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Cross-neutralization of four paramyxoviruses by a human monoclonal antibody

Nature volume 501, pages 439–443 (2013)Cite this article

Abstract

Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children2,3 and immune-compromised patients2,4,5, and play a role in asthma exacerbations6. Although antisera generated against either HRSV or HMPV are not cross-neutralizing7, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel β-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine.

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Figure 1: MPE8 cross-neutralizes four human and animal paramyxoviruses.
Figure 2: Somatic mutations broadening the MPE8 specificity.
Figure 3: MPE8 binds to a conserved site on the pre-fusion F protein.
Figure 4: Prophylactic and therapeutic efficacy of MPE8 against HRSV, HMPV and PVM.

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Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

The GenBank accession numbers for MPE8 antibody VH and VL are KF314816 and KF314817.

References

  1. Corti, D. & Lanzavecchia, A. Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31, 705–742 (2013)

    Article  CAS  Google Scholar 

  2. Hall, C. B. et al. The burden of respiratory syncytial virus infection in young children. N. Engl. J. Med. 360, 588–598 (2009)

    Article  CAS  Google Scholar 

  3. Edwards, K. M. et al. Burden of human metapneumovirus infection in young children. N. Engl. J. Med. 368, 633–643 (2013)

    Article  CAS  Google Scholar 

  4. Williams, J. V. et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N. Engl. J. Med. 350, 443–450 (2004)

    Article  CAS  Google Scholar 

  5. Falsey, A. R., Hennessey, P. A., Formica, M. A., Cox, C. & Walsh, E. E. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005)

    Article  CAS  Google Scholar 

  6. Edwards, M. R., Bartlett, N. W., Hussell, T., Openshaw, P. & Johnston, S. L. The microbiology of asthma. Nature Rev. Immunol. 10, 459–471 (2012)

    CAS  Google Scholar 

  7. Wyde, P. R., Chetty, S. N., Jewell, A. M., Boivin, G. & Piedra, P. A. Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by ribavirin and immune serum globulin in vitro. Antiviral Res. 60, 51–59 (2003)

    Article  CAS  Google Scholar 

  8. Collins, P. L. & Crowe, J. E., Jr in Fields Virology 6th edn. (eds Knipe D. M. & Howley P. M. ) Respiratory syncytial virus and metapneumovirus (Lippincott Williams & Wilkins, 2013)

    Google Scholar 

  9. van den Hoogen, B. G. et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nature Med. 7, 719–724 (2001)

    Article  CAS  Google Scholar 

  10. Groothuis, J. R., Simoes, E. A., Hemming, V. G. & Respiratory Syncytial Virus Immune Globulin Study Group Respiratory syncytial virus (RSV) infection in preterm infants and the protective effects of RSV immune globulin (RSVIG). Pediatrics 95, 463–467 (1995)

    CAS  PubMed  Google Scholar 

  11. The-IMpact–RSV Study Group Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102, 531–537 (1998)

    Article  Google Scholar 

  12. de Fontbrune, F. S. et al. Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 45, 1019–1024 (2007)

    Article  Google Scholar 

  13. Adams, O. et al. Palivizumab-resistant human respiratory syncytial virus infection in infancy. Clin. Infect. Dis. 51, 185–188 (2010)

    Article  CAS  Google Scholar 

  14. Traggiai, E. et al. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nature Med. 10, 871–875 (2004)

    Article  CAS  Google Scholar 

  15. Kwakkenbos, M. J. et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nature Med. 16, 123–128 (2010)

    Article  CAS  Google Scholar 

  16. Ulbrandt, N. D. et al. Isolation and characterization of monoclonal antibodies which neutralize human metapneumovirus in vitro and in vivo. J. Virol. 80, 7799–7806 (2006)

    Article  CAS  Google Scholar 

  17. Beeler, J. A. & van Wyke Coelingh, K. Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J. Virol. 63, 2941–2950 (1989)

    Article  CAS  Google Scholar 

  18. Magro, M. et al. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc. Natl Acad. Sci. USA 109, 3089–3094 (2012)

    Article  CAS  ADS  Google Scholar 

  19. Swanson, K. A. et al. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. Proc. Natl Acad. Sci. USA 108, 9619–9624 (2011)

    Article  CAS  ADS  Google Scholar 

  20. Calder, L. J. Electron microscopy of the human respiratory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies. Virology 271, 122–131 (2000)

    Article  CAS  Google Scholar 

  21. Connolly, S. A., Leser, G. P., Yin, H.-S., Jardetzky, T. S. & Lamb, R. A. Refolding of a paramyxovirus F protein from prefusion to postfusion conformations observed by liposome binding and electron microscopy. Proc. Natl Acad. Sci. USA 103, 17903–17908 (2006)

