# Rational design and B cell responses of HIV epitope vaccines

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $638,644

## Abstract

Project Summary
Many broadly neutralizing antibodies (bNAbs) recognize structurally discrete sites on the envelope glycoprotein
(Env) of human immunodeficiency virus type-1 (HIV-1), such as the CD4-binding site (CD4bs), the strand C of
variable regions 1 and 2 (V1V2), the N332 supersite at the base of variable region 3 (V3), and the membrane-
proximal external region (MPER). Crystallography and electron microscopy (EM) have revealed how these
bNAbs interact with individual epitopes, engineered Env domains, and gp140 trimers, providing a rational basis
for vaccine design. The scaffolding method has been used to design novel antigens in hope to elicit epitope-
specific, bNAb-like B cell responses. In this R01 application, we will combine the latest structural findings with
novel technologies in protein design, B cell engineering and knock-in mouse, and next-generation sequencing
(NGS) of B cell repertoire to develop and assess epitope-focused vaccine candidates for three bNAb epitopes.
The specific aims (SAs) of our R01 proposal are: (1) to design epitope-focused immunogens for three sites of
HIV-1 vulnerability. We hypothesize that the N332 supersite of V3 base, the trimeric V1V2 apex, and MPER
can be presented by scaffolds and nanoparticles in their bNAb-bound conformations. In a preliminary study, we
have designed a panel of antigens based on various principles such as epitope scaffolding, particulate display,
and Fc presentation. We have performed structural and antigenic profiling for a subset of antigens with positive
results, and will screen the whole panel of antigens to facilitate rational selection; (2) to assess epitope-focused
immunogens in bNAb-presenting B cell lines and knock-in mice. We hypothesize that successfully designed
epitope-focused immunogens can activate engineered bNAb-expressing B cells and elicit robust responses in
bNAb knock-in mice. Previously, we have developed mouse B cell lines expressing CD4bs-, V1V2- and N332-
specific bNAbs and b12 knock-in mouse, which were used to assess rationally designed HIV-1 immunogens.
We will develop PGT145-, PGT121/128-, and 10E8-expressing B cell lines and knock-in mice and use these
tools to assess epitope-focused immunogens selected in Aim 1; (3) to assess the trimer-prime/epitope-boost
strategy and B cell responses in NHPs. We hypothesize that a gp140 trimer will elicit NAbs to diverse epitopes
and sequential boosts with epitope-focused immunogens will direct B cell responses to the target epitopes. In
our preliminary study, we have tested the epitope-focusing effect and neutralization for selected N332 antigens
in C57BL/6 mice. Previously, we have conducted a longitudinal study of B cell responses to an HIV-1 gp140-
foldon trimer in non-human primates (NHPs). Here, we will first test the trimer-prime/epitope-boost strategy in
mice for different epitopes and then assess the immunogenicity and B cell responses in NHPs. In addition to
serological assays, we will use antibody NGS to ...

## Key facts

- **NIH application ID:** 9816614
- **Project number:** 5R01AI129698-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jiang Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,644
- **Award type:** 5
- **Project period:** 2016-11-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9816614

## Citation

> US National Institutes of Health, RePORTER application 9816614, Rational design and B cell responses of HIV epitope vaccines (5R01AI129698-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9816614. Licensed CC0.

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