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  • Review
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Nasal vaccines for respiratory infections

Nature volume 641, pages 321–330 (2025)Cite this article

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Abstract

Beginning with Edward Jenner’s discovery of the smallpox vaccine, the ever-expanding repertoire of vaccines against pathogens has saved many lives. During the COVID-19 pandemic, a revolutionary mRNA injectable vaccine emerged that effectively controlled the severity of disease caused by SARS-CoV-2. This vaccine induced potent antigen-specific neutralizing serum IgG antibodies, but was limited in its ability to prevent viral invasion at the respiratory surfaces. Nasal vaccines have attracted attention as a potential strategy to combat respiratory infections and prepare for future pandemics. Input from disciplines such as microbiology, biomaterials, bioengineering and chemistry have complemented the immunology to create innovative delivery systems. This approach to vaccine delivery has yielded nasal vaccines that induce secretory IgA as well as serum IgG antibodies, which are expected to prevent pathogen invasion, thereby diminishing transmission and disease severity. For a nasal vaccine to be successful, the complexity of the relevant anatomical, physiological and immunological properties, including the proximity of the central nervous system to the nasal cavity, must be considered. In this Review, we discuss past and current efforts as well as future directions for developing safe and effective nasal vaccines for the prevention of respiratory infections.

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Fig. 1: Comparison of injectable and mucosal vaccines.
Fig. 2: A strategy for the induction of antigen-specific mucosal immunity by nasal vaccines.
Fig. 3: A comparison of nasal vaccine formulations.
Fig. 4: cCHP nanogel, a promising nasal vaccine-delivery system.

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Change history

  • 21 July 2025

    In the version of the article initially published, ref. 86 was incorrect and has now been amended to “Sia, Z. R. et al. Respiratory vaccination with hemagglutinin nanoliposomes protects mice from homologous and heterologous strains of influenza virus. J. Virol. 96, e0100622 (2022)” in the HTML and PDF versions of the article.

References

  1. Sato, S. & Kiyono, H. The mucosal immune system of the respiratory tract. Curr. Opin. Virol. 2, 225–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Kiyono, H. & Azegami, T. The mucosal immune system: from dentistry to vaccine development. Proc. Jpn Acad. B 91, 423–439 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kiyono, H., Bienenstock, J., McGhee, J. R. & Ernst, P. B. The mucosal immune system: features of inductive and effector sites to consider in mucosal immunization and vaccine development. Reg. Immunol. 4, 54–62 (1992).

    CAS  PubMed  Google Scholar 

  4. Rusell, W. R. & Ogra, R. L. in Mucosal Vaccines—Innovation for Preventing Infections Diseases, 2nd edn (eds Kiyono, H. & Pascual, D. W.) 3–17 (Academic Press, 2020). This chapter provides a comprehensive summary of the history of research and development of mucosal vaccines including those of nasal vaccines.

  5. Okuno, Y. & Nakamura, K. Prophylactic effectiveness of live influenza vaccine in 1965. Biken J. 9, 89–95 (1966).

    CAS  PubMed  Google Scholar 

  6. Kiyono, H. & Fukuyama, S. NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4, 699–710 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Turner, J. S. et al. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature 596, 109–113 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bleier, B. S., Ramanathan, M. Jr & Lane, A. P. COVID-19 vaccines may not prevent nasal SARS-CoV-2 infection and asymptomatic transmission. Otolaryngol. Head Neck Surg. 164, 305–307 (2021).

    Article  PubMed  Google Scholar 

  9. Tiboni, M., Casettari, L. & Illum, L. Nasal vaccination against SARS-CoV-2: Synergistic or alternative to intramuscular vaccines? Int. J. Pharm. 603, 120686 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Azzi, L. et al. Mucosal immune response in BNT162b2 COVID-19 vaccine recipients. eBioMedicine 75, 103788 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Tang, J. et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7, eadd4853 (2022).

