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. 2020 Apr 1;14(2):149–159. doi: 10.1007/s11684-020-0764-y

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

Yulu Wang 1, Dan Hu 1, Yanling Wu 1,✉, Tianlei Ying 1,✉
PMCID: PMC7110985  PMID: 32239416

Abstract

Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates. Despite significant efforts to address influenza, it remains a major threat to human public health. This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants. Moreover, designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult. Some novel epitopes hidden in the hemagglutinin (HA) trimeric interface have been discovered recently, and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates. These findings may have important implications for the development of universal influenza vaccines and antiviral drugs. In this review, we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.

Keywords: influenza virus, neutralizing antibody, hemagglutinin, globular head region, trimeric interface

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81822027 and 81630090), the National Key R&D Program of China (No. 2019YFA0904400), the National Science and Technology Major Projects of Infectious Disease funds (No. 2018ZX10301403), and the grant from the Chinese Academy of Medical Sciences (No. 2019PT350002).

Compliance with ethics guidelines

Yulu Wang, Dan Hu, Yanling Wu, and Tianlei Ying declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Contributor Information

Yanling Wu, Email: yanlingwu@fudan.edu.cn.

Tianlei Ying, Email: tlying@fudan.edu.cn.

References

  • 1.Zhilinskaia IN, Tets VV, Golubev DB. Vopr Virusol. 1978. Genome structure of influenza virus; pp. 387–394. [PubMed] [Google Scholar]
  • 2.Rudneva IA, Sklyanskaya EI, Barulina OS, Yamnikova SS, Kovaleva VP, Tsvetkova IV, Kaverin NV. Phenotypic expression of HA-NA combinations in human-avian influenza A virus reassortants. Arch Virol. 1996;141(6):1091–1099. doi: 10.1007/BF01718612. [DOI] [PubMed] [Google Scholar]
  • 3.To J, Torres J. Viroporins in the influenza virus. Cells. 2019;8(7):654. doi: 10.3390/cells8070654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Zambon MC. Epidemiology and pathogenesis of influenza. J Antimicrob Chemother. 1999;44:3–9. doi: 10.1093/jac/44.suppl_2.3. [DOI] [PubMed] [Google Scholar]
  • 5.Krammer F. Emerging influenza viruses and the prospect of a universal influenza virus vaccine. Biotechnol J. 2015;10(5):690–701. doi: 10.1002/biot.201400393. [DOI] [PubMed] [Google Scholar]
  • 6.Pleschka S. Swine Influenza. Part of the Current Topics in Microbiology and Immunology book series. 2013. Overview of influenza viruses; pp. 1–20. [DOI] [PubMed] [Google Scholar]
  • 7.Grist NR. Epidemiology and pathogenesis of influenza. BMJ. 1970;3(5718):344–345. doi: 10.1136/bmj.3.5718.344-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Saw TA, et al. Isolation of avian influenza A (H5N1) viruses from humans — Hong Kong, May–December 1997. JAMA. 1998;279(4):263–264. doi: 10.1001/jama.279.4.263. [DOI] [PubMed] [Google Scholar]
  • 9.Tang RB, Chen HL. An overview of the recent outbreaks of the avian-origin influenza A (H7N9) virus in the human. J Chin Med Assoc. 2013;76(5):245–248. doi: 10.1016/j.jcma.2013.04.003. [DOI] [PubMed] [Google Scholar]
  • 10.Ding H, Xie L, Sun Z, Kao QJ, Huang RJ, Yang XH, Huang CP, Wen YY, Pan JC, Pu XY, Jin T, Zhou XH, Zheng L, Li J, Wang FJ. Epidemiologic characterization of 30 confirmed cases of human infection with avian influenza A(H7N9) virus in Hangzhou, China. BMC Infect Dis. 2014;14(1):175. doi: 10.1186/1471-2334-14-175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Tan W, Li M, Xie ZX. An overview of avian influenza A H10N8 subtype viruses. Pak Vet J. 2016;36(3):251–257. [Google Scholar]
