Tick-Borne Encephalitis Vaccine: Recommendations of the Advisory … – CDC
November 11, 2023
TBE Virus and Its Subtypes
TBE virus is a single-stranded RNA virus in the genus Flavivirus, family Flaviviridae (4). TBE virus is closely related to Powassan virus, a tickborne flavivirus transmitted in parts of the United States (5). The three main antigenic subtypes of TBE virus (i.e., European, Siberian, and Far Eastern) differ in the severity of disease they cause and geographic distribution (6). The principal geographic distribution of the European subtype virus is in parts of western and northern Europe through to the eastern European countries; the Siberian subtype virus is in Siberia and the Ural and European parts of Russia; and the Far Eastern subtype virus is in Japan, China, Mongolia, and the eastern parts of Russia; however, subtype virus distributions overlap substantially (69). Genomic studies have indicated two additional minor subtype viruses (i.e., Baikalian and Himalayan) (10,11).
TBE virus is primarily transmitted to humans by the bites of infected Ixodes sp. ticks but can also be acquired less frequently by alimentary transmission. Other rare modes of transmission include through breastfeeding, blood transfusion, solid organ transplantation, and slaughtering of viremic animals. Nymphs and adult ticks are believed to be responsible for causing most human infections. Approximately 60%70% of persons with TBE recall a bite (1219). Because TBE virus is present in the saliva of an infected tick, transmission likely occurs early during feeding (1,20).
Ixodes ricinus is the main vector for the European subtype TBE virus and Ixodes persulcatus for the Siberian and Far Eastern subtype viruses (21). I. ricinus is found in most of continental Europe and the United Kingdom and I. persulcatus in an area extending east from northeastern Europe through to China and Japan (22,23). The distributions of the two species overlap in certain countries, including Estonia, Finland, Latvia, and the European part of Russia (7,21,2327).
The preferred habitats for the vector ticks are woodland environments. The main habitats are deciduous forests for I. ricinus and coniferous forests for I. persulcatus (23,28). Ticks can be found either within the forest or on forest edges, where the forest transitions to grasslands, meadows, or marshlands, and they favor areas with low-growing dense brush and plant litter (23,2932). Recreational activities with increased risk for exposure to ticks include hiking, camping, cycling in woodland areas, hunting, fishing, birdwatching, and collecting mushrooms or berries (3336). Persons in certain occupations (e.g., farmers, forestry workers, military personnel, and researchers undertaking field work in rural areas) also might be at higher risk for exposure to infected ticks (17,37,38). Humans must enter a tick habitat to be at risk for infection because ticks do not, unaided, disperse widely (39,40). TBE virus infections acquired in urban areas (e.g., city parks) are occasionally reported; however, risk in urban areas is considered to be low (38,41,42).
The enzootic transmission cycle of TBE virus involves ticks and vertebrate hosts. Ticks are both virus vectors and reservoirs. A tick can become infected when feeding on a viremic host or through nonviremic transmission when co-feeding in close proximity to an infected tick (4345). After becoming infected, ticks remain infected through their various life stages and can transmit the virus sexually to other ticks and transovarially to their offspring (28,46,47). The main amplifying reservoir hosts are small mammals, particularly rodents (e.g., mice and voles). Larger forest animals (e.g., boar and deer) and domestic animals (e.g., cattle, dogs, goats, and sheep) do not have an important role in the maintenance of the virus in nature. However, deer and cattle have an important role in maintaining tick populations (22,23,40,48). Humans are incidental, dead-end hosts in the transmission cycle because they do not develop a level or duration of viremia sufficient to infect ticks or have sufficient numbers of attached ticks at one time to allow co-feeding (22,4951).
