1. Protective human monoclonal antibodies targeting different stages of MERS coronavirus entry
- Author
-
Bosch, Berend Jan, Widjaja, Ivy, Wang, Chengbao, Haperen, Rien van, Dieren, Brenda van, Okba, Nisreen M. A., Stalin Raj, V., Li, Wentao, Fernandez-Delgado, Raúl, Grosveld, Frank, Kuppeveld, Frank J. M. van, Haagmans, Bart L., Enjuanes Sánchez, Luis, and Drabek, Dubravka
- Abstract
Trabajo presentado en el European Congress of Virology, celebrado en Rotterdam (Países Bajos), del 28 de abril al 1 de mayo de 2019, Introduction: The Middle-East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease in humans with high mortality rates. Contact between humans and dromedary camels - the reservoir host of MERS-CoV - poses a continuous threat for human health. No approved antiviral drug or vaccine against MERS-CoV is currently available. Monoclonal antibodies (mAbs) targeting the spike (S) envelope glycoprotein hold promise for prophylaxis and treatment of MERS-CoV infection. The S protein displays a multi-domain architecture and functions in host-cell binding and membrane fusion via its S1 and S2 subunits, respectively. Efforts to develop antibody-based therapies have focused on neutralizing antibodies that target the receptor binding domain of the viral spike protein thereby blocking receptor binding. Aim: We aimed to develop of a set of human monoclonal antibodies that target functionally distinct domains of the MERSCoV spike protein and assess their protective efficacy in vivo. Results: From a large panel of MERS-CoV S mAbs derived from Harbour H2L2 transgenic mice encoding human immunoglobulin variable regions, eight human mAbs were generated targeting six antibody epitope groups in MERS-CoV S, suggesting the presence of at least six epitopes distributed over different domains of S1, and S2. Selected mAbs interfered with the three known entry functions of the MERS-CoV S protein: sialic acid binding, receptor binding or membrane fusion. Prophylactic administration of these mAbs protected mice from lethal MERSCoV challenge resulting in 40-100% survival rates. Complete protection from mortality was shown for antibodies that block receptor binding, but also for antibodies that inhibit membrane fusion regardless of their limited in-vitro neutralization capacity. Conclusion: The arsenal of protective antibodies that bind to and functionally inhibit the activity of multiple spike protein domains offers new ways to gain humoral protection against the emerging MERS coronavirus.
- Published
- 2019