scholarly journals Comparative Neuropathogenesis and Neurovirulence of Attenuated Flaviviruses in Nonhuman Primates

2008 ◽  
Vol 82 (11) ◽  
pp. 5255-5268 ◽  
Author(s):  
Olga A. Maximova ◽  
Jerrold M. Ward ◽  
David M. Asher ◽  
Marisa St. Claire ◽  
Brad W. Finneyfrock ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Virus Vaccine ◽  
Nonhuman Primates ◽  
Vaccine Candidate ◽  
Tick Borne Encephalitis ◽  
Langat Virus ◽  
The Central Nervous System ◽  
Attenuated Viruses ◽  
Tick Borne Encephalitis Virus ◽  
Far Eastern

ABSTRACT Based on previous preclinical evaluation in mice and monkeys, the chimeric TBEV/DEN4Δ30 virus, carrying the prM and E protein genes from a highly virulent Far Eastern strain of tick-borne encephalitis virus (TBEV) on the backbone of a nonneuroinvasive dengue type 4 virus (DEN4), has been identified as a promising live attenuated virus vaccine candidate against disease caused by TBEV. However, prior to use of this vaccine candidate in humans, its neurovirulence in nonhuman primates needed to be evaluated. In the present study, we compared the neuropathogeneses of the chimeric TBEV/DEN4Δ30 virus; Langat virus (LGTV), a former live TBEV vaccine; and yellow fever 17D virus vaccine (YF 17D) in rhesus monkeys inoculated intracerebrally. TBEV/DEN4Δ30 and YF 17D demonstrated remarkably similar spatiotemporal profiles of virus replication and virus-associated histopathology in the central nervous system (CNS) that were high in cerebral hemispheres but progressively decreased toward the spinal cord. In contrast, the neurovirulence of LGTV exhibited the reverse profile, progressing from the site of inoculation toward the cerebellum and spinal cord. Analysis of the spatiotemporal distribution of viral antigens in the CNS of monkeys revealed a prominent neurotropism associated with all three attenuated viruses. Nevertheless, TBEV/DEN4Δ30 virus exhibited higher neurovirulence in monkeys than either LGTV or YF 17D, suggesting insufficient attenuation. These results provide insight into the neuropathogenesis associated with attenuated flaviviruses that may guide the design of safe vaccines.

Evaluation of European tick-borne encephalitis virus vaccine against recent Siberian and far-eastern subtype strains

Vaccine ◽  
2001 ◽  
Vol 19 (32) ◽  
pp. 4774-4779 ◽  
Author(s):  
Daisuke Hayasaka ◽  
Akiko Goto ◽  
Kentarou Yoshii ◽  
Tetsuya Mizutani ◽  
Hiroaki Kariwa ◽  
...  
Keyword(s):  
Virus Vaccine ◽  
Encephalitis Virus ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Far Eastern

Development and testing of a new tick-borne encephalitis virus vaccine candidate for veterinary use

Vaccine ◽  
2018 ◽  
Vol 36 (48) ◽  
pp. 7257-7261 ◽  
Author(s):  
Jiří Salát ◽  
Petra Formanová ◽  
Milan Huňady ◽  
Luděk Eyer ◽  
Martin Palus ◽  
...  
Keyword(s):  
Virus Vaccine ◽  
Vaccine Candidate ◽  
Encephalitis Virus ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

scholarly journals Tick-Borne Langat/Mosquito-Borne Dengue Flavivirus Chimera, a Candidate Live Attenuated Vaccine for Protection against Disease Caused by Members of the Tick-Borne Encephalitis Virus Complex: Evaluation in Rhesus Monkeys and in Mosquitoes

2001 ◽  
Vol 75 (17) ◽  
pp. 8259-8267 ◽  
Author(s):  
Alexander G. Pletnev ◽  
Michael Bray ◽  
Kathryn A. Hanley ◽  
Jim Speicher ◽  
Randy Elkins
Keyword(s):  
Virus Vaccine ◽  
Rhesus Monkeys ◽  
Neutralizing Antibodies ◽  
Vaccine Candidate ◽  
Limit Of Detection ◽  
Encephalitis Virus ◽  
Live Virus ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Highly Virulent