Alimentary transmission is a less frequent means of acquisition of TBE virus and occurs after ingestion of unpasteurized dairy products (e.g., milk and cheese) from infected cattle, goats, or sheep; transmission from goats is most commonly reported (5260). Large outbreaks linked to infected dairy products have been reported from areas where TBE is endemic, including one with approximately 600 cases (58,61,62). Approximately 47 laboratory-acquired TBE virus infections have occurred globally (6365). TBE virus transmission from infected breastfeeding women to their infants has been described in at least two published reports; one infant remained healthy and the other had severe sequelae (30,66). Other rare modes of transmission include blood transfusion, solid organ transplantation, and slaughtering of viremic animals (6769).
TBE virus is focally endemic in a geographic region extending from western and northern Europe through to northern and eastern Asia (https://www.cdc.gov/tick-borne-encephalitis/geographic-distribution/index.html). Although the geographic range of TBE virus is restricted by the presence of the tick vectors, areas of TBE virus transmission are more limited and focal than the tick distribution. TBE virus-infected ticks typically are found in discrete areas (i.e., foci) confined by the presence of environmental conditions that allow maintenance of the natural transmission cycle rather than being distributed evenly across a region (13,70,71). Natural foci can be small, with locations <1 square mile (72). Multiple factors are required for maintenance of virus circulation (e.g., favorable microclimatic conditions, interactions of ticks and vertebrate hosts, and local vegetation), which likely contribute to the focal occurrence (73). Within affected areas, tick population density and TBE virus infection rates can be highly variable. Infection rates in ticks typically range from 0.1% to 5%, although rates of approximately 40% in I. persulcatus ticks have been reported (21,7477).
During recent decades, TBE virus has emerged in new geographical foci in countries where the disease is endemic, and the overall area of recognized transmission has expanded westward and northward (1,26,7889). Since 2016, three countries have reported their first autochthonous cases (Belgium, England, and the Netherlands) (9092). New TBE foci also have been detected at higher altitudes, reaching elevations up to 2,100 meters (6,890 feet) above sea level (52,81,9395). Concurrently, in certain countries, a reduction in virus transmission and possible loss of recognized geographical foci have been documented (81,93). Various factors might be contributing to the changing distribution, including changes in climatic and ecologic conditions altering tick habitats and transmission cycles and dispersal of ticks into new areas by birds, deer, or other animals (22,40,79,96103).
In areas where TBE is endemic, approximately 5,00010,000 new cases are reported annually (9,104). However, this figure likely represents an underestimate of the actual number of cases because of underdiagnosis, underreporting, or both in certain countries (13,105108).
Incidence rates differ from country to country and depend on the local ecology and geographic distribution of the virus within the country. However, national incidence rates are not directly comparable because of variable approaches to surveillance, the extent of human and laboratory resources applied to surveillance, and the population vaccination coverage (109). Higher incidence rates are most commonly reported from the Baltic states (Estonia, Latvia, and Lithuania), Slovenia, and the Czech Republic (110).
Annual variability in countries incidence rates is typical (86,109,110). The reasons for this variability are not completely understood but reflect the complex interactions among factors that affect risk for infection, including tick density, presence of animal hosts, ecologic conditions, weather, and human behavior (35,76,109112). Longer-term fluctuations in TBE incidence also occur (81). Incidence of reported cases has increased in multiple countries in recent decades while remaining stable or decreasing in others (27,111118). In addition to the factors affecting annual variability in the short term, socioeconomic factors (e.g., political instability and poverty) can affect disease incidence over the longer term (79,93,119123). Other factors that can lead to observed increases include improved awareness of TBE, increased access to laboratory diagnostics, and better surveillance (1,13,89,109,110,124). Of note, TBE became a reportable disease in the European Union in 2012 (125). Reduced incidence in certain countries is related to increased vaccine uptake over time; for example, in Austria, a vaccination program resulted in TBE incidence decreasing approximately sixfold from 5.7 cases per 100,000 population during 19721981 to 0.9 during 20022011 (126).
TBE can occur in persons of all ages, with encephalitis reported in one infant as young as 17 days (127). Incidence is typically low in children and increases with age, generally peaking in the 6069 years age group and then decreasing in the 70 years age group (17,86,110,111,115,128130). TBE is more common in males, with reported incidence rates often 1.52 times higher than in females, likely reflecting a greater risk for tick exposure (14,35,37,67,110112,115,131,132).
