Young hosts, old challenges: towards the development of a protective pediatric malaria vaccine 2263

Abstract Description 60–80% of malaria-associated deaths occur in children under the age of 5, yet no highly efficacious pediatric malaria vaccines exist. Attenuated malaria parasite vaccines that induce liver-resident memory CD8+ T cells (TRM) can foster sterilizing immunity in adults but not in young children. Age-associated differences in the phenotype, function, and maturation of human hepatic immunity remain understudied. To address this, we created a biorepository of human livers and compared age-associated hepatic immune profiles by single-cell spatial transcriptomics and proteomics. Early after birth, pediatric livers exhibit reduced frequencies of conventional ab T cells and increased frequencies of innate lymphocytes as compared to adults. Moreover, while mucosal and lymphoid tissues are enriched in Vd1 gdT cells, the pediatric liver is populated by Vd2 gdT cells and few Vd1 gdT cells. We also observed an age-associated switch from inflammatory macrophages in early life to non-inflammatory macrophages in adulthood. To explore the impact of altered pediatric hepatic immunity on vaccine outcomes, we developed a pediatric mouse model of malaria vaccination and show that attenuated parasite vaccines exhibit reduced efficacy in pediatric mice despite generating comparable frequencies of TRM. Together, our data indicate that alterations to hepatic immunity early in life impair the generation of functional TRM, and we are currently investigating the mechanisms behind this observation. Funding Sources Seattle Childrens Team Science Ignition Award Seattle Childrens Research Institute Seed Fund Topic Categories Vaccines and Immunotherapy (VAC)