Mucosal Vaccine Platforms for Respiratory and Enteric Pathogens: Current Advances, Key Barriers, and Translational Opportunities
DOI:
https://doi.org/10.64229/hbskck72Keywords:
Mucosal vaccines, Respiratory pathogens, Enteric pathogens, Mucosal immunity, Vaccine delivery systems, Clinical translation, Intranasal vaccines, Oral vaccinesAbstract
Respiratory and enteric pathogens cause significant global morbidity and mortality, transmitting efficiently across mucosal surfaces. Conventional injectable vaccines primarily induce systemic immunity, offering limited protection at these entry sites. Mucosal vaccination is a promising strategy to elicit local and systemic immunity, particularly secretory immunoglobulin A (IgA) and tissue-resident memory T cells, which block infection and reduce transmission. Licensed mucosal vaccines, including intranasal influenza (FluMist), oral rotavirus (Rotarix/RotaTeq), oral polio, and oral cholera (Dukoral) vaccines, demonstrate the feasibility of this approach. This review summarizes the immunological basis of mucosal immunity and evaluates delivery routes like intranasal and oral administration. A systematic search of PubMed, Scopus, and Web of Science (Jan 2020-Mar 2026) was conducted. Major vaccine platforms__live attenuated vectors, protein subunits, and nucleic acid-based systems__are discussed alongside adjuvants, nanoparticles, and bioadhesive formulations. Applications to key respiratory (influenza, SARS-CoV-2, RSV, Mycobacterium tuberculosis) and enteric (Shigella, ETEC, Campylobacter, rotavirus) pathogens are highlighted. Critical barriers include mucosal tolerance, antigen degradation, and manufacturing complexity. Emerging innovations in mRNA technology, synthetic biology, and artificial intelligence offer new opportunities to overcome these obstacles, enhancing herd immunity and global control of infections.
References
[1]Ecarnot F, Maggi S. Vaccination against respiratory infections in the immunosenescent older adult population: Challenges and opportunities. Seminars in Respiratory and Critical Care Medicine, 2025, 46(1), 53-62. DOI: 10.1055/a-2500-2121
[2]Torres A, Cilloniz C, Aldea M, Mena G, Miró JM, Trilla A, et al. Adult vaccinations against respiratory infections. Expert Review of Anti-infective Therapy, 2025, 23(2-4), 135-147. DOI: 10.1080/14787210.2025.2457464
[3]Chattha KS, Roth JA, Saif LJ. Strategies for design and application of enteric viral vaccines. Annual Review of Animal Biosciences, 2014, 3(1), 375-395. DOI: 10.1146/annurev-animal-022114-111038
[4]Sunagar R, Singh A, Kumar S. SARS-CoV-2: Immunity, challenges with current vaccines, and a novel perspective on mucosal vaccines. Vaccines, 2023, 11(4), 849. DOI: 10.3390/vaccines11040849
[5]Sutter RW, Kew OM, Cochi SL. Poliovirus vaccine – live. Elsevier, 2018, 866-917. DOI: 10.1016/B978-0-323-35761-6.00048-1
[6]Burnett E, Parashar UD, Tate JE. Rotavirus vaccines: Effectiveness, safety, and future directions. Pediatric Drugs, 2018, 20(3), 223-233. DOI: 10.1007/s40272-018-0283-3
[7]Carter NJ, Curran MP. Live attenuated influenza vaccine (FluMist®; Fluenz™): A review of its use in the prevention of seasonal influenza in children and adults. Drugs, 2011, 71(12), 1591-622. DOI: 10.2165/11206860-000000000-00000
[8]Clemens JD, Sack DA, Harris JR, Van Loon F, Chakraborty J, Ahmed F, et al. Field trial of oral cholera vaccines in Bangladesh: Results from three-year follow-up. Lancet, 1990, 335(8684), 270-273. DOI: 10.1016/0140-6736(90)90080-O
[9]Anggraeni R, Ana ID, Wihadmadyatami H. Development of mucosal vaccine delivery: An overview on the mucosal vaccines and their adjuvants. Clinical and Experimental Vaccine Research, 2022, 11(3), 235-248. DOI: 10.7774/cevr.2022.11.3.235
[10]Nian X, Zhang J, Huang S, Duan K, Li X, Yang X. Development of nasal vaccines and the associated challenges. Pharmaceutics, 2022, 14(10), 1983. DOI: 10.3390/pharmaceutics14101983
[11]Wang J, Thorson L, Stokes RW, Santosuosso M, Huygen K, Zganiacz A, et al. Single mucosal, but not parenteral, immunization with recombinant adenoviral-based vaccine provides potent protection from pulmonary tuberculosis. Journal of Immunology, 2004, 173(10), 6357-6365. DOI: 10.4049/jimmunol.173.10.6357
[12]Cesta MF. Normal structure, function, and histology of mucosa-associated lymphoid tissue. Toxicologic Pathology, 2006, 34(5), 599-608. DOI: 10.1080/01926230600865531
