Five year follow-up after a first booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates long-term antibody persistence and safety

Vaccine 32 (2014) 4275–4280

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Five year follow-up after a first booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates long-term antibody persistence and safety Jiˇrí Beran a , Fang Xie b , Olaf Zent c,∗ a

Vaccination and Travel Medicine Centre, Poliklinika, Hradec Králové, Czech Republic Novartis Vaccines, Emeryville, CA, USA c Novartis Vaccines, Basel, Switzerland b

a r t i c l e

i n f o

Article history: Received 10 April 2014 Received in revised form 19 May 2014 Accepted 6 June 2014 Available online 17 June 2014 Keywords: Tick-borne encephalitis Booster immunization Immunogenicity Persistence

a b s t r a c t Long-term vaccination programs are recommended for individuals living in regions endemic for tickborne encephalitis (TBE). Current recommendations suggest a first booster vaccine be administered 3 years after a conventional regimen or 12–18 months after a rapid regimen. However, the research supporting subsequent booster intervals is limited. The aim of this study was thus to evaluate the long-term persistence of TBE antibodies in adults and adolescents after a first booster dose with Encepur® . A total of 323 subjects aged 15 years and over, who had received one of four different primary TBE vaccination series in a parent study, participated in this follow-up Phase IV trial. Immunogenicity and safety were assessed for up to five years after a first booster dose, which was administered three years after completion of the primary series. One subset of subjects was excluded from the booster vaccination since they had already received their booster prior to enrolment. For comparison, immune responses were still recorded for these subjects on Day 0 and on an annual basis until Year 5, but safety information was not collected. Following a booster vaccination, high antibody titers were recorded in all groups throughout the study. Neutralization test (NT) titers of ≥10 were noted in at least 94% of subjects at every time point post-booster (on Day 21 and through Years 1–5). These results demonstrated that a first booster vaccination following any primary immunization schedule results in high and long-lasting (>5 years) immune responses. These data lend support to the current belief that subsequent TBE booster intervals could be extended from the current recommendation. NCT00387634. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Tick-borne encephalitis (TBE) is a serious, largely untreatable, viral infection of the central nervous system, associated with potentially life-threatening neurological sequelae [1]. It is endemic across broad regions of Europe, Asia and Russia [1] and prophylactic vaccination remains the most effective means of protection. In Europe, there are two TBE vaccines currently available: FSME-IMMUN® (Baxter Vaccine AG) and Encepur® (Novartis Vaccines). Both are inactivated vaccines based on different, but highly homologous, antigenic components (virus strain K23 and strain Neudoerfl,

Abbreviations: TBE, tick-borne encephalitis; NT, neutralization test; SmPC, Summary of Product Characteristics; GMT, geometric mean titer; AE, adverse events; SAE, serious adverse event; GMR, geometric mean ratio; CI, confidence interval. ∗ Corresponding author. Tel.: +41 613240427. E-mail address: [email protected] (O. Zent). http://dx.doi.org/10.1016/j.vaccine.2014.06.028 0264-410X/© 2014 Elsevier Ltd. All rights reserved.

respectively). Both are also safe, and effective in eliciting immunity against all TBE virus variants, including European and Far Eastern subtypes. In this study, the long-term immunogenicity following a booster vaccination with the TBE vaccine, Encepur (Encepur® Adults; Novartis Vaccines), was investigated in healthy subjects. Encepur is a purified, inactivated vaccine currently used in Europe for immunizing adolescents and adults [2]. It is typically administered in three doses according to a “conventional” or “rapid” schedule [3,4]. The former is recommended for individuals living permanently or working in endemic regions, and consists of two vaccinations administered one to three months apart with a third dose given nine to twelve months later. The rapid schedule was designed for individuals who require fast immunization (e.g. visiting endemic areas), and involves all three doses administered within three weeks. Two further schemes based on the conventional schedule have since been proposed, in which the timing of the third dose remains the same but the interval between the first two doses is

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reduced to either two (accelerated conventional) or three (modified conventional) weeks. Subsequent booster vaccinations are recommended if prolonged immunity is required. While the immunogenicity and safety profiles of primary TBE vaccination schedules have been demonstrated in several clinical studies [3,5,6], relatively little long-term persistence data exists to support interval recommendations following a first booster vaccination [7]. The aim of the present study was thus to evaluate the safety and long-term (five-year) antibody response to a first booster dose with Encepur in groups of healthy subjects. All subjects had previously received one of four different primary immunization regimes [6] and were invited back to participate in this follow-up analysis. Information from this trial was intended to help support or guide current recommendations for subsequent booster vaccinations with Encepur.

