ARCHIVED - Statement on tick-borne encephalitis

Canada Communicable Disease Report
Volume 32 • ACS-3 1 April 2006

An Advisory Committee Statement (ACS)

Committee to Advise on Tropical Medicine and Travel (CATMAT)*†

PDF Version 20 Pages - 415 KB

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Tick-borne encephalitis (TBE) is a viral disease affecting the central nervous system. The etiologic agent, tick-borne encephalitis virus (TBEV), belongs to the family of Flaviviridae (genus Flaviviruses). Like many flaviviruses, it is an arbovirus or arthropod-borne virus. In the tick-borne virus serocomplex, three genotypes of TBEV have been identified: the central European, Far Eastern, and Siberian subtypes¹. The virus exists in natural foci, where it circulates between vertebrate and arthropod hosts. The vertebrate hosts of the virus are mainly rodents, but other wild or domestic animals, such as fox, deer, dogs, or cows, may also be infected. The vector-competent hosts are ticks belonging to the family Ixodidae (hard ticks). Many species of hard tick are known to transmit the virus, but two species play a major role in TBEV transmission: Ixodes ricinus and Ixodes persulcatus².

2. Epidemiology

Ixodes ricinus is widespread in central and western Europe, where it transmits the European TBEV subtype (Central European TBE). Ixodes persulcatus is widely distributed in Russia and the Far East, where it transmits the Siberian and Far Eastern TBEV subtypes (Russian Spring Summer Encephalitis)^1,2. Overlapping subtypes exist in eastern European regions. Areas of risk are found through large sections of Europe from eastern France to southern Scandinavia to Croatia, and as far east as northern Japan^2-4. The current epidemiology of TBE has recently been reviewed in detail². The Web site of the International Scientific Working group on TBE can be consulted for reports and maps on TBE infections in specific European countries, including Russia (ISW-TBE Reports)⁵. Another source describing TBE epidemiology in European countries can be found in Eurosurveillance, a publication of the European Community⁶. The ticks are distributed in natural foci (hot spots) that tend to be stable over time⁷. Natural foci are usually in areas of moderate temperature, high humidity, and altitudes of up to 1000 m^8,9. According to some reports, ticks may be found as high as 1400 m^10,11. Preferred sites are the edges of forests and areas with deciduous trees, low-growing dense bush, and low ground cover⁸. Domestic and wild habitats with sufficient moisture, ground foliage, and vegetation litter can provide shelter for both ticks and their animal hosts⁹. Tick activity starts in March/April and ends in October/November, usually peaking in the months of May/June and September/October in central Europe^2,8.

Surveys of virus prevalence in ticks in natural foci show considerable variability by region and across time. Prevalence rates as low as 0.9% (Bavaria 1997-1998) and as high as 26.6% (Latvia 1995) have been reported in wild-caught ticks(7,12). TBEV prevalence in ticks removed from patients can be higher: for example 31% to 41% from Latvian patients between 1998 and 2002(12). The reason for the discrepancy in prevalence rates between ticks collected in the field and those collected from patients is not certain; however, it is known that TBEV titre in tick saliva increases during the feeding process (see Routes of Transmission).

The seroprevalence of TBE in human populations in endemic areas also varies widely. A survey of 1,896 unvaccinated forestry workers in the various counties of Baden-Württemberg (south-west Germany) from 1997 to 1999 showed a mean seroprevalence of 7.3%¹³. In 2002, TBE seroprevalence rates in the general populations of Lithuania and Denmark (Island of Bornholm) were reported to be 3% and 1.4% respectively^14,15. However, with increasing TBE immunization rates in the population, seroprevalence data become less reliable indicators of TBE infection rates.