  • 12.Guo Y, Li J, Cheng X. Discovery of men infected by avian influenza A (H9N2) virus. Chin J Exp Clin Viro (Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi) 1999;13(2):105–108. [PubMed] [Google Scholar]
  • 13.Stegeman A, Bouma A, Elbers AR, de Jong MC, Nodelijk G, de Klerk F, Koch G, van Boven M. Avian influenza A virus (H7N7) epidemic in the Netherlands in 2003: course of the epidemic and effectiveness of control measures. J Infect Dis. 2004;190(12):2088–2095. doi: 10.1086/425583. [DOI] [PubMed] [Google Scholar]
  • 14.Sautto GA, Kirchenbaum GA, Ross TM. Towards a universal influenza vaccine: different approaches for one goal. Virol J. 2018;15(1):17. doi: 10.1186/s12985-017-0918-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Yu F, Song H, Wu Y, Chang SY, Wang L, Li W, Hong B, Xia S, Wang C, Khurana S, Feng Y, Wang Y, Sun Z, He B, Hou D, Manischewitz J, King LR, Song Y, Min JY, Golding H, Ji X, Lu L, Jiang S, Dimitrov DS, Ying T. A potent germline-like human monoclonal antibody targets a pH-sensitive epitope on H7N9 influenza hemagglutinin. Cell Host Microbe. 2017;22(4):471–483. doi: 10.1016/j.chom.2017.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Wu Y, Gao GF. “Breathing” hemagglutinin reveals cryptic epitopes for universal influenza vaccine design. Cell. 2019;177(5):1086–1088. doi: 10.1016/j.cell.2019.04.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Watanabe A, McCarthy KR, Kuraoka M, Schmidt AG, Adachi Y, Onodera T, Tonouchi K, Caradonna TM, Bajic G, Song S, McGee CE, Sempowski GD, Feng F, Urick P, Kepler TB, Takahashi Y, Harrison SC, Kelsoe G. Antibodies to a conserved influenza head interface epitope protect by an IgG subtype-dependent mechanism. Cell. 2019;177(5):1124–1135. doi: 10.1016/j.cell.2019.03.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, Cottrell CA, Bowman CA, Crowe JE, Jr, Wilson IA, Ward AB. Potent antiinfluenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains. PLoS Biol. 2019;17(2):3000139. doi: 10.1371/journal.pbio.3000139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Pielak RM, Schnell JR, Chou JJ. Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc Natl Acad Sci USA. 2009;106(18):7379–7384. doi: 10.1073/pnas.0902548106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Chizhmakov IV, Geraghty FM, Ogden DC, Hayhurst A, Antoniou M, Hay AJ. Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells. J Physiol. 1996;494(2):329–336. doi: 10.1113/jphysiol.1996.sp021495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Saelens X. The role of matrix protein 2 ectodomain in the development of universal influenza vaccines. J Infect Dis. 2019;219(Supplement_1):S68–S74. doi: 10.1093/infdis/jiz003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Zhang X, Liu M, Liu C, Du J, Shi W, Sun E, Li H, Li J, Zhang Y. Vaccination with different M2e epitope densities confers partial protection against H5N1 influenza A virus challenge in chickens. Intervirology. 2011;54(5):290–299. doi: 10.1159/000319440. [DOI] [PubMed] [Google Scholar]
  • 23.Corti D, Cameroni E, Guarino B, Kallewaard NL, Zhu Q, Lanzavecchia A. Tackling influenza with broadly neutralizing antibodies. Curr Opin Virol. 2017;24:60–69. doi: 10.1016/j.coviro.2017.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Jones LV, Compans RW, Davis AR, Bos TJ, Nayak DP. Surface expression of influenza virus neuraminidase, an amino-terminally anchored viral membrane glycoprotein, in polarized epithelial cells. Mol Cell Biol. 1985;5(9):2181–2189. doi: 10.1128/mcb.5.9.2181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ohmit SE, Petrie JG, Cross RT, Johnson E, Monto AS. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J Infect Dis. 2011;204(12):1879–1885. doi: 10.1093/infdis/jir661. [DOI] [PubMed] [Google Scholar]