The main TBE virus transmission season is AprilNovember when ticks are most active because of warmer weather in the Northern Hemisphere (12,110,112,133,134). Peak transmission generally occurs for multiple weeks during the warm, humid summer months, typically during JuneAugust in European countries. However, in central and northern Europe, two peaks might occur in summer and early fall (12,15,16,23,37,111,112,115,135137). Unlike mosquitoborne diseases, large outbreaks of tickborne diseases do not occur. Occasional cases are reported during winter because tick activity is still possible at temperatures close to freezing (23,28,109,110,138).
Approximately three fourths of TBE virus infections are asymptomatic (67,139,140). Among patients who develop clinical symptoms after a bite from an infected tick, the incubation period is typically 714 days (range = 228 days) (17,90,141). For TBE acquired through the alimentary route, the typical incubation period is shorter, usually <2 weeks and often 24 days (53,57,60,142).
The most recognized clinical presentation of TBE is central nervous system infection (i.e., aseptic meningitis, meningoencephalitis, or meningoencephalomyelitis) (Box 1). Overall, meningitis is reported in approximately 35%45% of patients, meningoencephalitis in 45%55%, and meningoencephalomyelitis in 10% (14,17,18,37,137). However, younger patients (i.e., aged approximately 15 years) more frequently have meningitis, and the percentage of patients with more severe clinical presentations usually increases with age (12,14,17,18,131,133,143148). Relatively mild forms of disease (e.g., undifferentiated febrile illness) can occur (36,149). A chronic form of disease has been reported from Russia linked to infection with the Siberian subtype virus and, rarely, the Far Eastern subtype virus and is possibly associated with long-term viral persistence (18,36,150153). Progressive, slow development of neurologic symptoms often occurs, with or without an initial acute illness. In certain patients, the incubation period can be prolonged and symptoms can first manifest many years after a tick bite. A chronic relapsing form of disease also has been reported in Russia (152,153). Immunity after TBE virus infection is considered to be lifelong (49).
TBE can have a monophasic or biphasic illness course (i.e., an isolated neurologic illness alone or neurologic disease after an initial nonspecific illness). The monophasic disease course is the most common in infections caused by the Far Eastern and Siberian subtype viruses. The biphasic course is the most frequent in patients infected with the European subtype virus; approximately 65%75% of patients infected with the European subtype virus have a biphasic illness course (14,17,18,36,133,148,151,154). When biphasic illness occurs, the initial phase includes nonspecific symptoms (e.g., fever, headache, malaise, myalgia, nausea, and vomiting). These symptoms usually last for a median of approximately 4 days (range = 110 days), followed by a period of remission of approximately 7 days (range = 133 days), followed by the second (neurologic) phase (12,17,18,133,155).
Neurologic signs and symptoms of TBE vary but can include meningeal signs, altered mental status, cognitive dysfunction (e.g., decreased concentration and memory impairment), ataxia, rigidity, tremors, and cranial nerve and limb paresis or palsies. Limb involvement is more typically unilateral than bilateral, and the upper extremities are more often affected than the lower extremities (14). Seizures are not common with TBE caused by the European subtype virus (17,153,156,157).
Increasing age is a key risk factor for more severe disease. Other risk factors include infection with the Far Eastern subtype virus and being immunocompromised, and certain studies have found a correlation with the monophasic illness course (16,18,151,158163).
Among the limited number of published case reports of women infected during pregnancy, the clinical spectrum of illness appears similar to that of the nonpregnant population (164168). Apart from two reports from the 1960s in which the diagnostic methods used to confirm maternal infection were unclear, all infants born to infected mothers were reported to be healthy at birth and transplacental transmission of TBE virus had not been confirmed.
