Tickborne Encephalitis Vaccines

Clinical Description

Neurologic symptoms seen with TBE are similar to other forms of acute viral meningoencephalitis. The clinical course of TBE can be either monophasic or biphasic. If biphasic, the disease starts with an influenza-like illness, followed by a few days of well-being, and then a second phase with neurological symptoms. While the biphasic course is typical for TBEV-Eu (72%–87%) and TBEV-Sib (21%), the TBEV-Fe subtype is primarily a monophasic neurologic illness. Clinically TBEV-Sib and TBEV-FE subtypes induce more severe TBE disease than TBEV-Eu.

After a bite by an infected tick, there is an asymptomatic incubation period that lasts between 4 and 28 days, with most cases ranging between 7 and 14 days. The first stage of clinical illness, lasting for 1–8 days and corresponding to the viremic phase, is characterized by non-specific influenza-like symptoms such as fatigue, headache, aching back and limbs, nausea, and general malaise. Temperatures generally rise to 38°C or higher. Very high initial temperatures have been reported, particularly in children. ^,

An afebrile interval then follows the first stage of TBE, lasting 1–20 days, with most patients being asymptomatic during this time. Then another sudden rise in temperature marks the beginning of the second stage of the disease. The clinical manifestations during this second stage are far more serious than during the first. In approximately 50% of cases there is CNS involvement in the form of meningitis with pleocytosis. Approximately 40% of cases have more-severe disease with signs of encephalitis, including paralysis, stupor, and pyramidal tract signs. Meningoencephalomyelitis, defined as neurological symptoms including spinal nerves, the most-severe form of the disease, occurs in approximately 10% of patients and is more common in older individuals. In the paralytic forms of the disease, often seen in the region of the shoulder girdle, paralysis develops within 5–10 days after the remission of fever during the second phase. Paralysis may progress for up to 2 weeks, followed by a tendency toward improvement. The overall risk of long-term sequelae increases with the severity of the neurologic symptoms. One study showed that 80% of TBE patients with meningoencephalomyelitis did not fully recover within a 10-year follow-up period.

Approximately 5% to 12% of patients require intensive care secondary to respiratory paralysis or serious disorders of consciousness. Hospitalizations last between 3 and 40 weeks, depending on the severity of the illness, and long-term rehabilitation is required for approximately 20% to 30% of hospitalized patients.

Not all persons infected with TBEV experience the monophasic or full biphasic spectrum of clinical disease. Seroconversion without obvious disease is common (i.e., asymptomatic infection). On average, approximately 25% of infected persons develop clinical symptoms. Differences in proportions have been reported by viral subtype and age. In children, the proportion of asymptomatic infections may be higher and this normally results in seroconversion and establishment of immunity. ^,

Among those who develop clinical illness, 3%–8% of TBEV-Fe patients, 21% of TBEV-Sib patients, and 72%–87% of TBEV-Eu patients will experience the full biphasic course of disease ^{, ,} ; all other patients will experience the first phase of influenza-like illness only. In a minority of cases, the infection is asymptomatic during the first stage and the onset of clinical illness occurs in the second phase of the disease.

Disease manifestations vary also by age. ^{, , ,} Older patients tend to have more-severe disease and suffer more neurologic sequelae, whereas in children disease tends to be less severe and asymptomatic infection is more common. ^, However, there are scattered reports of severe, even fatal cases in very young children. In children and adolescents, meningitis rather than encephalitis is the predominant form of the disease. However, between 35% and 58% of hospitalized patients younger than age 15 years have long-term cognitive or neuropsychiatric sequelae, including sensory disturbances, ataxia, dysphasia, spinal nerve paralysis, hearing loss, concentration difficulties, memory impairment, and emotional instability. ^{, ,} Patients older than 40 years tend to have the encephalitic form of the disease, and those older than 60 years tend to have the most-severe disease, including paralysis and seizures, with the highest case-fatality rate, as described below. ^{, ,}

In Austria, Germany, Sweden, Switzerland, and Lithuania, more than 50% of TBE cases are reported in people 50 years of age or older. Thus, the elderly are a special target group for immunization. Reported cases in children are comparatively low, and in children younger than age 7 years, TBE tends to be less severe, with a lower probability of permanent sequelae. However, a recent review identified up to 10% of children with long term neurological sequelae after TBE infection.

