Abstract
The threat of novel influenza viruses emerging into the human population from animal reservoirs, as well as the short duration of protection conferred by licensed vaccines against human seasonal strains has spurred research efforts to improve upon current vaccines and develop novel therapeutics against influenza viruses. In recent years these efforts have resulted in the identification of novel, highly conserved epitopes for neutralizing antibodies on the influenza virus hemagglutinin protein, which are present in both the stalk and globular head domains of the molecule. The existence of such epitopes may allow for generation of novel therapeutic antibodies, in addition to serving as attractive targets of novel vaccine design. The aims of developing improved vaccines include eliciting broader protection from drifted strains, inducing long-lived immunity against seasonal strains, and allowing for the rational design of vaccines that can be stockpiled for use as pre-pandemic vaccines. In addition, an increased focus on influenza virus vaccine research has prompted an improved understanding of how the immune system responds to influenza virus infection.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- bnAb:
-
Broadly neutralizing antibody
- CDR:
-
Complementarity determining region
- DTT:
-
Dithiothreitol
- H1, H2, H3, etc:
-
Hemagglutinin subtype 1, 2, 3, etc
- HA:
-
Hemagglutinin
- HA1:
-
Hemagglutinin subunit 1
- HA2:
-
Hemaggltinin subunit 2
- HAI:
-
Hemagglutination inhibition
- mAb:
-
Monoclonal antibody
- N1, N2, etc:
-
Neuraminidase subtype 1, 2, etc
- nAb:
-
Neutralizing antibody
- pH1N1:
-
2009 pandemic H1N1
- RBS:
-
Receptor binding site
- sH1N1:
-
Seasonal H1N1
References
Beyer WE, McElhaney J, Smith DJ, Monto AS, Nguyen-Van-Tam JS, Osterhaus AD (2013) Cochrane re-arranged: support for policies to vaccinate elderly people against influenza. Vaccine 31:6030–6033. doi:S0264-410X(13)01339-X, 10.1016/j.vaccine.2013.09.063
Bommakanti G, Citron MP, Hepler RW et al (2010) Design of an HA2-based Escherichia coli expressed influenza immunogen that protects mice from pathogenic challenge. Proc Natl Acad Sci USA 107:13701–13706. doi:10.1073/pnas.1007465107
Bommakanti G, Lu X, Citron MP et al (2012) Design of Escherichia coli-expressed stalk domain immunogens of H1N1 hemagglutinin that protect mice from lethal challenge. J Virol 86:13434–13444. doi:10.1128/JVI.01429-12
Brandenburg B, Koudstaal W, Goudsmit J et al (2013) Mechanisms of hemagglutinin targeted influenza virus neutralization. PLoS One 8:e80034. doi:10.1371/journal.pone.0080034
Brown LE, Murray JM, White DO, Jackson DC (1990) An analysis of the properties of monoclonal antibodies directed to epitopes on influenza virus hemagglutinin. Arch Virol 114:1–26
Bucasas KL, Franco LM, Shaw CA et al (2011) Early patterns of gene expression correlate with the humoral immune response to influenza vaccination in humans. J Infect Dis 203:921–929. doi:10.1093/infdis/jiq156
Caton AJ, Brownlee GG, Yewdell JW, Gerhard W (1982) The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 31:417–427. doi:10.1016/0092-8674(82)90135-0
CDC (2010) Estimates of deaths associated with seasonal influenza—United States, 1976–2007. MMWR Morb Mortal Wkly Rep 59:1057–1062.
