Li, Y. & Nair, H. Trends in the global burden of lower respiratory infections: the knowns and the unknowns. Lancet Infect. Dis. 22, 1523–1525, https://doi.org/10.1016/S1473-3099(22)00445-5 (2022).
Qu, B. & Zhang, D. Evaluation of COVID-19 booster vaccine effectiveness. Viruses 17, https://doi.org/10.3390/v17020179 (2025).
Winklmeier, S. et al. Intramuscular vaccination against SARS-CoV-2 transiently induces neutralizing IgG rather than IgA in the saliva. Front. Immunol. 15, 1330864 (2024).
Li, M. et al. Mucosal vaccines: strategies and challenges. Immunol. Lett. 217, 116–125, https://doi.org/10.1016/j.imlet.2019.10.013 (2020).
Zhao, K., Xie, Y., Lin, X. & Xu, W. The mucoadhesive nanoparticle-based delivery system in the development of mucosal vaccines. Int. J. Nanomed. 17, 4579–4598, https://doi.org/10.2147/ijn.S359118 (2022).
Van der Ley, P. & Schijns, V. E. Outer membrane vesicle-based intranasal vaccines. Curr. Opin. Immunol. 84, 102376. https://doi.org/10.1016/j.coi.2023.102376 (2023).
Lei, H. et al. Intranasal delivery of a subunit protein vaccine provides protective immunity against JN.1 and XBB-lineage variants. Signal Transduct. Target. Ther. 9, 311, https://doi.org/10.1038/s41392-024-02025-6 (2024).
Diniz, M. O. et al. Airway-resident T cells from unexposed individuals cross-recognize SARS-CoV-2. Nat. Immunol. 23, 1324–1329, https://doi.org/10.1038/s41590-022-01292-1 (2022).
Nelson, C. E. et al. IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques. PLoS Pathog. 20, e1012339, https://doi.org/10.1371/journal.ppat.1012339 (2024).
Honda, T. et al. Intranasally inoculated SARS-CoV-2 spike protein combined with mucoadhesive polymer induces broad and long-lasting immunity. Vaccines 12, https://doi.org/10.3390/vaccines12070794 (2024).
Mettelman, R. C., Allen, E. K. & Thomas, P. G. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 55, 749–780, https://doi.org/10.1016/j.immuni.2022.04.013 (2022).
Butnarasu, C. et al. Structural determinants of mucins in influenza virus inhibition: the role of sialylated glycans and molecular size. Int. J. Biol. macromolecules 307, 142357. https://doi.org/10.1016/j.ijbiomac.2025.142357 (2025).
Iseli, A. N. et al. The neuraminidase activity of influenza A virus determines the strain-specific sensitivity to neutralization by respiratory mucus. J. Virol. 97, e0127123. https://doi.org/10.1128/jvi.01271-23 (2023).
Pan, J., Duggal, N. K., Lakdawala, S. S., Rockey, N. C. & Marr, L. C. Mucin colocalizes with influenza virus and preserves infectivity in deposited model respiratory droplets. Environ. Sci. Technol. 59, 2192–2200, https://doi.org/10.1021/acs.est.4c10886 (2025).
Agarwal, S., Veytsman, B., Fletcher, D. A. & Huber, G. Kinetics and optimality of influenza A virus locomotion. Phys. Rev. Lett. 133, 248402. https://doi.org/10.1103/PhysRevLett.133.248402 (2024).
Wilson, R., Dowling, R. B. & Jackson, A. D. The biology of bacterial colonization and invasion of the respiratory mucosa. Eur. Respiratory J. 9, 1523–1530, https://doi.org/10.1183/09031936.96.09071523 (1996).
Diamond, G., Legarda, D. & Ryan, L. K. The innate immune response of the respiratory epithelium. Immunol. Rev. 173, 27–38, https://doi.org/10.1034/j.1600-065x.2000.917304.x (2000).
Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell 168, 362–375, https://doi.org/10.1016/j.cell.2016.11.040 (2017).
Kim, J., Ryu, S. & Kim, H. Y. Innate lymphoid cells in tissue homeostasis and disease pathogenesis. Mol. Cells 44, 301–309, https://doi.org/10.14348/molcells.2021.0053 (2021).
Cortez, V. S. & Colonna, M. Diversity and function of group 1 innate lymphoid cells. Immunol. Lett. 179, 19–24, https://doi.org/10.1016/j.imlet.2016.07.005 (2016).
Meininger, I. et al. Tissue-specific features of innate lymphoid cells. Trends Immunol. 41, 902–917, https://doi.org/10.1016/j.it.2020.08.009 (2020).
Chan, L., Mehrani, Y., Minott, J. A., Bridle, B. W. & Karimi, K. Dendritic cell vaccines impact the type 2 innate lymphoid cell population and their cytokine generation in mice. Vaccines 11, https://doi.org/10.3390/vaccines11101559 (2023).
Li, Z., Roy, S. & Ranasinghe, C. IL-13Rα2 Regulates the IL-13/IFN-γ balance during innate lymphoid cell and dendritic cell responses to pox viral vector-based vaccination. Vaccines 9, https://doi.org/10.3390/vaccines9050440 (2021).
Sugimura, R. & Wang, C. Y. The role of innate lymphoid cells in cancer development and immunotherapy. Front. cell Develop. Biol. 10, 803563. https://doi.org/10.3389/fcell.2022.803563 (2022).
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, https://doi.org/10.4049/jimmunol.0903794 (2011).
Li, W. et al. Research Progress On Dendritic Cells In Hepatocellular Carcinoma Immune Microenvironments. Biomolecules 14, https://doi.org/10.3390/biom14091161 (2024).
Seefeld, M. L. et al. Harnessing the potential of the NALT and BALT as targets for immunomodulation using engineering strategies to enhance mucosal uptake. Front. Immunol. 15, 1419527. https://doi.org/10.3389/fimmu.2024.1419527 (2024).
Song, W. & Craft, J. T Follicular Helper Cell Heterogeneity. Annu. Rev. Immunol. 42, 127–152, https://doi.org/10.1146/annurev-immunol-090222-102834 (2024).
Kumar Bharathkar, S. & Stadtmueller, B. M. Structural and Biochemical Requirements For Secretory Component Interactions With Dimeric IgA. J. Immunol. 213, 226–234, https://doi.org/10.4049/jimmunol.2300717 (2024).
Cao, X., Zai, J., Zhao, Q., Xie, L. & Li, Y. Intranasal immunization with recombinant Vaccinia virus encoding trimeric SARS-CoV-2 spike receptor-binding domain induces neutralizing antibody. Vaccine 40, 5757–5763, https://doi.org/10.1016/j.vaccine.2022.08.054 (2022).
Chao, Y. X., Rötzschke, O. & Tan, E. K. The role of IgA in COVID-19. Brain Behav. Immun. 87, 182–183, https://doi.org/10.1016/j.bbi.2020.05.057 (2020).
Madissoon, E. et al. A spatially resolved atlas of the human lung characterizes a gland-associated immune niche. Nat. Genet. 55, 66–77, https://doi.org/10.1038/s41588-022-01243-4 (2023).
