Clinical impact of submicroscopic malaria on delivery outcomes and the role of VAR2CSA antibodies in pregnant women from Colombia

  • Author / Creator
    Gavina, Kenneth C
  • Malaria caused by the genus Plasmodium (P.) is one of the oldest and most important parasitic infections globally. Pregnant women are at an increased risk for malaria, where the disease poses a significant risk to both maternal and child health. Better diagnosis of malaria can have an immediate impact on patient care, and provide a valuable tool to describe the prevalence of disease and host-parasite interactions. Although microscopy is the gold standard for malaria diagnosis, more sensitive tests are needed to identify submicroscopic infections (SMIs). In this thesis, I developed an RT-qPCR assay to identify P. falciparum and P. vivax infections at the submicroscopic level, validated it using panel of clinical samples from Colombia, and demonstrated the superior sensitivity directly to qPCR for screening SMIs at the species level. The impact of malaria in pregnancy (MiP) has been well described. However, less is known about the effects of SMIs in pregnancy, particularly in areas of lower transmission where P. falciparum and P. vivax co-exist. To investigate the impact of SMIs in pregnancy, we performed a longitudinal study to follow pregnant women from an endemic area of Colombia with co-circulating P. falciparum and P. vivax. A cohort of 180 pregnant women from Colombia were followed through antenatal visits from recruitment until delivery. Malaria was diagnosed by light microscopy, SMIs by RT-qPCR, and placental malaria by histopathology. We evaluated the impact of SMI on maternal anemia, low birth weight (LBW), pre-mature birth (PTB), and small for gestational age (SGA) babies. We observed that SMIs occurred frequently in our pregnant population. Twenty-five percent (45/180) of the women were diagnosed with at least one SMI during follow-up. While SMIs were not generally associated with adverse outcomes at delivery, we showed a novel finding that women who had a mixed P. falciparum and P. vivax SMI during pregnancy, were significantly associated with risk for PTB compared to women without infection. VAR2CSA, a protein belonging to the P. falciparum erythrocyte membrane protein-1 family, is expressed on the surface of infected red blood cells (iRBCs) and mediates binding of the iRBC to chondroitin sulfate A (CSA) found in the placenta. Antibodies specific to VAR2CSA have been shown to confer protection against MiP based on studies conducted in Africa. To test this in our population, we measured serum VAR2CSA-specific antibody levels by ELISA, tested the function of these antibodies by the ability to inhibit adhesion of iRBCs to CSA in vitro, and evaluated their role in protection from adverse clinical outcomes at delivery. We showed that over 60% of women analyzed in our study had antibodies to the full-length VAR2CSA protein at inclusion, regardless of parity. Antibody levels decreased during pregnancy and boosting was not observed following subsequent Plasmodium exposure. We observed that the function of antibodies, defined as the ability to inhibit CSA adhesion in vitro, and not antibody levels, were significantly associated with protection from SMI-related maternal anemia at delivery. The work in this thesis involved the validation of a highly sensitive screening diagnostic for SMIs at the species level and also laid a framework for development of a direct-from-blood RNA-based diagnostic to be used in the field or at the point-of-care. Results from the longitudinal study revealed a high frequency of SMIs in pregnancy in this region and enhance our understanding of both the impact of SMI in pregnancy as well as the protective role of VAR2CSA-specific antibodies.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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