{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:23:19Z","timestamp":1771489399025,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T00:00:00Z","timestamp":1700092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shionogi and Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination. Baloxavir acid selectively inhibits the cap-dependent endonuclease of influenza viruses and exhibits marked viral titre reduction in patients. Here, we describe the prophylactic potency of baloxavir acid against lethal infection with influenza A and B viruses in mice. BALB\/c mice were subcutaneously administered once with baloxavir acid suspension, or orally administered once daily for 10 days with oseltamivir phosphate solution at human relevant doses. Next, the mice were intranasally inoculated with A\/PR\/8\/34 (H1N1) or B\/Hong Kong\/5\/72 strain at 24 to 96 h after the initial dosing. Prophylactic treatment with the antiviral drugs significantly reduced the lung viral titres and prolonged survival time. In particular, baloxavir acid showed a greater suppressive effect on lung viral titres compared to oseltamivir phosphate. In this model, baloxavir acid maintained significant prophylactic effects against influenza A and B virus infections when the plasma concentration at the time of infection was at least 0.88 and 3.58 ng\/mL, respectively. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of baloxavir marboxil for prophylaxis against influenza in humans.<\/jats:p>","DOI":"10.3390\/v15112264","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T00:49:47Z","timestamp":1700182187000},"page":"2264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prophylactic Treatment with Baloxavir Protects Mice from Lethal Infection with Influenza A and B Viruses"],"prefix":"10.3390","volume":"15","author":[{"given":"Keita","family":"Fukao","sequence":"first","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Noshi","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Shano","sequence":"additional","affiliation":[{"name":"Shionogi TechnoAdvance Research, Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Baba","sequence":"additional","affiliation":[{"name":"Shionogi TechnoAdvance Research, Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Sato","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Sakuramoto","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohisa","family":"Kitade","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Tanioka","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-6049","authenticated-orcid":false,"given":"Shinji","family":"Kusakabe","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0945","authenticated-orcid":false,"given":"Takao","family":"Shishido","sequence":"additional","affiliation":[{"name":"Shionogi & Co., Ltd., Osaka 561-0825, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Estimates of global seasonal influenza-associated respiratory mortality: A modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1750-2659.2009.00073.x","article-title":"Estimates of US influenza-associated deaths made using four different methods","volume":"3","author":"Thompson","year":"2009","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"F1000 Faculty Rev-305","DOI":"10.12688\/f1000research.22611.1","article-title":"Recent advances in influenza vaccines","volume":"9","author":"Pawelec","year":"2020","journal-title":"F1000Research"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1146\/annurev-virology-010320-044746","article-title":"Challenges of Making Effective Influenza Vaccines","volume":"7","author":"Gouma","year":"2020","journal-title":"Annu. Rev. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Klein, N.P., Fireman, B., Goddard, K., Zerbo, O., Asher, J., Zhou, J., King, J., and Lewis, N. (2020). Vaccine effectiveness of cell-culture relative to egg-based inactivated influenza vaccine during the 2017-18 influenza season. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229279"},{"key":"ref_6","first-page":"187","article-title":"Influenza treatment and prophylaxis with neuraminidase inhibitors: A review","volume":"6","author":"Amanda","year":"2013","journal-title":"Infect. Drug Resist."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1093\/jac\/dkx271","article-title":"Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: A systematic review of systematic reviews and\/or meta-analyses","volume":"72","author":"Doll","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3851\/IMP3189","article-title":"A meta-analysis of laninamivir octanoate for treatment and prophylaxis of influenza","volume":"23","author":"Higashiguchi","year":"2018","journal-title":"Antivir. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1016\/j.bmcl.2016.08.038","article-title":"Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease","volume":"26","author":"Miyagawa","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8101","DOI":"10.1021\/acs.jmedchem.9b00861","article-title":"Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease","volume":"62","author":"Miyagawa","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Taoda, Y., Miyagawa, M., Akiyama, T., Tomita, K., Hasegawa, Y., Ryu Yoshida, R., Noshi, T., Shishido, T., and Kawai, M. (2020). Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Bioorg. Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127547"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.antiviral.2018.10.008","article-title":"In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit","volume":"160","author":"Noshi","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Takashita, E., Morita, H., Ogawa, R., Nakamura, K., Fujisaki, S., Shirakura, M., Kuwahara, T., Kishida, N., Watanabe, S., and Odagiri, T. (2018). Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.03026"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1800666","DOI":"10.2807\/1560-7917.ES.2019.24.3.1800666","article-title":"Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016\/17 and 2017\/18 seasons","volume":"24","author":"Gubareva","year":"2019","journal-title":"Eurosurveillance"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.antiviral.2019.02.007","article-title":"Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012\u20132018","volume":"164","author":"Koszalka","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.3201\/eid2510.190607","article-title":"Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir","volume":"25","author":"Mishin","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/jac\/dky462","article-title":"Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection","volume":"74","author":"Fukao","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.coviro.2019.01.006","article-title":"Baloxavir marboxil: The new influenza drug on the market","volume":"35","author":"Shaw","year":"2019","journal-title":"Curr. Opin. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1056\/NEJMoa1915341","article-title":"Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts","volume":"383","author":"Ikematsu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kuroda, T., Fukao, K., Yoshida, S., Oka, R., Baba, K., Ando, Y., Taniguchi, K., Noshi, T., and Shishido, T. (2023). In Vivo Antiviral Activity of Baloxavir against PA\/I38T-Substituted Influenza A Viruses at Clinically Relevant Doses. Viruses, 15.","DOI":"10.3390\/v15051154"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1007\/s40261-018-0710-9","article-title":"Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings","volume":"38","author":"Koshimichi","year":"2018","journal-title":"Clin. Drug Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/jac\/dkaa393","article-title":"Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection","volume":"76","author":"Ando","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41541-019-0126-4","article-title":"A mosaic hemagglutinin-based influenza virus vaccine candidate protects mice from challenge with divergent H3N2 strains","volume":"4","author":"Broecker","year":"2019","journal-title":"npj Vaccines"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, L.Y.Y., Zhou, J., Frise, R., Goldhill, D.H., Koszalka, P., Mifsud, E.J., Baba, K., Noda, T., Ando, Y., and Sato, K. (2020). Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008395"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1056\/NEJM200011023431801","article-title":"Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group","volume":"343","author":"Hayden","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1007\/s10156-013-0622-9","article-title":"Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts","volume":"19","author":"Kashiwagi","year":"2013","journal-title":"J. Infect. Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1093\/cid\/ciw255","article-title":"Long-acting Neuraminidase Inhibitor Laninamivir Octanoate as Post-exposure Prophylaxis for Influenza","volume":"63","author":"Kashiwagi","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1093\/cid\/ciz908","article-title":"Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes","volume":"71","author":"Hirotsu","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e13336","DOI":"10.1111\/tid.13336","article-title":"Baloxavir for the treatment of Influenza in allogeneic hematopoietic stem cell transplant recipients previously treated with oseltamivir","volume":"22","author":"Salvatore","year":"2020","journal-title":"Transpl. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/infdis\/jiaa061","article-title":"Detection of Variants with Reduced Baloxavir Marboxil Susceptibility After Treatment of Children With Influenza A During the 2018\u20132019 Influenza Season","volume":"222","author":"Sato","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104828","DOI":"10.1016\/j.antiviral.2020.104828","article-title":"Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment","volume":"180","author":"Takashita","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/irv.12821","article-title":"Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil","volume":"15","author":"Hashimoto","year":"2021","journal-title":"Influenza Other Respir. Viruses."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/11\/2264\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:24:14Z","timestamp":1760131454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/11\/2264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,16]]},"references-count":32,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["v15112264"],"URL":"https:\/\/doi.org\/10.3390\/v15112264","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,16]]}}}