A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion
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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-024-00057-7 |
| _version_ | 1827277017983221760 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Debashree Goswami |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T07:12:43Z |
| format | Article |
| id | doaj.art-2fcc440695074e599b621cd9032c9199 |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T07:12:43Z |
| publishDate | 2024-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2fcc440695074e599b621cd9032c91992024-04-21T11:26:49ZengSpringer NatureEMBO Molecular Medicine1757-46842024-03-0116472375410.1038/s44321-024-00057-7A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletionDebashree Goswami0Hardik Patel1William Betz2Janna Armstrong3Nelly Camargo4Asha Patil5Sumana Chakravarty6Sean C Murphy7B Kim Lee Sim8Ashley M Vaughan9Stephen L Hoffman10Stefan HI Kappe11Center for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteSanaria Inc.Sanaria Inc.Department of Laboratory Medicine and Pathology, University of WashingtonSanaria Inc.Center for Global Infectious Disease Research, Seattle Children’s Research InstituteSanaria Inc.Center for Global Infectious Disease Research, Seattle Children’s Research InstituteAbstract 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.https://doi.org/10.1038/s44321-024-00057-7MalariaPre-erythrocyticGenetically Attenuated Parasite VaccineSporozoiteLiver Stage |
| spellingShingle | 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 A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion EMBO Molecular Medicine Malaria Pre-erythrocytic Genetically Attenuated Parasite Vaccine Sporozoite Liver Stage |
| title | A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion |
| title_full | A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion |
| title_fullStr | A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion |
| title_full_unstemmed | A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion |
| title_short | A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion |
| title_sort | replication competent plasmodium falciparum parasite completely attenuated by dual gene deletion |
| topic | Malaria Pre-erythrocytic Genetically Attenuated Parasite Vaccine Sporozoite Liver Stage |
| url | https://doi.org/10.1038/s44321-024-00057-7 |
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