Determining the key features of immunity associated with protection against pregnancy associated malaria

About This Grant

Abstract Approximately 36 million women are at risk of Plasmodium falciparum infection annually. Even asymptomatic, low-level parasitemia can lead to placental sequestration of parasites, primarily mediated by the P. falciparum VAR2CSA protein, which binds to placental tissue. This sequestration is associated with adverse pregnancy outcomes, including low birth weight (LBW), small-for-gestational age (SGA), preterm birth, and neonatal mortality. Current standard of care, intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine- pyrimethamine (SP), is increasingly compromised by widespread drug resistance. While alternatives such as dihydroartemisinin-piperaquine (DP) have shown promise in reducing parasitemia, they have not consistently improved fetal outcomes and may carry potential risks. Immunity to placental malaria is remarkably effective and often develops after a single pregnancy, mainly through antibodies targeting VAR2CSA. These antibodies inhibit parasite binding and are associated with better birth outcomes, motivating the potential for a vaccine. However, VAR2CSA is diverse, likely limiting the efficacy of current monovalent vaccines. Existing antibody assays have been limited to studying just a few VAR2CSA clades, restricting our understanding of the full breadth of naturally acquired immunity. Our preliminary work demonstrates our ability to assemble and analyze global VAR2CSA sequences from whole-genome data, and to comprehensively characterize the antibody response using phage immunoprecipitation sequencing (PhIP-seq). The objective of this K08 proposal is to leverage our VAR2CSA sequence database to design a high-resolution peptide library for PhIP-seq, enabling detailed profiling of antibody responses. We will leverage an existing longitudinal cohort of Ugandan pregnant women where blood and serum have already been collected. Specifically, we will: (1) sequence full-length VAR2CSA during pregnancy to assess how sequence variation influences infection and immunity (Aim 1); (2) evaluate how different treatments (SP vs. DP) affects the breadth of VAR2CSA-specific antibodies (Aim 2); and (3) compare primigravida and multigravida women to identify immunogenic epitopes associated with protective immunity (Aim 3). Through this research, we aim to deepen our understanding of naturally acquired immunity to VAR2CSA, inform vaccine development strategies, and ultimately contribute to reducing malaria- related maternal and neonatal morbidity. This proposal will build upon the applicant's background in malaria, bioinformatics, and genomics by providing targeted training in (1) advanced evolutionary genomics, (2) high- dimensional and longitudinal data analysis, and (3) epidemiological methodology and cohort design. An experienced mentorship team will oversee the training plan outlined. This program will thoroughly prepare the applicant for a successful independent research career as an infectious disease scientist, with a focus on host- pathogen interactions.