1887

Abstract

Human metapneumovirus (hMPV) is a paramyxovirus that causes acute respiratory-tract infections in humans. The histopathological and immunological responses to hMPV infection in BALB/c mice immunized with inactivated hMPV were characterized. Animals were immunized intraperitoneally with PBS, supernatant from non-infected LLC-MK2 cells and from heat-inactivated influenza A- or hMPV-infected cells, all in incomplete Freund's adjuvant, or with heat-inactivated hMPV without adjuvant, and then infected intranasally with 10 TCID virus. Following infection, lung samples and bronchoalveolar lavages were collected for determination of viral titre and cytokine levels and for histopathological studies. On day 1, 26 % of mice immunized with inactivated hMPV and adjuvant died, compared with none in the other groups. There was more significant lung inflammation associated with eosinophilic infiltration, as well as increased levels of interleukin-4 (IL-4) and IL-5, in the bronchoalveolar lavages of mice immunized with hMPV alone or with the adjuvant. Mice from the last two groups had a 4–5 log decrease in their pulmonary viral titres compared with controls. Our data demonstrate the risks associated with immunization using inactivated hMPV in this animal model and that this aberrant response should be considered in the development of hMPV vaccines.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83250-0
2007-12-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/88/12/3391.html?itemId=/content/journal/jgv/10.1099/vir.0.83250-0&mimeType=html&fmt=ahah

References

  1. Alvarez R., Tripp R. A. 2005; The immune response to human metapneumovirus is associated with aberrant immunity and impaired virus clearance in BALB/c mice. J Virol 79:5971–5978 [CrossRef]
    [Google Scholar]
  2. Bembridge G. P., Garcia-Beato R., Lopez J. A., Melero J. A., Taylor G. 1998; Subcellular site of expression and route of vaccination influence pulmonary eosinophilia following respiratory syncytial virus challenge in BALB/c mice sensitized to the attachment G protein. J Immunol 161:2473–2480
    [Google Scholar]
  3. Biacchesi S., Skiadopoulos M. H., Boivin G., Hanson C. T., Murphy B. R., Collins P. L., Buchholz U. J. 2003; Genetic diversity between human metapneumovirus subgroups. Virology 315:1–9 [CrossRef]
    [Google Scholar]
  4. Biacchesi S., Pham Q. N., Skiadopoulos M. H., Murphy B. R., Collins P. L., Buchholz U. J. 2005; Infection of nonhuman primates with recombinant human metapneumovirus lacking the SH, G, or M2–2 protein categorizes each as a nonessential accessory protein and identifies vaccine candidates. J Virol 79:12608–12613 [CrossRef]
    [Google Scholar]
  5. Boivin G., De Serres G., Cote S., Gilca R., Abed Y., Rochette L., Bergeron M. G., Dery P. 2003; Human metapneumovirus infections in hospitalized children. Emerg Infect Dis 9:634–640 [CrossRef]
    [Google Scholar]
  6. Boivin G., Mackay I., Sloots T. P., Madhi S., Freymuth F., Wolf D., Shemer-Avni Y., Ludewick H., Gray G. C., LeBlanc E. 2004; Global genetic diversity of human metapneumovirus fusion gene. Emerg Infect Dis 10:1154–1157 [CrossRef]
    [Google Scholar]
  7. Connors M., Giese N. A., Kulkarni A. B., Firestone C. Y., Morse H. C. III, Murphy B. R. 1994; Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10. J Virol 68:5321–5325
    [Google Scholar]
  8. De Swart R. L., Kuiken T., Timmerman H. H., van Amerongen G., Van Den Hoogen B. G., Vos H. W., Neijens H. J., Andeweg A. C., Osterhaus A. D. 2002; Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent RSV infection. J Virol 76:11561–11569 [CrossRef]
    [Google Scholar]
  9. Douville R. N., Bastien N., Li Y., Pochard P., Simons F. E., HayGlass K. T. 2006; Human metapneumovirus elicits weak IFN- γ memory responses compared with respiratory syncytial virus. J Immunol 176:5848–5855 [CrossRef]
    [Google Scholar]
  10. Edwards K. M., Dupont W. D., Westrich M. K., Plummer W. D. Jr, Palmer P. S., Wright P. F. 1994; A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 169:68–76 [CrossRef]
    [Google Scholar]
  11. Englund J. 2005; In search of a vaccine for respiratory syncytial virus: the saga continues. J Infect Dis 191:1036–1039 [CrossRef]
    [Google Scholar]
  12. Falsey A. R., Erdman D., Anderson L. J., Walsh E. E. 2003; Human metapneumovirus infections in young and elderly adults. J Infect Dis 187:785–790 [CrossRef]