ABSTRACT Langat virus (LGT), strain TP21, a naturally avirulent tick-borne flavivirus, was used to construct a chimeric candidate virus vaccine which contained LGT genes for premembrane (preM) and envelope (E) glycoprotein and all other sequences derived from dengue type 4 virus (DEN4). The live virus vaccine was developed to provide resistance to the highly virulent, closely related tick-borne flaviviruses that share protective E epitopes among themselves and with LGT. Toward that end the chimera, initially recovered in mosquito cells, was adapted to grow to high titer in qualified simian Vero cells. When inoculated intraperitoneally (i.p.), the Vero cell-adapted LGT TP21/DEN4 chimera remained completely attenuated for SCID mice. Significantly, the chimera protected immunocompetent mice against the most virulent tick-borne encephalitis virus (TBEV). Subsequently, rhesus monkeys were immunized in groups of 4 with 105 or 107 PFU of LGT strain TP21, with 105 PFU of DEN4, or with 103, 105, or 107 PFU of the chimera. Each of the monkeys inoculated with DEN4 or LGT TP21 became viremic, and the duration of viremia ranged from 1 to 5 days. In contrast, viremia was detected in only 1 of 12 monkeys inoculated with the LGT TP21/DEN4 chimera; in this instance the level of viremia was at the limit of detection. All monkeys immunized with the chimera or LGT TP21 virus developed a moderate to high level of neutralizing antibodies against LGT TP21 as well as TBEV and were completely protected against subsequent LGT TP21 challenge, whereas monkeys previously immunized with DEN4 virus became viremic when challenged with LGT TP21. These observations suggest that the chimera is attenuated, immunogenic, and able to induce a protective immune response. Furthermore, passive transfer of serum from monkeys immunized with chimera conferred significant protection to mice subsequently challenged with 100 i.p. 50% lethal doses of the highly virulent TBEV. The issue of transmissibility of the chimera by mosquitoes was addressed by inoculating a nonhematophagous mosquito,Toxorhynchites splendens, intrathoracically with the chimera or its DEN4 or LGT parent. Neither the LGT TP21/DEN4 vaccine candidate nor the wild-type LGT TP21 virus was able to infect this mosquito species, which is highly permissive for dengue viruses. Certain properties of the chimera, notably its attenuation for monkeys, its immunogenicity, and its failure to infect a highly permissive mosquito host, make it a promising vaccine candidate for use in immunization against severe disease caused by many tick-borne flaviviruses.

scholarly journals Molecular-genetic characteristics of the tick-borne encephalitis virus pathogenicity of far eastern subtype

2020 ◽  
Vol 12 (1) ◽  
pp. 48-55
Author(s):  
G. N. Leonova ◽  
L. M. Somova ◽  
S. I. Belikov
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Genetic ◽  
Far East ◽  
Primorsky Krai ◽  
The Far East ◽  
Tick Borne Encephalitis ◽  
The Central Nervous System ◽  
Tick Borne Encephalitis Virus ◽  
Far Eastern

The aim of the work: Using the data of genome-wide sequencing of tick-borne encephalitis virus strains of the Far Eastern population, reveal the peculiarities of the moleculargenetic characteristics and their relationship with the pathogenicity of the agent. Materials and methods. A full-genomic characteristic of 63 TBEV strains isolated in the Far East and registered in GeneBank wos given. A pathohistological study of the central nervous system of monkeys infected with the highly virulent strains Sofjin and Khabarovsk-17 TBEV was conducted. Results. All strains are assigned to the Far Eastern subtype of TBEV and are located in three clusters, the territorial attachment of individual strains groups is noted. In the cluster of Sofjin-like strains, independent groups were identified, isolated in the territories of Primorsky Krai only, and separate groups – only in northern focal territories (Khabarovsk Krai). The cluster Senzhang-like strains are represented by strains of different clusters, isolated in China and throughout the Far East. The Oshima-like cluster of strains, except for strains from Japan, consists of strains isolated only in the south of the Far East (in Primorsky Krai). The incubation period of the disease in experimental animals was shorter when infected with the Sofjin strain (3–5 days) than when infected with the Khabarovsk-17 strain (7 days or more). The strain-specific differences in the severity of morphological changes in the central nervous system were revealed. For primorsky TBEV strains, a higher degree of neuroinvasiveness was characteristed with a more rapid development of severe manifestations of neuroinfection, compared to khabarovsky strains.Findings: 1) based on full-genome sequencing and phylogenetic analysis of 63 TBEV strains, three main clusters were distinguished: Sofjin-, Senzhang- and Oshima-like; 2) in these clusters, territorial attachment of TBEV strains groups with a certain molecular genetic characteristic was established; 3) in primorsky TBEV strains, genetically determined advantages in the degree of neuroinvasiveness have been revealed, which provide them with the ability to more quickly overcome the blood-brain barrier compared to khabarovsky strains.

