Science foundations and prospects of the development mucosal inactivated influenza vaccines

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Abstract

It's examined the role of the innate and adoptive immune factors in the formation of the immune response against influenza virus, influenza vaccines on mucosa. It's discussed the possible mechanisms of the devel­opment subtypic and heterosubtypic immunity after different influenza vaccines immunization. Recently the problem of increase vaccination safety, efficacy and its deprecation is topical. This is especially important recently because of the threat of pandemic. It's viewed the mucosal influenza vaccines as alternative of the parenteral inactivated influenza vaccines. The advantages of the mucosal inactivated vaccines are the form­ing more broad spectrum of immune response as compared parenteral vaccines, low reactogenicity and risk of accidental contamination during vaccination, low price. It’s discussed the prospects of the mucosal inacti­vated vaccines creation, advantages and failing of existing adjuvants.

About the authors

L. A. Stepanova

Research institute of influenza of the RAMS

Author for correspondence.
Email: shabanov@mail.rcom.ru
Russian Federation, St. Petersburg

A. I. Migunov

Research institute of influenza of the RAMS

Email: shabanov@mail.rcom.ru
Russian Federation, St. Petersburg

А. V. Korotkov

Research institute of influenza of the RAMS

Email: shabanov@mail.rcom.ru
Russian Federation, St. Petersburg

О. К. Kuznetsov

Research institute of influenza of the RAMS

Email: shabanov@mail.rcom.ru
Russian Federation, St. Petersburg

References

  1. Гендон Ю. 3. Живые холодоадаптированные реассортантные гриппозные вакцины // Вопр. вирусол. 2001. Т. 46. № 3. С. 5-12.
  2. Грипп / Под ред. Г. Н. Карпухина. СПб.: Гиппократ, 2001. 380 с.
  3. Донина С. А., Найхин А. Н., Григорьева Е. П. и др. Местный иммунный ответ на живую холодоадаптированную реассортантную гриппозную вакцину у детей, взрослых и лиц пожилого возраста // Вопр. вирусол. 2003. Т. 48. № 2. С. 29-33.
  4. Кузнецов О. К., Ерофеева М. К., Мигунов А. И. Вакцинопрофилактика гриппа, разработка новых вакцин // Грипп и другие вирусные респираторные инфекции: эпидемиология, профилактика, диагностика и терапия / Под ред. О. И. Киселева, А. А. Сомининой, И. Г. Маркевича. М.: Боргес, 2002. С. 156-173.
  5. Найхин А., Руденко Д., Арден Н. и др. Иммунный ответ лиц пожилого возраста в зависимости от числа ежегодных сезонных иммунизаций живой и инактивированной гриппозными вакцинами // Вопр. вирусол. 1998. Т. 43. № 3. С.130-134.
  6. Найхин А. Н., Рекстин А. Р, Баранцева И. Б. и др. Иммунный ответ на живую гриппозную вакцину // Вестн. Рос. акад. мед. наук. 2002. № 12. С. 24-28.
  7. Найхин А. Н., Баранцева И. Б. Локальный иммунный ответ к вирусам гриппа в назоассоциированной лимфоидной ткани // Мед. иммунол. 2004. Т. 6. № 6. С. 487-492.
  8. Маркевич Н. А. Формирование специфических и неспецифических факторов защиты при локальной иммунизации инактивированной гриппозной вакциной со стимулятором иммуногенеза: Автореф. дис. ... канд. биол. наук. СПб., 1994. 15 с.
  9. Маркушин С. Г. Молекулярные механизмы действия мукоадгезивных адьювантов // Эпидемиология и вакцинопрофилактика. 2004. Т. 18. №5. С. 43-47; Т. 19. № 6. С. 51-52; Т. 20. № 7. С. 55-59.
  10. Мигунов А. И., Кузнецов О. К.. Киселев О. И. Использование липосом для конструирования вакцин // Вопр. вирусол. 2001. № 2. С. 4-7.
