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Review

Mucosal vaccination: onward and upward

ORCID Icon, , &
Pages 885-899 | Received 13 Jul 2023, Accepted 05 Oct 2023, Published online: 17 Oct 2023

References

  • Elphick DA, Mahida YR. Paneth cells: their role in innate immunity and inflammatory disease. Gut. 2005;54(12):1802–1809. doi: 10.1136/gut.2005.068601
  • Cesta MF. Normal structure, function, and histology of mucosa-associated lymphoid tissue. Toxicol Pathol. 2006;34(5):599–608. doi: 10.1080/01926230600865531
  • Pavot V, Rochereau N, Genin C, et al. New insights in mucosal vaccine development. Vaccine. 2012;30(2):142–154. doi: 10.1016/j.vaccine.2011.11.003
  • Kurashima Y, Kiyono H. Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol. 2017;35(1):119–147. doi: 10.1146/annurev-immunol-051116-052424
  • Kim DY, Sato A, Fukuyama S, et al. The airway antigen sampling system: respiratory M cells as an alternative gateway for inhaled antigens. J Immunol. 2011;186(7):4253–4262. doi: 10.4049/jimmunol.0903794
  • Anggraeni R, Ana ID, Wihadmadyatami H. Development of mucosal vaccine delivery: an overview on the mucosal vaccines and their adjuvants. Clin Exp Vaccine Res. 2022;11(3):235–248. doi: 10.7774/cevr.2022.11.3.235
  • Kaetzel CS, Robinson JK, Chintalacharuvu KR, et al. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci U S A. 1991;88(19):8796–8800. doi: 10.1073/pnas.88.19.8796
  • Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005;11(4 Suppl):S45–53. doi: 10.1038/nm1213
  • Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 2008;8(6):421–434. doi: 10.1038/nri2322
  • Kunkel EJ, Butcher EC. Plasma-cell homing. Nat Rev Immunol. 2003;3(10):822–829. doi: 10.1038/nri1203
  • Campbell DJ, Debes GF, Johnston B, et al. Targeting T cell responses by selective chemokine receptor expression. Semin Immunol. 2003;15(5):277–286. doi: 10.1016/j.smim.2003.08.005
  • Kaetzel CS. The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol Rev. 2005;206(1):83–99. doi: 10.1111/j.0105-2896.2005.00278.x
  • Czerkinsky C, Holmgren J. Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues. Curr Top Microbiol Immunol. 2012;354:1–18. doi: 10.1007/82_2010_112
  • Svennerholm AM, Lundgren A, Leach S, et al. Mucosal immune responses against an oral enterotoxigenic Escherichia coli vaccine evaluated in clinical trials. J Infect Dis. 2021;224(12 Suppl 2):S821–S828. doi: 10.1093/infdis/jiab475
  • Johansson M, Schon K, Ward M, et al. Genital tract infection with chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor-deficient mice despite a strong local immunoglobulin a response. Infect Immun. 1997;65(3):1032–1044. doi: 10.1128/IAI.65.3.1032-1044.1997
  • Ermak TH, Giannasca PJ, Nichols R, et al. Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses. J Exp Med. 1998;188(12):2277–2288. doi: 10.1084/jem.188.12.2277
  • Lamichhane A, Azegamia T, Kiyonoa H. The mucosal immune system for vaccine development. Vaccine. 2014;32(49):6711–6723. doi: 10.1016/j.vaccine.2014.08.089
  • Kiyono H, Azegami T. The mucosal immune system: from dentistry to vaccine development. Proc Jpn Acad Ser B Phys Biol Sci. 2015;91(8):423–439. doi: 10.2183/pjab.91.423
  • Kiyono H, Kweon MN, Hiroi T, et al. The mucosal immune system: from specialized immune defense to inflammation and allergy. Acta Odontol Scand. 2001;59(3):145–153. doi: 10.1080/000163501750266738
  • Fujkuyama Y, Tokuhara D, Kataoka K, et al. Novel vaccine development strategies for inducing mucosal immunity. Expert Rev Vaccines. 2012;11(3):367–379. doi: 10.1586/erv.11.196
  • Boyaka PN. Inducing mucosal IgA: a challenge for vaccine adjuvants and delivery systems. J Immunol. 2017;199(1):9–16. doi: 10.4049/jimmunol.1601775
  • Flemming A. ‘Prime and spike’ induces mucosal immunity and reduces SARS-CoV-2 transmission. Nat Rev Immunol. 2022;22(12):718. doi: 10.1038/s41577-022-00804-2
  • Tang J, Zeng C, Cox TM, et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci Immunol. 2022;7(76):eadd4853. doi: 10.1126/sciimmunol.add4853
  • Kraehenbuhl JP, Neutra MR. Mucosal vaccines: where do we stand? Curr Top Med Chem. 2013;13(20):2609–2628. doi: 10.2174/15680266113136660186
  • Moldoveanu Z, Clements ML, Prince SJ, et al. Human immune responses to influenza virus vaccines administered by systemic or mucosal routes. Vaccine. 1995;13(11):1006–1012. doi: 10.1016/0264-410x(95)00016-t
  • Russell MW, Mestecky J. Mucosal immunity: the missing link in comprehending SARS-CoV-2 infection and transmission. Front Immunol. 2022;13:957107. doi: 10.3389/fimmu.2022.957107