    Article  CAS  PubMed  Google Scholar 

  12. Yuki, Y. & Kiyono, H. Mucosal vaccines: novel advances in technology and delivery. Expert Rev. Vaccines 8, 1083–1097 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Kiyono, H., Yuki, Y., Nakahashi-Ouchida, R. & Fujihashi, K. Mucosal vaccines: wisdom from now and then. Int. Immunol. 33, 767–774 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Diallo, B. K. et al. Intranasal COVID-19 vaccine induces respiratory memory T cells and protects K18-hACE mice against SARS-CoV-2 infection. NPJ Vaccines 8, 68 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Uddback, I. et al. Prevention of respiratory virus transmission by resident memory CD8+ T cells. Nature 626, 392–400 (2024).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Holmgren, J. & Czerkinsky, C. Mucosal immunity and vaccines. Nat. Med. 11, S45–S53 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Dhama, K. et al. COVID-19 intranasal vaccines: current progress, advantages, prospects, and challenges. Hum. Vaccin. Immunother. 18, 2045853 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nakahashi-Ouchida, R., Fujihashi, K., Kurashima, Y., Yuki, Y. & Kiyono, H. Nasal vaccines: solutions for respiratory infectious diseases. Trends Mol. Med. 29, 124–140 (2023).

    Article  PubMed  Google Scholar 

  20. Tsai, C. J. Y., Loh, J. M. S., Fujihashi, K. & Kiyono, H. Mucosal vaccination: onward and upward. Expert Rev. Vaccines 22, 885–899 (2023).

    Article  CAS  PubMed  Google Scholar 

  21. Gizurarson, S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr. Drug Deliv. 9, 566–582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mitchison, H. M. & Valente, E. M. Motile and non-motile cilia in human pathology: from function to phenotypes. J. Pathol. 241, 294–309 (2017).

    Article  PubMed  Google Scholar 

  23. Voynow, J. A. & Rubin, B. K. Mucins, mucus, and sputum. Chest 135, 505–512 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Gizurarson, S. The effect of cilia and the mucociliary clearance on successful drug delivery. Biol. Pharm. Bull. 38, 497–506 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Pabst, R. Nose-associated lymphoid tissue (NALT)—structure, function and species differences. Vaccine 33, 4406–4413 (2015). This review introduces and discusses the basic immunological basis of the NALT as the inductive site for the initiation of antigen-specific immune responses, including species differences.

    Article  CAS  PubMed  Google Scholar 

  26. Ramirez, S. I. et al. Immunological memory diversity in the human upper airway. Nature 632, 630–636 (2024). This study provided evidence that the human nasopharynx, including adenoids, harbours an immunologic environment for IgA B cell induction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Corr, S. C., Gahan, C. C. & Hill, C. M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis. FEMS Immunol. Med. Microbiol. 52, 2–12 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Stavnezer, J. & Kang, J. The surprising discovery that TGFβ specifically induces the IgA class switch. J. Immunol. 182, 5–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Carrasco-Yepez, M. M. et al. Naegleria fowleri immunization modifies lymphocytes and APC of nasal mucosa. Parasite Immunol. 40, e12508 (2018).

    Article  Google Scholar 

  30. Wellford, S. A. et al. Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense. Mucosal Immunol. 17, 1102–1113 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu, J. et al. Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues. Nature 632, 637–646 (2024). This article provides evidence for the existence of a common mucosal immune system through the adoptive transfer of lymphoid B cells leading to their migration to distant and different mucosal tissues.

    Article  PubMed  Google Scholar 

  32. Nakahashi-Ouchida, R., Yuki, Y. & Kiyono, H. Development of a nanogel-based nasal vaccine as a novel antigen delivery system. Expert Rev. Vaccines 16, 1231–1240 (2017). This review describes how NALT-derived IgA+ B cells predominantly express CCR10 and migrate to immunological effector tissues with increased CCL28 expression.

    Article  CAS  PubMed  Google Scholar 

  33. Hieshima, K. et al. CC chemokine ligands 25 and 28 play essential roles in intestinal extravasation of IgA antibody-secreting cells. J. Immunol. 173, 3668–3675 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Wang, J. et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J. Exp. Med. 211, 2397–2410 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McDermott, M. R. & Bienenstock, J. Evidence for a common mucosal immunologic system: I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J. Immunol. 122, 1892–1898 (1979). This paper provided the evidence for the existence of the commensal mucosal immune system.

    Article  CAS  PubMed  Google Scholar 

  36. Wellford, S. A. et al. Mucosal plasma cells are required to protect the upper airway and brain from infection. Immunity 55, 2118–2134.e2116 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Moens, L. & Tangye, S. G. Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage. Front. Immunol. 5, 65 (2014). 