Although assessing clinical severity can be difficult when based on case reports from healthcare systems that differ in access to healthcare, case definitions, and diagnostic procedures, disease manifestations appear to differ by virus subtype. The clinical course of TBEV-Sib in children is more severe than TBEV-Eu, with half experiencing encephalitis. However, complete recovery from TBEV-Sib disease is reported in 80% of cases.

The clinical presentation of TBEV-Fe differs from TBEV-Eu. TBEV-Fe presents more gradually, with a prodromal phase that includes fever, headache, anorexia, nausea, vomiting, and photophobia. These symptoms are followed by a stiff neck, visual disturbances, and variable neurologic dysfunctions, including paresis, paralysis, sensory loss, and seizures. In a TBEV-Fe outbreak in Novosibirsk hemorrhagic manifestations in the form of gastrointestinal bleeding and local hemorrhages on mucosa and skin were observed. It has been reported that only 25% of patients with TBEV-Fe will recover without sequelae. Occasional chronic infections have also been reported, as further described below.

Besides age, the case-fatality rate of TBE appears to depend on the virus subtype. The case-fatality rates have been reported to be 1%–2% in TBEV-Eu, 6%–8% in TBEV-Sib, and up to 40% in TBEV-Fe. ^{, , , ,} However, the higher rates reported for TBE-Sib and TBE-Fe may be impacted by limited access to medical care or different healthcare-seeking behavior of patients in certain TBE-endemic regions.

A postencephalitic syndrome, with symptoms persisting beyond 3 months, has been described for all viral subtypes. ^, Chronic forms of TBE occur in 1% of cases caused by TBEV-Sib and have been verified by viral isolation. ^, Additionally, years after initial disease caused by TBEV-Fe or TBEV-Sib, rare cases of progressive neuritis and epileptic seizures have been described, but definitive proof of an etiological link to TBEV is lacking.

Virology and Pathogenesis

The TBEV particle is icosahedral, approximately 50 nm in diameter, and consists of an electron-dense spherical nucleocapsid of approximately 30 nm in diameter, surrounded by a lipid bilayer. The viral genome is single-stranded, positive-sense RNA of approximately 11,000 nucleotides in length. The many strains of all three subtypes have been sequenced (including vaccine strains TBEV-Eu–Neudörfl, K23, and TBEV-Fe–Sofjin, TBEV-Fe–205, and TBEV-Fe–Senzhang). ^, There is 16% or less nucleotide variation between TBEV-Eu and TBEV-Fe subtypes and only 4% or less amino acid variation between the subtypes, including less than 2.2% amino acid variation between the different TBEV-Eu strains. Consequently, the three subtypes of TBEV are serologically closely related and vaccines against one subtype are thought to induce cross-protective immunity to all three subtypes (see below). Although initial studies suggested that the three TBEV subtypes were restricted to geographically distinct locations, phylogenetic studies demonstrate that the three subtypes of TBEV overlap geographically.

Mature virions are composed of three structural proteins: envelope (E), core (C), and membrane (M) proteins, with molecular weights of 55, 15, and 8 kDa, respectively. The E protein is glycosylated and exists as 90 copies of a dimer orientated parallel to the viral surface as shown by x-ray crystallography. A glycosylated precursor of the membrane protein (prM) is present in immature virus particles. The mature nonglycosylated M protein is derived by a furin-mediated cleavage from the precursor protein prM. C is the only protein constituent of the isometric nucleocapsid that contains the virion RNA. The viral RNA also encodes seven nonstructural (NS) proteins. The coding sequence of the positively stranded RNA is 5′-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3′. All viral proteins are encoded within a single open reading frame and the individual proteins are released from a precursor polyprotein by co-and post-translational cleavage. Structural elements of the E protein are involved in the binding of virions to cell receptors, receptor-mediated endocytosis, and low-pH–dependent membrane-fusion. The E protein contains the important antigenic determinants responsible for hemagglutination inhibition (HI) and neutralization. E protein epitopes induce protective immune responses in the infected host and monoclonal antibodies to these epitopes have been extensively studied.

