A Replication Competent Plasmodium Falciparum Parasite Completely Attenuated by Dual Gene Deletion

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2024 Mar 22

PMID 38514791

Authors

Debashree Goswami

Hardik Patel

William Betz

Janna Armstrong

Nelly Camargo

Asha Patil

Sumana Chakravarty

Sean C Murphy

B Kim Lee Sim

Ashley M Vaughan

Stephen L Hoffman

Stefan Hi Kappe

Affiliations

Soon will be listed here.

Abstract

Vaccination with infectious Plasmodium falciparum (Pf) sporozoites (SPZ) administered with antimalarial drugs (PfSPZ-CVac), confers superior sterilizing protection against infection when compared to vaccination with replication-deficient, radiation-attenuated PfSPZ. However, the requirement for drug administration constitutes a major limitation for PfSPZ-CVac. To obviate this limitation, we generated late liver stage-arresting replication competent (LARC) parasites by deletion of the Mei2 and LINUP genes (mei2/linup or LARC2). We show that Plasmodium yoelii (Py) LARC2 sporozoites did not cause breakthrough blood stage infections and engendered durable sterilizing immunity against various infectious sporozoite challenges in diverse strains of mice. We next genetically engineered a PfLARC2 parasite strain that was devoid of extraneous DNA and produced cryopreserved PfSPZ-LARC2. PfSPZ-LARC2 liver stages replicated robustly in liver-humanized mice but displayed severe defects in late liver stage differentiation and did not form liver stage merozoites. This resulted in complete abrogation of parasite transition to viable blood stage infection. Therefore, PfSPZ-LARC2 is the next-generation vaccine strain expected to unite the safety profile of radiation-attenuated PfSPZ with the superior protective efficacy of PfSPZ-CVac.

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