Vaccines and maternally acquired immunity to prevent shigellosis in children

 性状（由申请方提供）：志贺氏菌属引起严重的腹泻疾病，继续与高发病率和死亡率相关，特别是在15岁以下的儿童中。 5岁以下，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，婴儿早期的志贺菌病发病率要低得多。志贺氏菌占0至11个月婴儿腹泻病例的16.6%，而它占2-5岁儿童病例的78.4%，超过了所有其他肠道病原体。我们推测，这种流行病学趋势反映了母体获得性免疫的贡献，这与疾病的发病率呈负相关。90年代初的研究报告了母乳喂养的保护作用，但确切的机制尚未探索。在这项提议中，我们试图了解母体免疫预防幼儿志贺菌病的机制，并确定一种适用于幼儿和幼儿的新型广泛保护性疫苗。在初步研究中，母体IgG仅通过胎盘或乳汁转移，并在幼鼠血清中检测到，可保护小鼠免受致死性志贺氏菌感染。志贺氏菌特异性血清IgG具有调理吞噬（OPA）和血清杀菌（SBA）活性。我们假设，循环志贺氏菌特异性IgG可能会穿过粘膜上皮屏障进入肠道，在那里它介导的新生儿片段C受体（FcRn）运输后的细菌清除。母乳中含有的IgG同样可以通过FcRn转运穿过肠上皮细胞并进入基底外侧，以进一步限制细菌传播。在本提案的目标1中，我们将确定保护婴儿免受志贺氏菌感染的母体免疫组分，并研究FcRn在转运IgG穿过粘膜表面中的参与。使用表达人FcRn的转基因小鼠，我们将检查人母乳中IgG的易位和保护能力。在目标2中，我们将研究疫苗接种者中志贺氏菌特异性IgG的OPA和SBA能力及其与疾病严重程度降低的相关性。我们还将在一项涉及生活在流行地区的母亲及其婴儿（随访至2岁）的纵向研究中测量母体获得性抗体的动力学。最后，使用人类肠模型，我们将剖析母乳中预防志贺氏菌感染的成分，特别是FcRn介导的母乳IgG肠道易位。在目标3中，我们将研究一种新的策略，将CVD 1208 S（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）结合，以诱导广泛的保护和强大的持久免疫。这项工作有可能揭示一种新的机制，涉及保护对志贺氏菌病和更有效的疫苗的方法，保护儿童后，母亲的免疫力减弱。

 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.