Olaf Zent

Clinical evaluation of a polygeline-free tick-borne encephalitis vaccine for adolescents and adults.

OBJECTIVE To evaluate immunogenicity and safety of a polygeline-free tick-born encephalitis (TBE) vaccine in a clinical program. METHOD A total of 3118 subjects aged 12-76 years were enrolled in three clinical trials. The clinical studies were conducted in 15 centers in three European countries. Evidence of neutralizing TBE antibodies was used as surrogate parameter for efficacy assessment. RESULTS All subjects analyzed achieved levels of TBE antibodies postimmunization to fulfill the definition of seroconversion or a four-fold increase. The new TBE vaccine appeared to be well tolerated by subjects. Only very few febrile reactions, mainly 38.5 degrees C were reported. No serious or unexpected adverse events related to vaccination were reported. CONCLUSION These successful results in terms of both immunogenicity and safety indicate that the TBE vaccination with this polygeline-free TBE vaccine can be used safely in adolescents and adults.

Tick-borne encephalitis vaccines: past and present.

Vaccines to protect against tick-borne encephalitis (TBE) are produced by two manufacturers and are widely used in European and Asian countries, where TBE virus is endemic. General trends in vaccine development during recent decades and extensive postmarketing experience resulted in several modifications to their formulations and practical implications for use. Modifications were made to the production process, such as the change of the virus master bank from mouse brain to primary cells; to the excipients, especially the stabilizers and preservative; and to include formulations for children. Additionally, a rapid vaccination schedule has been developed for persons who require a fast onset of protection. Recent data from clinical studies and postmarketing surveillance indicate that both vaccines are safe, efficacious and interchangeable. Further (major) changes to formulation or alternative targets for vaccine development are not anticipated in the next 5 years. Recent serologic studies indicate that the persistence of protective immunity was longer than expected. Thus, recommendations for prolongation of TBE booster intervals have been made in several European countries, and a harmonization for booster recommendations is predicted within the European Union. Based on epidemiologic trends, the use of TBE vaccines will continue to increase in all age groups, including children.

Tick-borne encephalitis (TBE) trends in epidemiology and current and future management

Tick-borne encephalitis (TBE) is considered an international health issue, as the number of risk areas and reported cases across Europe, Russia, and parts of Asia continues to increase. The incidence of TBE has fluctuated considerably from year to year in many countries, but in the past decade the number of TBE cases has significantly increased in the Baltic states, the Czech Republic, and Germany, in addition to occurring in countries previously considered to be free from TBE, such as Denmark (specifically the main island of Zealand), France, and Italy. A number of factors have been suggested to explain the increase in incidence, including climate change, and increased travel and outdoor pursuits, placing people in increased contact with infected ticks. There is no causal treatment available once infected, but TBE can be effectively prevented by vaccination, for which several vaccines are widely available. Three vaccination schedules are available for immunization against TBE, and the recommendations for TBE vaccination vary considerably across the countries in which TBE foci are found. However, plans are in place to raise awareness of TBE and to standardize the vaccination programme across Europe, with the aim of reducing the number of future cases of TBE.

Long-term immunity after vaccination against tick-borne encephalitis with Encepur® using the rapid vaccination schedule

148 of 157 invited adult subjects who had participated in previous studies were enrolled in this extension study for evaluation of immunogenicity and safety of the second TBE booster immunization. All subjects had been previously immunized in studies with Chirons formerly marketed TBE vaccine (containing polygeline as the stabilizer) according to the rapid vaccination schedule (i.e. primary immunization on days 0, 7, 21 and first booster immunization at month 15). All subjects were administered the second booster with Chirons new TBE vaccine, which is free of protein-derived stabilizers, 36 months after the first booster vaccination applied at study month 15. Blood samples were taken prior to booster and 1 month later. In 145 out of 148 subjects, blood samples suitable for measurements of TBE antibodies (ELISA assay) were provided. Prior to second booster immunization with Chirons new TBE vaccine, TBE antibodies (GMTs) had remained at a high level and were far above the detection limit of the used ELISA test. All subjects were still seropositive prior to the second booster immunization. The second booster immunization resulted in a further increase of TBE antibodies. The booster vaccination with Chirons new TBE vaccine was well tolerated by all the vaccinees. Neither febrile post-immunization reactions nor unexpected adverse events or serious adverse events were reported. To summarize, these data clearly show that the TBE vaccination with this new TBE vaccine can be used safely to boost subjects pre-immunized with the former TBE vaccine formulation. Long-lasting immunity following this second TBE booster immunization can be concluded.

