{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:58:15Z","timestamp":1792173495416,"version":"4.4.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100201300005C"],"award-info":[{"award-number":["HHSO100201300005C"]}],"id":[{"id":"10.13039\/100012399","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>Influenza H7N9 virus continues to cause infections in humans and represents a significant pandemic risk. During the most recent 5th epidemic wave in 2016\/17 two distinct lineages with increased human infections and wider geographical spread emerged. In preparation for any future adaptations, broadly reactive antibodies against H7N9 are required for surveillance, therapy and prophylaxis. In this study we have isolated a panel of nanobodies (Nbs) with broad reactivity across H7 influenza strains, including H7N9 strains between 2013 and 2017. We also describe Nbs capable of distinguishing between the most recent high and low pathogenicity Yangtze River Delta lineage H7N9 strains. Nanobodies were classified into 5 distinct groups based on their epitope footprint determined using yeast display and mutational scanning. The epitope footprint of Nbs capable of distinguishing high pathogenic (HP) A\/Guangdong\/17SF003\/2016 from low pathogenic (LP) A\/Hong Kong\/125\/2017 (H7N9) were correlated to natural sequence divergence in the head domain at lysine 164. Several Nbs binding to the head domain were capable of viral neutralisation. The potency of one nanobody NB7-14 could be increased over 1000-fold to 113\u00a0pM by linking two Nbs together. Nbs specific for distinct epitopes on H7N9 may be useful for surveillance or therapy in human or veterinary settings.<\/jats:p>","DOI":"10.1038\/s41598-021-82356-4","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T11:08:10Z","timestamp":1612436890000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Nanobodies mapped to cross-reactive and divergent epitopes on A(H7N9) influenza hemagglutinin using yeast display"],"prefix":"10.1038","volume":"11","author":[{"given":"Tiziano","family":"Gaiotto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Ramage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Ball","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Risley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George W.","family":"Carnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Temperton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Othmar G.","family":"Engelhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon E.","family":"Hufton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"82356_CR1","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/S1473-3099(12)70121-4","volume":"12","author":"FS Dawood","year":"2012","unstructured":"Dawood, F. S. et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect. Dis. 12, 687\u2013695. https:\/\/doi.org\/10.1016\/S1473-3099(12)70121-4 (2012).","journal-title":"Lancet Infect. Dis."},{"key":"82356_CR2","doi-asserted-by":"publisher","first-page":"S82","DOI":"10.1038\/nm1141","volume":"10","author":"P Palese","year":"2004","unstructured":"Palese, P. Influenza: old and new threats. Nat. Med. 10, S82-87. https:\/\/doi.org\/10.1038\/nm1141 (2004).","journal-title":"Nat. Med."},{"key":"82356_CR3","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nrmicro1208","volume":"3","author":"T Horimoto","year":"2005","unstructured":"Horimoto, T. & Kawaoka, Y. Influenza: lessons from past pandemics, warnings from current incidents. Nat. Rev. Microbiol. 3, 591\u2013600. https:\/\/doi.org\/10.1038\/nrmicro1208 (2005).","journal-title":"Nat. Rev. Microbiol."},{"key":"82356_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/cr.2017.154","volume":"28","author":"K Subbarao","year":"2018","unstructured":"Subbarao, K. Avian influenza H7N9 viruses: a rare second warning. Cell Res. 28, 1\u20132. https:\/\/doi.org\/10.1038\/cr.2017.154 (2018).","journal-title":"Cell Res."