[13]Jang MH, Kweon M-N, Iwatani K, Yamamoto M, Terahara K, Sasakawa C, et al. Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proceedings of the National Academy of Sciences, 2004, 101(16), 6110-6115. DOI: 10.1073/pnas.0400969101
[14]Kuper CF. Histopathology of mucosa-associated lymphoid tissue. Toxicologic Pathology, 2006, 34(5), 609-615. DOI: 10.1080/01926230600867735
[15]Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology, 2000, 68(1), 1-8. DOI: 10.1159/000028109
[16]Randall TD. Bronchus-associated lymphoid tissue (BALT) structure and function. Advances in Immunology, 2010, 107, 187-241. DOI: 10.1016/B978-0-12-381300-8.00007-1
[17]Yuki Y, Kiyono H. New generation of mucosal adjuvants for the induction of protective immunity. Reviews in Medical Virology, 2003, 13(5), 293-310. DOI: 10.1002/rmv.398
[18]Nochi T, Kiyono H. Innate immunity in the mucosal immune system. Current Pharmaceutical Design, 2006, 12(32), 4203-4213. DOI: 10.2174/138161206778743457
[19]Oh JE, Song E, Moriyama M, Wong P, Zhang S, Jiang R, et al. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Science Immunology, 2021, 6(66), eabj5129. DOI: 10.1126/sciimmunol.abj5129
[20]Cheon IS, Son YM, Sun J. Tissue-resident memory T cells and lung immunopathology. Immunological Reviews, 2023, 316(1), 63-83. DOI: 10.1111/imr.13201
[21]Luangrath MA, Schmidt ME, Hartwig SM, Varga SM. Tissue-resident memory T cells in the lungs protect against acute respiratory syncytial virus infection. ImmunoHorizons, 2021, 5(2), 59-69. DOI: 10.4049/immunohorizons.2000067
[22]Wilk MM, Misiak A, Mcmanus RM, Allen AC, Lynch MA, Mills KHG. Lung CD4 tissue-resident memory T cells mediate adaptive immunity induced by previous infection of mice with Bordetella pertussis. Journal of Immunology, 2017, 199(1), 233-243. DOI: 10.4049/jimmunol.1602051
[23]Xie D, Lu G, Mai G, Guo Q, Xu G. Tissue-resident memory T cells in diseases and therapeutic strategies. MedComm, 2025, 6(1), e70053. DOI: 10.1002/mco2.70053
[24]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), e85832. DOI: 10.1172/jci.insight.85832
[25]Nathan A, Asgari S, Ishigaki K, Valencia C, Amariuta T, Luo Y, et al. Single cell eQTL models reveal dynamic T cell state dependence of disease loci. Nature, 2022, 606(7912), 120-128. DOI: 10.1038/s41586-022-04713-1
[26]Ogongo P, Porterfield JZ, Leslie A. Lung tissue resident memory T cells in the immune response to Mycobacterium tuberculosis. Frontiers in Immunology, 2019, 10, 992. DOI: 10.3389/fimmu.2019.00992
[27]Poon MML, Rybkina K, Kato Y, Kubota M, Matsumoto R, Bloom NI, et al. SARS-CoV-2 infection generates tissue-localized immunological memory in humans. Science Immunology, 2021, 6(65), eabl9105. DOI: 10.1126/sciimmunol.abl9105
[28]Afkhami S, D'Agostino MR, Zhang A, Stacey HD, Marzok A, Kang A, 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, 2022, 185(5), 896-915.e19. DOI: 10.1016/j.cell.2022.02.005
[29]Pizzolla A, Nguyen TH, Sant S, Jaffar J, Loudovaris T, Mannering SI, et al. Influenza specific lung resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles. Journal of Clinical Investigation, 2018, 128(2), 721-733. DOI: 10.1172/JCI96957
[30]Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell, 2021, 184(4), 861-880. DOI: 10.1016/j.cell.2021.01.007
[31]Nachbagauer R, Krammer F. Universal influenza virus vaccines and therapeutic antibodies. Clinical Microbiology and Infection, 2017, 23(4), 222-228. DOI: 10.1016/j.cmi.2017.02.009
[32]Krammer F. The role of vaccines in the COVID-19 pandemic: what have we learned? Seminars in Immunopathology, 2024, 45(4-6), 451-468. DOI: 10.1007/s00281-023-00996-2
[33]McCool RS, Musayev M, Bush SM, Derrien-Colemyn A, Acreman CM, Wrapp D, et al. Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein elicits antibodies targeting a membrane-proximal epitope. Journal of Virology, 2023, 97(10), e0092923. DOI: 10.1128/jvi.00929-23
[34]Mazur NI, Terstappen J, Baral R, Bardají A, Beutels P, Buchholz UJ, et al. Respiratory syncytial virus prevention within reach: The vaccine and monoclonal antibody landscape. Lancet Infectious Diseases, 2023, 23(1), e2-e21. DOI: 10.1016/S1473-3099(22)00291-2
[35]Andersen P, Scriba TJ. Moving tuberculosis vaccines from theory to practice. Nature Reviews Immunology, 2023, 23(8), 511-525. DOI: 10.1038/s41577-023-00854-5
