# Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine

> **NIH NIH R01** · EPIVAX, INC. · 2021 · $1,123,469

## Abstract

ABSTRACT
Routine influenza exposure and vaccination generate inadequate cross-protective immunity against
novel avian influenza. This fuels concerns for pandemics that may cause high numbers of severe illness
and deaths in immune naïve populations. Avian H7N9 influenza poses a threat to human health because
of its high case fatality rate consistently observed in annual epidemic waves since it emergence in 2013.
The potential for virus adaptations that increase human-to-human transmissibility raises concern for an
H7N9 influenza virus pandemic.
H7N9 influenza HA elicits weak neutralizing antibody responses in natural infection and vaccination. To
prepare for an H7N9 influenza pandemic, vaccine strategies that overcome the poor immunogenicity of
H7N9 HA are needed. We hypothesize that a stronger CD4+ T cell response to H7N9 HA will support an
improved hemagglutination inhibition (HI) antibody response. To address this hypothesis, we propose to
introduce seasonal HA-specific CD4+ T cell epitopes into H7N9 HA, using a structure-guided approach,
to produce a novel immunogen capable of priming protective HI responses by inducing CD4+ T cell
memory. The proposed studies are grounded in our prior work showing that the H3-HA306-318 CD4+ T cell
epitope introduced into the corresponding site in H7N9 HA boosts effector T cell and antibody immune
responses while preserving neutralizing antibody epitopes that would be encountered in natural infection.
Here, we propose to introduce more memory CD4+ T cell epitopes into the existing optimized H7-HA
because the frequency of CD4+ T cells that recognize the H3-HA306-318 epitope varies among individuals
depending on their history of seasonal influenza exposure. Aim 1 will evaluate novel HAs composed of
different numbers of engineered CD4+ T cell epitopes. A new HA containing the fewest engineered
seasonal HA CD4+ T cell epitopes that best approximates the biophysical properties of wild type H7N9
HA and demonstrates enhanced mouse and human immune responses over wild type H7N9 HA will be
selected to go forward to Aim 2 refinement studies. In Aim 2, we will reduce the mutational load of the
immunogen that emerges from Aim 1 to generate an improved design that maintains the gain in
protective immunity while more closely preserving structural and biophysical properties of wild type H7-
HA. The benefits of a lower mutational load will be minimized perturbation to neutralizing antibody targets
and improved manufacturability. The proposed studies will identify a lead candidate with minimum
mutational load and maximal immunogenicity and protective efficacy that is ready for IND enabling
studies by the end of this Partnerships program.

## Key facts

- **NIH application ID:** 10216952
- **Project number:** 5R01AI132205-05
- **Recipient organization:** EPIVAX, INC.
- **Principal Investigator:** Anne Searls DeGroot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,123,469
- **Award type:** 5
- **Project period:** 2017-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216952

## Citation

> US National Institutes of Health, RePORTER application 10216952, Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine (5R01AI132205-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10216952. Licensed CC0.

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