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In a previous study, we demonstrated the superior protective efficacy of a three-dose regimen of late-arresting genetically attenuated parasites administered by mosquito bite (GA2-MB) compared with early-arresting counterparts (GA1-MB) against a homologous controlled human malaria infection. Encouraged by these results, we explored the potency of a single GA2-MB immunization in a placebo-controlled randomized trial. Primary outcomes were safety and tolerability, time-to-parasitemia and protective efficacy. Humoral and cellular immunological results were considered secondary outcomes. Here we report the safe administration of GA2-MB with no breakthrough malaria and sterile protection in nine of ten participants at 6 weeks after a single immunization with 50 GA2-infected mosquitoes, compared with none of five mock-immunized participants, against a homologous controlled human malaria infection. Immunization increased circulating\n                    <jats:italic>Pf<\/jats:italic>\n                    -specific polyfunctional effector memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells coexpressing tumor necrosis factor and interleukin-2. This unprecedented 90% protective efficacy after a single low-dose immunization holds great promise for the potency of GA2 immunization. Future studies should demonstrate whether GA2 is similarly efficacious in pre-exposed populations and whether the favorable safety profile reported here holds up in larger groups. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05468606\" ext-link-type=\"uri\">NCT05468606<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03347-2","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T05:01:44Z","timestamp":1735880504000},"page":"218-222","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Single immunization with genetically attenuated Pf\u2206mei2 (GA2) parasites by mosquito bite in controlled human malaria infection: a placebo-controlled randomized trial"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3979-4616","authenticated-orcid":false,"given":"Geert V. 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