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Here, we evaluated the effectiveness of Alcaligenes-derived lipid A as an adjuvant for sublingual immunization, a novel vaccination route. Mice sublingually immunized with Alcaligenes lipid A and ovalbumin (OVA) showed enhanced production of OVA-specific IgA in both the respiratory and gastrointestinal tracts. In addition, increased serum levels of OVA-specific and IgG antibodies were elicited through germinal center reactions in the draining lymph nodes without excessive inflammation at the administration sites. These results demonstrated superior efficacy not previously achieved through other routes of administration (e.g. intranasal, subcutaneous, intramuscular administration) or by existing adjuvants (e.g. CpG-ODN). In addition, sublingual immunization with cholera toxin B subunit (CTB) and lipid A led to an elevated CTB-specific IgG response in the systemic compartment and an elevated IgA response in the intestinal tract, effectively suppressing the diarrhea induced by oral challenge with cholera toxin. Furthermore, immunization with pneumococcal surface protein A (PspA) plus Alcaligenes lipid A elicited strong PspA-specific CD4+ T cell proliferation and Th17 responses, as well as IgA and IgG responses, in both the respiratory tract and the systemic compartment. These effects enhanced pneumococcal clearance in the lungs and subsequent protection against Streptococcus pneumoniae infection. Together, our findings suggest that Alcaligenes-derived lipid A is a potent sublingual vaccine adjuvant with potential efficacy against both respiratory and intestinal infectious diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxaf066","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T12:27:53Z","timestamp":1762777673000},"page":"264-277","source":"Crossref","is-referenced-by-count":2,"title":["<i>Alcaligenes<\/i>\n                    lipid A as a sublingual adjuvant to augment protective immune responses in the respiratory and gastrointestinal tracts"],"prefix":"10.1093","volume":"38","author":[{"given":"Ken","family":"Yoshii","sequence":"first","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilai","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]},{"name":"Graduate School of Pharmaceutical Sciences, The University of Osaka , Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Shimoyama","sequence":"additional","affiliation":[{"name":"Graduate School of Science, The University of Osaka , Osaka 560-0043 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]},{"name":"Graduate School of Pharmaceutical Sciences, The University of Osaka , Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keigo","family":"Iemitsu","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]},{"name":"Graduate School of Medicine, The University of Osaka , Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Node","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Hosomi","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]},{"name":"Graduate School of Veterinary Science, Osaka Metropolitan University , Osaka 598-8531 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kiyono","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD) School of Medicine, UC San Diego , San Diego, CA 92093 ,","place":["USA"]},{"name":"Chiba University (CU)\u2014UCSD Center for Mucosal Immunology, Allergy and Vaccines (cMAV), UC San Diego School of Medicine, UC San Diego , San Diego, CA 92093 ,","place":["USA"]},{"name":"Future Medicine Education and Research Organization, Chiba University , Chiba 260-8670 ,","place":["Japan"]},{"name":"Department of Human Mucosal Vaccinology, Chiba University Hospital , Chiba 260-8670 ,","place":["Japan"]},{"name":"Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Chiba University , Chiba 260-8670 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Fukase","sequence":"additional","affiliation":[{"name":"Graduate School of Science, The University of Osaka , Osaka 560-0043 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Kunisawa","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Materials and Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBN) , Osaka 567-0085 ,","place":["Japan"]},{"name":"Graduate School of Pharmaceutical Sciences, The University of Osaka , Osaka 565-0871 ,","place":["Japan"]},{"name":"Graduate School of Science, The University of Osaka , Osaka 560-0043 ,","place":["Japan"]},{"name":"Graduate School of Medicine, The University of Osaka , Osaka 565-0871 ,","place":["Japan"]},{"name":"International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 ,","place":["Japan"]},{"name":"Graduate School of Medicine, Kobe University , Kobe 650-0017 ,","place":["Japan"]},{"name":"Research Organization for Nano and Life Innovation, Waseda University , Tokyo 162-0041 ,","place":["Japan"]},{"name":"Graduate School of Dentistry, The University of Osaka , Osaka 565-0871 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