# Immunogen Design for Induction of HIV distal gp41 broadly neutralizing antibodies

> **NIH NIH P01** · DUKE UNIVERSITY · 2020 · $2,138,470

## Abstract

The overall objective is to develop immunogens that will initiate and select HIV-1 broad neutralizing antibody
(bnAb) lineages directed to the distal membrane proximal external region (MPER) of HIV Env gp41. Distal
gp41 MPER antibody types such as 10E8 and DH511 are desirable because they are among the most broad
and potent bnAbs isolated. There are two strategies for bnAb immunogen design lineages. (1) Define bnAb
clonal lineage genealogies, infer the bnAb unmutated common ancestor (UCA) and select autologous
Envs that bind—termed B cell lineage immunogen design. (2) Structural-based design, using structures of
sequential lineage Abs to design Envs that bind to bnAb lineage members. Here we propose to combine
the strengths of both strategies to design immunogens that can initiate and induce distal MPER
bnAbs. We will use the newly isolated DH511 lineage UCA, intermediate antibodies (IAs) and bnAbs as
reagents upon which to design sequential immunogens that will select DH511-like precursors and lead to
bnab development (Project 1, William Schief, PI), and to test these immunogens in physiologically relevant
knock-in mouse model of bnAb development (Project 2 (Munir Alam, PI, Small Animal Models Core,
Ming Tian, PI, Fred Alt, Co-I). A computational program, Antigen Receptor Mutation Analyzer for Detection
of Low Likelihood Occurrences (ARMADiLLO) (Project 2) that allows for definition of the critical antibody
somatic mutations to be induced will be used to determine key IAs that a successful vaccine will need to
target.
 Overall Specific Aim 1. Define the key IAs and antibody somatic mutations that a successful vaccine will
need to select to lead to distal MPER bnAb induction. (Projects 1 and 2)
 Overall Specific Aim 2. Design of germline targeting (GT) prime and boost immunogens that bind to the
DH511 precursors and to key IAs and mature DH511 bnAbs in optimal affinities and can select the
correct/desired IAs and bnAbs. (Project 1)
 Overall Specific Aim 3. Solve co-crystal and cryoEM structures of DH511 and DH511-like lineage
antibodies with Env immunogens that move the lineage along the bnAb maturation pathway and enable
design of additional immunogens to complete the induction of distal MPER bnAbs B cell lineages. (Project 1)
 Overall Specific Aim 4. Selection of optimal Env immunogens from immunizations of DH511 UCA and IA
VH and VL knock-in mice. This will be accomplished by use of the novel DH511 UCA VHDJH-rearranging
mouse recently developed by Ming Tian and Fred Alt at Harvard. (Small Animal Core; Projects 1 and 2).
 This collaboration of three leading academic teams in HIV vaccine immunogen design will bring
together expertise in structure-based and lineage-based design, and will be a powerful approach to the
problem of vaccine induction of disfavored antibody lineages in general and distal MPER bnAbs in particular.

## Key facts

- **NIH application ID:** 9912097
- **Project number:** 5P01AI138211-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,138,470
- **Award type:** 5
- **Project period:** 2019-04-09 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912097

## Citation

> US National Institutes of Health, RePORTER application 9912097, Immunogen Design for Induction of HIV distal gp41 broadly neutralizing antibodies (5P01AI138211-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9912097. Licensed CC0.

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