},{"key":"82356_CR5","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1038\/cr.2017.129","volume":"27","author":"J Shi","year":"2017","unstructured":"Shi, J. et al. H7N9 virulent mutants detected in chickens in China pose an increased threat to humans. Cell Res. 27, 1409\u20131421. https:\/\/doi.org\/10.1038\/cr.2017.129 (2017).","journal-title":"Cell Res."},{"key":"82356_CR6","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00921-17","author":"W Qi","year":"2018","unstructured":"Qi, W. et al. Emergence and adaptation of a novel highly pathogenic H7N9 influenza virus in birds and humans from a 2013 human-infecting low-pathogenic ancestor. J. Virol. https:\/\/doi.org\/10.1128\/JVI.00921-17 (2018).","journal-title":"J. Virol."},{"key":"82356_CR7","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.chom.2016.05.014","volume":"19","author":"CJ Henry-Dunand","year":"2016","unstructured":"Henry-Dunand, C. J. et al. Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection. Cell Host Microbe 19, 800\u2013813. https:\/\/doi.org\/10.1016\/j.chom.2016.05.014 (2016).","journal-title":"Cell Host Microbe"},{"key":"82356_CR8","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1001\/jama.2015.7916","volume":"314","author":"LA Jackson","year":"2015","unstructured":"Jackson, L. A. et al. Effect of varying doses of a monovalent H7N9 influenza vaccine with and without AS03 and MF59 adjuvants on immune response: a randomized clinical trial. JAMA 314, 237\u2013246. https:\/\/doi.org\/10.1001\/jama.2015.7916 (2015).","journal-title":"JAMA"},{"key":"82356_CR9","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1016\/S0140-6736(13)61125-3","volume":"381","author":"Y Hu","year":"2013","unstructured":"Hu, Y. et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 381, 2273\u20132279. https:\/\/doi.org\/10.1016\/S0140-6736(13)61125-3 (2013).","journal-title":"Lancet"},{"key":"82356_CR10","doi-asserted-by":"publisher","first-page":"599","DOI":"10.7326\/0003-4819-145-8-200610170-00139","volume":"145","author":"TC Luke","year":"2006","unstructured":"Luke, T. C., Kilbane, E. M., Jackson, J. L. & Hoffman, S. L. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?. Ann. Intern. Med. 145, 599\u2013609 (2006).","journal-title":"Ann. Intern. Med."},{"key":"82356_CR11","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMc070359","volume":"357","author":"B Zhou","year":"2007","unstructured":"Zhou, B., Zhong, N. & Guan, Y. Treatment with convalescent plasma for influenza A (H5N1) infection. N. Engl. J. Med. 357, 1450\u20131451. https:\/\/doi.org\/10.1056\/NEJMc070359 (2007).","journal-title":"N. Engl. J. Med."},{"key":"82356_CR12","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1038\/nbt1363","volume":"25","author":"WA Marasco","year":"2007","unstructured":"Marasco, W. A. & Sui, J. The growth and potential of human antiviral monoclonal antibody therapeutics. Nat. Biotechnol. 25, 1421\u20131434. https:\/\/doi.org\/10.1038\/nbt1363 (2007).","journal-title":"Nat. Biotechnol."},{"issue":"Suppl 6","key":"82356_CR13","doi-asserted-by":"publisher","first-page":"G33","DOI":"10.1016\/j.vaccine.2009.09.137","volume":"27","author":"P Lachmann","year":"2009","unstructured":"Lachmann, P. Anti-infective antibodies\u2013reviving an old paradigm. Vaccine 27(Suppl 6), G33-37. https:\/\/doi.org\/10.1016\/j.vaccine.2009.09.137 (2009).","journal-title":"Vaccine"},{"key":"82356_CR14","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.coviro.2012.02.005","volume":"2","author":"DC Ekiert","year":"2012","unstructured":"Ekiert, D. C. & Wilson, I. A. Broadly neutralizing antibodies against influenza virus and prospects for universal therapies. Curr. Opin. Virol. 2, 134\u2013141. https:\/\/doi.org\/10.1016\/j.coviro.2012.02.005 (2012).","journal-title":"Curr. Opin. Virol."},{"key":"82356_CR15","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1146\/annurev.biochem.69.1.531","volume":"69","author":"JJ Skehel","year":"2000","unstructured":"Skehel, J. J. & Wiley, D. C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu. Rev. Biochem. 