  11. Петухова Г. Д., Найхин А. Н., Баранцева И. Б. и др. Локальный гуморальный и клеточный иммунный ответ мышей при гриппозной инфекции и вакцинации // Мед. иммунол. 2006. Т. 8. № 4. С. 511-516.
  12. Abe Т., Takahashi Н., Hamazaki Н. et al. Baculovirus induces an innate immune response and confers protection from lethal influenza infection in mice // J. Immunol. 2003. Vol. 171. P. 1133-1139.
  13. Abe T., Hemmi H., Miyamoto H. et al. Involvement of the toll-like receptor 9 signaling pathway in the induction of iimate immunity by baculovirus // J. Virol. 2005. Vol. 79. № 5. P. 2847-2858.
  14. Asahi Y., Yoshikawa T, Watanabe I. et al. Protection against influenza virus infection in polymeric Ig receptor knockout mice immunized intranasally with adjuvant-combined vaccines // J. Immunol. 2002. Vol. 168. P. 2930-2938.
  15. Asahi-Ozaki Y, Yoshikawa T., Iwakura Y. et al. Secretory IgA antibodies provide cross-protection against infection with different strains of influenza В virus // J. Med. Virol. 2004. Vol. 74. № 2. P. 328-335.
  16. Barchet W, Krug A., Celia M. et al. Dendritic cells respond to influenza virus through TLR7- and PKR-independent pathways П Eur. J. Immunol. 2005. Vol. 35. № 1. P. 236-242.
  17. Barker E., Haverson K., Stokes C. R. et al. The larynx as an immunological organ: immunological architecture in the pig as a large animal model // Clin. Exp. Immunol. 2006. Vol. 143. № 1. P. 6-14.
  18. В els he R. В., Gruber W. C., Mendelman P. M. et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not con¬tained in the vaccine //J. Pediatr. 2000. Vol. 136. P. 168-175.
  19. Benton K. A., Mislon J. A., Lo C.-Y. et al. Heterosubtypic immunity to influenza A virus in mice lacking IgA, all 1g, NKT cells, or усг T cells // J. Immunol. 2001. Vol. 166. P. 7437-7445.
  20. Ben-Yehuda A., Joseph A., Zeira E. et al. Immunogenicity and safety of a novel liposomal influenza subunit vaccine (INFLUSOME-VAC) in young adults // J. Med. Virol. 2003. Vol. 69. №. 4. P. 560-567.
  21. Bernard P. A., Raeder R. H., Nedrud J. G. et al. IgA immunodeficiency leads to inadequate Th cell priming and increased susceptibility to influenza virus infection // J. Immunol. 2001. Vol. 166. P. 226-231.
  22. Bernstein J. M., Gorfien J. and Brandtzaeg P. The immunobiology of the tonsils and adenoids // Mucosal immunology / P. L. Ogra, J. Mestecky, M. E. Lamm, W. Strober, J. Bienenstock and J. R. McGhee (eds.). 2nd ed. Academic Press. New York, 1999. P. 1339-1362.
  23. Bizanov G., Janakova L., Knapstad S. E. et al. Immunoglobulin-A antibodies in upper airway secretions may inhibit intranasal influenza virus replication in mice but not protect against clinical illness// Scand. J. Immunol. 2005. Vol. 61. № 6. P. 503-510.
  24. Boon A. С. M., de Mutsert G., van Baarle D. et al. Recognition of homo- and heterosubtypic variants of influenza A viruses by human CD8+ T-lymphocytes // J. Immunol. 2004. Vol. 172. P. 2453-2460.
  25. Bot A., Bot S. and Bona K. A. Protective role of gamma interferon during the recall response to influenza virus // J. Virol. 1998. Vol. 72. № 8. P. 6637-6645.
  26. Boyce T. G.. Gruber W. C., Coleman-Dockery S. D. et al. Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children // Vaccine. 1999. Vol. 18. № 1-2. P. 82-88.
  27. Bracci L., Canini J., Puzelli S. et al. Type IIFN is a powerful mucosal adjuvant for a selective intranasal vaccination against influenza vims in mice and affects antigen capture at mucosal level // Vaccine. 2005. Vol. 23. №. 23. P. 2994-3004.
