Skip to main content
SpringerLink
Log in

Cutting-Edge Approaches Toward Novel and Cross-Protective Influenza Vaccines

  • Chapter
  • First Online:
Development of Novel Vaccines

  • 1111 Accesses

Abstract

The currently available vaccines against influenza are seasonal, viral strain specific, and hence, their efficacy is limited when the circulating strain is not the one included in them. We describe herewith some of the novel approaches for developing influenza vaccines, in particular peptide- or epitope-based vaccines. A discussion of the epitope-based approach is provided, emphasizing its limitations and advantages, as well as a detailed description of the known influenza epitopes. Finally, we describe our own approach for the design of an epitope-based broad-spectrum “universal” flu vaccine for human use, which is comprised of a synthetic protein expressing multiple copies of nine different conserved epitopes of influenza proteins. These epitopes are common to the vast majority of influenza virus strains regardless of their antigenic drifts and shifts. The vaccine, activating both the humoral and cellular arms of the immune response in both animal models and humans, is presently in phase II clinical trials and is expected to confer cross-strain immunity and to protect also against future strains of the influenza virus.

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
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
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

References

  • Adar Y, Singer Y, Levi R et al (2009) A universal epitope-based influenza vaccine and its efficacy against H5N1. Vaccine 27(15):2099–2107

    Article  PubMed  CAS  Google Scholar 

  • Ali A, Avalos R, Ponimaskin E, Nayak D (2000) Influenza virus assembly: effect of influenza virus glycoproteins on the membrane association of M1 protein. J Virol 74(18):8709–8719

    Article  PubMed  CAS  Google Scholar 

  • Assarsson E, Bui H, Sidney J et al (2008) Immunomic analysis of the repertoire of T-cell specificities for influenza A virus in humans. J Virol 82(24):12241–12251

    Article  PubMed  CAS  Google Scholar 

  • Ayash-Rashkovsky M, Borkow G, Davis H, Moss R, Bartholomew R, Bentwich Z (2005) Enhanced HIV-1 specific immune response by CpG ODN and HIV-1 immunogen-pulsed dendritic cells confers protection in the Trimera murine model of HIV-1 infection. FASEB J 19(9):1152–1154

    PubMed  CAS  Google Scholar 

  • Barbey-Martin C, Gigant B, Bizebard T, Calder L, Wharton S, Skehel J, Knossow M (2002) An antibody that prevents the hemagglutinin low pH fusogenic transition. Virology 294(1):70–74

    Article  PubMed  CAS  Google Scholar 

  • Belshe R (2010) The need for quadrivalent vaccine against seasonal influenza. Vaccine 28(Suppl 4):D45–D53

    Article  PubMed  Google Scholar 

  • Ben-Yedidia T, Abel L, Arnon R, Globerson A (1998) Efficacy of anti-influenza peptide vaccine in aged mice. Mech Ageing Dev 104:11–23

    Article  PubMed  CAS  Google Scholar 

  • Ben-Yedidia T, Marcus H, Reisner Y, Arnon R (1999) Intranasal administration of peptide vaccine protects human/mouse radiation chimera from influenza infection. Int Immunol 11:1043–1051

    Article  PubMed  CAS  Google Scholar 

  • Bouche F, Steinmetz A, Yanagi Y, Muller C (2005) Induction of broadly neutralizing antibodies against measles virus mutants using a polyepitope vaccine strategy. Vaccine 23(17–18):2074–2077

    Article  PubMed  CAS  Google Scholar 

  • Bui H, Peters B, Assarsson E, Mbawuike I, Sette A (2007) Ab and T cell epitopes of influenza A virus, knowledge and opportunities. Proc Natl Acad Sci USA 104(1):246–251

    Article  PubMed  CAS  Google Scholar 

  • Carreno B, Koenig S, Coligan J, Biddison W (1992) The peptide binding specificity of HLA class I molecules is largely allele-specific and non-overlapping. Mol Immunol 29:1131–1140

    Article  PubMed  CAS  Google Scholar 

  • Cebon J, Jager E, Shackleton M et al (2003) Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma. Cancer Immun 16(3):7

    Google Scholar 

  • Chen B, Leser G, Jackson D, Lamb R (2008) The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding. J Virol 82(20):10059–10070

