- Email: [email protected]
Seropersistence of TBE virus antibodies 10 years after first booster vaccination and response to a second booster vaccination with FSME-IMMUN 0.5 mL in adults
Vaccine 35 (2017) 3607–3613
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Seropersistence of TBE virus antibodies 10 years after first booster vaccination and response to a second booster vaccination with FSMEIMMUN 0.5 mL in adults R. Konior a, J. Brzostek b, E.M. Poellabauer c, Q. Jiang d, L. Harper d,⇑, W. Erber e a
John Paul II Hospital, Krakow, Poland Debica, Poland Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria d Pfizer Inc, Collegeville, PA, USA e Pfizer Inc, Vienna, Austria b c
a r t i c l e
i n f o
Article history: Received 16 December 2016 Received in revised form 16 March 2017 Accepted 17 March 2017 Available online 22 May 2017 Keywords: TBE FSME Tick-borne Encepahlitis
a b s t r a c t Tick-borne encephalitis (TBE) is a viral disease that can have a severe acute clinical course and considerable long-term morbidity. As there is no causal treatment currently available for TBE, vaccination is the only way to combat the disease in endemic areas. The studies presented here were conducted to obtain prospective long-term TBE serum antibody persistence data of subjects up to 10 years after the first booster with FSME-IMMUN. This report presents the results of 2 follow-up studies in the same study population of 315 healthy adults. Blood was drawn to assess the seropersistence of TBE virus antibodies yearly, from 2–5 and 7–10 years after the first booster vaccination with FSME-IMMUN administered during a previous study. The timing of the second booster vaccination was dependent on the level of serum TBE antibodies observed during yearly follow-up serology observations. The current follow up showed that adult recipients were 84.9% seropositive 10 years after a 3 dose primary series and the first booster vaccination of FSME-IMMUN. Seropositivity rates were even higher (88.6%) in subjects below 50 years of age. ClinicalTrials.gov Identifier: NCT00503529. ClinicalTrials.gov Identifier: NCT01582698. Ó 2017 Published by Elsevier Ltd.
1. Introduction Tick-borne encephalitis (TBE) is a viral disease caused by the tick-borne encephalitis virus (TBEV; family Flaviviridae) that can have a severe acute clinical course, and lead to a high percentage of sequelae among survivors [1,2]. The disease is endemic over a vast area of Europe, Siberia, Russia, northern China and Japan [2]. The worldwide incidence of TBE is reported to be between 10,000 and 15,000 cases per year [3], though this number is likely an underestimation as notification of the disease is not mandatory in all countries. The disease rates of TBE have increased in recent years [4], likely due to changes in environmental factors, increased awareness, and/or intensified travel to endemic areas.
⇑ Corresponding author. E-mail address: [email protected] (L. Harper). http://dx.doi.org/10.1016/j.vaccine.2017.03.059 0264-410X/Ó 2017 Published by Elsevier Ltd.
In the unvaccinated, TBE can lead to significant long-term morbidity. In one large German study, 12% of patients affected required admission to intensive care and 5% of patients required assisted ventilation [5]. No specific treatment for tick-borne encephalitis exists; therefore prevention of the disease via vaccination is the best strategy. Active immunization has been successfully implemented in many European countries [4]. Vaccines currently in Ò Ò use include FSME-IMMUN (Pfizer Vaccines, USA), Encepur Ò (GlaxoSmithKline), EnceVir (Scientific Production Association Ò Microgen, Russia) and TBE Vaccine Moscow (Federal State Enterprise of Chumakov Institute of Poliomyelitis and Viral Encephalitis, Russian Academy of Medical Sciences, Russia). Both FSME-IMMUN and Encepur are available and approved for use in the European Union. However, there is a lack of large-scale longitudinal studies evaluating the duration of immunity after vaccination with FSME-IMMUN.
3608
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Results from a previous Phase 4 study in adults demonstrated that FSME-IMMUN was well tolerated as a booster vaccination [6], and suggested that it was sufficient for the first booster to be administered 3 years after the completion of the primary vaccination series. Here we present the results of two successive studies investigating TBE virus antibody seropersistence from 2–5 and 7– 10 years after the first FMSE-IMMUN booster vaccination. In the context of both studies the response to a second booster vaccination was also investigated. Results of these studies will contribute to a better understanding of antibody seropersistence in subjects of different ages who received the complete 3 dose primary vaccination series as well as the first booster. 2. Methods 2.1. Study design This report presents the results of 2 follow-up studies in the same study population of healthy adults. We investigated prospective long-term TBE serum antibody persistence data of subjects from 2 to 10 years (2–5 years follow-up; ClinicalTrials.gov Identifier: NCT00503529; 7–10 years follow-up ClinicalTrials.gov Identifier: NCT01582698) after the first booster with FSME-IMMUN (precursor study, Clinical trial number: NCT00161785). Blood samples were taken before the tick season yearly to assess the long term immune response. Subjects who may not have been protected against TBE for an entire further tick season received the 2nd booster dose and the booster response was analyzed at a final study visit 1-month later. Safety was not evaluated for the following reasons: (1) an excellent safety and tolerability profile has been established for the vaccine over decades of use and (2) a relatively small number of subjects received a booster vaccination during the follow-up. Nevertheless, adverse events (AEs) and serious adverse events (SAEs) that occurred after the booster vaccination in the 2–5 year follow-up and SAEs that occurred after the booster vaccination in the 7–10 year follow-up were to be reported. The timing of a second booster vaccination was dependent on the level of serum TBE antibodies as evaluated by enzyme-linked immunosorbent assay (ELISA, IMMUNOZYM FSME IgG; PROGEN Biotechnik GmbH) and neutralization test (NT, according to Adner et al. [7]) at yearly visits. Both assays are based upon the Neudoerfl virus strain used in the FSME-IMMUN vaccine. The accepted cut off for seropositivity was an ELISA concentration >126 VIE U/mL and an NT titer 10 [7]. Based on the yearly decline rate determined in previous studies [6], it was calculated that an NT titer >20 is necessary for a subject to be considered protected for an entire tick-season until the next blood draw 1 year later. Therefore, the criteria for a second booster vaccination in this study were defined as an NT titer 20 and/or an ELISA concentration 126 VIE U/mL after the first booster, as applicable. Recommendations as to whether or not to administer the booster vaccination were given by the sponsor on an individual basis. The data monitoring committee was consulted for their opinion in case of inconclusive serological data. Blood was drawn 21– 35 days after vaccination to assess the booster response. Subjects participated in the study for up to 8 years. 2.2. Study subjects In general, subjects were enrolled from low-endemic regions in southeastern Poland (incidence of 1/100000 for TBE) [8]. A total of 78/315 subjects (24.8%) reported a known tick bite(s) since the last blood draw visit during the study (supplementary Table S1). Subjects who received their first booster dose in the
