Skip to main content
SpringerLink
Log in

Influenza Neuraminidase as a Vaccine Antigen

  • Chapter
  • First Online:
Influenza Pathogenesis and Control - Volume II

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 386))

Abstract

Neuraminidase (NA) is the second most abundant influenza surface glycoprotein and contributes to virus replication in several ways, most notably by removing sialic acids from the host and viral glycoproteins, releasing newly formed virus particles from infected cells. Antibodies that block this enzyme activity restrict virus replication in vitro. This chapter describes foundational epidemiologic and human influenza challenge studies that provide evidence of an association between NA inhibiting antibodies and resistance to disease. Mouse challenge studies show that while NA immunity is infection-permissive, NA-specific antibodies attenuate infection and prevent severe disease. NA immunity is most effective against homologous viruses but there is substantial protection against viruses with a heterologous NA (different lineage within a NA subtype). Monoclonal antibodies specific for conserved antigenic domains of subtype N1 protect against seasonal and pandemic H1N1 as well as H5N1 virus challenge. Clinical studies demonstrate that licensed seasonal vaccines contain immunogenic amounts of NA, but the contribution of this immunity to vaccine efficacy is currently not known. New types of influenza vaccines could be designed to elicit NA immunity. Because NA induces heterologous immunity, it could be an important constituent of universal influenza vaccines that aim to protect against unexpected emerging viruses.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ELISA:

Enzyme-linked immunosorbent assay

ELLA:

Enzyme-linked lectin assay

HA:

Hemagglutinin

HI:

Hemagglutination inhibition

NA:

Neuraminidase

NI:

Neuraminidase inhibition/inhibiting

TBA:

Thiobarbituric acid

VLP:

Virus-like particle

References

  • Air GM (2012) Influenza neuraminidase. Influenza Other Respir Viruses 6(4):245–256. doi:10.1111/j.1750-2659.2011.00304.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Air GM, Laver WG, Webster RG (1990) Mechanism of antigenic variation in an individual epitope on influenza virus N9 neuraminidase. J Virol 64(12):5797–5803

    CAS  PubMed Central  PubMed  Google Scholar 

  • Aminoff D (1959) The determination of free sialic acid in the presence of the bound compound. Virology 7(3):355–357

    Article  CAS  PubMed  Google Scholar 

  • Bodewes R, Kreijtz JH, Baas C, Geelhoed-Mieras MM, de Mutsert G, van Amerongen G, van den Brand JM, Fouchier RA, Osterhaus AD, Rimmelzwaan GF (2009a) Vaccination against human influenza A/H3N2 virus prevents the induction of heterosubtypic immunity against lethal infection with avian influenza A/H5N1 virus. PLoS ONE 4(5):e5538. doi:10.1371/journal.pone.0005538

    Article  PubMed Central  PubMed  Google Scholar 

  • Bodewes R, Kreijtz JH, Rimmelzwaan GF (2009b) Yearly influenza vaccinations: a double-edged sword? Lancet Infect Dis 9(12):784–788. doi:10.1016/S1473-3099(09)70263-4

    Article  PubMed  Google Scholar 

  • Brett IC, Johansson BE (2006) Variation in the divalent cation requirements of influenza A virus N1 neuraminidases. J Biochem 139(3):439–447. doi:10.1093/jb/mvj051

    Article  CAS  PubMed  Google Scholar 

  • Brown DM, Lee S, Garcia-Hernandez Mde L, Swain SL (2012) Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 86(12):6792–6803. doi:10.1128/JVI.07172-11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Burmeister WP, Ruigrok RW, Cusack S (1992) The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid. EMBO J 11(1):49–56

    CAS  PubMed Central  PubMed  Google Scholar 

  • Calder LJ, Wasilewski S, Berriman JA, Rosenthal PB (2010) Structural organization of a filamentous influenza A virus. Proc Natl Acad Sci USA 107(23):10685–10690. doi:10.1073/pnas.1002123107

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carrat F, Lavenu A, Cauchemez S, Deleger S (2006) Repeated influenza vaccination of healthy children and adults: borrow now, pay later? Epidemiol Infect 134(1):63–70. doi:10.1017/S0950268805005479