  • 26.Benjamin E, Wang W, McAuliffe JM, Palmer-Hill FJ, Kallewaard NL, Chen Z, Suzich JA, Blair WS, Jin H, Zhu Q. A broadly neutralizing human monoclonal antibody directed against a novel conserved epitope on the influenza virus H3 hemagglutinin globular head. J Virol. 2014;88(12):6743–6750. doi: 10.1128/JVI.03562-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Cho A, Wrammert J. Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine. Curr Opin Virol. 2016;17:110–115. doi: 10.1016/j.coviro.2016.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Wu NC, Grande G, Turner HL, Ward AB, Xie J, Lerner RA, Wilson IA. In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity. Nat Commun. 2017;8(1):15371. doi: 10.1038/ncomms15371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Laursen NS, Wilson IA. Broadly neutralizing antibodies against influenza viruses. Antiviral Res. 2013;98(3):476–483. doi: 10.1016/j.antiviral.2013.03.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hu W, Chen A, Miao Y, Xia S, Ling Z, Xu K, Wang T, Xu Y, Cui J, Wu H, Hu G, Tian L, Wang L, Shu Y, Ma X, Xu B, Zhang J, Lin X, Bian C, Sun B. Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Virology. 2013;435(2):320–328. doi: 10.1016/j.virol.2012.09.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Skehel JJ, Waterfield MD. Studies on the primary structure of the influenza virus hemagglutinin. Proc Natl Acad Sci USA. 1975;72(1):93–97. doi: 10.1073/pnas.72.1.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Russell CJ, Hu M, Okda FA. Influenza hemagglutinin protein stability, activation, and pandemic risk. Trends Microbiol. 2018;26(10):841–853. doi: 10.1016/j.tim.2018.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Gamblin SJ, Skehel JJ. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem. 2010;285(37):28403–28409. doi: 10.1074/jbc.R110.129809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Skehel JJ, Wiley DC. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem. 2000;69(1):531–569. doi: 10.1146/annurev.biochem.69.1.531. [DOI] [PubMed] [Google Scholar]
  • 35.Garcia NK, Guttman M, Ebner JL, Lee KK. Dynamic changes during acid-induced activation of influenza hemagglutinin. Structure. 2015;23(4):665–676. doi: 10.1016/j.str.2015.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gaudin Y, Ruigrok RW, Brunner J. Low-pH induced conformational changes in viral fusion proteins: implications for the fusion mechanism. J Gen Virol. 1995;76(Pt7):1541–1556. doi: 10.1099/0022-1317-76-7-1541. [DOI] [PubMed] [Google Scholar]
  • 37.Zhang Y, Xu C, Zhang H, Liu GD, Xue C, Cao Y. Targeting hemagglutinin: approaches for broad protection against the influenza A virus. Viruses. 2019;11(5):405. doi: 10.3390/v11050405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lee PS, Wilson IA. Structural characterization of viral epitopes recognized by broadly cross-reactive antibodies. Influenza Pathogenesis and Control—Volume II. Current Topics in Microbiology and Immunology. 2014;386:323–341. doi: 10.1007/82_2014_413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Sun X, Shi Y, Lu X, He J, Gao F, Yan J, Qi J, Gao GF. Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism. Cell Rep. 2013;3(3):769–778. doi: 10.1016/j.celrep.2013.01.025. [DOI] [PubMed] [Google Scholar]
  • 40.Zhu X, Yu W, McBride R, Li Y, Chen LM, Donis RO, Tong S, Paulson JC, Wilson IA. Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pHdependent fusion activities. Proc Natl Acad Sci USA. 2013;110(4):1458–1463. doi: 10.1073/pnas.1218509110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.PLoS Pathog. 2013.