69, 531\u2013569. https:\/\/doi.org\/10.1146\/annurev.biochem.69.1.531 (2000).","journal-title":"Annu. Rev. Biochem."},{"key":"82356_CR16","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/0092-8674(82)90135-0","volume":"31","author":"AJ Caton","year":"1982","unstructured":"Caton, A. J., Brownlee, G. G., Yewdell, J. W. & Gerhard, W. The antigenic structure of the influenza virus A\/PR\/8\/34 hemagglutinin (H1 subtype). Cell 31, 417\u2013427 (1982).","journal-title":"Cell"},{"key":"82356_CR17","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1056\/NEJMp048290","volume":"351","author":"J Treanor","year":"2004","unstructured":"Treanor, J. Weathering the influenza vaccine crisis. N. Engl. J. Med. 351, 2037\u20132040. https:\/\/doi.org\/10.1056\/NEJMp048290 (2004).","journal-title":"N. Engl. J. Med."},{"key":"82356_CR18","doi-asserted-by":"publisher","first-page":"7708","DOI":"10.1038\/ncomms8708","volume":"6","author":"Y Wu","year":"2015","unstructured":"Wu, Y. et al. A potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus. Nat. Commun. 6, 7708. https:\/\/doi.org\/10.1038\/ncomms8708 (2015).","journal-title":"Nat. Commun."},{"key":"82356_CR19","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1172\/JCI85317","volume":"126","author":"NJ Thornburg","year":"2016","unstructured":"Thornburg, N. J. et al. H7N9 influenza virus neutralizing antibodies that possess few somatic mutations. J. Clin. Invest. 126, 1482\u20131494. https:\/\/doi.org\/10.1172\/JCI85317 (2016).","journal-title":"J. Clin. Invest."},{"key":"82356_CR20","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.chom.2017.08.011","volume":"22","author":"F Yu","year":"2017","unstructured":"Yu, F. et al. A potent germline-like human monoclonal antibody targets a pH-sensitive epitope on H7N9 influenza hemagglutinin. Cell Host Microbe 22, 471-483 e475. https:\/\/doi.org\/10.1016\/j.chom.2017.08.011 (2017).","journal-title":"Cell Host Microbe"},{"key":"82356_CR21","doi-asserted-by":"publisher","first-page":"9115","DOI":"10.1128\/jvi.01295-15","volume":"89","author":"J Wang","year":"2015","unstructured":"Wang, J. et al. Characterization of two human monoclonal antibodies neutralizing influenza A H7N9 viruses. J. Virol. 89, 9115\u20139118. https:\/\/doi.org\/10.1128\/jvi.01295-15 (2015).","journal-title":"J. Virol."},{"key":"82356_CR22","doi-asserted-by":"publisher","first-page":"6714","DOI":"10.1038\/ncomms7714","volume":"6","author":"Z Chen","year":"2015","unstructured":"Chen, Z. et al. Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. Nat. Commun. 6, 6714. https:\/\/doi.org\/10.1038\/ncomms7714 (2015).","journal-title":"Nat. Commun."},{"key":"82356_CR23","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41564-018-0303-7","volume":"4","author":"KA Huang","year":"2019","unstructured":"Huang, K. A. et al. Structure-function analysis of neutralizing antibodies to H7N9 influenza from naturally infected humans. Nat. Microbiol. 4, 306\u2013315. https:\/\/doi.org\/10.1038\/s41564-018-0303-7 (2019).","journal-title":"Nat. Microbiol."},{"key":"82356_CR24","doi-asserted-by":"publisher","first-page":"104556","DOI":"10.1016\/j.antiviral.2019.104556","volume":"170","author":"M Li","year":"2019","unstructured":"Li, M. et al. A cross-reactive human monoclonal antibody targets the conserved H7 antigenic site A from fifth wave H7N9-infected humans. Antiviral Res. 170, 104556. https:\/\/doi.org\/10.1016\/j.antiviral.2019.104556 (2019).","journal-title":"Antiviral Res."},{"key":"82356_CR25","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nsmb.1566","volume":"16","author":"J Sui","year":"2009","unstructured":"Sui, J. et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat. Struct. Mol. Biol. 16, 265\u2013273. https:\/\/doi.org\/10.1038\/nsmb.1566 (2009).