Ma, J. et al. Exacerbated lung inflammation in offspring with high maternal antibody levels following secondary RSV exposure. Front. Immunol. 15, 1377374. https://doi.org/10.3389/fimmu.2024.1377374 (2024).
Long, B. et al. Tissue-Resident Memory T Cells in Allergy. Clin. Rev. Allergy Immunol. 66, 64–75, https://doi.org/10.1007/s12016-024-08982-8 (2024).
Xie, D., Lu, G., Mai, G., Guo, Q. & Xu, G. Tissue-resident memory T cells in diseases and therapeutic strategies. Med. Commun. 6, e70053. https://doi.org/10.1002/mco2.70053 (2025).
Roy, R., Das, T. & Biswas, N. Orchestration of immune response by innate lymphoid cell subtype 2 at various tumor microenvironment, a suitable target for cancer immunotherapy. Int. Rev. Immunol. 43, 74–82, https://doi.org/10.1080/08830185.2023.2247021 (2024).
Wei, L., Abraham, D. & Ong, V. The Yin and Yang of IL-17 in Systemic Sclerosis. Front. Immunol. 13, 885609. https://doi.org/10.3389/fimmu.2022.885609 (2022).
Lapuente, D. et al. IL-1β as mucosal vaccine adjuvant: the specific induction of tissue-resident memory T cells improves the heterosubtypic immunity against influenza A viruses. Mucosal Immunol. 11, 1265–1278, https://doi.org/10.1038/s41385-018-0017-4 (2018).
Pilapitiya, D., Wheatley, A. K. & Tan, H. X. Mucosal vaccines for SARS-CoV-2: triumph of hope over experience. EBioMedicine 92, 104585. https://doi.org/10.1016/j.ebiom.2023.104585 (2023).
Martinuzzi, E. et al. A single dose of BNT162b2 messenger RNA vaccine induces airway immunity in severe acute respiratory syndrome coronavirus 2 naive and recovered coronavirus disease 2019 subjects. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 75, 2053–2059, https://doi.org/10.1093/cid/ciac378 (2022).
Mostaghimi, D., Valdez, C. N., Larson, H. T., Kalinich, C. C. & Iwasaki, A. Prevention of host-to-host transmission by SARS-CoV-2 vaccines. Lancet Infect. Dis. 22, e52–e58, https://doi.org/10.1016/s1473-3099(21)00472-2 (2022).
Purushotham, J. N., van Doremalen, N. & Munster, V. J. SARS-CoV-2 vaccines: anamnestic response in previously infected recipients. Cell Res. 31, 827–828, https://doi.org/10.1038/s41422-021-00516-7 (2021).
Knisely, J. M. et al. Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report. npj Vaccines 8, 53. https://doi.org/10.1038/s41541-023-00654-6 (2023).
McMahan, K. et al. Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques. Nature 626, 385–391, https://doi.org/10.1038/s41586-023-06951-3 (2024).
Oh, J. E., et al. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Sci. Immunol. 6, eabj5129, https://doi.org/10.1126/sciimmunol.abj5129 (2021).
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, https://doi.org/10.1038/s41590-024-01951-5 (2024).
Zhang, X. et al. Progress and challenges in the clinical evaluation of immune responses to respiratory mucosal vaccines. Expert Rev. Vaccines 23, 362–370, https://doi.org/10.1080/14760584.2024.2326094 (2024).
Hong, W., et al. A chimeric adenovirus-vectored vaccine based on Beta spike and Delta RBD confers a broad-spectrum neutralization against Omicron-included SARS-CoV-2 variants. MedComm 5, e539, https://doi.org/10.1002/mco2.539 (2024).
Fuchs, J. et al. Evaluation of adenoviral vector Ad19a encoding RSV-F as novel vaccine against respiratory syncytial virus. NPJ Vaccines 9, 205. https://doi.org/10.1038/s41541-024-01001-z (2024).
Malloy, A. M. W. et al. Increased innate immune activation induces protective RSV-specific lung-resident memory T cells in neonatal mice. Mucosal Immunol. 16, 593–605, https://doi.org/10.1016/j.mucimm.2023.05.012 (2023).
Lei, H. et al. Intranasal administration of a recombinant RBD vaccine induces long-term immunity against Omicron-included SARS-CoV-2 variants. Signal Transduct. Target. Ther. 7, 159, https://doi.org/10.1038/s41392-022-01002-1 (2022).
Sinha, D., Yaugel-Novoa, M., Waeckel, L., Paul, S. & Longet, S. Unmasking the potential of secretory IgA and its pivotal role in protection from respiratory viruses. Antivir. Res. 223, 105823. https://doi.org/10.1016/j.antiviral.2024.105823 (2024).
Rudenko, L., Yeolekar, L., Kiseleva, I. & Isakova-Sivak, I. Development and approval of live attenuated influenza vaccines based on Russian master donor viruses: Process challenges and success stories. Vaccine 34, 5436–5441, https://doi.org/10.1016/j.vaccine.2016.08.018 (2016).
Jorba, J. et al. Update on vaccine-derived polioviruses – worldwide, January 2017-June 2018. Mmwr. Morbidity Mortal. Wkly. Rep. 67, 1189–1194, https://doi.org/10.15585/mmwr.mm6742a5 (2018).
Dotiwala, F. & Upadhyay, A. K. Next generation mucosal vaccine strategy for respiratory pathogens. Vaccines 11, https://doi.org/10.3390/vaccines11101585 (2023).
Li, Y., Jin, L. & Chen, T. The Effects of secretory IgA in the mucosal immune system. BioMed. Res. Int. 2020, 2032057. https://doi.org/10.1155/2020/2032057 (2020).
Zanin, M., Baviskar, P., Webster, R. & Webby, R. The interaction between respiratory pathogens and mucus. Cell Host Microbe 19, 159–168, https://doi.org/10.1016/j.chom.2016.01.001 (2016).
Wallace, L. E., Liu, M., van Kuppeveld, F. J. M., de Vries, E. & de Haan, C. A. M. Respiratory mucus as a virus-host range determinant. Trends Microbiol. 29, 983–992, https://doi.org/10.1016/j.tim.2021.03.014 (2021).
Huang, M., Zhang, M., Zhu, H., Du, X. & Wang, J. Mucosal vaccine delivery: a focus on the breakthrough of specific barriers. Acta pharmaceutica Sin. B 12, 3456–3474, https://doi.org/10.1016/j.apsb.2022.07.002 (2022).
Kayama, H. & Takeda, K. Regulation of intestinal homeostasis by innate and adaptive immunity. Int. Immunol. 24, 673–680, https://doi.org/10.1093/intimm/dxs094 (2012).
Lycke, N. Recent progress in mucosal vaccine development: potential and limitations. Nat. Rev. Immunol. 12, 592–605, https://doi.org/10.1038/nri3251 (2012).
Wu, L., Xu, W., Jiang, H., Yang, M. & Cun, D. Respiratory delivered vaccines: current status and perspectives in rational formulation design. Acta Pharmaceutica Sin. B 14, 5132–5160, https://doi.org/10.1016/j.apsb.2024.08.026 (2024).