    [Google Scholar]
  13. Fulginiti V. A., Eller J. J., Downie A. W., Kempe C. H. 1967; Altered reactivity to measles virus. Atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 202:1075–1080 [CrossRef]
    [Google Scholar]
  14. Gruber W. C., Taber L. H., Glezen W. P., Clover R. D., Abell T. D., Demmler R. W., Couch R. B. 1990; Live attenuated and inactivated influenza vaccine in school-age children. Am J Dis Child 144:595–600
    [Google Scholar]
  15. Guerrero-Plata A., Casola A., Garofalo R. P. 2005; Human metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. J Virol 79:14992–14997 [CrossRef]
    [Google Scholar]
  16. Hamelin M. E., Abed Y., Boivin G. 2004; Human metapneumovirus: a new player among respiratory viruses. Clin Infect Dis 38:983–990 [CrossRef]
    [Google Scholar]
  17. Hamelin M. E., Yim K., Kuhn K. H., Cragin R. P., Boukhvalova M., Blanco J. C., Prince G. A., Boivin G. 2005; Pathogenesis of human metapneumovirus lung infection in BALB/c mice and cotton rats. J Virol 79:8894–8903 [CrossRef]
    [Google Scholar]
  18. Hamelin M. E., Prince G. A., Gomez A. M., Kinkead R., Boivin G. 2006; Human metapneumovirus infection induces long-term pulmonary inflammation associated with airway obstruction and hyperresponsiveness in mice. J Infect Dis 193:1634–1642 [CrossRef]
    [Google Scholar]
  19. Hildreth S. W., Baggs R. R., Brownstein D. G., Castleman W. L., Paradiso P. R. 1993; Lack of detectable enhanced pulmonary histopathology in cotton rats immunized with purified F glycoprotein of respiratory syncytial virus (RSV) when challenged at 3–6 months after immunization. Vaccine 11:615–618 [CrossRef]
    [Google Scholar]
  20. Jartti T., van den Hoogen B., Garofalo R. P., Osterhaus A. D., Ruuskanen O. 2002; Metapneumovirus and acute wheezing in children. Lancet 360:1393–1394 [CrossRef]
    [Google Scholar]
  21. Johnson T. R., Graham B. S. 1999; Secreted respiratory syncytial virus G glycoprotein induces interleukin-5 (IL-5), IL-13, and eosinophilia by an IL-4-independent mechanism. J Virol 73:8485–8495
    [Google Scholar]
  22. Johnson T. R., Teng M. N., Collins P. L., Graham B. S. 2004; Respiratory syncytial virus (RSV) G glycoprotein is not necessary for vaccine-enhanced disease induced by immunization with formalin-inactivated RSV. J Virol 78:6024–6032 [CrossRef]
    [Google Scholar]
  23. Kakuk T. J., Soike K., Brideau R. J., Zaya R. M., Cole S. L., Zhang J. Y., Roberts E. D., Wells P. A., Wathen M. W. 1993; A human respiratory syncytial virus (RSV) primate model of enhanced pulmonary pathology induced with a formalin-inactivated RSV vaccine but not a recombinant FG subunit vaccine. J Infect Dis 167:553–561 [CrossRef]
    [Google Scholar]
  24. Kapikian A. Z., Mitchell R. H., Chanock R. M., Shvedoff R. A., Stewart C. E. 1969; An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 89:405–421
    [Google Scholar]
  25. Kim H. W., Canchola J. G., Brandt C. D., Pyles G., Chanock R. M., Jensen K., Parrott R. H. 1969; Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 89:422–434
    [Google Scholar]
  26. Larcher C., Geltner C., Fischer H., Nachbaur D., Muller L. C., Huemer H. P. 2005; Human metapneumovirus infection in lung transplant recipients: clinical presentation and epidemiology. J Heart Lung Transplant 24:1891–1901 [CrossRef]
    [Google Scholar]
  27. Murphy B. R., Sotnikov A. V., Lawrence L. A., Banks S. M., Prince G. A. 1990; Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization. Vaccine 8:497–502 [CrossRef]
    [Google Scholar]
  28. Openshaw P. J., Clarke S. L., Record F. M. 1992; Pulmonary eosinophilic response to respiratory syncytial virus infection in mice sensitized to the major surface glycoprotein G. Int Immunol 4:493–500 [CrossRef]
    [Google Scholar]
  29. Ottolini M. G., Porter D. D., Hemming V. G., Prince G. A. 2000; Enhanced pulmonary pathology in cotton rats upon challenge after immunization with inactivated parainfluenza virus 3 vaccines. Viral Immunol 13:231–236 [CrossRef]
    [Google Scholar]
  30. Oumouna M., Mapletoft J. W., Karvonen B. C., Babiuk L. A., van Drunen Littel-van den Hurk S. 2005; Formulation with CpG oligodeoxynucleotides prevents induction of pulmonary immunopathology following priming with formalin-inactivated or commercial killed bovine respiratory syncytial virus vaccine. J Virol 79:2024–2032 [CrossRef]
    [Google Scholar]
