Intranasal immunization with an RBD-hemagglutinin fusion protein harnesses preexisting immunity to enhance antigen-specific responses
Atsushi Kawai, Nagisa Tokunoh, Eigo Kawahara, Shigeyuki Tamiya, Shinya Okamura, Chikako Ono, Jessica Anindita, Hiroki Tanaka, Hidetaka Akita, Sho Yamasaki, Jun Kunisawa, Toru Okamoto, Yoshiharu Matsuura, Toshiro Hirai, Yasuo Yoshioka
Atsushi Kawai, Nagisa Tokunoh, Eigo Kawahara, Shigeyuki Tamiya, Shinya Okamura, Chikako Ono, Jessica Anindita, Hiroki Tanaka, Hidetaka Akita, Sho Yamasaki, Jun Kunisawa, Toru Okamoto, Yoshiharu Matsuura, Toshiro Hirai, Yasuo Yoshioka
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Research Article

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

Abstract

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.

Authors

Atsushi Kawai, Nagisa Tokunoh, Eigo Kawahara, Shigeyuki Tamiya, Shinya Okamura, Chikako Ono, Jessica Anindita, Hiroki Tanaka, Hidetaka Akita, Sho Yamasaki, Jun Kunisawa, Toru Okamoto, Yoshiharu Matsuura, Toshiro Hirai, Yasuo Yoshioka

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Figure 7

Intranasal subunit vaccine platform that utilizes preexisting immunity is highly versatile.

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Intranasal subunit vaccine platform that utilizes preexisting immunity i...
(A–E) IAV-mice were immunized intranasally with (A) NTD-HA, (B, D, and E) PspA-HA, or (C) G-HA at 30 and 51 days after IAV infection. (A–C) Levels of (A) NTD-, (B) PspA-, and (C) G-specific IgA in nasal wash were evaluated using ELISA. (D and E) Fourteen days after booster immunization, IAV-mice were challenged with S. pneumoniae to achieve lower respiratory tract infection. The percentage changes in (D) body weight and (E) survival were monitored after challenge with S. pneumoniae. (F) Experimental schematic: BALB/c mice were infected intranasally with S. pneumoniae, followed by intranasal immunization with RBD-PspA or RBD without adjuvant at 30 and 51 days after S. pneumoniae infection. (G) The RBD-specific nasal wash IgA levels were evaluated using ELISA. (H) Experimental schematic: BALB/c mice were subcutaneously immunized with 1 μg of mRNA vaccine encoding SARS-CoV-2 spike twice, followed by intranasal immunization with RBD-HA or HA plus c-di-GMP at 30 and 51 days after mRNA vaccine. (I) The HA-specific nasal wash IgA levels were evaluated using ELISA. (A–I) Data are represented as means ± SD. n = 5. Each experiment was performed more than twice. ****P < 0.0001, Tukey’s multiple-comparisons test.