[Honolulu] : [University of Hawaii at Manoa], [August 2013]
Abstract
Ph.D. University of Hawaii at Manoa 2013.Includes bibliographical references.Women are highly susceptible to malaria during pregnancy, because parasites express the VAR2CSA-adhesin that facilitates the binding of infected erythrocytes to placental syncytotrophoblasts, resulting in a condition known as placental malaria. Currently, vaccines to prevent placental malaria are being developed; however, testing vaccines for pregnant women will be challenging in the absence of serological assays that predict protection. This study sought to identify correlates of protection for placental malaria. Plasma from women with ≥ 3 pregnancies were evaluated, allowing us to delineate fine immunologic differences between placental malaria-positive and-negative women. First, we evaluated naturally acquired immunity to a recombinant protein, ID1-ID2a that contains the minimal sequence of VAR2CSA required for binding to the placenta. Our results showed that antibodies to ID1-ID2a were not associated with protection from placental malaria. Next, we employed a multi-assay approach and compared immune responses to full length and different VAR2CSA domains in 24 assays. Data showed that women in their 3rd and 4th pregnancies residing in a low transmission areas were acquiring immunity, and had lower antibody levels to VAR2CSA, recognized fewer VAR2CSA domains, and had lower avidity antibodies to VAR2CSA; whereas, women with ≥5 pregnancies were likely to have malaria only if they had low avidity IgG to VAR2CSA. Multivariate regression models and recursive partitioning methods resulted in Younden index of 0.39 and 0.45, respectively. Since models with different combinations of assays resulted in similar predictive power, it is likely that more than one correlate of protection exists depending on a woman's age, gravidity, exposure to VAR2CSA and antibodies to other malarial antigens. Lastly, we measured how long immunity to VAR2CSA persists. Antibody half-life estimates ranged from 4 years to a lifetime in multigravidae; but, antibodies to VAR2CSA in primigravidae were short lived, averaging less than a year. Thus, a single pregnancy is not sufficient to generate long-lived memory B cells. Knowing what assays correlate with protection and how long after vaccination protective immunity persists is imperative for development of a vaccine
