Immunity to Placental Malaria: Persistence of Antibodies to VAR2CSA

描述(由申请人提供)：对胎盘疟疾的免疫力在妇女中持续多长时间，特别是在一次或多次怀孕期间接受间歇性预防性治疗的妇女？关注疟疾孕妇护理的研究人员、临床医生和公共卫生政策官员提出了这个问题。这个问题特别重要，因为疟疾在世界许多地区的传播正在减少，在没有加强的情况下，抗体和T细胞对恶性疟原虫抗原的反应迅速下降。恶性疟原虫对孕妇来说很严重，因为感染的红细胞表达VAR2CSA，这是一种与滋养层细胞上的硫酸软骨素A结合的蛋白质，导致感染的红细胞在胎盘中积聚。因此，会发生炎症和病理，增加流产、早产和低出生体重婴儿的风险。幸运的是，VAR2CSA抗体可以改善妊娠结局。然而，对于长寿命浆细胞和记忆B细胞(MBC)对VAR2CA的诱导和维持，目前还知之甚少。数据表明，对VAR2CSA的反应不同于其他疟疾抗原，记忆可能在一次怀孕期间产生。这项拟议的研究旨在表征B细胞对VAR2CSA的记忆反应，并确定这种反应在两组妇女中持续多长时间，即不再怀孕的妇女和多次接受IPT的妇女。这项研究将在喀麦隆的雅温得�进行。自2009年以来，我们每月跟踪观察接受IPT的孕妇。在这些妇女中，430名妇女在分娩时对VAR2CSA有显著的抗体水平。我们建议在2015年进行一项横断面随访研究，并在这些女性中测量抗体水平和VAR2CSA的MBC数量，并在2016年再次测量保持阳性的女性的抗体水平和MBC数量；从而在1.5至8年期间监测免疫维持情况。如果免疫力持续8年，我们以前研究(1995-2005)中登记的妇女可以被研究，将期限从1.5年延长到20年。在临床试验、抗体对VAR2CSA的反应以及抗体半衰期建模方面有专长的科学家将进行这项研究。这项研究测试了一种创新的假设，即在分娩时对VAR2CSA具有35%高亲和力抗体的女性中，抗VAR2CSA抗体持续30年，而在具有35%高亲和力抗体的女性中，该抗体持续3年。AB水平到全长VAR2CA(FV2)、6个Duffy样结合结构域、多态变异、对FV2的抗体亲和力、MBC数量和临床数据将被用来定义长期记忆反应及其影响因素。结果将提供关于长寿命浆细胞和MBC对VAR2CSA的持续时间的关键信息；确定在具有高抗体水平的多胎患者中，如果他们在随后的怀孕中接受IPT，对VAR2CSA的抗体水平是保持还是下降；并确定高亲和力抗体与对VAR2CSA的长期记忆之间是否存在关联。如果是真的，可以开发一种基于对VAR2CSA亲和力的诊断试验来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.