Incidence rates, as well as the number of TBE cases, in several western and eastern European countries for the years 1976 to 2002 can be viewed on the Web site of the ISW-TBE⁵. The number of reported cases in a country depends on the prevalence of infected ticks, the outdoor activities of the population, and the diagnostic abilities and reporting system of the country. In Austria, a TBE mass vaccination program was introduced in 1981^16,17. Until then, the average number of TBE cases per year was 500 (range 280 to 700)¹⁶. Since 1982, there has been a significant reduction, down to 62 TBE cases in 1998 and 41 cases in 1999(16,17). Although Austria is the only European country to have a routine vaccination program, Hungary has also reported a significant decline in cases from 1996 (n = 224) to 1999 (n = 51). The decline in Hungary is not fully understood but may be due partially to vaccination and partially to declining economic conditions resulting in decreased diagnostic testing². In many countries without routine vaccination programs, such as Germany and the Czech Republic, the number of cases per year has remained high or has increased over time⁵.

3. Routes of transmission

Ixodes ticks normally have a 3-year life cycle (range 2 to 6 years) as they grow through the following four stages: egg, larva, sexually immature nymph, and sexually mature adult⁹. Larvae and nymphs feed principally on rodents, and adult ticks tend to feed on larger animals. Ticks can become infected at any stage, including infection through transovarial transmission, and they remain infected for life². Ticks at all stages are known to bite humans⁹.

Once a tick finds an appropriate host, the attachment and feeding process requires several days. The tick's saliva contains chemicals that counteract the hemostatic, inflammatory, and immune responses of the host. The bite is painless and is often not noticed^2,18. The saliva also contains and transmits TBEV^2,18. The virus titre in saliva can increase 10 to 100 fold from the first to the third day of the blood meal². However, transmission typically occurs early in the feeding process^2,18.

Another, less frequent, route of transmission is the ingestion of unpasteurized milk and milk products^2,19.

The same ticks (I. ricinus and I. persulcatus) that transmit TBEV can also transmit Borrelia burgdorferi, the agent of lyme borreliosis; Anaplasma phagocytophilum, the agent of human granulocytic ehrlichiosis; Babesia, the agent of babesiosis; and other, rarer, pathogens2,9. Simultaneous infection with multiple organisms is possible. The Web site of the European Union Concerted Action on Lyme Borreliosis can be consulted for further information on Lyme disease in Europe9.

4. Clinical features of tick-borne encephalitis

Central European variety

Asymptomatic infection is common. According to different sources, 10% to 30% of infected persons develop symptoms^4,20. The incubation period is usually 7 to14 days but ranges from 4 to 28 days^20,21. The illness is biphasic. The first phase, which usually resolves within 1 week and correlates with viremia, is frequently subclinical, or it presents as a nonspecific illness with fever, malaise, headaches, nausea, and vomiting^20,21. Following a temporary remission of approximately 1 week, in 10% to 30% of individuals there is a second neurologic phase after the virus has spread to the central nervous system^20,22. The second stage presents as aseptic meningitis (especially in children) or encephalitis, myelitis, radiculitis, or some combination⁸. Studies of patients with neurologic illness report that, overall, approximately 50% have meningitis, 40% meningoencephalitis, and 10% meningoencephalomyelitis^21,23,24.

The diagnosis is usually based on the history of exposure to ticks within the previous 3 to 4 weeks, clinical symptoms, and specific IgM and IgG antibodies to TBE, as measured by enzyme-linked immunosorbent assay (ELISA)^4,20,25. Antiviral antibodies are usually detectable at the beginning of the second phase^20,25. Other specific tests are nested reverse transcriptase polymerase chain reaction (nRT-PCR) to detect virus-specific nucleic acid, or Western blots, performed in specialized laboratories^20,25. There are no effective antiviral drugs for TBEV, therefore treatment consists of supportive care(20,22). The reported case fatality rate is approximately 0.5% to 2%^20,22,23. Long-term follow-up studies show that a significant proportion (36% to 94%) of cases have a postencephalitic syndrome for months to years after the acute illness, characterized by neuro-psychiatric symptoms such as asthenia, severe headaches, memory loss, lack of concentration, decreased stamina, depression, ataxia, incoordination, tremor, and/or hearing impairment^22,24. Residual paresis has been reported in 0.3% to 10% of patients^21,22. Residual neurologic sequelae are more likely to occur in the elderly and in those with severe disease^4,8. Children have a generally better prognosis than adults²¹.

Far Eastern variety

The course of this disease is monophasic and more severe, with rapid neurologic involvement. The case fatality rate is 20%, and residual neurologic sequelae occur in up to 60% of survivors⁸.

