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Tick-Borne Encephalitis Vaccines Axel T Lehrer1 and Michael R

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Tick-Borne Encephalitis Vaccines Axel T Lehrer1 and Michael R orism terr & io B B i f o o d l e a f e Lehrer and Holbrook, J Bioterr Biodef 2011, S1 n n r s u e o DOI: 10.4172/2157-2526.S1-003 J Journal of Bioterrorism & Biodefense ISSN: 2157-2526 Review Article Open Access Tick-borne Encephalitis Vaccines Axel T Lehrer1 and Michael R. Holbrook2* 1PanThera Biopharma, Aiea, HI 96701. 2NIAID Integrated Research Facility, Ft. Detrick, Frederick MD 21702 Abstract Tick-borne encephalitis (TBE) is a disease that is found from western Europe across Asia and into Japan. In recent years the incidence rate has been increasing as has the endemic range of the virus. Tick-borne encephalitis is caused by three genetically distinct sutypes of viruses within a single TBE virus (TBEV) serocomplex. These three subtypes consist of Far-eastern subtype TBEV (TBEV-FE), Siberian subtype (TBEV-Sib) and European subtype (TBEV-Eu). Each of these subtypes cause clinically distinct diseases with varying degrees of severity. Development of the first vaccines for TBEV began in the late 1930s shortly after the first isolation of TBEV-FE in Russia. In the 1970s Austria began large scale vaccine production and a nationalized vaccine campaign that significantly reduced the incidence rate of TBE. Currently there are four licensed TBE vaccines, two in Europe and two in Russia. These vaccines are all quite similar formalin-inactivated virus vaccines but the each use` a different virus strain for production. Published studies have shown that European vaccines are cross-protective in rodent studies and elicit cross-reactive neutralizing antibody responses in human vaccines. European vaccines have been licensed for a rapid vaccine schedule that could be used in response to a significant outbreak and reasonable neutralizing antibody titers can be achieved after a single dose although a second dose provides nearly complete and long-lasting protection. This review focuses on the current status of licensed TBE vaccines and provides a brief summary of technology currently being developed for new vaccines. Keywords: Tick-borne encephalitis; vaccine; arbovirus; biodefe 10,000-12,000 cases of TBE reported annually throughout Europe and Asia (Tick-borne encephalitis International Scientific Working Group Introduction (TBE-ISW), http://www.tbe-info.com) [9]. KFD accounts for 100- The tick-borne encephalitis (TBE) serocomplex of flaviviruses 500 cases per year in India with outbreaks in both humans and non- (Family Flaviviridae, genus Flavivirus) includes a number of viruses human primates [10]. The documented incidence of OHFV, ALKV and that cause disease in humans. These include the TBE viruses (TBEV) of POWV infection is very low. which there are three subtypes, Kyasanur Forest disease virus (KFDV) Transmission of TBE serocomplex viruses typically occurs through and the closely related Alkhurma (ALKV) and Nanjianyin viruses, the bite of an infected tick although outbreaks sometimes can also be Omsk hemorrhagic fever virus (OHFV) and Powassan virus (POWV). associated with consumption of un-pasteurized milk products from A subtype of POWV is deer tick virus (DTV). Also within the TBE infected sheep or goats, a disease termed “biphasic milk-fever” [2]. serocomplex is Langat virus (LGTV), a naturally attenuated virus Percutaneous injury in laboratory or medical settings along with direct that is generally apathogenic in humans following natural infection. exposure to blood or bodily fluids from infected humans or animals Members of the TBE serocomplex are genetically distinct, but closely are also potential routes of exposure. Infection from inhalation of enough related serologically that they are often difficult to distinguish TBE virus aerosols has been documented after laboratory accidents by antibody-based assays. [11,12]. Quoting the CDC` Special Pathogens Branch internet website: “Laboratory infections were common before the use of vaccines and The diseases caused by the TBE serocomplex viruses range from availability of biosafety precautions to prevent exposure to infectious asymptomatic or mild febrile illness to hemorrhagic fever or severe aerosols“. encephalitis with significant morbidity and mortality. OHFV, KFDV and ALKV are most frequently associated with hemorrhagic disease Flaviviruses are typically transmitted by either mosquitoes or while POWV and TBEV infections can result in encephalitic disease. ticks although there is a small subset of viruses that are not believed The three subtypes of TBEV can be distinguished genetically and to require an arthropod vector for transmission [13]. The flaviviruses often by clinical presentation. European subtype TBEV (TBEV-Eu) account