After the bite of an infected tick, the virus replicates in the dermal cells at the site of the bite. Then the virus is transferred through afferent lymphatic vessels to the regional lymph nodes where further replication occurs. The virus then spreads via the lymphatic system and the bloodstream, and invades susceptible tissues, including the reticuloendothelial system. There extensive viral replication occurs, leading to seeding of the CNS. High viral loads are required for the virus to cross the blood–brain barrier since the capillary endothelium is not easily infected. To evade host defenses, TBEV rearranges intracellular membranes to prevent recognition of double-stranded RNA (formed during virus replication) by cytoplasmic pathogen recognition receptors, allowing an approximate 24-h delay in interferon induction. The interferon response is further reduced by the NS TBEV protein NS5 that blocks JAK/STAT (Janus kinase–signal transducer and activator of transcription) signaling. ^, How TBEV enters the CNS is poorly understood but likely involves either crossing the blood–brain barrier via olfactory or autonomic neurons.

Diagnosis

Because the clinical manifestations of TBE are non-specific, TBE must be confirmed by laboratory techniques. In the initial viremic phase of the disease, the virus can be identified through inoculation of serum in a suitable cell line or in suckling mice. However, polymerase chain reaction (PCR) technology has largely replaced such culture technologies for virus identification. With the onset of the second phase of the disease, the virus has been cleared from the blood and is also difficult to detect in cerebrospinal fluid. Because the symptoms of CNS involvement are usually not observed until 2–4 weeks after the tick bite, antiviral antibodies are nearly always present at the time of admission to a hospital and can be detected readily by standard serologic tests. A recent TBEV infection can be confirmed by an increase in the HI titer, the neutralization titer (NT), or complement fixation titer, and by a decrease in HI titer after 2-mercaptoethanol treatment, suggesting the presence of immunoglobulin (Ig) M antibodies. These tests are now used mainly for confirmatory purposes and have been largely replaced by rapid, sensitive, and reliable enzyme-linked immunosorbent assays (ELISAs) directed at the detection of IgM antibodies in the early phase of TBE. A four-layer ELISA system for the detection of TBEV-specific IgM has been developed that is extremely sensitive and prevents interference when high-titer, virus-reactive IgG antibodies for TBEV are present. At an early stage after the onset of illness, TBEV-specific IgM can be detected in serum dilutions up to 1 : 10,000. However, in cases of other flavivirus exposures (e.g., vaccinations against yellow fever or Japanese encephalitis or following dengue virus infections), the use of an NT assay (e.g., rapid fluorescent focus inhibition test) is necessary to eliminate interference of flavivirus cross-reactive antibodies in ELISA and HI testing. ^, NT tests are only conducted in specialized laboratories with biosafety level 3 or 4 (depending on national requirements) and are not routinely available. However, thresholds and cut-offs of different NT tests vary significantly, making a direct comparison impossible and complicate interpretation of serologic results. An alternative approach to diagnosis is the comparison of ELISA antibody titers in paired sera collected 14 days apart, where a fourfold or greater increase in titer is considered a confirmatory diagnosis. A high correlation has been demonstrated between the ELISA IgG units and the HI and NT titers, provided there were no other exposures to flavivirus antigens by natural infection or vaccination. ^, NS1 IgG ELISA for differentiating infection versus vaccination antibody responses are increasingly becoming available. Standardized methods for serological and RT-PCR assays for European TBE have been published. ^,

Treatment

No specific therapy for TBE exists. Although reports of treatment with ribonuclease obtained from bovine pancreas or with emetine have been published, they are not generally accepted. Corticosteroids appear to hasten defervescence and improve subjective symptoms, but also prolong the period of hospitalization.