    Article  PubMed  CAS  Google Scholar 

  • Corti D, Suguitan AJ, Pinna D et al (2010) Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest 120(5):1663–1673

    Article  PubMed  CAS  Google Scholar 

  • Dias A, Bouvier D, Crépin T, McCarthy A, Hart D, Baudin F, Cusack S, Ruigrok R (2009) The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458(7240):914–918

    Article  PubMed  CAS  Google Scholar 

  • Ekiert D, Bhabha G, Elsliger M, Friesen R, Jongeneelen M, Throsby M, Goudsmit J, Wilson I (2009) Antibody recognition of a highly conserved influenza virus epitope. Science 324(5924):246–251

    Article  PubMed  CAS  Google Scholar 

  • Enami M, Enami K (1996) Influenza virus hemagglutinin and neuraminidase glycoproteins stimulate the membrane association of the matrix protein. J Virol 70(10):6653–6657

    PubMed  CAS  Google Scholar 

  • Engler O, Dai W, Sette A, Hunziker I, Reichen J, Pichler W, Cerny A (2001) Peptide vaccines against hepatitis B virus: from animal model to human studies. Mol Immunol 38(6):457–465

    Article  PubMed  CAS  Google Scholar 

  • Fiers W, De Filette M, El Bakkouri K, Schepens B, Roose K, Schotsaert M, Birkett A, Saelens X (2009) M2e-based universal influenza A vaccine. Vaccine 27(45):6280–6283

    Article  PubMed  CAS  Google Scholar 

  • Fleury D, Barrère B, Bizebard T, Daniels R, Skehel J, Knossow M (1999) A complex of influenza hemagglutinin with a neutralizing antibody that binds outside the virus receptor binding site. Nat Struct Biol 6(6):530–534

    Article  PubMed  CAS  Google Scholar 

  • Gahery H, Daniel N, Charmeteau B et al (2006) New CD4+ and CD8+ T cell responses induced in chronically HIV type-1-infected patients after immunizations with an HIV type 1 lipopeptide vaccine. AIDS Res Hum Retroviruses 22(7):684–694

    Article  PubMed  CAS  Google Scholar 

  • Gao W, Soloff A, Lu X 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  PubMed  CAS  Google Scholar 

  • Gerhard W, Yewdell J, Frankel M, Webster R (1981) Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies. Nature 290(5808):713–717

    Article  PubMed  CAS  Google Scholar 

  • Gómez-Puertas P, Albo C, Pérez-Pastrana E, Vivo A, Portela A (2000) Influenza virus matrix protein is the major driving force in virus budding. J Virol 74(24):11538–11547

    Article  PubMed  Google Scholar 

  • Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24(8):1159–1169

    Article  PubMed  CAS  Google Scholar 

  • Grandea A, Olsen O, Cox T et al (2010) Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses. Proc Natl Acad Sci USA 107(28):12658–12663

    Article  PubMed  CAS  Google Scholar 

  • Guilligay D, Tarendeau F, Resa-Infante P et al (2008) The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15(5):500–506

    Article  PubMed  CAS  Google Scholar 

  • Hans D, Young P, Fairlie D (2006) Current status of short synthetic peptides as vaccines. Med Chem 2(6):627–646

    PubMed  CAS  Google Scholar 

  • Honko A, Sriranganathan N, Lees C, Mizel S (2006) Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect Immun 74(2):1113–1120

    Article  PubMed  CAS  Google Scholar 

  • Hoof I, Peters B, Sidney J, Pedersen L, Sette A, Lund O, Buus S, Nielsen M (2009) NetMHCpan, a method for MHC class I binding prediction beyond humans. Immunogenetics 61(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Jegerlehner A, Schmitz N, Storni T, Bachmann M (2004) Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. J Immunol 172:5598–5605

    PubMed  CAS  Google Scholar 

  • Kashala O, Amador R, Valero M et al (2002) Safety, tolerability and immunogenicity of new formulations of the Plasmodium falciparum malaria peptide vaccine SPf66 combined with the immunological adjuvant QS-21. Vaccine 20(17–18):2263–2277