    Article  PubMed  PubMed Central  Google Scholar 

  38. Corthesy, B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front. Immunol. 4, 185 (2013). This article summarizes the immunobiological uniqueness of SIgA antibodies, which have crucial roles in creating a balanced state of mutualism and elimination in the harsh environment of mucosal surfaces.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wei, H. & Wang, J. Y. Role of polymeric immunoglobulin receptor in IgA and IgM transcytosis. Int. J. Mol. Sci. 22, 2284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brandtzaeg, P. Secretory IgA: designed for anti-microbial defense. Front. Immunol. 4, 222 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Miyamoto, S. et al. Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection. Proc. Natl Acad. Sci. USA 120, e2314808120 (2023). This paper demonstrated the importance of SARS CoV-2 S protein-specific SIgA antibodies in preventing infectious virus shedding and transmission in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marcotte, H. et al. Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages. Proc. Natl Acad. Sci. USA 121, e2315354120 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, D. Y. et al. The airway antigen sampling system: respiratory M cells as an alternative gateway for inhaled antigens. J. Immunol. 186, 4253–4262 (2011). 

    Article  CAS  PubMed  Google Scholar 

  44. Lee, H. et al. Phenotype and function of nasal dendritic cells. Mucosal Immunol. 8, 1083–1098 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tamura, S., Tanimoto, T. & Kurata, T. Mechanisms of broad cross-protection provided by influenza virus infection and their application to vaccines. Jpn J. Infect. Dis. 58, 195–207 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Oh, J. E. et al. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Sci. Immunol. 6, eabj5129 (2021). This paper showed that intranasal, but not injection, immunization induces lung-resident IgA B cells, leading to the induction of IgA-mediated protective immunity against influenza virus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Treanor, J. J. et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine 18, 899–906 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Thwaites, R. S. et al. Early mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine. Nat. Commun. 14, 8053 (2023).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ali, M. S. & Pearson, J. P. Upper airway mucin gene expression: a review. Laryngoscope 117, 932–938 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Dehghan, M. H., Gaikwad, V. M. & Dandge, B. Nasal absorption of drugs—barriers and solutions. Res. J. Pharm. Tech. 2, 634–641 (2009).

    CAS  Google Scholar 

  51. Singh, A. K., Singh, A. & Madhv, N. V. S. Nasal Cavity, a promising transmucosal platform for drug delivery and research approaches from nasal to blain targetting. J. Drug Delivery https://doi.org/10.22270/jddt.v2i3.163 (2012).

  52. Robert-Guroff, M. Replicating and non-replicating viral vectors for vaccine development. Curr. Opin. Biotechnol. 18, 546–556 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yahalom-Ronen, Y. et al. A single dose of recombinant VSV-∆G-spike vaccine provides protection against SARS-CoV-2 challenge. Nat. Commun. 11, 6402 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bezbaruah, R. et al. Developmental landscape of potential vaccine candidates based on viral vector for prophylaxis of COVID-19. Front. Mol. Biosci. 8, 635337 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ura, T., Okuda, K. & Shimada, M. Developments in viral vector-based vaccines. Vaccines 2, 624–641 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Spearman, P. et al. Intranasal parainfluenza virus type 5 (PIV5)-vectored RSV vaccine is safe and immunogenic in healthy adults in a phase 1 clinical study. Sci. Adv. 9, eadj7611 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ding, C., Ma, J., Dong, Q. & Liu, Q. Live bacterial vaccine vector and delivery strategies of heterologous antigen: a review. Immunol. Lett. 197, 70–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. LeCureux, J. S. & Dean, G. A. Lactobacillus mucosal vaccine vectors: immune responses against bacterial and viral antigens. mSphere 3, e00061–18 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li, L. et al. Mucosal IgA response elicited by intranasal immunization of Lactobacillus plantarum expressing surface-displayed RBD protein of SARS-CoV-2. Int. J. Biol. Macromol. 190, 409–416 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sakurai, F., Tachibana, M. & Mizuguchi, H. Adenovirus vector-based vaccine for infectious diseases. Drug Metab. Pharmacokinet. 42, 100432 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. De Leo, V., Milano, F., Agostiano, A. & Catucci, L. Recent advancements in polymer/liposome assembly for drug delivery: from surface modifications to hybrid vesicles. Polymers 13, 1027 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Mangla, B. et al. Nanocarriers-assisted needle-free vaccine delivery through oral and intranasal transmucosal routes: a novel therapeutic conduit. Front. Pharmacol. 12, 757761 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Schwendener, R. A. Liposomes as vaccine delivery systems: a review of the recent advances. Ther. Adv. Vaccines 2, 159–182 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zuglianello, C. & Lemos-Senna, E. The nanotechnological approach for nasal delivery of peptide drugs: a comprehensive review. J. Microencapsul. 39, 156–175 (2022).

