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•High VEs > 90% were observed in both countries irrespective of age and/or timing.•High VE after only two primary doses suggested sufficient seasonal protection.•Vaccination is high even after the first two doses.•Consistently high VEs support flexible schedules with longer booster intervals. Tick-borne encephalitis (TBE) is a vaccine-preventable disease which may cause long-term sequelae and even death. The data on the long-term effectiveness of TBE vaccines are limited. Additionally, the vaccination schedule is complex which in part contributes towards sub-optimal uptake in TBE-endemic areas. The current ecological study measures vaccine effectiveness (VE) in two European countries. TBE VE was measured from 2007 to 2018 in Latvia and Southern German states by age group, vaccination history, and schedule compliance. TBE cases and vaccination history were obtained from the public health agencies for Latvia and the southern German federal states of Bavaria and Baden-Wuerttemberg. Cases were “within schedule” if a TBE infection was diagnosed within the time interval preceding the next scheduled dose and “outside schedule” if the diagnosis occurred after the next scheduled dose. Vaccine uptake was estimated via representative nationwide surveys. VE after 2, 3, and ≥4 doses was high in both countries at 97.2%, 95.0%, and 95.4% for southern Germany, and 98.1%, 99.4%, and 98.8% for Latvia while within- schedule, and only showed marginal differences outside schedule at 90.6%, 89.9%, and 95.6% for southern Germany, and 97.4%, 98.4%, and 99.0% for Latvia regardless of age groups. In both countries, VE after two and three primary doses within-schedule was very high in all age groups. Once receiving booster doses, high VE continued to be observed even in persons with extended intervals since the last dose received, suggesting that longer and more flexible booster intervals may be considered for sustainable long-term protection.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause a serious disease involving the central nervous system (tick-borne encephalitis, TBE). Although approved inactivated vaccines are available, the number of TBE cases is rising, and breakthrough infections in fully vaccinated subjects have been reported in recent years. In the present study, we generated and characterized a recombinant Modified Vaccinia virus Ankara (MVA) for the delivery of the pre-membrane (prM) and envelope (E) proteins of TBEV (MVA-prME). MVA-prME was tested in mice in comparison with a licensed vaccine FSME-IMMUN® and proved to be highly immunogenic and afforded full protection against challenge infection with TBEV. Our data indicate that MVA-prME holds promise as an improved next-generation vaccine for the prevention of TBE.

► This review summarizes findings of the clinical development programme. ► Vaccination in adults, children and adolescents, the elderly and special patient populations. ► Determination of the optimal dose, conventional and rapid schedules, safety, immunopersistence. ► Comprehensive research programme demonstrated strong immunogenicity and safety of FSME-IMMUN®. ► An effective and well-tolerated solution to the endemic risk of TBE virus infection. The need for highly effective tick-borne encephalitis (TBE) vaccines has increased globally due to a variety of factors including climate, social, economic and demographic changes, which are thought to have promoted the expansion of the endemic region of TBE viruses. The first TBE vaccine, FSME-IMMUN® Inject, was introduced in the 1970s and has been continually improved since then to enhance both its safety and immunogenicity. The current formulation was established in 2001 and is marketed as FSME-IMMUN®. This review summarizes findings of the clinical development programme since 2001 regarding determination of the optimal dose, conventional and rapid vaccination schedules, vaccination in adults, the elderly and special patient populations, safety, immunogenicity, and immunopersistence in adults and children, comparison of FSME-IMMUN® with another commercially available TBE vaccine as well as post-marketing vaccination outcome. This successful research programme demonstrated the strong immunogenicity and continued safety of the FSME-IMMUN® vaccine, which is further confirmed by the performance reported under field conditions.

Vaccine effectiveness (VE) was consistently high following two doses (94.6–97.4%) and three doses (96.1%) of the tick-borne encephalitis (TBE) vaccine. These data support the public health value of providing two doses of the TBE vaccine to a traveller to an endemic area presenting with insufficient time to complete the full three-dose primary series.

Vaccines to protect against tick-borne encephalitis (TBE) are produced by two manufacturers and are widely used in European and Asian countries, where TBE virus is endemic. General trends in vaccine development during recent decades and extensive postmarketing experience resulted in several modifications to their formulations and practical implications for use. Modifications were made to the production process, such as the change of the virus master bank from mouse brain to primary cells; to the excipients, especially the stabilizers and preservative; and to include formulations for children. Additionally, a rapid vaccination schedule has been developed for persons who require a fast onset of protection. Recent data from clinical studies and postmarketing surveillance indicate that both vaccines are safe, efficacious and interchangeable. Further (major) changes to formulation or alternative targets for vaccine development are not anticipated in the next 5 years. Recent serologic studies indicate that the persistence of protective immunity was longer than expected. Thus, recommendations for prolongation of TBE booster intervals have been made in several European countries, and a harmonization for booster recommendations is predicted within the European Union. Based on epidemiologic trends, the use of TBE vaccines will continue to increase in all age groups, including children.

