes. We 
have also used our Signature-based Epitope Targeted (SET) immunogen design strategy to generate 
germline targeting Envs that engage multiple V2 apex bNAb precursors. Finally, by studying bNAb 
development in ~150 rhesus macaques (RMs) infected with 16 different SHIVs, we have identified 25 animals 
(17%) with heterologous breadth, 15 of which developed V2 apex bNAbs. Based on these data, we 
hypothesize that by (i) minimizing distracting glycan hole epitopes, (ii) increasing Env affinity for V2 apex 
bNAb precursors, (iii) increasing relevant epitope diversity in vaccine boosts, and (iv) incorporating B cell 
lineage designs, we will improve V2 bNAb germline engagement and bNAb lineage maturation. During the 
first 3 years of this R37 application, we have made significant progress toward all Specific Aims. In 
Aim 1, we optimized the glycan shield and improved the germline targeting properties of several SIVcpz and 
HIV-1 Envs, which allowed us to down-select the CAP256 Env as the most promising platform. In Aim 2, we 
cloned members of 12 new rhesus V2 apex bNAb lineages and inferred their unmutated common ancestors 
(UCAs), thereby tripling the number of V2 bNAb lineages for novel lineage-based immunogen design. SHIVs 
expressing the best performing germline targeting CAP256 Envs are being generated and envelope-antibody 
coevolution pathways are being determined for all SHIV infected animals that developed V2 neutralization 
breadth. In Aim 3, we generated nucleoside-modified mRNA containing lipid nanoparticle (mRNA/LNP) 
vaccines that express germline targeting, stabilized, membrane bound CAP256 Envs. The best performing 
constructs have been shown to express well and to bind multiple human and macaque V2 bNAb UCAs. In 
this five-year MERIT extension application, we propose to extend these studies and complete the rhesus 
macaque infection and immunization studies that were delayed by the COVID lockdown. Since the last 
competitive renewal, our group has been highly productive, publishing 38 papers relevant to HIV vaccine 
development. In this MERIT extension application, we will apply multiple vaccine improvement strategies to 
induce V2 apex bNAbs in RMs and then translate these findings to humans.

## Key facts

- **NIH application ID:** 10805651
- **Project number:** 4R37AI150590-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Beatrice H Hahn
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $879,161
- **Award type:** 4C
- **Project period:** 2019-09-19 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805651

## Citation

> US National Institutes of Health, RePORTER application 10805651, Optimizing glycan shield coverage, germline B cell receptor binding and epitope diversity of V2-apex targeted HIV-1 Env immunogens (4R37AI150590-06). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10805651. Licensed CC0.

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