A replication-competent late liver stage-attenuated human malaria parasite.

Debashree Goswami,Chaitra Parthiban,Ashley M Vaughan,Stefan H.I Kappe,Nelly Camargo,Spencer Y Kennedy,Carola Schäfer,Sean C Murphy,Thao Nguyen,Navin K Locham,Carolyn Brager,William Betz

doi:10.1172/jci.insight.135589

Abstract

Whole-sporozoite vaccines engender sterilizing immunity against malaria in animal models and importantly, in humans. Gene editing allows for the removal of specific parasite genes, enabling generation of genetically attenuated parasite (GAP) strains for vaccination. Using rodent malaria parasites, we have previously shown that late liver stage-arresting replication-competent (LARC) GAPs confer superior protection when compared with early liver stage-arresting replication-deficient GAPs and radiation-attenuated sporozoites. However, generating a LARC GAP in the human malaria parasite Plasmodium falciparum (P. falciparum) has been challenging. Here, we report the generation and characterization of a likely unprecedented P. falciparum LARC GAP generated by targeted gene deletion of the Mei2 gene: P. falciparum mei2-. Robust exoerythrocytic schizogony with extensive cell growth and DNA replication was observed for P. falciparum mei2- liver stages in human liver-chimeric mice. However, P. falciparum mei2- liver stages failed to complete development and did not form infectious exoerythrocytic merozoites, thereby preventing their transition to asexual blood stage infection. Therefore, P. falciparum mei2- is a replication-competent, attenuated human malaria parasite strain with potentially increased potency, useful for vaccination to protect against P. falciparum malaria infection.

Highlights

Malaria continues to be a global threat to public health
P. falciparum mei2– is a replicationcompetent, attenuated human malaria parasite strain with potentially increased potency, useful for vaccination to protect against P. falciparum malaria infection
Fah–/–RAG2–/–IL2rg–/– (FRG) mice repopulated with primary human hepatocytes (FRG huHep) [41] were infected with 1 million WT P. falciparum NF54 sporozoites, and infected livers were removed at different time points of liver stage development and subjected to tissue sectioning

Summary

Introduction

Malaria continues to be a global threat to public health. In 2018, 228 million new cases of clinical malaria were estimated to have occurred, including 405,000 fatalities. In malaria-endemic regions naturally acquired immunity develops after repeated episodes of malaria infection that prevents severe disease, mainly due to immunity against blood stages. There is recent evidence of immunity against the preerythrocytic stages, the sporozoite and liver stages [2,3,4,5,6,7]. A highly efficacious malaria vaccine that targets the clinically silent phase of parasite infection in the liver and thereby prevents blood stage infection would prevent the mortality and morbidity associated with malaria disease and block the cycle of transmission and, likely be essential for ultimate malaria eradication

Methods

Results

Conclusion