# Designing and optimizing candidate HIV vaccines and boosting protocols

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $962,348

## Abstract

Abstract
A major goal of HIV-1 vaccine research is the design of immunogens capable of inducing broadly
neutralizing antibodies (bnAbs) that bind to the viral envelope glycoprotein (Env). While many HIV
bnAbs have been isolated from chronically infected patients, raising bnAbs by immunization has been
difficult. The principal problems appear to be (1) that bnAb epitopes are sub-dominant and so the
response must be primed and boosted in such a way as to avoid off-target responses and favor the
desired specificities, (2) that most forms of Env bind poorly to unmutated precursors of bnAbs so that
bnAb responses are not typically primed appropriately and (3) we do not understand how best to
boost responses once primed to yield bnAbs that typically have an unusual amount of somatic
mutation. In this proposal, we address these problems by study of engineered immunogens in bnAb
knockin mice.
We focus on two classes of bnAbs, VRC01 and PGT130, which we predict will be readily raised by
vaccination in humans using appropriately engineered immunogens. VRC01 is the prototype bnAb of
a class that recognizes the CD4 binding site (CD4bs) and PGT130 is a representative of a class of
glycan-dependent bnAbs that bind the V3 loop and mannose patch on Env. Both antibody classes
have been described in many HIV infected individuals and are particularly potent and broad
suggesting that a vaccine able to elicit such Abs would provide protection at relatively low Ab
concentrations.
We have previously generated mice engineered to carry B cells with germline reverted (gl)-VRC01
immunoglobulin heavy (H) and light (L)-chains, and here we propose to generated new knock-in mice
carrying gl-PGT130 H- and L-chain genes. The mice express the B cell receptors that should be
triggered and matured to generate VRC01 or PGT130 class bnAbs and will be used to investigate
immunogens and immunization strategies. For priming, we will use existing germline-targeting
immunogens reactive to gl-VRC01 and we will generate novel engineered immunogens targeting gl-
PGT130 and. For boosting we will test a range of engineered and natural immunogens to focus and
enhance intermediate and final steps in bnAb maturation.
This study will test the generality of our germline-targeting approach, discover new vaccine
candidates, and teach us lessons on how to maximize subdominant anti-viral responses that should
inform human vaccination strategies in general.

## Key facts

- **NIH application ID:** 9816613
- **Project number:** 5R01AI128836-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DAVID NEMAZEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $962,348
- **Award type:** 5
- **Project period:** 2016-11-14 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9816613

## Citation

> US National Institutes of Health, RePORTER application 9816613, Designing and optimizing candidate HIV vaccines and boosting protocols (5R01AI128836-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9816613. Licensed CC0.

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