  28. Brandzaeg P. Krajci P., Lamm M. E. and Kaetzl C. S. Epithelial and hepatobiliary transport of polymeric immuniglobulins // Mucosal Immunology / P. L. Ogra, M. E. Lamm, J. R. McGhee, J. Mestecky, W. Strober and J. Bienenstock (eds.). AcademicPress. San Diego, 1994. P. 113.
  29. Brandzaeg P. Role of mucosal immunity in influenza // Dev. Biol. (Basel). 2003. Vol. 115. P. 39-48.
  30. Chu V. C. and Whittaker G. R. Influenza vims entry and infection require host cell N-linked glycoprotein // PNAS. 2004. Vol. 101. № 52. P. 18153-18158.
  31. Cluff C. W.. Baldridge J. R., Stover A. G. et al. Synthetic toll-like receptor 4 agonists stimulate innate resistance to infections challenge // Infection and Immunity. 2005. Vol. 73. № 5. P. 3044-3052.
  32. Coccia E. M., Severa M., Giacomini E. et al. Viral infection and toil-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells II Eur. J. Immunol. 2004. Vol. 34. № 3. P. 796-805.
  33. Conley M. E., Delacroix D. L. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defence? H Ann. Intern. Med. 1987. Vol. 106. № 6. P. 892-899.
  34. Corrigan E. M. and Clancy R. L. Is there a role for mucosal influenza vaccine in the elderly? // Dmgs and aging. 1999. Vol. 15. № 3. P. 169-181.
  35. Cox R. J., BrokstadK. A., Ogra P Influenza vims immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines H Scand. J. Immunol. 2004. Vol. 59. P. 1-15.
  36. Cusi M. G., Lomagistro M. M., Valassina M. etal. Immunopotentiating of mucosal and systemic antibody responses in mice by intranasal immunization with HLT-combined influenza virosomal vaccine I/ Vaccine. 2000. Vol. 18. № 25. P. 2838-2842.
  37. Dasari P. Nicholson 1. C.. Hodge G. et al. Expression of toll-like receptors on B-lymphocytes // Cell. Immunol. 2005. Vol. 236. № 1-2. P. 140-145.
  38. Dai J.. Megjugorac N. J.. Amrute S. B.. Fotzgerald-Bocarsly P. Regulation of IFN regulatory factor-7 and IFN-alpha production by enveloped vims and lipopolysaccharide in human plasmacytoid dendritic cells // J. Immunol. 2004. Vol. 173. № 3. P. 1535-1548.
  39. Diebold S. S., Montoya M.. Unger H. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers II Nature. 2003. Vol. 424. № 6946. P. 324-328.
  40. Diebold S. S., Kaisho T. Hemmi H. et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA H Science. 2004. Vol. 303. № 5663. P. 1529-1531.
  41. Epstein S. L., Kong W. P., Mispion J. A. et al. Protection against multiple influenza A subtypes by vaccination with highly conserved nucleopro¬tein II Vaccine. 2005. Vol. 9 (Epub ahead of print).
  42. Faith A., McDonald J., Peek E. et al. Functional plasticity of human respiratory tract dendritic cells: GM-CSF enhances T(H)2 development // J. Allerg. Clin. Immunol. 2005. Vol. 116. № 5. P. 1136-1143.
  43. Fan J., Liang X., Horton M. S. et al. Preclinical study of influenza virus A М2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys H Vaccine. 2004. Vol. 22. № 23-24. P. 2993-3003.
  44. Flynn K. L., Belz G. T., Altman J. D. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia H Immunity. 1998. Vol. 8. P. 683-691.
  45. Garcia-Sastre A., Durbin R. K., Zheng H. et al. The role of interferon in influenza virus tissue tropism // J. Virol. 1998. Vol. 72. P. 8550-8558.
  46. Gerhard W., Mozdzanowska K., Furchner M. The nature of heterosubtypic immunity // Options for the control of influenza III / L. E. Brown, A. W. Hampson, R. G. Webster (eds.). Amster¬dam: Elsevier, 1996. P. 235-243.
