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The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high levels of sterilizing immunity and constitute a promising approach to effective immunization against malaria. Here, we describe a novel WSp malaria vaccine that employs transgenic sporozoites of rodent<jats:italic>P. berghei<\/jats:italic>(<jats:italic>Pb<\/jats:italic>) parasites as cross-species immunizing agents and as platforms for expression and delivery of<jats:italic>Pf<\/jats:italic>CS (<jats:italic>Pb<\/jats:italic>Vac). We show that both wild-type<jats:italic>Pb<\/jats:italic>and<jats:italic>Pb<\/jats:italic>Vac sporozoites unabatedly infect and develop in human hepatocytes while unable to establish an infection in human red blood cells. In a rabbit model, similarly susceptible to<jats:italic>Pb<\/jats:italic>hepatic but not blood infection, we show that<jats:italic>Pb<\/jats:italic>Vac elicits cross-species cellular immune responses, as well as<jats:italic>Pf<\/jats:italic>CS-specific antibodies that efficiently inhibit<jats:italic>Pf<\/jats:italic>sporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus,<jats:italic>Pb<\/jats:italic>Vac is safe and induces functional immune responses in preclinical studies, warranting clinical testing and development.<\/jats:p>","DOI":"10.1038\/s41541-018-0068-2","type":"journal-article","created":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T14:08:50Z","timestamp":1530626930000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["A Plasmodium berghei sporozoite-based vaccination platform against human malaria"],"prefix":"10.1038","volume":"3","author":[{"given":"Ant\u00f3nio M.","family":"Mendes","sequence":"first","affiliation":[]},{"given":"Marta","family":"Machado","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5571-8616","authenticated-orcid":false,"given":"Nataniel","family":"Gon\u00e7alves-Rosa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1783-0735","authenticated-orcid":false,"given":"Isaie J.","family":"Reuling","sequence":"additional","affiliation":[]},{"given":"Lander","family":"Foquet","sequence":"additional","affiliation":[]},{"given":"Cl\u00e1udia","family":"Marques","sequence":"additional","affiliation":[]},{"given":"Ahmed M.","family":"Salman","sequence":"additional","affiliation":[]},{"given":"Annie S. 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