[36]Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. The New England Journal of Medicine, 2006, 354(1), 11-22. DOI: 10.1056/NEJMoa052434
[37]Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus vaccines: How well will they work where they are needed most? Journal of Infectious Diseases, 2009, 200(Suppl 1), S39-S48. DOI: 10.1086/605035
[38]Svennerholm AM, Qadri F, Lundgren A, Kaim J, Rahman Bhuiyan T, Akhtar M, et al. Induction of mucosal and systemic immune responses against the common O78 antigen of an oral inactivated ETEC vaccine in Bangladeshi children and infants. Vaccine, 2022, 40(2), 380-389. DOI: 10.1016/j.vaccine.2021.10.056
[39]Norton EB, Lawson LB, Freytag LC, Clements JD. Characterization of a mutant Escherichia coli heat labile toxin, LT(R192G/L211A), as a safe and effective oral adjuvant. Clinical and Vaccine Immunology, 2011, 18(4), 546-551. DOI: 10.1128/CVI.00538-10
[40]Talaat KR, Alaimo C, Martin P, Bourgeois AL, Dreyer AM, Kaminski RW, et al. Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection. EBioMedicine, 2021, 66, 103310. DOI: 10.1016/j.ebiom.2021.103310
[41]Cohen D, Ashkenazi S, Green MS, Gdalevich M, Robin G, Slepon R, et al. Double blind vaccine controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults. Lancet, 1997, 349(9046), 155-159. DOI: 10.1016/S0140-6736(96)06255-1
[42]Peng T, Phasouk K, Sodroski CN, Sun S, Hwangbo Y, Layton ED, et al. Tissue resident memory CD8+ T cells bridge innate immune responses in neighboring epithelial cells to control human genital herpes. Frontiers in Immunology, 2021, 12, 735643. DOI: 10.3389/fimmu.2021.735643
[43]Hellfritzsch M, Scherließ R. Mucosal vaccination via the respiratory tract. Pharmaceutics, 2019, 11(8), 375. DOI: 10.3390/pharmaceutics11080375
[44]Xu Y, Yuen PW, Lam JK. Intranasal DNA vaccine for protection against respiratory infectious diseases: The delivery perspectives. Pharmaceutics, 2014, 6(3), 378-415. DOI: 10.3390/pharmaceutics6030378
[45]Fu W, Guo M, Zhou X, Wang Z, Sun J, An Y, et al. Injectable hydrogel mucosal vaccine elicits protective immunity against respiratory viruses. ACS Nano, 2024, 18(17), 11200-11216. DOI: 10.1021/acsnano.4c00155
[46]Ochsner SP, Li W, Rajendrakumar AM, Palaniyandi S, Acharya G, Liu X, et al. FcRn Targeted mucosal vaccination against influenza virus infection. Journal of Immunology, 2021, 207(5), 1310-1321. DOI: 10.4049/jimmunol.2100297
[47]Lei H, Hong W, Yang J, He C, Zhou Y, Zhang Y, et al. Intranasal delivery of a subunit protein vaccine provides protective immunity against JN.1 and XBB lineage variants. Signal Transduction and Targeted Therapy, 2024, 9(1), 311. DOI: 10.1038/s41392-024-02025-6
[48]Kwon DI, Mao T, Israelow B, Santos Guedes de Sá K, Dong H, Iwasaki A. Mucosal unadjuvanted booster vaccines elicit local IgA responses by conversion of pre existing immunity in mice. Nature Immunology, 2025, 26(6), 908-919. DOI: 10.1038/s41590-025-02156-0
[49]Moriyama M, Rodrigues G, Wang J, Jayewickreme R, Hudak A, Dong H, et al. Intranasal hemagglutinin protein boosters induce protective mucosal immunity against influenza A viruses in mice. Proceedings of the National Academy of Sciences USA, 2025, 122(39), e2422171122. DOI: 10.1073/pnas.2422171122
[50]Santosuosso M, McCormick S, Zhang X, Zganiacz A, Xing Z. Intranasal boosting with an adenovirus vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infection and Immunity, 2006, 74(8), 4634-4643. DOI: 10.1128/IAI.00517-06
[51]Holmgren J. Mucosal immunity and vaccination. FEMS Immunology and Medical Microbiology, 1991, 4(1), 1-9. DOI: 10.1111/j.1574-6968.1991.tb04964.x
[52]Takaiwa F, Wakasa Y, Takagi H, Hiroi T. Rice seed for delivery of vaccines to gut mucosal immune tissues. Plant Biotechnology Journal, 2015, 13(8), 1041-1055. DOI: 10.1111/pbi.12423
[53]Van Der Weken H, Cox E, Devriendt B. Advances in oral subunit vaccine design. Vaccines (Basel), 2020, 9(1), 1. DOI: 10.3390/vaccines9010001
[54]Azizi A, Kumar A, Diaz Mitoma F, Mestecky J. Enhancing oral vaccine potency by targeting intestinal M cells. PLOS Pathogens, 2010, 6(11), e1001147. DOI: 10.1371/journal.ppat.1001147
[55]Rochereau N, Drocourt D, Perouzel E, Pavot V, Redelinghuys P, Brown GD, et al. Dectin 1 is essential for reverse transcytosis of glycosylated SIgA antigen complexes by intestinal M cells. PLOS Biology, 2013, 11(9), e1001658. DOI: 10.1371/journal.pbio.1001658
