Search

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.

submitted for positive strand meeting 2019. File available on request.