Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD
Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD
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DOI：
10.1016/j.vaccine.2013.04.045
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发表时间：
2013-06-19
期刊：
影响因子：
5.5
通讯作者：
Pasetti, Marcela F.
中科院分区：
文献类型：
--
作者：
Heine, Shannon J.;Diaz-McNair, Jovita;Pasetti, Marcela F.
志贺菌是引起志贺氏菌病的食源性和水源性病原体，志贺氏菌病是一种严重的腹泻和腹泻疾病，在资源贫乏的国家与高发病率和死亡率有关。没有许可的疫苗可用于预防志贺氏菌病。我们最近已经证明，志贺氏菌入侵质粒抗原（Ipas），IpaB和IpaD，这是细菌III型分泌系统（TTSS）的组成部分，可以防止感染的小鼠模型的鼻内免疫和致命的肺部挑战。因为它们在志贺氏菌属中是保守的。和高度免疫原性，这些蛋白质是交叉保护性疫苗的极好候选物。理想情况下，这种疫苗可以口服给予人类以诱导粘膜和全身免疫。在这项研究中，我们研究了志贺氏菌IpaB和IpaD口服与大肠杆菌不耐热毒素（dmLT）的双突变体作为粘膜佐剂的免疫原性和保护效力。我们使用小鼠肺部感染模型表征了口服与鼻内免疫诱导的免疫应答和保护效力。口服免疫后诱导血清IgG和粪便IgA抗IpaB。然而，尽管剂量增加了100倍，这些反应仍低于鼻内免疫后获得的反应。经口免疫IpaB和IpaD诱导的保护水平为40%，而鼻内免疫导致90%的保护效力。肺和脾中的IpaB和IpaD特异性IgA抗体分泌细胞以及T细胞衍生的IL-2、IL-5、IL-17和IL-10与保护相关。这些结果证明了口服IpaB和IpaD的免疫原性，并支持在人体中的进一步研究。(C)2013爱思唯尔有限公司保留所有权利。
Shigella spp. are food- and water-borne pathogens that cause shigellosis, a severe diarrheal and dysenteric disease that is associated with a high morbidity and mortality in resource-poor countries. No licensed vaccine is available to prevent shigellosis. We have recently demonstrated that Shigella invasion plasmid antigens (Ipas), IpaB and IpaD, which are components of the bacterial type III secretion system (TTSS), can prevent infection in a mouse model of intranasal immunization and lethal pulmonary challenge. Because they are conserved across Shigella spp. and highly immunogenic, these proteins are excellent candidates for a cross-protective vaccine. Ideally, such a vaccine could be administered to humans orally to induce mucosal and systemic immunity. In this study, we investigated the immunogenicity and protective efficacy of Shigella IpaB and IpaD administered orally with a double mutant of the Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant. We characterized the immune responses induced by oral vs. intranasal immunization and the protective efficacy using a mouse pulmonary infection model. Serum IgG and fecal IgA against IpaB were induced after oral immunization. These responses, however, were lower than those obtained after intranasal immunization despite a 100-fold dosage increase. The level of protection induced by oral immunization with IpaB and IpaD was 40%, while intranasal immunization resulted in 90% protective efficacy. IpaB- and IpaD-specific IgA antibody-secreting cells in the lungs and spleen and T-cell-derived IL-2, IL-5, IL-17 and IL-10 were associated with protection. These results demonstrate the immunogenicity of orally administered IpaB and IpaD and support further studies in humans. (C) 2013 Elsevier Ltd. All rights reserved.