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Principal Investigator: Daniel F. Hoft
Organization: SAINT LOUIS UNIVERSITY
Fiscal Year: 2021
Award: $753,206
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Influenza is responsible for significant morbidity and mortality worldwide every year and causes severe
pandemics when new strains evolve that have not previously circulated in humans. The high viral mutation rate
necessitates that new vaccines be generated based on the prevalence of circulating strains every year. These
reformulated versions of influenza vaccines are not always protective; vaccine effectiveness (VE) has varied
from 10 to 60% over the past 10 years based on how well vaccine strains are matched with circulating strains.
There is an urgent unmet need for influenza vaccines that induce greater cross-protective immunity. We
propose to harness the immunogenic potential of broadly reactive influenza-specific T cell epitopes to produce
vaccines with universal significance. Our previous R21 funded work has provided proof-of-principle that
advanced immunoinformatic tools can be used to efficiently identify highly conserved influenza A epitopes,
including promiscuous CD4+ T cell epitopes and HLA-A2-restricted CD8+ T cell epitopes, that are
immunogenic and can induce protective immunity. Furthermore, we have convincingly demonstrated that
T cell-based vaccines designed to stimulate human T cell responses can induce heterotypic protective
immunity. We now propose to extend our R21 studies to more fully evaluate promiscuous CD4+ T cell
epitopes to confirm that these epitopes can elicit potent CD4+ T cell responses in >95% of all humans
expressing diverse HLA class II alleles. We also will identify relevant CD8+ T cell epitopes restricted by
additional non-HLA-A2 class I supertypes, to obtain sufficient epitopes for broad population coverage (>95% of
humans). We then will develop and compare immunogenicity and protective efficacy of multi-epitope vaccines
using several state-of-the art vaccine delivery platforms including: recombinant ‘naked’ DNA, purified proteins
mixed with novel adjuvants, novel adenovirus (Ad) vaccines designed to evade preexisting human Ad
immunity, and virus-like particle (VLP) encapsidated RNA vaccines. Vaccines will be tested in vitro using
human PBMC and in vivo using humanized mice expressing transgenic HLA. Heterotypic efficacy will be
evaluated upon challenge with 3 distinct influenza A strains (H1N1, H3N2, and H5N1). The proposed work
can provide transformational new products and direction for influenza vaccine development, focusing
on a paradigm-shifting concept of inducing broadly protective T cell responses.
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