Smell impairment after tick-borne encephalitis vaccination: Case report

We present a case of hyposmia following administration of a tick-borne encephalitis (TBE) vaccine. The olfactory impairment did not recover during 1-year follow up. In the literature, there is no report of smell deterioration after vaccination against TBE. Physicians should be aware of this rare neurological complication.     

Antibody response following administration of two paediatric tick-borne encephalitis vaccines using two different vaccination schedules

Two paediatric tick-borne encephalitis vaccines, Encepur Children and FSME-IMMUN Junior, are used widely in Europe. This study compared the immunogenicity and safety of both vaccines, administered using the conventional (Days 0, 28, and 300) or accelerated (Days 0, 14, and 300) schedule and evaluated whether a third dose of Encepur Children can complete a primary vaccination course initiated with FSME-IMMUN Junior. A total of 334 children 1 to < 11 years of age were enrolled in this Phase IV randomized, controlled, single-blind, multi-centre trial. All subjects, irrespective of study arm, received Encepur Children as the third dose on Day 300. The percentage of subjects with antibody titres > or = 10, as determined by neutralization test (NT), was assessed and local and systemic reactions were monitored and solicited. Within both the conventional and accelerated schedules, the proportion of subjects achieving an NT > or = 10 was higher in the group that received Encepur Children, compared with the group that received FSME-IMMUN Junior, at Days 42 and 300 (conventional schedule Day 300, P < 0.001 Encepur Children versus FSME-IMMUN Junior; accelerated schedule Days 42 and 300, P<0.001 Encepur Children versus FSME-IMMUN Junior). The third dose of Encepur Children led to a substantial increase in the proportion of subjects in the FSME-IMMUN Junior groups achieving NT > or = 10. Overall, >95% of all children achieved NT > or = 10, on completion of the primary vaccination course. Encepur Children provides an immune response, measured by neutralizing TBE antibodies, that is superior to FSME-IMMUN Junior and can successfully be used to complete a primary vaccination course initiated with FSME-IMMUN Junior. Both vaccines were well tolerated, with comparable safety profiles; no vaccine-related serious adverse events were reported.     

High burden of tick-borne encephalitis in Slovenia--challenge for vaccination policy

Slovenia is one of the countries with the highest reported incidence rates of tick-borne encephalitis (TBE). Vaccination uptake is low, estimated to be 12.4%. TBE surveillance data for the last 20 years were analysed. Though nearly all of Slovenia is endemic for TBE with national yearly incidence rates up to 26.7/100,000, we showed that two regions (Gorenjska and Koroška) were much more affected than other seven regions, with annual incidence rates up to 57.2/100,000 and 76.9/100,000 population, respectively. In the last decade, there was a shift in the age distribution of reported TBE cases to the older age groups, which resulted in the highest age-specific incidence rates nationally in 55-64 age group (up to 33.4/100,000 in 2006). To reduce this high burden of TBE, ideally the whole population of Slovenia should be offered free of charge vaccination against TBE. Alternatively, in view of limited resources available, sensible approach would be increasing vaccination coverage of the general population using social marketing and increasing TBE awareness, and in addition, offering free of charge vaccination to the most affected groups. The following priority target groups should be considered to be prospectively covered with free of charge vaccination: (1) 45-69 years old individuals in the two most affected regions (Gorenjska, Koroška), (2) the remaining age groups in the two most affected regions, (3) 45-69 years old individuals in the region with the next highest TBE incidence rates (Ljubljana), and (4) individuals 45-69 years old in all remaining Slovenian regions.     

Cost-effectiveness of tick-borne encephalitis vaccination in Slovenian adults

Background

Slovenia is an endemic country with a high incidence rate of tick-borne encephalitis (TBE) and low vaccination coverage. TBE causes high costs for the health care insurances as well as the society due to hospitalization and frequent long term or permanent neurological sequelae. Vaccination is effective and a safe prophylaxis against TBE.

Objective

The purpose of this study was to evaluate the incremental cost-effectiveness ratio (ICER) between vaccination and no vaccination in Slovenia. The results are shown as cost per quality-adjusted life year (QALY) gained from the view of the health care payer and the society.

Methods

Based on the natural course of the disease, the Markov model was used for comparing the economic and health outcomes of vaccinated and unvaccinated groups from 18 to 80 years of age.

Results

The incremental cost-effectiveness ratio from the current Slovenian vaccination programme for FSME-Immun^® compared to no vaccination amounts to €15,128 per QALY gained and for Encepur^® €20,099 per QALY gained from the view of the health care payer. From the view of the society vaccination is cost saving, mainly due to avoiding the high indirect costs.

