# A genetic template for generating universally protective responses to influenza

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $29,007

## Abstract

Project Summary/Abstract
The majority of vaccine-elicited antibody responses to influenza are dominated by off-target, immunodominant,
and non-neutralizing activities. However, recent work indicates that human B cell receptors (BCRs) containing
the antibody VH gene IGHV1-69 possess V gene-encoded specificity for a functionally conserved site of
vulnerability, the stem-epitope of the influenza glycoprotein hemagglutinin (HA), a target of broadly neutralizing
antibody (bnAb) responses. To experimentally evaluate IGHV1-69 stem-epitope targeting as a gene-encoded
template for building a universal influenza vaccine, our lab has generated transgenic mice in which antibody
development proceeds via normal human VDJ recombination, but is constrained to a single V gene, IGHV1-69.
My preliminary data indicates that IGHV1-69 usage in itself is sufficient to refocus the antibody response to the
HA stem epitope and is protective from an unmatched viral challenge. This is a major paradigm shift in rational
vaccine design, namely that broad protection may be generated through activation and amplification of gene-
encoded antibody responses. I now propose to assess the breadth of the IGHV1-69 protective response as
well as examine if this encoded targeting activity is regulated by a single amino acid change, present in 15% of
the global population, using an IGHV1-69 SNP constrained mouse model. Additionally, to define a means for
clinical development, I have applied a RNA bacteriophage platform for peptide display and affinity selection to
derive multivalent virus like particles (VLPs) that specifically engage IGHV1-69 germline BCRs, allowing for
selective expansion of IGHV1-69 precursors from the full human immunoglobulin repertoire. I propose to
evaluate selective IGHV1-69 priming in two models: 1). C57BL/6 mice adoptively transferred with IGHV1-69 B
cells, and 2). The Trianni mouse, the latest industry-standard humanized vaccine model. Priming will then be
followed by boosting with HA immunogens to amplify HA stem-epitope targeting antibody responses. This
study will define a genetically encoded basis for bnAb elicitation and aims to overcome the failure of traditional
approaches to influenza vaccination.

## Key facts

- **NIH application ID:** 10017642
- **Project number:** 5F31AI138368-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Maya Sangesland
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,007
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-07-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017642

## Citation

> US National Institutes of Health, RePORTER application 10017642, A genetic template for generating universally protective responses to influenza (5F31AI138368-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017642. Licensed CC0.

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