  • Lue C, Tarkowski A, Mestecky J. Systemic immunization with pneumococcal polysaccharide vaccine induces a predominant IgA2 response of peripheral blood lymphocytes and increases of both serum and secretory anti-pneumococcal antibodies. J Immunol. 1988;140(11):3793–3800. doi: 10.4049/jimmunol.140.11.3793
  • Xu H, Cai L, Hufnagel S, et al. Intranasal vaccine: factors to consider in research and development. Int J Pharm. 2021;609:121180. doi: 10.1016/j.ijpharm.2021.121180
  • Brokstad KA, Eriksson JC, Cox RJ, et al. Parenteral vaccination against influenza does not induce a local antigen-specific immune response in the nasal mucosa. J Infect Dis. 2002;185(7):878–884. doi: 10.1086/339710
  • Hasegawa H, Ichinohe T, Ainai A, et al. Development of mucosal adjuvants for intranasal vaccine for H5N1 influenza viruses. Ther Clin Risk Manag. 2009;5(1):125–132. doi: 10.2147/tcrm.s3297
  • Jang YH, Byun YH, Lee YJ, et al. Cold-adapted pandemic 2009 H1N1 influenza virus live vaccine elicits cross-reactive immune responses against seasonal and H5 influenza a viruses. J Virol. 2012;86(10):5953–5958. doi: 10.1128/JVI.07149-11
  • Ainai A, Tamura S, Suzuki T, et al. Intranasal vaccination with an inactivated whole influenza virus vaccine induces strong antibody responses in serum and nasal mucus of healthy adults. Hum Vaccin Immunother. 2013;9(9):1962–1970. doi: 10.4161/hv.25458
  • Azegami T, Yuki Y, Kiyono H. Challenges in mucosal vaccines for the control of infectious diseases. Int Immunol. 2014;26(9):517–528. doi: 10.1093/intimm/dxu063
  • Burgess TH, Murray CK, Bavaro MF, et al. Self-administration of intranasal influenza vaccine: immunogenicity and volunteer acceptance. Vaccine. 2015;33(32):3894–3899. doi: 10.1016/j.vaccine.2015.06.061
  • Ambrose CS, Wu X. The safety and effectiveness of self-administration of intranasal live attenuated influenza vaccine in adults. Vaccine. 2013;31(6):857–860. doi: 10.1016/j.vaccine.2012.12.028
  • Couch RB, Atmar RL, Keitel WA, et al. Randomized comparative study of the serum antihemagglutinin and antineuraminidase antibody responses to six licensed trivalent influenza vaccines. Vaccine. 2012;31(1):190–195. doi: 10.1016/j.vaccine.2012.10.065
  • Grohskopf LA, Sokolow LZ, Fry AM, et al. Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4) - United States, 2018-19 influenza season. MMWR Morb Mortal Wkly Rep. 2018;67(22):643–645. doi: 10.15585/mmwr.mm6722a5
  • Konopka-Anstadt JL, Campagnoli R, Vincent A, et al. Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization. NPJ Vaccines. 2020;5(1):26. doi: 10.1038/s41541-020-0176-7
  • McNeil MM, Paradowska-Stankiewicz I, Miller ER, et al. Adverse events following adenovirus type 4 and type 7 vaccine, live, oral in the vaccine adverse event reporting system (VAERS). Vaccine. 2019;37(44):6760–6767. United States, October 2011-July 2018 doi: 10.1016/j.vaccine.2019.08.087
  • Pawinski R, Debrus S, Delem A, et al. Rotarix in developing countries: paving the way for inclusion in national childhood immunization programs in Africa. J Infect Dis. 2010;202(Suppl 1):S80–86. doi: 10.1086/653547
  • van Hoek AJ, Ngama M, Ismail A, et al. A cost effectiveness and capacity analysis for the introduction of universal rotavirus vaccination in Kenya: comparison between Rotarix and RotaTeq vaccines. PLoS One. 2012;7(10):e47511. doi: 10.1371/journal.pone.0047511
  • Yang B, Foley S. First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune((R)). BJU Int. 2018;121(2):289–292. doi: 10.1111/bju.14067
  • Lorenzo-Gomez MF, Padilla-Fernandez B, Garcia-Criado FJ, et al. Evaluation of a therapeutic vaccine for the prevention of recurrent urinary tract infections versus prophylactic treatment with antibiotics. Int Urogynecol J. 2013;24(1):127–134. doi: 10.1007/s00192-012-1853-5
  • Haas NL, Haas MRC, Gregory C. A case report of anaphylaxis to typhoid vaccine live oral Ty21a (Vivotif). J Travel Med. 2017;24(5):5. doi: 10.1093/jtm/tax022
  • Pennington SH, Ferreira DM, Caamano-Gutierrez E, et al. Nonspecific effects of oral vaccination with live-attenuated salmonella typhi strain Ty21a. Sci Adv. 2019;5(2):eaau6849. doi: 10.1126/sciadv.aau6849
  • Freedman DO. Re-born in the USA: another cholera vaccine for travellers. Travel Med Infect Dis. 2016;14(4):295–296. doi: 10.1016/j.tmaid.2016.07.008
  • Baik YO, Choi SK, Olveda RM, et al. A randomized, non-inferiority trial comparing two bivalent killed, whole cell, oral cholera vaccines (euvichol vs Shanchol) in the Philippines. Vaccine. 2015;33(46):6360–6365. doi: 10.1016/j.vaccine.2015.08.075
