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Previous studies have suggested that whole-sporozoite (WSpz) formulations based on parasites with longer liver stage development induce higher protection, but a comparative analysis of four different WSpz formulations has not been reported. We employed a rodent model of malaria to analyze the effect of immunization dosage on the protective efficacy of WSpz formulations consisting of (i) early liver arresting genetically attenuated parasites (EA-GAP) or (ii) radiation-attenuated sporozoites (RAS), (iii) late arresting GAP (LA-GAP), and (iv) sporozoites administered under chemoprophylaxis, that are eliminated upon release into the bloodstream (CPS). Our results show that, unlike all other WSpz formulations, EA-GAP fails to confer complete protection against an infectious challenge at any immunization dosage employed, suggesting that a minimum threshold of liver development is required to elicit fully effective immune responses. Moreover, while immunization with RAS, LA-GAP and CPS WSpz yields comparable, dosage-dependent protection, protection by EA-GAP WSpz peaks at an intermediate dosage and markedly decreases thereafter. In-depth immunological analyses suggest that effector CD8+ T cells elicited by EA-GAP WSpz immunization have limited developmental plasticity, with a potential negative impact on the functional versatility of memory cells and, thus, on protective immunity. Our findings point towards dismissing EA-GAP from prioritization for WSpz malaria vaccination and enhance our understanding of the complexity of the protection elicited by these WSpz vaccine candidates, guiding their future optimization.<\/jats:p>","DOI":"10.1038\/s41541-023-00778-9","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T03:02:19Z","timestamp":1700794939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The effect of dosage on the protective efficacy of whole-sporozoite formulations for immunization against malaria"],"prefix":"10.1038","volume":"8","author":[{"given":"Diana","family":"Moita","sequence":"first","affiliation":[]},{"given":"Catarina","family":"R\u00f4la","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-2879","authenticated-orcid":false,"given":"Helena","family":"Nunes-Caba\u00e7o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3836-6246","authenticated-orcid":false,"given":"Gon\u00e7alo","family":"Nogueira","sequence":"additional","affiliation":[]},{"given":"Teresa G.","family":"Maia","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2020-900X","authenticated-orcid":false,"given":"Ahmad Syibli","family":"Othman","sequence":"additional","affiliation":[]},{"given":"Blandine","family":"Franke-Fayard","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6410-6205","authenticated-orcid":false,"given":"Chris J.","family":"Janse","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-5325","authenticated-orcid":false,"given":"Ant\u00f3nio M.","family":"Mendes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1746-6029","authenticated-orcid":false,"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"778_CR1","unstructured":"WHO. 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