  • 42.Krause JC, Tsibane T, Tumpey TM, Huffman CJ, Albrecht R, Blum DL, Ramos I, Fernandez-Sesma A, Edwards KM, García-Sastre A, Basler CF, Crowe JE., Jr Human monoclonal antibodies to pandemic 1957 H2N2 and pandemic 1968 H3N2 influenza viruses. J Virol. 2012;86(11):6334–6340. doi: 10.1128/JVI.07158-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Lee PS, Ohshima N, Stanfield RL, Yu W, Iba Y, Okuno Y, Kurosawa Y, Wilson IA. Receptor mimicry by antibody F045-092 facilitates universal binding to the H3 subtype of influenza virus. Nat Commun. 2014;5(1):3614. doi: 10.1038/ncomms4614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Brandenburg B, Koudstaal W, Goudsmit J, Klaren V, Tang C, Bujny MV, Korse HJ, Kwaks T, Otterstrom JJ, Juraszek J, van Oijen AM, Vogels R, Friesen RH. Mechanisms of hemagglutinin targeted influenza virus neutralization. PLoS One. 2013;8(12):80034. doi: 10.1371/journal.pone.0080034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Raymond DD, Bajic G, Ferdman J, Suphaphiphat P, Settembre EC, Moody MA, Schmidt AG, Harrison SC. Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody. Proc Natl Acad Sci USA. 2018;115(1):168–173. doi: 10.1073/pnas.1715471115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Russier M, Yang G, Rehg JE, Wong SS, Mostafa HH, Fabrizio TP, Barman S, Krauss S, Webster RG, Webby RJ, Russell CJ. Molecular requirements for a pandemic influenza virus: an acidstable hemagglutinin protein. Proc Natl Acad Sci USA. 2016;113(6):1636–1641. doi: 10.1073/pnas.1524384113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Yoshida R, Igarashi M, Ozaki H, Kishida N, Tomabechi D, Kida H, Ito K, Takada A. Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog. 2009;5(3):1000350. doi: 10.1371/journal.ppat.1000350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Whittle JRR, Zhang R, Khurana S, King LR, Manischewitz J, Golding H, Dormitzer PR, Haynes BF, Walter EB, Moody MA, Kepler TB, Liao HX, Harrison SC. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA. 2011;108(34):14216–14221. doi: 10.1073/pnas.1111497108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Ekiert DC, Kashyap AK, Steel J, Rubrum A, Bhabha G, Khayat R, Lee JH, Dillon MA, O’Neil RE, Faynboym AM, Horowitz M, Horowitz L, Ward AB, Palese P, Webby R, Lerner RA, Bhatt RR, Wilson IA. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature. 2012;489(7417):526–532. doi: 10.1038/nature11414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Ohshima N, Iba Y, Kubota-Koketsu R, Asano Y, Okuno Y, Kurosawa Y. Naturally occurring antibodies in humans can neutralize a variety of influenza virus strains, including H3, H1, H2, and H5. J Virol. 2011;85(21):11048–11057. doi: 10.1128/JVI.05397-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Matsuda K, Huang J, Zhou T, Sheng Z, Kang BH, Ishida E, Griesman T, Stuccio S, Bolkhovitinov L, Wohlbold TJ, Chromikova V, Cagigi A, Leung K, Andrews S, Cheung CSF, Pullano AA, Plyler J, Soto C, Zhang B, Yang Y, Joyce MG, Tsybovsky Y, Wheatley A, Narpala SR, Guo Y, Darko S, Bailer RT, Poole A, Liang CJ, Smith J, Alexander J, Gurwith M, Migueles SA, Koup RA, Golding H, Khurana S, McDermott AB, Shapiro L, Krammer F, Kwong PD, Connors M. Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine. Sci Immunol. 2019;4(34):2710. doi: 10.1126/sciimmunol.aau2710. [DOI] [PubMed] [Google Scholar]