  • van Splunter M, van Hoffen E, Floris-Vollenbroek EG, et al. Oral cholera vaccination promotes homing of IgA(+) memory B cells to the large intestine and the respiratory tract. Mucosal Immunol. 2018;11(4):1254–1264. doi: 10.1038/s41385-018-0006-7
  • Moyle PM, Toth I. Modern subunit vaccines: development, components, and research opportunities. ChemMedchem. 2013;8(3):360–376. doi: 10.1002/cmdc.201200487
  • Favre D, Viret JF. Biosafety evaluation of recombinant live oral bacterial vaccines in the context of European regulation. Vaccine. 2006;24(18):3856–3864. doi: 10.1016/j.vaccine.2005.07.018
  • Kiyono H, Yuki Y, Nakahashi-Ouchida R, et al. Mucosal vaccines: wisdom from now and then. Int Immunol. 2021;33(12):767–774. doi: 10.1093/intimm/dxab056
  • Yuki Y, Nojima M, Kashima K, et al. Oral MucoRice-CTB vaccine is safe and immunogenic in healthy US adults. Vaccine. 2022;40(24):3372–3379. doi: 10.1016/j.vaccine.2022.04.051
  • Garg NK, Mangal S, Khambete H, et al. Mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymers. Recent Pat Drug Deliv Formul. 2010;4(2):114–128. doi: 10.2174/187221110791185015
  • 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. 2018;14(9):2189–2193. doi: 10.1080/21645515.2018.1461298
  • Kang H, Yan M, Yu Q, et al. Characteristics of nasal-associated lymphoid tissue (NALT) and nasal absorption capacity in chicken. PLoS One. 2013;8(12):e84097. doi: 10.1371/journal.pone.0084097
  • Kakutani H, Kondoh M, Fukasaka M, et al. Mucosal vaccination using claudin-4-targeting. Biomaterials. 2010;31(20):5463–5471. doi: 10.1016/j.biomaterials.2010.03.047
  • Zaman M, Chandrudu S, Toth I. Strategies for intranasal delivery of vaccines. Drug Deliv Transl Res. 2013;3(1):100–109. doi: 10.1007/s13346-012-0085-z
  • Yuki Y, Nojima M, Hosono O, et al. Oral MucoRice-CTB vaccine for safety and microbiota-dependent immunogenicity in humans: a phase 1 randomised trial. Lancet Microbe. 2021;2(9):e429–e440. doi: 10.1016/S2666-5247(20)30196-8
  • Shen Y, Hu Y, Qiu L. Nano-vesicles based on phospholipid-like amphiphilic polyphosphazenes to orally deliver ovalbumin antigen for evoking anti-tumor immune response. Acta Biomater. 2020;106:267–277. doi: 10.1016/j.actbio.2020.02.012
  • Moran HBT, Turley JL, Andersson M, et al. Immunomodulatory properties of chitosan polymers. Biomaterials. 2018;184:1–9. doi: 10.1016/j.biomaterials.2018.08.054
  • Carroll EC, Jin L, Mori A, et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS-STING-Dependent induction of type I interferons. Immunity. 2016;44(3):597–608. doi: 10.1016/j.immuni.2016.02.004
  • Shen Y, Qiu L. Effective oral delivery of gp100 plasmid vaccine against metastatic melanoma through multi-faceted blending-by-blending nanogels. Nanomedicine. 2019;22:102114. doi: 10.1016/j.nano.2019.102114
  • Verma AK, Sharma S, Gupta P, et al. Vitamin B12 grafted layer-by-layer liposomes bearing HBsAg facilitate oral immunization: effect of modulated biomechanical properties. Mol Pharm. 2016;13(7):2531–2542. doi: 10.1021/acs.molpharmaceut.6b00274
  • Yang M, Lai SK, Wang YY, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew Chem Int Ed Engl. 2011;50(11):2597–2600. doi: 10.1002/anie.201006849
  • Liu M, Zhang J, Zhu X, et al. Efficient mucus permeation and tight junction opening by dissociable “mucus-inert” agent coated trimethyl chitosan nanoparticles for oral insulin delivery. J Control Release. 2016;222:67–77. doi: 10.1016/j.jconrel.2015.12.008
  • Kimoto T, Kim H, Sakai S, et al. Oral vaccination with influenza hemagglutinin combined with human pulmonary surfactant-mimicking synthetic adjuvant SF-10 induces efficient local and systemic immunity compared with nasal and subcutaneous vaccination and provides protective immunity in mice. Vaccine. 2019;37(4):612–622. doi: 10.1016/j.vaccine.2018.12.002
  • Clements JD, Norton EB, Papasian CJ. The mucosal vaccine adjuvant LT(R192G/L211A) or dmLT. mSphere. 2018;3(4). doi: 10.1128/mSphere.00215-18
  • Norton EB, Bauer DL, Weldon WC, et al. The novel adjuvant dmLT promotes dose sparing, mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model. Vaccine. 2015;33(16):1909–1915. doi: 10.1016/j.vaccine.2015.02.069
  • Chen CH, Chen CC, Wang WB, et al. Intranasal immunization with Zika virus envelope domain III-Flagellin fusion protein elicits systemic and mucosal immune responses and protection against subcutaneous and intravaginal virus challenges. Pharmaceutics. 2022;14(5):1014. doi: 10.3390/pharmaceutics14051014
  • Zhang T, Chen X, Liu H, et al. A rationally designed flagellin-L2 fusion protein induced serum and mucosal neutralizing antibodies against multiple HPV types. Vaccine. 2019;37(30):4022–4030. doi: 10.1016/j.vaccine.2019.06.002