Co MD, Cruz J, Takeda A, Ennis FA, Terajima M (2012) Comparison of complement dependent lytic, hemagglutination inhibition and microneutralization antibody responses in influenza vaccinated individuals. Hum Vaccin Immunother 8:1218–1222. doi:10.4161/hv.21025
Corti D, Lanzavecchia A (2013) Broadly neutralizing antiviral antibodies. Annu Rev Immunol 31:705–742. doi:10.1146/annurev-immunol-032712-095916
Corti D, Suguitan AL Jr, Pinna D et al (2010) Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest 120:1663–1673. doi:10.1172/JCI41902
Corti D, Voss J, Gamblin SJ et al (2011) A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333:850–856. doi:10.1126/science.1205669
Dilillo DJ, Tan GS, Palese P, Ravetch JV (2014) Broadly neutralizing hemagglutinin stalk-specific antibodies require FcgammaR interactions for protection against influenza virus in vivo. Nat Med 20:143–151. doi:10.1038/nm.3443
Dreyfus C, Laursen NS, Kwaks T et al (2012) Highly conserved protective epitopes on influenza B viruses. Science 337:1343–1348. doi:10.1126/science.1222908
Dreyfus C, Ekiert DC, Wilson IA (2013) Structure of a classical broadly neutralizing stem antibody in complex with a pandemic H2 influenza virus hemagglutinin. J Virol 87:7149–7154. doi:10.1128/JVI.02975-12
Du L, Jin L, Zhao G et al (2013) Identification and structural characterization of a broadly neutralizing antibody targeting a novel conserved epitope on the influenza virus H5N1 hemagglutinin. J Virol 87:2215–2225. doi:10.1128/JVI.02344-12
Ekiert DC, Bhabha G, Elsliger MA et al (2009) Antibody recognition of a highly conserved influenza virus epitope. Science 324:246–251. doi:10.1126/science.1171491
Ekiert DC, Friesen RH, Bhabha G et al (2011) A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333:843–850. doi:10.1126/science.1204839
Ekiert DC, Kashyap AK, Steel J et al (2012) Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489:526–532. doi:10.1038/nature11414
Ellebedy AH, Webby RJ (2009) Influenza vaccines. Vaccine 27(Suppl 4):D65–D68. doi:S0264-410X(09)01214-6, 10.1016/j.vaccine.2009.08.038
Fox JP, Cooney MK, Hall CE, Foy HM (1982) Influenzavirus infections in Seattle families, 1975–1979. II. Pattern of infection in invaded households and relation of age and prior antibody to occurrence of infection and related illness. Am J Epidemiol 116:228–242
Friesen RH, Lee PS, Stoop EJ et al (2014) A common solution to group 2 influenza virus neutralization. Proc Natl Acad Sci USA 111:445–450. doi:10.1073/pnas.1319058110
Gerhard W, Yewdell J, Frankel ME, Webster R (1981) Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies. Nature 290:713–717
Glezen WP, Couch RB (1978) Interpandemic influenza in the Houston area, 1974–1976. N Engl J Med 298:587–592. doi:10.1056/NEJM197803162981103
Goff PH, Eggink D, Seibert CW, Hai R, Martínez-Gil L, Krammer F, Palese P (2013) Adjuvants and immunization strategies to induce influenza virus hemagglutinin stalk antibodies. PLoS One 8:e79194. doi:10.1371/journal.pone.0079194
Graves PN, Schulman JL, Young JF, Palese P (1983) Preparation of influenza virus subviral particles lacking the HA1 subunit of hemagglutinin: unmasking of cross-reactive HA2 determinants. Virology 126:106–116
Guo L, Zhang X, Ren L et al (2014) Human antibody responses to avian influenza A(H7N9) virus, 2013. Emerg Infect Dis 20:192–200. doi:10.3201/eid2002.131094
Hai R, Krammer F, Tan GS et al (2012) Influenza viruses expressing chimeric hemagglutinins: globular head and stalk domains derived from different subtypes. J Virol 86:5774–5781. doi:10.1128/JVI.00137-12
Hayden FG, Hay AJ (1992) Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine. Curr Top Microbiol Immunol 176:119–130
Hayward AC, Fragaszy EB, Bermingham A et al (2014) Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med 2(6):445–454. doi: 10.1016/52213-2600 (14) 70034-7
