Volume 30, Issue 6,
1 February 2012
, Pages 1165-1169
Author links open overlay panel, , , , , , ,
Tick-borne encephalitis virus (TBEV) is a flavivirus of wide geographic distribution and the causative agent of tick-borne encephalitis (TBE), an infection of the central nervous system. TBE has the highest incidence rate in Russia, where locally produced as well as Western European vaccines for the prevention of TBE are available. The Western European vaccines are based on TBE viruses that belong to the European subtype, while the Russian vaccines are based on Far Eastern subtype viruses. The question of to which extent vaccination with a vaccine based on the European subtype is effective in protecting against the heterologous Far Eastern virus subtype – and vice versa – has not been answered conclusively. Here we immunized mice with TBE vaccines based on European and Far Eastern subtype viruses, and used an unbiased hybrid virus test system to determine cross-neutralizing antibody titers and cross-protective efficacy. All vaccines tested elicited cross-protective responses against the heterologous strains, similar to those induced against the respective homologous vaccine strains. These data, therefore, fully support the use of TBE vaccines in geographic regions where virus subtypes heterologous to the vaccine strains are prevalent.
► Use of an unbiased test system for quantitative comparison of TBE vaccines. ► Efficacy against TBE viruses of Far Eastern and European suptypes was tested. ► Comparable neutralization titers induced by different vaccines in mouse model. ► Comparable protection from disease induced by different vaccines in mouse model. ► These data indicate equal protection provided by different vaccines tested.
Tick-borne encephalitis virus (TBEV) is a major human pathogenic flavivirus that is endemic in most European countries and in large parts of Central and Eastern Asia with the majority of tick-borne encephalitis (TBE) – a central nervous system infection – cases being reported from Russia , , , , . The TBEV genome is comprised of a single stranded RNA with one open reading frame that encodes three structural proteins: the core protein (C), the precursor of the membrane protein (prM) and the envelope protein (E) which is the major target of neutralizing antibodies against TBEV. Genetic analysis of a number of TBEV strains has revealed the existence of three lineages designated European, Siberian and Far Eastern. Within these genetic subtypes the variability of E at the amino acid level is below 2% and between the subtypes it is between 4 and 6% , , . All subtypes are transmitted by ticks, with Ixodes ricinus as the principal vector for the European subtypes, while the Asian viruses are mainly distributed by Ixodes persulcatus , , . In some regions, like the Northeastern parts of Europe, vector distribution areas overlap and TBEV subtypes can co-circulate .
TBE, while a serious and potentially fatal disease, is preventable by vaccination. The most successful vaccination campaign has been reported from Austria, using the vaccine FSME-IMMUN (Baxter BioScience, Vienna, Austria) that is based on the European lineage prototype TBEV strain Neudoerfl (Nd), which has resulted in a remarkable decrease in the incidence of TBE cases , . Despite the proven field effectiveness of TBE vaccination , vaccination rates in other European countries are significantly lower than in Austria. As a consequence, about 3000 hospitalized cases with a mortality rate of around 2% are reported throughout Western Europe annually . With an average of 5500 reported cases per year and peaks of 10,000 confirmed cases in some years, Russia has the highest incidence of TBE cases worldwide , , . In addition it has been speculated that the Far Eastern TBEV strains that circulate in Asia and Russia might be more pathogenic than their European counterparts, with mortality rates of up to 40% reported , , , . Besides vaccines based on the European TBEV subtype, for which adult and pediatric formulations are available, there are two locally manufactured TBE vaccines currently available in Russia: the IPVE vaccine (M.P. Chumakov Institute of Poliomyelitis and Viral Encephalitides of the Russian Academy of Medical Sciences; Moscow, Russia) and EnceVir (Microgen; Tomsk, Russia). All TBE vaccines contain formalin-inactivated TBE viruses derived from chicken embryo cells (CEC), with FSME-IMMUN based on the European subtype prototype strain Nd, while IPVE contains TBEV strain Sofjin that is the designated Far Eastern prototype strain and EnceVir contains the Sofjin-like Far Eastern subtype isolate 205 , .
The induction of cross-neutralizing antibody levels in humans against TBEV strains of the Far Eastern subtype has been demonstrated with all marketed TBE vaccines , , and has been extended against all geographic subtypes for FSME-IMMUN . While, for TBEV, neutralizing antibodies are understood to correlate with protection , , the question of whether Western European and Russian TBE vaccines may be more effectively protective against the specific TBEV subtype contained in the respective products is still open. In order to investigate whether a Western European vaccine is as effective in protecting against the virus subtype contained in the Russian vaccines – and vice versa – FSME-IMMUN was compared to IPVE and EnceVir with respect to their immunogenicity and protective efficacy in a mouse model. Vaccination-induced cross-protection against different TBEV subtypes in mice has previously been demonstrated with Western European TBE vaccines , , , . In the current study, however, highly standardized conditions were ensured for the first time by the determination of vaccination-induced neutralizing antibody titers in mice with a recently reported test platform that utilizes hybrid viruses that consist of a consensus backbone and encode the surface exposed structural proteins (prM and E) of TBEV prototype strains Nd or Sofjin, respectively . These specific hybrid viruses were further used to challenge mice for the evaluation of vaccination-induced cross-protection.
Mice immunization and challenge experiments
All animal experiments were conducted in duplicate and in compliance with the Austrian Animal Experiments Act (No. 501/1989). Groups of six female, adult Balb/c mice from Charles River Laboratories received two subcutaneous administrations of either FSME-IMMUN, EnceVir or IPVE, four weeks apart in the neck fold (first dose) or the knee fold (second dose) using a 25G, 26mm needle (ISO6009). Mock-treated were immunized with PBS with the same schedule. Two weeks after the second immunization, mice
Antibody response to TBE vaccination in mice
To compare the immunogenicity of the TBE vaccines, groups of mice received injections of different dilutions of either FSME-IMMUN, EnceVir or IPVE and pooled post-immunization sera were tested in μNT assays. Each vaccine was investigated in two independent experiments. After two immunizations, measureable NT titers against either subtype virus were induced by IPVE only when pre-diluted 1:3.16 or 1:10, whereas vaccination with FSME-IMMUN and EnceVir resulted in detectable neutralizing antibody
Active immunization is currently the only widely available and approved way of prevention of tick-borne encephalitis disease in humans. While in Russia, an immune globuline concentrate against TBEV is still in occasional use as pre- and postexposure prophylaxis, this TBE immune globuline is no longer available as antiviral therapy option in almost all Western European countries. The global spread of different TBE virus subtypes requires vaccines that induce a strong cross-protective immune
We thank Tanja Linzer, Angela Huschka and Helmut Schmidt for excellent technical assistance, Daniel Portsmouth for critically reading the manuscript, Reinhard Ilk for help with statistics, Elif Uzuner and Sergey Lvov for translations and Helga Savidis-Dacho and team for conduct of animal experiments.
Contributors: RF, KKO, PNB and TRK were responsible for the concept and design of the study. RF, KKO, YH, KJ, AT and LPB were responsible for data acquisition, analysis and interpretation. RF wrote
- P.N. Barrett et al.
Tick-borne encephalitis vaccines
- H. Holzmann et al.
Molecular epidemiology of tick-borne encephalitis virus: cross-protection between European and Far Eastern subtypes
- D. Hayasaka et al.
Evaluation of European tick-borne encephalitis virus vaccine against recent Siberain and far-eastern subtype strains
- T.S. Gritsun et al.
- G.N. Leonova et al.
Evaluation of vaccine encepur adult for induction of human neutralizing antibodies against recent Far Eastern subtype strains of tick-borne encephalitis virus
- G.N. Leonova et al.
Characterization of neutralizing antibodies to Far Eastern of tick-borne encephalitis virus subtype and the antibody avidity for four tick-borne encephalitis vaccines in human
- N. Chiba et al.
Protection against tick-borne encephalitis virus isolated in Japan by active and passive immunization
- U. Klockmann et al.
Protection against European isolates of tick-borne encephalitis virus after vaccination with a new tick-borne encephalitis vaccine
- K.K. Orlinger et al.
An inactivated West Nile Virus vaccine derived from a chemically synthesized cDNA system
- C. Wittermann et al.
Antibody response following administration of two paediatric tick-borne encephalitis vaccines using two different vaccination schedules
Safety and immunogenicity of the modified adult tick-borne encephalitis vaccine FSME-IMMUN: results of two large phase 3 clinical studies
Comparison of immunogenicity and safety between two paediatric TBE vaccines
Epidemiology and ecology of TBE relevant to the production of effective vaccines
Tick-borne encephalitis in Europe and beyond—the epidemiological situation as of 2007
Cited by (36)
Effectiveness of TBE vaccination in southern Germany and Latvia
Citation Excerpt :
However, this is expected to be minimal due to the extensive medical record systems of the contributing public health authorities and follow-up routinely conducted to verify vaccination status for these cases. Finally, although TBE vaccines are considered comparable in terms of their effectiveness, there is laboratory evidence from serological studies and from mouse challenge models that the two vaccines do not perform equally well against specific TBEV subtypes [44–47]. The two vaccines available in western Europe for the prevention of TBE are based on different seed virus strains, with one vaccine having an immunodominant point mutation of the seed virus that does not exist in nature .
Tick-borne encephalitis (TBE) is a vaccine-preventable disease which may cause long-term sequelae and even death. The data on the long-term effectiveness of TBE vaccines are limited. Additionally, the vaccination schedule is complex which in part contributes towards sub-optimal uptake in TBE-endemic areas. The current ecological study measures vaccine effectiveness (VE) in two European countries.
TBE VE was measured from 2007 to 2018 in Latvia and Southern German states by age group, vaccination history, and schedule compliance. TBE cases and vaccination history were obtained from the public health agencies for Latvia and the southern German federal states of Bavaria and Baden-Wuerttemberg. Cases were “within schedule” if a TBE infection was diagnosed within the time interval preceding the next scheduled dose and “outside schedule” if the diagnosis occurred after the next scheduled dose. Vaccine uptake was estimated via representative nationwide surveys.
VE after 2, 3, and ≥4 doses was high in both countries at 97.2%, 95.0%, and 95.4% for southern Germany, and 98.1%, 99.4%, and 98.8% for Latvia while within- schedule, and only showed marginal differences outside schedule at 90.6%, 89.9%, and 95.6% for southern Germany, and 97.4%, 98.4%, and 99.0% for Latvia regardless of age groups.
In both countries, VE after two and three primary doses within-schedule was very high in all age groups. Once receiving booster doses, high VE continued to be observed even in persons with extended intervals since the last dose received, suggesting that longer and more flexible booster intervals may be considered for sustainable long-term protection.
An RNA-dependent RNA polymerase inhibitor for tick-borne encephalitis virus
Citation Excerpt :
Vaccination is the most specific preventive tool against TBE (Chernokhaeva et al., 2016). Registered vaccines contain inactivated virion antigens as the active compound (Fritz et al., 2012; Vorovitch et al., 2015). Vaccines available today are known to induce a high degree of protection against the virus.
Tick-borne encephalitis virus (TBEV) is a medically important representative of the Flaviviridae family. The TBEV genome encodes a single polyprotein, which is co/post-translationally cleaved into three structural and seven non-structural proteins. Of the non-structural proteins, NS5, contains an RNA-dependent RNA polymerase (RdRp) domain that is highly conserved and is responsible for the genome replication. Screening for potential antivirals was done using a hybrid receptor and ligand-based pharmacophore search likely targeting the RdRp domain. For the identification of pharmacophores, a mixture of small probe molecules and nucleotide triphosphates were used. The ligand/receptor interaction screenings of structures from the ZINC database resulted in five compounds. Zinc 3677 and 7151 exhibited lower cytotoxicity and were tested for their antiviral effect against TBEV in vitro. Zinc 3677 inhibited TBEV at micromolar concentrations. The results indicate that Zinc 3677 represents a good target for structure-activity optimizations leading potentially to a discovery of effective TBEV antivirals.
A comparative analysis on the physicochemical properties of tick-borne encephalitis virus envelope protein residues that affect its antigenic properties
2017, Virus Research
Citation Excerpt :
Vaccines based on the TBEV Sofjin strain also prevents against Japanese encephalitis virus (Lai and Monath, 2003). The aforementioned vaccines were shown to be highly immunogenic (Wagner et al., 2004b; Fritz et al., 2012; Amicizia et al., 2013; Domnich et al., 2014). In Austria, after the introduction of a mass vaccination against TBEV, the incidence of TBE decreased by 95% (Romanenko et al., 2007; Heinz et al., 2008; Kunze and Böhm, 2015).
This work is dedicated to the study of the variability of the main antigenic envelope protein E among different strains of tick-borne encephalitis virus at the level of physical and chemical properties of the amino acid residues. E protein variants were extracted from then NCBI database. Four amino acid residues properties in the polypeptide sequences were investigated: the average volume of the amino acid residue in the protein tertiary structure, the number of amino acid residue hydrogen bond donors, the charge of amino acid residue lateral radical and the dipole moment of the amino acid residue. These physico-chemical properties are involved in antigen-antibody interactions. As a result, 103 different variants of the antigenic determinants of the tick-borne encephalitis virus E protein were found, significantly different by physical and chemical properties of the amino acid residues in their structure. This means that some strains among the natural variants of tick-borne encephalitis virus can potentially escape the immune response induced by the standard vaccine.
