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Cross-neutralization of four paramyxoviruses by a human monoclonal antibody

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.

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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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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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