Ashhurst, A. S., et al. Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice. Nat. Commun. 13, 6972, https://doi.org/10.1038/s41467-022-34297-3 (2022).
Nakahashi-Ouchida, R., Fujihashi, K., Kurashima, Y., Yuki, Y. & Kiyono, H. Nasal vaccines: solutions for respiratory infectious diseases. Trends Mol. Med. 29, 124–140, https://doi.org/10.1016/j.molmed.2022.10.009 (2023).
Kiyono, H. & Ernst, P. B. Nasal vaccines for respiratory infections. Nature 641, 321–330, https://doi.org/10.1038/s41586-025-08910-6 (2025).
Jeyanathan, M. et al. Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans. JCI Insight 7, https://doi.org/10.1172/jci.insight.155655 (2022).
Löffler, P. Review: vaccine myth-buster – cleaning up with prejudices and dangerous misinformation. Front. Immunol. 12, 663280, https://doi.org/10.3389/fimmu.2021.663280 (2021).
Igyártó, B. Z. & Qin, Z. The mRNA-LNP vaccines – the good, the bad and the ugly? Front. Immunol. 15, 1336906, https://doi.org/10.3389/fimmu.2024.1336906 (2024).
Xu, H., Cai, L., Hufnagel, S. & Cui, Z. Intranasal vaccine: factors to consider in research and development. Int. J. Pharmaceutics 609, 121180. https://doi.org/10.1016/j.ijpharm.2021.121180 (2021).
Jin, Z., Gao, S., Cui, X., Sun, D. & Zhao, K. Adjuvants and delivery systems based on polymeric nanoparticles for mucosal vaccines. Int. J. Pharmaceutics 572, 118731. https://doi.org/10.1016/j.ijpharm.2019.118731 (2019).
Correa, V. A., Portilho, A. I. & De Gaspari, E. Vaccines, adjuvants and key factors for mucosal immune response. Immunology 167, 124–138, https://doi.org/10.1111/imm.13526 (2022).
Cappelli, L. et al. Self-assembling protein nanoparticles and virus like particles correctly display β-barrel from meningococcal factor H-binding protein through genetic fusion. PLoS One 17, e0273322, https://doi.org/10.1371/journal.pone.0273322 (2022).
Zhao, T. et al. Vaccine adjuvants: mechanisms and platforms. Signal Transduct. Target. Ther. 8, 283, https://doi.org/10.1038/s41392-023-01557-7 (2023).
Lawson, L. B., Norton, E. B. & Clements, J. D. Defending the mucosa: adjuvant and carrier formulations for mucosal immunity. Curr. Opin. Immunol. 23, 414–420, https://doi.org/10.1016/j.coi.2011.03.009 (2011).
Gao, Y. & Guo, Y. Research progress in the development of natural-product-based mucosal vaccine adjuvants. Front. Immunol. 14, 1152855. https://doi.org/10.3389/fimmu.2023.1152855 (2023).
Kim, J. et al. Dual Adjuvant-Loaded Peptide Antigen Self-Assembly Potentiates Dendritic Cell-Mediated Tumor Immunotherapy. Adv. Sci.11, e2403663, https://doi.org/10.1002/advs.202403663 (2024).
Chen, R. et al. A respiratory mucosal vaccine based on chitosan/aluminum adjuvant induces both mucosal and systemic immune responses. Int. J. Pharmaceutics 670, 125168. https://doi.org/10.1016/j.ijpharm.2025.125168 (2025).
Zeng, L. Mucosal adjuvants: Opportunities and challenges. Hum. Vaccines Immunother. 12, 2456–2458, https://doi.org/10.1080/21645515.2016.1181236 (2016).
Freytag, L. C. & Clements, J. D. in Mucosal Immunology (Fourth Edition) (eds J. Mestecky et al.) 1183-1199 (Academic Press, 2015).
Clements, J. D. & Norton, E. B. The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT. mSphere 3, https://doi.org/10.1128/mSphere.00215-18 (2018).
Tregoning, J. S., Russell, R. F. & Kinnear, E. Adjuvanted influenza vaccines. Hum. vaccines immunother. 14, 550–564, https://doi.org/10.1080/21645515.2017.1415684 (2018).
Maciel, M. Jr. et al. Evaluation of the reactogenicity, adjuvanticity and antigenicity of LT(R192G) and LT(R192G/L211A) by intradermal immunization in mice. PLoS One 14, e0224073, https://doi.org/10.1371/journal.pone.0224073 (2019).
Pan, S.-C. et al. A randomized, double-blind, controlled clinical trial to evaluate the safety and immunogenicity of an intranasally administered trivalent inactivated influenza vaccine with adjuvant LTh(αK): A phase I study. Vaccine 37, 1994–2003, https://doi.org/10.1016/j.vaccine.2019.02.006 (2019).
Eriksson, A. M., Schön, K. M. & Lycke, N. Y. The cholera toxin-derived CTA1-DD vaccine adjuvant administered intranasally does not cause inflammation or accumulate in the nervous tissues1. J. Immunol. 173, 3310–3319 (2004). The Journal of Immunology.
van der Lubben, I. M., Verhoef, J. C., Borchard, G. & Junginger, H. E. Chitosan and its derivatives in mucosal drug and vaccine delivery. Eur. J. Pharm. Sci. Off. J. Eur. Federation Pharm. Sci. 14, 201–207, https://doi.org/10.1016/s0928-0987(01)00172-5 (2001).
Wen, Z.-S., Xu, Y.-L., Zou, X.-T. & Xu, Z.-R. Chitosan Nanopart. Act. Adjuv. Promot. both Th1 Th2 Immune Responses Induc. Ovalbumin Mice 9, 1038–1055 (2011).
Mills, K. H. G. 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. 71, 726-732, https://doi.org/10.1128/iai.71.2.726-732.2003 (2003).
Wang, M. et al. Sulfated glucan can improve the immune efficacy of Newcastle disease vaccine in chicken. Int. J. Biol. Macromol. 70, 193–198, https://doi.org/10.1016/j.ijbiomac.2014.05.048 (2014).
Mirza, Z., Soto, E. R., Dikengil, F., Levitz, S. M. & Ostroff, G. R. Beta-Glucan Particles as Vaccine Adjuvant Carriers. Methods Mol. Biol. 1625, 143–157, https://doi.org/10.1007/978-1-4939-7104-6_11 (2017).
Tsukada, C. et al. Immunopotentiation of intraepithelial lymphocytes in the intestine by oral administrations of beta-glucan. Cell. Immunol. 221, 1–5, https://doi.org/10.1016/s0008-8749(03)00061-3 (2003).
Lei, H. et al. Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2. Signal Transduct. Target. Ther. 5, 291, https://doi.org/10.1038/s41392-020-00434-x (2020).
Dong, C. et al. Polycationic HA/CpG nanoparticles induce cross-protective influenza immunity in mice. ACS Appl. Mater. interfaces 14, 6331–6342, https://doi.org/10.1021/acsami.1c19192 (2022).
