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Of several viral subtypes reported, the low pathogenic avian influenza H7N9 virus has since February 2013 caused more than 1,500 cases of human infection with an almost 40% case-fatality rate. Vaccination of poultry appears to reduce human infections. However, the emergence of highly pathogenic strains has increased concerns about H7N9 pandemics. To develop an efficacious H7N9 human vaccine, we designed vaccine viruses by changing the patterns of <jats:italic>N<\/jats:italic>-linked glycosylation (NLG) on the viral hemagglutinin (HA) protein based on evolutionary patterns of H7 HA NLG changes. Notably, a virus in which 2 NLG modifications were added to HA showed higher growth rates in cell culture and elicited more cross-reactive antibodies than did other vaccine viruses with no change in the viral antigenicity. Developed into an inactivated vaccine formulation, the vaccine virus with 2 HA NLG additions exhibited much better protective efficacy against lethal viral challenge in mice than did a vaccine candidate with wild-type (WT) HA by reducing viral replication in the lungs. In a ferret model, the 2 NLG-added vaccine viruses also induced hemagglutination-inhibiting antibodies and significantly suppressed viral replication in the upper and lower respiratory tracts compared with the WT HA vaccines. In a mode of action study, the HA NLG modification appeared to increase HA protein contents incorporated into viral particles, which would be successfully translated to improve vaccine efficacy. These results suggest the strong potential of HA NLG modifications in designing avian influenza vaccines.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001024","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T18:40:55Z","timestamp":1608748855000},"page":"e3001024","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Glycosylation generates an efficacious and immunogenic vaccine against H7N9 influenza virus"],"prefix":"10.1371","volume":"18","author":[{"given":"Jin Il","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon-Yong","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunmi","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7103-2662","authenticated-orcid":true,"given":"Jeonghun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirim","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9628-003X","authenticated-orcid":true,"given":"Yong Seok","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Soo","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mee Sook","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7427-486X","authenticated-orcid":true,"given":"Man-Seong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"pbio.3001024.ref001","volume-title":"Chapter 41: Orthomyxoviruses","author":"P Wright","year":"2013","edition":"6"},{"issue":"2","key":"pbio.3001024.ref002","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0042-6822(83)90150-2","article-title":"Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin","volume":"127","author":"GN Rogers","year":"1983","journal-title":"Virology"},{"issue":"18","key":"pbio.3001024.ref003","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1128\/JVI.74.18.8502-8512.2000","article-title":"Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals","volume":"74","author":"M Matrosovich","year":"2000","journal-title":"J Virol"},{"issue":"7250","key":"pbio.3001024.ref004","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/nature08182","article-title":"Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic","volume":"459","author":"GJ Smith","year":"2009","journal-title":"Nature"},{"issue":"7403","key":"pbio.3001024.ref005","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature10831","article-title":"Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA\/H1N1 virus in ferrets","volume":"486","author":"M Imai","year":"2012","journal-title":"Nature"},{"issue":"7470","key":"pbio.3001024.ref006","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nature12515","article-title":"The genesis and source of the H7N9 influenza viruses causing human infections in China","volume":"502","author":"TT Lam","year":"2013","journal-title":"Nature"},{"key":"pbio.3001024.ref007","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.coviro.2016.01.020","article-title":"Emergence and development of H7N9 influenza viruses in China","volume":"16","author":"H Zhu","year":"2016","journal-title":"Curr Opin Virol"},{"issue":"7554","key":"pbio.3001024.ref008","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature14348","article-title":"Dissemination, divergence and establishment of H7N9 influenza viruses in China","volume":"522","author":"TT Lam","year":"2015","journal-title":"Nature"},{"key":"pbio.3001024.ref009","unstructured":"FAO. 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