  • Zhao B, Yang J, He B, et al. A safe and effective mucosal RSV vaccine in mice consisting of RSV phosphoprotein and flagellin variant. Cell Rep. 2021;36(3):109401. doi: 10.1016/j.celrep.2021.109401
  • Lin SF, Jiang PL, Tsai JS, et al. Surface assembly of poly(I: C) on polyethyleneimine-modified gelatin nanoparticles as immunostimulatory carriers for mucosal antigen delivery. J Biomed Mater Res B Appl Biomater. 2019;107(4):1228–1237. doi: 10.1002/jbm.b.34215
  • Meijlink MA, Chua YC, Chan STS, et al. 6’’-modified alpha-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria. RSC Chem Biol. 2022;3(5):551–560. doi: 10.1039/d1cb00251a
  • Ahmed M, Smith DM, Hamouda T, et al. A novel nanoemulsion vaccine induces mucosal interleukin-17 responses and confers protection upon mycobacterium tuberculosis challenge in mice. Vaccine. 2017;35(37):4983–4989. doi: 10.1016/j.vaccine.2017.07.073
  • Bakshi S, Sanz Garcia R, Van der Weken H, et al. Evaluating single-domain antibodies as carriers for targeted vaccine delivery to the small intestinal epithelium. J Control Release. 2020;321:416–429. doi: 10.1016/j.jconrel.2020.01.033
  • Baert K, de Geest, BG, de Rycke R, et al. Beta-glucan microparticles targeted to epithelial APN as oral antigen delivery system. J Control Release. 2015;220(Pt A):149–159. doi: 10.1016/j.jconrel.2015.10.025
  • Sun Y, Qian J, Xu X, et al. Dendritic cell-targeted recombinantLactobacilli induce DC activation and elicit specific immune responses against G57 genotype of avian H9N2 influenza virus infection. Vet Microbiol. 2018;223:9–20. doi: 10.1016/j.vetmic.2018.07.009
  • Kataoka K, Fujihashi K, Oma K, et al. The nasal dendritic cell-targeting Flt3 ligand as a safe adjuvant elicits effective protection against fatal pneumococcal pneumonia. Infect Immun. 2011;79(7):2819–2828. doi: 10.1128/IAI.01360-10
  • Kim SH, Seo KW, Kim J, et al. The M cell-targeting ligand promotes antigen delivery and induces antigen-specific immune responses in mucosal vaccination. J Immunol. 2010;185(10):5787–5795. doi: 10.4049/jimmunol.0903184
  • Liebowitz D, Lindbloom JD, Brandl JR, et al. High titre neutralising antibodies to influenza after oral tablet immunisation: a phase 1, randomised, placebo-controlled trial. Lancet Infect Dis. 2015;15(9):1041–1048. doi: 10.1016/S1473-3099(15)00266-2
  • Liebowitz D, Gottlieb K, Kolhatkar NS, et al. Efficacy, immunogenicity, and safety of an oral influenza vaccine: a placebo-controlled and active-controlled phase 2 human challenge study. Lancet Infect Dis. 2020;20(4):435–444. doi: 10.1016/S1473-3099(19)30584-5
  • Joyce C, Scallan CD, Mateo R, et al. Orally administered adenoviral-based vaccine induces respiratory mucosal memory and protection against RSV infection in cotton rats. Vaccine. 2018;36(29):4265–4277. doi: 10.1016/j.vaccine.2018.05.112
  • Kim L, Martinez CJ, Hodgson KA, et al. Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule. Sci Rep. 2016;6(1):37295. doi: 10.1038/srep37295
  • Scallan CD, Tingley DW, Lindbloom JD, et al. An adenovirus-based vaccine with a double-stranded RNA adjuvant protects mice and ferrets against H5N1 avian influenza in oral delivery models. Clin Vaccine Immunol. 2013;20(1):85–94. doi: 10.1128/CVI.00552-12
  • Yurina V, Rahayu Adianingsih O, Widodo N. Oral and intranasal immunization with food-grade recombinant Lactococcus lactis expressing high conserved region of SARS-CoV-2 spike protein triggers mice’s immunity responses. Vaccine: X. 2023;13:100265. doi: 10.1016/j.jvacx.2023.100265
  • Mohseni AH, Razavilar V, Keyvani H, et al. Oral immunization with recombinant Lactococcus lactis NZ9000 expressing human papillomavirus type 16 E7 antigen and evaluation of its immune effects in female C57BL/6 mice. J Med Virol. 2019;91(2):296–307. doi: 10.1002/jmv.25303
  • Blanchett S, Tsai CJ, Sandford S, et al. Intranasal immunization with Ag85B peptide 25 displayed on Lactococcus lactis using the PilVax platform induces antigen-specific B- and T-cell responses. Immunol Cell Biol. 2021;99(7):767–781. doi: 10.1111/imcb.12462
  • Clow F, Peterken K, Pearson V, et al. PilVax, a novel Lactococcus lactis-based mucosal vaccine platform, stimulates systemic and mucosal immune responses to staphylococcus aureus. Immunol Cell Biol. 2020;98(5):369–381. doi: 10.1111/imcb.12325
  • Wagachchi D, Tsai JC, Chalmers C, et al. PilVax - a novel peptide delivery platform for the development of mucosal vaccines. Sci Rep. 2018;8(1):2555. doi: 10.1038/s41598-018-20863-7
  • Jia Z, Ma C, Yang X, et al. Oral immunization of recombinant Lactococcus lactis and Enterococcus faecalis expressing dendritic cell targeting peptide and Hexon protein of Fowl adenovirus 4 induces protective immunity against Homologous infection. Front Vet Sci. 2021;8:632218. doi: 10.3389/fvets.2021.632218
  • Tvinnereim AR, Hamilton SE, Harty JT. CD8(+)-T-cell response to secreted and nonsecreted antigens delivered by recombinant listeria monocytogenes during secondary infection. Infect Immun. 2002;70(1):153–162. doi: 10.1128/IAI.70.1.153-162.2002
  • Chen G, Dai Y, Chen J, et al. Oral delivery of the Sj23LHD-GST antigen by salmonella typhimurium type III secretion system protects against schistosoma japonicum infection in mice. PLoS Negl Trop Dis. 2011;5(9):e1313. doi: 10.1371/journal.pntd.0001313
  • Gould VMW, Francis JN, Anderson KJ, et al. Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre. Front Microbiol. 2017;8:900. doi: 10.3389/fmicb.2017.00900
  • Dong C, Wang Y, Gonzalez GX, et al. Intranasal vaccination with influenza HA/GO-PEI nanoparticles provides immune protection against homo- and heterologous strains. Proc Natl Acad Sci U S A. 2021;118(19). doi: 10.1073/pnas.2024998118
  • Varma DM, Batty CJ, Stiepel RT, et al. Development of an intranasal gel for the delivery of a broadly acting subunit influenza vaccine. ACS Biomater Sci Eng. 2022;8(4):1573–1582. doi: 10.1021/acsbiomaterials.2c00015
  • Lim JME, Tan AT, Le Bert N, et al. SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity. J Exp Med. 2022;219(10). doi: 10.1084/jem.20220780
  • Pilapitiya D, Wheatley AK, Tan HX. Mucosal vaccines for SARS-CoV-2: triumph of hope over experience. EBioMedicine. 2023;92:104585. doi: 10.1016/j.ebiom.2023.104585
  • Pitcovski J, Gruzdev N, Abzach A, et al. Oral subunit SARS-CoV-2 vaccine induces systemic neutralizing IgG, IgA and cellular immune responses and can boost neutralizing antibody responses primed by an injected vaccine. Vaccine. 2022;40(8):1098–1107. doi: 10.1016/j.vaccine.2022.01.025
  • Wu S, Huang J, Zhang Z, et al. Safety, tolerability, and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCov) in adults: preliminary report of an open-label and randomised phase 1 clinical trial. Lancet Infect Dis. 2021;21(12):1654–1664. doi: 10.1016/S1473-3099(21)00396-0
  • Lockhart A, Mucida D, Parsa R. Immunity to enteric viruses. Immunity. 2022;55(5):800–818. doi: 10.1016/j.immuni.2022.04.007
  • Yao Y, Jeyanathan M, Haddadi S, et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell. 2018;175(6):1634–1650, e1617. doi: 10.1016/j.cell.2018.09.042
  • D’Agostino MR, Lai R, Afkhami S, et al. Airway macrophages mediate mucosal vaccine-induced trained innate immunity against mycobacterium tuberculosis in early stages of infection. J Immunol. 2020;205(10):2750–2762. doi: 10.4049/jimmunol.2000532
  • Xing Z, Afkhami S, Bavananthasivam J, et al. Innate immune memory of tissue-resident macrophages and trained innate immunity: re-vamping vaccine concept and strategies. J Leukocyte Biol. 2020;108(3):825–834. doi: 10.1002/JLB.4MR0220-446R
  • Neutra MR, Pringault E, Kraehenbuhl JP. Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu Rev Immunol. 1996;14(1):275–300. doi: 10.1146/annurev.immunol.14.1.275
  • van Ginkel, FW, Jackson RJ, Yuki Y, et al. Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J Immunol. 2000;165(9):4778–4782. doi: 10.4049/jimmunol.165.9.4778
  • Mutsch M, Zhou W, Rhodes P, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N Engl J Med. 2004;350(9):896–903. doi: 10.1056/NEJMoa030595
  • Kraan H, Vrieling H, Czerkinsky C, et al. Buccal and sublingual vaccine delivery. J Control Release. 2014;190:580–592. doi: 10.1016/j.jconrel.2014.05.060
  • Czerkinsky C, Cuburu N, Kweon MN, et al. Sublingual vaccination. Hum Vaccin. 2011;7(1):110–114. doi: 10.4161/hv.7.1.13739
  • Brandtzaeg P. Potential of nasopharynx-associated lymphoid tissue for vaccine responses in the airways. Am J Respir Crit Care Med. 2011;183(12):1595–1604. doi: 10.1164/rccm.201011-1783OC
  • Seo KY, Han SJ, Cha HR, et al. Eye mucosa: an efficient vaccine delivery route for inducing protective immunity. J Immunol. 2010;185(6):3610–3619. doi: 10.4049/jimmunol.1000680
  • Nagatake T, Fukuyama S, Kim DY, et al. Id2-, RORgammat-, and LTbetaR-independent initiation of lymphoid organogenesis in ocular immunity. J Exp Med. 2009;206(11):2351–2364. doi: 10.1084/jem.20091436
  • Oya Y, Kimura S, Nakamura Y, et al. Characterization of M cells in tear duct-associated lymphoid tissue of mice: a potential role in Immunosurveillance on the ocular surface. Front Immunol. 2021;12:779709. doi: 10.3389/fimmu.2021.779709