precursor study (Clinical trial number: NCT00161785) were invited to participate in a subsequent yearly follow-up study to assess antibody persistence 2–5 years (as applicable, ClinicalTrials.gov Identifier: NCT00503529) after the first TBE booster vaccination and to receive a second booster vaccination if deemed necessary. Subsequently, subjects who did not receive the 2nd booster dose were followed yearly for TBE antibody persistence 7–10 years after TBE booster vaccination (ClinicalTrials.gov Identifier: NCT01582698) and were to receive a second booster vaccination if deemed necessary. Exclusion criteria included receiving any TBE vaccination (or other flavivirus vaccination) since their first booster vaccination with FSME-IMMUN outside study procedures, HIV positivity, or known or suspected drug or alcohol abuse. Any subject may have voluntarily withdrawn consent for continued participation and data collection. Discontinuation (ie, complete withdrawal from study participation) may have been due to dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by subject without notice or action). Additionally, the investigator and sponsor had the discretion to discontinue any subject from the study if, in their judgment, continued participation would pose an unacceptable risk for the subject. If a female subject became pregnant prior to the booster vaccination, the subject was not eligible for vaccination. All data collected up to withdrawal were used in the analysis. 2.3. Analysis population An all-enrolled population was defined as the Full Analysis Set, which consisted of all subjects enrolled into post-first booster follow-up. All subjects who consented were included in this population. Subject disposition, history of tick bites, AE, and demography was collected for this population. A per-protocol (PP) population included subjects who: (1.) were enrolled; (2.) met all inclusion/exclusion criteria at all visits; (3.) had valid and determinate assay results for the proposed analysis; (4.) had received no prohibited vaccines or treatment and; (5.) had no other important protocol deviations as determined by the sponsor’s global medical director. 2.4. Vaccines administered Subjects who were not considered protected against TBE for an entire further tick season as indicated by TBE serum antibody levels (NT titer 20 or ELISA concentration 126 VIE U/mL), were invited to receive a second booster vaccination, as applicable. FSME-IMMUN was provided in pre filled syringes containing 1 single dose of 0.5 mL each of 2–2.75 mg (target: 2.4 mg) TBE antigen. Vaccine was given by intramuscular injection into the right or left deltoid. 2.5. Measurements Blood was drawn to assess the seropersistence of TBE virus antibodies yearly between 25 and 7–10 years after the first booster vaccination with FSME-IMMUN. If a subject received their second booster vaccination, blood was drawn 21–35 days after booster vaccination to assess the booster response. TBE antibody response was determined by means of NT and ELISA. AEs and SAEs occurring after the booster vaccination in the 2– 5 year follow-up and SAEs occurring after a booster vaccination in the 7–10 year follow-up were recorded. 2.6. Statistical methodology Sample size was based on subject availability. Approximately 300 study participants were expected to provide information on
3609
R. Konior et al. / Vaccine 35 (2017) 3607–3613 Table 1 Disposition of subjects including both follow up studies (2–5 years and 7–10 years after 1st booster). Age Group (First booster day)
Enrolleda Completed 10-year follow-up Subjects who received booster dose Boostered before Month 34 Boostered at Month 36 Boostered at Month 48 Boostered at Month 60 Boostered at Month 84 Boostered at Month 108 Boostered at Month 120 Subjects who completed 10-year follow-up without booster dose Subjects who completed 5-year follow-up (study 690701 only) without booster dose Discontinued Subjects who did not return for booster dose No return at Month 108 Withdrawal by subject No return at Month 120 Withdrawal by subject Subjects who did not require booster dose No return at Month 34 Withdrawal by subject No return at Month 46 Lost to follow-up No return at Month 58 Withdrawal by subject Lost to follow-up No return at Month 94 Withdrawal by subject No return at Month 106 Withdrawal by subject No return at Month 118 Withdrawal by subject Reason for discontinuation Withdrawal by subject Lost to follow-up a
18–49 Years
50–60 Years
> 60 Years
Total
n (%)
n (%)
n (%)
n (%)
251 (100.0) 214 (85.3) 31 (12.4) 4 (1.6) 10 (4.0) 2 (0.8) 5 (2.0) 1 (0.4) 2 (0.8) 7 (2.8) 183 (72.9) 25 (10.0) 12 (4.8) 2 (0.8) 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 10 (4.0) 0 (0.0) 0 (0.0) 1 (0.4) 1 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.6) 4 (1.6) 1 (0.4) 1 (0.4) 4 (1.6) 4 (1.6)
54 (100.0) 44 (81.5) 13 (24.1) 2 (3.7) 4 (7.4) 0 (0.0) 2 (3.7) 2 (3.7) 0 (0.0) 3 (5.6) 31 (57.4) 5 (9.3) 5 (9.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (9.3) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 0 (0.0) 1 (1.9) 1 (1.9) 0 (0.0) 0 (0.0) 1 (1.9) 1 (1.9)
10 (100.0) 4 (40.0) 3 (30.0) 1 (10.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (10.0) 4 (40.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
315 (100.0) 262 (83.2) 47 (14.9) 7 (2.2) 16 (5.1) 2 (0.6) 7 (2.2) 3 (1.0) 2 (0.6) 10 (3.2) 215 (68.3) 34 (10.8) 19 (6.0) 2 (0.6) 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 17 (5.4) 1 (0.3) 1 (0.3) 2 (0.6) 2 (0.6) 3 (1.0) 1 (0.3) 2 (0.6) 5 (1.6) 5 (1.6) 1 (0.3) 1 (0.3) 5 (1.6) 5 (1.6)
11 (4.4) 1 (0.4)
4 (7.4) 1 (1.9)
0 (0.0) 2 (20.0)
15 (4.8) 4 (1.3)
All subjects were consented and enrolled in precedent study 690701. The values in this row are used as the denominators for percentages.
Table 2 Demographics and baseline characteristics – per-protocol population. N (Total = 315)
%
Age at enrollment (years) 20 21–30 31–40 41–50 51–60 >60
0 69 75 101 55 15
(0.0%) (21.9%) (23.8%) (32.1%) (17.5%) (4.8%)
Sex Female Male
162 153
(51.4%) (48.6%)
BMI (kg/m2) <20 20–25 >25
7 166 142
(2.2%) (52.7%) (45.1%)
Abbreviations: BMI = body mass index.
antibody persistence 27 months after the first booster vaccination with FSME-IMMUN 0.5 mL. The primary immunogenicity endpoint was the seropositivity rate as measured by NT (NT 10) after the first booster vaccination, at each year, and after the second booster vaccination in this study. Secondary immunogenicity endpoints included the seropositivity rate as measured by ELISA (ELISA > 126 VIE U/mL), geometric mean antibody concentration (ELISA), and geometric mean titer (GMT) at each blood draw time
point, and geometric mean fold rise (GMFR) from before second booster to after the second booster vaccination. For subjects with antibody response results available at all time points (from 1-month after first booster dose in the precursor study until year 10 blood draw), the actual values were used in the analysis. For subjects who discontinued from the study or received the second booster dose before year 10, an extrapolated value from a regression model was used. Only subjects with antibody response results available at the first 3 time points have the extrapolated values. Subjects with a more than 4-fold increase in TBE antibody levels between successive visits were excluded from the regression analysis as this increase may have indicated a natural booster effect from contact with the TBE virus. First, the NT titers measured at each blood sampling time point (except the post-booster visit) were logarithmically transformed. These log transformed data were then used as the dependent variable, with days after first booster dose as the independent variable, to calculate the annual decline rate, using regression model for each subject. The slope from the model multiplied by 365 was considered as the estimated annual decline rate for each subject. Second, antibody levels after the first booster vaccination for subjects who had received a booster vaccination and for dropouts were extrapolated using the annual decline rate. Lastly, summary statistics on the seropositivity rate or geometric means as measured by NT were estimated by including the extrapolated serology values as well as those serology results at time points without booster or without withdrawals.