Subjects were excluded due to: acute moderate/severe illness on the day of vaccination1 ; known or suspected immune system impairment (due to major injury/surgery, malnourishment etc.); major congenital defects; serious chronic illness (e.g. insulin dependent diabetes, cancer, autoimmune diseases); organic brain disturbances (including seizure disorders)1 ; progressive neurological disorders; history of febrile or afebrile convulsions1 ; hypersensitivity to the study vaccine or chemically related substances1 ; receipt of another vaccine within four weeks of the study1 ; participation in another clinical trial within three months of the study; pregnancy1 ; unwillingness to practice birth control ±28 days after vaccination (women of childbearing potential)1 ; treatment with immunosuppressant drugs or systemic corticosteroids four weeks prior to or during the study; treatment with immunoglobulins, whole blood or plasma derivatives within three months of enrollment.

2. Materials and methods

2.2. Vaccine

This Phase 4, open-label, single-center study was conducted in the Czech Republic between September 2006 and October 2011 (NCT00387634). Healthy adolescents and adults (aged 15 to ≥60 years), previously enrolled in a trial comparing different primary vaccination schedules with Encepur [6], were invited to participate in this extension study. The study protocol was designed in accordance with the Declaration of Helsinki and conformed to the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines as well as local regulatory requirements. The study was also approved by local Ethics Review Committees and written informed consent was obtained from all participants prior to enrollment.

Encepur is a purified, inactivated TBE vaccine. Pre-filled syringes containing a total volume of 0.5 mL TBE vaccine (Batch No. 059021C) were provided for intramuscular injections (into the deltoid muscle of the non-dominant arm). Each 0.5 mL dose contained 1.5 ␮g TBE virus (strain K23) adjuvanted with 0.3–0.4 mg aluminium hydroxide with sucrose as the stabilizer.

2.1. Subjects and study design The main objective of this study was to evaluate the immunogenicity of Encepur up to five years after a first booster dose. The safety of the booster vaccine (administered on Day 0) was also assessed with respect to local and systemic solicited reactions (up to Day 3), adverse events (up to Day 21), and unsolicited reactions including serious adverse events (throughout the study) in subjects who had received a booster dose in the study. In the original parent study [6], subjects were divided into the following four groups, each to receive a different primary vaccination schedule:

2.3. Immunogenicity assessments Blood samples (approximately 12 mL) for immunogenicity analysis were collected on Day 0 prior to vaccination, on Day 21 (except Group Rv ) and at Years 1–5. Antibody responses against the TBE virus were measured using a validated in-house neutralization test (NT), as described previously [4]. The NT assay was validated according to ICH guidelines and was also included in an external quality assessment (EQA) study in 2011 with seven other laboratories [8]. In the present study, the lowest limits of antibody detection were NT titers ≥2 (seroconversion), while NT titers ≥10 were considered protective (seroprotection). Results from NT analyses are expressed as: (1) geometric mean titers (GMTs), (2) geometric mean ratios (GMRs); (3) % subjects with titers ≥2; and (4) % subjects with titers ≥10. Serological evaluations were conducted at Novartis Vaccines, Clinical Laboratory Sciences Department, Marburg, Germany. 2.4. Safety assessments

• Group R (“rapid”): Received doses on Days 0, 7 and 21. • Group C (“conventional”): Received doses on Days 0, 28 and 300. • Group M (“modified conventional”): Received doses on Days 0, 21 and 300. • Group A (“accelerated conventional”): Received doses on Days 0, 14 and 300. According to the Summary of Product Characteristics (SmPC) for Encepur, a first booster vaccine is recommended three years following a conventional schedule, or 12–18 months following a rapid schedule. Of the 356 subjects enrolled in the parent study, 323 returned for this follow-up investigation. All subjects in all groups, except for a subset of Group R (categorized Group Rv ), received their first booster dose on Day 0 of this study, approximately three years after completing their primary schedules. Subjects in Group Rv (Rapid‘vaccinated’; N = 40) received their booster vaccination according to product recommendations (12–18 months after their primary schedule) therefore did not require vaccinating in this study and safety data was not collected. See Fig. 1 for study design.

