T Cell Regulatory and Suppression Mechanisms in Malaria

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Our published work in FY22 included: Zaidi I, Duffy PE. PfSPZ Vaccine learns a lesson. 2021. Med, Cell Press. Dec 10. In Kenya, the first trial of the attenuated whole organism PfSPZ Vaccine in infants has shown little efficacy against malaria infection, whereas trials in African adults have repeatedly observed protection. Differences in immune responses offer clues to the possible reasons. In this commentary, we explored the factors that might hinder the induction of protective immunity by PfSPZ Vaccine, including the effects of malaria and of presumptive antimalarial treatment before immunization in malaria-endemic areas. Our unpublished progress during this reporting period includes the following advances: We extended our immune cell studies of whole sporozoite malaria vaccines, using samples from human trials and models of malaria. Sanaria PfSPZ Vaccine, comprised of radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against Pf infection, and V delta 2+ gd T cell (hereafter Vd2 cell) expansion has been associated with induction of sterile immunity. In preclinical models, expansion of protective CD8+ T cells that confer sterile immunity require gd T cells during SPZ vaccinations, but gd T cells are not required as effectors during infectious challenge. To gain a deeper insight into immune cell subsets contributing to PfSPZ Vaccine protection, we performed whole blood RNA sequencing on 48 subjects from one US and two Mali PfSPZ Vaccine trials and applied novel tools to report gene expression level and impute immune cell changes. We collated 144 published RNAseq datasets spanning 27 sorted human immune cell subsets, including innate, B, and T cell subpopulations and differentiation status, then performed 27-way differential expression analysis and associated each gene to its cell type of highest differential expression to create canonical cell-type transcriptomes. We associated transcriptomes to mathematically describe each PfSPZ participant sample as a 27-cell-type composite mix and quantify changes in cell-type proportions. By this approach, we identified a subset of Vd2 cells that expand during PfSPZ vaccinations and associate with sterile immunity. In parallel, using a mouse model of whole SPZ vaccination, we identified the corresponding subset of gd T cells that play this role in SPZ-immunized mice and that are required to generate protective CD8 T cells.