Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice

ABSTRACT

Strategies that improve influenza vaccine immunogenicity are critical for the development of vaccines for pandemic preparedness. Hemagglutinin (HA)-specific CD4⁺ T cell epitopes support protective B cell responses against seasonal influenza. However, in the case of avian H7N9, which poses a pandemic threat, HA elicits only weak neutralizing antibody responses in infection and vaccination without adjuvant. We hypothesized that an immune-engineered H7N9 HA incorporating a broadly reactive H3N2 HA-specific memory CD4⁺ T cell epitope that replaces a regulatory T cell-inducing epitope at the corresponding position in H7N9 HA could harness preexisting influenza T cell immunity to increase CD4⁺ T cells that are needed for protective antibody development. We designed and produced a virus-like particle (VLP) vaccine that carries the epitope augmented H7N9 HA (OPT1) and immunized HLA-DR3 transgenic mice with established H3N2 immunity. OPT1-VLPs stimulated higher stem cell, central, and effector memory CD4⁺ T cell levels over wild type VLP immunization. In addition, activated, IL-21-producing follicular helper T cell frequencies were enhanced. This novel immunogen design strategy illustrates that site-specific modifications aimed to augment T cell epitope content enhance CD4⁺ T cell responses among critical subpopulations capable of aiding protective immune responses upon antigen re-encounter and that mobilization of immune memory can be used to overcome the poor immunogenicity of avian influenza viruses.

KEYWORDS:

• Vaccine
• influenza
• H7N9
• T cell
• T cell epitope
• immunoinformatics
• hemagglutinin
• virus-like particle

Disclosure statement

A.S. De Groot is a senior officer and shareholder, and L.M. Meyers, C.M. Boyle, M. Grizotte-Lake, B.G. McGonnigal, and L. Moise are employees of EpiVax, Inc., a privately owned biotechnology company located in Providence, RI. These authors acknowledge that there is a potential conflict of interest related to their relationship with EpiVax and attest that the work contained in this research report is free of any bias that might be associated with the commercial goals of the company. The other authors declare no competing interests exist.

Additional information

Funding

This work was supported by the National Institute of Allergy and Infectious Diseases (US) [R43AI118189 and R01AI132205] and the European Union Horizon H2020 program under Grant Agreement No. [H2020-SC1-2019-874653-INDIGO].