Tick-borne encephalitis virus

Tick-borne encephalitis virus is the most important tick-borne member of the genus Orthoflavivirus, causing thousands of cases of neurological disease each year across a broad belt of Europe and northern Asia. Unlike the mosquito-borne flaviviruses it is transmitted by hard Ixodes ticks and, distinctively, can also be caught by drinking unpasteurised milk from infected goats, sheep or cattle. Most infection is silent or a self-limiting febrile illness, but a minority develop meningitis, encephalitis or myelitis, and the outcome depends strongly on which of the three viral subtypes is involved. It is a vaccine-preventable disease, and its relevance outside the endemic zone is chiefly to travellers.

Discovery and historical significance

The virus was first isolated in 1937 from the brain tissue of fatal cases of a severe summer encephalitis in the far east of the Soviet Union, a form named Russian spring-summer encephalitis. A milder, related disease was described in Czechoslovakia in 1948 and shown to be caused by a serologically related virus, the Central European encephalitis form. These are now recognised as subtypes of a single virus transmitted by ixodid ticks across Europe and Asia.

Classification, structure, and genome

Classification

Tick-borne encephalitis virus belongs to the genus Orthoflavivirus (family Flaviviridae), current binomial Orthoflavivirus encephalitidis, within the tick-borne encephalitis serocomplex that also includes Powassan, Kyasanur Forest disease, Omsk haemorrhagic fever and louping ill viruses. Three subtypes are recognised, and they differ in geography and severity. A 2026 taxonomic revision began to split these subtypes into separate species, an evolving change that does not alter the clinically useful three-subtype framework.

Subtype	Distribution	Vector	Case-fatality
European (Western)	Western, central and northern Europe	Ixodes ricinus	~0.5% to 2%
Siberian	Siberia, Urals, European Russia	Ixodes persulcatus	~6% to 8%
Far-Eastern	Eastern Russia, China, Japan	Ixodes persulcatus	~20% to 40%

Virion structure

The virion is a small enveloped particle about 50 nm across, with the envelope (E) and membrane (M) proteins on its surface; E is the receptor-binding and fusion protein and the main neutralising target, and its structure has served as a prototype for understanding flavivirus fusion. Mature particles carry 90 flat E dimers, and immature particles the uncleaved precursor membrane (prM) protein.

Genome organisation

The genome is a positive-sense single-stranded RNA of about 11 kb with a single open reading frame, translated as one polyprotein and cleaved into three structural proteins (capsid C, prM/M, envelope E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5), with NS3 the protease and helicase, NS5 the polymerase and methyltransferase, and NS1 a secreted diagnostic antigen.

Replication cycle

The replication cycle is the canonical flavivirus one: E-mediated attachment and clathrin-mediated endocytosis, acid-triggered fusion in the endosome releasing the genome, translation and replication on endoplasmic-reticulum-derived vesicles with NS5 as the polymerase, and maturation of budded immature particles when furin cleaves prM to M in the trans-Golgi network.

Pathogenesis

After a tick bite the virus replicates locally and in draining lymph nodes, produces a viraemia, and in a minority of infections crosses into the central nervous system, where it is neurotropic for neurons of the cortex, brainstem and spinal cord. The Far-Eastern subtype has a particular predilection for the anterior horn cells of the cervical cord, producing a poliomyelitis-like paralysis, and it also involves the cerebral cortex more heavily than poliovirus does. Milk-borne infection is thought to establish in the oropharyngeal lymphoid tissue, since the virus is inactivated by gastric acid. The virus has a propensity for persistent infection, most evident with the Siberian subtype.

Epidemiology

Tick-borne encephalitis is maintained in a cycle between Ixodes ticks and small rodents, with Ixodes ricinus the vector in Europe and Ixodes persulcatus in Russia and Asia. Globally, up to 12,000 cases are identified each year, with Europe and Russia reporting the highest numbers, and disease is strongly seasonal, peaking in the summer months when ticks are most active. Larval and nymphal ticks acquire the virus by feeding on infected rodents or by co-feeding alongside infected ticks, a non-viraemic route, and the virus passes through the tick life stages and to a small proportion of eggs. Large mammals sustain the tick population but rarely transmit the virus. Human infection follows the seasonal activity of ticks in forests and grassland, so it is an occupational and recreational hazard for foresters, farmers and people gathering mushrooms or berries; up to two-thirds of patients recall a tick bite. A distinctive additional route is drinking unpasteurised milk or cheese from infected goats, sheep or cattle, which can cause family or village clusters. Most infection is subclinical, with a case-to-infection ratio in the range of 1 in 25 to 1 in 200, and the disease is not spread from person to person.