Protection against tick-borne encephalitis with a new vaccine formulation free of protein-derived stabilizers.

BACKGROUND Vaccination against tick-borne encephalitis (TBE) has been successfully employed for many years in TBE-endemic countries. Post-marketing experience gained from widespread use, however, prompted the development of improved TBE vaccines, the most modern versions of which do not contain the commonly used protein-derived stabilizers (human albumin or polygeline) of former vaccines. METHOD This article summarizes both the medical need for and clinical experience with a new TBE vaccine formulation (pediatric and adult versions). To this end, data from clinical trials and post-marketing experience are presented. The clinical database comprises immunogenicity and/or safety data of approximately 7,500 subjects ages 1 to 77 years who participated in eight clinical trials. The clinical trials were conducted at 69 centers in five European countries. Post-marketing experience includes safety data from passive pharmacovigilance systems in 18 countries where these vaccines have been licensed since 2001. RESULTS All subjects analyzed for immunogenicity achieved postimmunization levels of TBE antibodies that meet the definition of seroconversion or represent a fourfold increase. The pooled data of clinical trials revealed the expected rate of solicited local and systemic reactions. The majority of these transient postimmunization reactions were mild. Pharmacovigilance data confirm the high level of safety of these new TBE vaccines: only a common range of the side effects already noted for licensed TBE vaccines was reported. After the distribution of more than five million vaccine doses, no potential safety risk was noted. CONCLUSION Post-marketing experience supports results from clinical trials showing that these new TBE vaccines may safely be used for the vaccination of children, adolescents, and adults.

Long-term persistence of tick-borne encephalitis antibodies in adults 5 years after booster vaccination with Encepur® Adults

Tick-borne encephalitis (TBE) is a potentially serious disease, especially in adults. There is no treatment available for TBE; supportive therapy may help to ease symptoms of the disease. Vaccination is the most effective method of preventing TBE disease and is recommended for those who live, work, or travel in TBE-endemic areas. Regular booster vaccinations are recommended every 3-5 years to maintain protection. Evidence from recent clinical studies suggests that TBE antibodies persist at high levels for longer than the current recommended intervals for TBE booster vaccination. The aim of this study was to evaluate the long-term persistence of TBE antibodies in adults after primary vaccination using a rapid schedule and a first booster dose of Encepur Adults, an inactivated TBE vaccine. A total of 222 adults 19-51 years of age were invited for serological follow-up investigations 3 and 5 years following their first booster dose. High antibody titres were recorded throughout the follow-up period. Neutralization test (NT) titres > or =10 were noted in 99% of subjects 3 and 5 years after the first booster vaccination and 97% tested positive by enzyme-linked immunosorbent assay (ELISA). These results indicate that initially high levels of TBE antibodies following the first booster dose of the vaccine may lead to long-term persistence of TBE antibodies, confirming previous findings and suggesting it may be appropriate to extend the interval between booster doses from 3 to 5 years.

Tick-Borne Encephalitis (TBE) Vaccination in Children: Advantage of the Rapid Immunization Schedule (i.e., days 0, 7, 21)

Tick-borne encephalitis (TBE) is an important, vaccine-preventable arthropod-borne disease, causing severe illness in children too. In order to evaluate the immune response to different licensed primary immunization schedules, a total of 294 children aged 1 to 11 years of age were enrolled in a randomized, controlled, multi-center trial. The subjects were vaccinated with the pediatric formulation of a TBE vaccine (Encepur children) according to the conventional schedule (Group C; N=73, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M; N=139, vaccination on days 0, 21 and 300), or the rapid schedule (Group R; N=82, vaccination on Days 0, 7 and 21). Antibody titers as measured by neutralization-test (NT) and ELISA were determined on Days 0, 42, 180, 300, and 321. The demographic data of the study groups were similar. Most subjects (97%-100%) reached an NT titer of at least 1:10 on Day 42. On Day 42, the highest NT geometric mean titers (GMTs) were reached in Group C. In Group C and Group M, titers declined up to Day 300. Until Day 300, the highest NT-GMTs were maintained in Group R, notably without a decline compared to Day 42. Group M reached titers similar to Group R on Day 42, but these titers declined by 50% up to Day 180. Similar to the NT, on Day 42 highest geometric mean concentrations (GMCs) as measured by ELISA across all groups were reached in Group C. In all groups, titers declined until Day 300. On Day 300, GMC ELISA of Group R was higher compared to Group C and Group M. To conclude, the rapid immunization schedule in children not only provides fast protection but also leads to stable titers as measured by NT for at least 300 days after vaccination.

