Evidence for a 10-year TBE vaccine booster interval: an evaluation of current data

ABSTRACT

Introduction

Tick-borne encephalitis (TBE) is rapidly spreading to new areas in many parts of Europe. While vaccination remains the most effective method of protection against the disease, vaccine uptake is low in many endemic countries.

Areas covered

We conducted a literature search of the MEDLINE database to identify articles published from 2018 to 2023 that evaluated the immunogenicity and effectiveness of TBE vaccines, particularly Encepur, when booster doses were administered up to 10 years apart. We searched PubMed with the MeSH terms ‘Encephalitis, Tick-Borne/prevention and control’ and ‘Vaccination’ for articles published in the English language.

Expert opinion

Long-term immunogenicity data for Encepur and real-world data on vaccine effectiveness and breakthrough infections following the two European TBE vaccines, Encepur and FSME-Immun, have shown that extending the booster interval from 3–5 years to 10 years does not negatively impact protection against TBE, regardless of age. Such extension not only streamlines the vaccination schedules but may also increase vaccine uptake and compliance among those living in endemic regions.

KEYWORDS:

• TBE booster interval
• TBE vaccination
• TBE vaccine effectiveness
• tick-borne encephalitis
• vaccination management

1. Introduction

Tick-borne encephalitis (TBE) is an acute viral infection of the central nervous system caused by the TBE virus (TBEV; Orthoflavivirus encephalitidis). TBEV belongs to the Orthoflavivirus genus within the Flaviviridae family, which comprises around 70 viruses including dengue viruses, yellow fever virus, Japanese encephalitis virus, and West Nile virus [1–3]. Most infections with the virus are caused by the bite of an infected tick, but transmission through unpasteurized milk or milk products is also recorded [1,4]. There are three main subtypes of TBEV: (i) the European subtype, associated with milder disease with a case-fatality rate of <2%; (ii) the Far-Eastern subtype, associated with a more severe disease course, with a case-fatality rate of 20–40%; and (iii) the Siberian subtype, with slow or chronic progression of disease and a case-fatality rate of 6–8% [1,4]. Recently, the Baikalian, Himalayan and Obskaya subtypes have also been distinguished [5–7]. While TBE is asymptomatic in many individuals, it can be fatal and cause long-term neurologic sequelae in adults and children. These long-lasting residual symptoms, such as fatigue, headache, irritability, cognitive impairment, and concentration deficit, can seriously impact patients’ quality of life [8–13]. Although no curative treatment is currently available for TBE, patients with severe TBE require hospital admission for diagnostics and supportive care. Once recovered, evaluation for neurorehabilitation may also be needed [1,2,4,14]. TBE prevention strategies are thus especially important. This could be (i) avoiding being bitten by ticks, e.g. using personal protective clothing and tick repellents, finding and removing any ticks from your body, clothing, and gear; (ii) avoiding the consumption of unpasteurized milk; and (iii) being vaccinated. Of these, vaccination offers the most effective way of protecting against TBE, as seen in Austria, a country that previously had the highest recorded TBE-associated morbidity in Europe, until it witnessed remarkable success with its mass vaccination campaigns that started in 1981 [2,15,16]. Not only did the vaccination coverage increase from 6% in 1980 to 85% in 2015, the annual number of cases also reduced by 84% in the last two to three decades [16–18].

Converse to the decreased TBE incidence in Austria, there has been a gradual increase in reported TBE cases in the past two decades within the European Union, with 3,734 confirmed cases in 2020 [19]. In addition, due to the changing climate, ticks have been observed to have increased their distribution range, thus spreading TBE to new areas and new altitudes, including areas as high as 1,000 m above sea level in Norway and 1,500 m above sea level in Austria [17,20]. Cases in regions previously believed to be TBE-free have also been reported recently [17,21–24]. Despite high incidence in many regions, vaccination coverage rates are low in most TBE-endemic countries in Europe. Vaccine coverage rates (the percentage of individuals with at least one TBE vaccination at any time) across 20 countries in Europe were low in 2020, at an average of 36% in endemic countries and 5% in non-endemic countries [25]. In Germany, a country with increasing TBE incidence, vaccine coverage (with complete [≥3 doses] and on-time vaccination) ranged between 18.0% and 30.4% in the four high-risk federal states that contributed to approximately 85% of all TBE cases in Germany in 2021 (Bavaria, Baden-Württemberg, Hesse, and Thuringia) [23]. In addition to the low vaccine coverage, compliance with the recommended vaccination schedule was also low in these endemic countries, with an average of 21% for the primary immunization series and just 7% when including the first booster dose [25]. Increasing vaccination among the population thus represents the most effective and efficient strategy to reduce the burden of TBE in endemic areas [26].

