# Project 1. Design of immunogens that bind to the UCA and to IAs and mature DH511 bnAbs in optimal affinities

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $325,000

## Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a critical unmet goal of HIV vaccine development.
BnAb DH511 is of high interest as a vaccine lead due to its very high breadth and the high in vivo protective
potency of MPER bNAbs. Key challenges for inducing DH511-like bnAbs are: (a) the low affinity of DH511-
like precursors for HIV peptides and proteins, (b) the restriction on bnAb angle of approach imposed by the
recessed, membrane-proximal epitope environment and (c) the absence of the DH511 epitope from most
soluble, native-like trimers.
 A promising strategy to initiate DH511-like bnAb induction is germline targeting, in which suitable
DH511-class precursors are specifically activated using engineered immunogens, thus selecting BCRs with
the potential to develop broad neutralization in the absence of autoreactivity. This approach will also help
circumvent steric problems associated with the recessed location of the epitope, by priming precursors with
known genetic and structural potential to mature into bnAbs compatible with MPER steric restraints. In this
project, which is Project 1 of a multi-project collaborative proposal, we will engineer epitope-scaffold
immunogens that bind with high affinity to and activate DH511-like precursors, using computational design
and directed evolution.
 As known bnAbs are highly mutated, vaccine induction of bnAbs following a germline-targeting prime
will likely require sequential immunization with other immunogens designed to shepherd affinity maturation
of the B-cell receptor. We will develop different classes of boosting immunogens, including epitope-
scaffolds with more native epitopes, membrane-protein scaffolds and membrane-bound Env variants
stabilized in a conformation to which DH511 binds strongly. Structural studies of soluble and membrane-
bound immunogens in complex with DH511 lineage members will guide immunogen development.
 The Animal Core of this collaborative proposal will generate knock-in mice that express DH511-like
precursors, and Project 2 will use those mice to test B cell priming and boosting in vivo. Project 2 will
conduct sequential prime/boost immunization experiments in knock-in mice and use ELISA, cytometry,
single B cell sorting and sequencing and neutralization assays to track and optimize affinity maturation,
providing experimental feedback to Project 1 to allow for iterative improvement of immunogens.
 In summary, these studies seek to develop novel HIV vaccine candidates and also to shift HIV vaccine
research towards a reductionist approach based on state-of-the-art protein engineering to develop
germline-targeting and boosting immunogens, development of human Ig knock-in mouse models to enable
testing of human-repertoire-specific vaccines, and in-depth analysis of vaccine-induced affinity maturation
pathways in vivo to guide iterative vaccine optimization.

## Key facts

- **NIH application ID:** 10132977
- **Project number:** 5P01AI138211-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $325,000
- **Award type:** 5
- **Project period:** 2019-04-09 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132977

## Citation

> US National Institutes of Health, RePORTER application 10132977, Project 1. Design of immunogens that bind to the UCA and to IAs and mature DH511 bnAbs in optimal affinities (5P01AI138211-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10132977. Licensed CC0.

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