Symptomatic treatment includes maintenance of water and electrolyte balance, provision of sufficient caloric intake, and the administration of analgesics, vitamins, antipyretics, and antiepileptics, as needed. Physiotherapy of paralyzed limbs is essential to prevent muscle atrophy. Because person-to-person transmission of the virus has never been observed, there is no need to isolate patients with TBE. It is hoped that the improved knowledge of the structure of flavivirus proteins will soon lead to the development of antiviral agents.

Incidence and Prevalence Data

TBEV is exclusively restricted to Europe and Asia, with the distribution of TBEV including almost the entire southern part of the nontropical Eurasian forest belt, from Alsace-Lorraine in the west to Vladivostok, and the northern and eastern regions of China to Hokkaido in Japan and some regions of the Republic of Korea ( Figs. 60.1 and 60.2 ). ^{, ,} In 2018, 3092 confirmed cases were reported from EU/EEA following a strong seasonal pattern ( Fig 60.3 ). Between 2010–2019, the annual number of TBE cases reported in 33 countries was between 4492 and 6440 ( Table 60.1 ). The highest notification rate was obtained from Lithuania with >15/100000 population ( Fig. 60.2 ).

In 2020, TBE virus was isolated for the first time from ticks in UK and a serosurvey identified 4% of deer tick samples ELISA-positive, indicating that UK should also be considered as endemic although only one probable human case has been reported so far. ^, Although TBEV is found in valleys and nearby rivers with adequate habitats for ticks rather than in higher altitudes, in recent years it has been reported from altitudes up to 2100 m above sea level. Geographically restricted foci with very high TBEV activity have also been reported. ^, TBEV prevalence varies from year to year, possibly depending on microecological conditions such as humidity and temperature. A regression model has been developed for Germany, Austria, and Switzerland that proposes forecasts of TBE incidence for up to two year periods and could potentially be used for planning of vaccination activities.

In Europe, eight species of ticks have been identified that can transmit TBEV. Ixodes ricinus, the common castor bean tick, is the chief vector for the TBEV-Eu subtype and Ixodes persulcatus is the chief vector for the TBEV-Sib and TBEV-Fe subtypes. Other tick species have been associated with local TBE outbreaks in Siberia and the Far East. I. ricinus is found in much of Europe, extending to Turkey, northern Iran, and the Caucasus. I. persulcatus occurs mainly in eastern Europe, Russia, China, and Japan. The prevalence of TBEV in ticks has been shown to be as high as 21% in the District of Regen and 18% in the District of Freyung-Grafenau in southern Germany. Other studies have reported the TBEV prevalence in ticks to be as high as 39%. ^{, ,} The distribution of TBEV subtypes is correlated to the distribution of tick species. In regions where both I. ricinus and I. persulcatus are present, TBEV subtypes cocirculate. However, the TBEV-Sib subtype has also been isolated from I. ricinus , and the TBEV-Eu subtype has been found in I. persulcatus .

The TBEV-Eu subtype is most prevalent in western, northern, and eastern Europe and European parts of Russia, but it has also been detected in Asian regions of Russia, such as Altai, eastern Siberia, and the northern Caucasus. ^{, , ,} The TBEV-Sib subtype is prevalent in regions between Japan, the Baltic states, and Bosnia, ^{, , ,} and may have replaced the TBEV-Fe subtype in several regions of Russia. ^, The TBEV-Fe subtype has been detected in regions between the easternmost Japanese and Russian islands and the Baltic states, including regions in China and Mongolia. ^{, ,}