    Article  CAS  PubMed  Google Scholar 

  65. Yuki, Y. et al. Nanogel-based antigen-delivery system for nasal vaccines. Biotechnol. Genet. Eng. Rev. 29, 61–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Nakahashi-Ouchida, R., Yuki, Y. & Kiyono, H. Cationic pullulan nanogel as a safe and effective nasal vaccine delivery system for respiratory infectious diseases. Hum. Vaccin. Immunother. 14, 2189–2193 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Shimizu, T. et al. Nanogel DDS enables sustained release of IL-12 for tumor immunotherapy. Biochem. Biophys. Res. Commun. 367, 330–335 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Ayame, H., Morimoto, N. & Akiyoshi, K. Self-assembled cationic nanogels for intracellular protein delivery. Bioconjug. Chem. 19, 882–890 (2008). 

    Article  CAS  PubMed  Google Scholar 

  69. Nochi, T. et al. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. Nat. Mater. 9, 572–578 (2010). This is the first study to demonstrate that a nanogel consisting of cCHP is a promising nasal vaccine-delivery vehicle for universal protein-based vaccines.

    Article  ADS  CAS  PubMed  Google Scholar 

  70. Kong, I. G. et al. Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae. Infect. Immun. 81, 1625–1634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fukuyama, Y. et al. Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques. Mucosal Immunol. 8, 1144–1153 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nakahashi-Ouchida, R. et al. A nanogel-based trivalent PspA nasal vaccine protects macaques from intratracheal challenge with pneumococci. Vaccine 39, 3353–3364 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Nakahashi-Ouchida, R. et al. Induction of mucosal IgA-mediated protective immunity against nontypeable Haemophilus influenzae infection by a cationic nanogel-based P6 nasal vaccine. Front. Immunol. 13, 819859 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Crain, M. J. et al. Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae. Infect. Immun. 58, 3293–3299 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nabors, G. S. et al. Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules. Vaccine 18, 1743–1754 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Piao, Z. et al. Protective properties of a fusion pneumococcal surface protein A (PspA) vaccine against pneumococcal challenge by five different PspA clades in mice. Vaccine 32, 5607–5613 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. De Chiara, M. et al. Genome sequencing of disease and carriage isolates of nontypeable Haemophilus influenzae identifies discrete population structure. Proc. Natl Acad. Sci. USA 111, 5439–5444 (2014).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  78. Jain, S. et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N. Engl. J. Med. 372, 835–845 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shi, T. et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 390, 946–958 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Scheltema, N. M. et al. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob. Health 5, e984–e991 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Yu, X. et al. Antibody and local cytokine response to respiratory syncytial virus infection in community-dwelling older adults. mSphere 5, e00577–20 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Venkatesan, P. First RSV vaccine approvals. Lancet Microbe 4, e577 (2023).

    Article  PubMed  Google Scholar 

  83. Schepens, B. et al. Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein. EMBO Mol. Med. 6, 1436–1454 (2014). 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Umemoto, S. et al. Cationic-nanogel nasal vaccine containing the ectodomain of RSV-small hydrophobic protein induces protective immunity in rodents. NPJ Vaccines 8, 106 (2023). This paper demonstrated the feasibility of developing a nasal vaccine that induces both humoral and cell-mediated immunity against RSV infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. van Hoogevest, P. & Wendel, A. The use of natural and synthetic phospholipids as pharmaceutical excipients. Eur. J. Lipid Sci. Technol. 116, 1088–1107 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sia, Z. R. et al. Respiratory vaccination with hemagglutinin nanoliposomes protects mice from homologous and heterologous strains of influenza virus. J. Virol. 96, e0100622 (2022).