Conclusions

According to the cost-effectiveness threshold as proposed by the Slovenian Health Council, the current Slovenian vaccination programme against TBE is cost-effective from the health care payer's perspective and also economical from the society's perspective.     

Chimeric antibodies against tick-borne encephalitis virus

Two chimeric antibodies (ch) 13D6 and 10C2 against the glycoprotein E of tick-borne encephalitis virus (TBEV) were constructed by fusing variable regions of murine monoclonal antibodies (Mabs) 13D6 and 10C2 to human constant regions. Monovalent analogues of these antibodies in format of single-chain antibodies (scFv or sc) were developed, as well. The ch13D6, ch10C2, sc13D6 and sc10C2 exhibited binding characteristics similar to parental Mabs. Only the ch13D6 and sc13D6 were able to neutralize TBEV infectivity in vitro. The in vitro neutralization provided by ch13D6 suggests that this antibody can be further developed into a potent prophylaxis and therapy for tick-borne encephalitis (TBE) infection.     

Recombinant chimeric Japanese encephalitis virus/tick-borne encephalitis virus is attenuated and protective in mice

Tick-borne encephalitis virus (TBEV) represents one of the most dangerous human pathogens circulating in Europe and East Asia. No effective treatment for TBEV infection currently exists, and vaccination is the primary preventive measure. Although several inactivated vaccines have been licensed, the development of novel vaccines against TBEV remains a high priority in disease-endemic countries. In the present study, a live chimeric recombinant TBEV (ChinTBEV) was created by substituting the major structural genes of TBEV for the corresponding regions of Japanese encephalitis virus (JEV) live vaccine strain SA14-14-2. The resulting chimera had a small-plaque phenotype, replicated efficiently in both mammalian and mosquito cells. The preliminary data from in vitro passaging indicated the potential for stability of ChinTBEV. ChinTBEV also exhibited significantly attenuated neuroinvasiveness in mice upon either intraperitoneal or subcutaneous inoculation in comparison with its parental TBEV. Importantly, a single immunisation with ChinTBEV elicited TBEV-specific IgG and neutralising antibody responses in a dose-dependent manner, providing significant protection against lethal TBEV challenge in mice. Taken together, the results of this proof-of-concept study indicate that ChinTBEV can be further developed as a potential vaccine candidate against TBEV infection. Moreover, the construction of this type of flavivirus chimera using a JEV vaccine strain as the genetic backbone represents a universal vaccine approach.     

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

Long-term vaccination programs are recommended for individuals living in regions endemic for tick-borne 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.     

中国蜱传脑炎研究进展

蜱传脑炎(tick-borne encephalitis)是经蜱传播的由蜱传脑炎病毒(TBEV)引起的急性重症神经系统疾病.我国于1943年发现该病,1952年从患者及蜱中分离到蜱传脑炎病毒[1],并于东北、西北、西南等地区陆续发现多个自然疫源地[2].该病临床症状重,多伴有后遗症,病死率高,曾为我国法定职业传染病之一[3].近年来,由于地球气候变暖,使该病疫源地传播媒介活动季节延长、活动区域扩大,进而使蜱传脑炎有扩大流行的趋势[4].本文是对我国近年来开展蜱传脑炎相关工作的综述.     

Dermacentor reticulatus is a vector of tick-borne encephalitis virus

Tick-borne encephalitis virus (TBEV; family Flaviviridae) is the most medically important tick-borne virus in Europe and Asia. Ixodes ricinus and I. persulcatus ticks are considered to be the main vector ticks of TBEV in nature due to their specific ecological associations with the vertebrate hosts. Nevertheless, recent TBEV prevalence studies in ticks suggest that Dermacentor reticulatus ticks might play a relevant role in the maintenance of TBEV in nature. The goal of this study was to evaluate the vector competency of D. reticulatus for TBEV through experimental tick infections and comparative in vivo transmission studies involving D. reticulatus and I. ricinus ticks.We observed that after a transcoxal micro-capillary inoculation, adult female D. reticulatus ticks efficiently replicated TBEV during the observed period of 21 days. The mean virus load reached up to 2.5 × 10⁵ gene copies and 6.4 × 10⁴ plaque forming units per tick. The infected D. reticulatus ticks were able to transmit the virus to mice. The course of infection in mice was comparable to the infection after a tick bite by I. ricinus while the virus spread and clearance was slightly faster. Moreover, D. reticulatus ticks were capable of tick-to-tick non-viraemic transmission of TBEV to the Haemaphysalis inermis nymphs during co-feeding on the same animal. The co-feeding transmission efficiency was overall slightly lower (up to 54 %) in comparison with I. ricinus (up to 94 %) and peaked 1 day later, at day 3.In conclusion, our study demonstrated that D. reticulatus is a biologically effective vector of TBEV. In line with the recent reports of its high TBEV prevalence in nature, our data indicate that in some endemic foci, D. reticulatus might be an underrecognized TBEV vector which contributes to the expansion of the TBEV endemic areas.     

