Vaccines and maternally acquired immunity to prevent shigellosis in children

 描述(申请人提供)：志贺氏菌属。引起一种严重的痢疾，这种疾病仍然与严重的发病率和死亡率有关，特别是在以下儿童 5岁，生活在世界欠发达地区。最近的全球肠道多中心研究(GEMS)的一个重要观察结果是，与年龄较大的儿童相比，婴儿早期志贺氏菌病的发病率要低得多。志贺氏菌占0~11个月婴儿腹泻病例的16.6%，占2~5岁儿童腹泻病例的78.4%，高于所有其他肠道病原菌。我们假设这一流行病学趋势反映了母体获得性免疫的作用，母体获得性免疫与疾病发病率呈负相关。90年代初的研究报告了母乳喂养的保护作用，但确切的机制还没有被探索。在这项提案中，我们试图了解母体免疫预防婴幼儿志贺氏菌病的机制，并确定一种新的广泛保护幼儿和幼儿的疫苗。在初步研究中，母体免疫球蛋白仅通过胎盘或牛奶转移，并在幼鼠血清中检测到，对致死性志贺氏菌感染具有保护作用。我们还观察到志贺氏菌特异性血清免疫球蛋白具有吞噬细胞(OPA)和血清杀菌(SBA)活性。我们推测，循环中的志贺氏菌特异性免疫球蛋白可能穿过粘膜上皮屏障进入肠道，在那里它介导了新生儿片段C受体(FcRN)转运后的细菌清除。母乳中包含的免疫球蛋白也同样可以通过FcRN穿过肠细胞进入基底外侧，以进一步限制细菌的传播。在这项建议的目标1中，我们将确定保护婴儿免受志贺氏菌病侵袭的母体免疫成分，并调查FcRN在跨粘膜表面运输免疫球蛋白方面的参与。利用表达人FcRN的转基因小鼠，我们将检测人母乳中免疫球蛋白G的移位和保护能力。在目标2中，我们将调查疫苗接受者中志贺氏菌特异性免疫球蛋白OPA和SBA的能力及其与疾病严重程度降低的关系。我们还将在一项纵向研究中测量母体获得性抗体的动力学，该研究涉及居住在流行区的母亲和她们的婴儿(随访至2岁)。最后，使用人类肠样模型，我们将剖析防止志贺氏菌感染的母乳成分，特别是FcRN介导的母乳免疫球蛋白肠道易位。在目标3中，我们将研究一种新的策略，将CVD1208S(减毒活疫苗)与侵袭质粒抗原iPad(一种高度保守的III型分泌蛋白)和大肠杆菌双突变不耐热肠毒素(DmLT)相结合，以诱导广泛的保护和强大、持久的免疫。这项工作有可能发现一种预防志贺氏菌病的新机制，以及一种在母体免疫减弱后保护儿童的更有效的疫苗方法。

 DESCRIPTION (provided by applicant): Shigella spp. cause a severe dysenteric disease that continues to be associated with significant morbidity and mortality, particularly in children under 5 years of age living in less-developed areas of the world. An important observation from the recent Global Enteric Multicenter Study (GEMS) was that the incidence of shigellosis was much lower during early infancy as compared to older children. Shigella accounted for 16.6% of diarrheal cases in infants 0 to 11 months of age, whereas it was responsible for 78.4% of cases in children 2-5 years of age, surpassing all of the other enteric pathogens. We hypothesize that this epidemiological trend reflects the contribution of maternally acquired immunity, which inversely correlates with incidence of disease. Studies from the early 90s reported a protective benefit of breastfeeding but the exact mechanisms have not been explored. In this proposal, we seek to understand the mechanisms by which maternal immunity prevents shigellosis in young infants and identify a novel broadly protective vaccine for toddlers and young children. In preliminary studies, maternal IgG exclusively transferred through placenta or milk and detected in serum of infant mice, conferred protection against lethal Shigella infection. We also observed that Shigella-specific serum IgG had opsonophagocytic (OPA) and serum bactericidal (SBA) activity. We hypothesize that circulating Shigella-specific IgG may cross the mucosal epithelial barrier into the gut where it mediates bacterial clearance following transport by the neonatal fragment C receptor (FcRn). IgG contained in breast milk may likewise be transported through the FcRn across the enterocytes and into the basolateral side, to further limit bacterial spread. In Aim 1 of this proposal we will determine the maternal immune components that protect infants against shigellosis and investigate the involvement of FcRn in transporting IgG across the mucosal surfaces. Using transgenic mice expressing the human FcRn we will examine the translocation and protective capacity of IgG in human breast milk. In Aim 2, we will investigate OPA and SBA capacity of Shigella-specific IgG in vaccine recipients and their association with reduced severity of disease. We will also measure kinetics of maternally acquired antibodies in a longitudinal study involving mothers and their infants (followed up to 2 years of age) living in endemic regions. Lastly, using a human enteroid model, we will dissect the components of maternal milk that prevent Shigella infection; particularly FcRn-mediated intestinal translocation of breast milk IgG. In Aim 3, we will investigate a novel strategy that combines CVD1208S (a live attenuated vaccine) with the invasion plasmid antigen IpaD (a highly conserved type III secretion protein), and the Escherichia coli double mutant heat labile enterotoxin (dmLT) to induce broad protection and strong, long lasting immunity. This work has the potential to uncover a new mechanism involved in protection against shigellosis and a more effective vaccine approach for the protection of children after the waning of maternal immunity.