3610
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Seropositive rates as measured by NT were descriptively summarized at each blood sampling time point, along with the exact 2-sided 95% CI (or Clopper-Pearson confidence limit) for the proportion. NT titers measured at each blood sampling time point (including extrapolated from regression model) were logarithmically transformed for analysis and geometric mean neutralization titers (GMTs) were computed with 95% CI constructed by back transformation of the CIs for the logarithmical assay results using the Student t distribution. 3. Results A total of 315 subjects participated in follow-up study after first booster dose administration (Table 1). Of these 315 enrolled 18-49 years
subjects, 262 (83.2%) completed 10 years of follow-up and 19 subjects (6.0%) discontinued from the study. A total of 47 subjects (14.9%) received the second booster dose over the follow-up. Two (2) subjects required a second booster but did not return for the booster dose visit due to moving abroad. Among subjects aged 18–49 years, 31 subjects (12.4%) received a booster; aged 50–60, 13 subjects (24.1%) received a booster; and among subjects 60 years and above, 3 subjects (30%) received a booster. Slightly more female (51.4%) than male subjects (48.6%) were included in the immunogenicity and per protocol dataset (n = 315), with the largest percentage (32.1%) aged 41–50 years (range 21–70 years) (Table 2). Height and weight were normally distributed. Most subjects had a BMI of 20. 50-60 years
>60 years
100 90 80
Seroposivity (%)
70 60 50 40 30 20 10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0
Fig. 1. Seropositivity rates by NT (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster). 18-49 Years
50-60 Years
>60 Years
100 90 80
Seroposivity (%)
70 60 50 40 30 20 10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0
Fig. 2. Seropositivity rates by ELISA (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
3611
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Seropositivity rates for subjects included in the immunogenicity analysis set using extrapolated values based on annual decline rate as measured by NT are presented in Fig. 1 and supplementary Table S2. A total of 5 subjects (NT) and 9 subjects (ELISA) were excluded from the analysis of seropersistence due to a >4-fold increase of antibody levels within 2 consecutive visits. Seropositivity rates 4 weeks after the first booster (as measured by NT) were 100% for all age groups. At 3 years after the first booster, the seropositivity rates for all age groups remained 100%. At year 4, rates decreased to 97.6% (239/245), 92.2% (47/51), and 77.8% (7/9) for subjects aged 18–49 years, 50–60 years and >60 years, respectively. At year 5 these rates were 96.7% (237/245), 92.2% (47/51), and 75.0% (6/8), respectively. Seropositivity rates by NT continued to decrease from year 7 to year 10 for all subjects: at Year 7 rates were 92.7% (227/245), 82.4% (42/51), and 50.0% (4/8), at year 10 these rates were 88.6% (217/245), 74.5% (38/51), and 37.5% (3/8) for subjects aged 18 to 49 years, 50 to 60 years,
18-49 years
1000
and >60 years, respectively. Seropositivity rates as measured by the ELISA assay correlate well with the NT results and can be seen in Fig. 2. GMTs measured by NT for subjects included in this study using extrapolated values based on annual decline rate are presented in Fig. 3 and supplementary Table S3. GMTs dropped significantly between the first booster vaccination and year 2 for all age groups. GMTs decreased further until year 7 for all time points except year 3. There was a slight increase in GMTs from year 7 to year 8, and GMTs generally decreased from year 8 to year 10. As the sample size was smaller in the older age groups (50–60 years and >60 years), the CIs of the GMTs mostly overlapped; however, GMTs of antibody levels were numerically higher for younger adults compared with older adults. Geometric mean concentrations as measured by the ELISA assay correlate well with the NT results as illustrated by the similar slopes of the lines representing the different age groups in Fig. 4.
50-60 years
>60 years
Geometric Mean Titer
100
10
1
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0.1
Fig. 3. GMTs measured by NT (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
18-49 years
Geometric Mean Concentraon
10000
50-60 years
>60 years
1000
100
10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
1
Fig. 4. GMCs Measured by ELISA (Extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
3612
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Table 3 GMFRs from pre-2nd booster to post-2nd booster (measured by NT). Assay Age Group (Visit 1)
NT 18–49 Years 50–60 Years >60 Years
Prebooster
Post booster a
n
GM
(95% CI )
n
GM
(95% CIa)
n
GMFR
(95% CIa)
45 29 13 3
16.3 16.2 18.0 11.9
(14.48, 18.43) (14.06, 18.55) (13.39, 24.28) (7.82, 18.06)
47 31 13 3
190.5 178.2 232.4 160.0
(148.10, 244.92) (127.25, 249.50) (164.73, 327.91) (5.11, 5008.64)
45 29 13 3
12.4 12.1 12.9 13.5
(9.69, (8.71, (8.62, (0.53,
15.85) 16.74) 19.28) 342.45)
Abbreviations: GM = geometric mean; GMFR = geometric mean of fold increase; NT = neutralization test. a Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers, concentrations or the fold rises.
Except 2 subjects who did not return for their booster dose, all other subjects, whose antibody levels were below the protocol defined booster threshold (a titer 20 as measured by NT or a concentration 126 VIE U/mL as measured by ELISA) received a second booster dose, and regained seropositivity thereafter. GMTs and GMFRs from pre-booster to post-booster are presented in Table 3. For subjects who received a second booster, GMTs of antibody levels increased 12.1- to 13.5-fold. Safety assessment was not an endpoint in this study; however, any AE or SAE that occurred after a booster vaccination in the 2– 5 year follow-up and any SAE that occurred after the booster vaccination in the 7–10 year follow-up were to be reported. There were two subjects who reported 3 mild AEs after a booster vaccination in the 2–5 year follow-up; fatigue and injection site pain for one subject and malaise for the other. No vaccine-related SAEs were reported and no deaths occurred during the study.