[56]Platt LR, Estívariz CF, Sutter RW. Vaccine associated paralytic poliomyelitis: A review of the epidemiology and estimation of the global burden. Journal of Infectious Diseases, 2014, 210(Suppl 1), S380-S389. DOI: 10.1093/infdis/jiu184
[57]Bi Q, Ferreras E, Pezzoli L, Legros D, Ivers LC, Date K, et al. Protection against cholera from killed whole cell oral cholera vaccines: A systematic review and meta analysis. Lancet Infectious Diseases, 2017, 17(10), 1080-1088. DOI: 10.1016/S1473-3099(17)30359-6
[58]Czerkinsky C, Holmgren J. Mucosal delivery routes for optimal immunization: Targeting immunity to the right tissues. Current Topics in Microbiology and Immunology, 2010, 354, 1-18. DOI: 10.1007/82_2010_112
[59]Huo Z, Bissett SL, Giemza R, Beddows S, Oeser C, Lewis DJM. Systemic and mucosal immune responses to sublingual or intramuscular human papilloma virus antigens in healthy female volunteers. PLoS ONE, 2012, 7(3), e33736. DOI: 10.1371/journal.pone.0033736
[60]Czerkinsky C, Çuburu N, Kweon MN, Anjuere F, Holmgren J. Sublingual vaccination. Human Vaccines, 2011, 7(1), 110-114. DOI: 10.4161/hv.7.1.13739
[61]Jacob S, Nair AB, Boddu SHS, Gorain B, Sreeharsha N, Shah J. An updated overview of the emerging role of patch and film based buccal delivery systems. Pharmaceutics, 2021, 13(8), 1206. DOI: 10.3390/pharmaceutics13081206
[62]Mokabari K, Iriti M, Varoni EM. Mucoadhesive vaccine delivery systems for the oral mucosa. Journal of Dental Research, 2023, 102(7), 709-718. DOI: 10.1177/00220345231164111
[63]Trincado V, Gala RP, Morales JO. Buccal and sublingual vaccines: A review on oral mucosal immunization and delivery systems. Vaccines (Basel), 2021, 9(10), 1177. DOI: 10.3390/vaccines9101177
[64]Brako F, Boateng J. Transmucosal drug delivery: Prospects, challenges, advances, and future directions. Expert Opinion on Drug Delivery, 2025, 22(4), 525-553. DOI: 10.1080/17425247.2025.2470224
[65]Hua S. Advances in nanoparticulate drug delivery approaches for sublingual and buccal administration. Frontiers in Pharmacology, 2019, 10, 1328. DOI: 10.3389/fphar.2019.01328
[66]Sohi H, Ahuja A, Ahmad FJ, Khar RK. Critical evaluation of permeation enhancers for oral mucosal drug delivery. Drug Development and Industrial Pharmacy, 2010, 36(3), 254-282. DOI: 10.3109/03639040903117348
[67]Detmer A, Glenting J. Live bacterial vaccines – a review and identification of potential hazards. Microbial Cell Factories, 2006, 5, 23. DOI: 10.1186/1475-2859-5-23
[68]Garmory HS, Leary SE, Griffin KF, Williamson ED, Brown KA, Titball RW. The use of live attenuated bacteria as a delivery system for heterologous antigens. Journal of Drug Targeting, 2003, 11(8-10), 471-479. DOI: 10.1080/10611860410001670008
[69]Kotton CN, Hohmann EL. Enteric pathogens as vaccine vectors for foreign antigen delivery. Infection and Immunity, 2004, 72(10), 5535-5547. DOI: 10.1128/IAI.72.10.5535-5547.2004
[70]Lin I, Van T, Smooker P. Live attenuated bacterial vectors: Tools for vaccine and therapeutic agent delivery. Vaccines (Basel), 2015, 3(4), 940-972. DOI: 10.3390/vaccines3040940
[71]Tarahomjoo S. Development of vaccine delivery vehicles based on lactic acid bacteria. Molecular Biotechnology, 2011, 51(2), 183-199. DOI: 10.1007/s12033-011-9450-2
[72]Daudel D, Weidinger G, Spreng S. Use of attenuated bacteria as delivery vectors for DNA vaccines. Expert Review of Vaccines, 2007, 6(1), 97-110. DOI: 10.1586/14760584.6.1.97
[73]Gherardi MM, Esteban M. Recombinant poxviruses as mucosal vaccine vectors. Journal of General Virology, 2005, 86(11), 2925-2936. DOI: 10.1099/vir.0.81181-0
[74]Galen JE, Pasetti MF, Tennant S, Ruiz-Olvera P, Sztein MB, Levine MM. Salmonella enterica serovar Typhi live vector vaccines finally come of age. Immunology & Cell Biology, 2009, 87(5), 400-412. DOI: 10.1038/icb.2009.31
[75]Ranasinghe C. New advances in mucosal vaccination. Immunology Letters, 2014, 161(2), 204-206. DOI: 10.1016/j.imlet.2014.01.006
[76]Koirala P, Shalash AO, Chen SR, Faruck MO, Wang J, Hussein WM, et al. Polymeric nanoparticles as oral and intranasal peptide vaccine delivery systems: The role of shape and conjugation. Vaccines (Basel), 2024, 12(2), 198. DOI: 10.3390/vaccines12020198
[77]Vajdy M, Srivastava I, Polo J, Donnelly J, O'Hagan D, Singh M. Mucosal adjuvants and delivery systems for protein, DNA and RNA based vaccines. Immunology & Cell Biology, 2004, 82(6), 617-627. DOI: 10.1111/j.1440-1711.2004.01288.x
