SLAS Discovery Declaration of Conflicting Interests Mucosal Immune Responses in Oral Immunization Microbes The authors declared no potential conflicts of interest with respec Infect.2013,l5,895-902 to the research, authorship, and/or publication of this articl 5. Kim, S H. Seo, K. W; Kim, J. et al. The M Cell-Targeting Ligand Promotes Antigen Delivery and Induces Antigen- Specific Immune Responses in Mucosal Vaccination. J. Immunol.2010,185,5787-5795 The authors disclosed receipt of the following financial support 16. Hackett, D J; Zhang, C. Stefanescu, C; et al. Enzyme-Linked for the research, authorship, and/or publication of this article: This work was supported by the Major National Projects for Infectious Glycoprotein B Antibody in Serum. Clin. Vaccine Immunol. Diseases research(2008zX10002002,2012ZX10002-006002- 2010,17,836-839 003)and for New Drug Research Development(2009ZX0913- 17. Maciel, M; Fusaro, A. E; Oliveira, C.R.; et al. IgA Response 710, 2011AA02A114), the National Natural Science Foundation in Serum and gut secretion in sensitized mice Fed with the of China(30571650, 31370927), and project of the Science and Dust Mite Dermatophagoides pteronyssinus Extract. Braz J. Technology Commission of Shanghai(13431900602) Med.Biol.Res.2004,37,817-826 Tominaga, H. Ishiyama, M. Ohseto, F, et al. A Water- Soluble tetrazolium salt Useful for Colorimetric Cell References Viability Assay. Anal. Commun. 1999, 36, 47-50 1. Strugnell,R. A, Wijburg, O. L. The Role of Secretory 19. Fagarasan, S; Kawamoto, S: Kanagawa, O; et al. Adaptive Antibodies in Infection Immunity. Nat Rev Microbiol. 2010, Immune Regulation in the Gut: T Cell-Dependent and T Cell 8,656667 Independent IgA Synthesis. Annu. Rev. Immunol. 2010, 28, 2. Neutra M.R.: Mantis. N.J. Kraehenbuhl J. P Collaboration 243-273. of Epithelial Cells with Organized Mucosal Lymphoid 20. Cerutti, A. The Regulation of IgA Class Switching. Nat Rev Tissues. Nat Immunol. 2001. 2. 1004-1009 Immunol.2008.8.421-434 3. Chen, K, Cerutti, A. Vaccination Strategies to Promote 21. Iwasaki, A. Mucosal Dendritic Cells. Annu. Rev. Immunol Mucosal Antibody Responses. Immunity 2010, 33, 479-491 2007,25,381-418 4. Neutra, M.R., Kozlowski, P A Mucosal Vaccines: The Promise 22. Lamm. M. E. Interaction of Antigens and Antibodies at ind the Challenge. Nat Rev Immunol. 2006.6.148-158. Mucosal Surfaces. Annul. Rev. Microbiol. 1997.51.311-340 5. Kopecky-Bromberg, S.A. Fraser, K.A., Pica, N, et al. Alpha- 23. Higgins, L. M. Lambkin, I Donnelly, G. et al. In Viv C-Galactosylceramide as an Adjuvant for a Live Attenuated Phage Display to Identify M Cell-Targeting Ligands. Pharn Influenza Virus Vaccine Vaccine 2009.27. 3766-3774 Res.2004,21,695-70: 6. Brayden, D. J; Jepson, M. A; Baird, A. W et al. Keynote 24. Clark, M. A; Blair, H. Liang, L; et al. Targeting Polymerised Review: Intestinal Peyers Patch M Cells and Oral Vaccine Liposome Vaccine Carriers to Intestinal M Cells. Vaccine Targeting Drug Discov Today 2005, 10, 1145-1157 2001,20,208-217 7. Sun, J B; Czerkinsky, C; Holmgren, J Mucosally Induced Mantis, N.J. Frey, A: Neutra, M.R.; et al. Accessibility of Immunological Tolerance, Regulatory T Cells and the Glycolipid and Oligosaccharide Epitopes on Rabbit Villus and Adjuvant Effect by Cholera Toxin B Subunit. Scand. J. Follicle-Associated Epithelium. Am J Physiol. Gastrointest Nakato, G Hase, K. Suzuki, M.; et al. Cutting Edge: Brucella 26. Conacher, M. Alexander, J; Brewer, J M. Oral Immunisation abortus Exploits a Cellular Prion Protein on Intestinal M Cells with Peptide and Protein Antigens by Formulation in Lipid as an Invasive Receptor. J. Immunol. 