Hemozoin and liver stage malaria vaccine efficacy - Despite being linked to febrile disease nearly 150 years ago, malaria still kills more than 600,000 people each year; most of those individuals being children under the age of 5 in sub-Saharan Africa. These numbers highlight the urgent need to develop effective antimalarial vaccines. The plasmodium parasite replicates in an asymptomatic liver stage followed by the symptomatic blood stage. Our lab and others have found that circulating (TCIRCM) and liver resident memory (TRM) CD8+ T cells targeting liver stage malarial antigens can facilitate sterilizing immunity. The gold standard of inducing liver stage protection has long been immunization with Radiation Attenuated Sporozoites (RAS), which arrest in replication during the asymptomatic liver stage. It has been demonstrated in murine and human models that RAS immunization can provide sterilizing immunity to malaria in 100% of subjects. However, this protection drops precipitously in individuals with prior malaria exposure. Our lab and others have modeled this discrepancy and found that mice with prior malaria exposure have reduced CD8+ T cell responses to RAS immunization which drives this impaired protection. We have determined this to be a T cell extrinsic defect, implicating compromised functions of antigen presenting cells (APCs) as the primary driver of the T cell defect. Unfortunately, the mechanism nor the host and/or parasite- derived factors mediating this phenotype are unknown. Our long-term goal is to understand the biology that underlies the impaired CD8+ T cell responses observed in blood stage malaria experienced individuals. We have identified the blood stage malarial pigment hemozoin (Hz) as a candidate driver of impaired CD8+ T cell priming, as injection of synthetic Hz phenocopies our findings of CD8+ T cell impairment in plasmodium experienced mice. Moreover, Hz has been demonstrated to be taken up by APCs and we have found evidence that it impairs antigen uptake and chemokine-directed migration in these APCs. In Aim 1, we will determine the effects of Hz on CD8+ T cell priming using innovative approaches including intravital microscopy and scRNAseq. Importantly, we have designed an mRNA vaccine that elicits equivalent circulating CD8+ T cell responses in malaria experienced mice and naïve controls. In Aim 2, we will optimize mRNA LNP vaccination strategies to maximize both TCIRCM and TRM generation and protection in malaria experienced hosts utilizing cutting-edge LNP targeting strategies and cytokine encoding mRNAs. Finally, yellow fever virus (YFV) co-circulates in malaria endemic regions. Therefore, the YFV vaccine is recommended for individuals living in these regions. Despite the established impairment of malaria exposure on vaccine-induced T cell responses, it is unknown how malaria exposure impacts YFV vaccine efficacy. In Aim 3, we will incorporate a murine model of YFV vaccination to determine the impact of prior malaria exposure on YFV vaccine responses. The results of this proposal will provide a mechanistic understanding into CD8+ T cell mediated immunity to arthropodborne pathogens in malaria exposed individuals and define novel vaccination strategies to maximize immunity.
