Human antibodies to flavivirus threats

Infections caused by flaviviruses transmitted by mosquitoes and ticks have a significant impact on approximately one third of the global population, presenting a substantial medical concern due to their potential to cause severe illness and death. Among these viruses, tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and other related flaviviruses are emerging as particularly serious threats. In Europe, TBEV and WNV are endemic, leading to neuroinvasive diseases such as encephalitis (TBE and WNE). Switzerland is now predominantly considered endemic for TBE, while the Czech Republic exhibits some of the highest TBEV infection rates in Europe. Recent years have witnessed notable outbreaks of WNE, accompanied by a rise in severe cases of both TBE and WNE.

Despite the availability of an effective vaccine against TBE, its uptake remains suboptimal, and there is currently no specific treatment for either TBE or WNE. Consequently, alongside other flaviviruses, TBEV and WNV pose a significant threat to global public health, highlighting an urgent unmet medical need. The development of medical interventions to prevent infections, halt disease progression, and reduce mortality rates is imperative.

A comprehensive understanding of the ideal serological immune response to TBEV and WNV is crucial for guiding the development of immune-based interventions. Research aimed at identifying broadly effective immune-based strategies capable of targeting multiple flaviviruses simultaneously could pave the way for next-generation vaccines and innovative therapies. In addition to antibodies that directly neutralise the virus and mitigate disease progression, recent studies have shown that during infection the immune system can produce autoantibodies targeting its own immune factors, such as chemokines and cytokines, which may play a role in viral infection pathogenesis.

By discovering and investigating potent, broadly cross-reactive antibodies against TBEV and WNV, as well as unique anti-chemokine antibody responses in infected individuals, this study aims to characterise the human serological response to these viruses through three Aims:

1: Identification of human antibodies broadly effective against tick-borne flaviviruses.

2: Discovery and characterisation of human antibodies against WNV.

3: Investigation of autoantibodies in flavivirus infections.

The anticipated outcome includes the discovery of potent monoclonal antibodies with broad reactivity that could potentially be used therapeutically and inform the development of pan-vaccines against TBEV, WNV, and related flaviviruses. Monoclonal antibody therapies hold promise for populations where vaccines are ineffective or underutilised, particularly during the early viremic phase of TBEV and WNV infections to reduce the risk of progression to encephalitis.

Furthermore, unveiling anti-chemokine antibody responses during these infections will shed light on their role in disease pathogenesis and may identify antibody candidates for therapeutic applications if associated with positive disease outcomes. This research will lay the groundwork for future investigations aimed at developing specific immune-based interventions against flavivirus infections that pose an escalating global threat, addressing a critical unmet medical need.