5. Methods of prevention

The probability of human infection in an area with a natural TBEV focus depends on the prevalence of infected ticks, human exposure to ticks, and the preventive measures taken.

Environmental and personal protective measures, such as wearing clothing with a smooth weave, taping pants or tucking them inside footwear, applying DEET (N,N-diethyl-3-methylbenzamide), and using permethrin-impregnated clothing, help to minimize the risk of tick bites^26-28. Permethrin appears to be more effective than DEET, but the combination of DEET and permethrin gives almost 100% protection^26-28. If a tick bite has occurred, proper removal of the tick, as outlined under Recommendations, may decrease the risk of viral transmission²⁹ but will not prevent all cases because of early viral transmission of the virus during a blood meal^2,18.

Recommendations regarding environmental and personal protective measures are listed under Recommendations. Personal protective measures for the prevention of arthropod bites are fully described in CATMAT's Statement on Personal Protective Measures to Prevent Arthropod Bites³⁰.

6. Immunization

Canadians residing in or travelling to TBE-endemic areas should be evaluated for their risk of tick bites (see Recommendations). Since TBE vaccination is safe and highly immunogenic, it should be recommended for travellers considered to be at risk³¹.

6.1 Pre-exposure active immunization

Two TBE vaccines, available in Europe, will be discussed: Encepur® adults (and Encepur® children) marketed by Chiron Vaccines, Germany, and FSME-IMMUN®0.5 mL (and FSMEIMMUN ® 0.25 mL Junior) by Baxter Vaccine AG, Austria. Both are inactivated vaccines and provide safe and reliable protection^17,32,33. Immunity is induced against all TBEV variants, including the European and Far Eastern subtypes³⁴.

The antigenic components of the two available vaccines (virus strain K23 of Encepur® and strain Neudoerfl of FSMEIMMUN ®) are highly homologous and can be assumed to elicit the same immune response³⁵. In one study, > 400 subjects previously vaccinated with at least three doses of FSME-IMMUN® were successfully boosted with Encepur®³⁶. The result suggests that the strains are interchangeable.

The main manufacturing characteristics of the currently available vaccines are detailed in Table 1.

Table 1. Product characterization of vaccines referred to in text

The vaccination schedules, immunogenicity, and safety data of the FSME-IMMUN® and Encepur® vaccines are summarized in Table 2.

Table 2. Summary of vaccine characteristics of FSME-IMMUN® and Encepur®

FSME-IMMUN® 0.5 mL and FSME-IMMUN® 0.25 mL Junior (Baxter Vaccine AG)

FSME-IMMUN® was approved in Austria in 1976 and has been widely used for many years³³. It was reformulated in 1999 to eliminate mouse brain passage during manufacture³³. It is now marketed under the name FSME-IMMUN® 0.5 mL for those ≥ 16 years and FSME-IMMUN® 0.25 mL Junior for children 1 to 15 years of age (Summaries of Product Characteristics for FSME-IMMUN® 0.5 mL/FSME-IMMUN® 025 mL: unpublished work, Baxter Vaccine AG, Vienna, February 2004). It is a suspension of formaldehyde-inactivated TBEV (strain Neudoerfl) propagated in chick embryo cells. It is adsorbed onto aluminum hydroxide and contains 0.5 mg (junior 0.25 mg) human serum albumin as stabilizer and residues of protamine sulphate, gentamicin, neomycin, and formaldehyde³³. It is thimerosal-free. Each preloaded syringe contains a 0.5 mL (junior 0.25 mL) suspension and has a shelf life of 24 months when stored at 2° C to 8° C³³.

Many of the data upon which current recommendations are made were generated with the earlier formulation of FSME-IMMUN®. The efficacy and safety profiles of the earlier and current formulations appear to be very similar.

Scheduling and route of administration

The manufacturer’s recommendations with regard to primary and booster vaccinations for adults and children are stated in the Summaries of Products Characteristics for FSME-IMMUN® 0.5 mL and FSME-IMMUN® 0.25 mL Junior. The manufacturer recommends administration of a primary immunization series in three doses, at 0, 1 to 3 months, and 6 to 15 months (conventional schedule). The vaccine is given intra-muscularly into the deltoid muscle. If a rapid immune response is required, the second dose should be given 2 weeks after the first dose.

