Funding Information: Funding: This study was sponsored by Pfizer Inc. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccine failures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBE VF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution of TBE cases was similar for those <50 years versus those ≥50 years in all three countries, in Sweden, a higher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were <50 years of age and more evenly distributed between those <50 years versus those ≥50 in Southern Germany. Here, theoretical explanations were provided, including differences in diagnostic practices, vaccine uptake between age groups, behavioral patterns and underlying medical conditions, as to why VF were generally older in Sweden than the other countries. There is no scientific rationale to give an extra priming dose of TBE vaccine to subjects ≥50 years of age.publishersversionPeer reviewe

Dobler, Gerhard

Erber, Wilhelm

Fousteris, Dimitrios

Freimane, Zane

Jodar, Luis

Palmborg, Andreas

Schmitt, Heinz J.

Zavadska, Dace

Vaccines

English

Funding Information: Funding: This study was sponsored by Pfizer Inc. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccine failures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBE VF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution of TBE cases was similar for those <50 years versus those ≥50 years in all three countries, in Sweden, a higher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were <50 years of age and more evenly distributed between those <50 years versus those ≥50 in Southern Germany. Here, theoretical explanations were provided, including differences in diagnostic practices, vaccine uptake between age groups, behavioral patterns and underlying medical conditions, as to why VF were generally older in Sweden than the other countries. There is no scientific rationale to give an extra priming dose of TBE vaccine to subjects ≥50 years of age.Peer reviewe

