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Here, we developed multi-clade VLPs expressing two HAs (a chimera of clade 2.3.2.1c and clade 2.3.4.4c HA) within a single vector. We then compared its protective efficacy with that of a monovalent VLP and evaluated its potency against each homologous strain. Chickens vaccinated with the multi-clade VLP shed less virus and were better protected against challenge than birds receiving monovalent vaccines. Single vaccination with a multi-clade VLP resulted in 100% survival, with no clinical symptoms and high levels of pre-challenge protective immunity (7.6\u20138.5 log<jats:sub>2<\/jats:sub>). Moreover, the multi-clade VLP showed high productivity (128\u2013256 HAU) both in the laboratory and on a large scale, making it cheaper than whole inactivated vaccines produced in eggs. However, the PD<jats:sub>50<\/jats:sub> (protective dose 50%) of the multi-clade VLP against clades 2.3.2.1c and 2.3.4.4c was\u2009&lt;\u200950 PD<jats:sub>50<\/jats:sub> (28 and 42 PD<jats:sub>50<\/jats:sub>, respectively), and effective antibody response was maintained for 2\u20133\u00a0months. This multi-clade VLP protects against both clades of HPAI viruses and can be produced in high amounts at low cost. Thus, the vaccine has potential as a pandemic preparedness vaccine.<\/jats:p>","DOI":"10.1038\/s41598-021-93060-8","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T10:21:22Z","timestamp":1625221282000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Single dose of multi-clade virus-like particle vaccine protects chickens against clade 2.3.2.1 and clade 2.3.4.4 highly pathogenic avian influenza viruses"],"prefix":"10.1038","volume":"11","author":[{"given":"Yong-Myung","family":"Kang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun-Kyu","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju Hun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Jin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seo-Jeong","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Do-Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Yup","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-won","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myoung-Heon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Chul","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun-Mi","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"key":"93060_CR1","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.virusres.2013.09.009","volume":"178","author":"H Shen","year":"2013","unstructured":"Shen, H. et al. 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