Human antibodies to tick-borne flaviviruses

Tick-borne encephalitis virus (TBEV) is a flavivirus responsible for thousands of infections every year. TBEV can cause severe disease and death, and no specific treatments exist. Although a TBEV vaccine is available, immunity takes months to achieve and regular boosts to maintain. Moreover, it is not clear whether the TBEV vaccine protects against other tick-borne flaviviruses. There are also gaps in our understanding of TBEV pathogenesis, such as why only a fraction of TBEV infections progress to severe disease. The human antibody response to TBEV has been studied at the level of pools of antibodies circulating in blood. In contrast, the molecular make-up and properties of individual human antibodies that are induced by TBEV during natural infection or vaccination have not been examined. The overall objective of the study is the molecular characterization of the antibodies against TBEV that develop in individuals with exceptional serum neutralizing responses against the virus. In Aim 1, we will discover, characterize and compare the antibodies from the memory B cells of naturally infected and vaccinated individuals. In Aim 2, we will perform a deeper characterization of selected antibodies with stronger virus neutralizing capacity and broader neutralizing profile to investigate their mechanism of neutralization. Finally, since antibodies can play a dual role during flavivirus infection (protective versus disease enhancing), Aim 3 will examine antibody-mediated enhancement of TBEV infection by single monoclonal antibodies and by polyclonal sera from a large cohort of clinical samples. Drs. Davide Robbiani (Switzerland) and Daniel Ružek (Czech Republic) will combine their complementary expertise to achieve the goals of this proposal. Dr. Robbiani is a molecular immunologist with expertise in discovery and development of human antibodies against emerging viruses, such as Zika, while Dr. Ružek is an expert molecular virologist with a focus on TBEV. Furthermore, this joint effort will be complemented by the participation of Drs. Luca Varani (partner, biochemistry and NMR, Switzerland) and Pavel Plevka (collaborator, virus Cryo-EM, Czech Republic). We hypothesize that information gained from the molecular characterization of human anti-TBEV antibodies will advance our understanding of disease pathogenesis. Moreover, we postulate that the discovery and characterization of monoclonal antibodies with potent and broad anti-viral activity against TBEV and related flaviviruses will enable the development of novel countermeasures to comprehensively tackle this group of pathogens, which represent an emerging threat to public health in Europe and elsewhere