Itoh Y, Shinya K, Kiso M et al (2009) In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 460:1021–1025. doi:10.1038/nature08260
Janulíková J, Staneková Z, Mucha V, Kostolanský F, Varečková E (2012) Two distinct regions of HA2 glycopolypeptide of influenza virus hemagglutinin elicit cross-protective immunity against influenza. Acta Virol 56:169–176
Jegaskanda S, Job ER, Kramski M et al (2013) Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J Immunol 190:1837–1848. doi:10.4049/jimmunol.1201574
Kanekiyo M, Wei CJ, Yassine HM et al (2013) Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature. doi:10.1038/nature12202
Kashyap AK, Steel J, Oner AF et al (2008) Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci USA 105:5986–5991
Kashyap AK, Steel J, Rubrum A et al (2010) Protection from the 2009 H1N1 pandemic influenza by an antibody from combinatorial survivor-based libraries. PLoS Pathog 6:e1000990. doi:10.1371/journal.ppat.1000990
Katz JM, Hancock K, Xu X (2011) Serologic assays for influenza surveillance, diagnosis and vaccine evaluation. Expert Rev Anti Infect Ther 9:669–683. doi:10.1586/eri.11.51
Krammer F, Palese P (2013) Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr Opin Virol 3:521–530. doi:10.1016/j.coviro.2013.07.007
Krammer F, Palese P (2014) Universal influenza virus vaccines: need for clinical trials. Nat Immunol 15:3–5. doi:10.1038/ni.2761
Krammer F, Pica N, Hai R, Tan GS, Palese P (2012) Hemagglutinin stalk-reactive antibodies are boosted following sequential infection with seasonal and pandemic H1N1 influenza virus in mice. J Virol 86:10302–10307. doi:10.1128/JVI.01336-12
Krammer F, Pica N, Hai R, Margine I, Palese P (2013) Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. J Virol 87:6542–6550. doi:10.1128/JVI.00641-13
Krammer F, Hai R, Yondola M et al (2014a) Assessment of influenza virus hemagglutinin stalk-based immunity in ferrets. J Virol 88:3432–3442. doi:10.1128/JVI.03004-13
Krammer F, Margine I, Hai R et al (2014b) H3 Stalk-based chimeric hemagglutinin influenza virus constructs protect mice from H7N9 challenge. J Virol 88:2340–2343. doi:10.1128/JVI.03183-13
Krause JC, Tsibane T, Tumpey TM, Huffman CJ, Basler CF, Crowe JE Jr (2011) A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin. J Virol 85:10905–10908. doi:10.1128/JVI.00700-11
Lee PS, Yoshida R, Ekiert DC, Sakai N, Suzuki Y, Takada A, Wilson IA (2012) Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity. Proc Natl Acad Sci USA 109:17040–17045. doi:10.1073/pnas.1212371109
Li GM, Chiu C, Wrammert J et al (2012) Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc Natl Acad Sci USA 109:9047–9052. doi:10.1073/pnas.1118979109
Li S, Nakaya HI, Kazmin DA, Oh JZ, Pulendran B (2013) Systems biological approaches to measure and understand vaccine immunity in humans. Semin Immunol 25:209–218. doi:S1044-5323(13)00032-8, 10.1016/j.smim.2013.05.003
Lu Y, Welsh JP, Swartz JR (2014) Production and stabilization of the trimeric influenza hemagglutinin stem domain for potentially broadly protective influenza vaccines. Proc Natl Acad Sci USA 111:125–130. doi:10.1073/pnas.1308701110
Margine I, Hai R, Albrecht RA et al (2013a) H3N2 influenza virus infection induces broadly reactive hemagglutinin stalk antibodies in humans and mice. J Virol 87:4728–4737. doi:10.1128/JVI.03509-12
Margine I, Krammer F, Hai R et al (2013b) Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses. J Virol 87:10435–10446. doi:10.1128/JVI.01715-13
McNeil S, Shinde V, Andrew M, et al (2014) Interim estimates of 2013/2014 influenza clinical severity and vaccine effectiveness in the prevention of laboratory-confirmed influenza-related hospitalisation. Euro Surveill Mar 6; 19(9). pii 20729.