Recommendations regarding booster intervals have recently been published in the Austrian immunization plan³⁷ and are based on the results of a recent cross-sectional study³⁸.

For at risk adults < 60 years of age, the first booster dose should be given 3 years after the third dose of the primary series. Thereafter, booster intervals of 5 years are recommended. For those aged ≥ 60, booster doses are recommended every 3 years. For booster intervals exceeding 10 years, the Austrian immunization plan recommends administration of one dose with verification of TBE antibody titres 4 weeks later³⁷ (see section 6.3). However, this recommendation is not supported by a recent cross-sectional study, which indicated that a single booster dose is generally successful, regardless of the time interval following the last vaccination³⁶. The TBE vaccines are therefore similar to other inactivated alum-adsorbed viral vaccines in that a single booster usually re-establishes full protection independently of the time interval following the primary series.

Since long-term studies are not yet available for children, booster intervals of 3 years are recommended when administering the pediatric vaccine.

The vaccination series should ideally be started in winter. Effective immunity will then be present at the start of the tick season.

Protective efficacy, immunogenicity, and safety

Protective efficacy: The efficacy (protection) rates of previous generation FSME-IMMUN® vaccines administered on day 0, at 2 weeks to 3 months, and at 9 to 15 months have been calculated for the Austrian population to be 95.6% to 100% after the second and 96% to 98.7% after the third vaccine dose¹⁷. No other efficacy studies could be found for TBE vaccines.

Immunogenicity after primary immunization: The immunogenicity and safety of FSME-IMMUN® in adults and children receiving primary vaccination have been evaluated in several large studies sponsored by Baxter. These studies are listed in Appendix 1. Some of them have been described in a recent review article and in brief abstracts^33,39,40. In these studies, the adult and pediatric vaccines were administered on day 0, at 21 to 35 weeks, and between 6 months and 10 months. Seroconversions were measured by both enzyme-linked immunoassay (EIA) and neutralization test approximately 1 month after vaccination. In adults, the seroconversion rates after the second and third doses were found to be 92.9% to 97% and 100% respectively (Appendix 1: studies #062, #201, #202). In children, depending on their age, the seroconversion rates were 98.5% to 100% and 100% after the second and third doses respectively (Appendix 1: studies #199, 205, 206, 207).

The manufacturer’s recommendation for an accelerated schedule, in which the second dose is given 2 weeks after the first, is supported by one published pediatric study. In this study, of 37 children aged 8 to 14 years who were vaccinated on day 0 and 10, 95% had seroconverted at 2 weeks after the second dose, as measured by EIA⁴¹.

Long-term immunogenicity: Long-term immunogenicity has been assessed in a cross-sectional study of 430 previously vaccinated adults immunized with earlier generation FSME-IMMUN® vaccines. The authors concluded that, following a primary vaccination and ≥ 1 booster dose, the immune protection exceeded 3 years and appeared to be sufficient for up to 8 years after the last booster dose³⁸.

Safety: The current FSME-IMMUN® 0.5 mL vaccine and its earlier versions have an excellent safety record after 20 years of widespread use according to both published^17,33,42,43 and unpublished studies (Appendix 1). In adults and children, adverse reactions are typically transient local reactions classified as mostly mild to moderate. Fever and other systemic reactions, such as headaches, malaise, dizziness, anorexia, nausea, vomiting, diarrhea, and myalgia are also reported in a small proportion of vaccinees. In study #062 (Appendix 1), of a total study population of almost 1,200 adults approximately 300 subjects were randomly assigned to the group receiving the FSME-IMMUN® 0.5 mL vaccine. After the first dose, 29.9% of this group reported local and systemic adverse events compared with 19.5% of the placebo group (11.1% versus 7.3% respectively after the second dose). In another single-blind, randomized safety study (Appendix 1: #208) involving ≥ 3,700 adults, the current formulation of FSME-IMMUN® 0.5 mL was compared with an earlier version of the Encepur® vaccine, containing polygeline as stabilizer. Neither vaccine caused any serious adverse effects, although FSME- IMMUN® 0.5 mL had fewer adverse effects overall than Encepur®. In a study of 2,400 children aged 1 to < 16 years (Appendix 1: study #209), the incidence of adverse effects after the first (second) vaccine doses were reported by age group:

• 1 to 2 years old:
  • fever, 36.1% (12.6%); local reactions, 13.4% (8.1%); systemic excluding fever, 27% 11.4%);
• 3 to 6 years old:
  • fever, 12.9% (2.3%); local reactions, 22.9% (15.5%); systemic excluding fever, 18.8% (6.8%);
• 7 to 15 years old:
  • fever, 5.6% (1.2%); local reactions, 26.4% (18.6%); systemic excluding fever, 20% (8.5%).

No severe adverse effects were reported to be causally related to the vaccinations.

Following the administration of earlier generation FSME vaccines that had been passaged in suckling mouse brain, there were very rare, sporadic reports of neurologic complications, such as convulsion, neuritis of various degrees of severity (not further specified), polyradiculopathy, gait ataxia, hearing and balance disorders, meningitis, or encephalitis^42-44. Neurologic complications associated with these earlier formulations have been estimated to occur in 1:500,000 to 1:1,000,000 vaccinations⁴³. No similar reactions have been reported with the current FSME-IMMUN® formulation.

FSME-IMMUN® 0.5 mL and its pediatric version, distributed in Europe, contain a small amount of human serum albumin (HSA) of European (German or Austrian) origin. As a result, there is a theoretical risk of transmitting the prion that causes variant Creutzfeldt-Jakob disease (vCJD). No risk assessment is available for vaccines containing HSA of European origin. However, a generic risk assessment of vaccines incorporating bovine biological materials in their manufacture suggests that any such risk is likely to be extremely small: < 1 in 100 million vaccine doses (El Saadany S, Giulivi A. Preliminary quantitative risk assessment respecting vCJD in relation to Canadian vaccines incorporating bovine biological materials in their manufacture: unpublished work, Health Canada, Bloodborne Pathogens Division, Ottawa, 2002). Health Canada licensing regulations require that products containing plasma-derived substances use materials that originate from Canadian or US donors. A FSME-IMMUN® vaccine containing HSA of North American origin is approved for sale in Canada (see Availability of TBE vaccines in Canada).

Encepur® adults and Encepur® children (Chiron vaccines)

Encepur® and Encepur® K for children were registered in Germany in 1991 and 1994 respectively⁴⁵. Several clinical trials demonstrated the general immunogenicity and safety of these early formulations^46-48. However, post-marketing surveillance revealed that children had an increased frequency of allergic reactions, which were likely due to polygeline, a proteinaceous stabilizer in the vaccine^33,45. A polygeline-free TBE vaccine under the names of Encepur® adults and Encepur® children was subsequently introduced and evaluated in prospective, controlled, multi-centre clinical trials^45,49,50. These formulations have been on the market since 2001 and are sold in several European countries. Encepur® children is recommended for children between 1 and 11 years of age³².

The Encepur® vaccines are a suspension of formaldehyde-inactivated TBEV (strain K23), grown on chick embryo fibroblasts³². The adjuvant is aluminum hydroxide. There are trace amounts of formaldehyde, chlortetracycline, gentamicin, and neomycin in the solution. The current formulations contain no proteinderived stabilizers (e.g. HSA) and no polygeline. Preloaded syringes contain 1.5 µg/0.5 mL TBE antigen (adult) and 0.75 µg/ 0.25 mL TBE antigen (children). The vaccine should be stored between +2º C and +8º C and has a shelf life of ~15 months³² (Summary of Product Characteristics Encepur® adults/Summary of Product Characteristics Encepur® children: unpublished work, Chiron Behring GMBH & Co Kg, Marburg, Germany, June 2004).

Scheduling and route of administration

The vaccine is administered intramuscularly, preferably into the deltoid muscle. Like FSME, Encepur® vaccines can be administered according to a conventional or an accelerated schedule, both offering high protection^47,49,50.