[78]Wang S, Liu H, Zhang X, Qian F. Intranasal and oral vaccination with protein based antigens: Advantages, challenges and formulation strategies. Protein & Cell, 2015, 6(7), 480-503. DOI: 10.1007/s13238-015-0164-2
[79]Ongun M, Lokras AG, Baghel S, Shi Z, Schmidt ST, Franzyk H, et al. Lipid nanoparticles for local delivery of mRNA to the respiratory tract: Effect of PEG lipid content and administration route. European Journal of Pharmaceutics and Biopharmaceutics, 2024, 198, 114266. DOI: 10.1016/j.ejpb.2024.114266
[80]Zeng C, Zhang C, Walker PG, Dong Y. Formulation and delivery technologies for mRNA vaccines. Current Topics in Microbiology and Immunology, 2022, 440, 71-110. DOI: 10.1007/82_2020_217
[81]Omo-Lamai S, Wang Y, Patel MN, Milosavljevic A, Zuschlag D, Poddar S, et al. Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape. Nature Nanotechnology, 2025, 20(9), 1285-1297. DOI: 10.1038/s41565-025-01974-5
[82]Forenzo C, Larsen J. Complex coacervates as a promising vehicle for mRNA delivery: A comprehensive review of recent advances and challenges. Molecular Pharmacology, 2023, 20(9), 4387-4403. DOI: 10.1021/acs.molpharmaceut.3c00439
[83]Chadwick S, Kriegel C, Amiji M. Delivery strategies to enhance mucosal vaccination. Expert Opinion on Biological Therapy, 2009, 9(4), 427-440. DOI: 10.1517/14712590902849224
[84]Hameed SA, Paul S, Dellosa GKY, Jaraquemada D, Bello MB. Towards the future exploration of mucosal mRNA vaccines against emerging viral diseases; lessons from existing next generation mucosal vaccine strategies. NPJ Vaccines, 2022, 7(1), 1-15. DOI: 10.1038/s41541-022-00485-x
[85]Longet S, Lundahl MLE, Lavelle EC. Targeted strategies for mucosal vaccination. Bioconjugate Chemistry, 2018, 29(3), 613-623. DOI: 10.1021/acs.bioconjchem.7b00738
[86]Baldridge JR, McGowan P, Evans JT, Cluff C, Mossman S, Johnson D, et al. Taking a Toll on human disease: Toll like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opinion on Biological Therapy, 2004, 4(7), 1129-1138. DOI: 10.1517/14712598.4.7.1129
[87]Ebrahimian M, Hashemi M, Maleki M, Hashemitabar G, Abnous K, Ramezani M, et al. Co delivery of dual Toll like receptor agonists and antigen in poly(Lactic Co Glycolic) acid/polyethylenimine cationic hybrid nanoparticles promote efficient in vivo immune responses. Frontiers in Immunology, 2017, 8, 1077. DOI: 10.3389/fimmu.2017.01077
[88]Guo X, Wu N, Shang Y, Liu X, Wu T, Zhou Y, et al. The novel Toll like receptor 2 agonist SUP3 enhances antigen presentation and T cell activation by dendritic cells. Frontiers in Immunology, 2017, 8, 158. DOI: 10.3389/fimmu.2017.00158
[89]Kayesh MEH, Kohara M, Tsukiyama Kohara K. TLR agonists as vaccine adjuvants in the prevention of viral infections: An overview. Frontiers in Microbiology, 2023, 14, 1249718. DOI: 10.3389/fmicb.2023.1249718
[90]Kokatla HP, Sil D, Tanji H, Ohto U, Malladi SS, Fox LM, et al. Structure based design of novel human Toll like receptor 8 agonists. ChemMedChem, 2014, 9(4), 719-723. DOI: 10.1002/cmdc.201300573
[91]Kumar S, Sunagar R, Gosselin E. Bacterial protein toll like receptor agonists: A novel perspective on vaccine adjuvants. Frontiers in Immunology, 2019, 10, 1144. DOI: 10.3389/fimmu.2019.01144
[92]Shanmugam A, Rajoria S, George AL, Mittelman A, Suriano R, Tiwari RK. Synthetic Toll like receptor 4 (TLR 4) agonist peptides as a novel class of adjuvants. PLoS ONE, 2012, 7(2), e30839. DOI: 10.1371/journal.pone.0030839
[93]Liong CS, Smith AAA, Mann JL, Roth GA, Gale EC, Maikawa C, et al. Enhanced humoral immune response by high density TLR agonist presentation on hyperbranched polymers. Advances in Therapy, 2021, 4(4), 2000081. DOI: 10.1002/adtp.202000081
[94]Ou BS, Baillet J, Filsinger Interrante MV, Adamska JZ, Zhou X, Saouaf OM, et al. Saponin nanoparticle adjuvants incorporating Toll like receptor agonists drive distinct immune signatures and potent vaccine responses. Science Advances, 2024, 10(32), eadn7187. DOI: 10.1126/sciadv.adn7187
[95]Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland. The New England Journal of Medicine, 2004, 350(9), 896-903. DOI: 10.1056/NEJMoa030595
[96]Lewis DJ, Huo Z, Barnett S, Kromann I, Giemza R, Galiza E, et al. Transient facial nerve paralysis (Bell's palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS ONE, 2009, 4(9), e6999. DOI: 10.1371/journal.pone.0006999