for majority significant number of the arthropod-borne is generally a biphasic disease, occasionally resulting in neurologic viral diseases worldwide. Tick species associated with transmission disease, but with a low case fatality rate. In contrast, Far-eastern subtype of TBE serocomplex viruses include the hard ticks Ixodes ricinus, Ix. TBEV (TBEV-FE) is more frequently associated with severe neurologic disease, relatively high case fatality rate and an increased propensity for neurological sequelae in survivors. The Siberian subtype TBEV (TBEV- *Corresponding author: Michael R. Holbrook, PhD,NIAID Integrated Research Facility, 8200 Research Plaza,Ft. Detrick,Frederick, MD 21702,Tel:301-631- Sib) is intermediate in disease severity, but has been associated with 7265;Fax: 301-619-5029; E-mail: [email protected] chronic infection [1-5]. Received July 26, 2010; Accepted August 25, 2011; Published September 25, The incidence of TBE in Europe has increased significantly over the 2011 past 40 years despite active vaccination programs in many European Citation: Lehrer AT, Holbrook MR (2011) Tick-borne Encephalitis Vaccines. J countries [6,7]. The spread of TBE cases has been attributed to a number Bioterr Biodef S1:003. doi:10.4172/2157-2526.S1-003 of factors including incomplete vaccine coverage, increased abundance Copyright: © 2011 Lehrer AT, et al. This is an open-access article distributed under of ticks, an increased range of the Ixodes ricinus tick, changes in human the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and life-style, socio-economic conditions and climate change [8]. There are source are credited. J Bioterr Biodef ISSN:2157-2526 JBTBD an open access journal Special Issue 1 • 2011 Citation: Lehrer AT, Holbrook MR (2011) Tick-borne Encephalitis Vaccines. J Bioterr Biodef S1:003. doi:10.4172/2157-2526.S1-003 Page 2 of 7 persulcatus, Dermacentor spp. and Hyalomma spp. Soft ticks from Kyasanur Forest disease (KFD), given its locale, and subsequent the genus Ornithodoros have also been associated with transmission studies isolated the causative agent and characterized the virus as of some tick-borne flaviviruses including ALKV [14,15]. There has related to TBEV [30,31]. KFDV was clearly distinct from TBEV as been some suggestion that tick-borne flaviviruses are transmitted by this virus caused a disease that had both hemorrhagic and neurologic mosquitoes, but this has not been conclusively proven. components while TBEV was only associated with encephalitis. For four decades KFDV was thought to only exist in India. However, in The flaviviruses are a family of small, single-stranded RNA viruses 1996 Alkhurma virus was isolated from cases of hemorrhagic disease with a positive-sense genome and a host-derived lipid envelope. near Jeddah, Saudi Arabia. This virus was characterized and found to The viral genome encodes a single polyprotein that is co- and post- be closely related to KFDV both serologically and genetically. In 2009, translationally cleaved into ten individual proteins, three structural Nanjianyin virus was identified in south central China and found to and seven non-structural. The three structural proteins (C-capsid, virtually identical to KFDV [32]. prM/M-premembrane/membrane and E-envelope) organize to produce the viral particle. The non-structural proteins are principally Omsk hemorrhagic fever was first identified in 1947 in the associated with viral replication, polyprotein cleavage and may have Novosibirsk and Omsk Oblast regions of Russia. Few cases of OHF additional roles in regulating the host immune response [16,17]. The have been described, but clinical disease frequently has a hemorrhagic viral E protein is the major surface antigen for the flaviviruses and component with evidence of neurologic disease less common [33]. contains the receptor-binding domain and fusion peptide. The viral Following isolation of OHFV, serological and genetic characterization prM/M protein functions as a chaperone for the E protein and also clearly identified this virus as a member of the TBEV serocomplex. blocks the fusion peptide during virus assembly to prevent fusion with Langat virus was first isolated from rodents in Malaysia in 1956 exocytic vesicles. The prM protein is cleaved by furin following particle and was initially thought to be TBEV-FE based on serological results assembly to produce the mature fusogenic virus. Co-expression of the [34]. Further analysis found that LGTV was a virus within the TBEV prM and E genes in cell culture systems have been used to produce serocomplex that was less virulent that related viruses. Shortly after subviral particles which were used in early characterization of the isolation and characterization of LGTV, the Elantcev 15-20/3 strain of membrane fusion process of flavivirus
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