  • Kim ED, Han SJ, Byun YH, et al. Inactivated eyedrop influenza vaccine adjuvanted with poly(I: C) is safe and effective for inducing protective systemic and mucosal immunity. PLoS One. 2015;10(9):e0137608. doi: 10.1371/journal.pone.0137608
  • Yoon S, Kim ED, Song MS, et al. Eyedrop vaccination induced systemic and mucosal immunity against influenza virus in ferrets. PLoS One. 2016;11(6):e0157634. doi: 10.1371/journal.pone.0157634
  • Kim J, Kim ED, Shin HS, et al. Effectiveness and safety of injectable human papilloma virus vaccine administered as eyedrops. Vaccine. 2023;41(1):92–100. doi: 10.1016/j.vaccine.2022.09.070
  • Mestecky J, Moldoveanu Z, Russell MW. Immunologic uniqueness of the genital tract: challenge for vaccine development. Am J Reprod Immunol. 2005;53(5):208–214. doi: 10.1111/j.1600-0897.2005.00267.x
  • Lavelle EC, Ward RW. Mucosal vaccines - fortifying the frontiers. Nat Rev Immunol. 2022;22(4):236–250. doi: 10.1038/s41577-021-00583-2
  • Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol. 2012;12(8):592–605. doi: 10.1038/nri3251
  • Gordon SN, Kines RC, Kutsyna G, et al. Targeting the vaginal mucosa with human papillomavirus pseudovirion vaccines delivering simian immunodeficiency virus DNA. J Immunol. 2012;188(2):714–723. doi: 10.4049/jimmunol.1101404
  • Hopkins WJ, Elkahwaji J, Beierle LM, et al. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol. 2007;177(4):1349–1353. quiz 1591. doi: 10.1016/j.juro.2006.11.093
  • Kantele A, Hakkinen M, Moldoveanu Z, et al. Differences in immune responses induced by oral and rectal immunizations with salmonella typhi Ty21a: evidence for compartmentalization within the common mucosal immune system in humans. Infect Immun. 1998;66(12):5630–5635. doi: 10.1128/IAI.66.12.5630-5635.1998
  • Johansson EL, Bergquist C, Edebo A, et al. Comparison of different routes of vaccination for eliciting antibody responses in the human stomach. Vaccine. 2004;22(8):984–990. doi: 10.1016/j.vaccine.2003.09.002
  • Quiding M, Nordstrom I, Kilander A, et al. Intestinal immune responses in humans. Oral cholera vaccination induces strong intestinal antibody responses and interferon-gamma production and evokes local immunological memory. J Clin Invest. 1991;88(1):143–148. doi: 10.1172/JCI115270
  • Wu HY, Russell MW. Nasal lymphoid tissue, intranasal immunization, and compartmentalization of the common mucosal immune system. Immunol Res. 1997;16(2):187–201. doi: 10.1007/BF02786362
  • Johansson EL, Wassen L, Holmgren J, et al. Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect Immun. 2001;69(12):7481–7486. doi: 10.1128/IAI.69.12.7481-7486.2001
  • Stary G, Olive A, Radovic-Moreno AF, et al. VACCINES. A mucosal vaccine against chlamydia trachomatis generates two waves of protective memory T cells. Science. 2015;348(6241):aaa8205. doi: 10.1126/science.aaa8205
  • Woodrow KA, Bennett KM, Lo DD. Mucosal vaccine design and delivery. Annu Rev Biomed Eng. 2012;14(1):17–46. doi: 10.1146/annurev-bioeng-071811-150054
  • Mestecky J, Russell MW, Elson CO. Perspectives on mucosal vaccines: is mucosal tolerance a barrier? J Immunol. 2007;179(9):5633–5638. doi: 10.4049/jimmunol.179.9.5633
  • Ilan Y. Oral immune regulation toward disease-associated antigens: results of phase I clinical trials in Crohn’s disease and chronic hepatitis. Ann N Y Acad Sci. 2004;1029(1):286–298. doi: 10.1196/annals.1309.059
  • Roy K, Mao HQ, Huang SK, et al. Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med. 1999;5(4):387–391. doi: 10.1038/7385
  • Chen Y, Wu J, Wang J, et al. Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice. Diabetologia. 2018;61(6):1384–1396. doi: 10.1007/s00125-018-4593-3
  • Li Y, Jin L, Chen T. The effects of secretory IgA in the mucosal immune system. Biomed Res Int. 2020;2020:2032057. doi: 10.1155/2020/2032057
  • Fiyouzi T, Reche PA. Vaccine design: an introduction. Methods Mol Biol. 2023;2673:1–14. doi: 10.1007/978-1-0716-3239-0_1
  • Sun B, Zhang Y. Overview of orchestration of CD4+ T cell subsets in immune responses. Adv Exp Med Biol. 2014;841:1–13. doi: 10.1007/978-94-017-9487-9_1
  • Niess JH, Adler G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J Immunol. 2010;184(4):2026–2037. doi: 10.4049/jimmunol.0901936
  • Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009;2(5):403–411. doi: 10.1038/mi.2009.100
  • Jaffar Z, Ferrini ME, Herritt LA, et al. Cutting edge: lung mucosal Th17-mediated responses induce polymeric ig receptor expression by the airway epithelium and elevate secretory IgA levels. J Immunol. 2009;182(8):4507–4511. doi: 10.4049/jimmunol.0900237
  • Bettelli E, Korn T, Oukka M, et al. Induction and effector functions of T(H)17 cells. Nature. 2008;453(7198):1051–1057. doi: 10.1038/nature07036
