Syphilis in Pregnancy Study (SIPS): Molecular Diagnostics and Maternal and Infant Immune Response to Infection

妊娠期梅毒研究 (SIPS)：分子诊断以及母婴对感染的免疫反应

• 批准号: 10702053
• 负责人: Jodie Ann Dionne
• 金额: $ 70.46万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702053
• 关键词: Acceleration; Address; Africa; Aftercare; Age; Animals; Antibodies; Antigens; Area; Bacterial Infections; Binding; Biological Assay; Birth; Blood specimen; CD4 Positive T Lymphocytes; Cameroon; Childhood; Clinical; Communicable Diseases; Complement; Congenital Syphilis; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Enrollment; Fetus; Flow Cytometry; Future; Generations; Genome; Gestational Age; Goals; HIV; High Prevalence; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; Immunology procedure; Income; Infant; Infection; Integration Host Factors; International; Kinetics; Knowledge; Laboratories; Lesion; Live Birth; Low Birth Weight Infant; Maternal antibody; Maternally-Acquired Immunity; Measures; Mediating; Medical; Modeling; Molecular; Molecular Biology; Molecular Diagnostic Testing; Molecular Immunology; Natural History; Oral; Outcome; Participant; Pathogenesis; Penicillins; Performance; Perinatal; Peripheral Blood Mononuclear Cell; Placenta; Pregnancy; Pregnant Women; Premature Birth; Prevalence; Prospective, cohort study; Proteomics; Public Health; Reaction; Recording of previous events; Role; Sampling; Sampling Studies; Serology; Serum; Specificity; Spontaneous abortion; Swab; Syphilis; T cell response; T-Lymphocyte; Testing; Time; Treponema pallidum; Umbilical Cord Blood; United States; Vertical Transmission; Virulence Factors; Woman; Zambia; adaptive immune response; adverse birth outcomes; adverse outcome; antibody diagnostic; antigen-specific T cells; biomarker identification; case finding; co-infection; cohort; design; diagnostic algorithm; fetal; follow-up; genome sequencing; genomic data; improved; infection rate; insight; molecular diagnostics; multidisciplinary; neonatal death; neonate; novel; parity; placental transfer; pregnant; prevent; reproductive; response; sample collection; screening; stillbirth; success; syphilis vaccine; transmission process; treatment response; vaccine candidate; vaccine development; vaccine trial; whole genome

Project Summary/Abstract Syphilis in women is usually a silent infection caused by Treponema pallidum (T. pallidum) that can efficiently cross the placenta during all stages of pregnancy and infect the fetus. In the absence of timely diagnosis and treatment, the natural history of infection in pregnancy includes adverse birth outcomes in 80% (spontaneous abortion, stillbirth, low birthweight, preterm delivery, congenital syphilis, and neonatal death). Our team and others have documented elevated prevalence of syphilis in pregnancy in Cameroon and Zambia (3-6%) with high HIV coinfection rates (10-40%). Despite public health efforts, syphilis is the leading preventable cause of stillbirth globally and available diagnostic testing has critical limitations in pregnant women and infants. The Syphilis in Pregnancy Study (SIPS): Molecular Diagnostics and Maternal and Infant Immune Response to Infection brings together an international team of experts in perinatal and pediatric clinical infectious diseases, syphilis molecular biology and immunology to address priority questions in the STI field about the natural history of syphilis in pregnancy and vertical transmission. The SIPS team has designed an observational cohort to enroll and follow 750 well-characterized pregnant women with confirmed syphilis and their exposed infants as well as 750 pregnant controls in Cameroon and Zambia with follow up and repeated sample collection through 12 months after delivery. SIPS participants will have pre- and post-treatment blood samples, cord blood, and placentas collected from women, neonates, and infants to assess immune responses in addition to oral and lesion swabs for PCR testing to carry out the following aims: Aim 1: Identify clinical and host factors independently associated with favorable birth outcomes among pregnant women with syphilis; Aim 2: Characterize the adaptive T. pallidum immune response before and after treatment in pregnant women and their exposed infants; Aim 3: Evaluate quantitative PCR (qPCR) testing on oral and lesion swabs to detect T. pallidum and enhance diagnostic testing in pregnancy and neonates. Aim 1 will test the hypothesis that factors associated with robust maternal immunity will be associated with favorable birth outcomes in multivariable models with clinical and host factors. Aim 2 will test the hypothesis that a robust adaptive immune response (humoral immunity and CD4 T cells) will protect against vertical transmission and assess the role of T. pallidum-specific transplacental maternal antibodies in mediating fetal and infant protection. Aim 3 will test our hypothesis that newly developed molecular diagnostic testing of easily collected oral swabs will help refine and improve the diagnosis of syphilis in pregnant women and infants. Our expected outcome is to identify T. pallidum antigens with a role in dissemination, placental attachment, and vertical transmission. Our long-term goals are to advance these newly identified antigens as potential vaccine candidates for reproductive age women and to support syphilis diagnostic testing with highly specific molecular testing and specific antigens that can discern syphilis stage and treatment response in pregnant women and infants.