2. TBE vaccines in Europe

Two TBE vaccines are currently available in Europe: Encepur (manufactured by Bavarian Nordic) and FSME-Immun (also sold as TicoVac in some countries, manufactured by Pfizer). Both of these vaccines are manufactured using inactivated virus of the European subtype: K23 strain in Encepur and Neudörfl strain in FSME-Immun [27,28]. These vaccines have been used for decades and have been proven to be highly effective in preventing TBE [1,16,29,30]. The primary immunization schedule for Encepur consists of three doses, administered via one of three dosing schemes: conventional, accelerated conventional and rapid [31]. For the conventional and accelerated schedules, Dose 2 is administered 14 days (accelerated) to 3 months (conventional) after Dose 1; Dose 3 is administered 9–12 months after Dose 2. The first booster dose is then administered 3 years after completing the primary immunization series (Dose 3). For the rapid schedule, primary doses are administered at Days 0, 7 and 21, with the first booster dose at 12–18 months after Dose 3. For all dosing schedules, subsequent booster vaccinations are recommended every 5 years for individuals aged under 50 years or every 3 years for those aged 50 years and over [31]. Immunization with FSME-Immun also consists of three primary doses and a first booster dose after 3 years, with subsequent boosters administered every 5 years for those aged under 60 years and every 3 years for those aged 60 years and over [28]. Of note, while a rapid schedule exists for FSME-Immun (completed 5–12 months after Dose 2), it is closer to Encepur’s accelerated conventional schedule (completed 9–12 months after Dose 2) than Encepur’s rapid schedule (completed in 21 days). Most countries follow the vaccination schedules as recommended by manufacturers and approved by local regulatory bodies; however, variations exist, particularly regarding the timing of booster administration. Some countries adopt prolonged booster intervals, most notably Switzerland, Finland, and Belgium. In these countries, while booster vaccinations are still recommended by the manufacturers every 3–5 years, this is locally approved to extend up to every 10 years (Table 1) [32–34]. For Switzerland, this extension is based on a serologic evaluation conducted in the Swiss canton of Schaffhausen, which showed that TBE vaccination elicited a long-lasting immune response in vaccinated individuals [35]. Frequent boosting was thus not deemed necessary by the Swiss Federal Office of Public Health (FOPH), and extending the booster interval would increase vaccine coverage in the country and the cost-effectiveness of TBE vaccinations [32]. A similar expansion of the booster interval was introduced in Finland and Belgium in 2014 and 2019, respectively, with slight variations [33,34,36]. Since the introduction of extended booster intervals in these countries, valuable data have been collected that may support a change in the general recommendation by the national competent authorities.

Table 1. Booster dosing schedules for adults in Switzerland, Finland, and Belgium.

	Switzerland [32]	Finland [33]	Belgium [34]
First booster	After 10 years	After 3 years	After 3 years
Subsequent boosters	Every 10 years	Age <50 years: Every 10 years Age 50–60 years: Every 5 years Age >60 years: Every 3 years	Age <60 years: Every 5–10 years Age ≥60 years: Every 3 years

The impact of extended booster intervals on the duration of protection, vaccine effectiveness (VE), vaccine uptake, and compliance is reviewed in this article. As FSME-Immun is reviewed elsewhere, the focus is largely on Encepur; however, data from real-world studies include both Encepur and FSME-Immun without stratification [37].

3. Methods

To better document the impact of an extended booster interval for TBE vaccination, we performed a literature search using the database MEDLINE to identify all relevant publications evaluating 10-year booster intervals for TBE vaccination for the period 2018–2023. The following search terms were incorporated: ‘Encephalitis, tick-borne/prevention and control’ [MeSH]; ‘Vaccination’ [MeSH Terms]. The search was limited to human data and data pertaining to Encepur, unless from real-world studies. From each of the identified papers, citations were checked to ensure that no reports were missed.

4. Duration of protection against TBE

4.1. Antibody persistence – prospective Encepur data

The immunogenicity of TBE vaccines is commonly assessed via enzyme-linked immunosorbent assay, neutralization test (NT) or hemagglutination inhibition test, which detect the presence of circulating antibodies against TBEV. As no randomized controlled trials have been conducted to demonstrate the efficacy of these vaccines in protecting against TBE, largely due to ethical restrictions, an NT titer ≥10 is commonly considered to be a surrogate marker of protection, and this threshold is widely used in TBE vaccine clinical trials to indicate a strong immune response [1,38–42].

For Encepur, long-term immunogenicity following a booster vaccination was investigated prospectively in healthy adults and adolescents: three follow-up studies (NCT00387634, NCT01562444, and NCT03294135) were conducted 5, 10 and 15 years after the completion of the parent study and, together, form the first study to evaluate long-term antibody persistence up to 15 years after a first booster vaccination [38,43–45]. These studies have shown that ≥94%, ≥97% and ≥95.8% of all participants achieved an NT titer ≥10 at 5, 10 and 15 years after first booster vaccination, respectively, at every time point post-booster and regardless of the Encepur vaccination schedule received by the participants (Figure 1).

