The role of antigen in the maintenance and localisation of CD8+ T-cells in the context of liver stage malaria

Thesis

A highly effective vaccine against malaria is urgently needed, with leading vaccination strategies involving the induction of protective antigen-specific CD8⁺ T-cells via heterologous prime-boost viral vector immunization, targeting primarily the pre- erythrocytic liver stages of the Plasmodium falciparum lifecycle. To date, the greatest immunogenicity has been obtained through a heterologous prime boost regimen, where vaccination with an Adenoviral vector is followed 8 weeks later by a Modified Vaccinia Ankara virus (MVA) boost. Experimental work directed at providing a greater understanding of CD8⁺ T-cell memory responses induced by Ad-MVA vaccinations lead to the development of a novel vaccine strategy aimed at priming CD8⁺ T-cells in the periphery and subsequently targeting them to hepatic tissue with protein loaded poly(lactic- co-glycolic acid) nanoparticles or recombinant viral vectors. Durable Ag-specific CD8+ T- cells exhibiting a phenotype of tissue-resident memory T-cells were generated in the liver, with a ten-fold increase over the conventional heterologous vector regimen. Importantly, in P. berghei sporozoite challenge models of liver-stage malaria, this strategy was found to result in unprecedented levels of sterile protection across multiple clinically relevant antigens and mouse strains. This prime and target immunization strategy for liver-stage malaria may provide a novel general approach for prevention or immunotherapy against other hepato-trophic pathogens.

Authors: Gola, A

• DOI: 10.5287/ora-nobdxqbe5
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Immunology; Tissue-resident T-cells; Liver-stage malaria
• Subjects: Vaccinology; Liver-Stage Malaria; Immunology