Immunity to Placental Malaria: Persistence of Antibodies to VAR2CSA

对胎盘疟疾的免疫力：VAR2CSA 抗体的持久性

• 批准号: 8989517
• 负责人: Diane Wallace Taylor
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-19 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989517
• 关键词: African; Age; Antibodies; Antibody Avidity; Antibody Response; Antigens; Avidity; Binding; Binding Proteins; Cameroon; Caring; Characteristics; Chondroitin Sulfate A; Clinical Data; Clinical Trials; Country; Data; Diagnostic tests; Enrollment; Erythrocytes; Falciparum Malaria; Fetal Development; Fetal Growth; Fetus; Goals; Gravidity; Half-Life; Health; Health Policy; Healthcare; Immune; Immunity; Infection; Infection prevention; Inflammation; Length; Life; Longevity; Low Birth Weight Infant; Maintenance; Malaria; Maternal-Fetal Exchange; Measures; Memory; Memory B-Lymphocyte; Modeling; Monitor; Mothers; Parasites; Pathology; Placenta; Plasma Cells; Plasmodium falciparum; Policy Maker; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevalence; Preventive treatment; Proteins; Public Health; Research Personnel; Rest; Risk; Scientist; Second Pregnancy Trimester; Solid; Spontaneous abortion; Sulfadoxine; Surface Antigens; T cell response; Testing; Time; Variant; Woman; Women' s Group; acquired immunity; base; follow-up; improved; innovation; long term memory; malaria transmission; placental malaria; pregnant; reproductive; response; standard of care; trophoblast

DESCRIPTION (provided by applicant): How long does immunity to placental malaria persist in women, especially in women who receive intermittent preventive treatment (IPT) during one or more pregnancies? This question is being asked by researchers, clinicians and public health policy officials concerned with the care of pregnant women exposed to malaria. The question is particularly relevant since transmission of malaria is decreasing in many parts of the world and antibodies (Ab) and T cell responses to P. falciparum antigens quickly decline in the absence of boosting. Plasmodium falciparum malaria is severe in pregnant women because infected erythrocytes express VAR2CSA, a protein that binds to chondroitin sulfate A on trophoblasts, causing infected erythrocytes to accumulate in the placenta. As a result, inflammation and pathology occur, increasing the risk of miscarriages, premature deliveries, and low birth weight babies. Fortunately, antibodies (Ab) to VAR2CSA improve pregnancy outcomes. However, little is known about the induction and maintenance of long-lived plasma cells and memory B cells (MBC) to VAR2CA. Data suggest that the response to VAR2CSA differs from other malarial antigen and that memory may be produced during a single pregnancy. The proposed study seeks to characterized the B cell memory response to VAR2CSA and determine how long it persists in two groups of women, i.e., those who do not become pregnant again and those who receive IPT over several pregnancies. The study will take place in Yaound�, Cameroon. Since 2009, we have followed women monthly throughout pregnancy who received IPT. Among these women, >430 women had substantial Ab levels to VAR2CSA at delivery. We propose to conduct a cross-sectional follow-up study in 2015 and measure Ab levels and number of MBC to VAR2CSA in these women and again in 2016 in those who remained positive; thereby monitoring maintenance of immunity over a 1.5 to 8 year period. If immunity persists >8 years, women enrolled in our previous studies (1995-2005) can be studied, extending the period from 1.5 to 20 years. Scientists with expertise in clinical trials, Ab responses to VAR2CSA, and modeling of Ab half-life will conduct the study. The study tests an innovative hypothesis that Ab to VAR2CSA persist for >30 years in women who have >35% high avidity Ab to VAR2CSA at delivery compared to <3 years in women who have <35% high avidity Ab. Ab levels to full-length VAR2CA (FV2), the 6 Duffy-like binding domains, polymorphic variants, Ab avidity to FV2, number of MBC, and clinical data will be used to define the long-lasting memory response and factors that contribute to it. Results will provide key information on how long long-lived plasma cells and MBC to VAR2CSA persist; determine if Ab levels to VAR2CSA in multigravidae who have high Ab levels are maintained or declined if they receive IPT in subsequent pregnancies; and establish if an association exists between high avidity Ab and long-term memory to VAR2CSA. If true, a diagnostic test based on avidity to VAR2CSA could be developed for determining the immune status of pregnant women.

描述（由适用提供）：女性的胎盘疟疾的免疫力持续了多长时间，尤其是在一次或多个怀孕期间接受间歇性预防治疗（IPT）的妇女中的免疫力？研究人员，临床医生和公共卫生政策官员都问了这个问题，那些与暴露于疟疾的孕妇的照顾有关。这个问题尤其重要，因为在世界许多地方，疟疾的传播正在减少，而在没有增强的情况下，对恶性疟原虫抗原的T细胞反应迅速下降。恶性疟原虫疟疾在孕妇中很严重，因为感染的红细胞表达VAR2CSA，这种蛋白质与滋养细胞上的硫酸软骨素A结合，导致感染的红细胞积聚在子宫表中。结果，发生感染和病理学，增加了流产，过早分娩和低出生体重的风险。幸运的是，对VAR2CSA的抗体（AB）改善了妊娠结局。然而，关于长寿命的浆细胞和记忆B细胞（MBC）对VAR2CA的诱导和维护知之甚少。数据表明，对VAR2CSA的反应与其他疟疾抗原不同，并且在一次妊娠期间可能会产生记忆。拟议的研究旨在表征B细胞记忆对VAR2CSA的响应，并确定两组妇女（即不再怀孕的妇女以及在怀孕期间接受IPT的人）的持续时间。这项研究将在喀麦隆的Yaound进行。自2009年以来，我们在整个怀孕期间每月都跟随女性接受IPT。在这些妇女中，> 430名妇女在分娩时具有大量的AB水平。我们建议在2015年进行一项横断面的后续研究，并在这些妇女中测量AB水平和MBC数量到VAR2CSA，并在2016年再次在那些保持积极的人中；从而监视1.5到8年的免疫维护。如果免疫力持续> 8岁，则可以研究参加我们先前研究的妇女（1995-2005），从而将期限从1.5年延长到20年。具有临床试验专业知识的科学家，AB对VAR2CSA的反应以及AB半衰期的建模将进行研究。该研究检验了一个创新的假设，即AB至VAR2CSA在交付时高35％的AB至VAR2CSA的女性中持续了30年，而<35％的妇女的VAR2CSA持续了35％。 AB水平达到全长VAR2CA（FV2），6个Duffy样结合结构域，多态性变体，与FV2的AB亲和力，MBC数量和临床数据将用于定义持久的存储器响应及其对其有助的因素。结果将提供有关长时间寿命长的浆细胞和MBC到VAR2CSA持续存在多长时间的关键信息；确定如果在随后的妊娠中接受IPT，则保持高ab水平的Multigravidae中的AB水平是否会被维持或下降；并确定在高亲和力AB和VAR2CSA的长期记忆之间是否存在关联。如果是的，则可以开发基于与VAR2CSA的亲生的诊断测试，以确定孕妇的免疫状态。