Long-term persistence of tick-borne encephalitis antibodies in children 5 years after first booster vaccination with Encepur® Children.

Tick-borne encephalitis (TBE) is a serious viral infection, which can lead to permanent neurological sequelae in children. The incidence of TBE disease is increasing in many European countries and is particularly pronounced in some regional populations. Vaccination is the most effective method for preventing TBE disease and is recommended for all those living and working in TBE-endemic areas. Encepur Children is licensed for TBE vaccination in children 1-11 years of age. Following primary vaccination, booster vaccinations are recommended; however, the optimal timing for booster vaccination of children is not known. The aim of this study was to assess the persistence of TBE antibodies in children at 3 and 5 years after their first booster vaccination with Encepur Children and to re-evaluate booster vaccination recommendations. Children 1-11 years of age (n=335) who received primary TBE vaccination according to the rapid schedule (Days 0, 7, and 21) in a previous study received a booster vaccination 12-18 months later, and were invited for follow-up at 3 and 5 years post-booster. TBE antibodies were measured using a virus neutralization test (NT; in-house, Novartis Vaccines) and also using anti-TBE IgG ELISA (Enzygnost, Siemens, Germany). In this analysis, 275 of 278 (99%) subjects and all 190 (100%) subjects who completed the follow-up at 3 and 5 years, respectively, had NT titres > or = 10. Likewise, all 275 of 278 (99%) and 188 of 190 (99%) subjects tested positive by ELISA at 3 and 5 years after the booster vaccination, respectively. Based on serological data, the interval for subsequent booster vaccinations with Encepur Children can be extended from 3 to 5 years after receiving primary vaccination and a first booster vaccination 12-18 months later.

Protection against tick-borne encephalitis (TBE) for people living in and travelling to TBE-endemic areas.

Once considered a local health issue confined to certain regions in Russia and Central and Eastern Europe, tick-borne encephalitis (TBE) is now considered an international health concern, and the most important and widespread viral disease transmitted by ticks in Europe. The number of reported TBE cases continues to increase in many endemic regions, and new foci have been identified. Increases in travel, access to high-risk areas, and the pursuit of leisure activities within TBE-endemic areas are placing more people at risk of TBE. Travellers from non-endemic regions are often unaware of the risk of acquiring TBE and therefore many travellers are not protected against TBE. Active immunization is the most effective way to avoid TBE and its potentially life-threatening sequelae. After a tick bite, no post-exposure treatment including active/passive vaccination is available or recommended in the immunologically naive patient. Available vaccines have undergone a series of modifications and improvement in both composition (with special formulations for children) and schedules to further enhance the safety of immunization and to meet the needs of vaccinees. Efforts to develop internationally recognized recommendations for TBE vaccination for travellers are underway.

TBE booster immunization in adults--first experience with a new tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer.

A total of 222 adult subjects, all of whom received primary immunization according to the rapid immunization schedule in a preceding clinical trial with either a new (i.e. polygeline free) or formerly licensed (i.e. polygeline containing) TBE vaccine were invited for extension studies. The subjects received the first booster immunization with the new TBE vaccine at 12 to 18 months after primary immunization. Subsequently, a total of 191 of the 222 subjects could be enrolled in a serological follow-up one year after the booster immunization. Neutralizing TBE antibody titers were determined prior to, 21 days after and approximately 12 months after booster immunization. Prior to first booster immunization, TBE antibodies (GMTs) had remained on a high level and were far above the detection limit of the neutralization test used. All subjects of the per protocol population who were primarily immunized with the new TBE vaccine formulation and all but one subject of the control group were still seropositive prior to the booster. All subjects showed a sharp increase of TBE antibodies following the booster immunization. Within the 12 months follow-up period, neutralizing TBE antibody titers remained on a high level. The booster vaccination was well tolerated by the subjects. Only very few febrile reactions (< 1%) none higher than 38.5 degrees C were reported. No serious or unexpected adverse events related to vaccination were reported. These successful results in terms of both immunogenicity and safety indicate that TBE vaccination with this new TBE vaccine can be used safely in adults. A long lasting immunity can be concluded from the strong immune response following the booster immunization.