Tickborne Encephalitis Vaccines
2017, Plotkin's Vaccines
Protective immunity spectrum induced by immunization with a vaccine from the TBEV strain Sofjin
Tick-borne encephalitis (TBE) circulates widely in the territory of Eurasia with up to 10,000 cases registered annually. The TBE virus (TBEV) includes three main subtypes: European, Siberian and Far-Eastern, and two new Asiatic variants, phylogenetically distant from the others. The inactivated antigen of European or Far-Eastern strains is used in commercial TBE vaccines. A set of 14 TBEV strains, isolated in 1937–2008, with different passage histories, representing all subtypes and variants, was used in this work. The chosen set covers almost all the TBE area.
Sera of mice, immunized with the TBE vaccine Moscow, prepared from the TBEV strain Sofjin, were studied in a plaque neutralization test against the set of TBEV strains. The vaccine induced antibodies at a protective titer against all TBEV strains and Omsk hemorrhagic fever virus (OHFV) with Е protein amino acid distances of 0.008–0.069, but not against Powassan virus.
We showed that after a course of two immunizations, factors such as the period between vaccinations (1–4 weeks), the challenging virus dose (30–1000 LD50) and terms of challenge (1–4 weeks after the last immunization) did not significantly affect the assessment of protective efficacy of the vaccine in vivo. The protective effect of the TBE vaccine Moscow against the set of TBEV strains and the OHFV was demonstrated in in vivo experiments. TBE vaccine Moscow did not protect mice against 10 LD50 of the Powassan virus.
We showed that this range of Е protein amino acid distances between the vaccine strain and challenging virus do not have a decisive impact on the TBE vaccine protective effect in vitro and in vivo. Moreover, the TBE vaccine Moscow induces an immune response protective against a wide range of TBEV variants.
The International Scientific Working Group on Tick-Borne Encephalitis (ISW TBE): Review of 17 years of activity and commitment
2016, Ticks and Tick-borne Diseases
Citation Excerpt :
Both vaccines are [physically?] well tolerated and efficacious for immune-competent individuals aged >1 year and appear to protect against all TBEV subtypes circulating in Europe and Asia (WHO, 2011; Fritz et al., 2012). TBEv is endemic in many parts of Europe, Siberia, Far-Eastern Russia, northern China and Japan and has a huge geographic distribution, including at least 34 countries (Bogovic and Strle, 2015; Lindquist, 2014).
Tick-borne encephalitis (TBE) has been a growing public health problem in Europe and other parts of the world for the past 20 years. In 1999, in order to encourage the control of TBE, international experts created a new body: The International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE). This Working Group has been composed of internationally recognized scientific experts from tick-borne encephalitis virus (TBEv)-endemic and non-endemic regions with extensive personal expertise in the field and a high level of commitment to improve the knowledge of TBE and to increase the public awareness of TBE. Since the foundation of the Working Group, ISW-TBE members meet annually. Every meeting is dedicated to a specific topic, and since 2004 a yearly conference report has been published to inform the scientific community about the latest developments. Among the specific issues that have been extensively discussed over the years were the following: clinical aspects of the disease, TBE in children and golden agers, epidemiology, possible causes for the increase in TBE incidence in Europe, TBE and awareness, TBE and travel, (low) vaccination rates, and the cooperation with the European Centre for Disease Prevention and Control (ECDC). This paper gives an overview of the most important activities and achievements of the ISW-TBE over the past 17 years.
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Veterinary Parasitology, Volume 204, Issues 3–4, 2014, pp. 430-432
Changes in the distribution of tick species are among the major causes for the increase in prevalence of zoonotic diseases worldwide, with tick-borne diseases’ prevalence showing an emerging pattern. One of these ticks, Rhipicephalus rossicus, which is reported occasionally from humans, seems to be particularly interesting because of its demonstrated vectorial role for zoonotic pathogens like Francisella tularensis, Coxiella burnetii, or CCHF and West Nile viruses. Here we report a case of dominant occurrence of R. rossicus on household dogs in the wetlands of Eastern Europe (Romania). Ticks were collected from dogs in 5 distinct locations, with 1068 ticks of 6 species found. R. rossicus had a dominant occurrence in dogs in all but one location, accounting for 87.1% of all ticks (32.3–95.3% in different locations). Until this study, Rhipicephalus sanguineus was considered as the only important tick species on dogs in south-temperate regions of Europe, as well in Romania. The dominant presence of R. rossicus in dogs, its vectorial competence and broad host spectrum (including humans), make this tick species an important candidate for further analysis and highlight the paucity of our knowledge on disease vectors in this region of Europe.
Five year follow-up after a first booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates long-term antibody persistence and safety
Vaccine, Volume 32, Issue 34, 2014, pp. 4275-4280
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.