scholarly journals Stable and Highly Immunogenic MicroRNA-Targeted Single-Dose Live Attenuated Vaccine Candidate against Tick-Borne Encephalitis Constructed Using Genetic Backbone of Langat Virus

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Konstantin A. Tsetsarkin ◽  
Olga A. Maximova ◽  
Guangping Liu ◽  
Heather Kenney ◽  
Natalya L. Teterina ◽  
...  
Keyword(s):  
Single Dose ◽  
Vaccine Candidate ◽  
Encephalitis Virus ◽  
Chimeric Virus ◽  
Old World ◽  
Tick Borne Encephalitis ◽  
Attenuated Virus ◽  
Langat Virus ◽  
Active Research ◽  
Tick Borne Encephalitis Virus

ABSTRACTTick-borne encephalitis virus (TBEV), a member of the genusFlavivirus, is one of the most medically important tick-borne pathogens of the Old World. Despite decades of active research, attempts to develop of a live attenuated virus (LAV) vaccine against TBEV with acceptable safety and immunogenicity characteristics have not been successful. To overcome this impasse, we generated a chimeric TBEV that was highly immunogenic in nonhuman primates (NHPs). The chimeric virus contains the prM/E genes of TBEV, which are expressed in the genetic background of an antigenically closely related, but less pathogenic member of the TBEV complex—Langat virus (LGTV), strain T-1674. The neurovirulence of this chimeric virus was subsequently controlled by robust targeting of the viral genome with multiple copies of central nervous system-enriched microRNAs (miRNAs). This miRNA-targeted T/1674-mirV2 virus was highly stable in Vero cells and was not pathogenic in various mouse models of infection or in NHPs. Importantly, in NHPs, a single dose of the T/1674-mirV2 virus induced TBEV-specific neutralizing antibody (NA) levels comparable to those seen with a three-dose regimen of an inactivated TBEV vaccine, currently available in Europe. Moreover, our vaccine candidate provided complete protection against a stringent wild-type TBEV challenge in mice and against challenge with a parental (not miRNA-targeted) chimeric TBEV/LGTV in NHPs. Thus, this highly attenuated and immunogenic T/1674-mirV2 virus is a promising LAV vaccine candidate against TBEV and warrants further preclinical evaluation of its neurovirulence in NHPs prior to entering clinical trials in humans.IMPORTANCETick-borne encephalitis virus (TBEV) is one of the most medically important tick-borne pathogens of the Old World. Despite decades of active research, efforts to develop of TBEV live attenuated virus (LAV) vaccines with acceptable safety and immunogenicity characteristics have not been successful. Here we report the development and evaluation of a highly attenuated and immunogenic microRNA-targeted TBEV LAV.

Chapter 11: General epidemiology of TBE

2020 ◽  
Keyword(s):  
Eastern Siberia ◽  
Genetic Lineages ◽  
Phylogenetic Studies ◽  
Tick Borne Encephalitis ◽  
Natural Foci ◽  
Genetic Sequences ◽  
Tick Borne Encephalitis Virus ◽  
Almost All ◽  
Far Eastern ◽  
Reservoir Hosts

