ACIP Evidence to Recommendations Framework for Tick-Borne Encephalitis (TBE) Vaccination for Persons Who Travel Abroad

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Question: Should TBE vaccine be recommended for use in persons aged ≥1 year traveling to or residing in TBE risk areas?

Population: Persons aged ≥1 year traveling to or residing in TBE risk areas

Intervention: Vaccination with TBE vaccine according to recommended doses and schedules*

Comparison(s): No TBE vaccination*

Outcomes: Protection from disease after the 3-dose primary series and after a booster dose at 3 years following the primary series and serious adverse events

*With advice on tick bite prevention measures

Background:  TBE is focally endemic in a geographic region extending from western and northern Europe through to eastern and northern Asia. TBE virus is primarily transmitted to humans by infected ticks. The main TBE virus transmission season is during the warmer months from April through November. Ticks are typically found in woodland habitats including in and on the edges of deciduous forests. The highest risk for TBE is for persons undertaking recreational outdoor activities (e.g., hiking, camping, hunting, foraging, fishing, bird-watching) or who might be occupationally-exposed (e.g., forestry workers, farmers, military personnel) (1).

Since 2001, 20 TBE cases have been diagnosed among US adult and pediatric civilian and military persons who traveled to parts of Europe, Russia and China (2–5). Clinical manifestations of TBE virus infection can include febrile illness or neurologic disease, including meningitis, encephalitis, or meningoencephalomyelitis. No specific treatment is available and management is supportive. Mortality and sequelae rates vary with different subtypes of TBE virus, with mortality rates of 1–20%, and sequelae rates of 10–50%, reported from different areas (6). TBE vaccines have been available internationally for about 40 years, but until recently no TBE vaccine has been licensed in the United States and prevention has focused on personal protective measures to prevent tick bites.

On August 13, 2021, the Food and Drug Administration (FDA) approved a TBE vaccine (manufactured by Pfizer as TICOVAC) for use in persons aged ≥1 year. The vaccine is inactivated with a vaccination schedule of 3 primary doses, and 1 booster dose administered at ≥3 years after the primary series if there is ongoing risk of exposure. There is an adult formulation for individuals aged ≥16 years and a pediatric formulation for children and adolescents aged 1–15 years with the differences being the volume and the interval between doses 1 and 2 which for adults is 14 days –3 months and for children and adolescents is 1–3 months. The TBE vaccine currently is marketed in about 30 countries, primarily in Europe. The current formulation of the vaccine has been available since 2001, and >75 million doses have been administered in Europe, about two-thirds of those to adults and one third to children.

Additional background information supporting the ACIP recommendations on the use of TBE vaccine can be found in the “Tick-Borne Encephalitis  Vaccine: Recommendations of the Advisory Committee on Immunization Practices” document on the ACIP website.

Problem

Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? Varies TBE is of public health importance for residents of some TBE-endemic countries
  • Median incidence of reported cases in European countries that reported data in 2019 was 1.3 (range: 0.1–25.4) per 100,000 population (7)
  • Range of TBE virus in Europe is increasing

TBE is not an important public health problem overall for US persons traveling to risk areas

  • From 2000–2020, median of 1 (range: 0–5) case diagnosed per year among civilian and military persons (2)
  • With millions of U.S. travelers to TBE endemic countries annually, estimated risk is <1 case per million trips

TBE is an important concern for certain subpopulations of persons traveling abroad to risk areas

  • Some individuals are at higher likelihood of tick bites based on their itinerary and activities
  • Some persons are at higher risk of infection because of residence or recurrent periods spent in risk areas

TBE virus can cause severe disease and permanent sequelae and no specific anti-viral treatment is available

Costs and benefits of immunization are typically borne by the traveler so TBE is more an individual than societal concern

  • TBE vaccine is not covered by most insurance or under the Vaccines for Children program

There is negligible risk of subsequent local transmission if an infected traveler returns to the United States

