International Society for Antiviral Research

Antiviral therapy of tick-borne encephalitis: current options and challenges

Daniel Ruzek, Ph.D.¹, Marianna Agudelo, M.S.², Davide Robbiani, M.D., Ph.D.², Ludek Eyer, Ph.D.¹, Martin Palus, Ph.D.¹, Vaclav Hönig, Ph.D.¹, Jana Elsterova, M.S.¹, Tibor Fuzik, Ph.D.³, Petra Formanova, Ph.D.⁴, Pavel Plevka, Ph.D.³

¹Veterinary Research Institute, and Institute of Parasitology, Brno, Czechia; ²The Rockefeller University, New York, New York, United States of America; ³Central European Institute of Technology – Masaryk University, Brno, Czechia; ⁴Department of Virology, Veterinary Research Institute, Brno, Czechia

Tick-borne encephalitis (TBE) is a potentially lethal neuroinfection in humans caused by TBE virus (TBEV). Specific anti-TBEV immunoglobulin is currently used with well-documented efficacy for post-exposure prophylaxis and TBE treatment in Russia, but no immunotherapy is available in Europe. We have obtained the Cryo-EM structure of the native TBEV virion in complex with Fab fragments of a mouse neutralizing antibody. We found that the Fabs do not lock the E-proteins in the native-like arrangement, but rather prevent the virus proteins from inducing membrane fusion in the endosome and thus from releasing the viral nucleocapsid into the cytoplasm. In a parallel effort, from a large cohort of TBE patients we have identified 28 elite neutralizers, from which human monoclonal antibodies will be derived. Sera from these individuals exhibit increased neutralization of TBEV and high binding to TBEV envelope protein by ELISA when compared to sera from TBEV vaccinated individuals or from the general population.

Next to immunotherapy, treatment with small molecules interfering with the virus life cycle represents another promising approach to manage TBE in humans. Nucleoside analogues showed the highest anti-TBEV activity both in vitro and in vivo. TBEV-resistance to the C2' methylated inhibitors or galidesvir (BCX4430) was found to be conferred by a single conservative mutation that causes a structural change within the active site of viral NS5 RdRp that is subtle but associated with strong attenuation of the virus. Nucleoside analogues have, alone or in combination with immunotherapy, promising therapeutic potential for the treatment of TBEV infection.