  • 52.Dreyfus C, Laursen NS, Kwaks T, Zuijdgeest D, Khayat R, Ekiert DC, Lee JH, Metlagel Z, Bujny MV, Jongeneelen M, van der Vlugt R, Lamrani M, Korse HJ, Geelen E, Sahin, Sieuwerts M, Brakenhoff JP, Vogels R, Li OT, Poon LL, Peiris M, Koudstaal W, Ward AB, Wilson IA, Goudsmit J, Friesen RH. Highly conserved protective epitopes on influenza B viruses. Science. 2012;337(6100):1343–1348. doi: 10.1126/science.1222908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Shen C, Chen J, Li R, Zhang M, Wang G, Stegalkina S, Zhang L, Chen J, Cao J, Bi X, Anderson SF, Alefantis T, Zhang M, Cai X, Yang K, Zheng Q, Fang M, Yu H, Luo W, Zheng Z, Yuan Q, Zhang J, Wai-Kuo Shih J, Kleanthous H, Chen H, Chen Y, Xia N. A multimechanistic antibody targeting the receptor binding site potently cross-protects against influenza B viruses. Sci Transl Med. 2017;9(412):5752. doi: 10.1126/scitranslmed.aam5752. [DOI] [PubMed] [Google Scholar]
  • 54.Dreyfus C, Ekiert DC, Wilson IA. Structure of a classical broadly neutralizing stem antibody in complex with a pandemic H2 influenza virus hemagglutinin. J Virol. 2013;87(12):7149–7154. doi: 10.1128/JVI.02975-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA. Antibody recognition of a highly conserved influenza virus epitope. Science. 2009;324(5924):246–251. doi: 10.1126/science.1171491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Yamayoshi S, Uraki R, Ito M, Kiso M, Nakatsu S, Yasuhara A, Oishi K, Sasaki T, Ikuta K, Kawaoka Y. A broadly reactive human anti-hemagglutinin stem monoclonal antibody that inhibits influenza A virus particle release. EBioMedicine. 2017;17:182–191. doi: 10.1016/j.ebiom.2017.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Kallewaard NL, Corti D, Collins PJ, Neu U, McAuliffe JM, Benjamin E, Wachter-Rosati L, Palmer-Hill FJ, Yuan AQ, Walker PA, Vorlaender MK, Bianchi S, Guarino B, de Marco A, van zetta F, Agatic G, Foglierini M, Pinna D, Fernandez-Rodriguez B, Fruehwirth A, Silacci C, Ogrodowicz RW, Martin SR, Sallusto F, Suzich JA, Lanzavecchia A, Zhu Q, Gamblin SJ, Skehel JJ. Structure and function analysis of an antibody recognizing all influenza A subtypes. Cell. 2016;166(3):596–608. doi: 10.1016/j.cell.2016.05.073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009;16(3):265–273. doi: 10.1038/nsmb.1566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Ledgerwood JE, Wei CJ, Hu Z, Gordon IJ, Enama ME, Hendel CS, McTamney PM, Pearce MB, Yassine HM, Boyington JC, Bailer R, Tumpey TM, Koup RA, Mascola JR, Nabel GJ, Graham BS. VRC 306 Study Team. DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials. Lancet Infect Dis. 2011;11(12):916–924. doi: 10.1016/S1473-3099(11)70240-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Wheatley AK, Whittle JR, Lingwood D, Kanekiyo M, Yassine HM, Ma SS, Narpala SR, Prabhakaran MS, Matus-Nicodemos RA, Bailer RT, Nabel GJ, Graham BS, Ledgerwood JE, Koup RA, McDermott AB. H5N1 vaccine-elicited memory B cells are genetically constrained by the IGHV locus in the recognition of a neutralizing epitope in the hemagglutinin stem. J Immunol. 2015;195(2):602–610. doi: 10.4049/jimmunol.1402835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Whittle JRR, Wheatley AK, Wu L, Lingwood D, Kanekiyo M, Ma SS, Narpala SR, Yassine HM, Frank GM, Yewdell JW, Ledgerwood JE, Wei CJ, McDermott AB, Graham BS, Koup RA, Nabel GJ. Flow cytometry reveals that H5N1 vaccination elicits crossreactive stem-directed antibodies from multiple Ig heavy-chain lineages. J Virol. 2014;88(8):4047–4057. doi: 10.1128/JVI.03422-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009;16(3):265–273. doi: 10.1038/nsmb.1566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Dreyfus C, Laursen NS, Kwaks T, Zuijdgeest D, Khayat R, Ekiert DC, Lee JH, Metlagel Z, Bujny MV, Jongeneelen M, van der Vlugt R, Lamrani M, Korse HJ, Geelen E, Sahin, Sieuwerts M, Brakenhoff JP, Vogels R, Li OT, Poon LL, Peiris M, Koudstaal W, Ward AB, Wilson IA, Goudsmit J, Friesen RH. Highly conserved protective epitopes on influenza B viruses. Science. 2012;337(6100):1343–1348. doi: 10.1126/science.1222908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Ekiert DC, Friesen RH, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science. 2011;333(6044):843–850. doi: 10.1126/science.1204839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Corti D, Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D, Vachieri SG, Pinna D, Minola A, van zetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G, Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF, Temperton N, Langedijk JP, Skehel JJ, Lanzavecchia A. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science. 2011;333(6044):850–856. doi: 10.1126/science.1205669. [DOI] [PubMed] [Google Scholar]
