Lycke N. Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol. 2012;12(8):592–605.

Article  CAS  Google Scholar 

Jin Z, Gao S, Cui X, Sun D, Zhao K. Adjuvants and delivery systems based on polymeric nanoparticles for mucosal vaccines. Int J Pharm. 2019;572: 118731.

Article  CAS  Google Scholar 

Holmgren J, Czerkinsky C. Mucosal immunity and vaccines. Nat Med. 2005;11(4):S45–53.

Article  CAS  Google Scholar 

Taddio A, Ipp M, Thivakaran S, Jamal A, Parikh C, Smart S, et al. Survey of the prevalence of immunization non-compliance due to needle fears in children and adults. Vaccine. 2012;30(32):4807–12.

Article  Google Scholar 

Davitt CJ, Lavelle EC. Delivery strategies to enhance oral vaccination against enteric infections. Adv Drug Deliv Rev. 2015;91:52–69.

Article  CAS  Google Scholar 

Ramirez JEV, Sharpe LA, Peppas NA. Current state and challenges in developing oral vaccines. Adv Drug Deliv Rev. 2017;114:116–31.

Article  Google Scholar 

Talaat M, Kandeel A, El-Shoubary W, Bodenschatz C, Khairy I, Oun S, et al. Occupational exposure to needlestick injuries and hepatitis B vaccination coverage among health care workers in Egypt. Am J Infect Control. 2003;31(8):469–74.

Article  Google Scholar 

Wang L, Coppel RL. Oral vaccine delivery: can it protect against non-mucosal pathogens? Expert Rev Vaccines. 2008;7(6):729–38.

Article  Google Scholar 

Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GM, Schütte A, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260(1):8–20.

Article  CAS  Google Scholar 

Pasetti MF, Simon JK, Sztein MB, Levine MM. Immunology of gut mucosal vaccines. Immunol Rev. 2011;239(1):125–48.

Article  CAS  Google Scholar 

Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev. 2011;241(1):241–59.

Article  CAS  Google Scholar 

Park T-E, Singh B, Maharjan S, Jiang T, Yoon S-Y, Kang S-K, et al. Mucosal delivery of vaccine by M cell targeting strategies. Curr Drug Ther. 2014;9(1):9–20.

Article  CAS  Google Scholar 

Abautret-Daly AE, Davitt CJ, Lavelle EC. Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections. Biochem Pharmacol. 2014;92(2):173–83.

Article  CAS  Google Scholar 

Davitt CJ, Longet S, Albutti A, Aversa V, Nordqvist S, Hackett B, et al. Alpha-galactosylceramide enhances mucosal immunity to oral whole-cell cholera vaccines. Mucosal Immunol. 2019;12(4):1055–64.

Article  CAS  Google Scholar 

Lycke N, Lebrero-Fernández C. ADP-ribosylating enterotoxins as vaccine adjuvants. Curr Opin Pharmacol. 2018;41:42–51.

Article  CAS  Google Scholar 

Freytag L, Clements J. Mucosal adjuvants. Vaccine. 2005;23(15):1804–13.

Article  CAS  Google Scholar 

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. Clin Vaccine Immunol. 2011;18(4):546–51.

Article  CAS  Google Scholar 

Larena M, Holmgren J, Lebens M, Terrinoni M, Lundgren A. Cholera toxin, and the related nontoxic adjuvants mmCT and dmLT, promote human Th17 responses via cyclic AMP-protein kinase A and inflammasome-dependent IL-1 signaling. J Immunol. 2015;194(8):3829.

Article  CAS  Google Scholar 

Norton EB, Lawson LB, Mahdi Z, Freytag LC, Clements JD. The A subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA, and Th17 responses to vaccine antigens. Infect Immun. 2012;80(7):2426–35.

Article  CAS  Google Scholar 

Anosova N, Chabot S, Shreedhar V, Borawski J, Dickinson B, Neutra M. 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.

Article  CAS  Google Scholar 

Leach S, Clements JD, Kaim J, Lundgren A. The adjuvant double mutant Escherichia coli heat labile toxin enhances IL-17A production in human T cells specific for bacterial vaccine antigens. PLoS One. 2012;7(12): e51718.

Article  CAS  Google Scholar 

El-Kamary SS, Cohen MB, Bourgeois AL, Van DV, Bauers LN, Reymann M, et al. Safety and immunogenicity of a single oral dose of recombinant double mutant heat-labile toxin derived from enterotoxigenic Escherichia coli. Clin Vaccine Immunol Cvi. 2013;20(11):1764–70.

Article  CAS  Google Scholar 

Lu YJ, Yadav P, Clements JD, Forte S, Srivastava A, Thompson CM, et al. Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine. Clin Vaccine Immunol CVI. 2010;17(6):1005–12.