According to the conventional vaccination schedule, the primary vaccination consists of three doses, on day 0, 1 to 3 months, and 9 to 12 months. If risk of exposure continues, the manufacturer recommends booster doses every 3 years³².

In most clinical trials of Encepur® vaccines, the accelerated schedule has been used with three doses given on day 0, 7, and 21. After the accelerated schedule, the first booster dose is administered at 12 to 18 months.

It should be noted that the recent recommendations of the 2005 Austrian Immunization Guide with regard to longer booster intervals for individuals < 60 years of age apply to both FSME-IMMUN® and Encepur® vaccines(37) (see section on FSME-IMMUN® 0.5 mL and FSME-IMMUN® 0.25 mL Junior).

Immunogenicity and safety of Encepur® vaccines

Several large clinical trials to investigate the immunogenicity and safety of Encepur® vaccines in subjects 12 to 76 year old (adult formulation: n = > 3,000) and in children 1 to 11 years old (pediatric formulation: n = 390 for immunogenicity and > 3,000 for safety). All subjects were vaccinated on day 0, 7, and 21^49,50.

Immunogenicity after primary immunization: After the administration of the primary series, seroconversion, as measured by the neutralization test, occurred in 100% of adult and pediatric subjects^49,50.

Long-term immunogenicity: Several studies have demonstrated the long-term persistence of high (presumably protective) titres after primary vaccination: 99.5% and 100% immediately before the first (12 to 18 month) and second (36 month) booster doses respectively^51-53. These results support a recommended booster interval of > 3 years⁵⁴.

Safety: The reported adverse reactions following vaccination with Encepur® vaccines include local reactions and systemic reactions such as fever, malaise, headaches, myalgia, arthralgia, nausea in children ≥ 3 years and adults^49,50. Systemic symptoms are mostly mild and transient, and are reported in 1% (fever in adults) to 18% (myalgia in adults)⁴⁹. A small percentage (< 1% to 5%) of these adverse events are moderate to severe in nature (i.e. they cause temporary impairment in daily activities)^49,50. Systemic reactions in children 1 to 2 years old have been mainly fever, sleepiness, irritability, or change in eating habits (reported in 8% to 14%, depending on symptom reported)⁵⁰. In the large clinical trials conducted to date, there were no reports in adults or children of serious clinical events, such as seizures, or of systemic allergic reactions, considered to be causally related to the vaccinations^32,49,50.

Rare and isolated cases of central or peripheral nervous system complications, such as ascending paralysis, in severe cases with respiratory paralysis, have been reported following vaccination with previous generation Encepur® vaccines (summaries of the product characteristics of Encepur® vaccines).

Special considerations for the FSME-IMMUN® and Encepur® vaccines

Allergies

The viral strains of the TBE vaccines are propagated in purified chick embryo cells(3^2,33. Although purified, both of the available vaccines may still contain egg constituents. The summaries of product characteristics for the FSME-IMMUN® and Encepur® vaccines advise that individuals with prior anaphylactic reactions to eggs or egg products should be vaccinated only under close clinical monitoring with readiness for emergency treatment. However, FSME-IMMUN® vaccine has apparently been safely administered to > 100 persons with allergies to egg whites (note that the types of egg allergy were not described in this study)⁵⁵.

Impaired immune system

Immunosuppressed individuals may respond poorly to TBE vaccination^56-58. If they are at risk of TBE, it may be appropriate to determine their immune response after the primary series by serologic testing (where available)⁵⁸ (see Testing for Antibodies after TBE Vaccination). There are no guidelines for evidencebased recommendations concerning the timing of serologic testing in immunocompromised individuals.

Pregnancy and lactation

According to the summaries of product characteristics of the FSME-IMMUN® and Encepur® vaccines, the safety of the TBE vaccines during pregnancy and lactation has not been established. An individual risk-benefit assessment is required in these cases.

6.2 Availability of TBE vaccines in Canada

The FSME-IMMUN® 0.5 mL vaccine has been approved for sale in Canada as of 3 February, 2005, and is available on the Canadian market. The distributor of FSME-IMMUN® in Canada is Baxter Corporation (Mississauga) .The pediatric FSME vaccine and the Encepur® products are not licensed and not available in Canada.