Safety data were only collected from subjects who received a booster vaccination on Day 0 of this study (Groups C, R, M and A; N = 280). Three subjects did not receive a vaccination due to protocol deviations and two subjects were excluded from analysis due to unavailability of post-booster safety data. Consequently, 278 subjects were evaluated for safety. Subjects were observed for 30 min post-vaccination for any immediate local or systemic adverse events (AEs). They were then provided with a diary card to record solicited local and systemic AEs, (indicators of reactogenicity) for four days after the booster vaccination (Days 0 to 3). Selected solicited local reactions were: injection site pain, erythema, and swelling. Selected solicited systemic reactions were: nausea, myalgia, arthralgia, headache, malaise, and temperature ≥38 ◦ C. Solicited AEs were classed as mild (no limitation to normal activity), moderate (some limitation to normal activity) or severe (unable to perform normal activity) and were then classed

1 These exclusion criteria only applied to subjects receiving a booster vaccination as part of this study.

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Enrolled (N=323) Group R Rapid

Group Rv Rapid, preboosted

Group C Conventional

Group M Modified Conventional

Group A Accelerated Conventional

N=9 Booster vaccine Blood draw

N= 40 No vaccine Blood draw

N=55 Booster vaccine Blood draw

N=110 Booster vaccine Blood draw

N=109 Booster vaccine Blood draw

-

1 DE

-

-

-

Day 21

N=9 Blood draw

N=39 No blood draw

N=55 Blood draw

N=110 Blood draw

N=109 Blood draw

Year 1

N=9 Blood draw

N=39 Blood draw

N=55 Blood draw

N=110 Blood draw

N=109 Blood draw

Year 2

N=9 Blood draw

N=39 Blood draw

N=55 Blood draw

N=110 Blood draw

N=109 Blood draw

-

-

1 LTF

1 LTF

2 DE

N=9 Blood draw

N=39 Blood draw

N=54 Blood draw

N=110 Blood draw

N=109 Blood draw

-

-

-

1 PD

-

N=9 Blood draw

N=39 Blood draw

N=54 Blood draw

N=109 Blood draw

N=107 Blood draw

-

-

1 DE; 1 PD

1 PD

1 PD

N=9 Blood draw

N=39 Blood draw

N=54 Blood draw

N=107 Blood draw

N=106 Blood draw

Day 0

Year 3

Year 4

Completed Study Year 5

Fig. 1. Flow chart of study design for Groups R (rapid), Rv (rapid with prior booster vaccine), C (conventional), M (modified conventional), and A (accelerated conventional). Excluded subjects are noted in the white boxes. Abbreviations: DE, death; LTF, lost to follow-up; PD, protocol deviation.

as unrelated, possibly related or probably related to the study vaccination by the Investigator. Subjects were also asked to record any unsolicited AEs up to and including Day 21. All AEs necessitating a physician’s visit (if deemed medically relevant by the Investigator) and/or resulting in premature withdrawal from the study were collected up to Day 21. All serious AEs (SAEs) were collected throughout the study. Hospitalizations due to elective surgeries were not considered SAEs. Prescription medications, excluding minerals and vitamins, taken up to 7 days before and 21 days after the booster vaccination were recorded. For subjects who had not received a booster vaccination in this study, only medications taken up to 7 days before or ongoing at enrollment were recorded. Receipt of blood, blood products, or immunotherapeutic products (e.g. monoclonal antibodies) within 3 months of each blood draw was recorded for all subjects.