Article  CAS  Google Scholar 

Summerton NA, Welch RW, Bondoc L, Yang HH, Pleune B, Ramachandran N, et al. Toward the development of a stable, freeze-dried formulation of Helicobacter pylori killed whole cell vaccine adjuvanted with a novel mutant of Escherichia coli heat-labile toxin. Vaccine. 2010;28(5):1404–11.

Article  CAS  Google Scholar 

Ottsjö LS, Flach CF, Clements J, Holmgren J, Raghavan S. A Double mutant heat-labile toxin from Escherichia coli, LT(R192G/L211A), is an effective mucosal adjuvant for vaccination against Helicobacter pylori infection. Infect Immun. 2013;81:1532–40.

Article  Google Scholar 

Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alo. 2013.

Guillobel HC, Carinhanha JI, Cárdenas L, Clements JD, Almeida DF, De Ferreira LC. Adjuvant activity of a nontoxic mutant of Escherichia coli heat-labile enterotoxin on systemic and mucosal immune responses elicited against a heterologous antigen carried by a live Salmonella enterica Serovar Typhimurium vaccine strain. Infect Immun. 2000;68(7):4349–53.

Article  CAS  Google Scholar 

Holmgren J, Bourgeois L, Carlin N, Clements J, Gustafsson B, Lundgren A, et al. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant. Vaccine. 2013;31(20):2457–64.

Article  CAS  Google Scholar 

Lundgren A, Bourgeois L, Carlin N, Clements J, Gustafsson B, Hartford M, et al. Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled phase I study. Vaccine. 2014;32(52):7077–84.

Article  CAS  Google Scholar 

Harro C, Bourgeois AL, Sack D, Walker R, DeNearing B, Brubaker J, et al. Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge. Vaccine. 2019;37(14):1978–86.

Article  CAS  Google Scholar 

Lebens M, Terrinoni M, Karlsson SL, Larena M, Gustafsson-Hedberg T, Källgård S, et al. Construction and preclinical evaluation of mmCT, a novel mutant cholera toxin adjuvant that can be efficiently produced in genetically manipulated Vibrio cholerae. Vaccine. 2016;34(18):2121–8.

Article  CAS  Google Scholar 

Holmgren J, Nordqvist S, Blomquist M, Jeverstam F, Lebens M, Raghavan S. Preclinical immunogenicity and protective efficacy of an oral Helicobacter pylori inactivated whole cell vaccine and multiple mutant cholera toxin: a novel and non-toxic mucosal adjuvant. Vaccine. 2018;36(41):6223–30.

Article  CAS  Google Scholar 

Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.

Article  CAS  Google Scholar 

Zhou M, Zhang G, Ren G, Gnanadurai CW, Li Z, Chai Q, et al. Recombinant rabies viruses expressing GM-CSF or flagellin are effective vaccines for both intramuscular and oral immunizations. PLoS One. 2013;8(5): e63384.

Article  CAS  Google Scholar 

Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat Immunol. 2006;7(6):569–75.

Article  CAS  Google Scholar 

Vilander AC, Dean GA. Adjuvant strategies for lactic acid bacterial mucosal vaccines. Vaccines. 2019;7(4):150.

Article  CAS  Google Scholar 

Rhee JH, Lee SE, Kim SY. Mucosal vaccine adjuvants update. Clin Exp Vaccine Res. 2012;1(1):50.

Article  CAS  Google Scholar 

Cui B, Liu X, Fang Y, Zhou P, Zhang Y, Wang Y. Flagellin as a vaccine adjuvant. Expert Rev Vaccines. 2018;17(4):335–49.

Article  CAS  Google Scholar 

Ren Z, Zhao Y, Liu J, Ji X, Meng L, Wang T, et al. Inclusion of membrane-anchored LTB or flagellin protein in H5N1 virus-like particles enhances protective responses following intramuscular and oral immunization of mice. Vaccine. 2018;36(40):5990–8.

Article  CAS  Google Scholar 

Girard A, Saron W, Bergeron-Sandoval L-P, Sarhan F, Archambault D. Flagellin produced in plants is a potent adjuvant for oral immunization. Vaccine. 2011;29(38):6695–703.

Article  CAS  Google Scholar 

Hajam IA, Kim JH, Lee JH. Incorporation of membrane-anchored flagellin into Salmonella Gallinarum bacterial ghosts induces early immune responses and protection against fowl typhoid in young layer chickens. Vet Immunol Immunopathol. 2018;199:61–9.

Article  CAS  Google Scholar 

Eom JS, Kim JS, Im Jang J, Kim B-H, Yoo SY, Choi JH, et al. Enhancement of host immune responses by oral vaccination to Salmonella enterica serovar Typhimurium harboring both FliC and FljB flagella. PLoS One. 2013;8(9): e74850.

Article  CAS  Google Scholar 

Yamamoto S, Kutsukake K. FljA-mediated posttranscrip