Figure 1. Anti-TBEV NT geometric mean titers from Years 6–11 (a) and Years 11–15 (b) after the first booster dose, stratified by dosing schedule (rapid [Group R], conventional [Group C] and accelerated [Group A]) and age (at study entry of the respective extension studies; per-protocol set) [44,45].

NT, neutralization test; TBEV, tick-borne encephalitis virus.

While a decline in immune function is often observed in older adults, causing them to mount a weaker and less durable immune response to vaccination, these follow-up data have shown that NT geometric mean titers (GMTs) remained well above the threshold of 10 in individuals aged 60 years and over [46]. Between 11 and 15 years post-booster vaccination, NT GMTs remained stable for this age group, with no person having an NT titer below the protective threshold during this period (Figure 1) [45]. It is important to note that the number of elderly participants was low in these extension studies; hence, the generalizability of the results to the older population is limited. In addition, the age of the participants described was at entry of the respective extension studies, not of the parent study.

Based on antibody levels measured in the first two extension studies, the evolution of the immune response elicited by Encepur over time was predicted [43,44]. Anti-TBEV NT antibody levels 20 years post-first booster were modeled using several power-law models, all of which have shown stable antibody titers up to 20 years post-boosting, with the mean NT titer remaining considerably above the established threshold of 10 for more than 95% of individuals who were included in the analyses (Figure 2) [47]. These predictions are consistent with the 15-year data from the third extension study of Encepur, demonstrating that a single booster dose of Encepur provides long-lasting protection against TBE [45].

Figure 2. Mean anti-TBEV antibody NT levels over 20 years, as predicted by the different models [47].

AIC, Akaike information criterion; EPLM, extended PLM; MPPLM, monotone PPLM; NT, neutralization test; PLM, power-law model; PPLM, piecewise; TBEV, tick-borne encephalitis virus.

Overall, long-term immunogenicity assessment and modeled data have shown that not only does Encepur elicit a good immune response in adults and adolescents after primary immunization, but the high level of neutralizing antibodies also persists for at least 15 years after the first booster dose, regardless of the manufacturer-recommended dosing schedule used during primary immunization and regardless of age group.

4.2. Long-term real-world data

4.2.1. Vaccine effectiveness

As mentioned above, no prospective clinical studies with efficacy endpoints have been conducted on any of the licensed TBE vaccines. Effectiveness data are therefore available from epidemiologic investigations under real-world circumstances. TBE vaccines have been demonstrated to be highly effective through several nationwide studies, showing VE to be well above 90% [30,48,49]. Further studies on VE with prolonged intervals between booster doses were recently published and are summarized in Table 2. A retrospective, matched case–control analysis by booster interval was conducted in Switzerland for the period 2006–2020. Overall, VE in preventing TBE cases was determined to be 95.0% for those with complete vaccination (≥3 doses) and 76.8% for those with incomplete vaccination. Among those with complete vaccination, VE was found to be 98.5% and 95.2% when the most recent dose was received >10 years and 5–10 years prior, respectively, demonstrating that the prolonged TBE booster interval had no impact on VE (Table 3) [50].

Table 2. VE studies with prolonged intervals between booster doses.

Country	Study period	Study design	Vaccines used	Homologous/heterologous vaccination	Primary vaccination schedule	Number of doses	Time since last dose	VE, % (95% CI)
Switzerland [50]	2006–2020	Retrospective, matched case–control study	Encepur and FSME-Immun	Not specified	Not reported	≥3 doses	>10 years	98.5^a (96.8–99.2)
Germany [51]	2018–2020	Retrospective, matched case–control study	Encepur and FSME-Immun	Homologous and heterologous	Not reported	≥3 doses	>10 years	88.6^b(71.2–95.5)
			Encepur	Homologous	Not reported	≥3 doses	Anytime	95.8^b(89.7–98.3)
			FSME-Immun	Homologous	Not reported	≥3 doses	Anytime	93.1^b(86.6–96.5)
Latvia [52]	2018–2020	Observational study	Encepur and FSME-Immun	Homologous and heterologous	Not reported	≥4 doses	>10 years	96.6^c(86.5–99.2)
			FSME-Immmun	Homologous	Not reported	≥4 doses	>10 years	82.1^c(28.4–95.5)
Southern Germany [53]	2007–2018	Retrospective study	Encepur and FSME-Immun	Not specified	Not reported	≥4 doses	Outside schedule^d	95.6^e(92.2–97.5)
Latvia [53]								99.0^f(97.4–99.6)

^aVE in confirmed TBE cases (based on serology and clinical picture) reported by laboratories to the national disease surveillance system.