  • 66.DiLillo DJ, Tan GS, Palese P, Ravetch JV. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcgR interactions for protection against influenza virus in vivo. Nat Med. 2014;20(2):143–151. doi: 10.1038/nm.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14(3):167–182. doi: 10.1038/nrd4529. [DOI] [PubMed] [Google Scholar]
  • 68.Lee PS, Wilson IA. Structural characterization of viral epitopes recognized by broadly cross-reactive antibodies. Curr Top Microbiol Immunol. 2015;386:323–341. doi: 10.1007/82_2014_413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Seok JH, Kim J, Lee DB, Cho KJ, Lee JH, Bae G, Chung MS, Kim KH. Conformational modulation of influenza virus hemagglutinin: characterization and in vivo efficacy of monomeric form. Sci Rep. 2017;7(1):7540. doi: 10.1038/s41598-017-08021-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Angeletti D, Kosik I, Santos JJS, Yewdell WT, Boudreau CM, Mallajosyula VVA, Mankowski MC, Chambers M, Prabhakaran M, Hickman HD, McDermott AB, Alter G, Chaudhuri J, Yewdell JW. Outflanking immunodominance to target subdominant broadly neutralizing epitopes. Proc Natl Acad Sci USA. 2019;116(27):13474–13479. doi: 10.1073/pnas.1816300116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14(3):167–182. doi: 10.1038/nrd4529. [DOI] [PubMed] [Google Scholar]
  • 72.Raymond DD, Bajic G, Ferdman J, Suphaphiphat P, Settembre EC, Moody MA, Schmidt AG, Harrison SC. Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody. Proc Natl Acad Sci USA. 2018;115(1):168–173. doi: 10.1073/pnas.1715471115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Correia BE, Bates JT, Loomis RJ, Baneyx G, Carrico C, Jardine JG, Rupert P, Correnti C, Kalyuzhniy O, Vittal V, Connell MJ, Stevens E, Schroeter A, Chen M, Macpherson S, Serra AM, Adachi Y, Holmes MA, Li Y, Klevit RE, Graham BS, Wyatt RT, Baker D, Strong RK, Crowe JE, Jr, Johnson PR, Schief WR. Proof of principle for epitope-focused vaccine design. Nature. 2014;507(7491):201–206. doi: 10.1038/nature12966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Haynes BF, Kelsoe G, Harrison SC, Kepler TB. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol. 2012;30(5):423–433. doi: 10.1038/nbt.2197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Mascola JR, Haynes BF. HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev. 2013;254(1):225–244. doi: 10.1111/imr.12075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Bajic G, Maron MJ, Adachi Y, Onodera T, McCarthy KR, McGee CE, Sempowski GD, Takahashi Y, Kelsoe G, Kuraoka M, Schmidt AG. Influenza antigen engineering focuses immune responses to a subdominant but broadly protective viral epitope. Cell Host Microbe. 2019;25(6):827–835. doi: 10.1016/j.chom.2019.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Lavie M, Hanoulle X, Dubuisson J. Glycan shielding and modulation of hepatitis C virus neutralizing antibodies. Front Immunol. 2018;9:910. doi: 10.3389/fimmu.2018.00910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Watanabe Y, Raghwani J, Allen JD, Seabright GE, Li S, Moser F, Huiskonen JT, Strecker T, Bowden TA, Crispin M. Structure of the Lassa virus glycan shield provides a model for immunological resistance. Proc Natl Acad Sci USA. 2018;115(28):7320–7325. doi: 10.1073/pnas.1803990115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Hervé PL, Lorin V, Jouvion G, Da Costa B, Escriou N. Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity. Virology. 2015;486:134–145. doi: 10.1016/j.virol.2015.08.033. [DOI] [PubMed] [Google Scholar]