    Article  PubMed  CAS  Google Scholar 

  • Levi R, Arnon R (1996) Synthetic recombinant influenza vaccine induces efficient long-term immunity and cross-strain protection. Vaccine 14(1):85–92

    Article  PubMed  CAS  Google Scholar 

  • Li H, Ding J, Chen Y (2003) Recombinant protein comprising multi-neutralizing epitopes induced high titer of antibodies against influenza A virus. Immunobiology 207(5):305–313

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Ding J, Liu W, Chen Y (2002) A candidate vaccine against influenza virus intensively improved the immunogenicity of a neutralizing epitope. Int Arch Allergy Immunol 127:245–250

    Article  PubMed  CAS  Google Scholar 

  • Luke T, Kilbane E, Jackson J, Hoffman S (2006) Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 145(8):599–609

    PubMed  Google Scholar 

  • McEwen J, Levi R, Horwitz R, Arnon R (1992) Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice. Vaccine 10:405–411

    Article  PubMed  CAS  Google Scholar 

  • Misplon J, Lo C, Gabbard J, Tompkins S, Epstein S (2010) Genetic control of immune responses to influenza A matrix 2 protein (M2). Vaccine 28(36):5817–5827

    Article  PubMed  CAS  Google Scholar 

  • Nabel G, Fauci A (2010) Induction of unnatural immunity: prospects for a broadly protective universal influenza vaccine. Nat Med 16(12):1389–1391

    Article  PubMed  CAS  Google Scholar 

  • Nardin E, Oliveira G, Calvo-Calle J et al (2000) Synthetic malaria peptide vaccine elicits high levels of antibodies in vaccines of defined HLA genotypes. J Infect Dis 182(5):1486–1496

    Article  PubMed  CAS  Google Scholar 

  • Nielsen M, Lundegaard C, Lund O, Keşmir C (2005) The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage. Immunogenetics 57(1–2):33–41

    Article  PubMed  CAS  Google Scholar 

  • 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(5):2552–2558

    PubMed  CAS  Google Scholar 

  • Peters B, Bulik S, Tampe R, Van Endert P, Holzhütter H (2003) Identifying MHC class I epitopes by predicting the TAP transport efficiency of epitope precursors. J Immunol 171(4):1741–1749

    PubMed  CAS  Google Scholar 

  • Pinto L, Berzofsky J, Fowke K et al (1999) HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients. AIDS 13(15):2003–2012

    Article  PubMed  CAS  Google Scholar 

  • Pushko P, Tumpey T, Van Hoeven N et al (2007) Evaluation of influenza virus-like particles and Novasome adjuvant as candidate vaccine for avian influenza. Vaccine 25(21):4283–4290

    Article  PubMed  CAS  Google Scholar 

  • Richards K, Chaves F, Sant A (2009) Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus. J Virol 83(13):6566–6577

    Article  PubMed  CAS  Google Scholar 

  • Roose K, Fiers W, Saelens X (2009) Pandemic preparedness: toward a universal influenza vaccine. Drug News Perspect 22(2):80–92

    Article  PubMed  CAS  Google Scholar 

  • Roth A, Rohrbach F, Weth R, Frisch B, Schuber F, Wels W (2005) Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct. Br J Cancer 92(8):1421–1429

    Article  PubMed  CAS  Google Scholar 

  • Rötzschke O, Falk K, Stevanović S, Jung G, Walden P, Rammensee H (1991) Exact prediction of a natural T cell epitope. Eur J Immunol 21(11):2891–2894

    Article  PubMed  Google Scholar 

  • Sandbulte M, Jimenez G, Boon A, Smith L, Treanor J, Webby R (2007) Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med 4(2):e59

    Article  PubMed  Google Scholar 

  • Sette A, Moutaftsi M, Moyron-Quiroz J et al (2008) Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities. Immunity 28(6):847–858

    Article  PubMed  CAS  Google Scholar 

  • Shapira M, Jibson M, Muller G, Arnon R (1984) Immunity and protection against influenza virus by synthetic peptide corresponding to antigenic sites of hemagglutinin. Proc Natl Acad Sci USA 81(8):2461–2465

    Article  PubMed  CAS  Google Scholar 

  • Shapira M, Jolivet M, Arnon R (1985) A synthetic vaccine against influenza with built-in adjuvanticity. Int J Immunopharmacol 7:719–723