^bVE in routinely notified TBE cases from Bavaria or Baden-Württemberg meeting the German case definition.

^cVE in laboratory-identified TBE cases in patients who sought medical attention.

^dLast dose received beyond the interval recommended by the vaccine manufacturer.

^eVE in confirmed TBE cases, including cases with any non-CNS-specific symptoms in Bavaria and Baden-Württemberg in Germany.

^fVE in confirmed TBE cases, including cases with any non-CNS-specific symptoms.

CI, confidence interval; CNS, central nervous system; TBE, tick-borne encephalitis; VE, vaccine effectiveness.

Table 3. VE stratified by dose interval.

		VE, % (95% CI)
		TBE cases^a	TBE cases^b	TBEV infection^c	TBE hospitalization
Number of doses	Time since last dose	Switzerland [50]	Germany [51]	Latvia [52]
1–2 doses		76.8 (69.0–82.6)	82.4 (71.3–89.2)	–	–
≥3 doses	On time	–	96.6 (93.7–98.2)	–	–
	Anytime	95.0 (93.5–96.1)	95.2 (92.2–97.0)	–	–
	<5 years	91.6 (88.4–94.0)	–	–	–
	5–10 years	95.2 (92.4–97.0)	82.4 (63.0–91.7)	–	–
	≤10 years	–	91.2 (82.7–95.6)	–	–
	>10 years	98.5 (96.8–99.2)	88.6 (71.2–95.5)	–	–
	≤5 years	–	–	98.7 (96.6–99.5)	98.7 (96.6–99.5)
≥4 doses	≤10 years	–	–	98.9 (97.2–99.6)	98.9 (97.1–99.6)
	>10 years	–	–	96.6 (86.5–99.2)	96.5 (86.1–99.1)

^aConfirmed TBE cases (based on serology and clinical picture) reported by laboratories to the national disease surveillance system.

^bRoutinely notified TBE cases from Bavaria or Baden-Württemberg meeting the German case definition.

^cLaboratory-identified TBE cases in patients who sought medical attention.

CI, confidence interval; TBE, tick-borne encephalitis; TBEV, tick-borne encephalitis virus; VE, vaccine effectiveness.

Similar results were reported in a retrospective, matched-control study conducted in Germany between 2018 and 2020 that assessed VE in preventing TBE cases. VE was shown to be 96.6% for those who completed their primary vaccination and on time (≥3 doses) and 82.4% for those who received only 1–2 doses. For those who completed their primary vaccination, VE remained high at 91.2% and 88.6%, respectively, for those who received their last dose within and over 10 years prior (Table 3) [51].

In Latvia, VE in terms of protection against TBEV infection (in those with laboratory-identified TBE who sought medical attention) and hospitalization due to TBE was assessed [52]. In this nationwide study conducted during 2018–2020, consistently high VE was observed when the booster dose was administered ≤5 years and >10 years prior, at 98.7% and 96.6%, respectively, against medically attended TBEV infection. Similar results were observed for VE against TBE hospitalization (Table 3).

The age of individuals did not appear to influence the high VE observed in these studies. In the Swiss study, VE remained ≥90% for participants in all age groups (18–39, 40–59, and 60–79 years) who received ≥3 doses, irrespective of whether the last dose was administered within or over 10 years prior [50]. In the German study, VE for those who received ≥3 doses with the last dose administered up to 10 years prior was 99.8%, 95.7% and 95.3% for those aged <18, 18–64 and ≥65 years, respectively. The overall VE for those who received ≥4 doses was similar across all age groups and remained high at 97.1% for those aged 65 years and over [51]. In the Latvian study, while not stratified by time since last dose among the different age groups, VE (≥3 doses) was also consistently high in those aged over 60 years, at 98.2% in terms of protecting against medically attended TBEV infection and TBE hospitalization. Taken together, data from these real-world studies suggest that TBE protection is not compromised in older adults, even when the booster dose was not administered on time according to manufacturers' recommendations. VE data across different age groups for the German and Latvian study are summarized in Table 4.

Table 4. VE stratified by age.

			VE, % (95% CI)
			TBE cases^a	TBEV infection^b	TBE hospitalization
Number of doses	Age (years)	Time since last dose	Germany [51]	Latvia [52]
≥3 doses	<18	≤10 years	99.8^c	–	–
	18–64	≤10 years	95.7^c	–	–
	≥65	≤10 years	95.3^c	–	–
	1–15	–	–	95.5 (67.1–99.4)	95.4 (66.2–99.4)
≥3 doses	16–59	–	–	99.7 (97.8–100)	99.7 (97.7–100)
	>60	–	–	98.2 (92.9–99.6)	98.2 (92.7–99.5)
≥4 doses	2–13	–	100 (95.2–100.0)	–	–
	14–64	–	96.2 (92.2–98.1)	–	–
	≥65	–	97.1 (89.9–99.2)	–	–

^aRoutinely notified TBE cases from Bavaria or Baden-Württemberg meeting the German case definition.

