{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:06:21Z","timestamp":1740146781182,"version":"3.37.3"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1034596"],"award-info":[{"award-number":["OPP1034596"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Army Medical Research Institute of Infectious Diseases","award":["F0447_15_NM; work unit A1215"],"award-info":[{"award-number":["F0447_15_NM; work unit A1215"]}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1034596"],"award-info":[{"award-number":["OPP1034596"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides &gt;90% sterile protection against <jats:italic>Plasmodium falciparum<\/jats:italic> malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800\u20131200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately. VE was 55% in Cohort 1 but 90% in Cohort 2, the cohort that received a higher first dose and a reduced (fractional) fifth dose. Immune responses were better boosted by the fractional fifth dose in Cohort 2 and suggested the importance of the fractional fifth dose for increased protection in Cohort 2 responses. Three protected subjects were later boosted and were protected suggesting that protection could be extended to at least 67 weeks.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The <jats:italic>ex vivo<\/jats:italic> FluoroSpot assay was used to measure peripheral IFN-\u03b3, IL2, and IFN-\u03b3+IL2 responses to PfNF54 sporozoites and malaria antigens CSP, AMA1, TRAP, and CelTOS using pools of synthetic overlapping 15mer peptides spanning each antigen.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>There was no correlation between IFN-\u03b3, IL2, and IFN-\u03b3+IL2 responses to sporozoites and protection, but fold-increases between post-4<jats:sup>th<\/jats:sup> and post-5<jats:sup>th<\/jats:sup> responses greater than 1.0 occurred mostly in protected subjects. IFN-\u03b3 and IL2 responses to TRAP, CelTOS and CSP occurred only in protected subjects. Peripheral IFN-\u03b3, IL2, and IFN-\u03b3+IL2 responses were short-lived and low by 27 weeks post-CHMI but were restored by boosting.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>These studies highlight the importance of vaccine dose and schedule for vaccine efficacy, and suggest that CSP, TRAP, AMA1 and CelTOS may be targets of protective immunity. The correlation between fold-increases in responses and protection should be explored in other vaccine trials.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>ClinicalTrials.gov <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01994525\" xlink:type=\"simple\">NCT01994525<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0256396","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T17:45:20Z","timestamp":1629481520000},"page":"e0256396","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["IMRAS\u2014Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS"],"prefix":"10.1371","volume":"16","author":[{"given":"Martha","family":"Sedegah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2343-3824","authenticated-orcid":true,"given":"Michael 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