Hu, Y. et al. Highly enhanced antitumor immunity by a three-barreled strategy of the l-arginine-promoted nanovaccine and gene-mediated PD-L1 blockade. ACS Appl. Mater. interfaces 12, 41127–41137, https://doi.org/10.1021/acsami.0c12734 (2020).
Ko, S. Y. et al. alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor. J. Immunol. 175, 3309–3317, https://doi.org/10.4049/jimmunol.175.5.3309 (2005).
Verma, S. K. et al. New-age vaccine adjuvants, their development, and future perspective. Front. Immunol. 14, 1043109, https://doi.org/10.3389/fimmu.2023.1043109 (2023).
Veldhoen, M. Interleukin 17 is a chief orchestrator of immunity. Nat. Immunol. 18, 612–621, https://doi.org/10.1038/ni.3742 (2017).
Jaffar, Z., Ferrini, M. E., Girtsman, T. A. & Roberts, K. Antigen-specific Treg regulate Th17-mediated lung neutrophilic inflammation, B-cell recruitment and polymeric IgA and IgM levels in the airways. Eur. J. Immunol. 39, 3307–3314, https://doi.org/10.1002/eji.200939498 (2009).
Mosaheb, M. M., Reiser, M. L. & Wetzler, L. M. Toll-like receptor ligand-based vaccine adjuvants require intact MyD88 signaling in antigen-presenting cells for germinal center formation and antibody production. Front. Immunol. 8, 225, https://doi.org/10.3389/fimmu.2017.00225 (2017).
Liang, H. et al. The TLR4 agonist adjuvant SLA-SE promotes functional mucosal antibodies against a parenterally delivered ETEC vaccine. npj Vaccines 4, 19. https://doi.org/10.1038/s41541-019-0116-6 (2019).
Lavelle, E. C. & Ward, R. W. Mucosal vaccines – fortifying the frontiers. Nat. Rev. Immunol. 22, 236–250, https://doi.org/10.1038/s41577-021-00583-2 (2022).
Wang, S., Liu, H., Zhang, X. & Qian, F. Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies. Protein cell 6, 480–503, https://doi.org/10.1007/s13238-015-0164-2 (2015).
Matos, M. N. et al. Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi. PLoS Neglected Trop. Dis. 11, e0005300, https://doi.org/10.1371/journal.pntd.0005300 (2017).
An, X. et al. Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2. iScience 24, 103037, https://doi.org/10.1016/j.isci.2021.103037 (2021).
Allen, A. C. et al. Sustained protective immunity against Bordetella pertussis nasal colonization by intranasal immunization with a vaccine-adjuvant combination that induces IL-17-secreting T(RM) cells. Mucosal Immunol. 11, 1763–1776, https://doi.org/10.1038/s41385-018-0080-x (2018).
Sui, Y. et al. Protection against SARS-CoV-2 infection by a mucosal vaccine in rhesus macaques. JCI Insight 6, https://doi.org/10.1172/jci.insight.148494 (2021).
Wang, X. & Meng, D. Innate endogenous adjuvants prime to desirable immune responses via mucosal routes. Protein Cell 6, 170–184, https://doi.org/10.1007/s13238-014-0125-1 (2015).
Schmidt, A. et al. Inflammatory conditions shape phenotypic and functional characteristics of lung-resident memory T cells in mice. Nat. Commun. 16, 3612. https://doi.org/10.1038/s41467-025-58931-y (2025).
Oltmanns, F. et al. Mucosal tumor vaccination delivering endogenous tumor antigens protects against pulmonary breast cancer metastases. J. Immunother. Cancer 12, https://doi.org/10.1136/jitc-2023-008652 (2024).
Paris, O., Mennechet, F. J. D. & Kremer, E. J. Human innate lymphoid cell activation by adenoviruses is modified by host defense proteins and neutralizing antibodies. Front. Immunol. 13, 975910, https://doi.org/10.3389/fimmu.2022.975910 (2022).
Lacaille-Dubois, M. A. Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: a review. Phytomedicine Int. J. Phytother. Phytopharmacol. 60, 152905. https://doi.org/10.1016/j.phymed.2019.152905 (2019).
Cibulski, S. et al. Leaf saponins of Quillaja brasiliensis enhance long-term specific immune responses and promote dose-sparing effect in BVDV experimental vaccines. Vaccine 36, 55–65, https://doi.org/10.1016/j.vaccine.2017.11.030 (2018).
Sun, M. et al. Anticancer effects of ginsenoside Rg3 (Review). Int. J. Mol. Med. 39, 507–518, https://doi.org/10.3892/ijmm.2017.2857 (2017).
Ko, S.-Y. et al. α-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor1. J. Immunol. 175, 3309–3317, https://doi.org/10.4049/jimmunol.175.5.3309 (2005).
Lee, Y.-S. et al. An α-GalCer analogue with branched ACYL chain enhances protective immune responses in a nasal influenza vaccine. Vaccine 29, 417–425, https://doi.org/10.1016/j.vaccine.2010.11.005 (2011).
Boyaka, P. N., McGhee, J. R., Czerkinsky, C. & Mestecky, J. Mucosal Vaccines: An Overview. (Mucosal Immunology. 855-874. (2005) https://doi.org/10.1016/B978-012491543-5/50051-6. Epub 2007 May 9.
Nochi, T. et al. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. Nat. Mater. 9, 572–578, https://doi.org/10.1038/nmat2784 (2010).
Morein, B., Hu, K. F. & Abusugra, I. Current status and potential application of ISCOMs in veterinary medicine. Adv. drug Deliv. Rev. 56, 1367–1382, https://doi.org/10.1016/j.addr.2004.02.004 (2004).
Lenarczyk, A. et al. ISCOM based vaccines for cancer immunotherapy. Vaccine 22, 963–974, https://doi.org/10.1016/j.vaccine.2003.09.014 (2004).
Aguila, A. et al. Induction of protective and mucosal immunity against diphtheria by a immune stimulating complex (ISCOMS) based vaccine. Vaccine 24, 5201–5210, https://doi.org/10.1016/j.vaccine.2006.03.081 (2006).
Singh, B. et al. Chitosan-based particulate systems for the delivery of mucosal vaccines against infectious diseases. Int. J. Biol. Macromol. 110, 54–64, https://doi.org/10.1016/j.ijbiomac.2017.10.101 (2018).
Sadeghi, S., Lee, W. K., Kong, S. N., Shetty, A. & Drum, C. L. Oral administration of protein nanoparticles: an emerging route to disease treatment. Pharmacol. Res. 158, 104685, https://doi.org/10.1016/j.phrs.2020.104685 (2020).
Shakya, A. K., Chowdhury, M. Y. E., Tao, W. & Gill, H. S. Mucosal vaccine delivery: current state and a pediatric perspective. J. Controlled Release Off. J. Controlled Release Soc. 240, 394–413, https://doi.org/10.1016/j.jconrel.2016.02.014 (2016).
Lopes, P. D. et al. Inactivated infectious bronchitis virus vaccine encapsulated in chitosan nanoparticles induces mucosal immune responses and effective protection against challenge. Vaccine 36, 2630–2636, https://doi.org/10.1016/j.vaccine.2018.03.065 (2018).
