Tick-Borne Encephalitis: Novel Methods for Improved Serological Diagnostics

Tick-borne encephalitis (TBE) is caused by the tick-borne encephalitis virus (TBEV) and is mainly transmitted to humans through bites from infected Ixodes ticks. TBE is a growing public health challenge in Europe, including Sweden, and is a reportable disease in at least 37 European countries. TBEV can infect the central nervous system, causing symptoms from mild illness to severe disease or death. It may lead to lasting sequelae and reduced quality of life, although asymptomatic cases are likely common. TBEV is traditionally classified into three subtypes: European, Siberian, and Far Eastern. It belongs to the Flaviviridae family and the Orthoflavivirus genus and is the only endemic vector-borne flavivirus in Sweden. TBE vaccines are generally effective, though vaccine failures occur. Sweden lacks a national TBE vaccine register and seroprevalence studies are limited. TBEV-specific antibody detection in serum or cerebrospinal fluid is the most common diagnostic method. Antibody detection is generally reliable but occasionally limited by cross-reactivity and false positives. Diagnosing TBE in vaccinated individuals is even more challenging. Traditional serological methods cannot distinguish infection-induced from vaccine-induced antibodies. Viral RNA detection has low clinical sensitivity. This thesis aimed to improve TBE diagnostics by developing and evaluating new methods and to expand knowledge of TBEV, including vaccination data, through a seroprevalence study in Sweden. In Paper I, we developed and validated a method to differentiate between antibodies caused by infection and those from vaccination. Antibody patterns in TBE-infected patients were compared with those in vaccinated individuals to demonstrate the concept. In Paper II, we applied the method to samples from suspected vaccine failure cases. In Paper III, we evaluated the performance of a commercial TBEV test in a European multi-laboratory study. In Paper IV, we investigated TBEV seroprevalence and vaccination coverage in collaboration with eight Swedish regions. Our findings include vaccination and infection rates, estimated totals, and evidence that over 90% of TBEV infections go undiagnosed. In conclusion, this thesis presents improvements in TBEV diagnostics and new data on the seroprevalence of TBEV in Sweden, including vaccination data and information of the ratio between TBEV infections and reported TBE cases.