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"82356_CR26","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1126\/science.1171491","volume":"324","author":"DC Ekiert","year":"2009","unstructured":"Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246\u2013251. https:\/\/doi.org\/10.1126\/science.1171491 (2009).","journal-title":"Science"},{"key":"82356_CR27","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/nature11414","volume":"489","author":"DC Ekiert","year":"2012","unstructured":"Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526\u2013532. https:\/\/doi.org\/10.1038\/nature11414 (2012).","journal-title":"Nature"},{"key":"82356_CR28","doi-asserted-by":"publisher","first-page":"e0164296","DOI":"10.1371\/journal.pone.0164296","volume":"11","author":"T Gaiotto","year":"2016","unstructured":"Gaiotto, T. & Hufton, S. E. Cross-neutralising nanobodies bind to a conserved pocket in the hemagglutinin stem region identified using yeast display and deep mutational scanning. PLoS ONE 11, e0164296. https:\/\/doi.org\/10.1371\/journal.pone.0164296 (2016).","journal-title":"PLoS ONE"},{"key":"82356_CR29","doi-asserted-by":"publisher","first-page":"e103294","DOI":"10.1371\/journal.pone.0103294","volume":"9","author":"SE Hufton","year":"2014","unstructured":"Hufton, S. E. et al. The breadth of cross sub-type neutralisation activity of a single domain antibody to influenza hemagglutinin can be increased by antibody valency. PLoS ONE 9, e103294. https:\/\/doi.org\/10.1371\/journal.pone.0103294 (2014).","journal-title":"PLoS ONE"},{"key":"82356_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/antib8010014","author":"W Ramage","year":"2019","unstructured":"Ramage, W. et al. Cross-reactive and lineage-specific single domain antibodies against influenza B hemagglutinin. Antibodies https:\/\/doi.org\/10.3390\/antib8010014 (2019).","journal-title":"Antibodies"},{"key":"82356_CR31","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.vetimm.2008.10.299","volume":"128","author":"S Muyldermans","year":"2009","unstructured":"Muyldermans, S. et al. Camelid immunoglobulins and nanobody technology. Vet. Immunol. Immunopathol. 128, 178\u2013183. https:\/\/doi.org\/10.1016\/j.vetimm.2008.10.299 (2009).","journal-title":"Vet. Immunol. Immunopathol."},{"key":"82356_CR32","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.3201\/eid2506.181158","volume":"25","author":"S Murakami","year":"2019","unstructured":"Murakami, S. et al. Influenza D Virus Infection in Dromedary Camels, Ethopia. Emerg. Infect. Dis. 25, 1224\u20131226. https:\/\/doi.org\/10.3201\/eid2506.181158 (2019).","journal-title":"Emerg. Infect. Dis."},{"key":"82356_CR33","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1002\/art.21827","volume":"54","author":"K Coppieters","year":"2006","unstructured":"Coppieters, K. et al. Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis. Arthritis Rheum. 54, 1856\u20131866. https:\/\/doi.org\/10.1002\/art.21827 (2006).","journal-title":"Arthritis Rheum."},{"key":"82356_CR34","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1056\/NEJMoa1806311","volume":"380","author":"M Scully","year":"2019","unstructured":"Scully, M. et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N. Engl. J. Med. 380, 335\u2013346. https:\/\/doi.org\/10.1056\/NEJMoa1806311 (2019).","journal-title":"N. Engl. J. Med."},{"key":"82356_CR35","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/s0076-6879(00)28410-3","volume":"328","author":"ET Boder","year":"2000","unstructured":"Boder, E. T. & Wittrup, K. D. Yeast surface display for directed evolution of protein expression, affinity, and stability. Methods Enzymol. 328, 430\u2013444. https:\/\/doi.org\/10.1016\/s0076-6879(00)28410-3 (2000).","journal-title":"Methods Enzymol."},{"key":"82356_CR36","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/S0014-5793(03)00602-1","volume":"546","author":"T van den Beucken","year":"2003","unstructured":"van den Beucken, T. et al. Affinity maturation of Fab antibody fragments by fluorescent-activated cell sorting of yeast-displayed libraries. FEBS Lett. 546, 288\u2013294 (2003).","journal-title":"FEBS Lett."