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（由申请人提供）：女性，尤其是在一次或多次怀孕期间接受间歇性预防治疗（IPT）的女性，对胎盘疟疾的免疫力能持续多久？研究人员、民众和公共卫生政策相关官员正在询问这个问题。这个问题尤其重要，因为世界许多地区的疟疾传播正在减少，并且在缺乏疟原虫抗原的情况下，抗体（Ab）和 T 细胞对恶性疟原虫抗原的反应迅速下降。恶性疟原虫疟疾对孕妇的影响非常严重，因为受感染的红细胞表达 VAR2CSA（一种与滋养细胞上的硫酸软骨素 A 结合的蛋白质），导致受感染的红细胞在胎盘中积聚，从而增加发生炎症和病理的风险。幸运的是，VAR2CSA 抗体 (Ab) 可以改善妊娠结局。众所周知，长寿命浆细胞和记忆 B 细胞 (MBC) 对 VAR2CA 的诱导和维持。数据表明，对 VAR2CSA 的反应与其他疟疾抗原不同，并且记忆可能在单次妊娠期间产生。旨在描述 B 细胞对 VAR2CSA 的记忆反应，并确定两组妇女（即不再怀孕的妇女和多次怀孕期间接受 IPT 的妇女）的记忆反应持续时间。自 2009 年以来，我们在整个怀孕期间每月对接受 IPT 的妇女进行跟踪，其中超过 430 名妇女在分娩时具有大量 VAR2CSA 抗体水平。测量这些女性中 VAR2CSA 的抗体水平和 MBC 数量，并在 2016 年再次测量那些仍呈阳性的女性，从而监测 1.5 至 8 年期间免疫力的维持情况；持续>8年，可以对参与我们之前研究（1995-2005）的女性进行研究，将期限从1.5年延长至20年，具有临床试验、VAR2CSA抗体反应和抗体半衰期建模专业知识的科学家将进行研究。该研究测试了一项创新假设，即分娩时 VAR2CSA 抗体高亲和力超过 35% 的女性，其 VAR2CSA 抗体持续时间超过 30 年，而分娩时抗体持续时间不到 3 年。对全长 VAR2CA (FV2) 的高亲和力抗体水平 <35% 的女性、6 个 Duffy 样结合域、多态性变体、对 FV2 的抗体亲和力、MBC 数量和临床数据将用于定义持久记忆反应及其影响因素将提供有关 VAR2CSA 的长寿浆细胞和 MBC 持续时间的关键信息；如果在随后的妊娠中接受 IPT，具有高抗体水平的多妊娠科动物的抗体水平会维持或下降；并确定高亲和力抗体与 VAR2CSA 的长期记忆之间是否存在关联。如果属实，则可以开发基于对 VAR2CSA 亲和力的诊断测试。用于确定孕妇的免疫状态。