Given the highly focal and variable proportion of infected ticks, there is no internationally accepted definition for when a region is considered endemic for TBE. Regions are suggested to be at high risk for TBE (e.g., Austria, Czech Republic) if more than five cases of TBE per 100,000 people occurred before widespread use of TBE vaccines. ^{, ,}

Disease Surveillance and Reporting

TBE can be considered an “emerging disease” because it is spreading to regions where TBEV had not been previously detected. In the last few years, new foci of TBE cases have been identified in Austria, China, Denmark (mainland), Finland, Germany, UK, Kazakhstan, Kirgizstan, Mongolia, Norway, Sweden, Switzerland, France (Alsace), Italy (Northeast), Greece (Thessaloniki), and Uzbekistan. ^{, , , ,} This may be the result of many different factors, including climate change, migration of populations to suburban areas, changes in agricultural practices, increased reforestation, changes in leisure habits, and increased awareness and reporting. ^{, ,} Overall, awareness is limited in low-endemicity countries and cases may not be diagnosed unless there is a clustering. Additional factors contributing to this are underreporting of cases of TBE and the fact that the disease is still not notifiable in countries without a dedicated surveillance system or TBE surveillance systems are inadequate. ^, ( Table 60.1 ) shows reported cases of TBE by country over a period of 20 years. Strong seasonality patterns of cases may help to increase awareness ( Fig 60.3 ).

Furthermore, surveillance and reporting are hampered by the use of different case definitions for TBE, ^, limiting the comparison of data from different countries. Data on TBE are collected by national institutions, reference laboratories, regional institutions, and the European Center for Disease Prevention and Control (ECDC). ^, Although ECDC has provided a case definition for TBE, it is not yet systematically used in Europe ^{, ,} ( Table 60.2 ).

Since 1950, TBE is also a notifiable disease in Russia, although without a uniform case definition. Table 60.1 lists the numbers of reported cases of TBE between 2000 and 2019.

Risk Groups

The highest reported rates are among the age group of 45–64 years of age, with a female:male ratio of 1:1.5. A high percentage of detectable TBEV antibodies has been observed among high-risk groups, including persons working in agriculture and forestry, hikers, people engaged in outdoor sports, and collectors of mushrooms and berries. Increased tourism of nonvaccinated persons to central and eastern Europe exposes large numbers of people to a significant risk of TBEV infection. The United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have on their respective websites recommendations for vaccination of travelers.

Modes of Transmission and Reservoirs of Infection

TBE is a zoonotic disease, and ticks are the main vectors and reservoir hosts of TBEV in nature. Ticks become active at temperatures above 8°C and a relative humidity of 70%–80%, explaining the seasonality of the disease and the suitability of European and Asian forested areas as habitats. Vertebrates serve as amplifying reservoir hosts of TBEV and the primary source of infection for ticks, thus forming a cycle of transmission. Small rodents, such as mice and voles, are believed to be prominent reservoirs, but also large mammals, such as roe, deer, and goat, may be involved. ^{, ,} Transovarial transmission as well as transstadial transmission of the virus have been described when nymphs and larvae cofeed on the same host. Once infected, ticks carry the virus for life. TBEV is usually transferred to the host through the saliva of the infected tick. The virus can be transmitted to humans or other hosts by larvae, nymphs, and adult ticks. In humans, ticks attach themselves to the hair-covered portion of the head, ears, and the extremities. The epidermis is punctured with the chelicerae, and the hypostome is inserted. Because of the anesthetizing effect of the tick’s saliva, the bite causes no pain and often passes unnoticed by the host, leading the victim to not recall having been bitten by a tick.

While the main route of TBEV transmission occurs through tick bites, there are reports from several European countries of occasional transmission through the alimentary route by means of ingestion of unpasteurized dairy products. Goat, sheep, and cattle that are hosts for I. ricinus can be infected by TBEV. RT-PCR-testing demonstrated presence of TBEV in the milk of farm animals. Reports from Eastern European countries demonstrate that raw milk collected during the viremic phase can be infectious to humans. ^,