Immunity to Placental Malaria: Persistence of Antibodies to VAR2CSA

描述（由申请人提供）：女性对胎盘疟疾的免疫力持续多久，特别是在一次或多次妊娠期间接受间歇性预防治疗（IPT）的女性？关心接触疟疾的孕妇护理的研究人员、临床医生和公共卫生政策官员都在问这个问题。这个问题特别相关，因为疟疾的传播在世界许多地方正在减少，并且在没有加强的情况下，对恶性疟原虫抗原的抗体（Ab）和T细胞应答迅速下降。恶性疟原虫疟疾在孕妇中是严重的，因为受感染的红细胞表达VAR 2CSA，这是一种与滋养层上的硫酸软骨素A结合的蛋白质，导致受感染的红细胞在胎盘中积累。因此，炎症和病理学发生，增加流产，早产和低出生体重婴儿的风险。幸运的是，VAR 2CSA的抗体（Ab）可以改善妊娠结局。然而，很少有人知道的诱导和维持长寿的浆细胞和记忆B细胞（MBC）的VAR 2CA。数据表明，对VAR 2CSA的反应不同于其他疟疾抗原，并且记忆可能在单次妊娠期间产生。这项拟议的研究旨在表征B细胞对VAR 2CSA的记忆反应，并确定它在两组妇女中持续多久，即，那些没有再次怀孕的人和那些多次怀孕接受IPT的人。这项研究将在喀麦隆的雅温得进行。自2009年以来，我们在整个怀孕期间每月对接受IPT的妇女进行随访。在这些妇女中，>430名妇女在分娩时具有针对VAR 2CSA的大量Ab水平。我们建议在2015年进行一项横断面随访研究，测量这些妇女的抗体水平和MBC对VAR 2CSA的数量，并在2016年再次在那些保持阳性的妇女中进行，从而监测免疫力在1.5至8年期间的维持情况。如果免疫持续时间>8年，则可以研究我们以前研究（1995-2005）中招募的女性，将时间从1.5年延长至20年。在临床试验、抗体对VAR 2CSA的反应和抗体半衰期建模方面具有专业知识的科学家将进行这项研究。该研究测试了一个创新的假设，即在分娩时对VAR 2CSA具有>35%高亲和力Ab的女性中，对VAR 2CSA的Ab持续>30年，而在具有<35%高亲和力Ab的女性中，对VAR 2CSA的Ab持续<3年。针对全长VAR 2CA（FV 2）的抗体水平、6个Duffy样结合结构域、多态性变体、针对FV 2的抗体亲合力、MBC的数量和临床数据将用于定义持久记忆应答和促成其的因素。结果将提供关于针对VAR 2CSA的长寿浆细胞和MBC持续多久的关键信息;确定具有高Ab水平的经产妇中对VAR 2CSA的Ab水平是否维持或下降，如果他们在随后的怀孕中接受IPT;并确定高亲和力Ab和对VAR 2CSA的长期记忆之间是否存在关联。如果这是真的，那么可以开发一种基于对VAR 2CSA的亲合力的诊断测试，用于确定孕妇的免疫状态。

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.