Center for Vaccine Development and Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States.
Vaccine. 2013 Jun 19;31(28):2919-29. doi: 10.1016/j.vaccine.2013.04.045. Epub 2013 May 2.
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.
志贺氏菌属是食源性和水源性病原体，可引起志贺氏菌病，这是一种严重的腹泻和痢疾疾病，在资源匮乏的国家与高发病率和死亡率相关。目前尚无可用的疫苗来预防志贺氏菌病。我们最近证明，志贺氏菌侵袭质粒抗原（Ipas），IpaB 和 IpaD，它们是细菌 III 型分泌系统（TTSS）的组成部分，可以在鼻腔免疫接种和致命性肺攻击的小鼠模型中预防感染。由于它们在志贺氏菌属中具有保守性且高度免疫原性，因此这些蛋白是交叉保护疫苗的理想候选物。理想情况下，这种疫苗可以通过口服给予人类，以诱导粘膜和全身免疫。在这项研究中，我们研究了口服施用志贺氏菌 IpaB 和 IpaD 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。我们通过小鼠肺感染模型来描述口服与鼻腔免疫接种引起的免疫反应和保护效力。口服免疫后诱导了针对 IpaB 的血清 IgG 和粪便 IgA。然而，尽管剂量增加了 100 倍，但这些反应仍低于鼻腔免疫接种获得的反应。口服免疫接种 IpaB 和 IpaD 诱导的保护率为 40％，而鼻腔免疫接种的保护率为 90％。肺和脾中针对 IpaB 和 IpaD 的 IgA 抗体分泌细胞以及 T 细胞衍生的 IL-2、IL-5、IL-17 和 IL-10 与保护作用相关。这些结果表明，口服给予的 IpaB 和 IpaD 具有免疫原性，并支持进一步在人类中进行研究。