4. Discussion As no specific therapy exists for TBE, vaccination is the only effective preventative measure for individual protection. In many European regions, a steady increase of TBE cases has been observed over the last 20–30 years leading to new additions to the list of countries considered to be endemic for TBE [9]. Conversely, rates of TBE cases in Austria have stayed relatively low due to high vaccine coverage secondary to the institution of a mass immunization program against the virus [10,11]. However, incidence rates in the non-vaccinated population remain similarly high as compared to the pre-vaccination era, indicating the necessity of a continuous level of protection for the individual vaccinee. A previous phase IV study [6] evaluated the seropersistence of TBE antibodies 2 and 3 years after the primary immunization course with FSME-IMMUN. It showed that the first booster three years after primary immunization induced an excellent immune response. A first booster interval of 3 years is generally recommended for people of all ages who are at risk, including the elderly [12–14]. Our present long term prospective follow-up studies document for the first time the antibody persistence up to 10 years after primary vaccination and a first booster with FSME-IMMUN. When analyzing all subjects who were enrolled into the 10 year followup, seropositivity rates approximately one month after the first booster as measured by NT were 100%, regardless of age. Seropositivity rates decreased to 96.7% (18–49 years), 92.2% (50–60 years), and 75% (>60 years) at 5 years after the first booster as measured by NT. At 7 years after the first booster, seropositivity rates were 92.7% (18–49 years), 82.4% (50–60 years), and 50% (>60 years) as measured by NT. Although the sample sizes are small in the older age groups, there is a trend of faster decline of antibody levels in the older age groups, similar to previous reports [15]. Data as measured by ELISA were comparable to that of the NT (Fig. 2). Data on minimum durations of protection and booster intervals of TBE vaccination are of great interest. A relatively low number of
subjects (49/315, 15.6%) required a booster vaccination during the follow-up period of the current investigation. After a completed primary series consisting of three vaccinations and one booster dose 3 years later, the proportion of subjects in the 18–49 and 50–60 year age groups who remained seropositive up to 5 years after the first booster remained high. This supports the currently recommended booster interval for subjects from 16 up to 60 years of age. At 7 years post first booster, the proportion of subjects left potentially unprotected by prolonging the booster interval beyond 5 years was 7% in the 18–49 years age group and 18% in the 50– 60 years age group. By 10 years, these proportions increased to 11% and 26% in the 18–49 years and 50–60 years age groups, respectively. Nonetheless, the study population consisted of healthy and immuno-competent subjects. An extension of the recommended booster intervals remains to be discussed; however an ample safety buffer should always be maintained [15]. The results of the current investigation also confirm the correctness of the current booster recommendations for subjects >60 years of age (i.e. 3 years booster interval), as less than 80% of these subjects were seropositive prior to the fourth tick season. Also, FSME-IMMUN vaccination in subjects who received the second booster (n = 47) was highly effective in increasing antibody levels, indicating the establishment of a strong immune memory. These data are consistent with other prospective studies demonstrating stable anti-TBE antibody levels for many years after multiple immunizations in most vaccinees [16–20]. Acknowledgements Scott Vuocolo, PhD (Pfizer) provided editorial assistance for the preparation of this manuscript. This study was sponsored by Pfizer Q. Jiang, L. Harper and W. Erber are employees of Pfizer, Inc. and may hold stock/stock options in the company. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2017.03. 059. References [1] Kaiser R. Tick-borne encephalitis. Infect Dis Clin N Am 2008;22(3):561–75. [2] Lindquist L, Vapalahti O. Tick-borne encephalitis. The Lancet 2008;371 (9627):1861–71. [3] Dobler G. Zoonotic tick-borne flaviviruses. Vet Microbiol 2010;140(3– 4):221–8. [4] Kollaritsch H, Paulke-Korinek M, Holzmann H, Hombach J, Bjorvatn B, Barrett A. Vaccines and vaccination against tick-borne encephalitis. Exp Rev Vaccin 2012;11(9):1103–19. [5] Kaiser R. The clinical and epidemiological profile of tick-borne encephalitis in southern Germany 1994–98: a prospective study of 656 patients. Brain 1999;122(Pt 11):2067–78. [6] Loew-Baselli A, Poellabauer EM, Pavlova BG, et al. Seropersistence of tickborne encephalitis antibodies, safety and booster response to FSME-IMMUN 0.5 ml in adults aged 18–67 years. Hum Vaccin 2009;5(8):551–6.
R. Konior et al. / Vaccine 35 (2017) 3607–3613 [7] Adner N, Leibl H, Enzersberger O, Kirgios M, Wahlberg T. Pharmacokinetics of human tick-borne encephalitis virus antibody levels after injection with human tick-borne encephalitis immunoglobulin, solvent/detergent treated, FSME-BULIN S/D in healthy volunteers. Scand J Infect Dis 2001;33(11):843–7. [8] Infectious Diseases and Poisonings in Poland in 2015. [9] Suss J, Klaus C, Gerstengarbe FW, Werner PC. What makes ticks tick? Climate change, ticks, and tick-borne diseases. J Travel Med 2008;15(1):39–45. [10] Kunz C. TBE vaccination and the Austrian experience. Vaccine 2003;21(Suppl. 1):S50–55. [11] Heinz FX, Holzmann H, Essl A, Kundi M. Field effectiveness of vaccination against tick-borne encephalitis. Vaccine 2007;25(43):7559–67. [12] Zavadska D, Anca I, André F, et al. Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group (CEVAG). Hum Vaccin Immunother 2013;9(2):362–74. [13] Jelinek T. TBE—update on vaccination recommendations for children, adolescents, and adults. Wien Med Wochenschr 2012;162(11):248–51. [14] Weinberger B, Keller M, Fischer KH, et al. Decreased antibody titers and booster responses in tick-borne encephalitis vaccinees aged 50–90 years. Vaccine 2010;28(20):3511–5.