},{"key":"82356_CR37","doi-asserted-by":"publisher","first-page":"e17665","DOI":"10.1371\/journal.pone.0017665","volume":"6","author":"A Hultberg","year":"2011","unstructured":"Hultberg, A. et al. Llama-derived single domain antibodies to build multivalent, superpotent and broadened neutralizing anti-viral molecules. PLoS ONE 6, e17665. https:\/\/doi.org\/10.1371\/journal.pone.0017665 (2011).","journal-title":"PLoS ONE"},{"key":"82356_CR38","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1093\/infdis\/jiq168","volume":"203","author":"LI Ibanez","year":"2011","unstructured":"Ibanez, L. I. et al. Nanobodies with in vitro neutralizing activity protect mice against H5N1 influenza virus infection. J. Infect. Dis. 203, 1063\u20131072. https:\/\/doi.org\/10.1093\/infdis\/jiq168 (2011).","journal-title":"J. Infect. Dis."},{"key":"82356_CR39","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.ab.2005.09.034","volume":"349","author":"R Karlsson","year":"2006","unstructured":"Karlsson, R., Katsamba, P. S., Nordin, H., Pol, E. & Myszka, D. G. Analyzing a kinetic titration series using affinity biosensors. Anal. Biochem. 349, 136\u2013147. https:\/\/doi.org\/10.1016\/j.ab.2005.09.034 (2006).","journal-title":"Anal. Biochem."},{"key":"82356_CR40","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00375-18","author":"H Yang","year":"2018","unstructured":"Yang, H., Carney, P. J., Chang, J. C., Guo, Z. & Stevens, J. Structural and molecular characterization of the hemagglutinin from the fifth-epidemic-wave A(H7N9) influenza viruses. J. Virol. https:\/\/doi.org\/10.1128\/jvi.00375-18 (2018).","journal-title":"J. Virol."},{"key":"82356_CR41","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2017.22.19.30533","author":"W Zhu","year":"2017","unstructured":"Zhu, W. et al. Biological characterisation of the emerged highly pathogenic avian influenza (HPAI) A(H7N9) viruses in humans, in mainland China, 2016 to 2017. Euro Surveill. https:\/\/doi.org\/10.2807\/1560-7917.ES.2017.22.19.30533 (2017).","journal-title":"Euro Surveill."},{"key":"82356_CR42","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.chom.2017.09.008","volume":"22","author":"M Imai","year":"2017","unstructured":"Imai, M. et al. A highly pathogenic avian h7n9 influenza virus isolated from a human is lethal in some ferrets infected via respiratory droplets. Cell Host Microbe 22, 615-626 e618. https:\/\/doi.org\/10.1016\/j.chom.2017.09.008 (2017).","journal-title":"Cell Host Microbe"},{"key":"82356_CR43","doi-asserted-by":"publisher","first-page":"e1003202","DOI":"10.1371\/journal.ppat.1003202","volume":"9","author":"D Lutje Hulsik","year":"2013","unstructured":"Lutje Hulsik, D. et al. A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition. PLoS Pathog. 9, e1003202. https:\/\/doi.org\/10.1371\/journal.ppat.1003202 (2013).","journal-title":"PLoS Pathog."},{"key":"82356_CR44","doi-asserted-by":"publisher","first-page":"5485","DOI":"10.1128\/JVI.00338-16","volume":"90","author":"C Palomo","year":"2016","unstructured":"Palomo, C. et al. Influence of respiratory syncytial virus F glycoprotein conformation on induction of protective immune responses. J. Virol. 90, 5485\u20135498. https:\/\/doi.org\/10.1128\/JVI.00338-16 (2016).","journal-title":"J. Virol."},{"key":"82356_CR45","doi-asserted-by":"publisher","first-page":"e109367","DOI":"10.1371\/journal.pone.0109367","volume":"9","author":"S Terryn","year":"2014","unstructured":"Terryn, S. et al. Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice. PLoS ONE 9, e109367. https:\/\/doi.org\/10.1371\/journal.pone.0109367 (2014).","journal-title":"PLoS ONE"},{"key":"82356_CR46","doi-asserted-by":"publisher","first-page":"627","DOI":"10.3389\/fimmu.2020.00627","volume":"11","author":"JMM Del Rosario","year":"2020","unstructured":"Del Rosario, J. M. M. et al. Protection from influenza by intramuscular gene vector delivery of a broadly neutralizing nanobody does not depend on antibody dependent cellular cytotoxicity. Front. Immunol. 11, 627. https:\/\/doi.org\/10.3389\/fimmu.2020.00627 (2020).","journal-title":"Front. Immunol."