Immunity to Placental Malaria: Persistence of Antibodies to VAR2CSA

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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.