3613
[15] Jílková E, Vejvalková P, Stiborová I, Skorkovsky´ J, Král V. Serological response to tick-borne encephalitis (TBE) vaccination in the elderly – results from an observational study. Exp. Opin Biol Ther 2009;9(7):797–803. [16] Rendi-Wagner P, Kundi M, Zent O, et al. Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation. Vaccine 2004;23(4):427–34. [17] Rendi-Wagner P, Paulke-Korinek M, Kundi M, Wiedermann U, Laaber B, Kollaritsch H. Antibody persistence following booster vaccination against tickborne encephalitis: 3-year post-booster follow-up. Vaccine 2007;25 (27):5097–101. [18] Rendi-Wagner P, Zent O, Jilg W, Plentz A, Beran J, Kollaritsch H. Persistence of antibodies after vaccination against tick-borne encephalitis. Int J Med Microbiol 2006;296(Suppl 40):202–7. [19] Paulke-Korinek M, Rendi-Wagner P, Kundi M, Laaber B, Wiedermann U, Kollaritsch H. Booster vaccinations against tick-borne encephalitis: 6 Years follow-up indicates long-term protection. Vaccine 2009;27(50):7027–30. [20] Plentz A, Jilg W, Schwarz TF, Kuhr HB, Zent O. Long-term persistence of tickborne encephalitis antibodies in adults 5 years after booster vaccination with Encepur Adults. Vaccine 2009;27(6):853–6.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Seropersistence of TBE virus antibodies 10 years after first booster vaccination and response to a second booster vaccination with FSMEIMMUN 0.5 mL in adults R. Konior a, J. Brzostek b, E.M. Poellabauer c, Q. Jiang d, L. Harper d,⇑, W. Erber e a
John Paul II Hospital, Krakow, Poland Debica, Poland Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria d Pfizer Inc, Collegeville, PA, USA e Pfizer Inc, Vienna, Austria b c
a r t i c l e
i n f o
Article history: Received 16 December 2016 Received in revised form 16 March 2017 Accepted 17 March 2017 Available online 22 May 2017 Keywords: TBE FSME Tick-borne Encepahlitis
a b s t r a c t Tick-borne encephalitis (TBE) is a viral disease that can have a severe acute clinical course and considerable long-term morbidity. As there is no causal treatment currently available for TBE, vaccination is the only way to combat the disease in endemic areas. The studies presented here were conducted to obtain prospective long-term TBE serum antibody persistence data of subjects up to 10 years after the first booster with FSME-IMMUN. This report presents the results of 2 follow-up studies in the same study population of 315 healthy adults. Blood was drawn to assess the seropersistence of TBE virus antibodies yearly, from 2–5 and 7–10 years after the first booster vaccination with FSME-IMMUN administered during a previous study. The timing of the second booster vaccination was dependent on the level of serum TBE antibodies observed during yearly follow-up serology observations. The current follow up showed that adult recipients were 84.9% seropositive 10 years after a 3 dose primary series and the first booster vaccination of FSME-IMMUN. Seropositivity rates were even higher (88.6%) in subjects below 50 years of age. ClinicalTrials.gov Identifier: NCT00503529. ClinicalTrials.gov Identifier: NCT01582698. Ó 2017 Published by Elsevier Ltd.
1. Introduction Tick-borne encephalitis (TBE) is a viral disease caused by the tick-borne encephalitis virus (TBEV; family Flaviviridae) that can have a severe acute clinical course, and lead to a high percentage of sequelae among survivors [1,2]. The disease is endemic over a vast area of Europe, Siberia, Russia, northern China and Japan [2]. The worldwide incidence of TBE is reported to be between 10,000 and 15,000 cases per year [3], though this number is likely an underestimation as notification of the disease is not mandatory in all countries. The disease rates of TBE have increased in recent years [4], likely due to changes in environmental factors, increased awareness, and/or intensified travel to endemic areas.
⇑ Corresponding author. E-mail address: [email protected] (L. Harper). http://dx.doi.org/10.1016/j.vaccine.2017.03.059 0264-410X/Ó 2017 Published by Elsevier Ltd.
In the unvaccinated, TBE can lead to significant long-term morbidity. In one large German study, 12% of patients affected required admission to intensive care and 5% of patients required assisted ventilation [5]. No specific treatment for tick-borne encephalitis exists; therefore prevention of the disease via vaccination is the best strategy. Active immunization has been successfully implemented in many European countries [4]. Vaccines currently in Ò Ò use include FSME-IMMUN (Pfizer Vaccines, USA), Encepur Ò (GlaxoSmithKline), EnceVir (Scientific Production Association Ò Microgen, Russia) and TBE Vaccine Moscow (Federal State Enterprise of Chumakov Institute of Poliomyelitis and Viral Encephalitis, Russian Academy of Medical Sciences, Russia). Both FSME-IMMUN and Encepur are available and approved for use in the European Union. However, there is a lack of large-scale longitudinal studies evaluating the duration of immunity after vaccination with FSME-IMMUN.
3608
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Results from a previous Phase 4 study in adults demonstrated that FSME-IMMUN was well tolerated as a booster vaccination [6], and suggested that it was sufficient for the first booster to be administered 3 years after the completion of the primary vaccination series. Here we present the results of two successive studies investigating TBE virus antibody seropersistence from 2–5 and 7– 10 years after the first FMSE-IMMUN booster vaccination. In the context of both studies the response to a second booster vaccination was also investigated. Results of these studies will contribute to a better understanding of antibody seropersistence in subjects of different ages who received the complete 3 dose primary vaccination series as well as the first booster. 2. Methods 2.1. Study design This report presents the results of 2 follow-up studies in the same study population of healthy adults. We investigated prospective long-term TBE serum antibody persistence data of subjects from 2 to 10 years (2–5 years follow-up; ClinicalTrials.gov Identifier: NCT00503529; 7–10 years follow-up ClinicalTrials.gov Identifier: NCT01582698) after the first booster with FSME-IMMUN (precursor study, Clinical trial number: NCT00161785). Blood samples were taken before the tick season yearly to assess the long term immune response. Subjects who may not have been protected against TBE for an entire further tick season received the 2nd booster dose and the booster response was analyzed at a final study visit 1-month later. Safety was not evaluated for the following reasons: (1) an excellent safety and tolerability profile has been established for the vaccine over decades of use and (2) a relatively small number of subjects received a booster vaccination during the follow-up. Nevertheless, adverse events (AEs) and serious adverse events (SAEs) that occurred after the booster vaccination in the 2–5 year follow-up and SAEs that occurred after the booster vaccination in the 7–10 year follow-up were to be reported. The timing of a second booster vaccination was dependent on the level of serum TBE antibodies as evaluated by enzyme-linked immunosorbent assay (ELISA, IMMUNOZYM FSME IgG; PROGEN Biotechnik GmbH) and neutralization test (NT, according to Adner et al. [7]) at yearly visits. Both assays are based upon the Neudoerfl virus strain used in the FSME-IMMUN vaccine. The accepted cut off for seropositivity was an ELISA concentration >126 VIE U/mL and an NT titer 10 [7]. Based on the yearly decline rate determined in previous studies [6], it was calculated that an NT titer >20 is necessary for a subject to be considered protected for an entire tick-season until the next blood draw 1 year later. Therefore, the criteria for a second booster vaccination in this study were defined as an NT titer 20 and/or an ELISA concentration 126 VIE U/mL after the first booster, as applicable. Recommendations as to whether or not to administer the booster vaccination were given by the sponsor on an individual basis. The data monitoring committee was consulted for their opinion in case of inconclusive serological data. Blood was drawn 21– 35 days after vaccination to assess the booster response. Subjects participated in the study for up to 8 years. 2.2. Study subjects In general, subjects were enrolled from low-endemic regions in southeastern Poland (incidence of 1/100000 for TBE) [8]. A total of 78/315 subjects (24.8%) reported a known tick bite(s) since the last blood draw visit during the study (supplementary Table S1). Subjects who received their first booster dose in the
precursor study (Clinical trial number: NCT00161785) were invited to participate in a subsequent yearly follow-up study to assess antibody persistence 2–5 years (as applicable, ClinicalTrials.gov Identifier: NCT00503529) after the first TBE booster vaccination and to receive a second booster vaccination if deemed necessary. Subsequently, subjects who did not receive the 2nd booster dose were followed yearly for TBE antibody persistence 7–10 years after TBE booster vaccination (ClinicalTrials.gov Identifier: NCT01582698) and were to receive a second booster vaccination if deemed necessary. Exclusion criteria included receiving any TBE vaccination (or other flavivirus vaccination) since their first booster vaccination with FSME-IMMUN outside study procedures, HIV positivity, or known or suspected drug or alcohol abuse. Any subject may have voluntarily withdrawn consent for continued participation and data collection. Discontinuation (ie, complete withdrawal from study participation) may have been due to dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by subject without notice or action). Additionally, the investigator and sponsor had the discretion to discontinue any subject from the study if, in their judgment, continued participation would pose an unacceptable risk for the subject. If a female subject became pregnant prior to the booster vaccination, the subject was not eligible for vaccination. All data collected up to withdrawal were used in the analysis. 2.3. Analysis population An all-enrolled population was defined as the Full Analysis Set, which consisted of all subjects enrolled into post-first booster follow-up. All subjects who consented were included in this population. Subject disposition, history of tick bites, AE, and demography was collected for this population. A per-protocol (PP) population included subjects who: (1.) were enrolled; (2.) met all inclusion/exclusion criteria at all visits; (3.) had valid and determinate assay results for the proposed analysis; (4.) had received no prohibited vaccines or treatment and; (5.) had no other important protocol deviations as determined by the sponsor’s global medical director. 2.4. Vaccines administered Subjects who were not considered protected against TBE for an entire further tick season as indicated by TBE serum antibody levels (NT titer 20 or ELISA concentration 126 VIE U/mL), were invited to receive a second booster vaccination, as applicable. FSME-IMMUN was provided in pre filled syringes containing 1 single dose of 0.5 mL each of 2–2.75 mg (target: 2.4 mg) TBE antigen. Vaccine was given by intramuscular injection into the right or left deltoid. 2.5. Measurements Blood was drawn to assess the seropersistence of TBE virus antibodies yearly between 25 and 7–10 years after the first booster vaccination with FSME-IMMUN. If a subject received their second booster vaccination, blood was drawn 21–35 days after booster vaccination to assess the booster response. TBE antibody response was determined by means of NT and ELISA. AEs and SAEs occurring after the booster vaccination in the 2– 5 year follow-up and SAEs occurring after a booster vaccination in the 7–10 year follow-up were recorded. 2.6. Statistical methodology Sample size was based on subject availability. Approximately 300 study participants were expected to provide information on
3609
R. Konior et al. / Vaccine 35 (2017) 3607–3613 Table 1 Disposition of subjects including both follow up studies (2–5 years and 7–10 years after 1st booster). Age Group (First booster day)
Enrolleda Completed 10-year follow-up Subjects who received booster dose Boostered before Month 34 Boostered at Month 36 Boostered at Month 48 Boostered at Month 60 Boostered at Month 84 Boostered at Month 108 Boostered at Month 120 Subjects who completed 10-year follow-up without booster dose Subjects who completed 5-year follow-up (study 690701 only) without booster dose Discontinued Subjects who did not return for booster dose No return at Month 108 Withdrawal by subject No return at Month 120 Withdrawal by subject Subjects who did not require booster dose No return at Month 34 Withdrawal by subject No return at Month 46 Lost to follow-up No return at Month 58 Withdrawal by subject Lost to follow-up No return at Month 94 Withdrawal by subject No return at Month 106 Withdrawal by subject No return at Month 118 Withdrawal by subject Reason for discontinuation Withdrawal by subject Lost to follow-up a
18–49 Years
50–60 Years
> 60 Years
Total
n (%)
n (%)
n (%)
n (%)
251 (100.0) 214 (85.3) 31 (12.4) 4 (1.6) 10 (4.0) 2 (0.8) 5 (2.0) 1 (0.4) 2 (0.8) 7 (2.8) 183 (72.9) 25 (10.0) 12 (4.8) 2 (0.8) 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 10 (4.0) 0 (0.0) 0 (0.0) 1 (0.4) 1 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.6) 4 (1.6) 1 (0.4) 1 (0.4) 4 (1.6) 4 (1.6)
54 (100.0) 44 (81.5) 13 (24.1) 2 (3.7) 4 (7.4) 0 (0.0) 2 (3.7) 2 (3.7) 0 (0.0) 3 (5.6) 31 (57.4) 5 (9.3) 5 (9.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (9.3) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 1 (1.9) 0 (0.0) 1 (1.9) 1 (1.9) 0 (0.0) 0 (0.0) 1 (1.9) 1 (1.9)
10 (100.0) 4 (40.0) 3 (30.0) 1 (10.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (10.0) 4 (40.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (20.0) 0 (0.0) 2 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
315 (100.0) 262 (83.2) 47 (14.9) 7 (2.2) 16 (5.1) 2 (0.6) 7 (2.2) 3 (1.0) 2 (0.6) 10 (3.2) 215 (68.3) 34 (10.8) 19 (6.0) 2 (0.6) 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 17 (5.4) 1 (0.3) 1 (0.3) 2 (0.6) 2 (0.6) 3 (1.0) 1 (0.3) 2 (0.6) 5 (1.6) 5 (1.6) 1 (0.3) 1 (0.3) 5 (1.6) 5 (1.6)
11 (4.4) 1 (0.4)
4 (7.4) 1 (1.9)
0 (0.0) 2 (20.0)
15 (4.8) 4 (1.3)
All subjects were consented and enrolled in precedent study 690701. The values in this row are used as the denominators for percentages.
Table 2 Demographics and baseline characteristics – per-protocol population. N (Total = 315)
%
Age at enrollment (years) 20 21–30 31–40 41–50 51–60 >60
0 69 75 101 55 15
(0.0%) (21.9%) (23.8%) (32.1%) (17.5%) (4.8%)
Sex Female Male
162 153
(51.4%) (48.6%)
BMI (kg/m2) <20 20–25 >25
7 166 142
(2.2%) (52.7%) (45.1%)
Abbreviations: BMI = body mass index.
antibody persistence 27 months after the first booster vaccination with FSME-IMMUN 0.5 mL. The primary immunogenicity endpoint was the seropositivity rate as measured by NT (NT 10) after the first booster vaccination, at each year, and after the second booster vaccination in this study. Secondary immunogenicity endpoints included the seropositivity rate as measured by ELISA (ELISA > 126 VIE U/mL), geometric mean antibody concentration (ELISA), and geometric mean titer (GMT) at each blood draw time
point, and geometric mean fold rise (GMFR) from before second booster to after the second booster vaccination. For subjects with antibody response results available at all time points (from 1-month after first booster dose in the precursor study until year 10 blood draw), the actual values were used in the analysis. For subjects who discontinued from the study or received the second booster dose before year 10, an extrapolated value from a regression model was used. Only subjects with antibody response results available at the first 3 time points have the extrapolated values. Subjects with a more than 4-fold increase in TBE antibody levels between successive visits were excluded from the regression analysis as this increase may have indicated a natural booster effect from contact with the TBE virus. First, the NT titers measured at each blood sampling time point (except the post-booster visit) were logarithmically transformed. These log transformed data were then used as the dependent variable, with days after first booster dose as the independent variable, to calculate the annual decline rate, using regression model for each subject. The slope from the model multiplied by 365 was considered as the estimated annual decline rate for each subject. Second, antibody levels after the first booster vaccination for subjects who had received a booster vaccination and for dropouts were extrapolated using the annual decline rate. Lastly, summary statistics on the seropositivity rate or geometric means as measured by NT were estimated by including the extrapolated serology values as well as those serology results at time points without booster or without withdrawals.
