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To improve upon the malaria vaccine, RTS,S\/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S\/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic<jats:italic>Plasmodium berghei<\/jats:italic>sporozoites containing full-length<jats:italic>P. falciparum<\/jats:italic>CSP (tg<jats:italic>Pb-Pf<\/jats:italic>CSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S\/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 \u03bcg\/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 \u03bcg\/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models\u2019 relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S\/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods.<\/jats:p>","DOI":"10.1038\/s41541-024-00819-x","type":"journal-article","created":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T12:02:20Z","timestamp":1707566540000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Establishing RTS,S\/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model"],"prefix":"10.1038","volume":"9","author":[{"given":"Emily","family":"Locke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevel","family":"Flores-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2258-5276","authenticated-orcid":false,"given":"Bryan T.","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4566-1481","authenticated-orcid":false,"given":"Randall S.","family":"MacGill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavesh","family":"Borate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice","family":"Salgado-Jimenez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica W.","family":"Gerber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamika","family":"Mathis-Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-3319","authenticated-orcid":false,"given":"Sarah","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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