A campaign to increase the vaccination rate in a highly endemic tick-borne encephalitis region of Slovenia

Slovenia is one of the countries with the highest incidence of thick-borne encephalitis (TBE) (13.5/100,000) and has one of the lowest immunisation rates (3.1%). Gorenjska (approximately 10% Slovene inhabitants) is a region of Slovenia with the highest incidence (30/100,000). The Institute of Public Health Kranj in collaboration with Lions club Brnik and mayors of the municipalities initiated a campaign aimed to improve the vaccination rate.     

蜱传脑炎研究进展

蜱传脑炎又名森林脑炎是由蜱传脑炎病毒引起,经蜱传播的以中枢神经系统病变为主要特征的急性传染性疾病,病死率高达10%～20%,是近年来病毒学专家研究的重点和难点。本文从流行病学特点、发病机制及临床表现、转归、诊断、治疗等对蜱传脑炎进行综合性论述,为该病的预防和治疗策略的制定提供相应的理论依据。     

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.     

Clusteron structure of tick-borne encephalitis virus populations

Tick-borne encephalitis is a natural focal transmissible zooanthroponosis. The causative agent of the disease is a tick-borne encephalitis virus (TBEV) belonging to the genus Flavivirus of the family Flaviviridae and is widespread in Eurasia. Current TBEV classification based on molecular genetic data comprises three phylogenetically separate subtypes: Far Eastern, European and Siberian (TBEV-Sib). Further differentiation of TBEV isn’t developed, making it difficult to investigate the origins, distribution and evolution of the virus. In the present study we determined the nucleotide sequence of the gene E fragment for 282 TBEV-Sib isolates from Ixodes persulcatus ticks or their pools from various natural foci in Russia. Analysis of these sequences and sequences obtained from the GenBank database (more than 600), made it possible to cluster TBEV-Sib strains by identical amino acid sequences of a glycoprotein E fragment. In total, 18 groups were identified (from 3 to 285 strains in the group). It was shown that TBEV strains belonging to the same group are phylogenetically related and have a territorial attachment showing either a local or a corridor type distribution. These groups were named as clusterons showed to be the smallest unit of TBEV classification. The grouping of TBEV strains allows characterization of endemic areas both in quantitative and qualitative composition of the clusterons. The approach could be successfully used to record and monitor the TBEV populations.     

Five year follow-up after primary vaccination against tick-borne encephalitis in children

BackgroundA first tick-borne encephalitis (TBE) vaccine booster in children is currently suggested 3 years after completing either a conventional (doses on Days 0, 28 and 300) or accelerated conventional (doses on Days 0, 14 and 300) TBE immunization schedule. This recommendation, however, may not be appropriate in cases where different TBE vaccines have been used interchangeably during the primary immunization series.MethodsTo provide robust data to better inform such recommendations, TBE antibody persistence was evaluated after 3–5 years in four groups of children (aged 5–15 years): two groups previously primed with three doses of Encepur^® Children (conventional/accelerated conventional schedule); and two groups previously primed with two doses of FSME-IMMUN^® followed by a third dose of Encepur^® Children (conventional/accelerated conventional schedule). Immunogenicity was evaluated using neutralization (NT) assays based on both vaccine antigens as well as on the Enzyme Linked Immunosorbent Assay (ELISA).ResultsIn the two Encepur^® Children groups (full series), protective NT titers of ≥10 were detected in 98–100% of children up to 5 years after their last primary vaccination, irrespective of schedule. In contrast, only 65–70% subjects in the FSME-IMMUN^® Junior groups (mixed series) displayed NT titers ≥10 after 3 years. Thus, due to lower probability of achieving/maintaining long-term protective antibody levels (recently defined by the World Health Organization as an NT titer ≥10) after this time point, both FSME-IMMUN Junior groups were discontinued.ConclusionA strong antibody response persists for at least 5 years after full primary vaccination with Encepur^® Children. The study thus provides support for extending the time interval for a first booster dose after primary vaccination (conventional/accelerated conventional schedule) with Encepur^® Children from 3 to 5 years.     

