# Leveraging human organoid models for the development of broad interventions to mitigate emergent respiratory viral pandemics

> **NIH NIH U19** · STANFORD UNIVERSITY · 2024 · $347,463

## Abstract

PROJECT SUMMARY 
Human respiratory viruses not only contribute to substantial morbidity and mortality worldwide but also pose 
a massive pandemic threat. This broad range of viruses includes human coronavirus (hCoVs), influenza A, 
and human metapneumoviruses (HMPV). Vaccines are among the most powerful means for mitigating viral 
epidemics but require significant neutralizing antibody breadth to maximize the probability of effectiveness 
against unknown viral threats. While a number of components of a protective immune response could be 
targeted to form the basis of a broadly protective coronavirus vaccine, neutralizing antibodies are generally 
accepted to be a key component of protective immunity. Although development of effective first-generation 
SARS-CoV-2 vaccines that induced protective antibody responses against severe illness has proceeded 
with unprecedented speed and seasonal influenza A (IAV) vaccines continue to offer protection, their 
effectiveness against emergent seasonal variants (e.g., Omicron) and, importantly, against other potential 
zoonotic viruses is less likely. Indeed, risk of zoonotic spillover events of divergent CoVs, such as the 
recently documented cases of human transmission from a canine alpha-CoV and a porcine delta-CoV that 
led to flu-like symptoms in infected Haitian children, highlights the need for innovative approaches to identify 
countermeasures targeting highly-conserved sites on CoV spikes shared among the Orthocoronavirinae 
subfamily. Project 2 will prioritize the development of immunogens that elicit neutralizing antibodies 
that can be measured in vitro. We will synergize with other Project members to test as many 
immunization strategies as possible in human organoid models, where the multifaceted functions of 
antibodies, effector cells, and host factors can be used to inhibit viral replication in an exposed host. 
Specifically, this proposal will focus on three interrelated aims: 1) identify the structural correlates of broad 
and potent antibody neutralization against conserved viral epitopes in CoV-S and IAV-HA trimers, 2) design 
multivalent immunogens that stimulate cross-reactive immune responses in human organoid model systems, 
and 3) provide insights into the molecular mechanisms of feedback inhibition and immune imprinting that 
limit diversification of B cell responses. Overall, this proposal will employ immunology, bioinformatics, 
structural biology, protein engineering and immune system models to discover how to elicit antibodies 
capable of neutralizing a broad range of emerging pandemic threat RNA viruses. The results will inform our 
understanding of broadly-protective anti-CoV and anti-lAV immunity in recovered and vaccinated individuals 
and will inform ongoing and future vaccine efforts.

## Key facts

- **NIH application ID:** 10825316
- **Project number:** 2U19AI057229-21
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Christopher O'Neil Barnes
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $347,463
- **Award type:** 2
- **Project period:** 2003-09-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825316

## Citation

> US National Institutes of Health, RePORTER application 10825316, Leveraging human organoid models for the development of broad interventions to mitigate emergent respiratory viral pandemics (2U19AI057229-21). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825316. Licensed CC0.

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