Intranasal immunization with an RBD-hemagglutinin fusion protein harnesses preexisting immunity to enhance antigen-specific responses

J Clin Invest. 2023 Dec 1;133(23):e166827. doi: 10.1172/JCI166827.


Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS-CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor-binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV-infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and CD4+ T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines.

Keywords: Antigen; Antigen-presenting cells; Influenza; Vaccines.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Antibodies, Viral
  • Communicable Diseases*
  • Hemagglutinins
  • Immunity, Mucosal
  • Immunization
  • Immunoglobulin G
  • Influenza A virus* / genetics
  • Influenza Vaccines*
  • Mice
  • Vaccination


  • Hemagglutinins
  • Influenza Vaccines
  • Antibodies, Viral
  • Adjuvants, Immunologic
  • Immunoglobulin G