TBE vaccination strategies capable of inducing strong paediatric immunogenicity and acceptable reactogenicity are still under evaluation. This single-blind, multi-center, randomized, controlled, phase III clinical study compared the immunogenicity and safety of the two paediatric TBE vaccines available in Europe (FSME-IMMUN ® Junior and Encepur ® Children) following administration of two doses of either vaccine in 303 children aged 1–11 years. Regardless of immunological test or viral antigen used, immunological responses were consistently higher in children vaccinated with FSME-IMMUN ® Junior than those vaccinated with Encepur ® Children. FSME-IMMUN ® Junior is also non-inferior to Encepur ® Children, with respect to NT seropositivity rates ( p < 0.0001). Systemic reaction rates were low and similar between the vaccines. However, among children aged 7–11 years, local reactions were significantly higher after the first ( p < 0.01) and second ( p < 0.001) vaccination with Encepur ® Children than with FSME-IMMUN ® Junior, affecting half the children in the former group: 22.4% and 10.2% with FSME-IMMUN ® Junior vs. 49.0% and 51.0% for Encepur ® Children.

A prospective, randomised, multicentre, single-blind phase 3 study was performed to assess the safety of a vaccination schedule consisting of two vaccinations (21–35 days apart) with the tick-borne encephalitis (TBE) vaccine FSME-IMMUN ® “adults” (five consecutive lots) in comparison to another licensed TBE vaccine (Encepur ®, with polygeline) (two lots) in healthy volunteers ( n = 3966) aged 16–65 years. The safety of the third vaccination with FSME-IMMUN ® “adults” (6 months after the first vaccination) was investigated in a follow-up study on the same population ( n = 3705) and TBE antibody titres were analysed pre- and post-vaccination in a subgroup of volunteers ( n = 564). Following the first vaccination, the overall incidence of fever (≥38.0 °C) was 0.8% in the FSME-IMMUN ® “adults” study group and 5.6% in the comparator study group; fever was mainly mild. The fever rate after the second vaccination was 0.6% and 0.5% in the two study groups, respectively. Local and systemic reactions after the first vaccination occurred with a lower frequency in the FSME-IMMUN ® “adults” study group than in the comparator group. Upon analysing the tolerability of the third vaccination with FSME-IMMUN ® “adults”, similar results were determined in both study groups of volunteers previously vaccinated with FSME-IMMUN ® “adults” or with the comparator vaccine. The immunogenicity results demonstrated similar seroconversion rates (as determined by ELISA or neutralization test) before and after the third vaccination in the FSME-IMMUN ® “adults” group and in the comparator group respectively. The results of both studies demonstrate that: (1) FSME-IMMUN ® “adults” is safe and highly immunogenic, (2) all five production lots of FSME-IMMUN ® “adults” were consistent with respect to a low rate of adverse events, (3) FSME-IMMUN ® “adults” induces considerably lower adverse reaction rates than the comparator vaccine after the first vaccination, and (4) two vaccinations with the comparator vaccine can be successfully followed by a third vaccination with FSME-IMMUN ® “adults”.

Two clinical studies were conducted to identify the optimal dose of a modified tick-borne encephalitis (TBE) vaccine (FSME-IMMUN ® “new”) in adults. A prospective, randomised, phase II, double-blind dose-finding study with the FSME-IMMUN ® “new” vaccine was performed in volunteers aged 16–65 years ( n=405) to evaluate the immunogenicity and safety of two vaccinations with three vaccine doses (0.6, 1.2 and 2.4 μg antigen). The safety and immunogenicity of the third vaccination were investigated in a follow-up study on the same study population. Antibody response to vaccination was assessed by enzyme-linked immunosorbent assay (ELISA) and, after the third vaccination, by neutralisation test (NT). Seroconversion rates (ELISA) in the different dose groups (0.6, 1.2 and 2.4 μg) were 85.1, 96.2 and 97.0%, respectively, after the second vaccination, which 73% of the volunteers received only 21 days after the first vaccination. Seroconversion rates after the third vaccination were 96, 99.2 and 100% (ELISA) as well as 77, 93 and 96.6% (NT) with the 0.6, 1.2 and 2.4 μg doses, respectively. No unexpected AEs or vaccine-related serious adverse events (SAE) were observed during either study. Local and systemic reactions were mainly mild and not dose-dependent, with an overall fever rate of <1% after the first vaccination. The 2.4 μg dose is the optimal dose for the FSME-IMMUN ® “new” preparation in adults, as it was found to: (1) be non-inferior to the 1.2 μg dose with respect to fever rate after the first vaccination; (2) induce the highest seroconversion rate; and (3) be well-tolerated with respect to local and systemic reactions. The results of both studies demonstrate that the FSME-IMMUN ® “new” vaccine is safe and highly immunogenic in adults.

Two dose-finding studies and one open label safety study with a paediatric FSME-IMMUN ® formulation were conducted in children and adolescents aged 1–15 years ( N = 3697). The 1.2 μg antigen dose was identified as the optimal dose, inducing high seroconversion rates following the primary vaccination series. Adolescents (aged 12–15 years) vaccinated with the optimal paediatric dose (1.2 μg) attained similarly high seroprotective rates to adults (aged 16–35 years) vaccinated with the 2.4 μg formulation of FSME-IMMUN ®. We concluded that the FSME-IMMUN ® paediatric vaccine formulation is safe and highly immunogenic, not only for children <12 years, but also for adolescents <16 years.