项目概要/摘要 女性梅毒通常是由梅毒螺旋体（T. pallidum）引起的无声感染，可有效 在怀孕的各个阶段穿过胎盘并感染胎儿。在没有及时诊断和治疗的情况下 治疗期间，妊娠期感染的自然史包括 80% 的不良分娩结果（自发性 流产、死产、低出生体重、早产、先天性梅毒和新生儿死亡）。我们的团队和 其他人记录了喀麦隆和赞比亚妊娠期梅毒患病率升高（3-6%） HIV 合并感染率较高（10-40%）。尽管做出了公共卫生努力，梅毒仍然是可预防的主要病因 全球范围内的死产和可用的诊断检测对孕妇和婴儿来说具有严重的局限性。这 妊娠期梅毒研究 (SIPS)：分子诊断和母婴免疫反应 Infection汇集了围产期和儿科临床感染性疾病领域的国际专家团队， 梅毒分子生物学和免疫学，以解决性传播感染领域有关自然传播的优先问题 妊娠梅毒史及垂直传播。 SIPS团队设计了一个观察性的 队列招募并跟踪 750 名确诊梅毒孕妇及其接触者 对喀麦隆和赞比亚的婴儿以及 750 名怀孕对照进行跟踪和重复采样 交货后 12 个月内收集。 SIPS 参与者将获得治疗前和治疗后的血液样本， 从妇女、新生儿和婴儿身上收集脐带血和胎盘，以评估免疫反应 除了口腔和病变拭子进行 PCR 检测之外，还可以实现以下目标： 目标 1：识别临床和病变部位 宿主因素与梅毒孕妇的良好分娩结局独立相关； 目标 2：表征孕妇治疗前后的适应性梅毒螺旋体免疫反应 及其暴露的婴儿；目标 3：评估口腔和病变拭子的定量 PCR (qPCR) 检测以检测 梅毒螺旋体并加强妊娠和新生儿的诊断检测。目标 1 将检验以下假设： 与强大的孕产妇免疫力相关的因素将与良好的出生结果相关 具有临床和宿主因素的多变量模型。目标 2 将检验以下假设：强大的适应性免疫 反应（体液免疫和 CD4 T 细胞）将防止垂直传播并评估 梅毒螺旋体特异性经胎盘母体抗体介导胎儿和婴儿保护。目标 3 将进行测试 我们的假设是，新开发的针对容易收集的口腔拭子的分子诊断测试将有助于完善 提高孕妇和婴儿梅毒的诊断率。我们的预期结果是识别 T。 苍白球抗原在传播、胎盘附着和垂直传播中发挥作用。我们的长期 目标是推动这些新发现的抗原成为育龄期潜在的候选疫苗 女性并通过高度特异性的分子检测和特异性抗原支持梅毒诊断检测 可以辨别孕妇和婴儿的梅毒阶段和治疗反应。