{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T15:12:31Z","timestamp":1776179551779,"version":"3.50.1"},"posted":{"date-parts":[[2023,2,7]]},"group-title":"Microbiology","reference-count":49,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria \u201cchemical vaccine\u201d, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant,\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (\n                  <jats:italic>Anopheles stephensi<\/jats:italic>\n                  ) or African (\n                  <jats:italic>Anopheles gambiae<\/jats:italic>\n                  ) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from\n                  <jats:italic>An. stephensi<\/jats:italic>\n                  to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  in the mosquito, and they significantly lessen the likelihood of their transmission in the field.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>New tools are needed to protect individuals from malaria and to control malaria in the field. Atovaquone plus proguanil is a commonly used and well-tolerated medicine to prevent malaria. No drug resistance has been reported from its prophylactic use, but tablets must be taken daily. Giving atovaquone as a single injection may provide much longer-lasting protection, against both falciparum and vivax malaria, but there is concern this may create drug resistance. In this study we showed that clinically relevant atovaquone-resistant malaria parasites survive poorly, if at all, in mosquitoes, and that mosquitoes do not transmit drug-resistant parasites to humanized mice. These findings lessen the likelihood that an atovaquone \u201cchemical vaccine\u201d would lead to the spread of atovaquone resistance.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.02.07.527535","type":"posted-content","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:10:11Z","timestamp":1675815011000},"source":"Crossref","is-referenced-by-count":2,"title":["Transmissibility of clinically relevant atovaquone-resistant\n                  <i>Plasmodium falciparum<\/i>\n                  by anopheline mosquitoes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0685-6697","authenticated-orcid":false,"given":"Victoria A.","family":"Balta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Stiffler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abeer","family":"Sayeed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9848-0142","authenticated-orcid":false,"given":"Abhai K.","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rubayet","family":"Elahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godfree","family":"Mlambo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul P.","family":"Bakshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda G.","family":"Dziedzic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne E.","family":"Jedlicka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Nenortas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keyla","family":"Romero-Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Canonizado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Mann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-7651","authenticated-orcid":false,"given":"Andrew","family":"Owen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0319-0578","authenticated-orcid":false,"given":"David J.","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9684-1733","authenticated-orcid":false,"given":"Sean T.","family":"Prigge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2954-7547","authenticated-orcid":false,"given":"Photini","family":"Sinnis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-7536","authenticated-orcid":false,"given":"Theresa A.","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023021112350444000_2023.02.07.527535v2.1","unstructured":"World Health Organization, World Malaria Report 2022 (World Health Organization, 2022)."},{"key":"2023021112350444000_2023.02.07.527535v2.2","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1186\/s12936-018-2549-1","article-title":"Injectable anti-malarials revisited: Discovery and development of new agents to protect against malaria","volume":"17","year":"2018","journal-title":"Malar. 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