},{"key":"82356_CR47","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/289373a0","volume":"289","author":"DC Wiley","year":"1981","unstructured":"Wiley, D. C., Wilson, I. A. & Skehel, J. J. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289, 373\u2013378. https:\/\/doi.org\/10.1038\/289373a0 (1981).","journal-title":"Nature"},{"key":"82356_CR48","doi-asserted-by":"publisher","first-page":"e0117108","DOI":"10.1371\/journal.pone.0117108","volume":"10","author":"F Schmeisser","year":"2015","unstructured":"Schmeisser, F. et al. Antibodies to antigenic site A of influenza H7 hemagglutinin provide protection against H7N9 challenge. PLoS ONE 10, e0117108. https:\/\/doi.org\/10.1371\/journal.pone.0117108 (2015).","journal-title":"PLoS ONE"},{"key":"82356_CR49","doi-asserted-by":"publisher","first-page":"E5944","DOI":"10.1073\/pnas.1613225113","volume":"113","author":"PE Leon","year":"2016","unstructured":"Leon, P. E. et al. Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact. Proc. Natl. Acad. Sci. U. S. A. 113, E5944\u2013E5951. https:\/\/doi.org\/10.1073\/pnas.1613225113 (2016).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"82356_CR50","doi-asserted-by":"publisher","first-page":"e1005578","DOI":"10.1371\/journal.ppat.1005578","volume":"12","author":"GS Tan","year":"2016","unstructured":"Tan, G. S. et al. Broadly-reactive neutralizing and non-neutralizing antibodies directed against the H7 influenza virus hemagglutinin reveal divergent mechanisms of protection. PLoS Pathog 12, e1005578. https:\/\/doi.org\/10.1371\/journal.ppat.1005578 (2016).","journal-title":"PLoS Pathog"},{"key":"82356_CR51","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/0042-6822(91)90588-3","volume":"182","author":"E Nobusawa","year":"1991","unstructured":"Nobusawa, E. et al. Comparison of complete amino acid sequences and receptor-binding properties among 13 serotypes of hemagglutinins of influenza A viruses. Virology 182, 475\u2013485. https:\/\/doi.org\/10.1016\/0042-6822(91)90588-3 (1991).","journal-title":"Virology"},{"key":"82356_CR52","doi-asserted-by":"publisher","first-page":"10706","DOI":"10.1074\/jbc.M513415200","volume":"281","author":"J Shen","year":"2006","unstructured":"Shen, J. et al. Single variable domain-IgG fusion. A novel recombinant approach to Fc domain-containing bispecific antibodies. J. Biol. Chem. 281, 10706\u201310714. https:\/\/doi.org\/10.1074\/jbc.M513415200 (2006).","journal-title":"J. Biol. Chem."},{"key":"82356_CR53","doi-asserted-by":"publisher","first-page":"e0150958","DOI":"10.1371\/journal.pone.0150958","volume":"11","author":"DA Burmistrova","year":"2016","unstructured":"Burmistrova, D. A. et al. Genetic passive immunization with adenoviral vector expressing chimeric nanobody-Fc molecules as therapy for genital infection caused by mycoplasma hominis. PLoS ONE 11, e0150958. https:\/\/doi.org\/10.1371\/journal.pone.0150958 (2016).","journal-title":"PLoS ONE"},{"key":"82356_CR54","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.aca.2018.11.056","volume":"1053","author":"M Xiao","year":"2019","unstructured":"Xiao, M. et al. Ultrasensitive detection of avian influenza A (H7N9) virus using surface-enhanced Raman scattering-based lateral flow immunoassay strips. Anal. Chim. Acta 1053, 139\u2013147. https:\/\/doi.org\/10.1016\/j.aca.2018.11.056 (2019).","journal-title":"Anal. Chim. Acta"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82356-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82356-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82356-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T03:26:47Z","timestamp":1670038007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82356-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["82356"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-82356-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,4]]},"assertion":[{"value":"17 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3126"}}