Molecular Epidemiology of Malaria in Pregnancy

Malaria in pregnancy remains a significant public health problem with an estimated 125 million pregnant women at risk for Plasmodium falciparum malaria globally every year. Pregnancy associated malaria (PAM) causes several adverse pregnancy and birth outcomes including maternal anemia, low birth weight (LBW), and small-for-gestational age (SGA). PAM also results in 10,000 maternal and 70,000-200,000 infant deaths annually. The key biological mechanism by which the plasmodium parasite infects pregnant women is through sequestration of infected erythrocytes in the placenta. This sequestration facilitated by a large polymorphic plasmodium surface antigen, VAR2CSA. Efforts are underway to develop the first syndrome-specific malaria vaccine against PAM targeting VAR2CSA. The ID1-DBL2x region of VAR2CSA is the minimal binding epitope and has emerged as a lead vaccine candidate. However, there is limited data on the extent of genetic diversity of ID1-DBL2x in field isolates. Also it is unknown if particular variants are more pathogenic than others. In this dissertation, we leveraged advanced molecular methods, population genetics, and epidemiology to inform vaccine development efforts. Using samples from P. falciparum-infected pregnant women in Malawi and Benin, we characterized the genetic diversity of the ID1-DBL2x vaccine target and identified pathogenic clades. We demonstrated that ID1-DBL2x region is highly diverse in both countries. We found that the entire 1.6kb region is primarily under balancing selection, confirming its role as an important epitope. Importantly, our phylogenetic analyses showed clustering of ID1-DBL2x variants in multiple distinct clades. Two clades containing the vaccine referent strains (3D7 and FCR3) were found in both countries in addition to three unique clades in Benin. Across multiple birth outcomes we consistently identified variants from 3D7-like clade as pathogenic. We did detect LBW and SGA variants in FCR3-like clade. However, compared to FCR3-like clade, 3D7-like clade was associated with LBW, SGA, and lower infant birth weight. Overall, our results provide strong evidence for developing a polyvalent VAR2CSA-based vaccine against PAM. A vaccine that includes variants from most common and pathogenic clades will be more efficacious than current monovalent vaccines in phase I trials. The integrative approach used here can be employed to inform development of future malaria vaccine candidates targeting polymorphic antigens.Doctor of Philosoph