Miller MS, Gardner TJ, Krammer F, Aguado LC, Tortorella D, Basler CF, Palese P (2013a) Neutralizing antibodies against previously encountered influenza virus strains increase over time: a longitudinal analysis. Sci Transl Med 5:198ra107. doi:10.1126/scitranslmed.3006637
Miller MS, Tsibane T, Krammer F, Hai R, Rahmat S, Basler CF, Palese P (2013b) 1976 and 2009 H1N1 influenza virus vaccines boost anti-hemagglutinin stalk antibodies in humans. J Infect Dis 207:98–105. doi:10.1093/infdis/jis652
Moody MA, Zhang R, Walter EB et al (2011) H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLoS One 6:e25797. doi:10.1371/journal.pone.0025797
Muthuri SG, Venkatesan S, Myles PR et al (2014) Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2(5):395–404. doi: 10.1016/52213-2600 (14) 70041-4
Nakamura G, Chai N, Park S et al (2013) An in vivo human-plasmablast enrichment technique allows rapid identification of therapeutic influenza A antibodies. Cell Host Microbe 14:93–103. doi:10.1016/j.chom.2013.06.004
Neumann G, Noda T, Kawaoka Y (2009) Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459:931–939. doi:10.1038/nature08157
Ohshima N, Iba Y, Kubota-Koketsu R, Asano Y, Okuno Y, Kurosawa Y (2011) Naturally occurring antibodies in humans can neutralize a variety of influenza virus strains, including H3, H1, H2, and H5. J Virol 85:11048–11057. doi:10.1128/JVI.05397-11
Okuno Y, Isegawa Y, Sasao F, Ueda S (1993) A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J Virol 67:2552–2558
Okuno Y, Matsumoto K, Isegawa Y, Ueda S (1994) Protection against the mouse-adapted A/FM/1/47 strain of influenza A virus in mice by a monoclonal antibody with cross-neutralizing activity among H1 and H2 strains. J Virol 68:517–520
Osterholm MT, Kelley NS, Sommer A, Belongia EA (2012) Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 12:36–44. doi:http://dx.doi.org/10.1016/S1473-3099(11)70295-X
Palese P, Wang TT (2011) Why do influenza virus subtypes die out? A hypothesis. MBio 2. doi:10.1128/mBio.00150-11
Pica N, Hai R, Krammer F et al (2012) Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses. Proc Natl Acad Sci USA 109:2573–2578. doi:10.1073/pnas.1200039109
Polakova K, Russ G, Styk B (1978) Antigenic glycopolypeptides HA1 and HA2 of influenza virus haemagglutinin. I. Gel filtration in 6 M guanidine hydrochloride. Acta Virol 22:362–370
Renegar KB, Small PA Jr (1991) Immunoglobulin A mediation of murine nasal anti-influenza virus immunity. J Virol 65:2146–2148
Russ G, Styk B, Polakova K (1978a) Antigenic glycopolypeptides HA1 and HA2 of influenza virus haemagglutinin. II. Reactivity with rabbit sera against intact virus and purified undissociated haemagglutinin. Acta Virol 22:371–382
Russ G, Styk B, Polakova K (1978b) Radioimmunoassay of influenza A virus haemagglutinin. I. Preparation and properties of radioactive 125I-labelled bromelain-released haemagglutinin. Acta Virol 22:1–10
Sagawa H, Ohshima A, Kato I, Okuno Y, Isegawa Y (1996) The immunological activity of a deletion mutant of influenza virus haemagglutinin lacking the globular region. J Gen Virol 77 ( Pt 7):1483–1487
Samson M, Pizzorno A, Abed Y, Boivin G (2013) Influenza virus resistance to neuraminidase inhibitors. Antiviral Res 98:174–185. doi:S0166-3542(13)00068-5, 10.1016/j.antiviral.2013.03.014
Schneemann A, Speir JA, Tan GS, Khayat R, Ekiert DC, Matsuoka Y, Wilson IA (2012) A virus-like particle that elicits cross-reactive antibodies to the conserved stem of influenza virus hemagglutinin. J Virol 86:11686–11697. doi:10.1128/JVI.01694-12
Seibert CW, Rahmat S, Krause JC et al (2013) Recombinant IgA is sufficient to prevent influenza virus transmission in guinea pigs. J Virol 87:7793–7804. doi:10.1128/JVI.00979-13
Smirnov YA, Lipatov AS, Gitelman AK, Okuno Y, Van Beek R, Osterhaus AD, Claas EC (1999) An epitope shared by the hemagglutinins of H1, H2, H5, and H6 subtypes of influenza A virus. Acta Virol 43:237–244
Steel J, Lowen AC, Wang TT, et al (2010) Influenza virus vaccine based on the conserved hemagglutinin stalk domain. mBio 1. doi:10.1128/mBio.00018-10
Subbarao K, Matsuoka Y (2013) The prospects and challenges of universal vaccines for influenza. Trends Microbiol 21:350–358. doi:S0966-842X(13)00074-7, 10.1016/j.tim.2013.04.003
