{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T18:50:19Z","timestamp":1740163819245,"version":"3.37.3"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In post-stroke patients, a decreased adherence to antiplatelet drugs is a major challenge in the prevention of recurrent stroke. Previously, we reported an antiplatelet vaccine against S100A9 in mice, but the use of Freund\u2019s adjuvant and the difference in amino acid sequences in epitopes between mice and humans were problematic for clinical use. Here, we redesigned the S100A9 vaccine for the common sequence in both humans and monkeys and examined its effects in cynomolgus monkeys with Alum adjuvant. First, we assessed several candidate epitopes and selected 102 to 112 amino acids as the suitable epitope, which could produce antibodies. When this peptide vaccine was intradermally injected into 4 cynomolgus monkeys with Alum, the antibody against human S100A9 was successfully produced. Anti-thrombotic effects were shown in two monkeys in a mixture of vaccinated serum and fresh whole blood from another cynomolgus monkey. Additionally, the anti-thrombotic effects were partially inhibited by the epitope peptide, indicating the feasibility of neutralizing anti-thrombotic effects of produced antibodies. Prolongation of bleeding time was not observed in vaccinated monkeys. Although further studies on increasing the effect of vaccine and safety are necessary, this vaccine will be a promising approach to improve adherence to antiplatelet drugs in clinical settings.<\/jats:p>","DOI":"10.1038\/s41598-021-91153-y","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T15:32:54Z","timestamp":1622561574000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Development of anti-thrombotic vaccine against human S100A9 in rhesus monkey"],"prefix":"10.1038","volume":"11","author":[{"given":"Munehisa","family":"Shimamura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Kaikita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironori","family":"Nakagami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Kawano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Ju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Nakamaru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shota","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Mochizuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Tsujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Morishita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"91153_CR1","doi-asserted-by":"publisher","first-page":"35","DOI":"10.5692\/clinicalneurol.51.35","volume":"51","author":"Y Ito","year":"2011","unstructured":"Ito, Y. et al. Non-taking oral antithrombotic agents in patients with ischemic stroke. Rinsho Shinkeigaku 51, 35\u201337 (2011).","journal-title":"Rinsho Shinkeigaku"},{"key":"91153_CR2","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1161\/STROKEAHA.109.566950","volume":"41","author":"EL Glader","year":"2010","unstructured":"Glader, E. L., Sj\u00f6lander, M., Eriksson, M. & Lundberg, M. Persistent use of secondary preventive drugs declines rapidly during the first 2 years after stroke. Stroke 41, 397\u2013401 (2010).","journal-title":"Stroke"},{"key":"91153_CR3","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1212\/WNL.0b013e31822f0423","volume":"77","author":"CD Bushnell","year":"2011","unstructured":"Bushnell, C. D. et al. Secondary preventive medication persistence and adherence 1 year after stroke. Neurology 77, 1182\u20131190 (2011).","journal-title":"Neurology"},{"key":"91153_CR4","doi-asserted-by":"publisher","first-page":"e30","DOI":"10.1212\/WNL.0000000000011083","volume":"96","author":"LL Dalli","year":"2021","unstructured":"Dalli, L. L. et al. Patterns of use and discontinuation of secondary prevention medications after stroke. Neurology 96, e30\u2013e41 (2021).","journal-title":"Neurology"},{"key":"91153_CR5","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1172\/JCI70966","volume":"124","author":"Y Wang","year":"2014","unstructured":"Wang, Y. et al. Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis. J. Clin. Investig. 124, 2160\u20132171 (2014).","journal-title":"J. Clin. Investig."},{"key":"91153_CR6","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1161\/HYPERTENSIONAHA.118.11316","volume":"72","author":"T Kawano","year":"2018","unstructured":"Kawano, T. et al. Therapeutic vaccine against S100A9 (S100 calcium-binding protein A9) inhibits thrombosis without increasing the risk of bleeding in ischemic stroke in mice. Hypertension 72, 1355\u20131364 (2018).","journal-title":"Hypertension"},{"key":"91153_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0153770","author":"M Sharma","year":"2016","unstructured":"Sharma, M. et al. Daboxin p, a major phospholipase a2 enzyme from the Indian daboia russelii russelii venom targets factor x and factor xa for its anticoagulant activity. PLoS ONE. https:\/\/doi.org\/10.1371\/journal.pone.0153770 (2016).","journal-title":"PLoS ONE"},{"key":"91153_CR8","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1084\/jem.20051732","volume":"203","author":"AK Chauhan","year":"2006","unstructured":"Chauhan, A. K. et al. Systemic antithrombotic effects of ADAMTS13. J. Exp. Med. 203, 767\u2013776 (2006).","journal-title":"J. Exp. 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Thrombospondin-1 induces platelet activation through CD36-dependent inhibition of the cAMP\/protein kinase A signaling cascade. Blood 116, 4297\u20134306 (2010).","journal-title":"Blood"},{"key":"91153_CR12","doi-asserted-by":"publisher","first-page":"13905","DOI":"10.1074\/jbc.M211976200","volume":"278","author":"C Adessi","year":"2003","unstructured":"Adessi, C. et al. Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer\u2019s disease. J. Biol. Chem. 278, 13905\u201313911 (2003).","journal-title":"J. Biol. Chem."},{"key":"91153_CR13","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1172\/JCI89867","volume":"128","author":"T Vogl","year":"2018","unstructured":"Vogl, T. et al. Autoinhibitory regulation of S100A8\/S100A9 alarmin activity locally restricts sterile inflammation. J. Clin. Investig. 128, 1852\u20131866 (2018).","journal-title":"J. Clin. 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Basic Medical Laboratory Techniques (Delmar, cop., 2000)."},{"key":"91153_CR19","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1111\/jth.13256","volume":"14","author":"Y Arima","year":"2016","unstructured":"Arima, Y. et al. Assessment of platelet-derived thrombogenicity with the total thrombus-formation analysis system in coronary artery disease patients receiving antiplatelet therapy. J. Thromb. Haemost. 14, 850\u2013859 (2016).","journal-title":"J. Thromb. Haemost."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91153-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91153-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91153-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T08:53:46Z","timestamp":1670057626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91153-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["91153"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-91153-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,6,1]]},"assertion":[{"value":"25 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A patent application for the S100A9 vaccine has been filed (application no. 2017-30327; T.K., M.S., H.N., H.M., R.M.). The Department of Clinical Gene Therapy is financially supported by AnGes MG, Novartis, Shionogi, Boeringher, and Rohto. The Department of Health Development and Medicine is financially supported by AnGes MG and DAICEL. R.M. is a founder and stockholder of AnGes MG and a former board member. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11472"}}