Vaccines and maternally acquired immunity to prevent shigellosis in children

预防儿童志贺氏菌病的疫苗和母体获得性免疫力

• 批准号: 8876177
• 负责人: Marcela F Pasetti
• 金额: $ 37.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876177
• 关键词: 2 year old; 5 year old; Accounting; Active Biological Transport; Adjuvant; Adult; Age; Age-Months; Antibodies; Antigens; Area; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Blood Circulation; Breast Feeding; Cells; Child; Conjugate Vaccines; Country; Cryptosporidium; Developed Countries; Developing Countries; Diffuse; Disease; Enteral; Enterocytes; Enterotoxins; Epidemiology; Epithelial; Escherichia coli; Escherichia coli Proteins; Evaluation; Heating; Human; Human Milk; Human Volunteers; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Immunologic Memory; Incidence; Infant; Infection prevention; Intestines; Kinetics; Life; Longitudinal Studies; Low income; Lung; Maternal antibody; Maternally-Acquired Immunity; Measures; Mediating; Milk; Modeling; Morbidity - disease rate; Mothers; Multicenter Studies; Mus; Neonatal; Organism; Placenta; Plasmids; Property; Protein Secretion; Proteins; Reporting; Risk; Rotavirus; Sampling; Schools; Serotyping; Serum; Severity of illness; Shigella; Shigella Infections; Side; Source; Surface; Testing; Toddler; Transgenic Mice; Transport Process; Type III Secretion System Pathway; Vaccinated; Vaccination; Vaccines; Virulent; Work; absorption; aged; bactericide; base; child protection; early childhood; enteric pathogen; follow-up; in vitro activity; infancy; killings; mortality; mouse model; mutant; neonatal Fc receptor; novel; novel strategies; novel vaccines; oral vaccine; pathogen; prevent; public health relevance; receptor; response; trend; vaccine candidate; vaccine development

 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.

 描述（适用提供）：Shigella spp。引起严重的源自疾病，该疾病继续与明显的发病率和死亡率有关，尤其是在儿童下 5岁的生活在世界较发达地区。最近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，在婴儿早期期的志核病事件要低得多。在0至11个月大的婴儿中，志贺氏菌占腹泻病例的16.6％，而造成2-5岁儿童病例的78.4％，超过了所有其他肠道病原体。我们假设这种流行病学趋势反映了母体获得的免疫学的贡献，该免疫学与疾病的发生成反比。 90年代初期的研究报告了母乳喂养的受保护益处，但尚未探讨确切的机制。在此提案中，我们试图了解母体免疫学阻止志氏症的机制，并确定一种新型的幼儿和幼儿的广泛保护的疫苗。在初步研究中，孕产妇IgG专门通过plapeta或牛奶转移，并在婴儿小鼠的血清中检测到，赋予了抗致命志贺氏菌感染的保护。我们还观察到志贺氏菌特异性的血清IgG具有肠胃粘细胞（OPA）和血清细菌（SBA）活性。我们假设循环的志贺氏菌特异性IgG可能会穿过粘膜上皮屏障进入肠道，并在新生儿片段C受体（FCRN）转运后介导细菌清除率。母乳中包含的IgG也可以通过FCRN穿过肠上皮细胞并进入基底外侧，以进一步限制细菌扩散。在本提案的目标1中，我们将确定保护婴儿免受志氏病的母体免疫成分，并研究FCRN在跨粘膜表面运输IgG时的参与。使用表达人FCRN的转基因小鼠，我们将检查人类母乳中IgG的易位和保护能力。在AIM 2中，我们将研究疫苗接受者中志贺氏菌特异性IgG的OPA和SBA能力，并与疾病严重程度降低相关。我们还将测量一项涉及母亲及其婴儿（随后2岁）的纵向研究中，主要获得的抗体的动力学。最后，使用人类肠模型，我们将剖析预防志贺氏菌感染的母乳的成分。特别是FCRN介导的母乳IgG的肠道易位。在AIM 3中，我们将研究一种新型策略，该策略将CVD1208（一种活减毒的疫苗）与入侵质粒抗原iPad（高度组成的III型分泌蛋白）和大肠杆菌双重突变热脂肪libile肠毒素（DMLT）诱导广泛的保护和强烈的持久免疫力。这项工作有可能发现涉及保护志氏病的新机制，并在孕产妇免疫力减弱后采取更有效的疫苗方法来保护儿童。