Riga Stradins university

CommunicationTBE Vaccination Breakthrough Cases—Does Age Matter?Heinz-J. Schmitt 1, Gerhard Dobler 2, Dace Zavadska 3, Zane Freimane 3, Dimitrios Fousteris 4, Wilhelm Erber 4,Luis Jodar 1 and Andreas Palmborg 5,*Citation: Schmitt, H.-J.; Dobler, G.;Zavadska, D.; Freimane, Z.; Fousteris,D.; Erber, W.; Jodar, L.; Palmborg, A.TBE Vaccination BreakthroughCases—Does Age Matter?. Vaccines2021, 9, 932. https://doi.org/10.3390/vaccines9080932Academic Editors: Ralph A. Trippand Jorge H. LeitãoReceived: 11 June 2021Accepted: 15 August 2021Published: 21 August 2021Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1 Medical Development, Scientific and Clinical Affairs, Pfizer Vaccines, Collegeville, PA 19426, USA;qi.yan2@pfizer.com (H.-J.S.); Luis.Jodar@pfizer.com (L.J.)2 Department of Virology and Rickettsiology, German National TBE Consiliary Laboratory,Bundeswehr Institute of Microbiology, 85748 Munich, Germany; gerharddobler@msn.com3 Department of Paediatrics, Children’s Clinical University Hospital, Riga Stradin, š University,LV-1007 Riga, Latvia; dace.zavadska@rsu.lv (D.Z.); Zane.Freimane@rsu.lv (Z.F.)4 Global Medical, Scientific and Clinical Affairs, Pfizer Vaccines, 1210 Vienna, Austria;fousteris.dimitrio@gmail.com (D.F.); Wilhelm.Erber@pfizer.com (W.E.)5 Medical Development and Scientific Affairs, Pfizer Vaccines, 19138 Stockholm, Sweden* Correspondence: Andreas.Palmborg@pfizer.comAbstract: Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccinefailures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBEVF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution ofTBE cases was similar for those <50 years versus those ≥50 years in all three countries, in Sweden, ahigher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were <50 years ofage and more evenly distributed between those <50 years versus those ≥50 in Southern Germany.Here, theoretical explanations were provided, including differences in diagnostic practices, vaccineuptake between age groups, behavioral patterns and underlying medical conditions, as to why VFwere generally older in Sweden than the other countries. There is no scientific rationale to give anextra priming dose of TBE vaccine to subjects ≥50 years of age.Keywords: tick-borne encephalitis; vaccine failure; vaccination failure; older adults; Sweden1. IntroductionTick-borne encephalitis (TBE) is an infectious disease of the central nervous system,caused by the TBE virus (TBEV), a flavivirus, which is transmitted by infected ticks or rarelyby ingestion of unpasteurized dairy products. As recently reviewed in detail by Dobleret al., three main TBEV subtypes (European, Siberian, and Far-Eastern) and two proposedsubtypes (Baikalian, Himalayan) are found in the endemic areas reaching from the UnitedKingdom, France and Norway in the West to northern Italy in the South, and throughoutCentral and Eastern Europe to Asia with Japan in the East [1]. Persisting neurologicaland/or psychiatric sequelae of TBE can be detected in up to 50% of patients [1]. The casefatality rate varies by region and ranges between 0.4 and 6% in central Europe and is up to20% in Russia [1]. While there is no specific treatment, TBE is preventable by vaccination.There are six licensed vaccines globally, two of them (FSME-IMMUN, Pfizer; Encepur,Bavarian Nordic, formerly GSK) are licensed and available in the European Union. Arecent manuscript from Stockholm County reported that among 1004 TBE cases diagnosedbetween 2006 and 2015, a total of 53 had been fully vaccinated against the disease [2].As 43 cases (81%) of the vaccine failures (VF) occurred in patients aged >50 years witha median age of 62 years (underlying diseases: 51%), the authors recommend givingan additional priming dose of TBE vaccine to all persons ≥50 years [2]. Here, the agedistribution of TBE VF from other data sources was reviewed.Vaccines 2021, 9, 932. https://doi.org/10.3390/vaccines9080932 https://www.mdpi.com/journal/vaccinesVaccines 2021, 9, 932 2 of 52. Materials and MethodsVF was defined as a patient with “reported TBE” despite having received ≥2 doses ofeither FSME-IMMUN or Encepur at least 2 weeks prior to the onset of disease symptoms andwith the last dose given according to the vaccine labels. A systematic review of the literatureon TBE VF (Freimane et al., manuscript in preparation) revealed 18 articles; 15 of them werecase reports or smaller single-center-based case series, included largely overlapping patientcohorts, or did not contain any detailed age distribution data and were thus not further con-sidered. The three remaining studies which included the comparison of the age distributionof TBE VF were the retrospective study from southern Sweden [2], as well as two long-termpopulation-based cohorts with notified cases, one each from the Bayern and from Baden-Wurttemberg regions of Southern Germany. Data on TBE cases and TBE VF were providedupon request by the respective public health institutes, the National TBE Reference Centerin Munich (instmikrobiobw.de/startseite/einrichtungen/konsiliarlabore/konsiliarlabor-fuer-fsme. accessed on 20 November 2020) and the Centre for Disease Prevention and Con-trol of Latvia, Riga, Latvia (www.eurohealthnet.eu/member/centre-disease-prevention-and-control-latvia. accessed on 15 November 2020). Data on TBE cases in Sweden were extractedfrom the Swedish Public Health Agency database (https://www.folkhalsomyndigheten.se/folkhalsorapportering-statistik/statistik-a-o/sjukdomsstatistik/tick-borne-encephalitis-tbe/?t=county. accessed on 20 November 2020).3. ResultsThe analysis of the three data sources identified a total of 173 TBE VF. The median ageof TBE VF was 62 years (range: 6–83 years; n = 53), 55 years (range: 2–86 years; n = 97) and40 years (range: 1–70 years; n = 23) in Southern Sweden, Bayern and Baden-Wurttembergregions of Germany (southern Germany), and Latvia, respectively. In Latvia out of 23 VFs15 (65%) occurred in <50 and 8 (35%) in ≥50 years of age, in Southern Germany out of97 VFs 39 (40%) occurred in <50 and 58 (60%) in ≥50 years of age, whilst in Sweden outof 53 VFs 10 (19%) occurred in <50 and 43 (81%) in ≥50 years of age (Figure 1). In Latviaout of 2301 TBE cases 1174 (51%) occurred in <50 and 1127 (49%) in ≥50 years of age, inSouthern Germany out of 5168 TBE cases 2686 (52%) occurred in <50 and 2482 (48%) in≥50 years of age, and in Sweden out of 2182 TBE cases 1135 (52%) occurred in <50 and1047 (48%) in ≥50 years of age (Figure 1). Whilst the proportion of TBE cases in <50 yearsand ≥50 years age groups was similar in the three countries, the proportion of VF differedlargely (Figure 1). The proportion of VF was about evenly distributed between <50 yearsand ≥50 years age groups in Bayern and Baden-Wurttemberg regions of Germany (40% and60%, respectively), higher in the younger age group in Latvia (65% and 35%, respectively)and disproportionally higher in the older age group in Sweden (19% and 81%, respectively)(Figure 1).Vaccines 2021, 9, 932 3 of 5Vaccines 2021, 9, x FOR PEER REVIEW 3 of 5    (a)   (b) Figure 1. (a): Proportion of TBE cases <50 years (blue bars) and ≥50 years (green bars). (b): Proportion of TBE VF <50 years (blue bars) and ≥50 years (orange bars). Both panels include data from Latvia, Bayern and Baden-Wurttemberg regions of Germany and Sweden. Data for Latvia were based on Zavadska et al., 2018 and the Centre for Disease Prevention and Control of Latvia, Riga, Latvia (www.eurohealthnet.eu/member/centre-disease-prevention-and-control-latvia. Accessed Novem-ber 15, 2020). Data for Southern Germany were based on: Dobler et al., 2018; Erber et al., 2021 sub-mitted; and the National TBE Reference Center in Munich (instmikrobiobw.de/startseite/einrich-tungen/konsiliarlabore/konsiliarlabor-fuer-fsme. Accessed on 20 November 2020). For Sweden, TBE cases were from the Swedish Public Health Agency (https://www.folkhalsomyn-digheten.se/folkhalsorapportering-statistik/statistik-a-o/sjukdomsstatistik/tick-borne-encephalitis-tbe/?t=county. accessed on 20 November 2020). TBE VF in Stockholm were from Hansson et al., 2020. 4. Discussion In this manuscript, we have compared epidemiological features of TBE infections and VF in three European countries (Sweden, Germany and Latvia) and have shown that whereas the TBE infections are evenly distributed between younger and older age groups in the three countries, VF are disproportionally higher in the older age group in Sweden.  10%20%30%40%50%60%70%80%90%100%Latvia 2007–2018 (n = 2301) Southern Germany (Bayern and Baden-Wurttemberg) 2001–2018 (n = 5168)Sweden 2006–2015 (n = 2182)TBE cases, proportions by age<50 years of age ≥50 years of age 0%10%20%30%40%50%60%70%80%90%100%Latvia 2007–2018 (n = 23) Southern Germany (Bayern and Baden-Wurttemberg) 2001–2018 (n = 97)Sweden (Stockholm County) 2006–2015 (n = 53)Vaccination failures, proportions by age<50 years of age ≥50 years of age Figure 1. (a): Proportion of TBE cases <50 years (blue bars) and ≥50 years (green bars). (b): Proportion of TBE VF<50 years (blue bars) and ≥50 years (orange bars). Both panels include data from Latvia, Bayern and Baden-Wurttembergregions of Germany and Sweden. Data for Latvia were based on Zavadska et al. 2018 and the Centre for Disease Preven-tion and Control of Latvia, Riga, Latvia (www.eurohealthnet.eu/member/centre-disease-prevention-and-control-latvia.Accessed 15 November 2020). Data for Southern Germany were based on: Dobler et al. 2018; Erber et al. 2021 submit-ted; and the National TBE Reference Center in Munich (instmikrobiobw.de/startseite/einrichtungen/konsiliarlabore/konsiliarlabor-fuer-fsme. Accessed on 20 N vember 2020). For Sweden, TBE cases were from the Swedish PublicHealth Agency (https://www.folkhalsomyn ig eten.se/folkhalsorapport ring-statistik statistik-a-o/ jukdomsstatistik/tick-borne-encephalitis-tbe/?t=county. accessed on 20 November 2020). TBE VF in Stockholm were from Hans on et al. 2020.4. DiscussionIn this manuscript, we have compared epidemiological features of TBE infectionsand VF in three European countries (Sweden, Germany and Latvia) and have shown thatwhereas the TBE infections are evenly distributed between younger and older age groupsin the three countries, VF are disproportionally higher in the older age group in Sweden.Vaccines 2021, 9, 932 4 of 5There are several hypotheses that might explain the observed age-specific differencesin VF by country. For example, the variability of diagnostic practices in these countriesmay result in under-diagnosis of TBE in children and young adults versus older adults,possibly due to a milder disease spectrum of the acute disease in younger populations [3,4].Age-specific variances may also be explained by behavioral patterns. In some countriesTBE exposure may differ between younger and older age cohorts, as more senior citizensmay live or spend leisure time in the countryside compared to younger ages. Additionally,differences in vaccine uptake between age groups [5,6] or higher proportion of elderlypatients with co-morbid diseases or immunosuppressed conditions between countries mayalso explain these differences. In fact, the label of FSME-IMMUN explicitly states thatseroresponse should be checked in immunosuppressed patients after TBE vaccination andthat an additional dose should be given if there is no evidence of seroconversion [7]. Finally,disparities may be due to the combination of several or all the factors mentioned above.Regardless of the underlying conditions that might explain a higher proportion of VFin Sweden, the question remains around the need of administering an additional primingTBE vaccine dose to individuals older than 50 years of age [2].Seroresponse rates induced by FSME-IMMUN after the primary vaccination schedulein subjects 70–87 years of age is 99.3% [8] and there is no evidence that an additionalpriming dose could be of “immunological” or clinical benefit. Nevertheless, as for othervaccines, antibody titers wane over time [9]. The excellent boostability of priming withtwo doses of FSME-IMMUN has been documented for all age groups, including subjects≥60 years, even as long as 20 years after the last vaccine dose [10]. Furthermore, population-based field effectiveness data from Austria indicate a high vaccine effectiveness of >94% inpersons ≥61 years [11], and similarly high effectiveness rates were recently confirmed in aseparate study based on data from Germany and Latvia (W Erber et al., Effectiveness ofTBE vaccinations in Southern Germany and Latvia. Manuscript submitted for publication).High effectiveness and low rates of VFs have also been demonstrated in Switzerland, whereeven a prolonged booster interval—10 years—is officially recommended, instead of every5 or 3 years in other countries [7,12].5. ConclusionsIn conclusion, TBE VF are very rare events—173 VF cases described in this review—which relates favorably to more than 160 million doses of TBE vaccines globally distributedsince 1976. Whilst the higher proportion of VF in older age groups observed in Swedenwarrants further investigation, the current TBE primary vaccination schedule per age groupas described in the label remains the optimal choice to be continued.Author Contributions: Conceptualization: H.-J.S., G.D., D.Z., Z.F., W.E., A.P. Methodology: H.-J.S.,W.E., D.F., A.P. Software: D.F., A.P. Validation: H.-J.S., G.D., D.Z., Z.F., W.E., A.P. Formal analysis:H.-J.S., D.F., Z.F., A.P. Investigation: H.-J.S., G.D., D.Z., Z.F., D.F., W.E., A.P. Resources: D.F., A.P. Datacuration: D.F., A.P. Writing—original draft preparation: H.-J.S., A.P. Writing—review and editing:H.-J.S., G.D., D.Z., Z.F., W.E., L.J., A.P. Visualization: AP. Supervision: H.-J.S., W.E., L.J. Projectadministration: H.-J.S., A.P. Funding acquisition: H.-J.S. All authors have read and agreed to thepublished version of the manuscript.Funding: This study was sponsored by Pfizer Inc.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: The data that support the findings of this study are available from thecorresponding author, A.P., upon reasonable request.Acknowledgments: The authors acknowledge the editorial assistance by Qi Yan (Pfizer Inc.).Conflicts of Interest: H.-J.S., W.E., D.F., L.J., A.P. are full time employees of Pfizer Vaccines and mayhold stock or stock options. H.-J.S., W.E., L.J. and A.P. had a role in the design of the study: collection,analyses and interpretation of data as well as in the writing of the manuscript and in the decisionVaccines 2021, 9, 932 5 of 5to publish. G.D. is a lecturer and advisor on TBE for Pfizer Vaccines and lecturer and advisor forBavarian Nordic. Zavadska and Freimane report no conflicts of interest. All authors have submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors considerrelevant to the content of the manuscript have been disclosed.References1. Dobler, G.; Erber, W.; Bröker, M.; Schmitt, H.J. The TBE Book; Global Health Press: Singapore, 2019. [CrossRef]2. Hansson, K.E.; Rosdahl, A.; Insulander, M.; Vene, S.; Lindquist, L.; Gredmark-Russ, S.; Askling, H.H. Tick-borne EncephalitisVaccine Failures: A 10-year Retrospective Study Supporting the Rationale for Adding an Extra Priming Dose in IndividualsStarting at Age 50 Years. Clin. Infect. Dis. 2020, 70, 245–251. [CrossRef] [PubMed]3. Engman, M.L.; Lindstrom, K.; Sallamba, M.; Hertz, C.; Sundberg, B.; Hansson, M.E.; Lindquist, L.; Orvell, C.; Lidefelt, K.J.;Sundin, M. One-year follow-up of tick-borne central nervous system infections in childhood. Pediatr. Infect. Dis. J. 2012, 31,570–574. [CrossRef] [PubMed]4. Sundin, M.; Hansson, M.E.; Engman, M.L.; Orvell, C.; Lindquist, L.; Wide, K.; Lidefelt, K.J. Pediatric tick-borne infections of thecentral nervous system in an endemic region of Sweden: A prospective evaluation of clinical manifestations. Eur. J. Pediatr. 2012,171, 347–352. [CrossRef] [PubMed]5. Erber, W.; Schmitt, H.J. Self-reported tick-borne encephalitis (TBE) vaccination coverage in Europe: Results from a cross-sectionalstudy. Ticks Tick. Borne Dis. 2018, 9, 768–777. [CrossRef] [PubMed]6. Askling, H.H.; Insulander, M.; Hergens, M.P.; Leval, A. Tick borne encephalitis (TBE)-vaccination coverage and analysis ofvariables associated with vaccination, Sweden. Vaccine 2015, 33, 4962–4968. [CrossRef] [PubMed]7. FSME-IMMUN. Summary of Products Characteristics. Available online: https://mri.cts-mrp.eu/human/downloads/AT_H_0126_002_FinalSPC.pdf (accessed on 8 July 2021).8. Wanke, K.H.L.; Mekker, A.; Steffen, R.; Stiasny, K.; Heinz, F.X.; Unger, B.; Karrer, U. Immunogenicity and safety of tick borneencephalitis vaccination in healthy elderly individuals. In Proceedings of the European Congress of Clinical Microbiology andInfectious Diseases (ECCMID), London, UK, 31 March–3 April 2012.9. Konior, R.; Brzostek, J.; Poellabauer, E.M.; Jiang, Q.; Harper, L.; Erber, W. Seropersistence of TBE virus antibodies 10 years afterfirst booster vaccination and response to a second booster vaccination with FSME-IMMUN 0.5mL in adults. Vaccine 2017, 35,3607–3613. [CrossRef] [PubMed]10. Schosser, R.; Reichert, A.; Mansmann, U.; Unger, B.; Heininger, U.; Kaiser, R. Irregular tick-borne encephalitis vaccinationschedules: The effect of a single catch-up vaccination with FSME-IMMUN. A prospective non-interventional study. Vaccine 2014,32, 2375–2381. [CrossRef] [PubMed]11. Heinz, F.X.; Stiasny, K.; Holzmann, H.; Grgic-Vitek, M.; Kriz, B.; Essl, A.; Kundi, M. Vaccination and tick-borne encephalitis,central Europe. Emerg Infect. Dis 2013, 19, 69–76. [CrossRef] [PubMed]12. Baroutsou, V.; Zens, K.D.; Sinniger, P.; Fehr, J.; Lang, P. Analysis of Tick-borne Encephalitis vaccination coverage and compliancein adults in Switzerland, 2018. Vaccine 2020, 38, 7825–7833. [CrossRef] [PubMed]

TBE vaccination breakthrough cases—Does age matter?

Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccine failures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBE VF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution of TBE cases was similar for those &lt;50 years versus those ≥50 years in all three countries, in Sweden, a higher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were &lt;50 years of age and more evenly distributed between those &lt;50 years versus those ≥50 in Southern Germany. Here, theoretical explanations were provided, including differences in diagnostic practices, vaccine uptake between age groups, behavioral patterns and underlying medical conditions, as to why VF were generally older in Sweden than the other countries. There is no scientific rationale to give an extra priming dose of TBE vaccine to subjects ≥50 years of age

Heinz-J. Schmitt

Gerhard Dobler

Dace Zavadska

Zane Freimane

Dimitrios Fousteris

Wilhelm Erber

Luis Jodar

Andreas Palmborg

Multidisciplinary Digital Publishing Institute

TBE Vaccination Breakthrough Cases—Does Age Matter?

Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccine failures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBE VF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution of TBE cases was similar for those <50 years versus those ≥50 years in all three countries, in Sweden, a higher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were <50 years of age and more evenly distributed between those <50 years versus those ≥50 in Southern Germany. Here, theoretical explanations were provided, including differences in diagnostic practices, vaccine uptake between age groups, behavioral patterns and underlying medical conditions, as to why VF were generally older in Sweden than the other countries. There is no scientific rationale to give an extra priming dose of TBE vaccine to subjects ≥50 years of age

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TBE vaccination breakthrough cases—Does age matter?

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Riga Stradins university

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