Characterization of O-antigen delivered by Generalized Modules for Membrane Antigens (GMMA) vaccine candidates against nontyphoidal Salmonella

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• 作者：G. De Benedetto^a ; ^b ; R. Alfini^a ; P. Cescutti^b ; M. Caboni^c ; L. Lanzilao^a ; F. Necchi^a ; A. Saul^a ; C.A. MacLennan^d ; S. Rondini^a ; F. Micoli^a ; ^{francesca.x.micoli@gsk.com}
• 关键词：Salmonella Typhimurium ; Salmonella Enteritidis ; Vaccine ; O-antigen ; GMMA ; Outer membrane vesicles
• 刊名：Vaccine
• 出版年：2017
• 出版时间：11 January 2017
• 年：2017
• 卷：35
• 期：3
• 页码：419-426
• 全文大小：816 K
• 卷排序：35

文摘

Invasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O-antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O-antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium ΔtolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications.In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS.