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• TBE vaccination failures among those aged 50+ suggest declining immune response. • We studied the immunogenicity of the TBE vaccine FSME-Immun in various age groups. • Immune response to FSME-Immun declined with age. • We compared the immunogenicity of a three- and two different four-dose regimens. • For those aged 50+, the accelerated 0–7–21–360 regimen appeared most immunogenic. TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0–30–360) or one of two four-dose series (0–7–21–360; 0–30–90–360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neutralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0–7–21–360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60, 120, 360). Using the other four-dose schedule (0–30–90–360), no such difference was observed on day 400 (63 versus 41, NS). Immune response to the TBE vaccine declined with age. A four-dose schedule (0–7–21–360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. [ABSTRACT FROM AUTHOR]

• 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. [ABSTRACT FROM AUTHOR]

• Results show very low TBE vaccination uptake in Germany. • Vaccination uptake is higher in southern Germany. • Adherence to the vaccination schedule declines with each subsequent vaccination. • Simulated vaccination protection ranges from 10% to 51%, by federal state. Tick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. This retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. Vaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg. While there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis (TBE) is a viral disease that can have a severe clinical course and considerable long-term morbidity. As no curative treatment exists, vaccination is the primary means of prevention. Long-term antibody seropersistence 2–5 years after the 3-dose primary immunization and 3–10 years after first booster was evaluated, as well as booster responses in children, adolescents and young adults. Subjects who participated in these phase 4 prospective, open-label follow-up studies received all vaccinations with FSME-IMMUN. After 3-dose primary immunization, subjects were followed for 2–5 years. Overall, 205 out of 358 subjects (57%) received the first booster and 179 of these subjects (87%) enrolled in a further 10-year follow-up. Antibody seropersistence was assessed annually. Subjects with a TBE antibody titer below a pre-specified cut-off at the yearly blood draw received a booster. Seropositivity rates and geometric mean fold rises (GMFRs) were assessed. In children who received their 3-dose primary immunization between 1 and 15 years of age, the seropositivity rate 5 years after the 3rd dose was 84.9% by NT and 72.0% by ELISA. One month post-first booster, all subjects were seropositive by NT and 98.5% by ELISA. Response to first booster by GMFR ranged from 3.7 to 11.4. At 5 years post-first booster, seropositivity was 99.4% by NT and 97.5% by ELISA, and at 10 years, was 90.3% by NT and 87.7% by ELISA. Although seropositivity rates differed between age groups, all subjects (100%) who received a second booster responded with a robust increase of TBEV antibodies. Long-lasting seropersistence of TBEV antibodies after the 3-dose primary immunization and first booster was demonstrated as well as a competent immune memory response in those who received a first or second booster at any time during the 15-year follow-up. Therefore, an extension of FSME-IMMUN booster interval up to 10 years after the 3-dose primary immunization seems warranted. ClinicalTrials.gov Identifier: NCT00894686. [ABSTRACT FROM AUTHOR]

Abstract Background The number of notified cases of Tick-Borne Encephalitis (TBE) in Sweden has been increasing the past years despite the increased use of TBE-vaccine not subsidized by the healthcare system. Stockholm County is a high endemic area and an earlier study has shown that low-income households have lower vaccination coverage even when they are at high risk. This paper aims to determine the cost-effectiveness of a publicly funded TBE vaccination program in Stockholm. Methods In three different cohorts with individuals aged 3, 40 or 50 years, long-term costs and health outcomes of an out-of-pocket strategy (53% of the cohort is vaccinated on their own expenses) and a structured vaccination program (full cohort is vaccinated covered by the publicly funded health care system), were estimated using a Markov model. The Markov model predicts the costs and effects in term of Quality-adjusted Life Years (QALYs) over a lifetime horizon using a third-party healthcare payer perspective. The primary results are presented as an incremental cost effectiveness ratio (ICER) indicating the additional cost required to achieve one additional QALY with the structured vaccination program. Results The results show that the structured vaccination program is associated with a gain in QALYs and increased costs compared with an out-of-pocket strategy. The calculated ICERs were 27 761, 99 527 and 160 827 SEK/QALY in cohorts of age 3, 40 and 50, respectively. The sensitivity analyses showed that the results are robust when varying different parameters. Conclusion Given the setting of Stockholm county, this analysis shows a cost per QALY of a free vaccinations program, especially for children of 3 years old, below generally acceptable cost-effectiveness thresholds in Sweden. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis (TBE) is a viral disease that can have a severe acute clinical course and considerable long-term morbidity. As there is no causal treatment currently available for TBE, vaccination is the only way to combat the disease in endemic areas. The studies presented here were conducted to obtain prospective long-term TBE serum antibody persistence data of subjects up to 10 years after the first booster with FSME-IMMUN. This report presents the results of 2 follow-up studies in the same study population of 315 healthy adults. Blood was drawn to assess the seropersistence of TBE virus antibodies yearly, from 2–5 and 7–10 years after the first booster vaccination with FSME-IMMUN administered during a previous study. The timing of the second booster vaccination was dependent on the level of serum TBE antibodies observed during yearly follow-up serology observations. The current follow up showed that adult recipients were 84.9% seropositive 10 years after a 3 dose primary series and the first booster vaccination of FSME-IMMUN. Seropositivity rates were even higher (88.6%) in subjects below 50 years of age. ClinicalTrials.gov Identifier: NCT00503529 . ClinicalTrials.gov Identifier: NCT01582698 . [ABSTRACT FROM AUTHOR]

