Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI-EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

Department of Pharmacology and Pharmacy Faculty of Veterinary Medicine University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Division of Biology and Biological Engineering California Institute of Technology Pasadena CA

Faculty of Social and Health Sciences University of South Bohemia České Budějovice Czech Republic

Hospital České Budějovice České Budějovice Czech Republic

Howard Hughes Medical Institute The Rockefeller University New York NY

Institute for Research in Biomedicine Università della Svizzera italiana Bellinzona Switzerland

Institute of Parasitology Biology Centre of the Czech Academy of Sciences České Budějovice Czech Republic

Laboratory of Molecular Immunology The Rockefeller University New York NY

Laboratory of Virology and Infectious Disease The Rockefeller University New York NY

Royal Liverpool University Hospital Liverpool UK

Veterinary Research Institute Brno Czech Republic

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