  • 80.Liu WC, Jan JT, Huang YJ, Chen TH, Wu SC. Unmasking stemspecific neutralizing epitopes by abolishing N-linked glycosylation sites of influenza virus hemagglutinin proteins for vaccine design. J Virol. 2016;90(19):8496–8508. doi: 10.1128/JVI.00880-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Florek NW, Weinfurter JT, Jegaskanda S, Brewoo JN, Powell TD, Young GR, Das SC, Hatta M, Broman KW, Hungnes O, Dudman SG, Kawaoka Y, Kent SJ, Stinchcomb DT, Osorio JE, Friedrich TC. Modified vaccinia virus Ankara encoding influenza virus hemagglutinin induces heterosubtypic immunity in macaques. J Virol. 2014;88(22):13418–13428. doi: 10.1128/JVI.01219-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Kamlangdee A, Kingstad-Bakke B, Anderson TK, Goldberg TL, Osorio JE. Broad protection against avian influenza virus by using a modified vaccinia Ankara virus expressing a mosaic hemagglutinin gene. J Virol. 2014;88(22):13300–13309. doi: 10.1128/JVI.01532-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Yewdell JW, Taylor A, Yellen A, Caton A, Gerhard W, Bächi T. Mutations in or near the fusion peptide of the influenza virus hemagglutinin affect an antigenic site in the globular region. J Virol. 1993;67(2):933–942. doi: 10.1128/jvi.67.2.933-942.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Yewdell JW, Yellen A, Bächi T. Monoclonal antibodies localize events in the folding, assembly, and intracellular transport of the influenza virus hemagglutinin glycoprotein. Cell. 1988;52(6):843–852. doi: 10.1016/0092-8674(88)90426-6. [DOI] [PubMed] [Google Scholar]
  • 85.Yewdell JW, Gerhard W, Bachi T. Monoclonal anti-hemagglutinin antibodies detect irreversible antigenic alterations that coincide with the acid activation of influenza virus A/PR/834-mediated hemolysis. J Virol. 1983;48(1):239–248. doi: 10.1128/jvi.48.1.239-248.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Lee J, Boutz DR, Chromikova V, Joyce MG, Vollmers C, Leung K, Horton AP, DeKosky BJ, Lee CH, Lavinder JJ, Murrin EM, Chrysostomou C, Hoi KH, Tsybovsky Y, Thomas PV, Druz A, Zhang B, Zhang Y L, Kong WP, Park D, Popova LI, Dekker CL, Davis MM, Carter CE, Ross TM, Ellington AD, Wilson PC, Marcotte EM, Mascola JR, Ippolito GC, Krammer F, Quake SR, Kwong PD, Georgiou G. Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination. Nat Med. 2016;22(12):1456–1464. doi: 10.1038/nm.4224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Bangaru S, Lang S, Schotsaert M, van derven HA, Zhu X, Kose N, Bombardi R, Finn JA, Kent SJ, Gilchuk P, Gilchuk I, Turner HL, García-Sastre A, Li S, Ward AB, Wilson IA, Crowe JE., Jr A site of vulnerability on the influenza virus hemagglutinin head domain trimer interface. Cell. 2019;177(5):1136–1152. doi: 10.1016/j.cell.2019.04.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Das DK, Govindan R, Nikić-Spiegel I, Krammer F, Lemke EA, Munro JB. Direct visualization of the conformational dynamics of single influenza hemagglutinin trimers. Cell. 2018;174(4):926–937. doi: 10.1016/j.cell.2018.05.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Garcia NK, Lee KK. Dynamic viral glycoprotein machines: approaches for probing transient states that drive membrane fusion. Viruses. 2016;8(1):15. doi: 10.3390/v8010015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Puchades C, Kűkrer B, Diefenbach O, Sneekes-Vriese E, Juraszek J, Koudstaal W, Apetri A. Epitope mapping of diverse influenza hemagglutinin drug candidates using HDX-MS. Sci Rep. 2019;9(1):4735. doi: 10.1038/s41598-019-41179-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Copeland CS, Doms RW, Bolzau EM, Webster RG, Helenius A. Assembly of influenza hemagglutinin trimers and its role in intracellular transport. J Cell Biol. 1986;103(4):1179–1191. doi: 10.1083/jcb.103.4.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Gething MJ, McCammon K, Sambrook J. Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell. 1986;46(6):939–950. doi: 10.1016/0092-8674(86)90076-0. [DOI] [PubMed] [Google Scholar]
