Tick-borne Encephalitis

Tick-borne encephalitis is a viral infection of the brain and spinal cord, spread by the bites of ticks. It can leave people permanently affected. Research has made vaccines available. Other vaccines and treatments are being researched.

What is tick-borne encephalitis? Top

Tick-borne encephalitis (TBE) is a human viral infectious and inflammatory disease involving the central nervous system. The pathogenic agent is TBE virus, a member of the flavivirus family. Flaviviruses are responsible for a number of severe diseases, including yellow fever, Japanese encephalitis, dengue haemorrhagic fever and TBE.

TBE can manifest as: (i) meningitis, an inflammation of the lining that surrounds the brain and spinal cord; (ii) encephalitis, i.e. inflammation of the brain; and (iii) meningoencephalitis, which means inflammation of both the brain and meninges.  TBE is transmitted to animals and human beings through the bite of chronically infected ticks. The disease is endemic in certain areas. Cases correspond to the distribution of the ixoid tick reservoir and originate throughout temperate regions of Europe and the former Soviet Union Republics. The European areas affected include the east coast of Sweden, rural areas of Poland, Czechoslovakia and Central Europe including Austria, the southern part of Germany and Hungary.

Ixoid ticks – Ixodes ricinusis the predominant species in Europe – act as both the vector and reservoir for the disease. The main hosts are mice, other small rodents and some birds, with humans being accidental hosts. Large animals such as stag and venison are feeding hosts for the ticks, but do not play a role in the maintenance of the virus. From the saliva of ticks, scientists have isolated an array of “stealth“ molecules which the organism injects into the skin that suppresses normal defence mechanisms, leaving the tick undetected.

The asymptomatic incubation period of TBE is usually between one and two weeks. A characteristic biphasic febrile illness follows, with an initial elevation of body temperature that lasts two to four days and corresponds to the viraemic phase. During this phase of the disease, the virus can be detected in the blood. Symptoms may include fever, malaise, muscle aches, headache, nausea, and vomiting.

After about eight days of remission, the second phase of the disease may occur, involving the central nervous system, with symptoms of meningitis, (e.g. fever, headache, and a stiff neck), or of encephalitis, (e.g. drowsiness, confusion, sensory disturbances and motor abnormalities), or a combination of all of these. Specific diagnosis depends on detection of antibodies against the virus in either blood or cerebrospinal fluid, usually appearing during the second phase of the disease.

The disease can be fatal, but only rarely. Mortality has been reported to be two per cent, with death occurring around a week after the onset of neurological signs. In approximately 65 per cent of people infected with the virus, only the early viraemic phase is seen. In the remaining third, patients experience either the typical biphasic course or a clinical illness that begins with the second neurological phase. The convalescent period can be long and may result in permanent neurological symptoms. Complications of recovery are seen in 10-20 per cent of patients.

Who does tick-borne encephalitis affect? Top

Cases of TBE occur during the highest period of tick activity, i.e. between April and November. In disease-endemic areas, people with recreational or occupational exposure to rural or outdoor settings are potentially at risk. No known gender predilection for TBE exists, except as occupational exposures dictate. Furthermore, as tourism expands, travel to areas of endemicity broadens the definition of who is at risk.

The incidence varies from year to year, but several thousand cases are reported annually in Europe, despite historical under-reporting of the disease. In endemic regions, incidence has been shown to be around 0.5 per 100,000 population. Laboratory infections were common before the use of vaccines and availability of bio-safety precautions to prevent exposure to infectious airborne droplets. Person-to-person transmission has not been reported. Vertical transmission from an infected mother to foetus has occurred.

Distribution of the ixoid tick reservoir on European and Asian continents








Source: ISW-TBE

Present treatments Top

There is no specific antiviral medicine available for the treatment of TBE. Meningitis, encephalitis or meningoencephalitis require hospitalisation and intensive care based on severity. Anti-inflammatory medicines may be considered under specific circumstances for symptomatic relief. Intubation and ventilatory support may be required.

For pre-exposure prophylaxis, two vaccines containing inactivated TBE virus are available and recommended for people with occupational exposure, such as forestry workers, rangers and hunters. The recommended regime is three injections, the second dose usually being given one to three months after the first and the third after 9-12 months. The three initial doses provide immunity for three years, after which time a booster dose will be needed. Further boosters may subsequently be required every three years. Immunity can be checked by measuring the levels of antibodies against TBE virus in the blood of the individual.

For pre- and post-exposure prophylaxis in people without immunity, specific antiviral immune globulin can be administered. If given within four days after the bite, it is estimated to be effective in two-thirds of the patients. It may also be given in a situation where time for vaccination before entry into a endemic area was too short or if vaccination is contraindicated.

What’s in the development pipeline? Top

Clinical trials of the inactivated vaccines to determine the optimal immunisation scheme in children are still ongoing in Europe and approvals are expected soon. Scientists are also investigating whether TBE vaccination interferes with the activity or progression of inflammatory disorders of the human central nervous system.

To prolong the protection period after immunisation, research groups investigate other vaccination regimens with live-attenuated vaccines for TBE. A clinical trial phase 1 is underway to study the safety and immunogenicity of TBELGT/DEN4 vaccine which is derived from the Langat flavivirus and DEN4 dengue virus serotypes.

Ixoid tick

The longer-term future Top

Viral surface proteins usually determine the range of species that can be infected by an agent. Immunity to a viral infection mostly depends on recognition of such proteins by antibodies. Small changes in the protein structures may defeat specific immunity, so research groups are studying how structures of the TBE virus surface proteins could assist in developing further suitable vaccines.

The discovery that naked plasmid DNA can elicit humoral and cellular immunity has prompted research on genetic vaccines against viruses for which prevention and treatment opportunities are limited. Scientists suggest the possibility of using recombinant virus RNA molecules encoding envelope proteins of TBE virus as an approach in genetic vaccine development. They could show in animal models that antigen-specific antibody responses occur after vaccination.

There are first reports of animal studies which demonstrate that the combined use of systems employing so-called prime boost combination protocols, i.e. recombinant vaccinia virus and recombinant bacterial plasmids, can protect against flavivirus infection. Such systems expressing protective antigens of TBE virus, including NS1 protein, could be deployed to provide new methods of constructing vaccines against TBE and other infections caused by flaviviruses.

In September 2005, scientists published results of laboratory experiments explaining how the viral macromolecule NS5 from the tick-borne Langat flavivirus counteracts interferon to trigger a cascade of immune defences and to combat the pathogen. Apparently, the protein NS5 blocks the body’s attempt to signal for immune reaction and prevents the immune system from stopping the spread of virus material. Flaviviruses not transmitted by ticks have been known to use a protein called NS4B which prevents interferon from functioning properly. These findings may provide a target for therapeutics to counteract tick-borne flaviviruses and to find new medicines that interfere with virulent factors of the TBE agent.