  47. van Ginkel F. W., Nguen H. H. and McGhee J. R. Vaccines for mucosal immunity to combat emerging infectious diseases // Emerg. Infect. Dis. 2000. Vol. 6. № 2. P. 123-132.
  48. Gluck U., Gebbers J. O., Gluck R. Phase 1 evaluation of intranasal virosomal influenza vaccine with and without Escherichia coli heatlabile toxin in adult volunteers //J. Virol. 1999. Vol. 73. № 9. P. 7780-7786
  49. Gluck R., Mischler R., Durrer P. et al. Safety and immunogenicity of intranasally administered inactivated trivalent virosome-formulated influ¬enza vaccine containing Escherichia coli heat- labile toxin as a mucosal adjuvant// J. Infect. Dis. 2000. Vol. 181. P. 1129-1132.
  50. Greenbaum E., Engelhard D., Levy R. et al. Mucosal (slgA) and serum (IgG) immunologic responses in young adults following intranasal administration of one or two doses of inactivated, trivalent anti-influenza vaccine // Vaccine. 2004. Vol. 22. № 20. P. 2566-2577.
  51. Guillot L., Le Goffic R., Bloch S. et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-strand¬ed RNA and influenza A virus // J. Biol. Chern. 2005. Vol. 280. № 7. P. 5571-5580.
  52. Hartshorn K. L., Ligtenberg A., White M. R. et al. Salivary agglutinin and lung scavenger receptor cysteine-rich glycoprotein 340 have broad anti-influenza activities and interactions with surfactant protein D that vary according to donor source and sialylation H Biochem. J. 2006. Vol. 393. № 2. P. 545-553.
  53. Haynes L. M., Moore D. D., Kurt-Jones E. A. et al. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus // J. Virol. 2001. Vol. 75. № 22. P. 10730-10737.
  54. Heinen P. P, de Boer-Luijtze E. A., Bianchi A. T. Respiratory and systemic humoral and cellular immune response of pigs to a heterosubtypic influenza A virus infections H J. Gen. Virol. 2001. Vol. 82. № 11. P. 2697-2707.
  55. Hemmi H., Takeuchi O., Kawai T. et al. A toll-like receptor recognizes bacterial DNA // Nature. 2000. Vol. 408. № 6813. P. 740-745.
  56. Horimoto T., Takada A., Itwatsuki-Horimoto K., Kawaoka Y. A protective immune response in mice to viral components other than hemagglutinin in a live influenza A virus vaccine model // Vaccine. Vol. 22. № 17-18. P. 2244-2247.
  57. Huang J., Garmise R. J., Crowder T. M. et al. A novel dry powder influenza vaccine and intranasal delivery technology: induction of systemic and mucosal immune response in rats // Vaccine. 2004. Vol. 23. № 6. P. 794-801.
  58. Ichinohe T, Watanabe L, Ito S. et al. Synthetic double-stranded RNA poly (I:C) combined with mucosal vaccine protects against influenza virus infection // J. Virol. 2005. Vol. 79. № 5. P. 2910-2919.
  59. Ito T, Amakawa R., Kaisho T. et al. Interferon-a and interleukin-12 are induced differentially by toll-like receptor 7 ligands in human blood dendritic cell subsets // J. Exp. Med. 2002. Vol. 195. № 11. P. 1507-1512.
  60. Ito R., Ozaki Y. A., Yoshikawa T. et al. Roles of anti-hemagglutinin IgA and IgG antibodies in different sites of the respiratory tract of vaccinated mice in preventing lethal influenza pneumonia // Vaccine. 2003. Vol. 21. № 19-20. P. 2362-2371.
  61. Jefferson T, Smith S., Demicheli V. et al. Assess¬ment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review // Lancet. 2005. Vol. 26. № 9461. P. 773-780.
  62. Langley J. M., Halperin S. A., McNeil S. et al. Safety and immunogenicity of a Proteoso-me™ - trivalent inactivated influenza vaccine, given nasally to healthy adults // Vaccine. 2006. Vol. 24. № 10. P. 1601-1608.
