Franke-Fayard, BlandineBlandineFranke-FayardMarin-Mogollon, CatherinCatherinMarin-MogollonGeurten, Fiona J AFiona J AGeurtenChevalley-Maurel, SéverineSéverineChevalley-MaurelRamesar, JaiJaiRamesarKroeze, HansHansKroezeBaalbergen, ElsElsBaalbergenWessels, ElsElsWesselsBaron, LudivineLudivineBaronSoulard, ValérieValérieSoulardMartinson, ThomasThomasMartinsonAleshnick, MayaMayaAleshnickHuijs, Antonius T GAntonius T GHuijsSubudhi, Amit KAmit KSubudhiMiyazaki, YukikoYukikoMiyazakiOthman, Ahmad SyibliAhmad SyibliOthmanKolli, Surendra KumarSurendra KumarKolliLamers, Olivia A COlivia A CLamersRoques, Magali Hélène YvonneMagali Hélène YvonneRoquesLimenitakis, Rebecca RachelRebecca RachelLimenitakisMurphy, Sean CSean CMurphyFoquet, LanderLanderFoquetMoita, DianaDianaMoitaMendes, António MAntónio MMendesPrudêncio, MiguelMiguelPrudêncioDechering, Koen JKoen JDecheringHeussler, VolkerVolkerHeussler0000-0001-8028-9825Pain, ArnabArnabPainWilder, Brandon KBrandon KWilderRoestenberg, MetaMetaRoestenbergJanse, Chris JChris JJanse2024-10-112024-10-112022-11-04https://boris-portal.unibe.ch/handle/20.500.12422/88702Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.en500 - Science::570 - Life sciences; biologyarticle10.48350/1745363633333610.1038/s41541-022-00558-x