Box 1 Questions that can be addressed with NHP models

Parasite biology

• What molecular processes support hypnozoite development, maintain their dormancy, and trigger their activation? • How do hypnozoites manipulate hepatocytes to suppress innate immune mechanisms from inside the cell and preserve them until activation? • How do malaria parasites enter and remodel the infected RBC in vivo to suit their prime directive of multiplying and releasing new merozoite progeny? • What is the molecular genesis of gametocytogenesis of non-falciparum malaria parasites?

Immunology

• What are the mechanisms that thwart the formation of long-lived serological anti-parasite antibody responses, while memory cells remain persistent and protective? • What are the host–parasite mechanisms that enable antigenic variation and immune evasion? • What is the role of the spleen in these processes? • How does pre-existing immunity against malaria parasites impact vaccine-generated responses and subsequent infections with genetically heterologous parasites? • How do immune responses that are detected in the blood stream differ from what is occurring in various tissues and the systemic development of NAI and VCI? • What are key identifiable immune correlates of protection for NAI and VCI? • What immune responses and host molecules contribute to the development of anaemia?

Pathogenesis

• What systemic ramifications may occur due to the presence of LSFs in hepatocytes? • Can peripheral blood metabolites become diagnostic for hypnozoites? • What factors cause disease pathogenesis, inflammation, and pathology in various tissues? • What roles do extracellular vesicles play, or the microbiota, and in relation to immunity? • What factors contribute to loss of uninfected RBCs and bone marrow dysfunction? • What host-directed therapies can be developed to reverse adverse manifestations of malaria?

Vector-parasite biology and transmission

• The field is wide open for the application of the latest technologies to study mosquito infectivity, transmission, and subsequent host–parasite expression and interactions in NHPs