^bIn laboratory-identified TBE cases in patients who sought medical attention.

^c95% CI not reported in Nygren, et al.

CI, confidence interval; TBE, tick-borne encephalitis; TBEV, tick-borne encephalitis virus; VE, vaccine effectiveness.

In a study conducted in southern Germany (Bavaria and Baden-Württemberg) and Latvia for the period 2007–2018, results have shown that for individuals who have completed primary immunization, delayed administration of the booster dose (≥4^th dose, received beyond manufacturer-recommended interval) was not associated with significant differences in VE across all ages [53]. VE was reported to be 95.4% (95% confidence interval [CI] 93.6–96.6) and 95.6% (95% CI 92.2–97.5) in southern Germany for those who received their last dose within schedule and outside schedule, respectively, and 98.8% (95% CI 97.9–99.3) and 99.0% (97.4–99.6) in Latvia when the last dose was received within schedule and outside schedule, respectively. It is important to note that in this study, while data were stratified into ‘within schedule’ and ‘outside schedule,’ the exact length of elapsed time since last dose was not documented; hence, long-term VE cannot be formally assessed for this study.

Authors of the VE study in Germany have also noted that VE was similar between individuals who received homologous Encepur or FSME-Immun vaccine, and among those who received a combination of both vaccines (defined as having received one dose of another vaccine) [51]. For those who received ≥3 doses, VE was 95.8% (95% CI 89.7–98.3) and 93.1% (95% CI 86.6–96.5) for homologous vaccination with Encepur and FSME-Immun, respectively, and 93.9% (95% CI 86.1–97.3) for heterologous vaccination.

While VE data from these real-world studies mirror prospective Encepur data, which demonstrated a robust and long-lasting immune response regardless of age, this is not the case for prospective FSME-Immun data. In a long-term seropersistence study of FSME-Immun, a trend of faster decline of antibody levels in the older age groups was observed: seropositivity rates 10 years after the first booster vaccination, as measured by NT, was 88.6% for those aged 18–49 years, 74.5% for those aged 50–60 years and 37.5% for those aged >60 years [54]. This discrepancy highlights that humoral response, mediated by neutralizing antibodies, may not be the only immune response at play in the protection against TBE. It is clear from the FSME-Immun study and real-world VE studies that low NT titers may not necessarily indicate loss of protection. The adaptive immunity induced upon natural TBE infection and vaccination was extensively reviewed by Kubinski and colleagues, in which they concluded that ‘thorough understanding of the immune correlates of protection against TBEV is crucial and should be the subject of further investigations’ [55]. Nevertheless, while we should not solely rely on antibody levels as an indicator of protection against TBE, before the correlate of protection is established, NT titer may remain the standard endpoint for clinical trials.

4.2.2. Breakthrough infections

With the extended vaccine booster interval in Switzerland, the main concern for many public health experts was whether this extension would lead to an increased rate of vaccine breakthrough infections (VBIs). Results from a retrospective analysis of surveillance data based on mandatory reporting of TBE in Switzerland have shown that this has not been the case [56]. Data have shown that overall, across 2000–2019, VBIs were experienced by 103 (4%) individuals who received ≥3 doses out of 2,562 TBE cases with known vaccination status. Out of these VBI cases, 39 (1.5%) occurred in the initial 3 years after their last dose and 48 (1.9%) in the next 7 years; 16 (0.6%) individuals experienced VBI when their last dose was received >10 years prior or at an unknown date (Table 5).

Table 5. Vaccine breakthrough cases by interval since last dose.

		Vaccine breakthrough cases, n (%)
	TBE cases with known vaccination status	≤3 years	3–10 years	<10 years	>10 years	Last dose unknown
Switzerland^a [56]
2000–2019	2,562	39 (1.5)	48 (1.9)	–	8 (0.3)	8 (0.3)
2000–2009	992	16 (1.6)	10 (1.0)	–	1 (0.1)	0
2010–2019	1,570	23 (1.5)	38 (2.4)	–	7 (0.4)	8 (0.5)
Aged <50 years	801	5 (0.6)	18 (2.2)	–	3 (0.4)	2 (0.2)
Aged ≥50 years	769	18 (2.3)	20 (2.6)	–	4 (0.5)	6 (0.8)
Austria^b [57]
2000–2018	206	–	–	32 (15.5)^c	29 (14.1)^c	–

^aAmong laboratory-confirmed TBE cases reported to the national disease surveillance system and having received ≥3 vaccine doses.