Natural history

After an incubation of about 7 to 14 days, which tends to be shorter for milk-borne infection, the European and Siberian subtypes classically run a biphasic course: a first grippe-like phase of fever, headache and myalgia lasting about a week, then a symptom-free remission of up to three weeks, after which a minority develop a second, neurological phase. The Far-Eastern subtype is usually monophasic, with a gradual progression straight into severe neurological disease. Case-fatality tracks the subtype, from around 1% for the European form to as high as 40% for the Far-Eastern form, and death usually occurs within a week of neurological onset.

Clinical presentations and complications

The first phase is a nonspecific febrile illness. The second phase is neurological, and its severity spans aseptic meningitis, meningoencephalitis and encephalomyelitis. Encephalitic features include altered consciousness, ataxia and cranial-nerve signs, and the Far-Eastern subtype characteristically produces a flaccid paralysis of the shoulder girdle and arms from cervical anterior horn cell injury. Disease is generally milder in children than adults, and older adults fare worst. Sequelae are common after parenchymal disease, ranging from prolonged fatigue and cognitive difficulty to residual paralysis, and the Siberian subtype is associated with chronic progressive forms and with Kozhevnikov epilepsy, a continuous focal seizure disorder.

Diagnosis

Diagnosis rests on serology, with IgM-capture ELISA on serum and cerebrospinal fluid; a fourfold rise in titre in paired sera taken about two weeks apart is confirmatory, and serum IgM can persist for several months. Virus can occasionally be recovered from blood in the first phase but is rarely isolated once neurological disease has begun, so reverse-transcriptase PCR on blood is useful only early and PCR on brain tissue is mainly a post-mortem tool. As with the other flaviviruses, antibody cross-reacts with related viruses and with yellow fever or Japanese encephalitis vaccination.

Management

There is no specific antiviral, and management is supportive, with neurological intensive care for severe encephalitis and attention to airway and respiratory function where bulbar or cervical-cord involvement threatens breathing. Rehabilitation addresses residual motor and cognitive deficits.

Prevention and public health

Vector control

Prevention centres on avoiding tick bites: covering skin, using repellents, using permethrin-treated clothing, which is more effective against ticks than DEET, and checking for and removing attached ticks promptly. Because the virus can be milk-borne, avoiding unpasteurised dairy products from endemic areas is an additional measure.

Vaccination

Effective inactivated whole-virus vaccines are the mainstay of protection. The European-subtype vaccines FSME-IMMUN and Encepur are given as a three-dose primary series with periodic boosters, provide efficacy above 95%, and cross-protect against all three subtypes; Russian vaccines based on the Far-Eastern subtype are used in that region. Vaccination is recommended for residents of endemic areas with likely exposure and for travellers with substantial outdoor exposure during the tick season.

South African context

Tick-borne encephalitis does not occur in South Africa or elsewhere in Africa: the virus, its Ixodes vectors and its rodent reservoir are confined to Europe and northern Asia. Its relevance to South African practice is limited to pre-travel advice for people visiting endemic rural Europe and Asia, where the risk is tied to forest and grassland activity in spring and summer. At-risk travellers, particularly those planning extensive outdoor exposure, should be assessed for tick-borne encephalitis vaccination through a travel clinic and counselled on tick-bite avoidance and on avoiding unpasteurised dairy products. A returning traveller with a compatible neurological illness would be investigated with reference-laboratory serology through the National Institute for Communicable Diseases, allowing for cross-reactivity with the flaviviruses that circulate locally.

References and recommended reading

• Pierson TC, Lazear HM, Diamond MS. Flaviviruses: Dengue, Zika, West Nile, Yellow Fever and Other Flaviviruses. In: Fields Virology, 7th edition, Chapter 9. Philadelphia: Wolters Kluwer; 2023. The principal source for tick-borne encephalitis pathogenesis and clinical disease.
• Lindenbach BD, Randall G, Bartenschlager R, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition, Chapter 7. Philadelphia: Wolters Kluwer; 2023. The source for virion structure, genome organisation and the replication cycle.
• Petersen LR, Barrett ADT. Arthropod-Borne Flaviviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 53. Washington: ASM Press; 2016. The foundational account of tick-borne encephalitis subtypes, transmission and clinical disease.
• Centers for Disease Control and Prevention. Tick-borne Encephalitis. CDC Yellow Book: Health Information for International Travel; 2026. The source for subtype distribution, traveller risk and vaccination.