2.5. Statistical methods Immunogenicity analyses were performed on per protocol data. No formal statistical hypotheses were tested for the immunogenicity and safety data. NT results were analyzed descriptively. Percentages of subjects with NT titers ≥2, % subjects with NT titers ≥10, and their associated 95% confidence intervals (CIs) were estimated using the Clopper–Pearson method. GMTs, GMRs and 95% CIs were calculated using analysis of variance with logarithmically transformed titer values.

3. Results 3.1. Demographics A total of 323 healthy adults were recalled in this extension study. There were 143 males (44%) and 180 females (56%), and the male-to-female ratios were similar across groups; although Group C had slightly more females (64%). The mean age of subjects at the time of enrollment for this study was 37.1 (range: 15 to ≥60) and the means for each group were comparable with the exception of Group R (N = 9), which had a mean of 31.6. All subjects were Caucasian. See Table 1 for demographics.

3.2. Immunogenicity Immunogenicity data from 313 subjects were eligible for analysis. Ten subjects were excluded from the full data set due to: subject death (N = 4), loss of subject to follow up (N = 2) or protocol deviations (N = 4). Immunogenicity analysis were subsequently conducted on the per protocol data set, namely all evaluable samples were analyzed on Day 0, Day 21, and on an annual basis from Years 1–5. Since subjects in Group Rv were vaccinated prior to this study, they were only evaluated on an annual basis from Day 0 through Years 1–5. Fig. 1 shows the timeline for vaccinations, blood draws and exclusions. All subjects showed excellent immune responses to the first booster vaccination with Encepur. At every visit post-vaccination

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Table 1 Demographics of enrolled subjects.

Age (years) Sex Male Female Race: Caucasian Previous vaccine booster No Yes

Group R

Group Rv

Group C

Group M

Group A

Rapid

Rapid (pre-boostered)

Conventional

Modified conventional

Accelerated conventional

Total

N=9

N = 40

N = 55

N = 110

N = 109

N = 323

31.6 ± 9.2

38.1 ± 16.4

36.3 ± 14.5

37.5 ± 14.3

37.1 ± 14.4

37.1 ± 14.5

4 (44%) 5 (56%)

21 (53%) 19 (48%)

20 (36%) 35 (64%)

47 (43%) 63 (57%)

51 (47%) 58 (53%)

143 (44%) 180 (56%)

9 (100%)

40 (100%)

55 (100%)

110 (100%)

109 (100%)

323 (100%)

9 (100%) 0

0 40 (100%)

55 (100%) 0

109 (99%) 1 (<1%)

107 (98%) 2 (2%)

280 (87%) 43 (13%)

failed to maintain NT titers ≥10 at the five year time point. The three subjects were found to be male, aged 33 years (Group Rv ), 45 years (Group M) and 56 years (Group M). NT antibodies for the 45 and 56 year old males in Group M decreased to below 10 at five years and two years, respectively. In contrast, NT antibodies for the 33 year old male in Group Rv never reached a level of 10 or higher at any time point. Geometric mean titers (GMTs, Table 4) on Day 0 were comparable in Groups C, R and M. Subjects in Group R had the lowest mean GMTs on Day 0, while subjects in Group Rv had the highest. As expected, GMTs in all groups that received a booster vaccination

up to Year 5, all (100%) subjects exhibited seroconversion (NT titers ≥2; see Table 2). Prior to the booster vaccination (Day 0), only two subjects (one in Group Rv and one in Group M) did not attain seroconversion. Protective titers (NT titers ≥10) were achieved by almost all subjects throughout the study (Table 3). All subjects (100%) in Groups R, A, and C consistently exhibited NT titers ≥10 at every visit post-booster vaccination (Day 21 onwards). In Groups Rv and M, subjects exhibiting NT titers ≥10 was also very high (above 94% at every visit). Indeed, at Year 5, 97% and 98% of subjects had NT titers ≥10 in Groups Rv and M, respectively. A total of three subjects Table 2 Number (percentage; 95% Confidence Intervals) of subjects with NT titers ≥2 by visit. Study day

Day 0 Day 21 Year 1 Year 2 Year 3 Year 4 Year 5

Group R

Group Rv

Group C

Group M

Group A

Rapid

Rapid (pre-booster)

