Skip to main content

Influenza Neuraminidase as a Vaccine Antigen

  • Chapter
  • First Online:
Vaccines for Pandemic Influenza

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 333))

Abstract

The neuraminidase protein of influenza viruses is a surface glycoprotein that shows enzymatic activity to remove sialic acid, the viral receptor, from both viral and host proteins. The removal of sialic acid from viral proteins plays a key role in the release of the virus from the cell by preventing the aggregation of the virus by the hemagglutinin protein binding to other viral proteins. Antibodies to the neuraminidase protein can be protective alone in animal challenge studies, but the neuraminidase antibodies appear to provide protection in a different manner than antibodies to the hemagglutinin protein. Neutralizing antibodies to the hemagglutinin protein can directly block virus entry, but protective antibodies to the neuraminidase protein are thought to primarily aggregate virus on the cell surface, effectively reducing the amount of virus released from infected cells. The neuraminidase protein can be divided into nine distinct antigenic subtypes, where there is little cross-protection of antibodies between subtypes. All nine subtypes of neuraminidase protein are commonly found in avian influenza viruses, but only selected subtypes are routinely found in mammalian influenza viruses; for example, only the N1 and N2 subtypes are commonly found in both humans and swine. Even within a subtype, the neuraminidase protein can have a high level of antigenic drift, and vaccination has to specifically be targeted to the circulating strain to give optimal protection. The levels of neuraminidase antibody also appear to be critical for protection, and there is concern that human influenza vaccines do not include enough neuraminidase protein to induce a strong protective antibody response. The neuraminidase protein has also become an important target for antiviral drugs that target sialic acid binding which blocks neuraminidase enzyme activity. Two different antiviral drugs are available and are widely used for the treatment of seasonal influenza in humans, but antiviral resistance appears to be a growing concern for this class of antivirals.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
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

References

  • Abed Y et al (2002) Divergent evolution of hemagglutinin and neuraminidase genes in recent influenza A:H3N2 viruses isolated in Canada. J Med Virol 67(4):589–595

    Article  CAS  PubMed  Google Scholar 

  • Aoki FY et al (2003) Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 51(1):123–129

    Article  CAS  PubMed  Google Scholar 

  • Aymard M (2002) Quantification of neuramidase (NA) protein content. Vaccine 20(suppl 2):S59–S60

    Article  CAS  PubMed  Google Scholar 

  • Baum LG, Paulson JC (1991) The N2 neuraminidase of human influenza virus has acquired a substrate specificity complementary to the hemagglutinin receptor specificity. Virology 180(1):10–15

    Article  CAS  PubMed  Google Scholar 

  • Bottex C, Burckhart MF, Fontanges R (1981) Comparative immunogenicity of live influenza viruses and their solubilized neuraminidases: results of mouse protection experiments. Arch Virol 70(2):83–89

    Article  CAS  PubMed  Google Scholar 

  • Bragstad K, Nielsen LP, Fomsgaard A (2008) The evolution of human influenza A viruses from 1999 to 2006: a complete genome study. Virol J 5:40

    Article  PubMed  CAS  Google Scholar 

  • Brett IC, Johansson BE (2005) Immunization against influenza A virus: Comparison of conventional inactivated, live-attenuated and recombinant baculovirus produced purified hemagglutinin and neuraminidase vaccines in a murine model system. Virology 339(2):273–280

    Article  CAS  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

    Article  CAS  PubMed  Google Scholar 

  • Burmeister WP et al (1993) Comparison of structure and sequence of influenza B/Yamagata and B/Beijing neuraminidases shows a conserved “head” but much greater variability in the “stalk” and NB protein. Virology 192(2):683–686

    Article  CAS  PubMed  Google Scholar 

  • Chen J et al (2005) Protection against influenza virus infection in BALB/c mice immunized with a single dose of neuraminidase-expressing DNAs by electroporation. Vaccine 23(34):4322–4328

    Article  CAS  PubMed  Google Scholar 

  • Chen Z et al (1998) Comparison of the ability of viral protein-expressing plasmid DNAs to protect against influenza. Vaccine 16(16):1544–1549

    Article  CAS  PubMed  Google Scholar 

  • Chen Z et al (1999a) Enhanced protection against a lethal influenza virus challenge by immunization with both hemagglutinin- and neuraminidase-expressing DNAs. Vaccine 17(7–8):653–659

    Article  CAS  PubMed  Google Scholar 

  • Chen Z et al (1999b) Protection and antibody responses in different strains of mouse immunized with plasmid DNAs encoding influenza virus haemagglutinin, neuraminidase and nucleoprotein. J Gen Virol 80(Pt 10):2559–2564

    CAS  PubMed  Google Scholar 

  • Chen Z et al (2000) Cross-protection against a lethal influenza virus infection by DNA vaccine to neuraminidase. Vaccine 18(28):3214–3222