Evaluation of safety, immunogenicity and efficacy of vaccines during licensing studies is performed in relation to the selected vaccination route. For most adjuvanted vaccines, such as the TBE vaccine FSME-IMMUN, only intramuscular (i.m.) administration is licensed. Yet in certain situations, either because of medical indications, accidental application or due to a lack of sufficient muscular tissue, the vaccine might rather be applied subcutaneously (s.c.). With respect to the TBE vaccine there are currently however no data to support the use of the subcutaneous route of vaccination. In order to compare the reactogenicity and immune responsiveness upon i.m. and s.c. TBE vaccination 116 (58 females and 58 males) participants with a documented primary TBE vaccination course were randomized to receive either an i.m. or s.c. booster. Venous blood was collected before, 7 days, 1 month and 6 months after vaccination to determine antibody titer profiles. PBMC were isolated prior to and 7 days after booster to analyze lymphocyte subpopulations and cytokine production upon antigen restimulation. Subjects were monitored for the occurrence of side effects for 7 days post vaccination. Comparable levels of TBE specific neutralizing antibodies were induced after s.c. and i.m. vaccination. At the cellular level, IL-2, IFN gamma and IL-10 levels did not significantly differ using either route of vaccination and the distribution of T cell subsets was comparable along with a relative decrease of regulatory T-cells after both ways of administration. In contrast to the immunogenicity analyses, the data from safety diaries revealed a significantly higher rate of local, but not of systemic reactions after s.c. administration. In conclusion, this study demonstrates that both routes lead to comparable immune responses to the TBE antigen. The higher rate and intensity of local reactions, particularly among women, after s.c. vaccination however needs to be addressed during counseling. [ABSTRACT FROM AUTHOR]

Background A first tick-borne encephalitis (TBE) vaccine booster in children is currently suggested 3 years after completing either a conventional (doses on Days 0, 28 and 300) or accelerated conventional (doses on Days 0, 14 and 300) TBE immunization schedule. This recommendation, however, may not be appropriate in cases where different TBE vaccines have been used interchangeably during the primary immunization series. Methods To provide robust data to better inform such recommendations, TBE antibody persistence was evaluated after 3–5 years in four groups of children (aged 5–15 years): two groups previously primed with three doses of Encepur ® Children (conventional/accelerated conventional schedule); and two groups previously primed with two doses of FSME-IMMUN ® followed by a third dose of Encepur ® Children (conventional/accelerated conventional schedule). Immunogenicity was evaluated using neutralization (NT) assays based on both vaccine antigens as well as on the Enzyme Linked Immunosorbent Assay (ELISA). Results In the two Encepur ® Children groups (full series), protective NT titers of ≥10 were detected in 98–100% of children up to 5 years after their last primary vaccination, irrespective of schedule. In contrast, only 65–70% subjects in the FSME-IMMUN ® Junior groups (mixed series) displayed NT titers ≥10 after 3 years. Thus, due to lower probability of achieving/maintaining long-term protective antibody levels (recently defined by the World Health Organization as an NT titer ≥10) after this time point, both FSME-IMMUN Junior groups were discontinued. Conclusion A strong antibody response persists for at least 5 years after full primary vaccination with Encepur ® Children. The study thus provides support for extending the time interval for a first booster dose after primary vaccination (conventional/accelerated conventional schedule) with Encepur ® Children from 3 to 5 years. [ABSTRACT FROM AUTHOR]

Abstract: Information is scarce regarding the antibody response when TBE-vaccine booster doses are delayed, which is a common situation in daily life. We have investigated the immune response after a delayed booster dose compared to a normal booster interval in an every-day setting. Overall, 250/260 (96%) of the study participants had neutralizing antibodies post-booster, with no significant difference between normal and delayed booster intervals. Based on our findings we propose that healthy individuals who have failed adherence to the recommended schedule of TBE-vaccination can be given a delayed dose without concern of immunogenicity. [Copyright &y& Elsevier]