^bAmong patients hospitalized with CNS signs and symptoms or febrile illness without CNS signs or symptoms and with a serologically confirmed TBEV infection.

^cAmong those who completed primary immunization and received ≥1 booster dose, but the timing of the last dose has surpassed manufacturer-recommended interval.

CNS, central nervous system; TBE, tick-borne encephalitis; TBEV, tick-borne encephalitis virus.

During the 2010–2019 period in which the 10-year booster strategy was implemented, no increase in breakthrough rate was observed in this study. Breakthrough rate was calculated at 7.7 cases per year (95% CI 5.0–11.7) during the first 3 years after the last dose and 5.4 cases per year in the following 7 years (95% CI 3.9–7.5). The similar rates, with no statistically significant difference between them, serve as evidence that the rate of VBIs does not increase with time as would be expected because of decreasing antibody levels.

Similar findings were found in a retrospective case–control study conducted in Austria, which analyzed patients hospitalized with TBE over the period 2000–2018. Data have shown that the number of VBIs was similar when the last booster dose was received within or over 10 years prior [57]. Out of 206 TBE cases with known vaccination status, 32 (15.5%) and 29 (14.1%) had completed their primary immunization with ≥1 booster dose but received their last dose within and over 10 years prior, respectively (Table 5).

The authors of the Swiss study also noted that the older population was not observed to be at an increased risk of VBI if not boosted after 3 years (Table 5) [56]. Breakthrough rate among those aged 50 years and over was calculated to be 6.0 cases per year (95% CI 3.7–9.6) in the first 3 years after their last vaccine dose versus 2.9 cases per year (95% CI 1.8–4.5) in the subsequent 7 years, which is comparable to vaccine breakthrough rates in the overall population across 2000–2019 [56]. Similar results were found in a study conducted in Austria, southern Germany and Latvia, which also showed that the rate of VBIs is not associated with age [30,48,53]. These data are consistent with findings from a study that assessed the quality and functional activity of vaccination-induced antibodies against TBEV, which demonstrated that the quality of antibodies, as measured by antibody avidity, remained intact in healthy elderly people, albeit at lower titers [58]. Interestingly, in the Austrian study, patients with VBIs were significantly younger than non-vaccinated patients with TBE. The median age of vaccinated patients with TBE was 53.5 years (range 1–85), while that of unvaccinated patients with TBE was 55.0 years (range 0–88); p = 0.02. Out of the 206 VBIs, 117 (57%) were in those aged 50 years and over [57]. The authors of the study noted that this could be attributed to the mass vaccination campaigns that started in 1981, which led to a rapid increase of vaccine coverage in the country [16]. A high proportion of the now older adults would have received vaccination at a younger age, before immunosenescence came into effect. Having completed primary immunization at a young age may have resulted in high antibody levels sufficient to prevent the disease later in life.

On the contrary, a 10-year retrospective study in southern Sweden has shown higher breakthrough rates in older adults: 81% of VBIs (43 out of 53) observed were in those aged over 50 years [59]. However, the authors noted that half of the patients with TBE in the study had underlying medical conditions, with diseases affecting the immune system accounting for 26% of all cases, which could partly explain the higher breakthrough rate in older adults in this study. This highlights that in real-world studies described in this review, the populations were often not well defined, with no details on underlying medical conditions and immune status to aid in the drawing of meaningful conclusions in subpopulations. Furthermore, the age at which the individual was first vaccinated may also potentially impact the level of protection conferred by the TBE vaccine [57,58]. Other than these, factors that can also cause age-specific differences in VBIs include (i) different diagnostic practices between countries, which may result in under-diagnosis of TBE in children and young adults in some countries due to less severe symptoms; (ii) different levels of vaccine uptake between age groups, leaving some age groups more vulnerable to the disease than others; (iii) different behavioral patterns between age groups, as older adults may live or spend more leisure time in the countryside, increasing their potential exposure to TBEV; and (iv) many of the vaccination campaigns may focus on older adults, thus increasing vaccine uptake among this population [25,60–62]. Further evaluation of these factors will provide insight into the VE and VBIs observed in older adults.

5. Vaccine uptake and compliance

Switzerland was the first country to introduce an extended booster interval in 2006, followed by Finland in 2014 and Belgium in 2019 [32–34]. As a result of the recommendation by FOPH, the coverage of TBE vaccination has increased in the country. The number of individuals in Switzerland who received a TBE vaccination for the first time also increased between 2006 and 2009, the period immediately following the introduction of the official recommendation: 45% (95% CI 43–47) of those who received a TBE vaccine dose during this period were being vaccinated for the first time [63]. This striking increase suggests that the policy change prompted many individuals to receive TBE vaccination. It was also anecdotally reported that a TBE vaccine offering 10-year protection is perceived by the public as a ‘good vaccine,’ potentially contributing to the increased vaccine uptake during this period in Switzerland [37].