    Article  PubMed  CAS  Google Scholar 

  • Shimojo N, Cowan E, Engelhard V, Maloy W, Coligan J, Biddison W (1989) A single amino acid substitution in HLA-A2 can alter the selection of the cytotoxic T lymphocyte repertoire that responds to influenza virus matrix peptide 55–73. J Immunol 143:558–564

    PubMed  CAS  Google Scholar 

  • Sidney J, Grey H, Kubo R, Sette A (1996) Practical, biochemical and evolutionary implication of the discovery of HLA class I supermotifs. Immunol Today 17:261

    Article  PubMed  CAS  Google Scholar 

  • Sirskyj D, Diaz-Mitoma F, Golshani A, Kumar A, Azizi A (2011) Innovative bioinformatic approaches for developing peptide-based vaccines against hypervariable viruses. Immunol Cell Biol 89(1):81–89

    Article  PubMed  CAS  Google Scholar 

  • Solórzano A, Ye J, Pérez D (2010) Alternative live-attenuated influenza vaccines based on modifications in the polymerase genes protect against epidemic and pandemic flu. J Virol 84(9):4587–4596

    Article  PubMed  Google Scholar 

  • Steel J, Lowen A, Wang T, Yondola M, Gao Q, Haye K, García-Sastre A, Palese P (2010) Influenza virus vaccine based on the conserved hemagglutinin stalk domain. MBio 1(1):00018–10

    Article  Google Scholar 

  • Stocker B, Newton S (1994) Immune responses to epitopes inserted in Salmonella flagellin. Int Rev Immunol 11(2):167–178

    Article  PubMed  CAS  Google Scholar 

  • Stouffer A, Acharya R, Salom D et al (2008) Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451(7178):596–599

    Article  PubMed  CAS  Google Scholar 

  • Tan P, Heiny A, Miotto O, Salmon J, Marques E, Lemonnier F, August J (2010) Conservation and diversity of influenza A H1N1 HLA-restricted T cell epitope candidates for epitope-based vaccines. PLoS One 5(1):e8754

    Article  PubMed  Google Scholar 

  • 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(12):e3942

    Article  PubMed  Google Scholar 

  • Wang Y, Zhou L, Shi H et al (2009) Monoclonal antibody recognizing SLLTEVET epitope of M2e protein potently inhibited the replication of influenza viruses in MDCK cells. Biochem Biophys Res Commun 385(1):118–122

    Article  PubMed  CAS  Google Scholar 

  • Wei C, Boyington J, McTamney P et al (2010) Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 329(5995):1060–1064

    Article  PubMed  CAS  Google Scholar 

  • Wunderlich K, Mayer D, Ranadheera C et al (2009) Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication. PLoS One 4(10):e7517

    Article  PubMed  Google Scholar 

  • Yoshida R, Igarashi M, Ozaki H, Kishida N, Tomabechi D, Kida H, Ito K, Takada A (2009) Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog 5(3):e1000350

    Article  PubMed  Google Scholar 

  • Zebedee S, Lamb R (1989) Growth restriction of influenza A virus by M2 protein antibody is genetically linked to the M1 protein. Proc Natl Acad Sci USA 86:1061–1065

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Weizmann Institute of Science, Rehovot, Israel

    Ruth Arnon

  2. BiondVax Pharmaceuticals Ltd., Ness Ziona, Israel

    Tamar Ben-Yedidia

Authors
  1. Ruth Arnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tamar Ben-Yedidia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruth Arnon .

Editor information

Editors and Affiliations

  1. Intercell AG, Campus Vienna Biocenter 3, Vienna, 1030, Austria

    Alexander von Gabain

  2. Intercell AG, Campus Vienna Biocenter 3, Vienna, 1030, Austria

    Christoph Klade

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Wien

About this chapter

Cite this chapter

Arnon, R., Ben-Yedidia, T. (2012). Cutting-Edge Approaches Toward Novel and Cross-Protective Influenza Vaccines. In: von Gabain, A., Klade, C. (eds) Development of Novel Vaccines. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0709-6_8

Download citation

Publish with us

Policies and ethics

Search

Navigation