Impact of gestational SARS-CoV-2 and maternal inflammation on child growth and neurodevelopment in a malaria-endemic setting

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PROJECT SUMMARY / ABSTRACT Since the emergence of SARS-CoV-2 in 2020, millions of pregnancies in malaria-endemic sub-Saharan Africa have been impacted by SARS-CoV-2 infection. High rates of SARS-CoV-2 and malaria co-infections during pregnancy will continue as new SARS-CoV-2 variants emerge and cause re-infections in subsequent waves. SARS-CoV-2 and malaria in pregnancy are both associated with adverse birth and infant outcomes – including preterm birth, low birth weight, and impaired growth and neurodevelopment – possibly mediated through maternal inflammation. Data on long-term developmental effects of gestational SARS-CoV-2 in highly malaria exposed populations are lacking. To address this gap, I will leverage samples and data from mother-infant dyads enrolled in two complementary ongoing NIH-funded antimalarial chemoprevention trials in Busia, Uganda. In the pregnancy trial, pregnant women are randomized to one of three antimalarial chemoprevention regimens and followed through delivery; infants born to these women are being randomized in a separate clinical trial to receive antimalarial chemoprevention or placebo and followed to age 4 years. These trials have coincided with Uganda’s early SARS-CoV-2 surges, and preliminary data indicate high incidence of both SARS-CoV-2 and malaria during pregnancy. Using clinical data and samples collected as part of the ongoing trials, I will test the hypothesis that infants exposed to gestational SARS-CoV-2 will have impaired growth and neurodevelopment in early childhood when compared with unexposed infants, and that this is mediated by maternal inflammation. I further hypothesize that exposure to both SARS-CoV-2 and malaria in pregnancy increases adverse infant outcomes due to the synergistic inflammatory effects of both pathogens. In Aim 1, I will use serologic testing of stored plasma samples to retrospectively identify mothers who experienced SARS-CoV-2 during pregnancy and compare the growth of infants with and without gestational SARS-CoV-2 exposure through age 4 years. In Aim 2, I will compare neurocognitive test scores at ages 24 and 42 months among infants with and without gestational SARS-CoV-2. In Aim 3, I will explore maternal proteomic immune signatures of SARS-CoV-2 in pregnancy and determine if the effect of gestational SARS-CoV-2 on infant growth and neurodevelopment is mediated by specific inflammatory pathways. This cohort is uniquely poised to address the impact of SARS-CoV-2 in pregnancy in a malaria endemic setting, with longitudinal data and samples collected before widespread baseline SARS-CoV- 2 immunity. To accomplish these aims and become an independent translational researcher in tropical perinatal infections, I have assembled an interdisciplinary mentorship team of experts in in infectious diseases, obstetrics, pediatrics, neuropsychology, immunology, and global health. Results from this proposed study have immediate implications for improving care of at-risk infants, and could identify diagnostic or therapeutic targets for future clinical interventions.