[97]Illum L. Nasal drug delivery – recent developments and future prospects. Journal of Controlled Release, 2012, 161(2), 254-263. DOI: 10.1016/j.jconrel.2012.01.024
[98]Kim SH, Jang YS. Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines. Experimental & Molecular Medicine, 2014, 46(3), e85. DOI: 10.1038/emm.2013.165
[99]Clements JD, Norton EB. The mucosal vaccine adjuvant LT(R192G/L211A) or dmLT. mSphere, 2018, 3(4), e00215-18. DOI: 10.1128/mSphere.00215-18
[100]Bolhassani A, Javanzad S, Saleh T, Hashemi M, Aghasadeghi MR, Sadat SM. Polymeric nanoparticles. Human Vaccines & Immunotherapeutics, 2013, 10(2), 321-332. DOI: 10.4161/hv.26796
[101]Ghaffar K, Giddam A, Zaman M, Skwarczynski M, Toth I. Liposomes as nanovaccine delivery systems. Current Topics in Medicinal Chemistry, 2014, 14(9), 1194-1208. DOI: 10.2174/1568026614666140329232757
[102]Musacchio T, Torchilin VP. Recent developments in lipid based pharmaceutical nanocarriers. Frontiers in Bioscience, 2011, 16(4), 1388-1412. DOI: 10.2741/3795
[103]Cho CS, Hwang SK, Gu MJ, Kim CG, Kim SK, Ju DB et al. Mucosal vaccine delivery using mucoadhesive polymer particulate systems. Tissue Engineering and Regenerative Medicine, 2021, 18(5), 693-712. DOI: 10.1007/s13770-021-00373-w
[104]Garg NK, Mangal S, Khambete H, Tyagi RK. Mucosal delivery of vaccines: Role of mucoadhesive/biodegradable polymers. Recent Advances in Drug Delivery and Formulation, 2010, 4(2), 114-128. DOI: 10.2174/187221110791185015
[105]Mishra N, Goyal AK, Tiwari S, Paliwal R, Paliwal SR, Vaidya B, et al. Recent advances in mucosal delivery of vaccines: Role of mucoadhesive/biodegradable polymeric carriers. Expert Opinion on Therapeutic Patents, 2010, 20(5), 661-679. DOI: 10.1517/13543771003730425
[106]Shim S, Yoo HS. The application of mucoadhesive chitosan nanoparticles in nasal drug delivery. Marine Drugs, 2020, 18(12), 605. DOI: 10.3390/md18120605
[107]Smith A, Perelman M, Hinchcliffe M. Chitosan: A promising safe and immune-enhancing adjuvant for intranasal vaccines. Human Vaccines & Immunotherapeutics, 2014, 10(3), 797-807. DOI: 10.4161/hv.27449
[108]Ambrose CS, Levin MJ, Belshe RB. The relative efficacy of live attenuated and inactivated influenza vaccines in children and adults. Influenza and Other Respiratory Viruses, 2011, 5(2), 67-75. DOI: 10.1111/j.1750-2659.2010.00183.x
[109]Sui Y, Li J, Zhang R, Prabhu SK, Andersen H, Venzon D, et al. Protection against SARS CoV 2 infection by a mucosal vaccine in rhesus macaques. JCI Insight, 2021, 6(10), e148494. DOI: 10.1172/jci.insight.148494
[110]Chen J, Wang P, Yuan L, Zhang L, Zhang L, Zhao H, et al. A live attenuated virus based intranasal COVID 19 vaccine provides rapid, prolonged, and broad protection against SARS CoV 2. Science Bulletin, 2022, 67(13), 1372-1387. DOI: 10.1016/j.scib.2022.05.018
[111]Zhang L, Jiang Y, He J, Chen J, Qi R, Yuan L, et al. Intranasal influenza vectored COVID 19 vaccine restrains the SARS CoV 2 inflammatory response in hamsters. Nature Communications, 2023, 14(1), 4117. DOI: 10.1038/s41467-023-39560-9
[112]Afkhami S, D'Agostino MR, Zhang A, Stacey HD, Marzok A, Kang A, 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, 2022, 185(5), 896-915.e19. DOI: 10.1016/j.cell.2022.02.005
[113]Xing M, Hu G, Wang X, Wang YH, He FR, Dai WQ, et al. An intranasal combination vaccine induces systemic and mucosal immunity against COVID 19 and influenza. NPJ Vaccines, 2024, 9(1), 64. DOI: 10.1038/s41541-024-00857-5
[114]Kampmann B, Madhi SA, Munjal I, Simões EAF, Pahud BA, Llapur C, et al. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants. The New England Journal of Medicine, 2023, 388(16), 1451-1464. DOI: 10.1056/NEJMoa2216480
[115]Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced respiratory syncytial virus disease. Clinical and Vaccine Immunology, 2015, 23(3), 189-195. DOI: 10.1128/CVI.00609-15
[116]Tameris M, Mearns H, Penn Nicholson A, Gregg Y, Bilek N, Mabwe B, et al. Live attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double blind dose escalation trial. The Lancet Respiratory Medicine, 2019, 7(9), 1-14. DOI: 10.1016/S2213-2600(19)30251-6
[117]Satti I, Meyer J, Harris SA, Thomas ZRM, Griffiths K, Antrobus RD, et al. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: A phase 1, double-blind, randomised controlled trial. The Lancet Infectious Diseases, 2014, 14, 939-946.
