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.

项目摘要/摘要 女性中的梅毒通常是由毛毛虫（T. pallidum）引起的沉默感染，可以有效地 在怀孕的所有阶段越过胎盘，并感染胎儿。在没有及时诊断的情况下 治疗，怀孕中感染的自然病史包括80％的不良出生结果（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 其他人则记录了喀麦隆和赞比亚怀孕中梅毒的患病率升高（3-6％） 高HIV共感染率（10-40％）。尽管努力了公共卫生，但梅毒还是可预防的主要原因 全球死产和可用的诊断测试在孕妇和婴儿中具有关键的局限性。这 妊娠研究（SIP）的梅毒：分子诊断，母亲和婴儿免疫反应 感染汇集了一个国际围产期和儿科临床传染病专家的国际专家团队， 梅毒分子生物学和免疫学，以解决STI领域的优先问题有关自然的问题 怀孕和垂直传播中梅毒的历史。 SIPS团队设计了一个观察性 队列入学并关注750名已确认梅毒的特征良好的孕妇及其暴露 喀麦隆和赞比亚的婴儿以及750个怀孕对照，随访和重复样本 分娩后12个月的收集。 SIPS参与者将有治疗前后的血液样本， 脐带血和从女性，新生儿和婴儿收集的胎盘，以评估免疫反应 除口头和病变拭子以进行PCR测试以执行以下目的：目标1：确定临床和 宿主因素与梅毒孕妇中有利的出生结果独立相关； AIM 2：特征孕妇治疗前后的适应性T. pallidum免疫反应 和他们暴露的婴儿； AIM 3：评估口服和病变拭子上的定量PCR（QPCR）测试以检测 T. pallidum并增强妊娠和新生儿的诊断测试。 AIM 1将检验以下假设 与强大的孕产妇免疫相关的因素将与有利的出生结果有关 具有临床和宿主因素的多变量模型。 AIM 2将检验以下假设是强大的自适应免疫 反应（体液免疫和CD4 T细胞）将防止垂直传播并评估 T. pallidum特异性的移植孕产妇抗体介导胎儿和婴儿保护。 AIM 3将测试 我们的假设是，新开发的对口头拭子的分子诊断测试将有助于完善 并改善孕妇和婴儿梅毒的诊断。我们的预期结果是确定T。 Pallidum抗原在传播，胎盘附着和垂直传播中发挥作用。我们的长期 目标是将这些新近确定的抗原作为生殖时代的潜在疫苗候选物 妇女并通过高度特异性的分子测试和特定抗原支持梅毒诊断测试 这可以辨别梅毒阶段和孕妇和婴儿的治疗反应。