# Project 2. Animal studies to elucidate the optimal sequence of Env immunogens for induction of distal MPER bnAbs

> **NIH NIH P01** · DUKE UNIVERSITY · 2022 · $293,911

## Abstract

The recent isolation of several key broad neutralizing antibodies (bnAb) from HIV infected subjects have set
the stage for the development of novel strategies for the induction of similar classes of vaccine induced
neutralizing antibody responses. Among these recent bnAb isolates, both 10E8 and DH511 target the distal
MPER epitopes on HIV Envelope (Env) gp41. Structural and functional analysis of DH511 lineage antibodies
have shown that distal MPER epitope bnAbs are among the most broad and potent HIV neutralizing
antibodies, thus establishing them as important for vaccine design. For immunogen design, we will partner with
the Scripps team in Project 1, and use our new computational program, Antigen Receptor Mutation Analyzer
for Detection of Low Likelihood Occurrences (ARMADiLLO), that allows for definition of the critical antibody
somatic mutations to be induced, to determine the key IAs that a successful vaccine will need to target. The
use of KI mouse models bearing BCR of BnAbs and their UCAs (Unmutated Common Ancestor) has been a
major advance that will allow the optimization of unmutated precusor-targeting sequential immunogens, and
allow the course of antibody affinity maturation of candidate immunogens to be followed. We will use the newly
isolated DH511 distal MPER bnAb clonal lineage UCA, intermediate antibodies (IAs) and bnAbs as reagents
upon which to design sequential immunogens and to test these immunogens in a powerful, new knock-in
mouse model of bnAb development developed by the Fred Alt laboratory in the Animal Models Core.
Moreover, recent breakthoughs in understanding Rhesus macaque immunobiology has allowed similar HIV
neutralizing antibody genealogies to be defined and followed throughout vaccination regimens. Our specific
Aims are:
Aim 2.1. Define functional improbable intermediate antibody (IA) somatic mutations that a successful vaccine
will need to select to lead to bnAb induction.
Aim 2.2. Define immunogens derived from Project 1 that activate DH511 unmutated precursors and
intermediate antibodies in small animal models and in Rhesus macaques.
The studies in Project 2 will synergize with studies in Project 1 and Small Animal Models Core to lead to novel
designs of immunogens that will lead to initiation and selection of affinity matured distal MPER bnAbs.

## Key facts

- **NIH application ID:** 10365963
- **Project number:** 5P01AI138211-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $293,911
- **Award type:** 5
- **Project period:** 2019-04-09 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365963

## Citation

> US National Institutes of Health, RePORTER application 10365963, Project 2. Animal studies to elucidate the optimal sequence of Env immunogens for induction of distal MPER bnAbs (5P01AI138211-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10365963. Licensed CC0.

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