Conventional

Modified Conventional

Accelerated conventional

N

N

n

N

N

8 8 8 8 8 7 8

7 (88%) (47–100) 8 (100%) (63–100) 8 (100%) (63–100) 8 (100%) (63–100) 8 (100%) (63–100) 7 (100%) (59–100) 8 (100%) (63–100)

37

37 (100%) (91–100) NA 35 (100%) (90–100) 35 (100%) (90–100) 34 (97%) (85–100) 34 (100%) (90–100) 36 (100%) (90–100)

35 35 35 34 36

51 51 50 51 49 48 48

51 (100%) (93–100) 51 (100%) (93–100) 50 (100%) (93–100) 51 (100%) (93–100) 49 (100%) (93–100) 48 (100%) (93–100) 48 (100%) (93–100)

101 101 100 99 100 99 98

100 (99%) (95–100) 101 (100%) (96–100) 100 (100%) (96–100) 99 (100%) (96–100) 100 (100%) (96–100) 99 (100%) (96–100) 98 (100%) (96–100)

101 100 101 100 100 100 99

101 (100%) (96–100) 100 (100%) (96–100) 101 (100%) (96–100) 100 (100%) (96–100) 100 (100%) (96–100) 100 (100%) (96–100) 99 (100%) (96–100)

Table 3 Number (percentage; 95% Confidence Intervals) of subjects with NT titers ≥10 by visit. Study day

Day 0 Day 21 Year 1 Year 2 Year 3 Year 4 Year 5

Group R

Group Rv

Group C

Group M

Group A

Rapid

Rapid (pre-booster)

Conventional

Modified Conventional

Accelerated conventional

N

N

N

N

N

8 8 8 8 8 7 8

6 (75%) (35–97) 8 (100%) (63–100) 8 (100%) (63–100) 8 (100%) (63–100) 8 (100%) (63–100) 7 (100%) (59–100) 8 (100%) (63–100)

37

36 (97%) (86–100) NA 34 (97%) (85–100) 34 (97%) (85–100) 34 (97%) (85–100) 32 (94%) (80–99) 35 (97%) (85–100)

35 35 35 34 36

51 51 50 51 49 48 48

50 (98%) (90–100) 51 (100%) (93–100) 50 (100%) (93–100) 51 (100%) (93–100) 49 (100%) (93–100) 48 (100%) (93–100) 48 (100%) (93–100)

100 101 100 99 100 99 98

98 (97%) (92–99) 101 (100%) (96–100) 100 (100%) (96–100) 98 (99%) (95–100) 95 (95%) (89–98) 96 (97%) (91–99) 96 (98%) (93–100)

101 100 101 100 100 100 99

100 (99%) (95–100) 100 (100%) (96–100) 101 (100%) (96–100) 100 (100%) (96–100) 100 (100%) (96–100) 100 (100%) (96–100) 99 (100%) (96–100)

Table 4 GMTs of subjects by visit. Study day

Day 0 Day 21 Year 1 Year 2 Year 3 Year 4 Year 5

Group R

Group Rv

Group C

Group M

Group A

Rapid

Rapid (vaccinated)

Conventional

Modified conventional

Accelerated conventional

N

N

N

8 8 8 8 8 7 8

67 (22–201) 1476 (646–3373) 378 (152–936) 370 (150–913) 331 (121–910) 137 (50–379) 429 (151–1217)

37 35 35 34 34 36

395 (236–658) NA 234 (152–362) 235 (152–362) 235 (145–380) 192 (121–304) 358 (219–586)

51 51 50 51 49 48 48

N 232 (150–359) 1182 (852–1640) 240 (167–345) 229 (160–327) 230 (153–346) 250 (169–368) 300 (196–460)

100 101 100 99 100 99 98

N 206 (151–281) 1024 (812–1293) 249 (193–322) 211 (163–272) 211 (159–281) 208 (159–273) 281 (208–378)

101 100 101 100 100 100 99

237 (174–323) 1059 (838–1338) 246 (190–317) 232 (180–300) 228 (171–303) 253 (193–331) 305 (227–410)

