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The licensed malaria vaccines (RTS,S\/AS01 and R21\/Matrix-M) have shown significant efficacy in human phase 3 trials. Vaccination with radiation-attenuated sporozoites has achieved high levels of protection against malaria in controlled infection studies, although protection was more moderate in clinical trials conducted in malaria-endemic areas. RTS,S\/AS01, and R21\/Matrix-M contain the repeating NANP motif and the C-terminal domain of the dominant surface circumsporozoite protein (CSP) of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    (Pf) sporozoites, but do not include the CSP N-terminal domain or epitopes in the junctional region between the N-terminal domain and the NANP repeats. In pursuit of a second-generation malaria\n                    <jats:italic>PfCSP<\/jats:italic>\n                    vaccine that surpasses the protection elicited by attenuated sporozoites and current subunit vaccines, we developed self-assembling nanoparticle immunogens each displaying one or more of four different classes of\n                    <jats:italic>PfCSP<\/jats:italic>\n                    epitope regions: NANP-repeat epitopes, junctional region-repeat epitopes, and epitopes from the N-terminal and C-terminal domains. In a mouse model of malaria infection, immunization with protein nanoparticles displaying different CSP epitope regions showed a reduction in liver burden ranging from minimal to 90%, with N- and C-terminal domains providing little reduction, but a combination of junctional and NANP repeat epitopes providing a strong reduction. mRNA-delivered nanoparticle and membrane-anchored immunogens displaying both the junctional and NANP repeat epitopes were most effective, exhibiting 99% reduction in liver burden and sterilizing immunity from parasitemia in some mice. The mRNA immunogens represent promising candidates for rapid translation to human challenge studies and could be combined with T cell vaccines to comprise a potential next-generation malaria vaccine.\n                  <\/jats:p>","DOI":"10.1038\/s41541-025-01296-6","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T16:13:13Z","timestamp":1763482393000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["mRNA delivery of circumsporozoite protein epitope-based malaria vaccines induces protection in a mouse model"],"prefix":"10.1038","volume":"10","author":[{"given":"Nelson R.","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Beutler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick D.","family":"Skog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Liguori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevel","family":"Flores-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Maiorino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sierra","family":"Terada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Chung","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Ndihokubwayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Schiffner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Cottrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Eskandarzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nushin","family":"Alavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kubitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Phelps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Tingle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Hodges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Youhanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Amirzehni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell J.","family":"Irvine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Himansu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fidel","family":"Zavala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis R.","family":"Burton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Schief","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"1296_CR1","unstructured":"WHO. 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