An epitope-optimized human H3N2 influenza vaccine induces broadly protective immunity in mice and ferrets

Abstract

There is a crucial need for an improved H3N2 influenza virus vaccine due to low vaccine efficacy rates and increased morbidity and mortality associated with H3N2-dominated influenza seasons. Here, we utilize a computational design strategy to produce epitope-optimized, broadly cross-reactive H3 hemagglutinins in order to create a universal H3N2 influenza vaccine. The Epigraph immunogens are designed to maximize the viral population frequency of epitopes incorporated into the immunogen. We compared our Epigraph H3 vaccine to the traditional egg-based inactivated influenza vaccine from 2018–19, FluZone. Epigraph vaccination-induced stronger cross-reactive antibody responses than FluZone against 18 H3N2 viruses isolated from 1968 to 2019 in both mice and ferrets, with protective hemagglutination inhibition titers against 93–100% of the contemporary H3N2 strains compared to only 27% protection measured from FluZone. In addition, Epigraph vaccination-induced strong cross-reactive T-cell immunity which significantly contributes to protection against lethal influenza virus infection. Finally, Epigraph vaccination protected ferrets from influenza disease after challenge with two H3N2 viruses. The superior cross-reactive immunity induced by these Epigraph immunogens supports their development as a universal H3N2 influenza vaccine.

Multivalent Epigraph Hemagglutinin Vaccine Protects against Influenza B Virus in Mice

“…Here, we report a vaccine strategy that utilizes a computational algorithm to maximize potential epitopes incorporated into the immunogen design and provide broad protection against antigenically diverse IBV. Our group has previously demonstrated the utility of Epigraph HA immunogens against swine H3 [ 28 ] and human H3 influenza A virus [ 29 ] and here we show similar improved cross-reactive efficacy when applied to IBV. Mice immunized with IBV-Epi developed highly cross-reactive HI and neutralizing antibody responses.…”

“…Further, an important note for this study is that direct comparison of our hexavalent Epigraph vaccine and quadrivalent Fluzone is not entirely equivalent due to the differences in valency. We have previously interrogated the contribution of individual Epigraph immunogens targeting human H3 IAV, and observed that the first and second Epigraph HA proteins induced the strongest cross-reactive antibody responses, and the third Epigraph HA protein elicited strong cross-reactive T cell responses [ 29 ]. These data indicate that each Epigraph HA protein is uniquely contributing to immunity and a trivalent cocktail is likely necessary to provide broadly cross-reactive responses.…”

“…The Epigraph vaccine antigen designer uses a graph-based algorithm to create vaccine antigens with maximized potential epitope coverage of a highly diverse sequence population. We have recently shown that the Epigraph HA design can induce significantly improved cross-reactive responses against swine H3 [ 28 ] and human H3 influenza A virus [ 29 ] than those induced by commercial vaccines and a wildtype comparator vaccine. Here, we build on this previous success to evaluate the protective efficacy of Epigraph immunogens designed against the HA protein of IBV (IBV-Epi).…”

Assessment of the immune interference effects of multivalent vaccine for influenza epidemic strain in 2022–2023 and evaluation of its efficacy

“…Notably, there were no significant differences among the various multivalent vaccine formulations, regardless of whether antigens were mixed in equal proportions or with a specific antigen dominant proportion. All vaccines demonstrated sufficiently robust levels of protection against infection [ 20 ]. Furthermore, the results of our immunoglobulin analyses revealed that the expression of immunoglobulins increased in the experimental groups administered with the multivalent vaccines compared to the monovalent vaccines.…”

Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

“…In M7-CpG NP-vaccinated mice, 100% survival was achieved in the HK/ 68 challenge model, an event only achieved in this experimental group with the CpG group also illustrating considerable survival (70%). epitope-based vaccines induced protection in ferrets and mice a total clearance of H3N2 in lungs (8,73).…”