Baliban Scott M, Yang Mingjun, Ramachandran Girish, Curtis Brittany, Shridhar Surekha, Laufer Rachel S, Wang Jin Y, Van Druff John, Higginson Ellen E, Hegerle Nicolas, Varney Kristen M, Galen James E, Tennant Sharon M, Lees Andrew, MacKerell Alexander D, Levine Myron M, Simon Raphael
Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
PLoS Negl Trop Dis. 2017 Apr 7;11(4):e0005493. doi: 10.1371/journal.pntd.0005493. eCollection 2017 Apr.
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 CRM197 provided 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.
与非伤寒沙门氏菌（NTS）血清型肠炎沙门氏菌（SE）、鼠伤寒沙门氏菌（STm）及单相变体1,4,[5],12:i:-相关的侵袭性感染是撒哈拉以南非洲婴幼儿面临的一个主要健康问题，目前尚无获批的人用NTS疫苗。NTS O-多糖和鞭毛蛋白是侵袭性NTS感染动物模型中的保护性抗原。与SE鞭毛蛋白化学连接的SE核心与O-多糖（COPS）缀合物增强了抗COPS免疫反应，并保护小鼠免受来自马里SE血液分离株的致命攻击。我们在此报告一种STm糖缀合物疫苗的研发，该疫苗由与同源血清型1期鞭毛蛋白（FliC）缀合的STm COPS组成，并评估了COPS O-乙酰基在功能性免疫中的作用。通过多糖还原端与FliC连接的Sun型COPS缀合物在受到马里STm血液分离株攻击的小鼠中比多点晶格缀合物更具免疫原性和保护性（疫苗效力[VE]＞95%，而后者为30 - 43%）。与用天然STm-COPS:CRM197免疫的小鼠相比，用与CRM197缀合的去O-乙酰化STm-COPS免疫可提供显著但降低的针对STm攻击的保护作用（VE为63 - 74%，而后者为100%）。尽管OPS O-乙酰基具有高度免疫原性，但当检测等效滴度的抗COPS IgG时，含有各种O-乙酰基表位特异性抗体谱的疫苗接种后血清显示出相似的体外杀菌活性。计算机模拟分子建模进一步表明，STm OPS形成单一优势构象，无论O-乙酰化情况如何，其中O-乙酰基向外延伸且高度暴露于溶剂中。这些临床前结果为一种STm疫苗确立了重要的质量属性，该疫苗可与SE-COPS:FliC糖缀合物共同配制为一种二价NTS疫苗，用于撒哈拉以南非洲。
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