Structures of Foot-and-mouth Disease Virus with neutralizing antibodies derived from recovered natural host reveal a mechanism for cross-serotype neutralization

The development of a universal vaccine against foot-and-mouth disease virus (FMDV) is hindered by cross-serotype antigenic diversity and by a lack of knowledge regarding neutralization of the virus in natural hosts. In this study, we isolated serotype O-specific neutralizing antibodies (NAbs) (F145 and B77) from recovered natural bovine hosts by using the single B cell antibody isolation technique. We also identified a serotype O/A cross-reacting NAb (R50) and determined virus-NAb complex structures by cryo-electron microscopy at near-atomic resolution. F145 and B77 were shown to engage the capsid of FMDV-O near the icosahedral threefold axis, binding to the BC/HI-loop of VP2. In contrast, R50 engages the capsids of both FMDV-O and FMDV-A between the 2- and 5-fold axes and binds to the BC/EF/GH-loop of VP1 and to the GH-loop of VP3 from two adjacent protomers, revealing a previously unknown antigenic site. The cross-serotype neutralizing epitope recognized by R50 is highly conserved among serotype O/A. These findings help to elucidate FMDV neutralization by natural hosts and provide epitope information for the development of a universal vaccine for cross-serotype protection against FMDV. Author summary FMDV is the causative agent of foot-and-mouth disease, one of the most contagious and economically devastating diseases of cloven-hoofed animals. The antigenic diversities of the currently known epitopes throughout FMDV serotypes and the lack of understanding of FMDV neutralization in natural hosts limit the development of a vaccine that is able to provide cross-serotype protection. In this work, we isolated FMDV serotype O-specific neutralizing antibodies (NAbs) (F145 and B77) and a serotype O/A cross-reacting NAb (R50) from recovered natural bovine hosts and determined virus-NAb complex structures by cryo-electron microscopy at near-atomic resolution. Structures of virus-NAb complex reveal F145 and B77 engage the capsid of FMDV-O near the icosahedral threefold axis. In contrast, R50 engages the capsids of both FMDV-O and FMDV-A between the 2- and 5-fold axes, revealing a previously unknown antigenic site. This is the first time to present structure details of FMDV neutralization by natural hosts. And this work also provides epitope information for the development of a universal vaccine for cross-serotype protection against FMDV.