Clinical laboratory findings with TBE are nonspecific. In the initial phase of a biphasic illness, findings can include leukopenia, thrombocytopenia, or elevated hepatic enzymes (145,149,154). In the neurologic phase of disease, findings can include a peripheral leukocytosis, an elevated erythrocyte sedimentation rate, and increased C-reactive protein levels (12,17,37,133,146). Cerebrospinal fluid (CSF) testing usually indicates a pleocytosis, typically lymphocytic, with moderately elevated protein levels (12,17,37,131,133). However, early in disease, neutrophils can predominate in CSF.
Magnetic resonance imaging (MRI) occasionally detects abnormalities in the brain or spinal cord; however, sensitivity is low for diagnosis of TBE (169). In one prospective study in Germany, 18% (18 of 102) of patients with MRI results had abnormal findings, and in a retrospective study from Austria, 9% (four of 45) of patients with MRI results had abnormalities considered TBE related (17,170). Changes, when present, are most commonly observed in the thalamus, often bilaterally, and less often in the cerebellum, basal ganglia, brainstem, or other locations (17,147,171174). In patients with myelitis, radiculitis, or both, either alone or in association with encephalitis, spinal MRI can indicate changes such as T2-hyperintensities in the anterior horns of the cervical cord (171,175179). Computerized tomography scans do not usually identify any abnormalities (169). Abnormal electroencephalogram findings are common and can include diffuse slowing and focal abnormalities (17,132,133,147,173).
The laboratory diagnosis of TBE usually is based on detection of virus-specific immunoglobulin M (IgM) antibody in CSF or serum (180). An IgM enzyme-linked immunosorbent assay is routinely used for testing samples and usually is positive when neurologic symptoms are present. However, cross-reactivity with other flavivirus antibodies can occur because TBE virus shares common antigenic sites within its E protein with multiple other flaviviruses (49). Plaque reduction neutralization tests can be performed to discriminate between cross-reacting antibodies attributable to another primary flavivirus infection or to confirm recent TBE virus infection on the basis of a fourfold or higher increase in virus-specific neutralizing antibodies between acute- and convalescent-phase serum specimens. However, in patients who have been infected previously by another flavivirus or vaccinated with a different flavivirus vaccine (e.g., Japanese encephalitis or yellow fever vaccine), cross-reactive antibodies can make identifying a specific etiologic agent difficult (180). Vaccination history, date of symptom onset, and information about other flaviviruses known to circulate in the geographic area that might cross-react in serologic assays should be considered when interpreting results. In addition, possible antibody persistence from a previous TBE virus infection should be considered; serum IgM antibodies typically are detectable for approximately 34 months after infection but can persist for 3 years (12,181,182).
TBE virus occasionally has been isolated, or TBE viral RNA has been detected by nucleic acid amplification tests (NAATs), in serum, whole blood, urine, or CSF samples when a patient has neurologic illness (50,51,67,92,127,168,183187). Although these methods are insufficiently sensitive for routine diagnostic purposes, NAATs can be of value in patients who are immunocompromised (158,188,189). In addition, if testing is done during the initial febrile (viremic) phase of illness before neurologic symptoms develop and antibodies are measurable, RNA often can be detected; however, patients usually only are tested after neurologic disease manifests (49,169,184). In fatal encephalitis cases, TBE virus RNA has been detected in brain tissue (68,184).
No commercially available tests for TBE virus infection are available in the United States. Diagnostic testing can be performed at CDC. Clinicians should contact their state or local health department or the Arboviral Diseases Branch, Division of Vector-Borne Diseases (970-221-6400) for assistance with diagnostic testing.
No specific antiviral treatment for TBE is available. Patient management consists of supportive care, treatment of symptoms, and interventions to prevent secondary complications (e.g., aspiration pneumonia or urinary tract infection) (153,169). Patients with meningoencephalitis should be closely observed because coma or neuromuscular paralysis leading to respiratory failure can develop rapidly (36).