  • Liang Y, Pan HF, Ye DQ. Tc17 cells in immunity and systemic autoimmunity. Int Rev Immunol. 2015;34(4):318–331. doi: 10.3109/08830185.2014.954698
  • Nanjappa SG, Heninger E, Wuthrich M, et al. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells. PLOS Pathog. 2012;8(7):e1002771. doi: 10.1371/journal.ppat.1002771
  • Nanjappa SG, Hernandez-Santos N, Galles K, et al. Intrinsic MyD88-Akt1-mTOR signaling coordinates disparate Tc17 and Tc1 responses during vaccine immunity against fungal pneumonia. PLOS Pathog. 2015;11(9):e1005161. doi: 10.1371/journal.ppat.1005161
  • Mudalagiriyappa S, Sharma J, Vieson MD, et al. GM-CSF(+) Tc17 cells are required to bolster vaccine immunity against lethal fungal pneumonia without causing overt pathology. Cell Rep. 2022;41(4):111543. doi: 10.1016/j.celrep.2022.111543
  • Bielinska AU, Gerber M, Blanco LP, et al. Induction of Th17 cellular immunity with a novel nanoemulsion adjuvant. Crit Rev Immunol. 2010;30(2):189–199. doi: 10.1615/critrevimmunol.v30.i2.60
  • Hirahara K, Kokubo K, Aoki A, et al. The role of CD4(+) resident memory T cells in local immunity in the mucosal tissue - protection versus pathology. Front Immunol. 2021;12:616309. doi: 10.3389/fimmu.2021.616309
  • Lin R, Zhang H, Yuan Y, et al. Fatty acid oxidation controls CD8(+) tissue-resident memory T-cell Survival in gastric adenocarcinoma. Cancer Immunol Res. 2020;8(4):479–492. doi: 10.1158/2326-6066.CIR-19-0702
  • de Vries, NL, van Unen V, Ijsselsteijn ME, et al. High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut. 2020;69(4):691–703. doi: 10.1136/gutjnl-2019-318672
  • Buggert M, Nguyen S, Salgado-Montes de Oca G, et al. Identification and characterization of HIV-specific resident memory CD8(+) T cells in human lymphoid tissue. Sci Immunol. 2018;3(24): doi: 10.1126/sciimmunol.aar4526
  • Smith NM, Wasserman GA, Coleman FT, et al. Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol. 2018;11(1):220–235. doi: 10.1038/mi.2017.43
  • Ogongo P, Porterfield JZ, Leslie A. Lung tissue resident memory T-Cells in the immune response to mycobacterium tuberculosis. Front Immunol. 2019;10:992. doi: 10.3389/fimmu.2019.00992
  • Szabo PA, Dogra P, Gray JI, et al. Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis. medRxiv. 2020. doi: 10.1101/2020.10.15.20208041
  • Iijima N, Iwasaki A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014;346(6205):93–98. doi: 10.1126/science.1257530
  • O’Hara JM, Redhu NS, Cheung E, et al. Generation of protective pneumococcal-specific nasal resident memory CD4(+) T cells via parenteral immunization. Mucosal Immunol. 2020;13(1):172–182. doi: 10.1038/s41385-019-0218-5
  • Zens KD, Chen JK, Farber DL. Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection. JCI Insight. 2016;1(10). doi: 10.1172/jci.insight.85832
  • Zhao J, Zhao J, Mangalam AK, et al. Airway memory CD4(+) T cells mediate protective immunity against emerging respiratory coronaviruses. Immunity. 2016;44(6):1379–1391. doi: 10.1016/j.immuni.2016.05.006
  • Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol. 2021;21(2):83–100. doi: 10.1038/s41577-020-00479-7
  • Squier CA, Mantz MJ, Schlievert PM, et al. Porcine vagina ex vivo as a model for studying permeability and pathogenesis in mucosa. J Pharm Sci. 2008;97(1):9–21. doi: 10.1002/jps.21077
  • Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–384. doi: 10.1038/ni.1863
  • van Egmond M, Damen CA, van Spriel AB, et al. IgA and the IgA fc receptor. Trends Immunol. 2001;22(4):205–211. doi: 10.1016/s1471-4906(01)01873-7
  • Bruder MC, Spanhaak S, Bruijntjes JP, et al. Intestinal T lymphocytes of different rat strains in immunotoxicity. Toxicol Pathol. 1999;27(2):171–179. doi: 10.1177/019262339902700204
  • Church JA, Parker EP, Kirkpatrick BD, et al. Interventions to improve oral vaccine performance: a systematic review and meta-analysis. Lancet Infect Dis. 2019;19(2):203–214. doi: 10.1016/S1473-3099(18)30602-9
  • Zimmermann P, Curtis N. The influence of probiotics on vaccine responses - a systematic review. Vaccine. 2018;36(2):207–213. doi: 10.1016/j.vaccine.2017.08.069
  • Woof JM, Mestecky J. Mucosal immunoglobulins. Immunol Rev. 2005;206(1):64–82. doi: 10.1111/j.0105-2896.2005.00290.x
  • Elson CO, Cong Y, McCracken VJ, et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206(1):260–276. doi: 10.1111/j.0105-2896.2005.00291.x
  • Lajeunesse M, Zhang Q, Finn A. Mucosal immunity to infections and its importance in future vaccinology. Adv Exp Med Biol. 2004;549:13–22. doi: 10.1007/978-1-4419-8993-2_4