A national, cross-sectional study conducted in 2018 in adults in Switzerland based on vaccination records indicated that approximately 80% of adults who began primary immunization completed it, with nearly 90% and 80% of study participants being on time for their second and third doses, respectively. High compliance with booster vaccination was also observed, with approximately 80% of adults who completed their primary immunization having received a booster in the last 10 years [63]. In comparison, in TBE-endemic countries in Europe as a whole, 46% of those who were vaccinated had completed their primary immunization, with only 21% overall having completed their primary immunization on time. With decreasing compliance after each dose, only 28% of all participants in the study received their first booster vaccination [25].

6. Potential impact on clinical practice

TBE does not only impact society clinically but also economically. In addition to hospitalization costs due to TBE treatment, long-term or permanent neurologic sequelae can lead to high costs for healthcare systems and society. A recent study in Sweden has shown that compared with persons without TBE, patients with TBE were hospitalized for more days during the first year of disease (11.5 vs 1.1 days) and logged more specialist outpatient visits (3.6 vs 1.2 visits) and sick leave days (66 vs 10.7 days) [64]. A similar burden was reported in Germany in terms of length of hospital stay and sick leave duration [8]. While most healthcare services were covered by healthcare systems or health insurance, significant out-of-pocket expenses were incurred for many patients, such as physio-, occupational or speech therapy, supportive medical devices or adapting their home due to their sequelae [8].

TBE and its sequelae can have wide-reaching and long-lasting consequences on patients’ lives, and vaccination offers the most effective protection against the disease [1]. However, despite TBE being vaccinepreventable, vaccine uptake is low in many endemic countries [25]. Other than low perceived infection risk, cost and fear of adverse events were reported to be the main barriers to TBE vaccination by adults living in or visiting endemic and non-endemic areas in Europe [25,51,65]. In most European countries, the cost of TBE vaccination is not covered by national healthcare services [66]. Extending the booster interval would translate into lower vaccine costs per person and lower associated costs in vaccine service delivery, thus not only improving the cost-effectiveness of the TBE vaccine but also possibly leading to increased compliance and uptake among the public, as seen in Switzerland [63]. When compliance and vaccine coverage improve, indirect societal costs such as sick leave or decreased work/school performance may be reduced. Fear of side effects is another barrier to TBE vaccination – safety concerns and lack of trust in the vaccine have prevented people from being vaccinated against TBE [25,51]. An extension of the booster interval may reduce patients’ fears and confer trust in the vaccine, which may further increase vaccine uptake among the general public.

In clinical practice, physicians need to manage the quickly evolving vaccine environment and multiple-vaccination schedules. There are currently two TBE vaccines available in Europe, each with its own dosing schedule with different dosing intervals for primary and booster vaccinations (the latter dependent on age) [28,31]. The complexity of the vaccination schedule poses a major barrier not only for the general public but also for healthcare professionals, and it is a key reason why these healthcare professionals do not vaccinate or inform their patients of the availability of the vaccine [65]. In addition, the lack of structured patient recall systems and/or electronic vaccination records in some countries may further exacerbate the situation. With the ever-increasing number of vaccines being recommended, reducing the number of TBE booster doses and streamlining the vaccination schedule (e.g. co-administering TBE boosters with other vaccine boosters with 10-year intervals, such as the tetanus-diphtheria vaccine, with or without combination with acellular pertussis and/or inactivated polio antigens) can greatly reduce the number of visits required and reduce physicians’ vaccination burden, giving them the time they need to keep up with trends and dosing schedules of other vaccines [67].

7. Limitations

Limitations of this review are that the quality of the studies was not formally assessed, and data pertaining to retrospective analyses of VE and VBIs were not exclusively for Encepur. Country-specific differences such as diagnostic practices and TBE case definitions exist within the cited studies. Methods and definitions of outcomes may also be different across analyzed papers. Natural exposure to TBEV was not monitored; it may potentially boost neutralizing antibodies in individuals and contribute to a prolonged period of protection after vaccination. For data pertaining to older adults in the real-world studies, further stratification of data such as by underlying medical conditions or immune status was not available for every study; further analysis of data in this population therefore could not be made. Lastly, reporting bias cannot be excluded, as only publications written in English were included in the literature search.