  • 93.Chen J, Lee KH, Steinhauer DA, Stevens DJ, Skehel JJ, Wiley DC. Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell. 1998;95(3):409–417. doi: 10.1016/S0092-8674(00)81771-7. [DOI] [PubMed] [Google Scholar]
  • 94.Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology. 1999;258(1):1–20. doi: 10.1006/viro.1999.9716. [DOI] [PubMed] [Google Scholar]
  • 95.Suzuki K, Grigorova I, Phan TG, Kelly LM, Cyster JG. Visualizing B cell capture of cognate antigen from follicular dendritic cells. J Exp Med. 2009;206(7):1485–1493. doi: 10.1084/jem.20090209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Heesters BA, Chatterjee P, Kim YA, Gonzalez SF, Kuligowski MP, Kirchhausen T, Carroll MC. Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation. Immunity. 2013;38(6):1164–1175. doi: 10.1016/j.immuni.2013.02.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, Fiebiger BM, Ravetch JV. Type I and type II Fc receptors regulate innate and adaptive immunity. Nat Immunol. 2014;15(8):707–716. doi: 10.1038/ni.2939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Bohn AB, Nederby L, Harbo T, Skovbo A, Vorup-Jensen T, Krog J, Jakobsen J, Hokland ME. The effect of IgG levels on the number of natural killer cells and their Fc receptors in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2011;18(6):919–924. doi: 10.1111/j.1468-1331.2010.03333.x. [DOI] [PubMed] [Google Scholar]
  • 99.Nimmerjahn F. Fc-receptors and innate immune effector cells involved in IgG activity. Immunology. 2011;135:19. [Google Scholar]
  • 100.Munro JB, Lee KK. Probing structural variation and dynamics in the HIV-1 Env fusion glycoprotein. Curr HIV Res. 2018;16(1):5–12. doi: 10.2174/1570162X16666171222110025. [DOI] [PubMed] [Google Scholar]
  • 101.Rey FA, Stiasny K, van ey MC, Dellarole M, Heinz FX. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep. 2018;19(2):206–224. doi: 10.15252/embr.201745302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Yuan Y, Cao D, Zhang Y, Ma J, Qi J, Wang Q, Lu G, Wu Y, Yan J, Shi Y, Zhang X, Gao GF. Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains. Nat Commun. 2017;8(1):15092. doi: 10.1038/ncomms15092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Wu Y, Li S, Du L, Wang C, Zou P, Hong B, Yuan M, Ren X, Tai W, Kong Y, Zhou C, Lu L, Zhou X, Jiang S, Ying T. Neutralization of Zika virus by germline-like human monoclonal antibodies targeting cryptic epitopes on envelope domain III. Emerg Microbes Infect. 2017;6(10):89. doi: 10.1038/emi.2017.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease pathogenesis: insights for new treatments. Nat Med. 2013;19(2):156–167. doi: 10.1038/nm.3073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Mozdzanowska K, Feng J, Gerhard W. Virus-neutralizing activity mediated by the Fab fragment of a hemagglutinin-specific antibody is sufficient for the resolution of influenza virus infection in SCID mice. J Virol. 2003;77(15):8322–8328. doi: 10.1128/JVI.77.15.8322-8328.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Wu Y, Jiang S, Ying T. Single-domain antibodies as therapeutics against human viral diseases. Front Immunol. 2017;8:1802. doi: 10.3389/fimmu.2017.01802. [DOI] [PMC free article] [PubMed] [Google Scholar]

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