Tick-borne encephalitis virus (TBEV) exists in natural foci, which are areas where TBEV is circulating among its vectors (ticks of different species and genera) and reservoir hosts (usually rodents and small mammals). Based on phylogenetic studies, four TBEV subtypes (Far-Eastern, Siberian, European, Baikalian) and two putative subtypes (Himalayan and “178-79” group) are known. Within each subtype, some genetic lineages are described. The European subtype (TBEV-EU) (formerly known also as the “Western subtype”) of TBEV is prevalent in Europe, but it was also isolated in Western and Eastern Siberia in Russia and South Korea. The Far-Eastern subtype (TBEV-FE) was preferably found in the territory of the far-eastern part of Eurasia, but some strains were isolated in other regions of Eurasia. The Siberian (TBEV-SIB) subtype is the most common and has been found in almost all TBEV habitat areas. The Baikalian subtype is prevalent around Lake Baikal and was isolated several times from ticks and rodents. In addition to the four TBEV subtypes, one single isolate of TBEV (178-79) and two genetic sequences (Himalayan) supposed to be new TBEV subtypes were described in Eastern Siberia and China. The data on TBEV seroprevalence in humans and animals can serve as an indication for the presence or absence of TBEV in studied area.

scholarly journals Computational and Rational Design of Single-Chain Antibody against Tick-Borne Encephalitis Virus for Modifying Its Specificity

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1494
Author(s):  
Ivan K. Baykov ◽  
Pavel Y. Desyukevich ◽  
Ekaterina E. Mikhaylova ◽  
Olga M. Kurchenko ◽  
Nina V. Tikunova
Keyword(s):  
Rational Design ◽  
Fold Increase ◽  
Encephalitis Virus ◽  
Chimeric Antibody ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Glycoprotein E ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus ◽  
Far Eastern

Tick-borne encephalitis virus (TBEV) causes 5−7 thousand cases of human meningitis and encephalitis annually. The neutralizing and protective antibody ch14D5 is a potential therapeutic agent. This antibody exhibits a high affinity for binding with the D3 domain of the glycoprotein E of the Far Eastern subtype of the virus, but a lower affinity for the D3 domains of the Siberian and European subtypes. In this study, a 2.2-fold increase in the affinity of single-chain antibody sc14D5 to D3 proteins of the Siberian and European subtypes of the virus was achieved using rational design and computational modeling. This improvement can be further enhanced in the case of the bivalent binding of the full-length chimeric antibody containing the identified mutation.

scholarly journals Tick populations from endemic and non-endemic areas in Germany show differential susceptibility to TBEV

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katrin Liebig ◽  
Mathias Boelke ◽  
Domenic Grund ◽  
Sabine Schicht ◽  
Andrea Springer ◽  
...  
Keyword(s):  
Differential Susceptibility ◽  
Feeding Rates ◽  
Infection Rates ◽  
Lower Saxony ◽  
Tick Borne Encephalitis ◽  
The Central Nervous System ◽  
Tick Borne Encephalitis Virus ◽  
In Vitro Feeding ◽  
Tbev Infection

Abstract Tick-borne encephalitis virus (TBEV) is endemic in twenty-seven European countries, transmitted via the bite of an infected tick. TBEV is the causative agent of one of the most important viral diseases of the central nervous system (CNS). In Germany, 890 human cases were registered between the years 2018–2019. The castor bean tick, Ixodes ricinus, is the TBEV vector with the highest importance in Central Europe, including Germany. Despite the nationwide distribution of this tick species, risk areas of TBEV are largely located in Southern Germany. To increase our understanding of TBEV-tick interactions, we collected ticks from different areas within Germany (Haselmühl/Bavaria, Hanover/Lower Saxony) and infected them via an in vitro feeding system. A TBEV isolate was obtained from an endemic focus in Haselmühl. In two experimental series conducted in 2018 and 2019, ticks sampled in Haselmühl (TBEV focus) showed higher artificial feeding rates, as well as higher TBEV infections rates than ticks from the non-endemic area (Hanover). Other than the tick origin, year and month of the infection experiment as well as co-infection with Borrelia spp., had a significant impact on TBEV Haselmühl infection rates. Taken together, these findings suggest that a specific adaptation of the tick populations to their respective TBEV virus isolates or vice versa, leads to higher TBEV infection rates in those ticks. Furthermore, co-infection with other tick-borne pathogens such as Borrelia spp. can lower TBEV infection rates in specific populations.

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