  31. Peret T. C., Boivin G., Li Y., Couillard M., Humphrey C., Osterhaus A. D., Erdman D. D., Anderson L. J. 2002; Characterization of human metapneumoviruses isolated from patients in North America. J Infect Dis 185:1660–1663 [CrossRef]
    [Google Scholar]
  32. Piedra P. A., Wyde P. R., Castleman W. L., Ambrose M. W., Jewell A. M., Speelman D. J., Hildreth S. W. 1993; Enhanced pulmonary pathology associated with the use of formalin-inactivated respiratory syncytial virus vaccine in cotton rats is not a unique viral phenomenon. Vaccine 11:1415–1423 [CrossRef]
    [Google Scholar]
  33. Polack F. P., Auwaerter P. G., Lee S. H., Nousari H. C., Valsamakis A., Leiferman K. M., Diwan A., Adams R. J., Griffin D. E. 1999; Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody. Nat Med 5:629–634 [CrossRef]
    [Google Scholar]
  34. Prince G. A., Curtis S. J., Yim K. C., Porter D. D. 2001; Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J Gen Virol 82:2881–2888
    [Google Scholar]
  35. Reed L. J., Muench H. 1938; A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497
    [Google Scholar]
  36. Schildgen O., Wilkesmann A., Simon A. 2006; Wheezing in patients with human metapneumovirus infection. J Allergy Clin Immunol 117:223
    [Google Scholar]
  37. Skiadopoulos M. H., Biacchesi S., Buchholz U. J., Amaro-Carambot E., Surman S. R., Collins P. L., Murphy B. R. 2006; Individual contributions of the human metapneumovirus F, G, and SH surface glycoproteins to the induction of neutralizing antibodies and protective immunity. Virology 345:492–501 [CrossRef]
    [Google Scholar]
  38. Sparrevohn S., Wulff H. R. 1967; The nuclear segmentation of eosinophils under normal and pathological conditions. Acta Haematol 37:120–125 [CrossRef]
    [Google Scholar]
  39. Tang R. S., Mahmood K., Macphail M., Guzzetta J. M., Haller A. A., Liu H., Kaur J., Lawlor H. A., Stillman E. A. other authors 2005; A host-range restricted parainfluenza virus type 3 (PIV3) expressing the human metapneumovirus (hMPV) fusion protein elicits protective immunity in African green monkeys. Vaccine 23:1657–1667 [CrossRef]
    [Google Scholar]
  40. Tebbey P. W., Hagen M., Hancock G. E. 1998; Atypical pulmonary eosinophilia is mediated by a specific amino acid sequence of the attachment (G) protein of respiratory syncytial virus. J Exp Med 188:1967–1972 [CrossRef]
    [Google Scholar]
  41. van den Hoogen B. G., de Jong J. C., Groen J., Kuiken T., de Groot R., Fouchier R. A., Osterhaus A. D. 2001; A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 7:719–724 [CrossRef]
    [Google Scholar]
  42. van den Hoogen B. G., Bestebroer T. M., Osterhaus A. D., Fouchier R. A. 2002; Analysis of the genomic sequence of a human metapneumovirus. Virology 295:119–132 [CrossRef]
    [Google Scholar]
  43. Vaux-Peretz F., Chapsal J. M., Meignier B. 1992; Comparison of the ability of formalin-inactivated respiratory syncytial virus, immunopurified F, G and N proteins and cell lysate to enhance pulmonary changes in Balb/c mice. Vaccine 10:113–118 [CrossRef]
    [Google Scholar]
  44. Waris M. E., Tsou C., Erdman D. D., Zaki S. R., Anderson L. J. 1996; Respiratory synctial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol 70:2852–2860
    [Google Scholar]
  45. Williams J. V., Harris P. A., Tollefson S. J., Halburnt-Rush L. L., Pingsterhaus J. M., Edwards K. M., Wright P. F., Crowe J. E., Jr. 2004; Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 350:443–450 [CrossRef]
    [Google Scholar]
  46. Williams J. V., Tollefson S. J., Heymann P. W., Carper H. T., Patrie J., Crowe J. E. 2005; Human metapneumovirus infection in children hospitalized for wheezing. J Allergy Clin Immunol 115:1311–1312 [CrossRef]
    [Google Scholar]
  47. Williams J. V., Wang C. K., Yang C. F., Tollefson S. J., House F. S., Heck J. M., Chu M., Brown J. B., Lintao L. D. other authors 2006; The role of human metapneumovirus in upper respiratory tract infections in children: a 20-year experience. J Infect Dis 193:387–395 [CrossRef]
    [Google Scholar]
  48. Yim K. C., Cragin R. P., Boukhvalova M. S., Blanco J. C., Hamlin M. E., Boivin G., Porter D. D., Prince G. A. 2007; Human metapneumovirus: enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine and challenged. Vaccine 25:5034–5040 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83250-0
Loading
/content/journal/jgv/10.1099/vir.0.83250-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error