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on Day 0 (Groups C, R, M and A) peaked at Day 21 (>1000) before stabilizing in Years 1–5 (<430). The GMTs of subjects in Group Rv , however, remained fairly similar at every time point. Geometric mean ratios (GMRs) followed a similar pattern in Groups C, M and A, increasing to approximately 5 (4.11–5.15) on Day 21 before decreasing to approximately 1 (0.92–1.46) at subsequent time points. In contrast, while GMTs in Group R on Day 21 were within the same range as those of other groups, because of very low GMTs on Day 0, their GMR on Day 21 reached as high as 22. This value decreased at subsequent time points, but was still at 6 by Year 5. GMRs for Group Rv were fairly constant at each time point from Years 1–5 (0.5–1). 3.3. Safety All available safety data from subjects receiving a booster vaccination on Day 0 were included for analysis. Within three days post-booster vaccination, 64% of subjects reported at least one solicited AE. Of these, 56% experienced local reactions, 30% experienced systemic reactions and 5% experienced other solicited AEs. The most frequently reported local solicited AEs were pain (55%), erythema (8%) and swelling (6%). The most frequently reported systemic solicited AEs were myalgia (17%), headache (14%), malaise (7%), arthralgia (5%) and nausea (4%). One percent of subjects (N = 4) reported a temperature of ≥38 ◦ C (one subject in Group R, two subjects in Group M, and one subject in Group A) and four percent of subjects used analgesics/antipyretic medications. Across the four groups, the rates of solicited AEs were highest in Group R (78%) compared to Groups C (71%), M (64%), and A (58%). Severe local and systemic solicited reactions were reported in ≤1% of subjects. Thirteen percent of subjects reported at least one unsolicited AE across the study groups. Possibly related unsolicited AEs were reported in 4% (N = 12) of patients across the groups (range: 11–16%). Headache (1–11% across the groups) and pain (0–2% across the groups) were the most frequently reported possibly related AEs. SAEs were reported in 5% of subjects (N = 15), all of which were considered unrelated to the study vaccine. A total of four deaths were reported during this five-year study: one in Groups C and Rv , and two in Group A. All deaths (one suicide, two Grade IV glioblastomas and one myocardial infarction) were considered unrelated to the study vaccination by the Investigator. Since the subject in Group Rv (suicide) did not receive a booster vaccination in this study and safety data was not collected, only three deaths were reported as SAEs. 4. Discussion With new cases emerging in regions previously not considered endemic, TBE is becoming an international health concern [1,9]. Vaccination programs have been implemented in several TBEendemic countries [1]. However, since relatively few studies have examined duration of protection following different primary or booster regimes, the data upon which intervals between booster doses have been based are limited [7,9–14]. Recommended booster intervals thus vary between endemic countries. For example, intervals of 3–5 years after a first booster vaccination are recommended in Austria and Germany; whereas, 10-year intervals are implemented in Switzerland [1]. Such inconsistencies reflect knowledge gaps warranting further research to determine optimal timing of second (and subsequent) boosters. To address this need, the present study sought to compare the long-term immunogenicity and safety of a first booster vaccination with Encepur in subjects that had previously completed one of four primary immunization schedules [6]. Antibody titers against TBE in all subjects, including those that had received a booster vaccination