Antibody dynamics after tick-borne encephalitis and measles-mumps-rubella vaccination in children post early thymectomy

Thymectomized patients (TP) showed a delayed humoral immune response to tick-borne-encephalitis-virus (TBEV) vaccination, which served as a neo-antigen. From the previously published cohort, the TBEV-specific IgG concentrations and avidities were analyzed in 17 TP compared to 30 non-thymectomized healthy controls (HC) 220 weeks after the first TBE vaccination to identify patients with waning antibodies. Only in HC, increase of avidity was significant between 8 and 220 weeks (p<0.001), whereas TP showed a lower avidity maturation at week 48 (p<0.05). Cytomegalovirus (CMV) seropositivity at vaccination did not influence the humoral immune response. The ability of TP to maintain measles, mumps and rubella (MMR)-specific antibodies at least 8 years post (MMR) vaccination was evaluated in the serum samples of TP, retrospectively. Although all TP had MMR vaccination at least 6 months after thymectomy, TP showed no significant difference regarding MMR-specific IgG concentrations or avidities compared to HC. Regarding TBE vaccination, the data confirmed the previous observation of a delayed primary immune response in TP to TBE vaccine and also revealed an altered memory priming by paucity of high-avidity antibodies.     

A protective chimeric antibody to tick-borne encephalitis virus

The efficiency of several mouse monoclonal antibodies (mAbs) specific to the tick-borne encephalitis virus (TBEV) glycoprotein E in post-exposure prophylaxis was assessed, and mAb14D5 was shown to be the most active of all those studied. It was proven that the hybridoma cell line 14D5 produced one immunoglobulin H chain and two L chains. They were used to construct chimeric antibodies ch14D5a and ch14D5b, the affinity constants of which were 2.6 × 10¹⁰ M⁻¹ and 1.0 × 10⁷ M⁻¹, respectively, according to the SPR-based ProteOn biosensor assay. The neutralization index (IC₅₀) of ch14D5a was 0.04 μg/ml in the focus reduction neutralization test. In in vivo experiments, ch14D5a at a dose of 10 μg/mouse resulted in a 100% survival of the mice infected with 240 LD₅₀ of TBEV. This chimeric antibody is promising for further development of prevention and therapeutic drugs against TBEV.     

Predicting tick-borne encephalitis using Google Trends

Data generated through public Internet searching offers a promising alternative source of information for monitoring and forecasting of infectious disease. Here future cases of tick-borne encephalitis (TBE) were predicted using traditional weekly case reports, both with and without Google Trends data (GTD). Data on the weekly number of acute, confirmed TBE cases in Germany were obtained from the Robert Koch Institute. Data relating to the volume of Internet searching on TBE was downloaded from the Google Trends website. Data were split into training and validation parts. A SARIMA (0,1,1) (1,1,1) [52] model was used to describe the weekly TBE case number time series. Google Trends Data was used as an external regressor in a second, as optimal identified SARIMA (4,1,1) (1,1,1) [52] model. Predictions for the number of future cases were made with both models and compared with the validation dataset. GTD showed a significant correlation with reported weekly case numbers of TBE (p < 0.0001). A comparison of forecasted values with reported ones resulted in an RMSE (residual mean squared error) of 0.71 for the model without Google search values, and an RMSE of 0.70 for the Google Trends values enhanced model. However, difference between predictive performances was not significant (Diebold Mariano test, p-value = 0.14).     

Reliable surveillance of tick-borne encephalitis in European countries is necessary to improve the quality of vaccine recommendations

In July-November 2009, 26 European Union (EU) Member States (MSs), Norway and Iceland, participated in a survey seeking information on national tick-borne encephalitis (TBE) vaccination recommendations. Information on TBE surveillance, methods used to ascertain endemic areas, vaccination recommendations, vaccine coverage and methods of monitoring of vaccine coverage were obtained. Sixteen countries (57%) reported presence of TBE endemic areas on their territory. Vaccination against TBE was recommended for the general population in 8 (28%) countries, for occupational risk groups - in 13 (46%) countries, and for tourists going abroad - in 22 (78%) countries. Although vaccination recommendations for country residents, and for tourists always referred to endemic areas, there was no uniform, standardized method used to define endemic areas. For this reason, clear recommendations for tourists need to be developed, and standardized surveillance directed to efficient assessment of TBE risk need to be implemented in European countries.     

Vaccines against tick-borne encephalitis: WHO position paper--recommendations

This article presents the WHO recommendations on the use of vaccines against tick-borne encephalitis excerpted from the recently published Vaccines against tick-borne encephalitis: WHO position paper. This is the first WHO position paper on the use of tick-borne encephalitis. It was published in the Weekly Epidemiological Record in June 2011. In this paper, footnotes provide a limited number of core references including references to grading tables that assess the quality of scientific evidence for a few key conclusions; a more comprehensive list of references is offered in the Background document on vaccines and vaccination against tick-borne encephalitis available at http://www.who.int/immunization/sage/6_TBE_backgr_18_Mar_net_apr_2011.pdf.In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2011 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html.     

Vaccine failures after active immunisation against tick-borne encephalitis

Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly.