Development of Prevention, Diagnostic, and Treatment Strategies for Zoonotic Diseases

  • Influenza A viruses have wild aquatic birds as their natural hosts. The viruses replicate in the birds' intestinal tracts and are shed into nesting lakes via feces, where they can be preserved in frozen water during the winter, allowing them to persist in the natural environment. Notably, all four influenza pandemics experienced by humans over the past 100 years were caused by reassortant viruses which were generated in the respiratory tracts of pigs coinfected with seasonal human influenza A viruses and avian influenza viruses that circulate among wild waterfowl. Based on these findings, we have systematically preserved over 4,500 virus strains collected through global surveillance of avian and animal influenza. These strains represent all 144 possible combinations of the 16 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes. They are organized into a publicly available virus strain library, which serves as a vital resource for pandemic influenza vaccine development and diagnostics.
  • In Japan, pandemic influenza is often treated separately from seasonal influenza and referred to as “novel influenza,” but this distinction is misguided. If we can significantly enhance the immunogenicity of seasonal influenza vaccines, then in the event of a pandemic, we would only need to replace the vaccine strain with the pandemic virus strain. However, the majority of seasonal influenza vaccines worldwide are split vaccines, in which virus particles are broken down using ether or detergents. These split (HA) vaccines were developed with a primary focus on reducing side effects (which are actually signs of immune activation), at the cost of immunogenicity. As a result, their effectiveness is extremely limited, particularly in inducing protective immunity in children and the elderly populations at higher risk of severe disease (Figure 1). Development of seasonal influenza vaccines that are both highly immunogenic and safe is an urgent global priority. Our laboratory works under the premise that effective pandemic influenza preparedness must begin with improving and solidifying seasonal influenza countermeasures. To that end, we have launched the All-Japan Influenza Vaccine Research Consortium in collaboration with all five Japanese influenza vaccine manufacturers, Shiga University of Medical Science, Kumamoto University, the University of Melbourne, and the National Institute of Infectious Diseases (NIID). Together, this industry-academia-government collaboration is promoting the development and practical implementation of world-class influenza vaccines (Figure 2).
  • We have conducted a series of studies using whole virus particle vaccines and the current HA (split) vaccines, provided by four vaccine manufacturers. These studies included in-house tests by the manufacturers as well as animal trials using mice and/or monkeys conducted at Hokkaido University and Shiga University of Medical Science. The results clearly demonstrated that whole particle vaccines induce significantly stronger innate and adaptive immune responses compared to current HA vaccines. Moreover, we found that diluting the whole particle vaccines can suppress the induction of inflammatory cytokines while maintaining immunogenicity (Figure 3: Differences in Immune Activation Mechanisms Between Vaccines). This project has advanced to Phase I/II clinical trials, which confirmed the safety of the whole particle vaccine. We are currently conducting a detailed analysis of the immune responses elicited (Figure 4).