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Principal Investigator: Masaru Kanekiyo
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $4,261,000
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 influenza as well as emergence of new pandemic influenza viruses. Influenza vaccines have the potential to reduce the risk of symptomatic infection and severe disease caused by influenza viruses. This study aims to develop new platforms and vaccination strategies against ever-changing influenza viruses.
The vaccine effectiveness of the current influenza vaccines can vary and is influenced by such factors as antigenic match between vaccine and circulating viruses and the limitations around vaccine production (acquisition of mutations, etc.). The major goals of our program are to develop next-generation influenza vaccines candidates that can provide 1) supraseasonal protection from antigenically drifted seasonal influenza virus strains and 2) protection from potential pandemic virus subtypes. Moreover, the immune response elicited by our vaccine candidates should also provide durable immunity. To fulfill our research goals, we employ structure-based immunogen design and self-assembling nanoparticle display platforms.
In order to achieve the supraseasonal influenza immunity by improving vaccine-elicited breadth across homotypic and heterosubtypic viruses we computationally designed a two-component mosaic nanoparticle immunogen. One such mosaic nanoparticle we designed co-displayed the hemagglutinins (HAs) of the four influenza strains in the licensed 2017-2018 seasonal influenza vaccine. When we vaccinated mice, ferrets, and nonhuman primates with our mosaic nanoparticles we noted that it was highly immunogenic at eliciting vaccine-matched immunity comparable to the current influenza vaccines in animals. More importantly, our mosaic vaccine induced a broadly protective response to not only vaccine-matched strains but also heterologous viruses including heterosubtypic viruses. Based on these promising preclinical results, a Phase I clinical trial using a version of this quadrivalent mosaic nanoparticle has been initiated to assess safety and immunogenicity. More recently, we also designed a next generation hexavalent mosaic vaccine candidate which incorporates two additional HAs from non-circulating influenza viruses and have completed pre-clinical studies in mice and nonhuman primates. We also noted that the hexavalent vaccine candidate was immunogenic in both animal models and have started enrolling healthy adults in a Phase I clinical trial to assess safety, tolerability and immunogenicity.
We continue our efforts to use the ferritin-based nanoparticle vaccine platform for displaying the stabilized HA stem trimers of group 1 and 2 influenza A viruses, H1ssF and H10ssF, both of which have advanced into individual Phase I clinical trials. We have also co-immunized with our stem-based immunogens and shown that co-immunization of mice, ferrets, and nonhuman primates elicits group-specific and cross-group protective immunity and neutralizing antibody responses. A broadly neutralizing antibody was also isolated from an immunized nonhuman primate. We have also started testing if combining an adjuvant with our stabilized stem or mosaic immunogens can improve the vaccine-induced immune responses in preclinical models as well as a Phase I clinical trial. We continue to work on developing a nucleic acid-based vaccine platform such as mRNA. Our results suggest that our vaccine candidates have the potential to be used for supraseasonal or pre-pandemic influenza. We also continue to structurally and functionally characterize the influenza surface glycoprotein neuraminidase (NA) to gain a better understanding of how it can be used as an improved vaccine candidate.
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