  63. Liang S., Mozdzanovska K., Pallandino G. and Gerhard W. Heterosubtypic immunity to influenza type A virus in mice: effector mechanisms and their longevity // J. Immunol. 1994. Vol. 152. P. 1653-1661.
  64. Liang В., Hyland L. and Hou S. Nasal-associated lymphoid tissue is a site of long-term virus-specific antibody production following respiratory virus infection of mice // J. Virol. 2001. Vol. 75. № 11. P. 5416-5420.
  65. Lipatov A. S., Webby R. J., Govorkova E. A. et al. Efficacy of H5 influenza vaccines produced by reverse genetics in a lethal mouse model // J. Infect. Dis. 2005. Vol. 191. № 8. P. 1216-1220.
  66. Lopez С. B., Moltedo B., Alexopoulou L. et al. TLR-independent induction of dendritic cell maturation and adaptive immunity be negativestrand RNA viruses // J. Immunol. 2004. Vol. 173. P. 6882-6889.
  67. Lund J. M., Alexopoulou L., Sato A. et al. Reco¬gnition of single-stranded RNA viruses by toll-like receptor 7 // PNAS. 2004. Vol. 101. № 15. P. 5598-5603.
  68. Matsuo K., Yoshikawa T., Asanuma H. etal. Induction of innate immunity by nasal influenza vaccine administrated in combination with an adju¬vant (cholera toxin) // Vaccine. 2000. Vol. 18. P. 2713-2722.
  69. Mazanec M. B., Kaetzel C. S, Lamm M. E. et al. Intracellular neutralization of virus by immunoglobulin A antibodies // Proc. Natl. Acad. Sci. USA. 1992. Vol. 89. P. 6901-6905.
  70. Miettinen M., Sareneva T., Julkunen I., Matikainen S. IFNs activate toll-like receptor gene expression in viral infections // Genes Immund. 2001. Vol. 2. № 6. P. 349-355.
  71. Muszkat M., Greenbaum E., Ben-Yehuda A. et al. Local and systemic immune response in nursing-home elderly following intranasal or intramus¬cular immunization with inactivated influenza vaccine // Vaccine. 2003. Vol. 21. № 11-12. P. 1180-1186.
  72. Nichol K. L., Mendelman P. M., Mallon К. P. et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults // JAMA. 1999. Vol. 282. № 2. P. 137-144.
  73. Nguen H. H., van Ginkel E W, Vu H. L. et al. Gamma-interferon is not required for mucosal cytotoxic T-lymphocyte response or heterosub- typic immunitu to influenza A virus infection in mice // J. Virol. 2000. Vol. 74. № 12. P. 5459-5501.
  74. Nguen H. H., van Ginkel E W, Vu H. L. et al. Heterosubtypuc immunity to influenza A virus infection requires В cells but not CD8+ cytotoxic T lymphocytes // J. Infect. Dis. 2001. Vol. 183. P. 368-376.
  75. Ogra P. L., Eaden H. and Welliver R. C. Vaccination strategies for mucosal immune responses II Clin. Microbiol. Rev. 2001. Vol. 14. № 2. P. 430-445.
  76. Pauligk C., Nain M., Reiling N. et al. CD 14 required for influenza A virus-induced cytokine and chemokine production // Immunobiol. 2004. Vol. 209. № 1-2. P. 3-10.
  77. Pizza M., Giuliani M. M., Eontana M. R. et al. Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants // Vaccine. 2001. Vol. 19. №. 17-19. P. 2534-2541.
  78. Price G. E., Gaszewska-Mastarlarz A. and Mos- kophidis D. The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice // J. Virol. 2000. Vol. 74. № 9. P. 3996-4003.
  79. Ramalho-Santos J.. De Lima P. M. C. The role of target membrane sialic acid residues in the fusion activity of the influenza virus: the effect of two types of ganglioside on the kinetics of membrane merging // Cell. Mol. Biol. Lett. 2004. Vol. 9. № 2. P. 337-351.
  80. Read R. C., Naylor S. C., Potter C. W. et al. Effective nasal influenza vaccine delivery using chitosan // Vaccine. 2005. Vol. 23. № 25. P. 4367-1374.