    Article  PubMed  Google Scholar 

  87. Islam, N. & Ferro, V. Recent advances in chitosan-based nanoparticulate pulmonary drug delivery. Nanoscale 8, 14341–14358 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  88. Sonaje, K. et al. Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations. Mol. Pharm. 9, 1271–1279 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Gong, X., Gao, Y., Shu, J., Zhang, C. & Zhao, K. Chitosan-based nanomaterial as immune adjuvant and delivery carrier for vaccines. Vaccines 10, 1906 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Xing, L. et al. Chemical modification of chitosan for efficient vaccine delivery. Molecules 23, 229 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Mills, K. H. et al. Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a. Infect. Immun. 71, 726–732 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Atmar, R. L. et al. Norovirus vaccine against experimental human Norwalk Virus illness. N. Engl. J. Med. 365, 2178–2187 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. El-Kamary, S. S. et al. Adjuvanted intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that express homing receptors for mucosal and peripheral lymphoid tissues. J. Infect. Dis. 202, 1649–1658 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Patel, D. R. et al. Intranasal SARS-CoV-2 RBD decorated nanoparticle vaccine enhances viral clearance in the Syrian hamster model. Microbiol. Spectr. 12, e0499822 (2024).

    Article  PubMed  Google Scholar 

  95. Wagstaffe, H. R. et al. Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults. Sci. Immunol. 9, eadj9285 (2024).

    Article  CAS  PubMed  Google Scholar 

  96. Park, H. S. et al. Intranasal immunization with avian paramyxovirus type 3 expressing SARS-CoV-2 spike protein protects hamsters against SARS-CoV-2. NPJ Vaccines 7, 72 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Le Nouen, C. et al. Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys. Cell 185, 4811–4825.e4817 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Liu, X. et al. A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters. Proc. Natl Acad. Sci. USA 118, e2109744118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  99. van Doremalen, N. et al. Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models. Sci. Transl. Med. 13, eabh0755 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ying, B. et al. Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection. Nat. Immunol. 25, 537–551 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Madhavan, M. et al. Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial. eBioMedicine 85, 104298 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mudrick, H. E. et al. Comparison of replicating and nonreplicating vaccines against SARS-CoV-2. Sci. Adv. 8, eabm8563 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ahi, Y. S., Bangari, D. S. & Mittal, S. K. Adenoviral vector immunity: its implications and circumvention strategies. Curr. Gene Ther. 11, 307–320 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Adler, J. M. et al. An intranasal live-attenuated SARS-CoV-2 vaccine limits virus transmission. Nat. Commun. 15, 995 (2024). 

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mao, T. et al. Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses. Science 378, eabo2523 (2022). This paper presented a vaccine strategy of ‘prime and spike’, which uses the existing systemic immunity induced by primary injection vaccination (prime) to induce mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike) for protection against SARS-CoV-2 infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. McMahan, K. et al. Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques. Nature 626, 385–391 (2024). This study showed that intratracheal booster vaccination with an Ad26-based bivalent SARS-CoV-2 vaccine in systemically primed non-human primates induced potent mucosal humoral and cellular immunity that provided near-complete protection against a SARS-CoV-2 BQ.1.1 challenge.

    Article  ADS  CAS  PubMed  Google Scholar 

  107. Gagne, M. et al. Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates. Nat. Immunol. 25, 1913–1927 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chen, J. et al. A live attenuated virus-based intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2. Sci. Bull. 67, 1372–1387 (2022).

    Article  CAS  Google Scholar 

  109. Sun, W. et al. A Newcastle disease virus (NDV) expressing a membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine. Vaccines 8, 771 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Logunov, D. Y. et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 396, 887–897 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Beavis, A. C. et al. Efficacy of parainfluenza virus 5 (PIV5)-vectored intranasal COVID-19 vaccine as a single dose primer and booster against SARS-CoV-2 variants. J. Virol. 99, e01989-24 (2025).

  112. An, D. et al. Protection of K18-hACE2 mice and ferrets against SARS-CoV-2 challenge by a single-dose mucosal immunization with a parainfluenza virus 5-based COVID-19 vaccine. Sci. Adv. 7, eabi5246 (2021).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  113. Tioni, M. F. et al. Mucosal administration of a live attenuated recombinant COVID-19 vaccine protects nonhuman primates from SARS-CoV-2. NPJ Vaccines 7, 85 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang, Y. et al. Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy. Proc. Natl Acad. Sci. USA 118, e2102775118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. O’Neill, A. et al. Mucosal SARS-CoV-2 vaccination of rodents elicits superior systemic T central memory function and cross-neutralising antibodies against variants of concern. eBioMedicine 99, 104924 (2024).