An anti-TBE virus intravenous immunoglobulin (IVIG) preparation was previously used in Europe for postexposure prophylaxis or treatment. However, no effectiveness data from controlled clinical trials are available, and IVIG use was discontinued after reports of suspected antibody-dependent enhancement of infection resulting in a more severe course of disease (190193). In Russia and Kazakhstan, specific anti-TBE virus IVIG preparations continue to be used; information on their effectiveness is published primarily in the non-English literature (153).
The outcome of TBE largely depends on the patients age, clinical form of the disease, and virus subtype (194). Among patients with neurologic disease and infected with the European subtype virus, the case fatality rate is usually <2% (14,17,18,37,86,110,111,114,146,195,196). Fatality rates from infection with the Siberian subtype virus are higher but rarely exceed 6%8% (151). Rates of 20%40% were historically described with the Far Eastern subtype virus, although the extent of study methodology and patient inclusion criteria as contributing factors is unclear (62,151,197). In China, where the Far Eastern subtype virus is found, case-fatality rates were >25% in the 1950s; however, rates of <10% have been reported since the 1980s, purportedly related to improved disease awareness and quality of medical care (151,198). In Russia, where the Far Eastern and Siberian subtype viruses predominate, TBE mortality rates of approximately 2% have recently been reported (153).
Studies to assess frequency of sequelae have used variable symptom definitions, types of cohorts, investigation approaches, and durations of follow-up after illness to measure outcomes, making interpretation and comparison of studies difficult. A limitation of multiple studies is incomplete follow-up among the persons in the cohort, potentially biasing results. Among patients infected with the European subtype virus, sequelae have been reported in 20%40% overall, including neurologic sequelae (e.g., limb paresis or paralysis) in up to 10% (17,18,155,194,196). Sequelae have been reported with higher frequency after infection with the Far Eastern and Siberian subtype viruses, but the reported differences might be a result of methodologic differences in published reports.
The severity of reported sequelae ranges from mild symptoms with limited to no effect on quality of life to severe sequelae that interfere with activities of daily living. Reported serious outcomes of infection include permanent limb or cranial nerve palsies or paralysis, ataxia, and dysphasia (155,194). Milder symptoms include cognitive impairment (e.g., difficulties with memory or concentration), headaches, fatigue, tremors, hearing loss, emotional lability, or minor problems with balance or coordination (17,18,37,196). In a case-control study in Sweden with 92 patients and 58 controls with follow-up conducted from 2 to 15 years (median = 5.5 years) after TBE virus infection, patients scored significantly lower than controls in the domains of memory and learning, executive function (i.e., initiative and motivation), vigilance (i.e., concentration, attention, and fatigue), and physical impairment (i.e., fine motor skills, coordination, and balance) (199).
Certain symptoms can improve or resolve during the weeks to months after hospitalization (200). In one study, the median time to recovery was 13 weeks (range = 2156 weeks) among the patients who recovered completely or had only unrelated ongoing health issues (63%; 72 of 114) (196). However, patients occasionally have worsening of sequelae over time (18,173).
Severe outcomes are more frequent with increasing age and might be of particular concern for persons aged approximately 60 years (201). Older age has been correlated with a longer duration of hospitalization, lengthier time to recovery, higher case-fatality rate, and increased risk for sequelae (17,86,111,131,194,196). The association between older age and poor outcomes is likely related to immunosenescence with increasing age (202). Among children, deaths are rare and neurologic sequelae occur at low rates (<3%) (12,14,129,133,148,203). However, permanent, severe neurologic deficits can occur and subtle deficits (e.g., cognitive problems, headache, fatigue, or irritability) might be common (19,127,173,204).
TBE is rare among U.S. travelers to areas where the disease is endemic. Twelve TBE cases have been reported among U.S. adult and pediatric civilian (i.e., nonmilitary) travelers, including one case in 1979 and 11 cases during 20012021 (180,205,206) (Table 1). During 20012021, the mean was <1 reported case (range = 02 cases) annually. However, TBE cases might not have been identified if the illness was diagnosed overseas or if a clinician did not consider TBE in the differential diagnosis for a returning traveler with a compatible illness. On the basis of approximately 2025 million U.S. citizen trips to countries with TBE risk each year, and a mean of <1 diagnosed TBE case each year, the overall incidence of TBE among U.S. civilian travelers is low (207). However, certain persons who travel abroad will be at increased risk for infection because of location and season of travel, their activities, and other factors (Box 2).