3610
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Seropositive rates as measured by NT were descriptively summarized at each blood sampling time point, along with the exact 2-sided 95% CI (or Clopper-Pearson confidence limit) for the proportion. NT titers measured at each blood sampling time point (including extrapolated from regression model) were logarithmically transformed for analysis and geometric mean neutralization titers (GMTs) were computed with 95% CI constructed by back transformation of the CIs for the logarithmical assay results using the Student t distribution. 3. Results A total of 315 subjects participated in follow-up study after first booster dose administration (Table 1). Of these 315 enrolled 18-49 years
subjects, 262 (83.2%) completed 10 years of follow-up and 19 subjects (6.0%) discontinued from the study. A total of 47 subjects (14.9%) received the second booster dose over the follow-up. Two (2) subjects required a second booster but did not return for the booster dose visit due to moving abroad. Among subjects aged 18–49 years, 31 subjects (12.4%) received a booster; aged 50–60, 13 subjects (24.1%) received a booster; and among subjects 60 years and above, 3 subjects (30%) received a booster. Slightly more female (51.4%) than male subjects (48.6%) were included in the immunogenicity and per protocol dataset (n = 315), with the largest percentage (32.1%) aged 41–50 years (range 21–70 years) (Table 2). Height and weight were normally distributed. Most subjects had a BMI of 20. 50-60 years
>60 years
100 90 80
Seroposivity (%)
70 60 50 40 30 20 10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0
Fig. 1. Seropositivity rates by NT (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster). 18-49 Years
50-60 Years
>60 Years
100 90 80
Seroposivity (%)
70 60 50 40 30 20 10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0
Fig. 2. Seropositivity rates by ELISA (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
3611
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Seropositivity rates for subjects included in the immunogenicity analysis set using extrapolated values based on annual decline rate as measured by NT are presented in Fig. 1 and supplementary Table S2. A total of 5 subjects (NT) and 9 subjects (ELISA) were excluded from the analysis of seropersistence due to a >4-fold increase of antibody levels within 2 consecutive visits. Seropositivity rates 4 weeks after the first booster (as measured by NT) were 100% for all age groups. At 3 years after the first booster, the seropositivity rates for all age groups remained 100%. At year 4, rates decreased to 97.6% (239/245), 92.2% (47/51), and 77.8% (7/9) for subjects aged 18–49 years, 50–60 years and >60 years, respectively. At year 5 these rates were 96.7% (237/245), 92.2% (47/51), and 75.0% (6/8), respectively. Seropositivity rates by NT continued to decrease from year 7 to year 10 for all subjects: at Year 7 rates were 92.7% (227/245), 82.4% (42/51), and 50.0% (4/8), at year 10 these rates were 88.6% (217/245), 74.5% (38/51), and 37.5% (3/8) for subjects aged 18 to 49 years, 50 to 60 years,
18-49 years
1000
and >60 years, respectively. Seropositivity rates as measured by the ELISA assay correlate well with the NT results and can be seen in Fig. 2. GMTs measured by NT for subjects included in this study using extrapolated values based on annual decline rate are presented in Fig. 3 and supplementary Table S3. GMTs dropped significantly between the first booster vaccination and year 2 for all age groups. GMTs decreased further until year 7 for all time points except year 3. There was a slight increase in GMTs from year 7 to year 8, and GMTs generally decreased from year 8 to year 10. As the sample size was smaller in the older age groups (50–60 years and >60 years), the CIs of the GMTs mostly overlapped; however, GMTs of antibody levels were numerically higher for younger adults compared with older adults. Geometric mean concentrations as measured by the ELISA assay correlate well with the NT results as illustrated by the similar slopes of the lines representing the different age groups in Fig. 4.
50-60 years
>60 years
Geometric Mean Titer
100
10
1
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
0.1
Fig. 3. GMTs measured by NT (extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
18-49 years
Geometric Mean Concentraon
10000
50-60 years
>60 years
1000
100
10
Year 10 (month 118)
Year 9 (month 106)
Year 8 (month 94)
Year 7 (month 82)
Year 5 (month 58)
Year 4 (month 46)
Year 3 (month 34)
Year 2 (month 27)
21-35 days aer 1st booster
1
Fig. 4. GMCs Measured by ELISA (Extrapolated) – per-protocol population including both follow-up studies (2–5 years and 7–10 years after 1st booster).
3612
R. Konior et al. / Vaccine 35 (2017) 3607–3613
Table 3 GMFRs from pre-2nd booster to post-2nd booster (measured by NT). Assay Age Group (Visit 1)
NT 18–49 Years 50–60 Years >60 Years
Prebooster
Post booster a
n
GM
(95% CI )
n
GM
(95% CIa)
n
GMFR
(95% CIa)
45 29 13 3
16.3 16.2 18.0 11.9
(14.48, 18.43) (14.06, 18.55) (13.39, 24.28) (7.82, 18.06)
47 31 13 3
190.5 178.2 232.4 160.0
(148.10, 244.92) (127.25, 249.50) (164.73, 327.91) (5.11, 5008.64)
45 29 13 3
12.4 12.1 12.9 13.5
(9.69, (8.71, (8.62, (0.53,
15.85) 16.74) 19.28) 342.45)
Abbreviations: GM = geometric mean; GMFR = geometric mean of fold increase; NT = neutralization test. a Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers, concentrations or the fold rises.
Except 2 subjects who did not return for their booster dose, all other subjects, whose antibody levels were below the protocol defined booster threshold (a titer 20 as measured by NT or a concentration 126 VIE U/mL as measured by ELISA) received a second booster dose, and regained seropositivity thereafter. GMTs and GMFRs from pre-booster to post-booster are presented in Table 3. For subjects who received a second booster, GMTs of antibody levels increased 12.1- to 13.5-fold. Safety assessment was not an endpoint in this study; however, any AE or SAE that occurred after a booster vaccination in the 2– 5 year follow-up and any SAE that occurred after the booster vaccination in the 7–10 year follow-up were to be reported. There were two subjects who reported 3 mild AEs after a booster vaccination in the 2–5 year follow-up; fatigue and injection site pain for one subject and malaise for the other. No vaccine-related SAEs were reported and no deaths occurred during the study.
