Adjuvant effect of the human metapneumovirus (HMPV) matrix protein in HMPV subunit vaccines Free

Abstract

The human metapneumovirus (HMPV) fusion (F) protein is the most immunodominant protein, yet subunit vaccines containing only this protein do not confer complete protection. The HMPV matrix (M) protein induces the maturation of antigen-presenting cells The inclusion of the M protein into an F protein subunit vaccine might therefore provide an adjuvant effect. We administered the F protein twice intramuscularly, adjuvanted with alum, the M protein or both, to BALB/c mice at 3 week intervals. Three weeks after the boost, mice were infected with HMPV and monitored for 14 days. At day 5 post-challenge, pulmonary viral titres, histopathology and cytokine levels were analysed. Mice immunized with F+alum and F+M+alum generated significantly more neutralizing antibodies than mice immunized with F only [titres of 47±7 (<0.01) and 147±13 (<0.001) versus 17±2]. Unlike F only [1.6±0.5×10 TCID (g lung)], pulmonary viral titres in mice immunized with F+M and F+M+alum were undetectable. Mice immunized with F+M presented the most important reduction in pulmonary inflammation and the lowest T-helper T2/T1 cytokine ratio. In conclusion, addition of the HMPV-M protein to an F protein-based vaccine modulated both humoral and cellular immune responses to subsequent infection, thereby increasing the protection conferred by the vaccine.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.000031
2015-04-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/4/767.html?itemId=/content/journal/jgv/10.1099/vir.0.000031&mimeType=html&fmt=ahah

References

  1. Anderson L. J. 2013; Respiratory syncytial virus vaccine development. Semin Immunol 25:160–171 [View Article][PubMed]
    [Google Scholar]
  2. Bagnaud-Baule A., Reynard O., Perret M., Berland J. L., Maache M., Peyrefitte C., Vernet G., Volchkov V., Paranhos-Baccalà G. 2011; The human metapneumovirus matrix protein stimulates the inflammatory immune response in vitro. PLoS One 6:e17818 [View Article][PubMed]
    [Google Scholar]
  3. Biacchesi S., Skiadopoulos M. H., Yang L., Lamirande E. W., Tran K. C., Murphy B. R., Collins P. L., Buchholz U. J. 2004; Recombinant human metapneumovirus lacking the small hydrophobic SH and/or attachment G glycoprotein: deletion of G yields a promising vaccine candidate. J Virol 78:12877–12887 [View Article][PubMed]
    [Google Scholar]
  4. Cox R. G., Erickson J. J., Hastings A. K., Becker J. C., Johnson M., Craven R. E., Tollefson S. J., Boyd K. L., Williams J. V. 2014; Human metapneumovirus virus-like particles induce protective B and T cell responses in a mouse model. J Virol 88:6368–6379 [View Article][PubMed]
    [Google Scholar]
  5. Cseke G., Wright D. W., Tollefson S. J., Johnson J. E., Crowe J. E. Jr, Williams J. V. 2007; Human metapneumovirus fusion protein vaccines that are immunogenic and protective in cotton rats. J Virol 81:698–707 [View Article][PubMed]
    [Google Scholar]
  6. de Swart R. L., van den Hoogen B. G., Kuiken T., Herfst S., van Amerongen G., Yüksel S., Sprong L., Osterhaus A. D. 2007; Immunization of macaques with formalin-inactivated human metapneumovirus induces hypersensitivity to hMPV infection. Vaccine 25:8518–8528 [View Article][PubMed]
    [Google Scholar]
  7. Feuillet F., Lina B., Rosa-Calatrava M., Boivin G. 2012; Ten years of human metapneumovirus research. J Clin Virol 53:97–105 [View Article][PubMed]
    [Google Scholar]
  8. 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 [View Article][PubMed]
    [Google Scholar]
  9. 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 [View Article][PubMed]
    [Google Scholar]
  10. 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 [View Article][PubMed]
    [Google Scholar]
  11. Hamelin M. E., Couture C., Sackett M. K., Boivin G. 2007; Enhanced lung disease and Th2 response following human metapneumovirus infection in mice immunized with the inactivated virus. J Gen Virol 88:3391–3400 [View Article][PubMed]
    [Google Scholar]
  12. Herfst S., de Graaf M., Schrauwen E. J., Ulbrandt N. D., Barnes A. S., Senthil K., Osterhaus A. D., Fouchier R. A., van den Hoogen B. G. 2007; Immunization of Syrian golden hamsters with F subunit vaccine of human metapneumovirus induces protection against challenge with homologous or heterologous strains. J Gen Virol 88:2702–2709 [View Article][PubMed]
    [Google Scholar]
  13. Kolli D., Bao X., Casola A. 2012; Human metapneumovirus antagonism of innate immune responses. Viruses 4:3551–3571 [View Article][PubMed]
    [Google Scholar]
  14. Le Nouën C., Hillyer P., Brock L. G., Winter C. C., Rabin R. L., Collins P. L., Buchholz U. J. 2014; Human metapneumovirus SH and G glycoproteins inhibit macropinocytosis-mediated entry into human dendritic cells and reduce CD4+ T cell activation. J Virol 88:6453–6469 [View Article][PubMed]
    [Google Scholar]
  15. Mok H., Tollefson S. J., Podsiad A. B., Shepherd B. E., Polosukhin V. V., Johnston R. E., Williams J. V., Crowe J. E. Jr 2008; An alphavirus replicon-based human metapneumovirus vaccine is immunogenic and protective in mice and cotton rats. J Virol 82:11410–11418 [View Article][PubMed]
    [Google Scholar]
  16. National Inistitute of Allergy and Infectious Diseases 2000; Evaluation of the safety and immunogenicity of a live attenuated human metapneumovirus vaccine. Bethesda (MD): National Library of Medicine (US). https://clinicaltrials.gov/show/NCT01255410 (accessed 28 August 2014)
  17. Ren J., Liu G., Go J., Kolli D., Zhang G., Bao X. 2014; Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells. PLoS One 9:e91865 [View Article][PubMed]
    [Google Scholar]
  18. Schickli J. H., Dubovsky F., Tang R. S. 2009; Challenges in developing a pediatric RSV vaccine. Hum Vaccin 5:582–591 [View Article][PubMed]
    [Google Scholar]
  19. 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 [View Article][PubMed]
    [Google Scholar]
  20. Ulbrandt N. D., Ji H., Patel N. K., Riggs J. M., Brewah Y. A., Ready S., Donacki N. E., Folliot K., Barnes A. S.other authors 2006; Isolation and characterization of monoclonal antibodies which neutralize human metapneumovirus in vitro and in vivo. J Virol 80:7799–7806 [View Article][PubMed]
    [Google Scholar]
  21. Williams J. V., Chen Z., Cseke G., Wright D. W., Keefer C. J., Tollefson S. J., Hessell A., Podsiad A., Shepherd B. E.other authors 2007; A recombinant human monoclonal antibody to human metapneumovirus fusion protein that neutralizes virus in vitro and is effective therapeutically in vivo. J Virol 81:8315–8324 [View Article][PubMed]
    [Google Scholar]
  22. 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 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.000031
Loading
/content/journal/jgv/10.1099/vir.0.000031
Loading

Data & Media loading...

Most cited Most Cited RSS feed