    Article  PubMed  Google Scholar 

  116. Yunis, J., Short, K. R. & Yu, D. Severe respiratory viral infections: T-cell functions diverging from immunity to inflammation. Trends Microbiol. 31, 644–656 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Schlom, J. & Donahue, R. N. The importance of cellular immunity in the development of vaccines and therapeutics for COVID-19. J. Infect. Dis. 222, 1435–1438 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kalimuddin, S. et al. Vaccine-induced T cell responses control Orthoflavivirus challenge infection without neutralizing antibodies in humans. Nat. Microbiol. 10, 374–387 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gonzalez Delgado, C. A. Adaptive phase I / II clinical trial, randomized, of parallel groups, to evaluate the safety and immunogenicity in adults of two vaccine candidates, based on recombinant RBD subunits for the prevention of COVID-19 in regimens that use the nasal route of administration (RPCEC, accessed 2 March 2024); https://rpcec.sld.cu/en/trials/RPCEC00000345-En.

  120. Lam, J. H. et al. Next-generation intranasal Covid-19 vaccine: a polymersome-based protein subunit formulation that provides robust protection against multiple variants of concern and early reduction in viral load of the upper airway in the golden Syrian hamster model. Preprint at bioRxiv https://doi.org/10.1101/2022.02.12.480188 (2022).

  121. Lam, J. H. et al. Polymersomes as stable nanocarriers for a highly immunogenic and durable SARS-CoV-2 spike protein subunit vaccine. ACS Nano 15, 15754–15770 (2021).

    Article  CAS  PubMed  Google Scholar 

  122. Li, J. X. et al. Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial. Lancet Respir. Med. 10, 739–748 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhou, R. et al. Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination in mouse models. eBioMedicine 75, 103762 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Hassan, A. O. et al. A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2. Cell 183, 169–184.e113 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bricker, T. L. et al. A single intranasal or intramuscular immunization with chimpanzee adenovirus-vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters. Cell Rep. 36, 109400 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Banihashemi, S. R. et al. Safety and efficacy of combined intramuscular/intranasal RAZI-COV PARS vaccine candidate against SARS-CoV-2: a preclinical study in several animal models. Front. Immunol. 13, 836745 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Logunov, D. Y. et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397, 671–681 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Liu, T., Liang, Y. & Huang, L. Development and delivery systems of mRNA vaccines. Front. Bioeng. Biotechnol. 9, 718753 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Yang, L., Tang, L., Zhang, M. & Liu, C. Recent advances in the molecular design and delivery technology of mRNA for vaccination against infectious diseases. Front. Immunol. 13, 896958 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Release 228, 9–19 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  131. Shah, P., Lalan, M. & Barve, K. Intranasal delivery: An attractive route for the administration of nucleic acid based therapeutics for CNS disorders. Front. Pharmacol. 13, 974666 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Dhaliwal, H. K., Fan, Y., Kim, J. & Amiji, M. M. Intranasal delivery and transfection of mRNA therapeutics in the brain using cationic liposomes. Mol. Pharm. 17, 1996–2005 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Suberi, A. et al. Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination. Sci. Transl. Med. 15, eabq0603 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Baldeon Vaca, G. et al. Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection. Sci. Adv. 9, eadh1655 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Waltz, E. How nasal-spray vaccines could change the pandemic. Nature 609, 240–242 (2022).

    Article  ADS  CAS  PubMed  Google Scholar 

  136. Topol, E. J. & Iwasaki, A. Operation Nasal Vaccine—lightning speed to counter COVID-19. Sci. Immunol. 7, eadd9947 (2022).

    Article  PubMed  Google Scholar 

  137. Lavelle, E. C. & Ward, R. W. Mucosal vaccines—fortifying the frontiers. Nat. Rev. Immunol. 22, 236–250 (2022).

    Article  CAS  PubMed  Google Scholar 

  138. US Food and Drug Administration. FluMist Quadrivalent. FDA https://www.fda.gov/vaccines-blood-biologics/vaccines/flumist-quadrivalent (2023).

