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: 9206438
• 负责人: Marcela F Pasetti
• 金额: $ 39.72万
• 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/9206438
• 关键词: 2 year old; 5 year old; Active Biological Transport; Adjuvant; Adult; Age; Age-Months; Antibodies; Antigens; Area; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Blood Circulation; Breast Feeding; Cells; Child; Clinical; Conjugate Vaccines; Cryptosporidium; Developed Countries; Developing Countries; Diffuse; Disease; Dysentery; Enteral; Enterocytes; Enterotoxins; Epidemiological trend; Epithelial; Escherichia coli; Evaluation; Human; Human Milk; Human Volunteers; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin G; Immunologic Memory; Immunologics; Incidence; Infant; Infection prevention; Intestines; Kinetics; Knockout Mice; Life; Longitudinal Studies; Lung; Maternal antibody; Maternally-Acquired Immunity; Measures; Mediating; Milk; Modeling; Morbidity - disease rate; Mothers; Multicenter Studies; Mus; Neonatal; Organism; Placenta; Plasmids; Preschool Child; Property; Protein Secretion; Proteins; Reporting; Risk; Rotavirus; Sampling; 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; low income country; mortality; mouse model; mutant; 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（由申请人提供）：志贺氏菌属。引起严重的痢疾，这种疾病仍然与显着的发病率和死亡率相关，特别是对于 1 岁以下的儿童 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，婴儿早期志贺氏菌病的发病率要低得多。志贺氏菌占 0 至 11 个月婴儿腹泻病例的 16.6%，而占 2-5 岁儿童腹泻病例的 78.4%，超过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性免疫力的贡献，这与疾病的发病率成反比。 90 年代初的研究报道了母乳喂养的保护作用，但具体机制尚未探索。在这项提案中，我们试图了解母体免疫力预防幼儿志贺氏菌病的机制，并确定一种针对幼儿和幼儿的新型广泛保护性疫苗。在初步研究中，母体 IgG 完全通过胎盘或乳汁转移，并在幼鼠血清中检测到，可提供针对致命志贺氏菌感染的保护作用。我们还观察到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 可能穿过粘膜上皮屏障进入肠道，在新生儿片段 C 受体 (FcRn) 转运后介导细菌清除。母乳中含有的 IgG 同样可以通过 FcRn 转运穿过肠细胞并进入基底外侧，以进一步限制细菌传播。在该提案的目标 1 中，我们将确定保护婴儿免受志贺氏菌病侵害的母体免疫成分，并研究 FcRn 在跨粘膜表面转运 IgG 中的作用。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，该研究涉及生活在流行地区的母亲及其婴儿（随访至 2 岁）。最后，我们将利用人类肠样模型，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，我们将研究一种新策略，将 CVD1208S（一种减毒活疫苗）与入侵质粒抗原 IpaD（一种高度保守的 III 型分泌蛋白）和大肠杆菌双突变体热不稳定肠毒素 (dmLT) 相结合，以诱导广泛的保护和强大、持久的免疫力。这项工作有可能揭示一种预防志贺氏菌病的新机制，以及一种在母体免疫力减弱后保护儿童的更有效的疫苗方法。