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Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape

Publication ,  Journal Article
Wang, L; Shi, W; Chappell, JD; Joyce, MG; Zhang, Y; Kanekiyo, M; Becker, MM; Doremalen, NV; Fischer, R; Wang, N; Corbett, KS; Choe, M ...
Published in: Journal of Virology
May 1, 2018

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1- specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the "out" position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERSCoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.

Duke Scholars

Published In

Journal of Virology

DOI

EISSN

1098-5514

ISSN

0022-538X

Publication Date

May 1, 2018

Volume

92

Issue

10

Related Subject Headings

  • Virology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 30 Agricultural, veterinary and food sciences
  • 11 Medical and Health Sciences
  • 07 Agricultural and Veterinary Sciences
  • 06 Biological Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, L., Shi, W., Chappell, J. D., Joyce, M. G., Zhang, Y., Kanekiyo, M., … Graham, B. S. (2018). Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape. Journal of Virology, 92(10). https://doi.org/10.1128/JVI.002002-17
Wang, L., W. Shi, J. D. Chappell, M. G. Joyce, Y. Zhang, M. Kanekiyo, M. M. Becker, et al. “Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape.” Journal of Virology 92, no. 10 (May 1, 2018). https://doi.org/10.1128/JVI.002002-17.
Wang L, Shi W, Chappell JD, Joyce MG, Zhang Y, Kanekiyo M, Becker MM, Doremalen NV, Fischer R, Wang N, Corbett KS, Choe M, Mason RD, Van Galen JG, Zhou T, Saunders KO, Tatti KM, Haynes LM, Kwong PD, Modjarrad K, Kong WP, McLellan JS, Denison MR, Munster VJ, Mascola JR, Graham BS. Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape. Journal of Virology. 2018 May 1;92(10).

Published In

Journal of Virology

DOI

EISSN

1098-5514

ISSN

0022-538X

Publication Date

May 1, 2018

Volume

92

Issue

10

Related Subject Headings

  • Virology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 30 Agricultural, veterinary and food sciences
  • 11 Medical and Health Sciences
  • 07 Agricultural and Veterinary Sciences
  • 06 Biological Sciences