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Background: 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., Methods: 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., Results: 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)., Conclusion: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4 + T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4 + T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-γ, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4 + T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4 + T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4 + T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-γ response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Background: Southern Sweden is endemic for tick-borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. Our aim in this study was to describe cases of vaccine failures and to optimize future vaccination recommendations., Methods: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in Stockholm County during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least 2 doses. Clinical data were extracted from medical records., Results: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group, the median age was 62 years (6-83). Forty-three (81%) patients were aged >50 years and 2 were children. Approximately half of the patients had comorbidities, with diseases affecting the immune system accounting for 26% of all cases. Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases., Conclusions: To our knowledge, this is the largest documented cohort of TBE vaccine failures. Vaccine failure after 5 TBE vaccine doses is rare. Our data provide rationale for adding an extra priming dose to those aged ≥50 years., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

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 © 2011 Elsevier Ltd. All rights reserved.)

Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly., ((c) 2010 Elsevier Ltd. All rights reserved.)

The antibody response to vaccination against tick-borne encephalitis (TBE) with FSME-Immun Inject (Immuno AG/Baxter) was studied in 535 persons, mainly adults, attending a vaccination centre in Stockholm, Sweden. Emphasis was laid on long-term follow-up. Antibody activity was measured by three different serological test systems: a commercial ELISA kit, a hemagglutination inhibition (HI) test and a neutralization test (RFFIT). The neutralization test proved to be the most sensitive assay for the detection of the vaccine response, which was demonstrable in the majority of vaccinees (>90% after three and >98% after four and five vaccinations, respectively). ELISA and HI were less sensitive for antibody measurement during primary immunization. Neutralizing antibody activity persisted prior to the third dose in 77% of the vaccinees and prior to the fourth to sixth doses in 89-95% of the vaccinees. ELISA activity, but no neutralizing activity, was found in some individuals. Based on our data and previous experience of vaccine failures after two doses, a more condensed three-dose vaccination schedule may be advantageous and ought to be tested. The persistence of neutralizing antibodies justifies further studies of the antibody responses after the fourth dose for periods beyond the recommended 3-year booster intervals.