Until one of the pediatric formulations is licensed in Canada, there are two options possible, namely to procure a European licensed pediatric product through the Special Access Program (SAP) or to use a half-dose of the adult FSME vaccine to immunize children < 16 years of age. If the latter option is used, the vaccinees and their parents should be advised that the distribution of antigen in the vaccine portions may not be even. The main concern is the possibility of inadequate protection against TBE if the administered vaccine portion contains insufficient antigen.

6.3 Testing for antibodies after TBE vaccination

The EIA for IgG antibodies is a rapid and reliable test for TBE immunity. It is commonly used to assess immunity after an infection or vaccination²⁵. A comparison of six commercial IgG ELISA kits suggests that they have generally high sensitivity (73% to 99%)⁵⁹. However, there is extensive cross-reactivity with other flavivirus antibodies, such as West Nile fever, dengue, yellow fever, and Japanese encephalitis antibodies^25,60,61. These crossreactive antibodies do not neutralize TBEV and are not protective against TBE infections^60,61. Therefore, when interpreting positive EIA results, consideration must be given to possible crossreactivity with other flaviviruses. False-positive results can be minimized by taking a proper history of past flavivirus exposures and/or vaccinations. Alternatively, if available, a pre-vaccination EIA can establish a baseline, or a highly specific and sensitive neutralization test can be used^25,60,61. The neutralization test, which measures the presence of TBE-specific neutralizing antibodies, is only available in specialized laboratories (Dr. H. Peters Dade Behring, Marburg, Germany: personal communication, 2002). In the absence of prior exposure to other flaviviruses, IgG EIA results for TBE correlate well with the results of the neutralization test^25,61,62. According to Health Canada’s Medical Devices Active Licence Listing (http://www.mdall.ca), there are no TBE serologic tests currently licensed for sale in Canada.

7. Recommendations

To identify travellers who are at risk of contracting the TBE virus, travel medicine professionals should consider the season of travel, travel itinerary, and the activities of the traveller.

• Season of travel: ticks are active from March to November.

• Itinerary: several referenced Web sites^5,6 indicate risk areas. Furthermore, tick activity should be considered at altitudes up to 1400 m (see Epidemiology)^10,11.

• Activities: risk activities include fieldwork, biking, hiking or camping outdoors, particularly at the edge of forests, in parks or meadows, and where the countryside is moist and uncultivated, containing low brush and ground foliage (see Epidemiology).

Travellers meeting all of these criteria should be advised regarding prevention of tick bites, tick removal, and vaccination.

Table 3 presents the evidence-based categories for the strength and quality of evidence for the following recommendations⁶³.

Table 3. Strength and quality of evidence summary sheet⁶³

Environmental methods

• Grass around residences should be kept cut. (CIII)
• Wild animals should be kept away from residential areas. (CIII)
• Brush should be kept away from areas of human activity. (CIII)

Prevention of tick-bites

• There is recent evidence that dark-coloured clothing may attract fewer ticks than light clothing⁶⁴. (CII).

• Smoothly-woven clothing makes it more difficult for ticks to attach²⁷. (BII)

• As much as possible, body parts should be covered by clothing. This includes taping the cuffs of pants or placing them inside footwear²⁷. (BII)

• For maximal effectiveness (nearly 100% protection) DEET (N,N-diethyl-mtoluamide) and permethrin on clothing should be used concurrently²⁶. (AII)

• Body and clothing should be inspected for ticks during and/or after risk activities. (CIII)

Personal preventive means after a tick bite has occurred

• Attached ticks should be removed by grasping the tick as close as possible to the skin with blunt curved forceps or tweezers and pulling steadily upward, without twisting or jerking²⁹. (BIII)

• Alcohol, matches, or vaseline should not be used when removing ticks, since these methods can cause the tick to release an increased number of virus particles into the host²⁹. (CIII)

• Handling of the tick with bare hands should be avoided, since tick fluids containing infectious agents may enter through breaks in the skin²⁹. (CIII)

• The bite site should be disinfected after tick removal and hands should be washed with soap and water²⁹. (CIII)

