title: Monoclonal antibodies against Vibrio vulnificus RtxA1 elicit protective immunity through distinct mechanisms.
abstract: Vibrio vulnificus causes rapidly progressing septicemia with an extremely high mortality rate (≥50%), even with aggressive antibiotic treatment. The bacteria secrete multifunctional autoprocessing repeats-in-toxin (MARTX) toxins, which are involved in the pathogenesis of Gram-negative Vibrio species. Recently, we reported that immunization with the C-terminal region of V. vulnificus RtxA1/MARTXVv, RtxA1-C, elicits a protective immune response against V. vulnificus through a poorly defined mechanism. In this study, we generated a panel of new monoclonal antibodies (MAbs) against V. vulnificus RtxA1-C and investigated their protective efficacies and mechanisms in a mouse model of infection. Prophylactic administration of seven MAbs strongly protected mice against lethal V. vulnificus infection (more than 90% survival). Moreover, three of these MAbs (21RA, 24RA, and 47RA) demonstrated marked efficacy as postexposure therapy. Notably, 21RA was therapeutically effective against lethal V. vulnificus infection by a variety of routes. Using Fab fragments and a neutropenic mouse model, we showed that 21RA and 24RA mediate protection from V. vulnificus infection through an Fc-independent and/or neutrophil-independent pathway. In contrast, 47RA-mediated protection was dependent on its Fc region and was reduced to 50% in neutropenic mice compared with 21RA-mediated and 24RA-mediated protection. Bacteriological study indicated that 21RA appears to enhance the clearance of V. vulnificus from the blood. Overall, these studies suggest that humoral immunity controls V. vulnificus infection through at least two different mechanisms. Furthermore, our panel of MAbs could provide attractive candidates for the further development of immunoprophylaxis/therapeutics and other therapies against V. vulnificus that target the MARTX toxin.
authors.affiliation: Department of Microbiology and Immunology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea.
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Marine Biotechnology Research Division, Korea Institute of Ocean Science and Technology, Ansan, South Korea Department of Convergence Study on the Ocean Science and Technology, Ocean Science and Technology School, Korea Maritime and Ocean University, Pusan, South Korea Department of Marine Biotechnology, Korea University of Science and Technology, DaeJeon, South Korea.
authors.forename: Sun-Shin
authors.initials: SS
authors.lastname: Cha
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea.
authors.forename: Chang-Seop
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.
authors.forename: Joon Haeng
authors.initials: JH
authors.lastname: Rhee
authors.affiliation: Department of Microbiology and Immunology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea kmin@jbnu.ac.kr.
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Chung
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000911:Antibodies, Monoclonal / Q000276:immunology*; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D001428:Bacterial Vaccines; D005260:Female; D007116:Immunization, Passive; D051379:Mice; D014735:Vibrio Infections; D041261:Vibrio vulnificus / Q000235:genetics / Q000378:metabolism*
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D001428:Bacterial Vaccines