# Triggering germline-encoded broadly neutralizing antibody responses against influenza virus

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $520,617

## Abstract

Project Summary / Abstract
This is an application by Dr. Daniel Lingwood and Dr. Facundo Batista, faculty members of the Ragon Institute
of MGH, MIT and Harvard. Both investigators define B cell-antigen recognition principles to inform antibody
vaccine design, and for this, have developed two orthogonal transgenic mouse models that recapitulate human
antibody responses in vivo. The investigators propose to apply these models to evaluate germline stimulation
of human B cell lineages known to give rise to broadly neutralizing antibody (bnAbs) against influenza A
viruses (IAV), which account for the majority of flu-hospitalizations and pandemic threats. Most antibody
responses to IAV are dominated by off-target, non-neutralizing activities, however, work from the investigators
indicates that human BCRs assembled from the antibody VH gene, IGHV1-69, possess natural specificity for a
conserved site of vulnerability, the stem-bnAb epitope on the hemagglutinin spike proteins from Group 1 IAV
(IAV subtypes: H1, H2, H5, H6, H8, H9, H11, H12, H12, H16). To test if this genetically endows for vaccine-
amplifiable bnAb development pathways, the investigators have engineered the LINGWOOD mouse system,
where antibodies develop with human antibody VH genes (e.g. IGHV1-69) and full human CDRH3 diversity.
Genetic manipulation of this system enables in vivo B cell titration to match the IGHV1-69 B cell frequency
found in humans. Sequentially immunizing these mice with SS-np, a nanoparticle displaying the bnAb target,
has succeeded in germline stimulation of IGVH1-69 bnAb precursors and IGHV1-69-dependent expansion of
bnAb responses; the first example of eliciting high titer IAV bnAbs through vaccination. This response also
provided broad protection against Group 1 IAV, including pandemic bird flu, supporting the investigators'
central hypothesis that broadly protective bnAbs can be elicited by germline antibody-targeting vaccines. In
Aim 1, the investigators will define whether SS-np stands as a universal booster of the IGHV1-69-encoded
bnAb response after introduction of B cell memory to diverse IAV `swarms' that simulate human immune
history to influenza. In Aim 2, the investigators will define how refocusing serum antibodies against this specific
bnAb target also enhances antibody Fc effector functions, potentially co-enabling protection through activation
of innate immunity. In Aim 3, the BATISTA mouse system will be used to evaluate vaccine-expansion of
IGHV1-69 bnAbs alongside the human IGHV1-18- and IGHV6-1-class bnAb lineages, which neutralize the
remaining Group 2 IAV subtypes (H3, H4, H7, H10, H14, H15). In this system, murine IgM B cells bearing
individual human bnAb precursors of each pathway are co-transferred to a single recipient mouse. Following
immunization, lineage expansions are individually tracked via their progression through B cell germinal centers
and then into immune memory. The animals will be co-immunized with SS-np, SS-np2, and SS-np3; ...

## Key facts

- **NIH application ID:** 10241949
- **Project number:** 5R01AI153098-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Facundo Damian Batista
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,617
- **Award type:** 5
- **Project period:** 2020-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241949

## Citation

> US National Institutes of Health, RePORTER application 10241949, Triggering germline-encoded broadly neutralizing antibody responses against influenza virus (5R01AI153098-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241949. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*