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Development of a glycoconjugate vaccine to prevent invasive Salmonella Typhimurium infections in sub-Saharan Africa
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نویسنده
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baliban s.m. ,yang m. ,ramachandran g. ,curtis b. ,shridhar s. ,laufer r.s. ,wang j.y. ,van druff j. ,higginson e.e. ,hegerle n. ,varney k.m. ,galen j.e. ,tennant s.m. ,lees a. ,mackerell a.d. ,levine m.m. ,simon r.
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منبع
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plos neglected tropical diseases - 2017 - دوره : 11 - شماره : 4
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چکیده
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Invasive infections associated with non-typhoidal salmonella (nts) serovars enteritidis (se),typhimurium (stm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-saharan africa,and currently,there are no approved human nts vaccines. nts o-polysaccharides and flagellin proteins are protective antigens in animal models of invasive nts infection. conjugates of se core and o-polysaccharide (cops) chemically linked to se flagellin have enhanced the anti-cops immune response and protected mice against fatal challenge with a malian se blood isolate. we report herein the development of a stm glycoconjugate vaccine comprised of stm cops conjugated to the homologous serovar phase 1 flagellin protein (flic) with assessment of the role of cops o-acetyls for functional immunity. sun-type cops conjugates linked through the polysaccharide reducing end to flic were more immunogenic and protective in mice challenged with a malian stm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [ve] versus 30–43% ve). immunization with de-o-acetylated stm-cops conjugated to crm197provided significant but reduced protection against stm challenge compared to mice immunized with native stm-cops:crm197(63–74% ve versus 100% ve). although ops o-acetyls were highly immunogenic,post-vaccination sera that contained various o-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-cops igg were assayed. in-silico molecular modeling further indicated that stm ops forms a single dominant conformation,irrespective of o-acetylation,in which o-acetyls extend outward and are highly solvent exposed. these preclinical results establish important quality attributes for an stm vaccine that could be co-formulated with an se-cops:flic glycoconjugate as a bivalent nts vaccine for use in sub-saharan africa. © 2017 baliban et al.
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آدرس
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center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, university of maryland computer-aided drug design center,department of pharmaceutical sciences,school of pharmacy,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, fina biosolutions,rockville,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, department of biochemistry and molecular biology,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States, fina biosolutions,rockville,md, United States, jr.,university of maryland computer-aided drug design center,department of pharmaceutical sciences,school of pharmacy,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md,united states,department of pediatrics,university of maryland school of medicine,baltimore,md, United States, center for vaccine development,institute for global health,university of maryland school of medicine,baltimore,md,united states,department of medicine,university of maryland school of medicine,baltimore,md, United States
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Authors
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