    Article  CAS  PubMed  Google Scholar 

  • Colman PM (1989) In: Krug RM (ed) Neuraminidase enzyme and antigen, in the influenza viruses. Plenum, New York, pp 175–218

    Google Scholar 

  • Colman PM, Varghese JN, Laver WG (1983) Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 303(5912):41–44

    Article  CAS  PubMed  Google Scholar 

  • Colmenero P, Liljestrom P, Jondal M (1999) Induction of P815 tumor immunity by recombinant Semliki Forest virus expressing the P1A gene. Gene Ther 6(10):1728–1733

    Article  CAS  PubMed  Google Scholar 

  • de Jong MD et al (2005) Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 353(25):2667–2672

    Article  CAS  PubMed  Google Scholar 

  • Deroo T, Jou WM, Fiers W (1996) Recombinant neuraminidase vaccine protects against lethal influenza. Vaccine 14(6):561–569

    Article  CAS  PubMed  Google Scholar 

  • Deshpande KL, Naeve CW, Webster RG (1985) The neuraminidases of the virulent and avirulent A/Chicken/Pennsylvania/83 (H5N2) influenza A viruses: sequence and antigenic analyses. Virology 147(1):49–60

    Article  CAS  PubMed  Google Scholar 

  • Downie JC (1970) Neuraminidase- and hemagglutinin-inhibiting antibodies in serum and nasal secretions of volunteers immunized with attenuated and inactivated influenza B-Eng-13–65 virus vaccines. J Immunol 105(3):620–626

    CAS  PubMed  Google Scholar 

  • Epstein SL et al (1993) Beta 2-microglobulin-deficient mice can be protected against influenza A infection by vaccination with vaccinia-influenza recombinants expressing hemagglutinin and neuraminidase. J Immunol 150(12):5484–5493

    CAS  PubMed  Google Scholar 

  • Flynn KJ et al (1999) In vivo proliferation of naive and memory influenza-specific CD8(+) T cells. Proc Natl Acad Sci USA 96(15):8597–8602

    Article  CAS  PubMed  Google Scholar 

  • Gao W et al (2006) Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization. J Virol 80(4):1959–1964

    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

    CAS  PubMed  Google Scholar 

  • Gottschalk A (1957) Neuraminidase: the specific enzyme of influenza virus and Vibrio cholerae. Biochim Biophys Acta 23(3):645–646

    Article  CAS  PubMed  Google Scholar 

  • Govorkova EA et al (2007) Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother 51(4):1414–1424

    Article  CAS  PubMed  Google Scholar 

  • Hartshorn KL et al (1996) Neutrophil deactivation by influenza A viruses: mechanisms of protection after viral opsonization with collectins and hemagglutination-inhibiting antibodies. Blood 87(8):3450–3461

    CAS  PubMed  Google Scholar 

  • Hashimoto G, Wright PF, Karzon DT (1983) Antibody-dependent cell-mediated cytotoxicity against influenza virus-infected cells. J Infect Dis 148(5):785–794

    CAS  PubMed  Google Scholar 

  • Herlocher ML et al (2004) Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 190(9):1627–1630

    Article  CAS  PubMed  Google Scholar 

  • Ho HT et al (2007) Neuraminidase inhibitor drug susceptibility differs between influenza N1 and N2 neuraminidase following mutagenesis of two conserved residues. Antiviral Res 76(3):263–266

    Article  CAS  PubMed  Google Scholar 

  • Johansson BE (1999) Immunization with influenza A virus hemagglutinin and neuraminidase produced in recombinant baculovirus results in a balanced and broadened immune response superior to conventional vaccine. Vaccine 17(15–16):2073–2080

    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  Google Scholar 

  • Johansson BE et al (1987a) Immunologic response to influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. III. Reduced generation of neuraminidase-specific helper T cells in hemagglutinin-primed mice. J Immunol 139(6):2015–2019

    CAS  PubMed  Google Scholar 

  • Johansson BE et al (1987b) 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 

  • Johansson BE, Moran TM, Kilbourne ED (1987c) Antigen-presenting B cells and helper T cells cooperatively mediate intravirionic antigenic competition between influenza A virus surface glycoproteins. Proc Natl Acad Sci USA 84(19):6869–6873

    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  Google Scholar 

  • Johansson BE, Grajower B, Kilbourne ED (1993) Infection-permissive immunization with influenza virus neuraminidase prevents weight loss in infected mice. Vaccine 11(10):1037–1039

    Article  CAS  PubMed  Google Scholar 

  • Johansson BE, Price PM, Kilbourne ED (1995) Immunogenicity of influenza A virus N2 neuraminidase produced in insect larvae by baculovirus recombinants. Vaccine 13(9):841–845

    Article  CAS  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, Pokorny BA, Tiso VA (2002) Supplementation of conventional trivalent influenza vaccine with purified viral N1 and N2 neuraminidases induces a balanced immune response without antigenic competition. Vaccine 20(11–12):1670–1674

    Article  CAS  PubMed  Google Scholar 

  • Kasel JA et al (1973) Effect of influenza anti-neuraminidase antibody on virus neutralization. Infect Immun 8(1):130–131

    CAS  PubMed  Google Scholar 

  • Kawaoka Y et al (1988) Is the gene pool of influenza viruses in shorebirds and gulls different from that in wild ducks? Virology 163(1):247–250

    Article  CAS  PubMed  Google Scholar 

  • Kendal AP, Noble GR, Dowdle WR (1977) Neuraminidase content of influenza vaccines and neuraminidase antibody responses after vaccination of immunologically primed and unprimed populations. J Infect Dis 136(suppl):S415–S424

    PubMed  Google Scholar 

  • Kilbourne ED et al (1968a) Antiviral activity of antiserum specific for an influenza virus neuraminidase. J Virol 2(4):281–288

    CAS  PubMed  Google Scholar 

  • Kilbourne ED, Christenson WN, Sande M (1968b) Antibody response in man to influenza virus neuraminidase following influenza. J Virol 2(7):761–762

    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  Google Scholar 

  • Kilbourne ED et al (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 et al (2004) Protection of mice with recombinant influenza virus neuraminidase. J Infect Dis 189(3):459–461

    Article  CAS  PubMed  Google Scholar 

  • Kiso M et al (2004) Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364(9436):759–765

    Article  CAS  PubMed  Google Scholar 

  • Kobasa D et al (1999) Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J Virol 73(8):6743–6751

    CAS  PubMed  Google Scholar 

  • Le QM et al (2005) Avian flu: isolation of drug-resistant H5N1 virus. Nature 437(7062):1108

    Article  CAS  PubMed  Google Scholar 

  • Lee CW, Senne DA, Suarez DL (2004) Effect of vaccine use in the evolution of Mexican lineage H5N2 avian influenza virus. J Virol 78(15):8372–8381

    Article  CAS  PubMed  Google Scholar 

  • Lee YJ et al (2007) Effects of homologous and heterologous neuraminidase vaccines in chickens against H5N1 highly pathogenic avian influenza. Avian Dis 51(suppl 1):476–478

    Article  CAS  PubMed  Google Scholar 

  • Li X et al (2006) Essential sequence of influenza neuraminidase DNA to provide protection against lethal viral infection. DNA Cell Biol 25(4):197–205

    Article  PubMed  Google Scholar 

  • Liu C et al (1995) Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding. J Virol 69(2):1099–1106

    CAS  PubMed  Google Scholar 

  • Martinet W et al (1997) Protection of mice against a lethal influenza challenge by immunization with yeast-derived recombinant influenza neuraminidase. Eur J Biochem 247(1):332–338

    Article  CAS  PubMed  Google Scholar 

  • Matrosovich M et al (1999) The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J Virol 73(2):1146–1155

    CAS  PubMed  Google Scholar 

  • Matrosovich MN et al (2004) Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 78(22):12665–12667

    Article  CAS  PubMed  Google Scholar 

  • McNulty M, Allan G, McKracken R (1986) Efficacy of avian influenza neuraminidase-specific vaccines in chickens. Avian Pathol 15(1):107–115

    Article  CAS  PubMed  Google Scholar 

  • Monto AS et al (2006) Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 50(7):2395–2402

    Article  CAS  PubMed  Google Scholar 

  • Moscona A (2005) Neuraminidase inhibitors for influenza. N Engl J Med 353(13):1363–1373

    Article  CAS  PubMed  Google Scholar 

  • Mozdzanowska K et al (2006) Enhancement of neutralizing activity of influenza virus-specific antibodies by serum components. Virology 352(2):418–426

    Article  CAS  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

    Article  CAS  PubMed  Google Scholar 

  • Nerome K et al (1995) Genetic analysis of porcine H3N2 viruses originating in southern China. J Gen Virol 76(Pt 3): 613–624

    Article  CAS  PubMed  Google Scholar 

  • Oh S, Belz GT, Eichelberger MC (2001) Viral neuraminidase treatment of dendritic cells enhances antigen-specific CD8(+) T cell proliferation, but does not account for the CD4(+) T cell independence of the CD8(+) T cell response during influenza virus infection. Virology 286(2):403–411

    Article  CAS  PubMed  Google Scholar 

  • Qiao CL et al (2003) Protection of chickens against highly lethal H5N1 and H7N1 avian influenza viruses with a recombinant fowlpox virus co-expressing H5 haemagglutinin and N1 neuraminidase genes. Avian Pathol 32(1):25–32

    Article  CAS  PubMed  Google Scholar 

  • Regoes RR, Bonhoeffer S (2006) Emergence of drug-resistant influenza virus: population dynamical considerations. Science 312(5772):389–391

    Article  CAS  PubMed  Google Scholar 

  • Reichert E, Mauler R (1975) Effect of neuraminidase on potency of inactivated influenza virus vaccines in mice. Dev Biol Stand 28:319–323

    CAS  PubMed  Google Scholar 

  • Rott R, Becht H, Orlich M (1974) The significance of influenza virus neuraminidase in immunity. J Gen Virol 22(1):35–41

    Article  CAS  PubMed  Google Scholar 

  • Sandbulte MR et al (2006) 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  CAS  Google Scholar 

  • Schulman JL (1969) The role of antineuraminidase antibody in immunity to influenza virus infection. Bull World Health Organ 41(3):647–650

    CAS  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  Google Scholar 

  • Slemons RD et al (1974) Type-A influenza viruses isolated from wild free-flying ducks in California. Avian Dis 18(1):119–124

    Article  CAS  PubMed  Google Scholar 

  • Stitz L et al (1985) Cytotoxic T cell lysis of target cells fused with liposomes containing influenza virus haemagglutinin and neuraminidase. J Gen Virol 66(Pt 6):1333–1339

    Article  CAS  PubMed  Google Scholar 

  • Suarez DL, Schultz-Cherry S (2000) Immunology of avian influenza virus: a review. Dev Comp Immunol 24(2–3):269–283

    Article  CAS  PubMed  Google Scholar 

  • Suzuki Y (2005) Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses. Biol Pharm Bull 28(3):399–408

    Article  CAS  PubMed  Google Scholar 

  • Sylte MJ, Hubby B, Suarez DL (2007) Influenza neuraminidase antibodies provide partial protection for chickens against high pathogenic avian influenza infection. Vaccine 25(19):3763–3772

    Article  CAS  PubMed  Google Scholar 

  • Tanimoto T, et al. (2005) Estimation of the neuraminidase content of influenza viruses and split-product vaccines by immunochromatography. Vaccine 23(37):4598–4609

    Article  CAS  PubMed  Google Scholar 

  • Varghese JN, Laver WG, Colman PM (1983) Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 303(5912):35–40

    Article  CAS  PubMed  Google Scholar 

  • Vidalin O et al   (2000) Use of conventional or replicating nucleic acid-based vaccines and recombinant Semliki forest virus-derived particles for the induction of immune responses against hepatitis C virus core and E2 antigens. Virology 276(2):259–270

    Article  CAS  PubMed  Google Scholar 

  • Vonka V et al (1977) Small-scale field trial with neuraminidase vaccine. Dev Biol Stand 39:337–339

    CAS  PubMed  Google Scholar 

  • Webster RG, Laver WG, Kilbourne ED (1968) Reactions of antibodies with surface antigens of influenza virus. J Gen Virol 3(3):315–326

    Article  CAS  PubMed  Google Scholar 

  • Webster RG, Reay PA, Laver WG (1988) Protection against lethal influenza with neuraminidase. Virology 164(1):230–237

    Article  CAS  PubMed  Google Scholar 

  • Whitley RJ et al (2001) Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20(2):127–133

    Article  CAS  PubMed  Google Scholar 

  • Wiley JA et al (2001) Antigen-specific CD8(+) T cells persist in the upper respiratory tract following influenza virus infection. J Immunol 167(6):3293–3299

    CAS  PubMed  Google Scholar 

  • Xu G et al (1995) Sialidase of swine influenza A viruses: variation of the recognition specificities for sialyl linkages and for the molecular species of sialic acid with the year of isolation. Glycoconj J 12(2):156–161

    Article  CAS  PubMed  Google Scholar 

  • Xu X et al (1996) Genetic variation in neuraminidase genes of influenza A (H3N2) viruses. Virology 224(1):175–183

    Article  CAS  PubMed  Google Scholar 

  • Yano T et al (2008) Effects of single-point amino acid substitutions on the structure and function neuraminidase proteins in influenza A virus. Microbiol Immunol 52(4):216–223

    Article  CAS  PubMed  Google Scholar 

  • Yen HL et al (2006) Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses. J Virol 80(17):8787–8795

    Article  CAS  PubMed  Google Scholar 

  • Zhang F et al (2005) Maternal immunization with both hemagglutinin- and neuraminidase-expressing DNAs provides an enhanced protection against a lethal influenza virus challenge in infant and adult mice. DNA Cell Biol 24(11):758–765

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David L. Suarez .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Sylte, M.J., Suarez, D.L. (2009). Influenza Neuraminidase as a Vaccine Antigen. In: Compans, R., Orenstein, W. (eds) Vaccines for Pandemic Influenza. Current Topics in Microbiology and Immunology, vol 333. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-92165-3_12

Download citation

Publish with us

Policies and ethics