# Design and testing of germline-targeting and boosting immunogens to elicit 10E8-like broadly neutralizing antibodies against HIV

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $911,231

## Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a critical unmet goal of HIV vaccine 
development. BnAb 10E8 is of particular interest as a vaccine lead due to its (1) very high 
breadth, (2) low number of mutations required to develop broad neutralization, (3) low 
auto-reactivity, (4) expected high frequency of precursors in the human na'ive B-cell pool and (5) 
ability to provide surprisingly potent in vivo sterilizing protection in passive transfer studies. 
Key challenges for inducing 10E8-like bnAbs are: (a) the low germline affinity by HIV peptides and 
proteins, (b) the severe restriction on bnAb angle of approach imposed by the recessed, 
membrane-proximal epitope environment and (c) the absence of the 10E8 epitope from most soluble, 
native-like trimers (e.g. SOSIP or NFL or UFO).
A promising strategy to initiate 10E8-like bnAb induction is germline targeting, in which suitable 
10E8-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 proposal, we will engineer epitope-scaffold immunogens that 
activate 10E8-like precursors, using computational design and directed evolution. We will initially 
test immunogens ex vivo using human na'ive B cell sorting. We will further generate knock-in mice 
that over-express 10E8-like precursors, and we will use those mice to test B-cell priming and 
boosting in vivo, first adoptively transferring knockin B cells to wild- type mice in order to 
mimic frequencies of 10E8 bnAb precursor and competitor B cells in humans.
As known bnAbs are highly mutated, vaccine induction of bnAbs following a germline 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 10E8 binds strongly. We 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.
In summary, these studies seek to develop novel HIV vaccine candidates and also to 
shift HIV vaccine research towards a reductionist approach based on strategic 
identification of bNAb precursors, 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 pat...

## Key facts

- **NIH application ID:** 9973061
- **Project number:** 5R01AI147826-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** WILLIAM R. SCHIEF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $911,231
- **Award type:** 5
- **Project period:** 2019-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973061

## Citation

> US National Institutes of Health, RePORTER application 9973061, Design and testing of germline-targeting and boosting immunogens to elicit 10E8-like broadly neutralizing antibodies against HIV (5R01AI147826-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973061. Licensed CC0.

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