Cleary, J., Bromberg, L. & Magner, E. Adhesion of polyether-modified poly(acrylic acid) to mucin. Langmuir ACS J. Surf. Colloids 20, 9755–9762, https://doi.org/10.1021/la048993s (2004).
Bernkop-Schnürch, A. Thiomers: a new generation of mucoadhesive polymers. Adv. drug Deliv. Rev. 57, 1569–1582, https://doi.org/10.1016/j.addr.2005.07.002 (2005).
Sarma, P. P., Rai, A. & Baruah, P. K. Recent advances in the development of antibiotics-coated gold nanoparticles to combat antimicrobial resistance. Antibiotics 13, 124, https://doi.org/10.3390/antibiotics13020124 (2024).
Abdullah et al. Recent advances in the development of metal/metal oxide nanoparticle and antibiotic conjugates (MNP-Antibiotics) to address antibiotic resistance: review and perspective. Int J. Mol. Sci. 25, 8915, https://doi.org/10.3390/ijms25168915 (2024).
Kim, K. & Park, M. H. Advancing cancer treatment: enhanced combination therapy through functionalized porous nanoparticles. Biomedicines 12, https://doi.org/10.3390/biomedicines12020326 (2024).
Parvin, N., Joo, S. W. & Mandal, T. K. Enhancing vaccine efficacy and stability: a review of the utilization of nanoparticles in mRNA vaccines. Biomolecules 14, https://doi.org/10.3390/biom14081036 (2024).
Kelly, H. G. et al. Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation. JCI Insight 5, https://doi.org/10.1172/jci.insight.136653 (2020).
Pyles, G. M. et al. Virus-like particles displaying the mature C-terminal domain of filamentous hemagglutinin are immunogenic and protective against Bordetella pertussis respiratory infection in mice. Infect. Immun. 92, e0027024. https://doi.org/10.1128/iai.00270-24 (2024).
Lacasta, A. et al. Design and immunological evaluation of two-component protein nanoparticle vaccines for East Coast fever. Front. Immunol. 13, 1015840. https://doi.org/10.3389/fimmu.2022.1015840 (2022).
Subbarao, K. Live Attenuated Cold-Adapted Influenza Vaccines. Cold Spring Harbor perspectives in medicine 11, https://doi.org/10.1101/cshperspect.a038653 (2021).
Grohskopf, L. A., Sokolow, L. Z., Fry, A. M., Walter, E. B. & Jernigan, D. B. Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4) – United States, 2018-19 Influenza Season. Mmwr. Morbidity Mortal. Wkly. Rep. 67, 643–645, https://doi.org/10.15585/mmwr.mm6722a5 (2018).
Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices–United States, 2013-2014. MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports 62, 1-43 (2013).
Grohskopf, L. A. et al. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices – United States, 2020-21 Influenza Season. Mmwr. Recommendations Rep. : Morbidity Mortal. Wkly. Report. Recommendations Rep. 69, 1–24, https://doi.org/10.15585/mmwr.rr6908a1 (2020).
Block, S. L. et al. Immunogenicity and safety of a quadrivalent live attenuated influenza vaccine in children. Pediatr. Infect. Dis. J. 31, 745–751, https://doi.org/10.1097/INF.0b013e31825687b0 (2012).
Belshe, R. B. et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N. Engl. J. Med. 338, 1405–1412, https://doi.org/10.1056/nejm199805143382002 (1998).
De Villiers, P. J. et al. Efficacy and safety of a live attenuated influenza vaccine in adults 60 years of age and older. Vaccine 28, 228–234, https://doi.org/10.1016/j.vaccine.2009.09.092 (2009).
Amanna, I. J. Balancing the efficacy and safety of vaccines in the elderly. Open Longev. Sci. 6, 64–72, https://doi.org/10.2174/1876326×01206010064 (2012).
Boyaka, P. N. Inducing mucosal IgA: a challenge for vaccine adjuvants and delivery systems. J. Immunol. 199, 9–16, https://doi.org/10.4049/jimmunol.1601775 (2017).
Nigwekar, P. V. et al. Safety of Russian-backbone trivalent, live attenuated seasonal influenza vaccine in healthy subjects: open-label, non-randomized phase 4 study. Drug Saf. 41, 171–177, https://doi.org/10.1007/s40264-017-0605-3 (2018).
Kulkarni, P. S., Raut, S. K. & Dhere, R. M. A post-marketing surveillance study of a human live-virus pandemic influenza A (H1N1) vaccine (Nasovac (®)) in India. Hum. Vaccines Immunotherapeutics 9, 122–124, https://doi.org/10.4161/hv.22317 (2013).
Shurygina, A. P. et al. Truncated NS1 Influenza A virus induces a robust antigen-specific tissue-resident T-cell response and promotes inducible bronchus-associated lymphoid tissue formation in mice. Vaccines 13, https://doi.org/10.3390/vaccines13010058 (2025).
Avanthay, R. et al. Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model. PLoS Pathog. 20, e1012393, https://doi.org/10.1371/journal.ppat.1012393 (2024).
Rathnasinghe, R. et al. Sequential immunization with chimeric hemagglutinin ΔNS1 attenuated influenza vaccines induces broad humoral and cellular immunity. NPJ Vaccines 9, 169. https://doi.org/10.1038/s41541-024-00952-7 (2024).
Ko, K. H. et al. A vaccine platform targeting lung-resident memory CD4(+) T-cells provides protection against heterosubtypic influenza infections in mice and ferrets. Nat. Commun. 15, 10368. https://doi.org/10.1038/s41467-024-54620-4 (2024).
Fan, R. L. et al. Generation of live attenuated influenza virus by using codon usage bias. J. Virol. 89, 10762–10773, https://doi.org/10.1128/jvi.01443-15 (2015).
Stauft, C. B. et al. Live-attenuated H1N1 influenza vaccine candidate displays potent efficacy in mice and ferrets. PLoS One 14, e0223784, https://doi.org/10.1371/journal.pone.0223784 (2019).
Sarawar, S. et al. Longevity and mechanism of heterosubtypic protection induced by M2SR (M2-Deficient Single-Replication) live influenza virus vaccine in mice. Vaccines 10, https://doi.org/10.3390/vaccines10122131 (2022).
Hill-Batorski, L. et al. Quadrivalent formulation of intranasal influenza vaccine M2SR (M2-Deficient Single Replication) protects against drifted influenza A and B virus challenge. Vaccines 11, https://doi.org/10.3390/vaccines11040798 (2023).
Eiden, J. et al. M2-deficient single-replication influenza vaccine-induced immune responses associated with protection against human challenge with highly drifted H3N2 influenza strain. J. Infect. Dis. 226, 83–90, https://doi.org/10.1093/infdis/jiab374 (2022).
Eiden, J. et al. Intranasal M2SR (M2-Deficient Single Replication) H3N2 influenza vaccine provides enhanced mucosal and serum antibodies in adults. J. Infect. Dis. 227, 103–112, https://doi.org/10.1093/infdis/jiac433 (2022).