[118]Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, et al. Safety and immunogenicity of the recombinant Mycobacterium bovis BCG vaccine VPM1002 in HIV unexposed newborn infants in South Africa. Clinical and Vaccine Immunology, 2017, 24(2), e00439-16. DOI: 10.1128/CVI.00439-16
[119]Parker EP, Ramani S, Lopman BA, Church JA, Iturriza-Gómara M, Prendergast AJ, et al. Causes of impaired oral vaccine efficacy in developing countries. Future Microbiology, 2018, 13(1), 97-118. DOI: 10.2217/fmb-2017-0128
[120]Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human bovine (116E) rotavirus vaccine in Indian infants: A randomised, double blind, placebo controlled trial. Lancet, 2014, 383(9935), 2136-2143. DOI: 10.1016/S0140-6736(13)62630-6
[121]Guo M, Tao W, Flavell RA, Zhu S. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nature Reviews Gastroenterology & Hepatology, 2021, 18(4), 269-283. DOI: 10.1038/s41575-021-00416-6
[122]Song D, Moon H, Kang B. Porcine epidemic diarrhea: A review of current epidemiology and available vaccines. Clinical and Experimental Vaccine Research, 2015, 4(2), 166-176. DOI: 10.7774/cevr.2015.4.2.166
[123]Atmar RL, Estes MK. Norovirus vaccine development: Next steps. Expert Review of Vaccines, 2012, 11(9), 1023-1025. DOI: 10.1586/erv.12.78
[124]O'Ryan M, Vidal R, Del Canto F, Salazar JC, Montero D. Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines for Shigella, Salmonella, enterotoxigenic E. coli (ETEC) enterohemorragic E. coli (EHEC) and Campylobacter jejuni. Human Vaccines & Immunotherapeutics, 2015, 11(3), 601-619. DOI: 10.1080/21645515.2015.1011578
[125]Seo H, Duan Q, Zhang W. Vaccines against gastroenteritis, current progress and challenges. Gut Microbes, 2020, 11(6), 1486-1517. DOI: 10.1080/19490976.2020.1770666
[126]Woodrow KA, Bennett KM, Lo DD. Mucosal vaccine design and delivery. Annual Review of Biomedical Engineering, 2012, 14(1), 17-46. DOI: 10.1146/annurev-bioeng-071811-150054
[127]Ranallo RT, Barnoy S, Thakkar S, Urick T, Venkatesan MM. Developing live Shigella vaccines using λ Red recombineering. FEMS Immunology and Medical Microbiology, 2006, 47(3), 462-469. DOI: 10.1111/j.1574-695X.2006.00118.x
[128]Barry EM, Levine MM. A tale of two bacterial enteropathogens and one multivalent vaccine. Cellular Microbiology, 2019, 21(11), e13067. DOI: 10.1111/cmi.13067
[129]Turbyfill KR, Oaks EV, Kaminski RW, et al. A randomized, placebo controlled, phase 1 study to evaluate the safety and immunogenicity of an intranasal Shigella flexneri 2a InvaplexAR vaccine in healthy adults. Vaccine, 2024, 42(5), 1123-1134. DOI: 10.1016/j.vaccine.2024.01.045
[130]Liang H, Poncet D, Seydoux E, Rintala N, Maciel M, Ruiz S, et al. The TLR4 agonist adjuvant SLA SE promotes functional mucosal antibodies against a parenterally delivered ETEC vaccine. NPJ Vaccines, 2019, 4(1), 1-8. DOI: 10.1038/s41541-019-0116-6
[131]Uddin MS, Kaldis A, Menassa R, Ortiz Guluarte J, Barreda DR, Guan LL, et al. Mucosal immunization with spore based vaccines against Mannheimia Haemolytica enhances antigen specific immunity. Vaccines (Basel), 2024, 12(4), 375. DOI: 10.3390/vaccines12040375
[132]Poly F, Noll AJ, Riddle MS, Porter CK. Update on Campylobacter vaccine development. Human Vaccines & Immunotherapeutics, 2019, 15(6), 1389-1400. DOI: 10.1080/21645515.2018.1528410
[133]Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunology, 2022, 15(4), 678-688. DOI: 10.1038/s41385-022-00534-1
[134]Scott CL, Aumeunier AM, Mowat AM. Intestinal CD103⁺ dendritic cells: Master regulators of tolerance? Trends in Immunology, 2011, 32(9), 412-419. DOI: 10.1016/j.it.2011.06.003
[135]Iweala OI, Nagler CR. The microbiome and food allergy. Annual Review of Immunology, 2019, 37, 377-403. DOI: 10.1146/annurev-immunol-042718-041621
[136]Rezende RM, Weiner HL. Oral tolerance: An updated review. Immunological Reviews, 2022, 245, 29-37. DOI: 10.1016/j.imlet.2022.03.007
[137]Fujkuyama Y, Tokuhara D, Kataoka K, Gilbert RS, McGhee JR, Yuki Y, et al. Novel vaccine development strategies for inducing mucosal immunity. Expert Review of Vaccines, 2012, 11(3), 367-379. DOI: 10.1586/erv.11.196
[138]Gebril A, Alsaadi M, Acevedo R, Mullen AB, Ferro VA. Optimizing efficacy of mucosal vaccines. Expert Review of Vaccines, 2012, 11(9), 1139-1155. DOI: 10.1586/erv.12.81
[139]Rele S. COVID 19 vaccine development during pandemic: Gap analysis, opportunities, and impact on future emerging infectious disease development strategies. Human Vaccines & Immunotherapeutics, 2020, 17(4), 1122-1127. DOI: 10.1080/21645515.2020.1822136
[140]Das S, Chatterjee A, Manna J, Das Mandal SK, Maiti TK, Bhattacharyya TK. Systems integrated thermostable vaccine delivery: Converging cold chain free design, AI augmented formulation, and climate resilient infrastructure. Molecular Pharmacology, 2025, 22(12), 7285-7312. DOI: 10.1021/acs.molpharmaceut.5c01296
