Tick-borne encephalitis virus seroprevalence and infection incidence in Switzerland, 2020-2021

Abstract

Tick-borne encephalitis virus (TBEV) infection can manifest as disease of variable severity, ranging from subclinical infection to severe disease with neurological involvement and potentially fatal outcome. Although TBE is recognized as a major public health problem in Europe, the true burden of disease is potentially underestimated. Here, we investigated TBEV-specific antibody prevalence, infection incidence, and seroreversion and antibody decline rates in a prospective Swiss healthcare worker (HCW) cohort. We screened serum samples from 1444 HCWs between June and October 2020, and from a subset again between August and September 2021, using a TBEV envelope (E) protein IgG ELISA. Positive samples underwent further analysis with a TBEV non-structural protein 1 (NS1) IgG ELISA, and seroconversions in unvaccinated individuals were confirmed by seroneutralization testing. Questionnaire data were used to determine vaccination status and risk factors. TBEV E protein-specific IgG prevalence was 72.1% (95% CI 68.2-75.7%) in TBEV-vaccinated and 6% (95% CI 4.4-7.8%) in unvaccinated individuals. The estimated annual incidence of infection was 735/100,000. Age was the only factor significantly associated with seroprevalence. The seroreversion rate in unvaccinated individuals was 30.3% within one year, which is almost ten times higher than in vaccinated individuals (3.4%, annual decline rate 8.0%). NS1-specific IgG antibodies were six times more common in vaccinated than unvaccinated HCWs. In conclusion, undetected TBEV infections are common, and infection incidence is much higher than reported clinical cases. Individuals with abortive infections have high antibody decline and seroreversion rates. Whether lifelong protection is conferred and by which immune subsets remain unclear.

Keywords: Abortive; Asymptomatic; Incidence; Orthoflavivirus; Prevalence; TBE; TBEV; Tick-borne encephalitis.

Fig. 1

Study catchment area. The map shows the number of study participants per 100,000 inhabitants per canton. Participants from neighboring countries are not shown (n = 24 for Austria, n = 16 for Germany, and n = 12 for the Principality of Liechtenstein). Abbreviations of cantons: AG Aargau, AI Appenzell Innerrhoden, AR Appenzell Ausserrhoden, BE Bern, BL Basel Landschaft, BS Basel Stadt, FR Fribourg, GL Glarus, GR Graubünden, SG St. Gallen, SH Schaffhausen, SO Solothurn, SZ Schwyz, TG Thurgau, TI Ticino, ZG Zug, ZH Zürich. The map was generated using R (version 4.3.2, https://cran.r-project.org) with the packages readxl, tidyverse, dplyr, janitor, stringr, sf, rgeoboundaries, ggplot2, and ggspatial.

Fig. 2

Data set selection algorithm. For all questions, individuals who provided inconsistent information about their TBE vaccination status were excluded (“yes” at time 1 and “no” at time 2; “no” at time 1 and “yes” at time 2, but reported a year of vaccination prior to 2021 or did not report the year of vaccination). The flowchart shows the criteria used to select the datasets used to calculate the results for questions a) through f). The light grey box with dark border indicates the data set used to create Fig. 4.

Fig. 3

TBEV antibody prevalence. Prevalence of TBEV E protein-specific antibodies (A) and NS1 protein-specific antibodies (B) in unvaccinated and vaccinated study participants. Whiskers indicate the upper 95% confidence limits.

Fig. 4

TBEV E protein-specific antibody titer plots of vaccinated (A) and unvaccinated individuals (B). The black dashed lines indicate the cut-off for a positive test result (150 U/ml). Seroconversions appear in the upper left section delimited by the black dashed lines, seroreversions in the lower right section. Red squares indicate individuals who reported vaccination during 2020 or 2021. The points to the left above the blue dot and dash line are those with a ≥ fourfold titer increase from time point 1 to time point 2. The quantification limit of the ELISA (30–3000 U/ml) is shown as a white square. The dataset used to create this plot appears as a light grey box with dark border in Fig. 2 (n = 1,128, thereof 533 vaccinated and 595 unvaccinated at time point 1).