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Principal Investigator: Masaru Kanekiyo
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $22,147,857
Funding agency: National Institute of Allergy and Infectious Diseases
Improvements in vaccines against influenza that increase potency, breadth and durability of protection would improve worldwide ability to combat seasonal changes in influenza viruses (drift) and emergence of new pandemic strains (shift). This study aims to develop new platforms and vaccination strategies against ever-changing influenza viruses. Nanoparticle-, and nucleic acid-based vaccines have been developed against multiple seasonal and pandemic strains of influenza viruses, including H7N9, and H5N1 avian influenza viruses. In addition, studies are ongoing to design and optimize vaccine antigens to present conserved regions of the influenza virus hemagglutinin (HA) in order to develop a vaccine that provides broader universal protection. These include nanoparticle display of the stabilized HA stem trimers of both group 1 and group 2 influenza HA, multiple HAs from different subtypes, as well as a collection of less-conserved HA globular head domains. Testing has been conducted to evaluate candidates, as well as adjuvants to boost immune response, and determine the optimal strategies for immunization. Several candidates showed promising results that lead to further evaluations in animal infection models of influenza viruses. Multiple cycles of iterative structure-based design yielded a structurally stabilized trimer of the HA stem derived from both group 1 and group 2 HA subtypes of influenza A viruses. Several versions of these immunogens were generated and tested its immunogenicity in animal models. Immunization with these nanoparticles induces cross-reactive antibody responses in mice, ferrets, and nonhuman primates with neutralizing activity. Immunization confers significant protective immunity in mice as well as ferrets against heterosubtypic lethal influenza virus challenges. Passive transfer of immunoglobulins from immunized mice provides complete protection against lethal influenza virus challenges in recipient mice, indicating the protection is antibody-mediated. Further studies to determine the immunological basis of protection are underway. A phase 1 clinical trial of a lead candidate of both group 1 HA stem nanoparticle vaccine and group 2 HA stem nanoparticle vaccine has begun. In addition, collaborations to develop gene-based vaccine platforms such as mRNA are underway. The first-in-human clinical trial of ferritin nanoparticle vaccine displaying influenza HA has recently been finished. Collaborations to utilize designed nanoparticle to display influenza antigens yield promising immunogenicity and protective efficacy results in animal models. A variant of such nanoparticles has been manufactured and a phase 1 clinical trial has been initiated. Exploring alternative vaccine antigens such as viral neuraminidase (NA) has made progress in the past year and continues to discover and design desired universal influenza vaccine antigens.
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