{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:46:20Z","timestamp":1777873580792,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014167","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01KI20172A"],"award-info":[{"award-number":["01KI20172A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009508","name":"Medizinische Fakult\u00e4t, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg","doi-asserted-by":"publisher","award":["IZKF A95"],"award-info":[{"award-number":["IZKF A95"]}],"id":[{"id":"10.13039\/501100009508","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009508","name":"Medizinische Fakult\u00e4t, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg","doi-asserted-by":"publisher","award":["IZKF A101"],"award-info":[{"award-number":["IZKF A101"]}],"id":[{"id":"10.13039\/501100009508","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR130 215346292"],"award-info":[{"award-number":["TRR130 215346292"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RTG 2504 401821119"],"award-info":[{"award-number":["RTG 2504 401821119"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021711","name":"Bayerisches Staatsministerium f\u00fcr Wissenschaft und Kunst","doi-asserted-by":"publisher","award":["For-COVID"],"award-info":[{"award-number":["For-COVID"]}],"id":[{"id":"10.13039\/501100021711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Advanced age is one of the greatest risk factors for a severe outcome of COVID-19. Although mRNA vaccines were highly successful in protecting the elderly, the strongest increase in morbidity and mortality upon infection with emerging SARS-CoV-2 variants was among the elderly. To better understand SARS-CoV-2 pathogenicity and to thoroughly evaluate novel vaccination strategies, better models reliably reproducing human SARS-CoV-2 pathogenicity are needed. Here, we generated mice expressing a human-mouse chimera of ACE2 (chACE2) by CRISPR\/Cas9-mediated gene editing in C57BL\/6 mouse zygotes. ChACE2 mice express the chimeric viral receptor at physiological levels, enabling efficient SARS-CoV-2 infection without the heightened mortality seen in K18-hACE2 mice due to neuroinvasion. We used the chACE2 model to analyze SARS-CoV-2 infection as well as antiviral immune responses in vitro and in vivo. Similar to SARS-CoV-2 in elderly humans, aged chACE2 mice suffered from a highly aggravated disease. In addition, we found that a live attenuated vaccine candidate, LAV\n                    <jats:sup>Nsp16<\/jats:sup>\n                    , induces robust mucosal and systemic immune responses in these mice despite being highly attenuated. The immunization with LAV\n                    <jats:sup>Nsp16<\/jats:sup>\n                    protected aged chACE2 mice from otherwise severe pathogenicity of SARS-CoV-2 by blocking viral replication of homologous and heterologous SARS-CoV-2 variants. The newly developed chACE2 model allows for longer observation periods of SARS-CoV-2 infection in mice, which is essential for assessing the immunogenicity of novel vaccine designs or monitoring viral pathogenicity over time. Immunization with LAV\n                    <jats:sup>Nsp16<\/jats:sup>\n                    induced robust and protective immune responses in young and aged mice, making viruses lacking 2\u2019-O-methyltrasferse activity promising candidates for future live attenuated vaccine development.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014167","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:38:58Z","timestamp":1776879538000},"page":"e1014167","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Live attenuated vaccination protects aged chimeric ACE2 mice from severe SARS-CoV-2 pathogenicity in vivo"],"prefix":"10.1371","volume":"22","author":[{"given":"Alina","family":"Russ","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera","family":"Viherlehto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Brey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Wittmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Irrgang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natascha","family":"Leicht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne","family":"Cordsmeier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armin","family":"Ensser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf 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H.","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-6721","authenticated-orcid":true,"given":"Thomas","family":"Gramberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"issue":"1","key":"ppat.1014167.ref001","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41541-021-00292-w","article-title":"SARS-CoV-2 vaccines strategies: A comprehensive review of phase 3 candidates","volume":"6","author":"NC Kyriakidis","year":"2021","journal-title":"NPJ Vaccines"},{"issue":"27","key":"ppat.1014167.ref002","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine","volume":"383","author":"FP Polack","year":"2020","journal-title":"N Engl J 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inoculation of SARS-CoV-2 in K18-hACE2 Mice","volume":"13","author":"P Kumari","year":"2021","journal-title":"Viruses"},{"issue":"3","key":"ppat.1014167.ref027","doi-asserted-by":"crossref","DOI":"10.3390\/v14030535","article-title":"Fatal neurodissemination and SARS-CoV-2 tropism in K18-hACE2 mice is only partially dependent on hACE2 expression","volume":"14","author":"M Carossino","year":"2022","journal-title":"Viruses"},{"issue":"4","key":"ppat.1014167.ref028","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2020.03.045","article-title":"Structural and functional basis of SARS-CoV-2 entry by using human ACE2","volume":"181","author":"Q Wang","year":"2020","journal-title":"Cell"},{"issue":"1","key":"ppat.1014167.ref029","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/imr.13091","article-title":"Correlates of protection against SARS-CoV-2 infection and COVID-19 disease","volume":"310","author":"D Goldblatt","year":"2022","journal-title":"Immunol 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