2012, 189, 1540-1544 Vesicles Incorporating Bile Salts(Bilosomes) Vaccine 2001 9. Pavot, V: Rochereau, N; Genin, C. et al. New Insights in 19.2965-2974 Mucosal Vaccine Development. Vaccine 2012, 30, 142-154. 27. Cusi, M. G. Zurbriggen, R, Correale, P; et al. Influenza 10. Hase, K, Kawano, K, Nochi, T, et al. Uptake through Virosomes Are an Efficient Delivery System for Respiratory Glycoprotein 2 of FimH(+) Bacteria by M Cells Initiates Syncytial Virus-F Antigen Inducing Humoral and Cell Mucosal Immune Response. Nature 2009, 462, 226-230. Mediated Immunity Vaccine 2002, 20, 3436-3442 11. Vodnik, M; Zager, U, Strukelj, B, et al. Phage Display: 28. Gluck, R. Adjuvant Activity of Immunopotentiating Recon- electing Straws Instead of a Needle from a Haystack. stituted Influenza Virosomes (IRIVs). Vaccine 1999, 17, Molecules 2011.16. 790-817. 1782-1787 12. Padmanaban. G: Park. H. ChoiJ. S: et al. Identific 29. Senior, K. Bilosomes: The Answer to Oral Vaccine Delivery? Peptides That Selectively Bind to Myoglobin by Bi Drug Discov. Today 2001, 6, 1031-1032. f Phage Displayed-Peptide Library. J. biotechno 30. Kyd, J. M: Cripps, A. W. Functional Differences between l87.43-50 M Cells and Enterocytes in Sampling Luminal Antigens 13. Huang. J: Khan, I; Liu, R; et al. Single Primer-Mediated accIne2008,26,6221-6224 Circular Polymerase Chain Reaction for Hairpin DNA 31. Kuolee, R; Chen, w. M Cell-Targeted Delivery of Vaccines Cloning and Plasmid Editing. Anal. Biochem. 2016, 500, 18- and Therapeutics. Exp. Opin. Drug Deliv. 2008, 5, 693-702 20 32. Singh, A. N. McGuire, M. J: Li, S; et al. Dimerization of a 14. Kim, S.H. ; Yang, I. Y; Jang, S.H. et al C5a Receptor- Phage-Display Selected Peptide for Imaging of Alphavbeta6- Targeting Ligand-Mediated Delivery of Dengue Virus Integrin: Two Approaches to the Multivalent Effect. Theranostics Antigen to M Cells Evokes Antigen-Specific Systemic and 2014,4,745-760.8 SLAS Discovery Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Major National Projects for Infectious Diseases Research (2008ZX10002002, 2012ZX10002-006-002- 003) and for New Drug Research & Development (2009ZX0913- 710, 2011AA02A114), the National Natural Science Foundation of China (30571650, 31370927), and project of the Science and Technology Commission of Shanghai (13431900602). References 1. Strugnell, R. A.; Wijburg, O. L. The Role of Secretory Antibodies in Infection Immunity. Nat. Rev. Microbiol. 2010, 8, 656–667. 2. Neutra, M. R.; Mantis, N. J.; Kraehenbuhl, J. P. Collaboration of Epithelial Cells with Organized Mucosal Lymphoid Tissues. Nat. Immunol. 2001, 2, 1004–1009. 3. Chen, K.; Cerutti, A. Vaccination Strategies to Promote Mucosal Antibody Responses. Immunity 2010, 33, 479–491. 4. Neutra, M. R.; Kozlowski, P. A. Mucosal Vaccines: The Promise and the Challenge. Nat. Rev. Immunol. 2006, 6, 148–158. 5. Kopecky-Bromberg, S. A.; Fraser, K. A.; Pica, N.; et al. Alpha￾C-Galactosylceramide as an Adjuvant for a Live Attenuated Influenza Virus Vaccine. Vaccine 2009, 27, 3766–3774. 6. Brayden, D. J.; Jepson, M. A.; Baird, A. W.; et al. Keynote Review: Intestinal Peyer’s Patch M Cells and Oral Vaccine Targeting. Drug Discov. Today 2005, 10, 1145–1157. 