Eiden, J. et al. Safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication influenza vaccine alone or coadministered with an inactivated influenza vaccine (Fluzone High-Dose Quadrivalent) in adults aged 65-85 years in the USA: a multicentre, randomised, double-blind, double-dummy, phase 1b trial. Lancet Infect. Dis. 24, 1118–1129, https://doi.org/10.1016/s1473-3099(24)00351-7 (2024).
Hill-Batorski, L. et al. Mucosal immunization with dual influenza/COVID-19 single-replication virus vector protects hamsters from SARS-CoV-2 challenge. Vaccine 42, 2770–2780, https://doi.org/10.1016/j.vaccine.2024.03.040 (2024).
Moser, M. J. et al. Intranasal single-replication influenza vector induces cross-reactive serum and mucosal antibodies against SARS-CoV-2 variants. Vaccines 11, https://doi.org/10.3390/vaccines11061063 (2023).
Zhao, T. et al. Development and evaluation of mosaic VLPs vaccine for enhanced broad-Spectrum immunity against influenza B virus lineages in mice. Vaccine 51, 126882. https://doi.org/10.1016/j.vaccine.2025.126882 (2025).
Wang, J. et al. A VLP-based vaccine displaying HBHA and MTP antigens of mycobacterium tuberculosis induces protective immune responses in M. tuberculosis H37Ra infected mice. Vaccines 11, https://doi.org/10.3390/vaccines11050941 (2023).
Mao, J. et al. Influenza A hemagglutinin virus-like particles confer protection against influenza B virus infection. Emerg. microbes Infect. 14, 2494702. https://doi.org/10.1080/22221751.2025.2494702 (2025).
Mao, J. et al. Crossprotection induced by virus-like particles containing influenza dual-hemagglutinin and M2 ectodomain. Nanomed. (Lond., Engl.) 19, 741–754, https://doi.org/10.2217/nnm-2023-0353 (2024).
Meade, P. et al. Antigenic landscape analysis of individuals vaccinated with a universal influenza virus vaccine candidate reveals induction of cross-subtype immunity. J. Virol. 97, e0107022. https://doi.org/10.1128/jvi.01070-22 (2023).
Widge, A. T. et al. An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults. Sci. Transl. Med 15, eade4790. https://doi.org/10.1126/scitranslmed.ade4790 (2023).
Rijnink, W. F. et al. Characterization of non-neutralizing human monoclonal antibodies that target the M1 and NP of influenza A viruses. J. Virol. 97, e0164622. https://doi.org/10.1128/jvi.01646-22 (2023).
Raha, J. R. et al. Intranasal vaccination with multi-neuraminidase and M2e virus-like particle vaccine results in greater mucosal immunity and protection against influenza than intramuscular injection. Vaccine 57, 127206. https://doi.org/10.1016/j.vaccine.2025.127206 (2025).
Pankhurst, T. E. et al. MAIT cells activate dendritic cells to promote T(FH) cell differentiation and induce humoral immunity. Cell Rep. 42, 112310. https://doi.org/10.1016/j.celrep.2023.112310 (2023).
Imagawa, T., Arasaki, Y., Maegawa, K., Sugita, S. & Nerome, K. Advancing usability of an influenza hemagglutinin virus-like particle vaccine expressing a chimeric cytokine. Virol. J. 20, 102. https://doi.org/10.1186/s12985-023-02076-1 (2023).
Sun, Y. X. et al. A single vaccination of chimeric bivalent virus-like particle vaccine confers protection against H9N2 and H3N2 avian influenza in commercial broilers and allows a strategy of differentiating infected from vaccinated animals. Front. Immunol. 13, 902515. https://doi.org/10.3389/fimmu.2022.902515 (2022).
Ewer, K. et al. Chimpanzee adenoviral vectors as vaccines for outbreak pathogens. Hum. Vaccines Immunother. 13, 3020–3032, https://doi.org/10.1080/21645515.2017.1383575 (2017).
Zhu, F. C. et al. Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 389, 621–628, https://doi.org/10.1016/s0140-6736(16)32617-4 (2017).
Kumar, D. et al. Immunogenicity of a candidate ebola hemorrhagic fever vaccine in mice based on controlled in vitro expression of ebolavirus glycoprotein. Viral Immunol. 31, 500–512, https://doi.org/10.1089/vim.2017.0122 (2018).
Mendonça, S. A., Lorincz, R., Boucher, P. & Curiel, D. T. Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic. NPJ Vaccines 6, 97. https://doi.org/10.1038/s41541-021-00356-x (2021).
Dickson, A. et al. The role of vaccination route with an adenovirus-vectored vaccine in protection, viral control, and transmission in the SARS-CoV-2/K18-hACE2 mouse infection model. Front. Immunol. 14, 1188392. https://doi.org/10.3389/fimmu.2023.1188392 (2023).
King, R. G. et al. Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 and fully protects mice from lethal challenge. Vaccines 9, https://doi.org/10.3390/vaccines9080881 (2021).
Tukhvatulin, A. I. et al. Immunogenicity and protectivity of intranasally delivered vector-based heterologous prime-boost COVID-19 vaccine Sputnik V in mice and non-human primates. Emerg. Microbes Infect. 11, 2229–2247, https://doi.org/10.1080/22221751.2022.2119169 (2022).
Astakhova, E. A. et al. Antibody avidity maturation following booster vaccination with an intranasal adenovirus salnavac vaccine. Vaccines 12, 1362, https://doi.org/10.3390/vaccines12121362 (2024).
Yahalom-Ronen, Y. et al. Induction of superior systemic and mucosal protective immunity to SARS-CoV-2 by nasal administration of a VSV-ΔG-spike vaccine. Vaccines 12, 491, https://doi.org/10.3390/vaccines12050491 (2024).
Kawai, A. et al. Intranasal immunization with an RBD-hemagglutinin fusion protein harnesses preexisting immunity to enhance antigen-specific responses. J. Clin. Investig. 133, https://doi.org/10.1172/jci166827 (2023).
Hashimoto, S. et al. Hypertonic intranasal vaccines gain nasal epithelia access to exert strong immunogenicity. Mucosal Immunol. 18, 793–809, https://doi.org/10.1016/j.mucimm.2025.03.006 (2025).
Dong, D. et al. Molecular basis of Ad5-nCoV vaccine-induced immunogenicity. Structure https://doi.org/10.1016/j.str.2025.02.009 (2025).
Tang, R. et al. Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial. Lancet Respir. Med. 11, 613–623, https://doi.org/10.1016/s2213-2600(23)00049-8 (2023).
Jin, P. F. et al. Immunogenicity and safety of heterologous immunisation with Ad5-nCOV in healthy adults aged 60 years and older primed with an inactivated SARS-CoV-2 vaccine (CoronaVac): a phase 4, randomised, observer-blind, non-inferiority trial. Lancet Regional Health West. Pac. 38, 100829. https://doi.org/10.1016/j.lanwpc.2023.100829 (2023).