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cate TR, Rayford Y, Nino D, Winokur P, Brady R, Belshe R, Chen W, Atmar RL, Couch RB (2010) A high dosage influenza vaccine induced significantly more neuraminidase antibody than standard vaccine among elderly subjects. Vaccine 28(9):2076–2079

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen Z, Kim L, Subbarao K, Jin H (2012) The 2009 pandemic H1N1 virus induces anti-neuraminidase (NA) antibodies that cross-react with the NA of H5N1 viruses in ferrets. Vaccine 30(15):2516–2522. doi:10.1016/j.vaccine.2012.01.090

    Article  CAS  PubMed  Google Scholar 

  • Chong AK, Pegg MS, von Itzstein M (1991) Influenza virus sialidase: effect of calcium on steady-state kinetic parameters. Biochim Biophys Acta 1077(1):65–71

    Article  CAS  PubMed  Google Scholar 

  • Clements ML, Betts RF, Tierney EL, Murphy BR (1986) Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol 24(1):157–160

    CAS  PubMed Central  PubMed  Google Scholar 

  • Colacino JM, Chirgadze NY, Garman E, Murti KG, Loncharich RJ, Baxter AJ, Staschke KA, Laver WG (1997) A single sequence change destabilizes the influenza virus neuraminidase tetramer. Virology 236(1):66–75. doi:10.1006/viro.1997.8709

    Article  CAS  PubMed  Google Scholar 

  • Couch RB, Atmar RL, Franco LM, Quarles JM, Wells J, Arden N, Nino D, Belmont JW (2013) Antibody correlates and predictors of immunity to naturally occurring influenza in humans and the importance of antibody to the neuraminidase. J Infect Dis 207(6):974–981

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Couch RB, Atmar RL, Keitel WA, Quarles JM, Wells J, Arden N, Nino D (2012) Randomized comparative study of the serum antihemagglutinin and antineuraminidase antibody responses to six licensed trivalent influenza vaccines. Vaccine 31(1):190–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Couch RB, Kasel JA, Gerin JL, Schulman JL, Kilbourne ED (1974) Induction of partial immunity to influenza by a neuraminidase-specific vaccine. J Infect Dis 129(4):411–420

    Article  CAS  PubMed  Google Scholar 

  • Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, Sigurdardottir B, Hoeper A, Graham IL, Edelman R, He F, Nino D, Capellan J, Ruben FL (2007) Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 25(44):7656–7663. doi:10.1016/j.vaccine.2007.08.042

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • De Groot AS, Ardito M, McClaine EM, Moise L, Martin WD (2009) Immunoinformatic comparison of T-cell epitopes contained in novel swine-origin influenza A (H1N1) virus with epitopes in 2008–2009 conventional influenza vaccine. Vaccine 27(42):5740–5747. doi:10.1016/j.vaccine.2009.07.040

    Article  PubMed  Google Scholar 

  • Dowdle WR (1972) Influenza anti-neuraminidase: the second best antibody. N Engl J Med 286(25):1360–1361. doi:10.1056/NEJM197206222862511

    Article  CAS  PubMed  Google Scholar 

  • Dowdle WR, Coleman MT, Mostow SR, Kaye HS, Schoenbaum SC (1973) Inactivated influenza vaccines. 2. Laboratory indices of protection. Postgrad Med J 49(569):159–163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doyle TM, Hashem AM, Li C, Van Domselaar G, Larocque L, Wang J, Smith D, Cyr T, Farnsworth A, He R, Hurt AC, Brown EG, Li X (2013) Universal anti-neuraminidase antibody inhibiting all influenza A subtypes. Antiviral Res 100(2):567–574. doi:10.1016/j.antiviral.2013.09.018

    Article  CAS  PubMed  Google Scholar 

  • Easterbrook JD, Schwartzman LM, Gao J, Kash JC, Morens DM, Couzens L, Wan H, Eichelberger MC, Taubenberger JK (2012) Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice. Virology 432(1):39–44. doi:10.1016/j.virol.2012.06.003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fazekas de St G, Webster RG (1966) Disquisitions of original antigenic sin. I. evidence in man. J Exp Med 124(3):331–345

    Google Scholar 

  • Forrest BD, Pride MW, Dunning AJ, Capeding MR, Chotpitayasunondh T, Tam JS, Rappaport R, Eldridge JH, Gruber WC (2008) Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children. Clin Vaccine Immunol 15(7):1042–1053. doi:10.1128/CVI.00397-07

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fries LF, Smith GE, Glenn GM (2013) A recombinant viruslike particle influenza A (H7N9) vaccine. N Engl J Med 369(26):2564–2566. doi:10.1056/NEJMc1313186

    Article  CAS  PubMed  Google Scholar 

  • Fritz R, Sabarth N, Kiermayr S, Hohenadl C, Howard MK, Ilk R, Kistner O, Ehrlich HJ, Barrett PN, Kreil TR (2012) A vero cell-derived whole-virus H5N1 vaccine effectively induces neuraminidase-inhibiting antibodies. J Infect Dis 205(1):28–34. doi:10.1093/infdis/jir711

    Article  CAS  PubMed  Google Scholar 

  • Gerentes L, Kessler N, Aymard M (1999) Difficulties in standardizing the neuraminidase content of influenza vaccines. Dev Biol Stand 98:189–196; discussion 197

    Google Scholar 

  • Getie-Kebtie M, Sultana I, Eichelberger M, Alterman M (2013) Label-free mass spectrometry-based quantification of hemagglutinin and neuraminidase in influenza virus preparations and vaccines. Influenza Other Respir Viruses 7(4):521–530. doi:10.1111/irv.12001

    Article  CAS  PubMed  Google Scholar 

  • Gillim-Ross L, Subbarao K (2007) Can immunity induced by the human influenza virus N1 neuraminidase provide some protection from avian influenza H5N1 viruses? PLoS medicine 4(2):e91. doi:10.1371/journal.pmed.0040091

    Article  PubMed Central  PubMed  Google Scholar 

  • Gorse GJ, Falsey AR, Fling JA, Poling TL, Strout CB, Tsang PH (2013) Intradermally-administered influenza virus vaccine is safe and immunogenic in healthy adults 18–64 years of age. Vaccine 31(19):2358–2365. doi:10.1016/j.vaccine.2013.03.008

    Article  PubMed  Google Scholar 

  • Gulati U, Hwang CC, Venkatramani L, Gulati S, Stray SJ, Lee JT, Laver WG, Bochkarev A, Zlotnick A, Air GM (2002) Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus (A/Memphis/31/98). J Virol 76(23):12274–12280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hassantoufighi A, Zhang H, Sandbulte M, Gao J, Manischewitz J, King L, Golding H, Straight TM, Eichelberger MC (2010) A practical influenza neutralization assay to simultaneously quantify hemagglutinin and neuraminidase-inhibiting antibody responses. Vaccine 28(3):790–797

    Article  CAS  PubMed  Google Scholar 

  • Hensley SE, Das SR, Gibbs JS, Bailey AL, Schmidt LM, Bennink JR, Yewdell JW (2011) Influenza A virus hemagglutinin antibody escape promotes neuraminidase antigenic variation and drug resistance. PLoS ONE 6(2):e15190. doi:10.1371/journal.pone.0015190

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jameson J, Cruz J, Ennis FA (1998) Human cytotoxic T-lymphocyte repertoire to influenza A viruses. J Virol 72(11):8682–8689

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johansson BE, Brett IC (2003) Variation in the divalent cation requirements of influenza a virus N2 neuraminidases. J Biochem 134(3):345–352

    Article  CAS  PubMed  Google Scholar 

  • Johansson BE, Bucher DJ, Kilbourne ED (1989) Purified influenza virus hemagglutinin and neuraminidase are equivalent in stimulation of antibody response but induce contrasting types of immunity to infection. J Virol 63(3):1239–1246

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johansson BE, Cox MM (2011) Influenza viral neuraminidase: the forgotten antigen. Expert Rev Vaccines 10(12):1683–1695. doi:10.1586/erv.11.130

    Article  CAS  PubMed  Google Scholar 

  • Johansson BE, Kilbourne ED (1993) Dissociation of influenza virus hemagglutinin and neuraminidase eliminates their intravirionic antigenic competition. J Virol 67(10):5721–5723

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johansson BE, Matthews JT, Kilbourne ED (1998) Supplementation of conventional influenza A vaccine with purified viral neuraminidase results in a balanced and broadened immune response. Vaccine 16(9–10):1009–1015

    Article  CAS  PubMed  Google Scholar 

  • Johansson BE, Moran TM, Bona CA, Popple SW, Kilbourne ED (1987) Immunologic response to influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. II. Sequential infection of mice simulates human experience. J Immunol 139(6):2010–2014

    CAS  PubMed  Google Scholar 

  • Khan MW, Gallagher M, Bucher D, Cerini CP, Kilbourne ED (1982) Detection of influenza virus neuraminidase-specific antibodies by an enzyme-linked immunosorbent assay. J Clin Microbiol 16(1):115–122

    CAS  PubMed Central  PubMed  Google Scholar 

  • Khandaker G, Dierig A, Rashid H, King C, Heron L, Booy R (2011) Systematic review of clinical and epidemiological features of the pandemic influenza A (H1N1) 2009. Influenza Other Respir Viruses 5(3):148–156. doi:10.1111/j.1750-2659.2011.00199.x

    Article  PubMed  Google Scholar 

  • Khurana S, Chearwae W, Castellino F, Manischewitz J, King LR, Honorkiewicz A, Rock MT, Edwards KM, Del Giudice G, Rappuoli R, Golding H (2010) Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci Transl Med 2(15):15ra5. doi:10.1126/scitranslmed.3000624

  • Kilbourne ED (1972) Orthomyxoviruses and paramyxoviruses. In: Melnick JL (ed) International virology, 2nd edn. Karger, Basel, Switzerland, pp 121–137

    Google Scholar 

  • Kilbourne ED (1976) Comparative efficacy of neuraminidase-specific and conventional influenza virus vaccines in induction of antibody to neuraminidase in humans. J Infect Dis 134(4):384–394

    Article  CAS  PubMed  Google Scholar 

  • Kilbourne ED, Cerini CP, Khan MW, Mitchell JW Jr, Ogra PL (1987) Immunologic response to the influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. I. Studies in human vaccinees. J Immunol 138(9):3010–3013

    CAS  PubMed  Google Scholar 

  • Kilbourne ED, Couch RB, Kasel JA, Keitel WA, Cate TR, Quarles JH, Grajower B, Pokorny BA, Johansson BE (1995) Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans. Vaccine 13(18):1799–1803

    Article  CAS  PubMed  Google Scholar 

  • Kilbourne ED, Johansson BE, Grajower B (1990) Independent and disparate evolution in nature of influenza A virus hemagglutinin and neuraminidase glycoproteins. Proc Natl Acad Sci USA 87(2):786–790

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kilbourne ED, Laver WG, Schulman JL, Webster RG (1968) Antiviral activity of antiserum specific for an influenza virus neuraminidase. J Virol 2(4):281–288

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koel BF, Burke DF, Bestebroer TM, van der Vliet S, Zondag GC, Vervaet G, Skepner E, Lewis NS, Spronken MI, Russell CA, Eropkin MY, Hurt AC, Barr IG, de Jong JC, Rimmelzwaan GF, Osterhaus AD, Fouchier RA, Smith DJ (2013) Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science 342(6161):976–979. doi:10.1126/science.1244730

    Article  CAS  PubMed  Google Scholar 

  • Lakdawala SS, Lamirande EW, Suguitan AL Jr, Wang W, Santos CP, Vogel L, Matsuoka Y, Lindsley WG, Jin H, Subbarao K (2011) Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. PLoS Pathog 7(12):e1002443. doi:10.1371/journal.ppat.1002443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lambre CR, Terzidis H, Greffard A, Webster RG (1990) Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates. J Immunol Methods 135(1–2):49–57

    Article  CAS  PubMed  Google Scholar 

  • Lentz MR, Air GM, Laver WG, Webster RG (1984) Sequence of the neuraminidase gene of influenza virus A/Tokyo/3/67 and previously uncharacterized monoclonal variants. Virology 135(1):257–265

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Qi J, Zhang W, Vavricka CJ, Shi Y, Wei J, Feng E, Shen J, Chen J, Liu D, He J, Yan J, Liu H, Jiang H, Teng M, Li X, Gao GF (2010) The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. Nat Struct Mol Biol 17(10):1266–1268. doi:10.1038/nsmb.1909

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Sun X, Li Z, Liu Y, Vavricka CJ, Qi J, Gao GF (2012) Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus. Proc Natl Acad Sci USA 109(46):18897–18902. doi:10.1073/pnas.1211037109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Malby RL, Tulip WR, Harley VR, McKimm-Breschkin JL, Laver WG, Webster RG, Colman PM (1994) The structure of a complex between the NC10 antibody and influenza virus neuraminidase and comparison with the overlapping binding site of the NC41 antibody. Structure 2(8):733–746

    Article  CAS  PubMed  Google Scholar 

  • Marcelin G, Bland HM, Negovetich NJ, Sandbulte MR, Ellebedy AH, Webb AD, Griffin YS, DeBeauchamp JL, McElhaney JE, Webby RJ (2010) Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner. J Infect Dis 202(11):1634–1638. doi:10.1086/657084

    Article  PubMed Central  PubMed  Google Scholar 

  • Marcelin G, DuBois R, Rubrum A, Russell CJ, McElhaney JE, Webby RJ (2011) A contributing role for anti-neuraminidase antibodies on immunity to pandemic H1N1 2009 influenza A virus. PLoS ONE 6(10):e26335. doi:10.1371/journal.pone.0026335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 78(22):12665–12667. doi:10.1128/JVI.78.22.12665-12667.2004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McKinstry KK, Strutt TM, Kuang Y, Brown DM, Sell S, Dutton RW, Swain SL (2012) Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. J Clin Investig 122(8):2847–2856. doi:10.1172/JCI63689

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Moise L, Tassone R, Latimer H, Terry F, Levitz L, Haran JP, Ross TM, Boyle CM, Martin WD, De Groot AS (2013) Immunization with cross-conserved H1N1 influenza CD4 T-cell epitopes lowers viral burden in HLA DR3 transgenic mice. Hum Vaccines Immunotherapeutics 9(10):2060–2068

    Google Scholar 

  • Monto AS, Kendal AP (1973) Effect of neuraminidase antibody on Hong Kong influenza. Lancet 1(7804):623–625

    Article  CAS  PubMed  Google Scholar 

  • Mostow SR, Schoenbaum SC, Dowdle WR, Coleman MT, Kaye HS (1969) Studies with inactivated influenza vaccines purified by zonal centrifugation. 1. Adverse reactions and serological responses. Bull World Health Organ 41(3):525–530

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murphy BR, Kasel JA, Chanock RM (1972) Association of serum anti-neuraminidase antibody with resistance to influenza in man. N Engl J Med 286(25):1329–1332. doi:10.1056/NEJM197206222862502

    Article  CAS  PubMed  Google Scholar 

  • Nuss JM, Whitaker PB, Air GM (1993) Identification of critical contact residues in the NC41 epitope of a subtype N9 influenza virus neuraminidase. Proteins 15(2):121–132. doi:10.1002/prot.340150204

    Article  CAS  PubMed  Google Scholar 

  • Ogra PL, Chow T, Beutner KR, Rubi E, Strussenberg J, DeMello S, Rizzone C (1977) Clinical and immunologic evaluation of neuraminidase-specific influenza A virus vaccine in humans. J Infect Dis 135(4):499–506

    Article  CAS  PubMed  Google Scholar 

  • Oh S, Eichelberger MC (1999) Influenza virus neuraminidase alters allogeneic T cell proliferation. Virology 264(2):427–435. doi:10.1006/viro.1999.0019

    Article  CAS  PubMed  Google Scholar 

  • Oh S, Eichelberger MC (2000) Polarization of allogeneic T-cell responses by influenza virus-infected dendritic cells. J Virol 74(17):7738–7744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ohuchi M, Asaoka N, Sakai T, Ohuchi R (2006) Roles of neuraminidase in the initial stage of influenza virus infection. Microbes Infect/Institut Pasteur 8(5):1287–1293. doi:10.1016/j.micinf.2005.12.008

    Article  CAS  Google Scholar 

  • Palese P, Tobita K, Ueda M, Compans RW (1974) Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology 61(2):397–410

    Article  CAS  PubMed  Google Scholar 

  • Price GE, Soboleski MR, Lo CY, Misplon JA, Quirion MR, Houser KV, Pearce MB, Pappas C, Tumpey TM, Epstein SL (2010) Single-dose mucosal immunization with a candidate universal influenza vaccine provides rapid protection from virulent H5N1, H3N2 and H1N1 viruses. PLoS ONE 5(10):e13162. doi:10.1371/journal.pone.0013162

    Article  PubMed Central  PubMed  Google Scholar 

  • Quan FS, Kim MC, Lee BJ, Song JM, Compans RW, Kang SM (2012) Influenza M1 VLPs containing neuraminidase induce heterosubtypic cross-protection. Virology 430(2):127–135. doi:10.1016/j.virol.2012.05.006

    Article  CAS  PubMed  Google Scholar 

  • Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP, Blackburn GM, Hay AJ, Gamblin SJ, Skehel JJ (2006) The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 443(7107):45–49. doi:10.1038/nature05114

    Article  CAS  PubMed  Google Scholar 

  • Saito T, Taylor G, Laver WG, Kawaoka Y, Webster RG (1994) Antigenicity of the N8 influenza A virus neuraminidase: existence of an epitope at the subunit interface of the neuraminidase. J Virol 68(3):1790–1796

    CAS  PubMed Central  PubMed  Google Scholar 

  • Saito T, Taylor G, Webster RG (1995) Steps in maturation of influenza A virus neuraminidase. J Virol 69(8):5011–5017

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sandbulte MR, Gao J, Straight TM, Eichelberger MC (2009) A miniaturized assay for influenza neuraminidase-inhibiting antibodies utilizing reverse genetics-derived antigens. Influenza Other Respir Viruses 3(5):233–240

    Article  CAS  PubMed  Google Scholar 

  • Sandbulte MR, Jimenez GS, Boon AC, Smith LR, Treanor JJ, Webby RJ (2007) Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med 4(2):e59. doi:10.1371/journal.pmed.0040059

    Article  PubMed Central  PubMed  Google Scholar 

  • Sandbulte MR, Westgeest KB, Gao J, Xu X, Klimov AI, Russell CA, Burke DF, Smith DJ, Fouchier RA, Eichelberger MC (2011) Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses. Proc Natl Acad Sci USA 108(51):20748–20753

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schoenbaum SC, Mostow SR, Dowdle WR, Coleman MT, Kaye HS (1969) Studies with inactivated influenza vaccines purified by zonal centrifugation. 2. Efficacy. Bull World Health Organ 41(3):531–535

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schulman JL, Khakpour M, Kilbourne ED (1968) Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice. J Virol 2(8):778–786

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sultana I, Gao J, Markoff L, Eichelberger MC (2011) Influenza neuraminidase-inhibiting antibodies are induced in the presence of zanamivir. Vaccine 29(14):2601–2606. doi:10.1016/j.vaccine.2011.01.047

    Article  CAS  PubMed  Google Scholar 

  • Tulip WR, Varghese JN, Baker AT, van Donkelaar A, Laver WG, Webster RG, Colman PM (1991) Refined atomic structures of N9 subtype influenza virus neuraminidase and escape mutants. J Mol Biol 221(2):487–497

    Article  CAS  PubMed  Google Scholar 

  • Tulip WR, Varghese JN, Laver WG, Webster RG, Colman PM (1992) Refined crystal structure of the influenza virus N9 neuraminidase-NC41 Fab complex. J Mol Biol 227(1):122–148

    Article  CAS  PubMed  Google Scholar 

  • Varghese JN, Colman PM (1991) Three-dimensional structure of the neuraminidase of influenza virus A/Tokyo/3/67 at 2.2 A resolution. J Mol Biol 221(2):473–486

    Article  CAS  PubMed  Google Scholar 

  • Venkatramani L, Bochkareva E, Lee JT, Gulati U, Graeme Laver W, Bochkarev A, Air GM (2006) An epidemiologically significant epitope of a 1998 human influenza virus neuraminidase forms a highly hydrated interface in the NA-antibody complex. J Mol Biol 356(3):651–663. doi:10.1016/j.jmb.2005.11.061

    Article  CAS  PubMed  Google Scholar 

  • Wan H, Gao J, Xu K, Chen H, Couzens LK, Rivers KH, Easterbrook JD, Yang K, Zhong L, Rajabi M, Ye J, Sultana I, Wan XF, Liu X, Perez DR, Taubenberger JK, Eichelberger MC (2013) Molecular basis for broad neuraminidase immunity: conserved epitopes in seasonal and pandemic H1N1 as well as H5N1 influenza viruses. J Virol 87(16):9290–9300. doi:10.1128/JVI.01203-13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang M, Qi J, Liu Y, Vavricka CJ, Wu Y, Li Q, Gao GF (2011) Influenza A virus N5 neuraminidase has an extended 150-cavity. J Virol 85(16):8431–8435. doi:10.1128/JVI.00638-11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Warren L (1959) The thiobarbituric acid assay of sialic acids. J Biol Chem 234(8):1971–1975

    CAS  PubMed  Google Scholar 

  • Webster RG (1966) Original antigenic sin in ferrets: the response to sequential infections with influenza viruses. J Immunol 97(2):177–183

    CAS  PubMed  Google Scholar 

  • Webster RG, Air GM, Metzger DW, Colman PM, Varghese JN, Baker AT, Laver WG (1987) Antigenic structure and variation in an influenza virus N9 neuraminidase. J Virol 61(9):2910–2916

    CAS  PubMed Central  PubMed  Google Scholar 

  • Webster RG, Brown LE, Laver WG (1984) Antigenic and biological characterization of influenza virus neuraminidase (N2) with monoclonal antibodies. Virology 135(1):30–42

    Article  CAS  PubMed  Google Scholar 

  • Webster RG, Laver WG (1967) Preparation and properties of antibody directed specifically against the neuraminidase of influenza virus. J Immunol 99(1):49–55

    CAS  PubMed  Google Scholar 

  • Wu ZL, Ethen C, Hickey GE, Jiang W (2009) Active 1918 pandemic flu viral neuraminidase has distinct N-glycan profile and is resistant to trypsin digestion. Biochem Biophys Res Commun 379(3):749–753. doi:10.1016/j.bbrc.2008.12.139

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Zhu X, Dwek RA, Stevens J, Wilson IA (2008) Structural characterization of the 1918 influenza virus H1N1 neuraminidase. J Virol 82(21):10493–10501. doi:10.1128/JVI.00959-08

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yen HL, Liang CH, Wu CY, Forrest HL, Ferguson A, Choy KT, Jones J, Wong DD, Cheung PP, Hsu CH, Li OT, Yuen KM, Chan RW, Poon LL, Chan MC, Nicholls JM, Krauss S, Wong CH, Guan Y, Webster RG, Webby RJ, Peiris M (2011) Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. Proc Natl Acad Sci USA 108(34):14264–14269. doi:10.1073/pnas.1111000108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu X, Yang H, Guo Z, Yu W, Carney PJ, Li Y, Chen LM, Paulson JC, Donis RO, Tong S, Stevens J, Wilson IA (2012) Crystal structures of two subtype N10 neuraminidase-like proteins from bat influenza A viruses reveal a diverged putative active site. Proc Natl Acad Sci USA 109(46):18903–18908. doi:10.1073/pnas.1212579109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Suzanne Epstein, Jerry Weir, and Hana Golding for critical reading of this chapter and are indebted to Gillian Air, Bob Couch, Bert Johansson, Arnold Monto, Jeff Taubenberger, and Rob Webster for past discussions and their research programs that have provided invaluable tools and information toward understanding NA immunity. Work in the authors’ laboratory is supported by intramural CBER Panflu funds.

Author information

Authors and Affiliations

  1. Division of Viral Products, Office of Vaccine Research and Review, Center for Biologics Research and Regulation, US Food and Drug Administration, HFM445, Silver Spring, MD, 20892, USA

    Maryna C. Eichelberger & Hongquan Wan

Authors
  1. Maryna C. Eichelberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongquan Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maryna C. Eichelberger .

Editor information

Editors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Michael B. A. Oldstone

  2. IDepartment of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA

    Richard W. Compans

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Eichelberger, M.C., Wan, H. (2014). Influenza Neuraminidase as a Vaccine Antigen. 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_398

Download citation

Publish with us

Policies and ethics

Search

Navigation