Structure defining of ultrapotent neutralizing nanobodies against MERS-CoV with novel epitopes on receptor binding domain

Author summary MERS-CoV is one of the most prevalent zoonotic virus that has spread through 27 countries and infected more than 2,605 people since its first outbreak in Saudi Arabia in 2012. The high fatality rate and its persistent wide spread infectiousness in animal reservoirs have generated tremendous global public health concern. However, no licensed therapeutic agents or vaccines against MERS-CoV are currently available. To address the risk of MERS-CoV and its variants re-emergence, we developed four highly effective Nbs from alpaca and solved two crystal complexes of Nb9 and Nb14 with RBD. Remarkably, the neutralizing activity of Nb14 represents the highest of MERS-CoV antibodies reported to date. The novel epitopes of Nb14 and Nb9 locate outside the RBD and hDPP4 interface, and the unique different epitopes and mechanisms of Nb14 and Nb9 provide a better neutralizing for synergistically against MERS-CoV infection. Our findings provide insights into the cryptic epitopes on RBD and the development of antibodies against MERS-CoV infection.