  81. Renegar К. B.. Small P. A. Jr, Boykins L. G., Wright P E Role of IgA versus IgG in the control of influenza viral infection un the murine respiratory tract // J. Immunol. 2004. Vol. 173. № 3. P. 1978-1986.
  82. Riberdy J. M., Elynn K. J., Stech J. et al. Protec¬tion against a lethal avian influenza A virus in mammalian system H J. Virol. 1999. Vol. 73. P. 1453-1459.
  83. Schnare M., Barton G. M., Holt A. C. et al. Toll-like receptors control activation of adaptive immune response //Nat. Immunol. 2001. Vol. 2. № 10. P. 947-950.
  84. Siren J., Pirhonen J., Julkunen L, Matikainen S. IFN-a regulated TLR-depended gene expression of IFN-a, IFN-P, IL-28 and IL-29 // J. Immunol. 2005. Vol. 174. P. 1932-1937.
  85. Sjolander S., Drane D.. Davis R. et al. Intranasal immunisation with influenza-ISCOM induces strong mucosal as well as systemic antibody and cytotoxic T-lymphocyte responses // Vaccine. 2001. Vol. 19. №. 28-29. P. 4072-1080.
  86. Stepanova L., Naykhin A., Kolmskog C. et al. The humoral response to live and inactivated influenza vaccines administrated alone and in combination to young adults and elderly // J. Clin. Virol. 2002. Vol. 24. P. 193-201.
  87. Stevenson P. G., HawkeS. and Bangham C. R. M. Protection against lethal influenza virus ence-phalitis by intranasally primed CD8+ memory T cells // J. Immunol. 1996. Vol. 157. P. 3065-3073.
  88. Takada A., Matsushita S., Ninomiya A. et al. Intranasal immunization with formalin-inactivated virus vaccine induces a broad spectrum of heterosubtypic immunity against influenza A virus infection in mice // Vaccine. 2003. Vol. 21. № 23. P. 3212-3218.
  89. Tamura S. and Kurata T. Defense Mechanisms against influenza virus infection in the respiratory tract mucosa // Jpn. J. Infect. Dis. 2004. Vol. 57. P. 236-247.
  90. Tamura S., Tanimoto T. and Kurata T. Mechanisms of broad cross-protection provided by influenza virus infection and their application to vaccines // Jpn. J. Infect. Dis. 2005. Vol. 58. P. 195-207.
  91. Tomoda T, Morita H., Kurashige T. and Maassab H. F. Prevention of influenza by the int¬ranasal administration of cold-recombinant, live-attenuated influenza virus vaccine: importance of interferon-y production and local IgA response // Vaccine. 1995. Vol. 13. № 2. P. 185-190.
  92. Tumpey T. M., Renshaw M., Clements J. D. and Katz J. M. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection // J. Virol. 2001. Vol. 75. № 11. P. 5141-5150.
  93. Wang D., Christopher M. E., Nagata L. P. et al. Intranasal immunization with liposome-encapsulated plasmid DNA encoding influenza virus hemagglutinin elicits mucosal, cellular and humoral immune responses // J. Clin. Virol. 2004. Vol. 31. P. 99-106.
  94. Wiley J. A., Hogan R. J., Woodland D. L. and Harmsen A. G. Antigen-specific CD8+ T cells persist in the upper respiratory tract following influenza virus infection // J. Immunol. 2001. Vol. 167. P. 3293-3299.
  95. White M. R., Crouch E., van Eijk M. et al. Coope¬rative anti-influenza activities of respiratory innate immune proteins and neuraminidase inhibitor // Am. J. Physiol. Lung Cell. Mol. Physiol. 2005. Vol. 288. № 5. P. L831-840.
  96. Yoshikawa T, Matsuo Keiko, Matsuo Kaz et al. Total viral genome copies and virus-Ig complexes after infection with influenza virus in the nasal secretions of immunized mice // J. Gen. Virol. 2004. Vol. 85. P. 2339-2346.

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