[141]Raut R, Shrestha R, Adhikari A, Fatima A, Naeem M. Revolutionizing veterinary vaccines: Overcoming cold chain barriers through thermostable and novel delivery technologies. Applied Microbiology, 2025, 5(3), 83. DOI: 10.3390/applmicrobiol5030083
[142]Damjanovic D, Zhang X, Mu J, Fe Medina M, Xing Z. Organ distribution of transgene expression following intranasal mucosal delivery of recombinant replication defective adenovirus gene transfer vector. Genetic Vaccines and Therapy, 2008, 6, 5. DOI: 10.1186/1479-0556-6-5
[143]Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. Journal of Immunology, 2004, 172(5), 2731-2738. DOI: 10.4049/jimmunol.172.5.2731
[144]Bartfeld S, Clevers H. Stem cell derived organoids and their application for medical research and patient treatment. Journal of Molecular Medicine, 2017, 95(7), 729-738. DOI: 10.1007/s00109-017-1531-7
[145]Lynn DJ, Benson SC, Lynn MA, Pulendran B. Modulation of immune responses to vaccination by the microbiota: Implications and potential mechanisms. Nature Reviews Immunology, 2022, 22(1), 33-46. DOI: 10.1038/s41577-021-00554-7
[146]Cone RA. Barrier properties of mucus. Advanced Drug Delivery Reviews, 2009, 61(2), 75-85. DOI: 10.1016/j.addr.2008.09.008
[147]Levine MM. Immunogenicity and efficacy of oral vaccines in developing countries: Lessons from a live cholera vaccine. BMC Biology, 2010, 8, 129. DOI: 10.1186/1741-7007-8-129
[148]Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: A randomised, placebo controlled phase 2b trial. Lancet, 2013, 381(9871), 1021-1028. DOI: 10.1016/S0140-6736(13)60177-4
[149]Haynes BF, Burton DR. Developing an HIV vaccine. Science, 2017, 355(6330), 1129-1130. DOI: 10.1126/science.aan0662
[150]Cai X, Li JJ, Liu T, Brian O, Li J. Infectious disease mRNA vaccines and a review on epitope prediction for vaccine design. Briefings in Functional Genomics, 2021, 20(5), 289-303. DOI: 10.1093/bfgp/elab027
[151]Rzymski P, Szuster Ciesielska A, Dzieciątkowski T, Gwenzi W, Fal A. mRNA vaccines: The future of prevention of viral infections? Journal of Medical Virology, 2023, 95(2), e28572. DOI: 10.1002/jmv.28572
[152]Zhou W, Jiang L, Liao S, Wu F, Yang G, Hou L, et al. Vaccines' new wra RNA vaccine. Viruses, 2023, 15(8), 1760. DOI: 10.3390/v15081760
[153]Xu Y, Masuda K, Groso C, Hassan R, Zhou Z, Broderick K, et al. Microfluidic synthesis of scalable layer by layer multiple antigen nano delivery platform for SARS CoV 2 vaccines. Vaccines (Basel), 2024, 12(3), 339. DOI: 10.3390/vaccines12030339
[154]Pulendran B, Davis MM. The science and medicine of human immunology. Science, 2020, 369(6511), eaay4014. DOI: 10.1126/science.aay4014
[155]Imani S, Li X, Chen K, Maghsoudloo M, Jabbarzadeh Kaboli P, Hashemi M, et al. Computational biology and artificial intelligence in mRNA vaccine design for cancer immunotherapy. Frontiers in Cellular and Infection Microbiology, 2025, 14, 1501010. DOI: 10.3389/fcimb.2024.1501010
[156]Bloom K, van den Berg F, Arbuthnot P. Self amplifying RNA vaccines for infectious diseases. Gene Therapy, 2021, 28(3-4), 117-129. DOI: 10.1038/s41434-020-00204-y
[157]Zhao Y, Wang H. Artificial intelligence driven circRNA vaccine development: Multimodal collaborative optimization and a new paradigm for biomedical applications. Briefings in Bioinformatics, 2025, 26(3), bbaf263. DOI: 10.1093/bib/bbaf263
[158]Zhu J, Ananthaswamy N, Jain S, Batra H, Tang WC, Lewry DA, et al. A universal bacteriophage T4 nanoparticle platform to design multiplex SARS-CoV-2 vaccine candidates by CRISPR engineering. Science Advances, 2021, 7(37), eabh1547. DOI: 10.1126/sciadv.abh1547
[159]Lavelle EC, Ward RW. Mucosal vaccines – fortifying the frontiers. Nature Reviews Immunology, 2021, 22(4), 236-250. DOI: 10.1038/s41577-021-00583-2
[160]Yuki Y, Kiyono H. Mucosal vaccines: Novel advances in technology and delivery. Expert Review of Vaccines, 2009, 8(8), 1083-1097. DOI: 10.1586/erv.09.61
[161]Dotiwala F, Upadhyay AK. Next generation mucosal vaccine strategy for respiratory pathogens. Vaccines (Basel), 2023, 11(10), 1585. DOI: 10.3390/vaccines11101585
[162]Azegami T, Yuki Y, Kiyono H. Challenges in mucosal vaccines for the control of infectious diseases. International Immunopharmacology, 2014, 26(9), 517-528. DOI: 10.1093/intimm/dxu063
[163]Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nature Medicine, 2005, 11(4 Suppl), S45-S53. DOI: 10.1038/nm1213
[164]Lycke N. Recent progress in mucosal vaccine development: Potential and limitations. Nature Reviews Immunology, 2012, 12(8), 592-605. DOI: 10.1038/nri3251
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Shoaib Manzoor (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