4. Discussion As no specific therapy exists for TBE, vaccination is the only effective preventative measure for individual protection. In many European regions, a steady increase of TBE cases has been observed over the last 20–30 years leading to new additions to the list of countries considered to be endemic for TBE [9]. Conversely, rates of TBE cases in Austria have stayed relatively low due to high vaccine coverage secondary to the institution of a mass immunization program against the virus [10,11]. However, incidence rates in the non-vaccinated population remain similarly high as compared to the pre-vaccination era, indicating the necessity of a continuous level of protection for the individual vaccinee. A previous phase IV study [6] evaluated the seropersistence of TBE antibodies 2 and 3 years after the primary immunization course with FSME-IMMUN. It showed that the first booster three years after primary immunization induced an excellent immune response. A first booster interval of 3 years is generally recommended for people of all ages who are at risk, including the elderly [12–14]. Our present long term prospective follow-up studies document for the first time the antibody persistence up to 10 years after primary vaccination and a first booster with FSME-IMMUN. When analyzing all subjects who were enrolled into the 10 year followup, seropositivity rates approximately one month after the first booster as measured by NT were 100%, regardless of age. Seropositivity rates decreased to 96.7% (18–49 years), 92.2% (50–60 years), and 75% (>60 years) at 5 years after the first booster as measured by NT. At 7 years after the first booster, seropositivity rates were 92.7% (18–49 years), 82.4% (50–60 years), and 50% (>60 years) as measured by NT. Although the sample sizes are small in the older age groups, there is a trend of faster decline of antibody levels in the older age groups, similar to previous reports [15]. Data as measured by ELISA were comparable to that of the NT (Fig. 2). Data on minimum durations of protection and booster intervals of TBE vaccination are of great interest. A relatively low number of
subjects (49/315, 15.6%) required a booster vaccination during the follow-up period of the current investigation. After a completed primary series consisting of three vaccinations and one booster dose 3 years later, the proportion of subjects in the 18–49 and 50–60 year age groups who remained seropositive up to 5 years after the first booster remained high. This supports the currently recommended booster interval for subjects from 16 up to 60 years of age. At 7 years post first booster, the proportion of subjects left potentially unprotected by prolonging the booster interval beyond 5 years was 7% in the 18–49 years age group and 18% in the 50– 60 years age group. By 10 years, these proportions increased to 11% and 26% in the 18–49 years and 50–60 years age groups, respectively. Nonetheless, the study population consisted of healthy and immuno-competent subjects. An extension of the recommended booster intervals remains to be discussed; however an ample safety buffer should always be maintained [15]. The results of the current investigation also confirm the correctness of the current booster recommendations for subjects >60 years of age (i.e. 3 years booster interval), as less than 80% of these subjects were seropositive prior to the fourth tick season. Also, FSME-IMMUN vaccination in subjects who received the second booster (n = 47) was highly effective in increasing antibody levels, indicating the establishment of a strong immune memory. These data are consistent with other prospective studies demonstrating stable anti-TBE antibody levels for many years after multiple immunizations in most vaccinees [16–20]. Acknowledgements Scott Vuocolo, PhD (Pfizer) provided editorial assistance for the preparation of this manuscript. This study was sponsored by Pfizer Q. Jiang, L. Harper and W. Erber are employees of Pfizer, Inc. and may hold stock/stock options in the company. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2017.03. 059. References [1] Kaiser R. Tick-borne encephalitis. Infect Dis Clin N Am 2008;22(3):561–75. [2] Lindquist L, Vapalahti O. Tick-borne encephalitis. The Lancet 2008;371 (9627):1861–71. [3] Dobler G. Zoonotic tick-borne flaviviruses. Vet Microbiol 2010;140(3– 4):221–8. [4] Kollaritsch H, Paulke-Korinek M, Holzmann H, Hombach J, Bjorvatn B, Barrett A. Vaccines and vaccination against tick-borne encephalitis. Exp Rev Vaccin 2012;11(9):1103–19. [5] Kaiser R. The clinical and epidemiological profile of tick-borne encephalitis in southern Germany 1994–98: a prospective study of 656 patients. Brain 1999;122(Pt 11):2067–78. [6] Loew-Baselli A, Poellabauer EM, Pavlova BG, et al. Seropersistence of tickborne encephalitis antibodies, safety and booster response to FSME-IMMUN 0.5 ml in adults aged 18–67 years. Hum Vaccin 2009;5(8):551–6.
R. Konior et al. / Vaccine 35 (2017) 3607–3613 [7] Adner N, Leibl H, Enzersberger O, Kirgios M, Wahlberg T. Pharmacokinetics of human tick-borne encephalitis virus antibody levels after injection with human tick-borne encephalitis immunoglobulin, solvent/detergent treated, FSME-BULIN S/D in healthy volunteers. Scand J Infect Dis 2001;33(11):843–7. [8] Infectious Diseases and Poisonings in Poland in 2015. [9] Suss J, Klaus C, Gerstengarbe FW, Werner PC. What makes ticks tick? Climate change, ticks, and tick-borne diseases. J Travel Med 2008;15(1):39–45. [10] Kunz C. TBE vaccination and the Austrian experience. Vaccine 2003;21(Suppl. 1):S50–55. [11] Heinz FX, Holzmann H, Essl A, Kundi M. Field effectiveness of vaccination against tick-borne encephalitis. Vaccine 2007;25(43):7559–67. [12] Zavadska D, Anca I, André F, et al. Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group (CEVAG). Hum Vaccin Immunother 2013;9(2):362–74. [13] Jelinek T. TBE—update on vaccination recommendations for children, adolescents, and adults. Wien Med Wochenschr 2012;162(11):248–51. [14] Weinberger B, Keller M, Fischer KH, et al. Decreased antibody titers and booster responses in tick-borne encephalitis vaccinees aged 50–90 years. Vaccine 2010;28(20):3511–5.
3613
[15] Jílková E, Vejvalková P, Stiborová I, Skorkovsky´ J, Král V. Serological response to tick-borne encephalitis (TBE) vaccination in the elderly – results from an observational study. Exp. Opin Biol Ther 2009;9(7):797–803. [16] Rendi-Wagner P, Kundi M, Zent O, et al. Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation. Vaccine 2004;23(4):427–34. [17] Rendi-Wagner P, Paulke-Korinek M, Kundi M, Wiedermann U, Laaber B, Kollaritsch H. Antibody persistence following booster vaccination against tickborne encephalitis: 3-year post-booster follow-up. Vaccine 2007;25 (27):5097–101. [18] Rendi-Wagner P, Zent O, Jilg W, Plentz A, Beran J, Kollaritsch H. Persistence of antibodies after vaccination against tick-borne encephalitis. Int J Med Microbiol 2006;296(Suppl 40):202–7. [19] Paulke-Korinek M, Rendi-Wagner P, Kundi M, Laaber B, Wiedermann U, Kollaritsch H. Booster vaccinations against tick-borne encephalitis: 6 Years follow-up indicates long-term protection. Vaccine 2009;27(50):7027–30. [20] Plentz A, Jilg W, Schwarz TF, Kuhr HB, Zent O. Long-term persistence of tickborne encephalitis antibodies in adults 5 years after booster vaccination with Encepur Adults. Vaccine 2009;27(6):853–6.