8. Conclusion

Encepur is a well-established vaccine with more than 30 years of post-marketing experience. Long-term immunogenicity data for Encepur have shown sustainable neutralizing antibody levels 15 years after a single booster dose, and up to 20 years using modeled data. These results are consistent with real-world data, which have shown that VE does not appreciably change or decrease among individuals who have completed Encepur or FSME-Immun vaccination, regardless of age, even if these individuals received their last dose ≥10 years prior. Furthermore, data also suggest that a prolonged time interval is not a predisposing factor for higher VBI rates – the risk of VBI did not increase when the booster dose was given up to 10 years after completion of primary immunization in Switzerland. While the real-world data pertain to both Encepur and FSME-Immun, VE at ≥3 doses was similar for homologous vaccination with either Encepur or FSME-Immun. Taken together, these data support the longevity of the protective response following complete TBE vaccination with Encepur. Beyond a sustained immune response, extending the booster interval may also increase vaccine uptake and compliance among the general public, thereby improving public health and reducing the vaccination burden for physicians.

9. Expert opinion

Among the most effective ways to increase TBE vaccination coverage are nationwide vaccination campaigns in endemic countries, similar to that implemented in Austria, and a universal vaccine recommendation within an endemic country [16]. However, another, perhaps simpler, way to improve vaccine coverage may be through extending the booster interval – as successfully pioneered by Switzerland. This not only simplifies the vaccination schedule but also reduces overall cost associated with vaccination, the latter being an important factor for countries or individuals with financial constraints – TBE boosters may be deprioritized.

The prospect of such an extension is promising, demonstrated by newly emerged prospective and real-world data. Findings similar to those discussed herein were published in a systematic review on the long-term effectiveness of the other European TBE vaccine, FSME-Immun, by Steffen and colleagues, in which an extension of TBE booster intervals to 10 years after completing the primary series was recommended by the authors [37]. In light of these prospective and real-world data, we invite public health experts to work with national recommending bodies in updating the national guidance. Only when the extension is officially adopted can the booster interval extension be implemented in routine clinical practice and impact public health. In addition, there appears to be some indication that the durability of vaccine-elicited antibody response may be associated with earlier age of primary immunization. This is an interesting area that warrants further investigation. Such data, upon validation, would be invaluable in informing national recommending bodies to further optimize vaccination guidelines.

We also recommend improved surveillance in endemic countries. In some countries, TBE surveillance only takes place in high-risk regions. For example, in Romania, TBE surveillance is limited to high-risk areas, with passive surveillance only between May and October [68]. Indeed, most of the surveillance systems adopted by countries reported in the European Centre for Disease Prevention and Control Annual Epidemiological Report for 2020 were passive [19]. This is inadequate, as reported incidence is likely not reflective of the actual risk; this can lead to a poor understanding of TBE endemicity and potentially inadequate vaccine recommendations in the country. This is especially important in the face of a shift in the pattern of TBE risk areas, which now includes a wider geographical distribution and higher altitudes [17,20–24]. An improved surveillance strategy will aid in the timely identification of new endemic regions and better inform the TBE burden and improve TBE risk management.

There is a growing body of evidence that substantiates the longevity of protection conferred by TBE vaccines. With the success seen in Switzerland, we hope that the adoption of a 10-year booster interval will gain traction in other countries, which, combined with improved surveillance and increased disease awareness, we believe will reduce the burden of TBE in Europe.

Article highlights

• Long-term persistence of immune response elicited by Encepur across recipients in all age groups was demonstrated through prospective and modeled data (up to 15 years using prospective data and 20 years using modeled data).

• Data from real-world studies on the two European TBE vaccines, Encepur and FSME-Immun, have shown that vaccine effectiveness remains high among those who are completely vaccinated, regardless of age, even when the last dose was received up to 10 years prior. This prolonged time interval also did not increase the rate of breakthrough infections in those who are fully vaccinated.

• Other than reducing the complexity of vaccination schedules, extending the interval for booster vaccination up to 10 years may also improve vaccine uptake and compliance in those living in endemic regions.

Declaration of interests

J Schelling received payment for talks and advisory boards from Bavarian Nordic. S Einmahl is a paid consultant for Bavarian Nordic. R Torgler is employed by Bavarian Nordic AG. CS Larsen has received payment for lectures and participation in advisory boards from Pfizer. He is also employed by European LifeCare Group as Medical Director. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received honoraria for lectures and/or research grants from Pfizer and Bavarian Nordic. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Author contributions

All authors meet the International Committee of Medical Journal Editors criteria for authorship for this article. All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature; they were also involved in revising the manuscript for intellectual content. Authors take responsibility for all aspects of the work and have given their approval for this manuscript to be published.

Acknowledgments

The authors would like to thank Jamy Feng and Helen Smith from Nucleus Global for providing medical writing support. Permission has been granted by these individuals to mention their name in the manuscript.

Additional information

Funding

This manuscript was funded by Bavarian Nordic.