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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\n                    <jats:italic>Mei2<\/jats:italic>\n                    and\n                    <jats:italic>LINUP<\/jats:italic>\n                    genes (\n                    <jats:italic>mei2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2013<\/jats:italic>\n                    <\/jats:sup>\n                    \/\n                    <jats:italic>linup<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2013<\/jats:italic>\n                    <\/jats:sup>\n                    or LARC2). We show that\n                    <jats:italic>Plasmodium yoelii<\/jats:italic>\n                    (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.\n                  <\/jats:p>","DOI":"10.1038\/s44321-024-00057-7","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T06:02:05Z","timestamp":1711000925000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-0482","authenticated-orcid":false,"given":"Debashree","family":"Goswami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-4510","authenticated-orcid":false,"given":"Hardik","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5709-2223","authenticated-orcid":false,"given":"William","family":"Betz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Camargo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asha","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumana","family":"Chakravarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean C","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-8905","authenticated-orcid":false,"given":"B Kim Lee","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5815-756X","authenticated-orcid":false,"given":"Ashley M","family":"Vaughan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1540-1731","authenticated-orcid":false,"given":"Stefan HI","family":"Kappe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"57_CR1","doi-asserted-by":"publisher","first-page":"e1001685","DOI":"10.1371\/journal.pmed.1001685","volume":"11","author":"ST Agnandji","year":"2014","unstructured":"Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Kabwende AL, Adegnika AA, Mordm\u00fcller B, Issifou S, Kremsner PG, Loembe MM et al (2014) Efficacy and safety of the RTS,S\/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. 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