Sui J, Hwang WC, Perez S et al (2009) Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16:265–273. doi:10.1038/nsmb.1566
Sui J, Sheehan J, Hwang WC et al (2011) Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza a antibodies. Clin Infect Dis 52:1003–1009. doi:10.1093/cid/cir121
Talaat KR, Luke CJ, Khurana S et al (2014) A live attenuated H5N1 vaccine induces long-term immunity in the absence of a primary antibody response. J Infect Dis. doi:10.1093/infdis/jiu123
Tan GS, Krammer F, Eggink D, Kongchanagul A, Moran TM, Palese P (2012) A pan-H1 anti-hemagglutinin monoclonal antibody with potent broad-spectrum efficacy in vivo. J Virol 86:6179–6188. doi:10.1128/JVI.00469-12
Terajima M, Cruz J, Co MD et al (2011) Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies. J Virol 85:13463–13467. doi:10.1128/JVI.05193-11
Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, Fukuda K (2004) Influenza-associated hospitalizations in the United States. J Am Med Assoc 292:1333–1340. doi:10.1001/jama.292.11.1333
Thomson CA, Wang Y, Jackson LM et al (2012) Pandemic H1N1 influenza infection and vaccination in humans induces cross-protective antibodies that target the hemagglutinin stem. Front Immunol 3:87. doi:10.3389/fimmu.2012.00087
Throsby M, van den Brink E, Jongeneelen M et al (2008) Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE 3:e3942
Tricco AC, Chit A, Soobiah C et al (2013) Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis. BMC Med 11:153. doi:10.1186/1741-7015-11-153
Wang TT, Tan GS, Hai R et al (2010a) Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. Proc Nat Acad Sci USA 107:18979–18984. doi:10.1073/pnas.1013387107
Wang TT, Tan GS, Hai R, Pica N, Petersen E, Moran TM, Palese P (2010b) Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. PLoS Pathog 6:e1000796. doi:10.1371/journal.ppat.1000796
Wei CJ, Boyington JC, McTamney PM et al (2010) Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 329:1060–1064. doi:10.1126/science.1192517
Weis W, Brown JH, Cusack S, Paulson JC, Skehel JJ, Wiley DC (1988) Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature 333:426–431. doi:10.1038/333426a0
Whittle JR, Zhang R, Khurana S et al (2011) Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA 108:14216–14221. doi:10.1073/pnas.1111497108
Whittle JR, Wheatley AK, Wu L et al (2014) Flow cytometry reveals that H5N1 vaccination elicits cross-reactive stem-directed antibodies from multiple Ig heavy chain lineages. J Virol. doi:10.1128/JVI.03422-13
Wilson IA, Skehel JJ, Wiley DC (1981) Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289:366–373
Wrammert J, Smith K, Miller J et al (2008) Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453:667–671. doi:10.1038/nature06890
Wrammert J, Koutsonanos D, Li GM et al (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181–193. doi:10.1084/jem.20101352
Xu R, Krause JC, McBride R, Paulson JC, Crowe JE Jr, Wilson IA (2013) A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin. Nat Struct Mol Biol 20:363–370. doi:10.1038/nsmb.2500
Yoshida R, Igarashi M, Ozaki H et al (2009) Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog 5:e1000350. doi:10.1371/journal.ppat.1000350
Zhu X, Guo YH, Jiang T et al (2013) A unique and conserved neutralization epitope in H5N1 influenza viruses identified by an antibody against the A/Goose/Guangdong/1/96 hemagglutinin. J Virol 87:12619–12635. doi:10.1128/JVI.01577-13
Acknowledgments
PP and FK are supported, in part, by NIH P01 AI097092, U19 AI109946, and HHSN272201400008C. JS is supported in part by HHSN272201400004C. We very much thank Caitlin Mullarkey for helpful discussions and editorial review.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Krammer, F., Palese, P., Steel, J. (2014). Advances in Universal Influenza Virus Vaccine Design and Antibody Mediated Therapies Based on Conserved Regions of the Hemagglutinin. In: Oldstone, M., Compans, R. (eds) Influenza Pathogenesis and Control - Volume II. Current Topics in Microbiology and Immunology, vol 386. Springer, Cham. https://doi.org/10.1007/82_2014_408
Download citation
DOI: https://doi.org/10.1007/82_2014_408
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-11157-5
Online ISBN: 978-3-319-11158-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)