Among the 12 TBE cases diagnosed in U.S. civilian travelers during 19792021, a total of 10 (83%) occurred in males, the median age was 38 years (range = 479 years), and infections were acquired in Europe, Russia, or China. Travel, and thus exposure to TBE virus, for all patients occurred during MayAugust. Among 11 travelers for whom information was available on duration of travel in areas where TBE is endemic, the median travel duration was 18 days (range = 769 days). All eight travelers with available data reported activities with risk for tick exposure, including hiking, camping, fishing, and trail running. Clinical illness occurred in a biphasic manner in eight (67%) patients. Eight (67%) patients had meningoencephalitis and four (33%) had meningitis, and no deaths occurred. Seven (58%) patients recovered completely, two (17%) had mild cognitive sequelae, one (8%) recovered but information on possible sequelae was unavailable, one (8%) had severe neurologic sequelae including dysarthria and mild limb bradykinesia, and one (8%) was discharged from acute care to a rehabilitation facility but their clinical outcome was unknown.
In addition to the 12 cases among civilian travelers, 12 TBE cases were diagnosed among U.S. military personnel (n = 8) or their dependent children (n = 4) during 20122021 (208210) (Table 2). One case occurred in 2012, and the remaining 11 occurred during 20172021. At the time of infection, all persons were living in Germany; nine persons had specific information available and all were living in Baden-Wrttemberg or Bavaria, Germanys two states with the highest number of reported annual TBE cases (86). On the basis of a mean of 1.2 cases per year among approximately 50,000 U.S. military personnel and dependents living in Germany, the TBE risk was similar to that of the local population of Baden-Wrttemberg and Bavaria where annual TBE incidence during 20122018 ranged from 0.7 to 2.0 cases per 100,000 population (86). Among the 12 TBE cases, 10 (83%) were in males, the median age was 33 years (range = 247 years), illness onsets occurred during AprilNovember, and nine (75%) had neurologic illness. Five (42%) patients recovered, including two who had short-term sequelae before complete recovery; four (33%) had no outcome information reported; and three (25%) experienced moderate sequelae.
In Europe, a median of 36 traveler cases (range = 2565 cases) wase reported to the European Centre for Disease Prevention and Control each year during 20142020 among the approximately 2,0003,800 TBE cases reported annually (211). However, because TBE is endemic in multiple areas of Europe and TBE vaccines are available, the number of traveler cases prevented by vaccination is unknown (212). Most cases occurred among persons who reported undertaking activities with risk for tick exposure, with only rare case reports of travelers with TBE acquired through ingestion of unpasteurized dairy products (142,213216). Local population TBE incidence data for multiple countries where the disease is endemic in Europe are published annually by the European Centre for Disease Prevention and Control; however, infection risk for a traveler cannot be inferred from these data because the data might be influenced by surveillance methods, reporting practices, and vaccination coverage (104).
At least 47 laboratory-acquired TBE virus infections have been reported globally, and approximately all occurred before 1980 (6365,67). Among these 47 infections, 37 (79%) resulted in disease, and the remainder were asymptomatic infections. At least four of the infections occurred among U.S. laboratory workers; three cases were overt disease with two deaths reported, one was an asymptomatic infection, and all occurred before 1980. None of the infected laboratory workers was known to have received TBE vaccine. Limited information was available on transmission routes; however, all 10 cases with information reported were attributed to aerosolization during laboratory procedures or handling of infected animal waste. Transmission through accidental percutaneous or mucosal exposures is possible. Work with TBE virus typically is restricted to biosafety level (BSL)-4 facilities and practices (217).
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Tick-Borne Encephalitis Vaccine: Recommendations of the Advisory ... - CDC