• The date of the tick bite and the onset of any symptoms should be documented. (CIII)

• A physician should be contacted if any signs of unusual illness occur within 28 days of a tick bite. (CIII)

Primary prevention of TBE infection

• Unpasteurized milk and milk products should be avoided^2,19. (AIII)

• Vaccination of adults and children with FSME-IMMUN® 0.5 mL and FSME-IMMUN® 0.25 mL Junior respectively is safe and immunogenic (see Appendix 1). (AI)

• The vaccination of adults and children with Encepur® adults or Encepur® children respectively is safe and immunogenic^49,50. (AI)

• Booster doses are recommended for persons at risk:

  • Following the accelerated schedule of Encepur® adults or Encepur® children, the first booster dose should be given 12 to 18 months after the primary series^51,52. (CII)

  • The second booster dose of Encepur® may be given 3 years later, as recommended by the manufacturer. (CII). For adults < 60 years of age, see below.

  • Following the conventional vaccination schedule (Encepur®/FSME-IMMUN®), the first booster dose should be given 3 years after completion of the primary series³⁸. (CIII)

  • The time interval of booster vaccinations using the pediatric vaccines of FSME-IMMUN® or Encepur® has not been evaluated. The manufacturers recommend 3 year intervals. (CIII)

  • Adults < 60 years of age who have received at least one previous booster dose may be offered subsequent booster doses at 5-year intervals³⁷. (AII)

  • Adults ≥ 60 years of age should continue to receive booster vaccinations at 3-year intervals^37,38. (BII)

• FSME-IMMUN® and Encepur® vaccines are interchangeable^35,36. (AII)

• Persons with anaphylactic reactions to eggs should be closely monitored, and emergency treatment should be kept available during vaccination with either FSME-IMMUN® or Encepur® vaccines. (CIII)

• Immunosuppressed persons should consider serologic testing (where available) to determine the effectiveness of the primary series^56,58. (CIII)

• Pregnant or breast-feeding women should receive a risk-benefit assessment regarding the administration of TBE vaccine. (CIII)

• Until one of the pediatric formulations is licensed in Canada or is made available through the SAP, it may be reasonable to use a half-dose of the adult FSME vaccine to immunize children < 16 years of age. The possibility of uneven antigen distribution in the split doses, possibly resulting in inadequate immune protection, has to be addressed. (CIII)

Serology

• Past infections with or vaccinations against other flaviviruses must be taken into consideration in the interpretation of TBE EIA results²⁵. (AII)

• In the absence of a previous flavivirus infection or vaccination, EIA results are highly correlated with those of the neutralization test ⁶¹. (AII)

Expiration

This document will be updated every 4 years or when new information becomes available.

Acknowledgements

CATMAT gratefully acknowledges the assistance in the preparation of this statement from Dr. Michael Bröker, Chiron Vaccines, Marburg; Dr. Eva Maria Poellabauer, Baxter Bioscience, Vienna; Dr. Jochen Süss, Nat. Ref.-Lab., Tick-borne Diseases, Federal Research Centre for Virus Diseases in Animals, Jena, Germany.

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Appendix 1

Immunogenicity and safety studies involving the vaccines FSME-IMMUN® 0.5 mL and FSME-IMMUN® 0.25 mL Junior, sponsored by Baxter Vaccines AG.

* Members: Dr. B.Ward (Chair); Dr. C. Beallor; M. Bodie-Collins (Executive Secretary); Dr. K. Gamble; Ms. A. Henteleff; Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. P.J. Plourde; Dr. J.R. Salzman.

Liaison Representatives: Dr. R.J. Birnbaum; Dr. C. Greenaway; Dr. C. Hui; Dr. R. Saginur; Dr. P. Teitelbaum; Dr. M.Woo.

Ex-Officio Representatives: Dr. E. Callary; Dr. N. Gibson; Dr. J. Given, Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. R. Paradis; Dr. C.Reed; Dr. M. Smith; Dr. M. Tepper

Members Emeritus: Dr. C.W.L. Jeanes.

Consultant: Dr. S. Schofield

†This statement was prepared by Dr. E. Callary and Dr. B.Ward, and approved by CATMAT.