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the desirable anticipated effects? Large Results of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evaluation were used to address this question (Advisory Committee on Immunization Practices (ACIP) GRADE | CDC). Results from 10 observational studies among adults and children with data at 1 month after the 3-dose primary series indicated seropositivity was high (≥96%) in all but one study. When subjects in one of the adult and one of the pediatric studies were followed up at 3 years after the primary series (i.e., immediately prior to the booster dose), seropositivity remained high (≥94%). Two observational studies with data after a booster dose, including one adult and one pediatric study, demonstrated that seropositivity rates were high at 1 month (100%), 5 years (≥94%), and 10 years (≥85%) later. There are no efficacy data for the TBE vaccine and low TBE incidence would make trials infeasible. No field effectiveness studies for the FDA-approved TBE vaccine alone are available, but an Austrian study showed a vaccine effectiveness estimate of 99% during a period when 90%–95% of the TBE vaccine in use was the FDA-approved TBE vaccine (8). These data were not included in the GRADE as subjects were vaccinated according to the Austrian schedule and many persons received the older TBE vaccine formulation.
Using immunogenicity data creates some uncertainties. A neutralizing antibody titer of ≥10 (at 50% cut off) is generally used to indicate protection, but there is no established correlate of protection.
The vaccine is based on a European subtype TBE virus, one of three main subtypes. Limited data from human and animal studies and the genetic and antigenic similarity of the subtypes suggest there likely is cross-protection, but protection against infection from subtypes found in eastern parts of the TBE endemic region has not been proven.
How substantial are the undesirable anticipated effects? Minimal The GRADE assessment found no serious adverse events considered vaccine-related (Advisory Committee on Immunization Practices (ACIP) GRADE | CDC) among ~7,000 adult and pediatric subjects who received ≥1 dose of vaccine in the primary series in four randomized controlled and nine observational studies. Among ~2,700 subjects in three active post-marketing surveillance studies, only one serious adverse event was considered vaccine-related and that event had possible contributing factors. The vaccine has been used for >20 years in Europe with >75 million doses administered and no safety signal has been identified. However, no English language publications describe results from post-marketing adverse event surveillance in large populations.
Do the desirable effects outweigh the undesirable effects? Favors intervention Overall, with high seropositivity rates following vaccination and no serious safety concerns identified, the desirable effects of a vaccine to prevent a rare but potentially serious, untreatable disease outweigh the undesirable effects. However, as with any vaccine, rare serious adverse events can occur and for some travelers with lower risk itineraries, even a low probability of a vaccine-related serious adverse event might be higher than the disease risk. Therefore, for each traveler, a healthcare provider should discuss the desirable and undesirable effects of vaccination and the individual’s risk based on itinerary and activities to effectively target TBE vaccination to travelers at increased risk for disease.
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention is Level 3 (low)
Safety of the intervention is Level 2 (moderate)
 The overall certainty of the evidence for protection from disease was level 3 (low) based on 1) Results from observational studies only; 2) Indirectness because the likelihood of protection from disease was based on seropositivity with no established correlate of protection and the likely but unconfirmed protection against non-European TBE virus subtypes; and 3) Upgrading for magnitude of effect (Advisory Committee on Immunization Practices (ACIP) GRADE | CDC).
The overall certainty of the evidence for serious adverse events was level 2 (moderate). Data were available from randomized controlled trials but evidence type was downgraded because of the risk of bias from inadequate blinding (Advisory Committee on Immunization Practices (ACIP) GRADE | CDC).

Values

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Varies Three studies provided indirect information on the value a TBE vaccine to the US traveler population.
One publication described TBE vaccination practices among non-US adults from both endemic and non-endemic areas who had recently traveled to a TBE endemic country (9). Results showed:
  • Among all participants (n=4,375), 32% had heard of TBE vaccine
  • Among those engaging in a higher risk activity for TBE (n=375), 15% had received vaccine; reasons for lack of vaccination included a perception of insufficient risk (34%), lack of consideration of vaccination (27%), not advised of need (23%), insufficient information (15%), and lack of time (11%)
  • TBE awareness and vaccination rates were higher in travelers from TBE endemic countries

A publication described practices and perceptions of TBE vaccine in Sweden, a country where TBE is focally endemic and TBE vaccine must be paid for out-of-pocket (10).

  • TBE vaccination rates were 33% in risk areas and 18% in other areas
  • Factors associated with vaccination were older age, frequency of visits to risk areas, income, and knowledge of risks of a tick bite
  • Reasons for non-vaccination included procrastination (25%), rarely visiting area with ticks or TBE risk (24–25%), concern about side effects (18%), low perceived risk (15%), and cost (15%)

One publication considered perceptions among the US population of the value of Japanese encephalitis (JE) vaccine (11).  Both JE and TBE risk for travelers is very low, both diseases have a potentially high impact, and both vaccines are safe and effective and cost >$250/dose. In an online survey, information on JE disease risk, possible outcomes, vaccine effectiveness and safety, and vaccine cost were presented.

  • The likelihood participants (n=6,427) would receive the vaccine was very or somewhat likely in 32%, very or somewhat unlikely in 43%, or unsure in 25%
  • Regarding factors important in their decision, some valued availability of a vaccine to prevent an untreatable, potentially severe disease but others were less likely to value an expensive vaccine with possible serious side effects

Overall, studies of non-US travelers to TBE-endemic countries, residents of endemic countries, and US persons questioned about a disease and vaccine with similar characteristics to TBE, all suggest the US traveler population will have variable opinions on the desirability of vaccination. Vaccination rates were low to moderate even in risk settings but individuals who perceive they are at risk will probably value availability of vaccine.

 Unpublished data from a Pfizer-sponsored study on traveler acceptance of TBE vaccine among US persons who had recently traveled abroad or planned to travel were also reviewed. It was difficult to extrapolate findings from this study that investigated acceptance of a free vaccine when the vaccine will cost >$250/dose and there were concerns about methodologic limitations. These issues resulted in low certainty in study results, so they were not incorporated into the body of evidence for this domain.

Value placed on vaccination is likely to be influenced by knowledge of TBE risks and vaccine effectiveness and safety which is currently low among the US population. Many persons value the advice of their healthcare provider, so providers will have a key role in assisting travelers to make an informed decision about vaccination.
Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability The Work Group considered the information described in the row above and concluded there is substantial variability.