Abstract: Tick-borne encephalitis (TBE) is a potentially life-threatening disease in humans and is caused by a flavivirus spread by infected ticks (Ixodes ricinus and Ixodes persulcatus). TBE is endemic across much of Central and Eastern Europe and the incidence is increasing, with numbers estimated to be as many as 8755 cases per year. The reasons for this increase are multi-faceted and may involve improvements in diagnosis and reporting of TBE cases, increases in recreational activities in areas inhabited by infected ticks and changes in climatic conditions affecting tick habitats. Vaccination is the most effective method of preventing TBE; following a successful nationwide vaccination campaign in Austria, the annual number of TBE cases fell to about 10% of those reported in the pre-vaccination era. This report describes the findings of a group of leading experts from six Central and Eastern European countries who convened to discuss TBE in their region during the 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID) Nice, France, 4–8 May 2010. [Copyright &y& Elsevier]

Abstract: 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 1.2μg 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 (1.2μg) attained similarly high seroprotective rates to adults (aged 16–35 years) vaccinated with the 2.4μg 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. [Copyright &y& Elsevier]

Abstract: Five and 6 years post-booster, immunity to tick-borne encephalitis (TBE) virus was assessed in 225 and 195 vaccinees, respectively, out of 430 healthy volunteers with at least three TBE-immunizations prior to study inclusion and booster intervals exceeding recommended limits. Neutralizing antibody titers of ≥1:10 (reliable level of protection) were present in 86–96% depending on age group, with lower percentages in participants >60 years. TBE antibody levels remained stable for many years in most vaccinees. However, in a few persons a shorter period of protection against TBE was indicated. Therefore, recommendations on booster intervals in TBE endemic areas should be adapted by weighting the risk of infection against the risk of short-lived immunity. [Copyright &y& Elsevier]

Summary: If a person suffers a tick bite in tick-borne encephalitis (TBE) endemic areas, there is uncertainty on post-exposure treatment of naϊve (non-immune) persons in order to protect the patient against TBE. Particularly, there are no distinct positions on the use of TBE active immunization as post-exposure treatment. Of special concern is the possibility of antibody-dependent enhancement of infection and exacerbation of disease in case of post-exposure vaccination. Such phenomena have been reported for other flavivirus infections. In the past, immune globulin treatment was recommended, but these preparations are no longer available. Active immunization by using the current immunization schedules after a tick bite will not result in appropriate neutralizing antibody concentrations within due time. Based on the assumptions that vaccination is not quick acting enough after a tick bite and that the theoretical risk of antibody-dependent enhancement cannot be excluded, no vaccination or other specific measure is currently recommended after a tick bite in non-vaccinated patients, leaving the patient in a completely dissatisfactory position. A risk/benefit analysis has been re-assessed for persons with a history with at least one vaccine injection, certain patient groups and in relation to the vaccination schedule which has been used and to the geographic area where the tick bite has occurred. In order to evaluate the value of the vaccine for post-exposure immunization, new immunization schedules have to be evaluated with respect to their capacity to induce antibodies more quickly. [Copyright &y& Elsevier]

Summary: This is a case report on a 50-year-old patient, working as a forest guard in a high-endemic region. The subject was immunized with two doses of FSME Immun 0.5 Baxter vaccine (with a time interval of 18 days between the two doses). Approx. two months after the second vaccination the subject developed symptoms of Tick-borne encephalitis. Clinical course and laboratory findings confirmed diagnosis of meningo-encephalo-myelitis with moderate sequelae 1 year after infection. Based on this clinical case we recommend in subjects with an accumulation of risk factors, as age older than 50 years who are living and working in high-endemic areas, a vaccination with conventional schedule (at least two doses applied at 0 to 1–3 months) ahead of TBE season or a rapid schedule with three doses (0, 7 and 21 days) of vaccine. [Copyright &y& Elsevier]

Abstract: Tick-borne encephalitis (TBE) is caused by an arthropod-borne virus, belonging to the family of Flaviviridae. In case of disease, which can lead to neurological sequelae or even fatal outcomes, only symptomatic treatment is available. TBE can be prevented by vaccination. Various primary immunization schedules have been developed. To identify the most suitable schedule, the present randomised, controlled study was designed to provide data on the immune response elicited by four different immunization schedules obtained by ELISA and by neutralization test (NT). A total of 398 healthy subjects aged ≥12 years were randomised to vaccination according to either the rapid schedule (Group R, vaccination on days 0, 7 and 21), the conventional schedule (Group C, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M, vaccination on days 0, 21 and 300) or the accelerated conventional schedule (Group A, vaccination on days 0, 14 and 300). Within 3 weeks (i.e. by day 21) antibody levels were higher in Group R and Group A than in Group M and Group C. Group R and Group C both had higher titres on days 42, 180 and 300, than Group A and Group M. The rapid schedule thus combines the advantages of fast protection and of high titres over the observation period of 300 days. [Copyright &y& Elsevier]