A matrix metalloproteinase 9 (MMP9) gene single nucleotide polymorphism is associated with predisposition to tick-borne encephalitis virus-induced severe central nervous system disease
Ticks and Tick-borne Diseases, Volume 9, Issue 4, 2018, pp. 763-767
The progression of infectious diseases depends on causative agents, the environment and the host’s genetic susceptibility. To date, human genetic susceptibility to tick-borne encephalitis (TBE) virus-induced disease has not been sufficiently studied. We have combined whole-exome sequencing with a candidate gene approach to identify genes that are involved in the development of predisposition to TBE in a Russian population. Initially, six exomes from TBE patients with severe central nervous system (CNS) disease and seven exomes from control individuals were sequenced. Despite the small sample size, two nonsynonymous single nucleotide polymorphisms (SNPs) were significantly associated with TBE virus-induced severe CNS disease. One of these SNPs is rs6558394 (G/A, Pro422Leu) in the scribbled planar cell polarity protein (SCRIB) gene and the other SNP is rs17576 (A/G, Gln279Arg) in the matrix metalloproteinase 9 (MMP9) gene. Subsequently, these SNPs were genotyped in DNA samples of 150 non-immunized TBE patients with different clinical forms of the disease from two cities and 228 control randomly selected samples from the same populations. There were no statistically significant differences in genotype and allele frequencies between the case and control groups for rs6558394. However, the frequency of the rs17576 G allele was significantly higher in TBE patients with severe CNS diseases such as meningo-encephalitis (43.5%) when compared with TBE patients with milder meningitis (26.3%; P = 0.01), as well as with the population control group (32.5%; P = 0.042). The results suggest that the MMP9 gene may affect genetic predisposition to TBE in a Russian population.
A protective chimeric antibody to tick-borne encephalitis virus
Vaccine, Volume 32, Issue 29, 2014, pp. 3589-3594
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 2.6×1010M−1 and 1.0×107M−1, respectively, according to the SPR-based ProteOn biosensor assay. The neutralization index (IC50) of ch14D5a was 0.04μg/ml in the focus reduction neutralization test. In in vivo experiments, ch14D5a at a dose of 10μg/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.
Association of single nucleotide polymorphism rs3775291 in the coding region of the TLR3 gene with predisposition to tick-borne encephalitis in a Russian population
Antiviral Research, Volume 99, Issue 2, 2013, pp. 136-138
Tick-borne encephalitis (TBE) is a central nervous system (CNS) disease caused by the neurotropic, positive-sense RNA virus, tick-borne encephalitis virus (TBEV). A possible association between predisposition to TBE in a Russian population and two polymorphisms, a 32bp deletion in the coding region of the chemokine receptor CCR5 gene and the rs3775291 single nucleotide polymorphism (SNP) (G/A, Leu412Phe) in exon 4 of the toll-like receptor TLR3 gene, was investigated. The genotypic and allelic frequencies of these polymorphisms were analyzed in 137 non-immunized TBE patients with different clinical manifestations, including fever (35), meningitis (62), and severe CNS disease (40), as well as in a control population (269 randomly selected Novosibirsk citizens). The frequencies of the TLR3 G allele and G/G homozygotes were significantly higher among the patients with TBE compared with the control group (P=0.029 and 0.037, respectively), especially among patients with severe disease (P=0.018 and 0.017, respectively). These results indicate that the G allele (within the G/G homozygous genotype) of the TLR3 rs3775291 SNP is associated with predisposition to TBE in the Russian population.
Development and testing of a new tick-borne encephalitis virus vaccine candidate for veterinary use
Vaccine, Volume 36, Issue 48, 2018, pp. 7257-7261
In tick-borne encephalitis (TBE) endemic areas, consumption of unpasteurized milk or milk products from grazing domestic ruminants (goats, cattle, and sheep) represents a risk of TBE virus (TBEV) infection for humans. In addition to vaccination of humans, human alimentary TBEV infections can be avoided by pasteurizing milk or by vaccination of the ruminants. However, there is presently no TBEV vaccine for veterinary use. Here, we developed a new veterinary TBE vaccine candidate based on cell culture-derived, purified, and formaldehyde-inactivated TBEV (strain Hypr). The safety and immunogenicity of the vaccine was evaluated in mice and sheep and was well-tolerated while eliciting the production of high levels of virus-neutralizing antibodies. Vaccination provided full protection against lethal TBE in mice, prevented development of viremia in sheep and presence of TBEV in milk of lactating ewes. This vaccine is a good candidate for immunization of ruminants to prevent alimentary milk-borne TBEV infections in humans.
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