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Summary The human malaria parasite Plasmodium vivax remains vastly understudied, mainly due to the lack of suitable laboratory models. Here, we report a humanized mouse model to test interventions that block P. vivax parasite transition from liver stage infection to blood stage infection. Human liver-chimeric FRGN huHep mice infected with P. vivax sporozoites were infused with human reticulocytes, allowing transition of exo-erythrocytic merozoites to reticulocyte infection and development into all erythrocytic forms, including gametocytes, in vivo. In order to test the utility of this model for preclinical assessment of interventions, the invasion blocking potential of a monoclonal antibody targeting the essential interaction of the P. vivax Duffy Binding Protein with the Duffy antigen receptor was tested by passive immunization. This antibody inhibited invasion by over 95%, providing unprecedented in vivo evidence that PvDBP constitutes a promising blood stage vaccine candidate and proving our model highly suitable to test blood stage interventions.

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A highly efficacious malaria vaccine that prevents disease and breaks the cycle of infection remains an aspirational goal of medicine. Whole parasite vaccines based on the sporozoite forms of the parasite that target the clinically silent pre-erythrocytic stages of infection have emerged as one of the leading candidates. In animal models of malaria, these vaccines elicit potent neutralizing Ab responses against the sporozoite stage and cytotoxic T cells that eliminate parasite-infected hepatocytes. Among whole-sporozoite vaccines, immunization with live, replication-competent whole parasites engenders superior immunity and protection when compared with live replication-deficient sporozoites. As such, the genetic design of replication-competent vaccine strains holds the promise for a potent, broadly protective malaria vaccine. In this report, we will review the advances in whole-sporozoite vaccine development with a particular focus on genetically attenuated parasites both as malaria vaccine candidates and also as valuable tools to interrogate protective immunity against Plasmodium infection.