Chapter 14: Prevention: vaccines and immunoglobulins

Worldwide there are 6 different TBE vaccines – two from Western Europe, three from Russia and one from China. The two western European vaccines and one of the Russian vaccines have an adult and a pediatric formulation. The products names are FSME IMMUN and FSME-IMMUN Junior; Encepur adults and Encepur children, Klesch-E-Vac, EnceVir and EnceVir Neo, Dry lyophilized TBE Moscow and Sen Tai Bao. All TBE vaccines except the one from China have similar but not identical immunization schedules with primary immunization (>3 doses) and regular booster vaccinations. For FSME-IMMUN, Encepur and EnceVir rapid immunization schedules are also licensed. The Chinese vaccine is given with 2 primary doses 2 weeks apart followed by annual boosters. All vaccines induce significant immune responses. In the absence of a formal correlate of protection, the presence of neutralizing antibodies is used as a surrogate marker for protection. Recent clinical studies show long-term seropersistence of TBE antibodies after the first booster vaccination (dose 4) with the two European vaccines. An effectiveness of approximately 99% (years 2000–2006) and 98.7% (years 2000-2011) was calculated for regularly vaccinated persons in Austria, a country with established high vaccination uptake. Whereas in Western Europe post-exposure prophylaxis with immunoglobulins was discontinued in the late 1990s, in the highly endemic regions of Russia it continues to be common practice. Both – FSME-IMMUN and Encepur are well tolerated with a well-established safety profile. TBE-Moscow and EnceVir appear to be somewhat more reactogenic.

TBE in Latvia

Aggregated data on TBE cases in Latvia are available from 1955,1 but serological testing for TBE began in the 1970’s.2 Since TBE became notifiable in Latvia, epidemiological changes of disease incidence have been dramatic. Between 1990–2000 Latvia had the highest rates of TBE incidence in the world, ranging from 8 to 53 cases per 100,000 population.2 Although the incidence decreased significantly in the past 10 years to about half – from 14.58/100,000 in 2010 to 7.86/100,000 in 2018 – Latvia still ranks very high among all countries in Europe with an annual incidence of 11.45/100,000 in 2020. The distribution of TBE cases in Latvia varies between different regions with the highest incidence usually registered near the northwestern coast.

TBE in Mongolia

Since the 1980s, Mongolian scientists worked together with researchers from the Institute of Epidemiology and Microbiology of Irkutsk, Russia to investigate the spread of ticks carrying the TBEV in the forest areas of Khuvsgul, Khentii, Bulgan, Selenge, Orkhon, Tuv, Dornod, Arkhangai and Uvurkhangai provinces, which had been identified as TBEV-endemic regions.1 Finally in 1989, following available local information on diseases suspected to be TBE, Abmed et al. documented natural foci of the TBEV in the administrative districts of Zelter, Bugant and Khuder in the Selenge province and noted that it is important to plan and implement preventive measures.2

TBE in Poland

Clinical symptoms of tick-borne encephalitis (TBE) were first described in Poland in 1948 by Demiaszkiewicz. All patients had been living in the Białowieża region (in northeastern Poland). Similar infections were described to those that had been diagnosed in the same region before World War II as complicated cases of typhoid fever or influenza.1

TBE in Serbia

Tick-borne encephalitis virus (TBEV) was first isolated in the former Yugoslavia in 1953 from the blood of infected human patients in Slovenia.1 The virus was isolated from ticks in 1954, also in Slovenia.2 Thereafter a number of tick-borne encephalitis (TBE) foci were registered in the western part of the country, while in the Republic of Serbia such foci were not registered. In the period following 1969, no new infections with TBEV could be confirmed in the Republic of Serbia through the routine serological testing of samples from more than 1,000 patients with clinical signs of meningitis and encephalitis, as conducted in laboratories of the Institute of Immunobiology and Virology “Torlak” in Belgrade.3

Chapter 5: TBE in adults

TBE is the most important tick-borne arbovirus disease of humans. Epidemiological data indicate a trend towards an increasing severity with higher age. A number of possible genetic and non-genetic risk factors have been identified, which might have an impact on the manifestation and severity of human disease. Different TBEV strains seem to cause differing clinical courses of disease. While the TBE-EU mainly causes a biphasic course, the clinical course of TBEV-FE and TBEV-SIB are mainly monophasic. The diagnosis of TBE is based on serological tests. So far there is no effective treatment of TBEV infections.

Chapter 2a: Virology

TBEV is the most medically important member of the tick-borne serocomplex group within the genus Flavivirus, family Flaviviridae. Three antigenic subtypes of TBEV correspond to the 3 recognized genotypes: European (TBEV-EU), also known as Western, Far Eastern (TBEV-FE), and Siberian (TBEV-SIB). An additional 2 genotypes have been identified in the Irkutsk region of Russia, currently named TBE virus Baikalian subtype (TBEV-BKL) and TBE virus Himalayan subtype (Himalayan and “178-79” group; TBEV-HIM). TBEV virions are small enveloped spherical particles about 50 nm in diameter. The TBEV genome consists of a single-stranded positive sense RNA molecule. The genome encodes one open reading frame (ORF), which is flanked by untranslated (non-coding) regions (UTRs). The 5′-UTR end has a methylated nucleotide cap for canonical cellular translation. The 3′-UTR is not polyadenylated and is characterized by extensive length and sequence heterogeneity. The ORF encodes one large polyprotein, which is co- and post-translationally cleaved into 3 structural proteins (C, prM, and E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). TBEV replicates in the cytoplasm of the host cell in close association with virus-induced intracellular membrane structures. Virus assembly occurs in the endoplasmic reticulum. The immature virions are transported to the Golgi complex, and mature virions pass through the host secretory pathway and are finally released from the host cell by fusion of the transport vesicle membrane with the plasma membrane.

Chapter 9: Immunology of TBEV-Infection

Tick-borne encephalitis (TBE) is a viral infectious disease of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is usually a biphasic disease and in humans the virus can only be detected during the first (unspecific) phase of the disease. Pathogenesis of TBE is not well understood, but both direct viral effects and immune-mediated tissue damage of the central nervous system may contribute to the natural course of TBE. The effect of TBEV on the innate immune system has mainly been studied in vitro and in mouse models. Characterization of human immune responses to TBEV is primarily conducted in peripheral blood and cerebrospinal fluid, due to the inaccessibility of brain tissue for sample collection. Natural killer (NK) cells and T cells are activated during the second (meningo-encephalitic) phase of TBE. The potential involvement of other cell types has not been examined to date. Immune cells from peripheral blood, in particular neutrophils, T cells, B cells and NK cells, infiltrate into the cerebrospinal fluid of TBE patients.

TBE in Bosnia and Herzegovina

Very limited information is available for Bosnia showing the occurrence of TBE Even though there have been some elder case reports in the northern parts of the country, including alimentary infections, details have not been published. In early 1996 United States military forces were deployed to Bosnia as part of Operation Joint Endeavor. Only 4 (0.42%) unvaccinated individuals, all males, demonstrated a 4-fold seroconversion. All 4 seemingly were infected with TBE virus (or a closely-related variant) during their 6–9-month deployment period in Bosnia, but did not report with symptoms to any health care provider.

TBE in Finland

Finland is at the northernmost edge of the TBE endemic area in Europe. Here TBE is focally endemic. An aseptic encephalitis disease has been known in Kumlinge Island in Åland Islands since the 1940s.1 TBE is also known in Finland by name Kumlinge disease.