Chen, Z. et al. Waning neutralizing antibodies through 180 days after homologous and heterologous boosters of inactivated COVID-19 vaccine. Front. Public Health 13, 1478627. https://doi.org/10.3389/fpubh.2025.1478627 (2025).
Jiang, H. et al. The 6-month antibody durability of heterologous convidecia plus coronavac and homologous coronavac immunizations in people aged 18-59 years and over 60 years based on two randomized controlled trials in China. Vaccines 11, https://doi.org/10.3390/vaccines11121815 (2023).
Zhang, H. et al. Safety and immunogenicity of Ad5-nCoV immunization after three-dose priming with inactivated SARS-CoV-2 vaccine in Chinese adults. Nat. Commun. 14, 4757 https://doi.org/10.1038/s41467-023-40489-2 (2023).
Jin, P. et al. Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): a randomized, observer-blinded, placebo-controlled trial. PLoS Med. 19, e1003953, https://doi.org/10.1371/journal.pmed.1003953 (2022).
Li, J. X. et al. Safety, immunogenicity and protection of heterologous boost with an aerosolised Ad5-nCoV after two-dose inactivated COVID-19 vaccines in adults: a multicentre, open-label phase 3 trial. Lancet Infect. Dis. 23, 1143–1152, https://doi.org/10.1016/s1473-3099(23)00350-x (2023).
Zhang, X. et al. Effectiveness of a booster dose of COVID-19 vaccines during an outbreak of SARS-CoV-2 Omicron BA.2.2 in China: a case-control study. Hum. Vaccines Immunother. 19, 2194189. https://doi.org/10.1080/21645515.2023.2194189 (2023).
Göbel, C. H. et al. Comparison of phenotypes of headaches after COVID-19 vaccinations differentiated according to the vaccine used. Vaccines 13, https://doi.org/10.3390/vaccines13020113 (2025).
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, https://doi.org/10.1016/j.cell.2020.08.026 (2020).
Sunagar, R., Prasad, S. D., Ella, R. & Vadrevu, K. M. Preclinical evaluation of safety and immunogenicity of a primary series intranasal COVID-19 vaccine candidate (BBV154) and humoral immunogenicity evaluation of a heterologous prime-boost strategy with COVAXIN (BBV152). Front. Immunol. 13, 1063679. https://doi.org/10.3389/fimmu.2022.1063679 (2022).
Singh, C. et al. Phase III Pivotal comparative clinical trial of intranasal (iNCOVACC) and intramuscular COVID 19 vaccine (Covaxin®). npj Vaccines 8, 125. https://doi.org/10.1038/s41541-023-00717-8 (2023).
Kulkarni, P. S. et al. Seropersistence of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine): 6-month follow-up of a randomized, controlled, observer-blind, phase 2/3 immuno-bridging study in Indian adults. Hum. vaccines immunotherapeutics 20, 2304974. https://doi.org/10.1080/21645515.2024.2304974 (2024).
van Doremalen, N. et al. ChAdOx1 nCoV-19 (AZD1222) or nCoV-19-Beta (AZD2816) protect Syrian hamsters against Beta Delta and Omicron variants. Nat. Commun. 13, 4610. https://doi.org/10.1038/s41467-022-32248-6 (2022).
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. https://doi.org/10.1126/scitranslmed.abh0755 (2021).
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. https://doi.org/10.1016/j.ebiom.2022.104298 (2022).
Wang, P. et al. Generation of DelNS1 influenza viruses: a strategy for optimizing live attenuated influenza vaccines. mBio 10, https://doi.org/10.1128/mBio.02180-19 (2019).
Zhu, F. et al. Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Respiratory Med. 10, 749–760, https://doi.org/10.1016/s2213-2600(22)00131-x (2022).
Chu, K. et al. A randomized phase I trial of intranasal SARS-CoV-2 vaccine dNS1-RBD in children aged 3-17 years. NPJ Vaccines 10, 50. https://doi.org/10.1038/s41541-025-01096-y (2025).
Zhu, F. et al. Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respiratory Med. 11, 1075–1088, https://doi.org/10.1016/s2213-2600(23)00349-1 (2023).
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, https://doi.org/10.1016/j.scib.2022.05.018 (2022).
Carreño, J. M. et al. An inactivated NDV-HXP-S COVID-19 vaccine elicits a higher proportion of neutralizing antibodies in humans than mRNA vaccination. Sci. Transl. Med. 15, eabo2847. https://doi.org/10.1126/scitranslmed.abo2847 (2023).
González-Domínguez, I. et al. Trivalent NDV-HXP-S vaccine protects against phylogenetically distant SARS-CoV-2 variants of concern in mice. Microbiol. Spectr. 10, e0153822 https://doi.org/10.1128/spectrum.01538-22 (2022).
Duc Dang, A. et al. Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam. Vaccine 40, 3621–3632, https://doi.org/10.1016/j.vaccine.2022.04.078 (2022).
González-Domínguez, I. et al. Mucosal multivalent NDV-based vaccine provides cross-reactive immune responses against SARS-CoV-2 variants in animal models. Front. Immunol. 16, 1524477 https://doi.org/10.3389/fimmu.2025.1524477 (2025).
2022).
Lin, D. Y. et al. Durability of bivalent boosters against omicron subvariants. N. Engl. J. Med. 388, 1818–1820, https://doi.org/10.1056/NEJMc2302462 (2023).
Sui, Y. et al. Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants. Front. Immunol. 14, 1154496 https://doi.org/10.3389/fimmu.2023.1154496 (2023).
Zhang, B. D. et al. STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation. Nano Res. 15, 6328–6339, https://doi.org/10.1007/s12274-022-4282-x (2022).
Sun, B. et al. An intranasally administered adenovirus-vectored SARS-CoV-2 vaccine induces robust mucosal secretory IgA. JCI Insight 9, https://doi.org/10.1172/jci.insight.180784 (2024).
Chen, Y. et al. SARS-CoV-2 Omicron infection augments the magnitude and durability of systemic and mucosal immunity in triple-dose CoronaVac recipients. mBio 15, e0240723 https://doi.org/10.1128/mbio.02407-23 (2024).
Batra, L. et al. Mucosal and Serum Neutralization Immune Responses Elicited by COVID-19 mRNA Vaccination In Vaccinated And Breakthrough-infection Individuals: A Longitudinal Study From Louisville Cohort. Vaccines 13, 559, https://doi.org/10.3390/vaccines13060559 (2025).
López-Macías, C. et al. Phase 2/3 study evaluating safety, immunogenicity, and noninferiority of single booster dose of AVX/COVID-12 vaccine. Sci. Adv. 11, eadq2887. https://doi.org/10.1126/sciadv.adq2887 (2025).
Bricker, T. L. et al. Prototype and BA.5 protein nanoparticle vaccines protect against Omicron BA.5 variant in Syrian hamsters. J. Virol. 98, e0120623. https://doi.org/10.1128/jvi.01206-23 (2024).
Alpuche-Lazcano, S. P. et al. Preclinical evaluation of manufacturable SARS-CoV-2 spike virus-like particles produced in Chinese Hamster Ovary cells. Commun. Med. 3, 116, https://doi.org/10.1038/s43856-023-00340-7 (2023).
