Structural insights into tick-borne encephalitis virus neutralization and animal protection by a therapeutic antibody

Abstract

Tick-borne encephalitis virus (TBEV) causes about 5-6 thousand cases annually, while there is still no effective treatment for this virus. To fill this gap, a high-affinity chimeric anti-TBEV antibody ch14D5 has previously been constructed, and high protective activity in a murine TBEV model has been shown for this antibody. However, the mechanism of action of this antibody and the recognized epitope have not been known yet. In this study, it is shown by X-ray crystallography that this antibody recognizes a unique epitope on the lateral ridge of the D3 domain of glycoprotein E, which is readily accessible for binding. The orientation of this antibody relative to the virion surface makes bivalent binding possible, which facilitates the cross-linking of glycoprotein E molecules and thus blocking of surface rearrangements required for infection. Since the antibody tightly binds to this protein even at pH ~ 5.0, it locks the virion in an acidic environment inside the late endosomes or phagosomes and, therefore, effectively blocks the fusion of the viral and endosomal/phagosomal membranes. We believe that this is why the ch14D5 antibody does not induce an antibody-dependent enhancement of infection in vivo, which is critical in the development of antibody-based therapeutic agents. In addition, the structure of the antibody-glycoprotein E interface can be used for the rational design of this antibody for enhancing its properties.

The structure of inactivated mature tick-borne encephalitis virus at 3.0 Å resolution

“…The superposition of the iTBEV E protein domain III with the corresponding regions of 5O6V, 6J5F, and 7LSE by C α atoms showed that our iTBEV has the same conformation of the main chain for the epitopes of all three antibodies ( Figure 4 ). An X-ray structure of a therapeutic antibody ch14D5 with TBEV E protein DIII was also reported, but not yet published [ 34 ]. The superposition of the epitope of this antibody (residues 308–315, 331–336, 367, and 387) on the DIII structure of TBEV-Sofjin (PDB ID 7LSE) with the corresponding regions of our structure also did not reveal substantial differences (Supplementary Figure S2).…”

Defining the “Correlate(s) of Protection” to tick-borne encephalitis vaccination and infection – key points and outstanding questions

“…Potent orthoflaviviral neutralizing antibodies have been shown to interfere with the process of virus-induced membrane fusion ( 83 , 109 , 110 ). Other antibodies are thought to block the binding of the virion to cellular receptors, block the interaction of the virion with cellular receptors through steric hindrance, or block membrane fusion inside endosomes or phagosomes through the cross-linking of E molecules ( 111 ). It is plausible that the mechanism of neutralization of many E-specific antibodies involves both steps of virus entry and is modulated by the composition of antibody populations in polyclonal sera ( 108 ), complicating potential therapeutic development.…”