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prior to the study (Group Rv ), were examined at regular time points from Day 0 to five years. As expected, Group Rv already exhibited protective NT titers on Day 0. However, the majority of subjects in the other groups (75–99%) also exhibited protective titers on Day 0. This finding is not entirely unexpected since previous studies have indicated that antibody levels persist for many years after primary TBE vaccination [11,15]. By Day 21, all subjects that had received a booster vaccination had titers of ≥10 and these protective titers were maintained by almost all subjects until the end of the study. Of particular interest is TBE antibody persistence in the elderly (60+ years) since this age group tends to suffer a higher disease burden. While this study was not designed to compare different age groups, it should be noted that there was also a high maintenance of TBE antibodies in the elderly across all vaccination groups. Notably, of the three subjects who failed to exhibit NT titers ≥10 at five years, all were aged <60 years; no specific pattern or causal effect could be established. Reports suggesting long-term antibody persistence following booster vaccinations exist in the literature with both Encepur [7,11,16,17] and FSME-IMMUN [14,18] or with the two European TBE vaccines used interchangeably [19,20]. Unfortunately, in the absence of an international standard test of TBE vaccine immunogenicity, and with different laboratories employing different assays [9], comparisons across TBE vaccines are difficult. However, the over-riding impression is that TBE booster vaccinations elicit substantial and long lasting (>3 years) immune responses after any primary immunization regimen. Moreover, a very recent report has demonstrated that protective antibody levels can be elicited even when a booster dose is given to subjects with irregular vaccination histories [21]. To date, very few formally evaluated large scale studies have looked at immunogenicity beyond three years. One exception is a study by Plentz et al. [7] who examined persistence of antibodies up to five years in subjects that had previously received the rapid vaccination regime with Encepur and a booster at 12–18 months (equivalent to Group Rv in the present study). Their results are highly consistent with those of this study in terms of both GMTs as well as % subjects with NT titers ≥10 (>99% at Years 3 and 5) [7]. Together, these findings provide evidence that TBE booster vaccinations elicit high antibody responses in most subjects for at least five years. Booster vaccinations in the present study were generally well tolerated. While initial (pre-2001) formulations of Encepur containing polygeline were associated with increased AEs, since being reformulated, postmarketing surveillance has reported <2 SAEs per 100,000 administered doses [9]. In this study, reactions were typically mild to moderate and similar to those previously described [3]. However, three deaths (plus one suicide) were reported during the five years of this study. Of note, two of the reported deaths were from Grade IV glioblastoma. Given that the annual rate of glioblastoma in Europe and in North America is approximately 2–3 cases per 100,000 people, the incidence of glioblastoma in this study was surprisingly high. However, a comprehensive review of all clinical and postmarketing information on Encepur revealed no evidence to suggest that the vaccine increases risk of glioblastoma. Moreover, with no known pathomechanism, no class effect, no supporting evidence from nonclinical investigations, and no reports with sufficient evidence as to ascribe causality, it was deemed very unlikely that the condition was related to the vaccine. Overall, the results of this study demonstrate that a first booster with Encepur following different primary vaccination regimens elicits high and long lasting immunogenicity for at least five years. This suggests that the current interval between a first and second TBE booster vaccination could potentially be extended. To further understand longer term antibody persistence following booster vaccinations, subjects from the present investigation are currently

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involved in a second extension study for an additional five years. This information could be potentially useful in establishing guidelines for long-term booster intervals with Encepur.

[6]

Financial disclosures

[7]

This study was supported by funds provided by Novartis Vaccines.

[8]

Author contributions

[9]

ZO and JB were involved in the conception and design of the study. JB conducted the study. FX was involved in the statistical analysis and interpretation of the data. All authors contributed to the development of the initial draft of the manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted.

[11]

Conflicts of interest statement

[13]

OZ is a permanent employee of Novartis Vaccines. FX is a contract employee of Novartis Vaccines. JB declares no potential conflicts of interest.

[14]

Acknowledgments

[15]

The authors are grateful to all volunteers who participated in the clinical trial; to Yvonna Fisher-Jeffes (Novartis Vaccines) for her writing and editorial assistance in the preparation of this manuscript; and to Katalin Csermak Renner for her critical review of the manuscript. References [1] WHO. Vaccines against tick-borne encephalitis: WHO position paper. Wkly Epidemiol Rec 2011;24:241–56. [2] Novartis Vaccines and Diagnostics GmbH & Co. KG. Encepur Erwachsene summary of product characteristics/Fachinformation 2008. [3] Zent O, Beran J, Jilg W, Mach T, Banzhoff A. Clinical evaluation of a polygelinefree tick-borne encephalitis vaccine for adolescents and adults. Vaccine 2003;21:738–41. [4] Zent O, Banzhoff A, Hilbert AK, Meriste S, Sluzewski W, Wittermann C. Safety, immunogenicity and tolerability of a new pediatric tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer. Vaccine 2003;21:3584–92. [5] Zent O, Jilg W, Plentz A, Schwarz TF, Fruhwein N, Kuhr HB, et al. Kinetics of the immune response after primary and booster immunization against tick-borne

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