학술논문
A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion.
Document Type
Academic Journal
Author
Goswami D; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Patel H; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Betz W; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Armstrong J; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Camargo N; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Patil A; Sanaria Inc., 9800 Medical Center Dr., Rockville, MD, 20850, USA.; Chakravarty S; Sanaria Inc., 9800 Medical Center Dr., Rockville, MD, 20850, USA.; Murphy SC; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.; Sim BKL; Sanaria Inc., 9800 Medical Center Dr., Rockville, MD, 20850, USA.; Vaughan AM; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Hoffman SL; Sanaria Inc., 9800 Medical Center Dr., Rockville, MD, 20850, USA.; Kappe SH; Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA, 98109, USA. stefan.kappe@seattlechildrens.org.; Department of Pediatrics, University of Washington, Seattle, WA, USA. stefan.kappe@seattlechildrens.org.
Source
Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101487380 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE
Subject
Language
English
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.
(© 2024. The Author(s).)
(© 2024. The Author(s).)