21 March 2024 | 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
This study presents the development of a genetically attenuated *Plasmodium falciparum* (Pf) parasite, *PfLARC2*, which is a late liver stage-arresting replication-competent (LARC) strain. The *mei2* and *linup* genes were deleted to create *PfLARC2*, resulting in a parasite that undergoes extensive liver stage (LS) replication but arrests before differentiating into mature merozoites. This LARC2 strain was shown to be completely attenuated in both humanized mice and rodent malaria models, as it did not cause breakthrough blood stage infections and provided durable sterilizing immunity against various infectious sporozoite challenges. The *PfLARC2* vaccine strain was also cryopreserved and demonstrated robust sporozoite production in mosquitoes. In humanized mice, *PfLARC2* sporozoites replicated robustly in the liver but failed to form merozoites, preventing the transition to blood stage infection. These findings suggest that *PfLARC2* is a promising next-generation vaccine strain, combining the safety profile of radiation-attenuated sporozoites with the superior protective efficacy of replication-competent sporozoites.This study presents the development of a genetically attenuated *Plasmodium falciparum* (Pf) parasite, *PfLARC2*, which is a late liver stage-arresting replication-competent (LARC) strain. The *mei2* and *linup* genes were deleted to create *PfLARC2*, resulting in a parasite that undergoes extensive liver stage (LS) replication but arrests before differentiating into mature merozoites. This LARC2 strain was shown to be completely attenuated in both humanized mice and rodent malaria models, as it did not cause breakthrough blood stage infections and provided durable sterilizing immunity against various infectious sporozoite challenges. The *PfLARC2* vaccine strain was also cryopreserved and demonstrated robust sporozoite production in mosquitoes. In humanized mice, *PfLARC2* sporozoites replicated robustly in the liver but failed to form merozoites, preventing the transition to blood stage infection. These findings suggest that *PfLARC2* is a promising next-generation vaccine strain, combining the safety profile of radiation-attenuated sporozoites with the superior protective efficacy of replication-competent sporozoites.