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

Chapter

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.

Keywords

Hepatitis Pneumonia Influenza Malaria Threonine 

References

  1. Adar Y, Singer Y, Levi R et al (2009) A universal epitope-based influenza vaccine and its efficacy against H5N1. Vaccine 27(15):2099–2107PubMedCrossRefGoogle Scholar
  2. 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):8709–8719PubMedCrossRefGoogle Scholar
  3. 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):12241–12251PubMedCrossRefGoogle Scholar
  4. 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):1152–1154PubMedGoogle Scholar
  5. 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):70–74PubMedCrossRefGoogle Scholar
  6. Belshe R (2010) The need for quadrivalent vaccine against seasonal influenza. Vaccine 28(Suppl 4):D45–D53PubMedCrossRefGoogle Scholar
  7. Ben-Yedidia T, Abel L, Arnon R, Globerson A (1998) Efficacy of anti-influenza peptide vaccine in aged mice. Mech Ageing Dev 104:11–23PubMedCrossRefGoogle Scholar
  8. 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 11:1043–1051PubMedCrossRefGoogle Scholar
  9. 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):2074–2077PubMedCrossRefGoogle Scholar
  10. 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):246–251PubMedCrossRefGoogle Scholar
  11. 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 29:1131–1140PubMedCrossRefGoogle Scholar
  12. 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):7Google Scholar
  13. 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):10059–10070PubMedCrossRefGoogle Scholar
  14. 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):1663–1673PubMedCrossRefGoogle Scholar
  15. 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):914–918PubMedCrossRefGoogle Scholar
  16. 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):246–251PubMedCrossRefGoogle Scholar
  17. Enami M, Enami K (1996) Influenza virus hemagglutinin and neuraminidase glycoproteins stimulate the membrane association of the matrix protein. J Virol 70(10):6653–6657PubMedGoogle Scholar
  18. 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):457–465PubMedCrossRefGoogle Scholar
  19. 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):6280–6283PubMedCrossRefGoogle Scholar
  20. 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):530–534PubMedCrossRefGoogle Scholar
  21. 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):684–694PubMedCrossRefGoogle Scholar
  22. 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):1959–1964PubMedCrossRefGoogle Scholar
  23. Gerhard W, Yewdell J, Frankel M, Webster R (1981) Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies. Nature 290(5808):713–717PubMedCrossRefGoogle Scholar
  24. 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):11538–11547PubMedCrossRefGoogle Scholar
  25. Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24(8):1159–1169PubMedCrossRefGoogle Scholar
  26. 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):12658–12663PubMedCrossRefGoogle Scholar
  27. 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):500–506PubMedCrossRefGoogle Scholar
  28. Hans D, Young P, Fairlie D (2006) Current status of short synthetic peptides as vaccines. Med Chem 2(6):627–646PubMedGoogle Scholar
  29. 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):1113–1120PubMedCrossRefGoogle Scholar
  30. 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):1–13PubMedCrossRefGoogle Scholar
  31. 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 172:5598–5605PubMedGoogle Scholar
  32. 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):2263–2277PubMedCrossRefGoogle Scholar
  33. Levi R, Arnon R (1996) Synthetic recombinant influenza vaccine induces efficient long-term immunity and cross-strain protection. Vaccine 14(1):85–92PubMedCrossRefGoogle Scholar
  34. 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):305–313PubMedCrossRefGoogle Scholar
  35. 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 127:245–250PubMedCrossRefGoogle Scholar
  36. 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):599–609PubMedGoogle Scholar
  37. 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 10:405–411PubMedCrossRefGoogle Scholar
  38. 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):5817–5827PubMedCrossRefGoogle Scholar
  39. Nabel G, Fauci A (2010) Induction of unnatural immunity: prospects for a broadly protective universal influenza vaccine. Nat Med 16(12):1389–1391PubMedCrossRefGoogle Scholar
  40. 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):1486–1496PubMedCrossRefGoogle Scholar
  41. 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):33–41PubMedCrossRefGoogle Scholar
  42. 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):2552–2558PubMedGoogle Scholar
  43. 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):1741–1749PubMedGoogle Scholar
  44. 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):2003–2012PubMedCrossRefGoogle Scholar
  45. 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):4283–4290PubMedCrossRefGoogle Scholar
  46. 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):6566–6577PubMedCrossRefGoogle Scholar
  47. Roose K, Fiers W, Saelens X (2009) Pandemic preparedness: toward a universal influenza vaccine. Drug News Perspect 22(2):80–92PubMedCrossRefGoogle Scholar
  48. 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):1421–1429PubMedCrossRefGoogle Scholar
  49. 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):2891–2894PubMedCrossRefGoogle Scholar
  50. 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):e59PubMedCrossRefGoogle Scholar
  51. 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):847–858PubMedCrossRefGoogle Scholar
  52. 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):2461–2465PubMedCrossRefGoogle Scholar
  53. Shapira M, Jolivet M, Arnon R (1985) A synthetic vaccine against influenza with built-in adjuvanticity. Int J Immunopharmacol 7:719–723PubMedCrossRefGoogle Scholar
  54. 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 143:558–564PubMedGoogle Scholar
  55. Sidney J, Grey H, Kubo R, Sette A (1996) Practical, biochemical and evolutionary implication of the discovery of HLA class I supermotifs. Immunol Today 17:261PubMedCrossRefGoogle Scholar
  56. 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):81–89PubMedCrossRefGoogle Scholar
  57. 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):4587–4596PubMedCrossRefGoogle Scholar
  58. 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):00018–10CrossRefGoogle Scholar
  59. Stocker B, Newton S (1994) Immune responses to epitopes inserted in Salmonella flagellin. Int Rev Immunol 11(2):167–178PubMedCrossRefGoogle Scholar
  60. 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):596–599PubMedCrossRefGoogle Scholar
  61. 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):e8754PubMedCrossRefGoogle Scholar
  62. 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):e3942PubMedCrossRefGoogle Scholar
  63. 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):118–122PubMedCrossRefGoogle Scholar
  64. Wei C, Boyington J, McTamney P et al (2010) Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 329(5995):1060–1064PubMedCrossRefGoogle Scholar
  65. 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):e7517PubMedCrossRefGoogle Scholar
  66. 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):e1000350PubMedCrossRefGoogle Scholar
  67. 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 86:1061–1065PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  1. 1.Weizmann Institute of ScienceRehovotIsrael
  2. 2.BiondVax Pharmaceuticals Ltd.Ness ZionaIsrael

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