Collett, S. et al. Development of virus-like particles with inbuilt immunostimulatory properties as vaccine candidates. Front. Microbiol. 14, 1065609. https://doi.org/10.3389/fmicb.2023.1065609 (2023).
Huang, Z. et al. Modularized viromimetic polymer nanoparticle vaccines (VPNVaxs) to elicit durable and effective humoral immune responses. Natl Sci. Rev. 11, nwad310. https://doi.org/10.1093/nsr/nwad310 (2024).
Yang, Y. et al. Enhancing anti-SARS-CoV-2 neutralizing immunity by genetic delivery of enveloped virus-like particles displaying SARS-CoV-2 spikes. Vaccines 11, 1438, https://doi.org/10.3390/vaccines11091438 (2023).
Nguyen, H. T., Falzarano, D., Gerdts, V. & Liu, Q. Construction and immunogenicity of SARS-CoV-2 virus-like particle expressed by recombinant baculovirus BacMam. Microbiol. Spectr. 12, e0095924 https://doi.org/10.1128/spectrum.00959-24 (2024).
Karron, R. A. et al. Safety and Immunogenicity of the respiratory syncytial virus vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-seronegative children. J. Infect. Dis. 222, 82–91, https://doi.org/10.1093/infdis/jiz408 (2020).
Russell, C. D., Unger, S. A., Walton, M. & Schwarze, J. The human immune response to respiratory syncytial virus infection. Clin. Microbiol. Rev. 30, 481–502, https://doi.org/10.1128/cmr.00090-16 (2017).
Cunningham, C. K. et al. Evaluation of recombinant live-attenuated respiratory syncytial virus (RSV) vaccines RSV/ΔNS2/Δ1313/I1314L and RSV/276 in RSV-seronegative children. J. Infect. Dis. 226, 2069–2078, https://doi.org/10.1093/infdis/jiac253 (2022).
(2024).
Levy, M. et al. Intranasal respiratory syncytial virus vaccine attenuated by codon-pair deoptimization of seven open reading frames is genetically stable and elicits mucosal and systemic immunity and protection against challenge virus replication in hamsters. PLoS Pathog. 20, e1012198, https://doi.org/10.1371/journal.ppat.1012198 (2024).
Lee, M. A. et al. Codon pair deoptimization (CPD)-attenuated PRRSV-1 vaccination exhibit immunity to virulent PRRSV challenge in Pigs. Vaccines 11, https://doi.org/10.3390/vaccines11040777 (2023).
2021).
Hause, A. M. et al. Early safety findings among persons aged ≥60 years who received a respiratory syncytial virus vaccine – United States, May 3, 2023-April 14, 2024. Mmwr. Morbidity Mortal. Wkly. Rep. 73, 489–494, https://doi.org/10.15585/mmwr.mm7321a3 (2024).
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. https://doi.org/10.1126/sciadv.adj7611 (2023).
Xu, Y. et al. Cold-adapted influenza-vectored RSV vaccine protects BALB/c mice and cotton rats from RSV challenge. J. Med. Virol. 96, e29308. https://doi.org/10.1002/jmv.29308 (2024).
Pulkina, A. et al. IgGκ signal peptide enhances the efficacy of an influenza vector vaccine against respiratory syncytial virus infection in mice. Int J. Mol. Sci. 24, 11445, https://doi.org/10.3390/ijms241411445 (2023).
Vasilyev, K. et al. Enhancement of the local CD8(+) T-cellular immune response to mycobacterium tuberculosis in BCG-primed mice after intranasal administration of influenza vector vaccine carrying TB10.4 and HspX antigens. Vaccines 9, https://doi.org/10.3390/vaccines9111273 (2021).
Maier, C. et al. Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity. Front. Immunol. 13, 920256. https://doi.org/10.3389/fimmu.2022.920256 (2022).
Eberlein, V. et al. Mucosal immunization with a low-energy electron inactivated respiratory syncytial virus vaccine protects mice without Th2 immune bias. Front. Immunol. 15, 1382318. https://doi.org/10.3389/fimmu.2024.1382318 (2024).
Cheng, X. et al. A first-in-human trial to evaluate the safety and immunogenicity of a G protein-based recombinant respiratory syncytial virus vaccine in healthy adults 18-45 years of age. Vaccines 11, https://doi.org/10.3390/vaccines11050999 (2023).
Jung, Y. J. et al. Recombinant live attenuated influenza virus expressing conserved G-protein domain in a chimeric hemagglutinin molecule induces G-specific antibodies and confers protection against respiratory syncytial virus. Vaccines 8, https://doi.org/10.3390/vaccines8040716 (2020).
Chandler, R. et al. Immunogenicity, reactogenicity, and safety of AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) when co-administered with a seasonal quadrivalent influenza vaccine in older adults: results of a phase 3, open-label, randomized controlled trial. Clin. Infect. Dis. Off. Pub. Infect. Dis. Soc. Am. https://doi.org/10.1093/cid/ciad786 (2024).
Athan, E. et al. Safety and immunogenicity of bivalent RSVpreF vaccine coadministered with seasonal inactivated influenza vaccine in older adults. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 78, 1360–1368, https://doi.org/10.1093/cid/ciad707 (2024).
Croda, J. Exploring the potential benefits of mucosal COVID-19 vaccines: opportunities and challenges. Lancet Infect. Dis. 23, 1099–1100, https://doi.org/10.1016/s1473-3099(23)00363-8 (2023).
Srivastava, A., Gowda, D. V., Madhunapantula, S. V., Shinde, C. G. & Iyer, M. Mucosal vaccines: a paradigm shift in the development of mucosal adjuvants and delivery vehicles. APMIS : Acta Pathologica, Microbiologica, Et. Immunologica Scandinavica 123, 275–288, https://doi.org/10.1111/apm.12351 (2015).
Afkhami, S. et al. Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell 185, 896–915.e819, https://doi.org/10.1016/j.cell.2022.02.005 (2022).
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines – a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279, https://doi.org/10.1038/nrd.2017.243 (2018).
Tsai, C. J. Y., Loh, J. M. S., Fujihashi, K. & Kiyono, H. Mucosal vaccination: onward and upward. Expert Rev. Vaccines 22, 885–899, https://doi.org/10.1080/14760584.2023.2268724 (2023).
García-Silva, I., Govea-Alonso, D. O. & Rosales-Mendoza, S. Current status of mucosal vaccines against SARS-CoV2: a hope for protective immunity. Expert Opin. Biol. Ther. 23, 207–222, https://doi.org/10.1080/14712598.2022.2156284 (2023).
Azegami, T., Yuki, Y. & Kiyono, H. Challenges in mucosal vaccines for the control of infectious diseases. Int. Immunol. 26, 517–528, https://doi.org/10.1093/intimm/dxu063 (2014).
Pasetti, M. F. et al. Safety and immunogenicity in humans of enterotoxigenic Escherichia coli double mutant heat-labile toxin administered intradermally. NPJ Vaccines 10, 23. https://doi.org/10.1038/s41541-025-01071-7 (2025).