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

Area of Science:

• Infectious Diseases
• Vaccinology
• Parasitology

Background:

• Whole-sporozoite vaccines induce sterilizing immunity against malaria.
• Genetically attenuated parasites (GAPs) are generated by removing specific parasite genes.
• Late liver stage-arresting replication-competent (LARC) GAPs offer superior protection compared to other attenuated strains.

Purpose of the Study:

• To generate and characterize a novel LARC GAP strain of the human malaria parasite Plasmodium falciparum (P. falciparum).
• To assess the potential of this new GAP for malaria vaccination.

Main Methods:

• Targeted gene deletion of the Mei2 gene in P. falciparum to create the P. falciparum mei2- GAP.
• Infection of human liver-chimeric mice with the P. falciparum mei2- strain.
• Evaluation of liver stage development, replication, and merozoite formation in vivo.

Main Results:

• The P. falciparum mei2- GAP exhibited robust exoerythrocytic schizogony, including significant cell growth and DNA replication in liver stages.
• Developmental arrest occurred before the formation of infectious exoerythrocytic merozoites.
• The P. falciparum mei2- strain failed to transition to the asexual blood stage, indicating attenuation.

Conclusions:

• The P. falciparum mei2- strain represents a novel, replication-competent, and attenuated P. falciparum GAP.
• This strain successfully arrests in the liver stage without forming infectious merozoites, making it a promising candidate for malaria vaccines.
• The P. falciparum mei2- GAP has the potential for increased vaccine potency against P. falciparum malaria.