  139. Carter, N. J. & Curran, M. P. Live attenuated influenza vaccine (FluMist; Fluenz): a review of its use in the prevention of seasonal influenza in children and adults. Drugs 71, 1591–1622 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Jeyanathan, M. et al. Immunological considerations for COVID-19 vaccine strategies. Nat. Rev. Immunol. 20, 615–632 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Vignuzzi, M., Wendt, E. & Andino, R. Engineering attenuated virus vaccines by controlling replication fidelity. Nat. Med. 14, 154–161 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Aoshi, T. Modes of action for mucosal vaccine adjuvants. Viral Immunol. 30, 463–470 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. US Centers for Disease Control and Prevention. Adjuvants and Vaccines. CDC https://www.cdc.gov/vaccine-safety/about/adjuvants.html (2024).

  144. Zhao, T. et al. Vaccine adjuvants: mechanisms and platforms. Signal Transduct. Target Ther. 8, 283 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wrobel, B. B. & Leopold, D. A. Olfactory and sensory attributes of the nose. Otolaryngol. Clin. North Am. 38, 1163–1170 (2005).

    Article  PubMed  Google Scholar 

  146. Alvites, R. D. et al. The nasal cavity of the rat and mouse–source of mesenchymal stem cells for treatment of peripheral nerve injury. Anat. Rec. 301, 1678–1689 (2018).

    Article  CAS  Google Scholar 

  147. Ramvikas, M., Arumugam, M., Chakrabarti, S. R. & Jaganathan, K. S. in Micro and Nanotechnology in Vaccine Development (eds Skwarczynski, M. & Toth, I.) 279–301 (Elsevier, 2017).

  148. Verma, A. K., Zheng, J., Meyerholz, D. K. & Perlman, S. SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways. JCI Insight 7, e160277 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Mutsch, M. et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N. Engl. J. Med. 350, 896–903 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Miller, E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. Brit. Med. J. 346, f794 (2013).

    Article  PubMed  Google Scholar 

  151. Nohynek, H. et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7, e33536 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  152. Stowe, J. et al. Risk of narcolepsy after AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in adults: a case-coverage study in England. Sleep 39, 1051–1057 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Dauvilliers, Y. et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 136, 2486–2496 (2013).

    Article  PubMed  Google Scholar 

  154. Fukuyama, Y. et al. Nasal administration of cholera toxin as a mucosal adjuvant damages the olfactory system in mice. PLoS ONE 10, e0139368 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP223fa627003, JP233fa627003, JP243fa627003 (cSIMVa), JP23fk0108668, JP24fk0108668, JP233fa827014, JP243fa827014, JP233fa827016, JP243fa827016, JP233fa827016, JP243fa827016, JP233fa827014, JP243fa827014 and JP24ae0121040 (NeDDTrim); Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Challenging Research Pioneering 20K20495 and JSPS Grant-in-Aid for Scientific Research B 20H03856, 23K27429 and 24K02659; IMSUT International Joint Research Program K22-3045; the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (cMAV) Program; Chiba University and Shionogi Human Mucosal Vaccinology Program; and NIH NIDDK grants P30 DK120515 and R01 DK051677. The authors thank S. Umemoto, M. Nagira, M. Yamamoto, M. Rokushima, Y. Ishioka and S. Shigaki for their expertise in the preparation of this Review; and R. Nakahashi-Ouchida, K. Fujihashi, S. Sawada, Y. Kurashima and Y. Yuki for their contributions to the research and development of mucosal vaccines and for their help and reading of the article.

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Authors and Affiliations

  1. Chiba University–UCSD Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), Departments of Medicine and Pathology, University of California, San Diego, CA, USA

    Hiroshi Kiyono & Peter B. Ernst

  2. Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University (cSIMVa), Chiba, Japan

    Hiroshi Kiyono & Peter B. Ernst

  3. Future Medicine Education and Research Organization, Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Chiba University, Chiba, Japan

    Hiroshi Kiyono & Peter B. Ernst

  4. Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan

    Hiroshi Kiyono

  5. Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA, USA

    Peter B. Ernst

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  2. Peter B. Ernst
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H.K. and P.B.E. wrote and edited the manuscript. The authors have read the final manuscript and have agreed to its publication.

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H.K. is a co-founder of HanaVax. P.B.E. declares no competing interests.

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Supplementary Information

This file contains Supplementary Fig. 1 and Supplementary Table 1. Supplementary Fig. 1: Current status of nasal vaccine development for influenza virus and SARS-CoV-2. Supplementary Table 1: Source of information summarized in Supplementary Fig. 1.

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Kiyono, H., Ernst, P.B. Nasal vaccines for respiratory infections. Nature 641, 321–330 (2025). https://doi.org/10.1038/s41586-025-08910-6

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