# Determine the minimal level of replication required for broad protective immunity of influenza vaccine

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $234,000

## Abstract

Project Summary
Influenza A virus causes disease in 5%-20% of the population with over 200,000 hospitalizations annually in
US. The antigen drift and shift of influenza virus due to rapid evolution pose a serious challenge for annual flu
vaccination program, which is effective depending on the accurate prediction of the influenza serotypes that
will be circulating in the next flu season. The recent failure of influenza vaccine and potential outbreak of
influenza pandemics highlights the urgent need for a vaccine that can provide broad protection. Interferon
(IFN) is a critical component of the innate immune system and also the bridge between the innate and adaptive
immune responses. We recently studied the anti-IFN function of influenza genome using a quantitative and
high-throughput genomics system. By incorporating eight IFN-sensitive mutations into influenza genome, we
generated a Hyper Interferon Sensitive (HIS) virus as a vaccine candidate. HIS virus is highly attenuated in
wild type and immune-deficient SCID mice, but fully competent in IFNAR-deficient mice. HIS provides
protection against homologous and heterologous viral challenges. Our central hypothesis is that systematical
elimination of IFN-evasion functions on multiple segments of the virus genome generates proper induction of
innate immune response, which is essential for establishing long term memory B cell response and T cell
response by live attenuated influenza vaccine. Our objective is to determine the minimal replication
capacity required for live attenuated influenza virus vaccine, identify and generate single-round
infection HIS virus, which can induce strong IFNR signaling in vitro, but has no replication capacity in
vivo due to innate immune response. Such vaccine virus candidate would have confined one-round
infection during immunization whereas the IFN inducing activity would be strong enough to illicit
broad protective immunity. We will generate hyper IFN sensitive virus that has no replication capacity in
vivo, and characterize its replication kinetics and responsiveness to IFN in lung epithelial cells. After we obtain
such virus, we will infect mice with vaccine candidate viruses and characterize the induced immune responses.
Finally, we will determine protection efficacy of vaccine candidate viruses against different strains of influenza
virus in vivo. The results achieved from this project will advance our understanding of influenza vaccine
development and facilitate the development of universal influenza vaccine.

## Key facts

- **NIH application ID:** 10084270
- **Project number:** 5R21AI149648-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yuan Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,000
- **Award type:** 5
- **Project period:** 2020-01-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084270

## Citation

> US National Institutes of Health, RePORTER application 10084270, Determine the minimal level of replication required for broad protective immunity of influenza vaccine (5R21AI149648-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10084270. Licensed CC0.

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