7. Sun, J. B.; Czerkinsky, C.; Holmgren, J. Mucosally Induced Immunological Tolerance, Regulatory T Cells and the Adjuvant Effect by Cholera Toxin B Subunit. Scand. J. Immunol. 2010, 71, 1–11. 8. Nakato, G.; Hase, K.; Suzuki, M.; et al. Cutting Edge: Brucella abortus Exploits a Cellular Prion Protein on Intestinal M Cells as an Invasive Receptor. J. Immunol. 2012, 189, 1540–1544. 9. Pavot, V.; Rochereau, N.; Genin, C.; et al. New Insights in Mucosal Vaccine Development. Vaccine 2012, 30, 142–154. 10. Hase, K.; Kawano, K.; Nochi, T.; et al. Uptake through Glycoprotein 2 of FimH(+) Bacteria by M Cells Initiates Mucosal Immune Response. Nature 2009, 462, 226–230. 11. Vodnik, M.; Zager, U.; Strukelj, B.; et al. Phage Display: Selecting Straws Instead of a Needle from a Haystack. Molecules 2011, 16, 790–817. 12. Padmanaban, G.; Park, H.; Choi, J. S.; et al. Identification of Peptides That Selectively Bind to Myoglobin by Biopanning of Phage Displayed-Peptide Library. J. Biotechnol. 2014, 187, 43–50. 13. Huang, J.; Khan, I.; Liu, R.; et al. Single Primer-Mediated Circular Polymerase Chain Reaction for Hairpin DNA Cloning and Plasmid Editing. Anal. Biochem. 2016, 500, 18– 20. 14. Kim, S. H.; Yang, I. Y.; Jang, S. H.; et al. C5a Receptor￾Targeting Ligand-Mediated Delivery of Dengue Virus Antigen to M Cells Evokes Antigen-Specific Systemic and Mucosal Immune Responses in Oral Immunization. Microbes Infect. 2013, 15, 895–902. 15. Kim, S. H.; Seo, K. W.; Kim, J.; et al. 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Immunol. 2008, 8, 421–434. 21. Iwasaki, A. Mucosal Dendritic Cells. Annu. Rev. Immunol. 2007, 25, 381–418. 22. Lamm, M. E. Interaction of Antigens and Antibodies at Mucosal Surfaces. Annu. Rev. Microbiol. 1997, 51, 311–340. 23. Higgins, L. M.; Lambkin, I.; Donnelly, G.; et al. In Vivo Phage Display to Identify M Cell–Targeting Ligands. Pharm. Res. 2004, 21, 695–705. 24. Clark, M. A.; Blair, H.; Liang, L.; et al. Targeting Polymerised Liposome Vaccine Carriers to Intestinal M Cells. Vaccine 2001, 20, 208–217. 25. Mantis, N. J.; Frey, A.; Neutra, M. R.; et al. Accessibility of Glycolipid and Oligosaccharide Epitopes on Rabbit Villus and Follicle-Associated Epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 278, G915–G923. 26. Conacher, M.; Alexander, J.; Brewer, J. M. Oral Immunisation with Peptide and Protein Antigens by Formulation in Lipid Vesicles Incorporating Bile Salts (Bilosomes). Vaccine 2001, 19, 2965–2974. 27. Cusi, M. G.; Zurbriggen, R.; Correale, P.; et al. Influenza Virosomes Are an Efficient Delivery System for Respiratory Syncytial Virus-F Antigen Inducing Humoral and Cell￾Mediated Immunity. Vaccine 2002, 20, 3436–3442. 28. Gluck, R. Adjuvant Activity of Immunopotentiating Recon￾stituted Influenza Virosomes (IRIVs). Vaccine 1999, 17, 1782–1787. 29. Senior, K. Bilosomes: The Answer to Oral Vaccine Delivery? Drug Discov. Today 2001, 6, 1031–1032. 30. Kyd, J. M.; Cripps, A. W. Functional Differences between M Cells and Enterocytes in Sampling Luminal Antigens. Vaccine 2008, 26, 6221–6224. 31. Kuolee, R.; Chen, W. M Cell–Targeted Delivery of Vaccines and Therapeutics. Exp. Opin. Drug Deliv. 2008, 5, 693–702. 32. Singh, A. N.; McGuire, M. J.; Li, S.; et al. Dimerization of a Phage-Display Selected Peptide for Imaging of Alphavbeta6- Integrin: Two Approaches to the Multivalent Effect. Theranostics 2014, 4, 745–760