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Using the rodent <jats:italic>Plasmodium yoelii<\/jats:italic> model we report here that immunization with CSP adjuvanted with 5\u2019ppp-dsRNA, a RIG-I agonist, confers early and long-lasting sterile protection in mice against stringent sporozoite and mosquito bite challenges. The immunization induced high levels of antibodies, which were functional in targeting and killing the sporozoites and were sustained over time through the accumulation of long-lived plasma cells in the bone marrow. Moreover, 5\u2019ppp-dsRNA-adjuvanted immunization with the CSP of <jats:italic>P. falciparum<\/jats:italic> was also significantly protective against challenges using a transgenic <jats:italic>Pf<\/jats:italic>CSP-expressing <jats:italic>P. yoelii<\/jats:italic> parasite. Conversely, using the TLR3 agonist poly(A:U) as adjuvant resulted in a formulation that despite inducing high antibody levels was unable to generate equally functional antibodies and was, consequently, less protective. In conclusion, we demonstrate that using 5\u2019ppp-dsRNA as an adjuvant to vaccines targeting CSP induces effective anti-<jats:italic>Plasmodium<\/jats:italic> humoral immunity.<\/jats:p>","DOI":"10.3389\/fimmu.2022.868305","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T04:49:30Z","timestamp":1653022170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunization with CSP and a RIG-I Agonist is Effective in Inducing a Functional and Protective Humoral Response Against Plasmodium"],"prefix":"10.3389","volume":"13","author":[{"given":"Ana Rafaela","family":"Teixeira","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bego\u00f1a","family":"P\u00e9rez-Cabezas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David 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