    Article  CAS  ADS  Google Scholar 

  22. McLellan, J. S. et al. Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F. J. Virol. 84, 12236–12244 (2010)

    Article  CAS  Google Scholar 

  23. McLellan, J. S. et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340, 1113–1117 (2013)

    Article  CAS  ADS  Google Scholar 

  24. Zhu, Q. et al. Natural polymorphisms and resistance-associated mutations in the fusion protein of respiratory syncytial virus (RSV): effects on RSV susceptibility to palivizumab. J. Infect. Dis. 205, 635–638 (2012)

    Article  CAS  Google Scholar 

  25. Zhao, X. Respiratory syncytial virus escape mutant derived in vitro resists palivizumab prophylaxis in cotton rats. Virology 318, 608–612 (2004)

    Article  CAS  Google Scholar 

  26. Durbin, J. E. et al. The role of IFN in respiratory syncytial virus pathogenesis. J. Immunol. 168, 2944–2952 (2002)

    Article  CAS  Google Scholar 

  27. Domachowske, J. B., Bonville, C. A. & Rosenberg, H. F. Animal models for studying respiratory syncytial virus infection and its long term effects on lung function. Pediatr. Infect. Dis. J. 23, S228–S234 (2004)

    Article  Google Scholar 

  28. Shah, J. N. & Chemaly, R. F. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 117, 2755–2763 (2011)

    Article  CAS  Google Scholar 

  29. Bonville, C. A. et al. Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo. J. Virol. 78, 7984–7989 (2004)

    Article  CAS  Google Scholar 

  30. Greensill, J. et al. Human metapneumovirus in severe respiratory syncytial virus bronchiolitis. Emerg. Infect. Dis. 9, 372–375 (2003)

    Article  Google Scholar 

  31. Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008)

    Article  CAS  Google Scholar 

  32. Lefranc, M.-P. et al. IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res. 37, D1006–D1012 (2009)

    Article  CAS  Google Scholar 

  33. Tamura, K. et al. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731–2739 (2011)

    Article  CAS  Google Scholar 

  34. Timmerman, P., Puijk, W. C. & Meloen, R. H. Functional reconstruction and synthetic mimicry of a conformational epitope using CLIPS technology. J. Mol. Recognit. 20, 283–299 (2007)

    Article  CAS  Google Scholar 

  35. Slootstra, J. W., Puijk, W. C., Ligtvoet, G. J., Langeveld, J. P. & Meloen, R. H. Structural aspects of antibody-antigen interaction revealed through small random peptide libraries. Mol. Divers. 1, 87–96 (1996)

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank M. Nussenzweig and H. Wardemann for providing reagents for antibody cloning and expression, I. Capua, B. Zecchin and L. Selli for experiments involving BRSV and R. Wepf for electron microscopy. This work was supported by the European Research Council (grant no. 250348 IMMUNExplore) and the Swiss National Science Foundation (grant no. 141254). A.L. is supported by the Helmut Horten Foundation.

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Authors and Affiliations

  1. Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland,

    Davide Corti, Siro Bianchi, Fabrizia Vanzetta, Gloria Agatic & Barbara Guarino

  2. Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland,

    Davide Corti, Andrea Minola, Laurent Perez, Chiara Silacci, Jessica Marcandalli, Federica Sallusto & Antonio Lanzavecchia

  3. University of Lausanne, Service de Pneumologie, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland,

    Benjamin J. Marsland

  4. Policlinico San Matteo, IRCCS, Piazzale Camillo Golgi 1, 27100 Pavia, Italy,

    Antonio Piralla, Elena Percivalle & Fausto Baldanti

  5. Institute of Microbiology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland,

    Antonio Lanzavecchia

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  1. Davide Corti
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Contributions

D.C. designed experiments, analysed the data and wrote the manuscript; S.B., F.V., C.S., B.G. performed and analysed in vitro experiments; A.M., G.A., B.J.M. performed and analysed in vivo experiments; L.P. and J.M. prepared pre- and post-fusion F proteins and performed SPR experiments; F.B., E.P. and A.P. isolated and sequenced HRSV and HMPV strains; F.S. wrote the manuscript; A.L. provided overall supervision, analysed the data and wrote the manuscript.

Corresponding authors

Correspondence to Davide Corti or Antonio Lanzavecchia.

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Competing interests

A.L. is the scientific founder of Humabs BioMed SA. A.L. and F.S. hold shares in Humabs BioMed SA.

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Corti, D., Bianchi, S., Vanzetta, F. et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature 501, 439–443 (2013). https://doi.org/10.1038/nature12442

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