Synthetic multi-component influenza vaccines to elicit broad immunity

项目总结

PROJECT SUMMARY Seasonal influenza viruses cause significant disease burden. While seasonal influenza vaccines are available, these are often poorly efficacious due to mismatch with circulating virus strains, particularly in the populations at greatest risk of complications from infection, including the elderly, infant, and immunocompromised. Influenza A viruses (IAV) also pose a pandemic risk for which seasonal influenza vaccines provide no cross protection. In 2018, the National Institute of Allergy and Infectious Diseases (NIAID) released a strategic plan for developing a universal influenza vaccine and subsequently released the FOA PA-18-859, “Advancing Research Needed to Develop a Universal Influenza Vaccine.” The long-term goal of this proposal is to develop a universal influenza vaccine. We hypothesize that a flu vaccine composed of broadly cross-reactive B-and T-epitopes covalently linked to an immune adjuvant will elicit potent immune responses and protect against diverse influenza A virus infections and associated disease. This expectation is supported by our prior studies which demonstrated a fully multi- component vaccine composed of tumor associated glycopeptide B- and CTL-epitope, a peptide CD4 T cell epitope and a TLR2 agonist (Pam3CysSK4) elicited robust immune responses and protected against a stringent tumor challenge in a murine cancer model. We will chemically synthesize multi-component vaccines that are composed of conserved peptide antigens derived from IAV and an adjuvant such as Pam3CysSK4 or monophosphoryl lipid A (Aim 1). In addition, we will employ an enzymatic glycan remodeling strategy to modify recombinant hemagglutinin (rHA), which is used as a licensed flu vaccine, with various TLR agonists and DC targeting moieties (Aim 2). To focus immunity to the more conserved stalk domain of HA, novel HAstalk proteins will be examine modified by immune-potentiating moieties. The immunogenicity and efficacy will be evaluated in murine (Aims 1 and 2) and ferret (Aim 3) vaccination and challenge models, using innovative approaches and antigen probes to assess polyfunctional T cell responses and geminal center (GC) B cell response. This research is significant as it directly addresses multiple NIAID priorities in their strategic plan for developing a universal influenza vaccine. The results of these studies could have a significant impact as the universal influenza vaccines developed should be suitable for advancement to pre-clinical studies. Moreover, the adjuvants and approaches developed in this proposal will be applicable to other vaccines and study of the host response to influenza infection, and will have broader impacts beyond universal influenza vaccine development.