  • Thwaites RS, Jarvis HC, Singh N, et al. Absorption of nasal and bronchial fluids: precision sampling of the human respiratory mucosa and laboratory processing of samples. J Vis Exp. 2018;(131). doi: 10.3791/56413
  • Wolsk HM, Chawes BL, Thorsen J, et al. Noninvasive sampling of mucosal lining fluid for the quantification of in vivo upper airway immune-mediator levels. J Vis Exp. 2017;(126). doi: 10.3791/55800
  • Holmgren J, Parashar UD, Plotkin S, et al. Correlates of protection for enteric vaccines. Vaccine. 2017;35(26):3355–3363. doi: 10.1016/j.vaccine.2017.05.005
  • Aase A, Sommerfelt H, Petersen LB, et al. Salivary IgA from the sublingual compartment as a novel noninvasive proxy for intestinal immune induction. Mucosal Immunol. 2016;9(4):884–893. doi: 10.1038/mi.2015.107
  • Ahren C, Jertborn M, Svennerholm AM. Intestinal immune responses to an inactivated oral enterotoxigenic Escherichia coli vaccine and associated immunoglobulin a responses in blood. Infect Immun. 1998;66(7):3311–3316. doi: 10.1128/IAI.66.7.3311-3316.1998
  • Kantele A. Peripheral blood antibody-secreting cells in the evaluation of the immune response to an oral vaccine. J Biotechnol. 1996;44(1–3):217–224. doi: 10.1016/0168-1656(95)00134-4
  • Saletti G, Cuburu N, Yang JS, et al. Enzyme-linked immunospot assays for direct ex vivo measurement of vaccine-induced human humoral immune responses in blood. Nat Protoc. 2013;8(6):1073–1087. doi: 10.1038/nprot.2013.058
  • Chang HS, Sack DA. Development of a novel in vitro assay (ALS assay) for evaluation of vaccine-induced antibody secretion from circulating mucosal lymphocytes. Clin Diagn Lab Immunol. 2001;8(3):482–488. doi: 10.1128/CDLI.8.3.482-488.2001
  • Anosova NG, Chabot S, Shreedhar V, et al. Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer’s patches. Mucosal Immunol. 2008;1(1):59–67. doi: 10.1038/mi.2007.7
  • Liang S, Hajishengallis G. Heat-labile enterotoxins as adjuvants or anti-inflammatory agents. Immunol Invest. 2010;39(4–5):449–467. doi: 10.3109/08820130903563998
  • Fukuyama Y, Okada K, Yamaguchi M, et al. Nasal administration of cholera toxin as a mucosal adjuvant damages the olfactory system in mice. PLoS One. 2015;10(9):e0139368. doi: 10.1371/journal.pone.0139368
  • Levine MM, Kaper JB, Black RE, et al. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol Rev. 1983;47(4):510–550. doi: 10.1128/mr.47.4.510-550.1983
  • Freytag LC, Clements JD. Bacterial toxins as mucosal adjuvants. Curr Top Microbiol Immunol. 1999;236:215–236. doi: 10.1007/978-3-642-59951-4_11
  • Pizza M, Giuliani MM, Fontana MR, et al. Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants. Vaccine. 2001;19(17–19):2534–2541. doi: 10.1016/s0264-410x(00)00553-3
  • Freytag LC, Clements JD. Mucosal adjuvants. Vaccine. 2005;23(15):1804–1813. doi: 10.1016/j.vaccine.2004.11.010
  • van Ginkel, FW, Jackson RJ, Yoshino N, et al. Enterotoxin-based mucosal adjuvants alter antigen trafficking and induce inflammatory responses in the nasal tract. Infect Immun. 2005;73(10):6892–6902. doi: 10.1128/IAI.73.10.6892-6902.2005
  • Mori I, Komatsu T, Takeuchi K, et al. Parainfluenza virus type 1 infects olfactory neurons and establishes long-term persistence in the nerve tissue. J Gen Virol. 1995;76(Pt 5):1251–1254. doi: 10.1099/0022-1317-76-5-1251
  • van den Brand JM, Stittelaar KJ, van Amerongen G, et al. Comparison of temporal and spatial dynamics of seasonal H3N2, pandemic H1N1 and highly pathogenic avian influenza H5N1 virus infections in ferrets. PLoS One. 2012;7(8):e42343. doi: 10.1371/journal.pone.0042343
  • Cheng Q, Yang Y, Gao J. Infectivity of human coronavirus in the brain. EBioMedicine. 2020;56:102799. doi: 10.1016/j.ebiom.2020.102799
  • Huang J, Zheng M, Tang X, et al. Potential of SARS-CoV-2 to cause CNS infection: biologic fundamental and clinical experience. Front Neurol. 2020;11:659. doi: 10.3389/fneur.2020.00659
  • van Riel D, Verdijk R, Kuiken T. The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. J Pathol. 2015;235(2):277–287. doi: 10.1002/path.4461
  • Jerusalmi A, Morris-Downes MM, Sheahan BJ, et al. Effect of intranasal administration of Semliki Forest virus recombinant particles expressing reporter and cytokine genes on the progression of experimental autoimmune encephalomyelitis. Mol Ther. 2003;8(6):886–894. doi: 10.1016/j.ymthe.2003.09.010
  • Kong IG, Sato A, Yuki Y, et al. Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by streptococcus pneumoniae. Infect Immun. 2013;81(5):1625–1634. doi: 10.1128/IAI.00240-13
  • Fukuyama Y, Yuki Y, Katakai 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. 2015;8(5):1144–1153. doi: 10.1038/mi.2015.5