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakehold-ers? Yes Key stakeholders were considered to be US travel medicine and other healthcare providers who might administer vaccine, and persons who travel abroad. No formal evaluation of acceptability was undertaken, but the Work Group discussed the following issues: 1) Several European countries have traveler recommendations and encourage vaccination of persons who will be exposed to ticks in rural locations in endemic areas; 2) Authors have called for greater TBE awareness and clear vaccine recommendations for travelers visiting risk areas (12–14); and 3) The International Society of Travel Medicine (ISTM) TravelMed Listserv and CDC occasionally have received requests for information on availability of TBE vaccine for US travelers
For the public, TBE vaccine recommendations are expected to be acceptable as availability of a vaccine will give an option, in addition to tick bite prevention measures, for protection from a potentially severe disease, and the recommendations will provide guidance on who will benefit most from vaccination. Recommendations might allow insurance coverage and so benefit any travelers with insurance that covers travel vaccines.
 The Work Group membership includes several travel medicine providers including members of the ISTM, pediatricians, and other physicians.

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Varies A cost-effectiveness analysis (CEA) for TBE vaccination of travelers has not been conducted. Most travel vaccines are not cost-effective. For TBE, the number of US travelers needed to be vaccinated to prevent one case is very high, so TBE vaccination is unlikely to be cost effective. However, cost-effectiveness considerations are less relevant when vaccination is for an individual traveler vs the population. Travel vaccines are not covered by the Vaccines for Children program and usually not by insurance, and travelers will make individual decisions based on their willingness to pay and perceptions and tolerance of risk.
Among populations in endemic areas, CEA results have been variable and programs are often not projected to be cost-effective, with incidence and vaccine cost being important variables in predicting cost-effectiveness (15–19).
In considering resource use, vaccine recommendations targeted to higher risk groups are probably a reasonable allocation of resources as the financial implications of vaccine purchase and the most benefit will be for travelers at highest risk of a severe disease. However, even among higher risk travelers, whether vaccine purchase is a reasonable allocation of their resources will reflect several factors including actual risk of disease, likelihood of use of other tick prevention measures, and opportunity costs (e.g., buying TBE vaccine vs purchasing travel insurance or other vaccines).
Healthcare costs for management of TBE presenting as neurologic illness are potentially large.

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact of the intervention on health equity? Probably reduced TBE vaccine will be paid for out-of-pocket by most travelers, or by insurers or employers in some cases. Currently, protection from TBE relies on tick bite prevention measures. Vaccine availability could lead to health disparities because some travelers will have resources (e.g., insurance, money)  and others will not. However, the absolute risk of TBE is low, so availability of vaccine will not cause substantial disparities overall. Equity issues cannot be addressed by TBE vaccine recommendations.

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Probably yes Administration of TBE vaccine is feasible as part of a pre-travel consultation. Key barriers might include:
  • At least 5 months needed to complete the 3-dose primary series
  • Lack of understanding among providers of factors that might increase the risk for tick exposure and therefore which travelers are at highest TBE risk and might benefit most from vaccination
 The possibility of low vaccine uptake with the risk of expiration and wastage might result in some providers being reluctant to stock vaccine.

Balance of consequences

Desirable consequences probably outweigh undesirable consequences in most settings

Is there sufficient information to move forward with a recommendation? Yes.

Policy options for ACIP consideration

Two types of recommendations were presented. Based on likely exposure to ticks for persons traveling abroad, ACIP recommends the intervention OR ACIP recommends the intervention for individuals based on shared clinical decision-making.

Draft recommendation (text)

TBE vaccine is recommended for persons who are moving or traveling to a TBE-endemic area and will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

In addition, TBE vaccine may be considered for persons traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas ticks are likely to be found. The decision to vaccinate should be based on an assessment of their planned activities and itinerary, risk factors for a poor medical outcome, and personal perception and tolerance of risk.

Additional considerations (optional)

The recommendations will be presented with additional text to allow them to be interpreted in context and an information box will be provided to assist with the decision-making process (see MMWR Recommendations and Reports document).

Final deliberation and decision by the ACIP

Final ACIP recommendation

Two types of recommendations were approved. Based on likely exposure to ticks for persons traveling abroad, ACIP recommends the intervention OR ACIP recommends the intervention for individuals based on shared clinical decision-making.

TBE vaccine is recommended for persons who are moving or traveling to an area where TBE is endemic area and will have extensive exposure to ticks because of their planned outdoor activities and itinerary.

TBE vaccine may be considered for persons traveling or moving to an area where TBE is endemic who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of their planned activities and itinerary, risk factors for a poor medical outcome, and personal perception and tolerance of risk.

References

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  2. Hills SL, Broussard KR, Broyhill JC, et al. Tick-borne encephalitis among U.S. travelers, 2010–2020. J Travel Med 2021;taab167.
  3. Mancuso JD, Bazaco S, Stahlman S et al. Tick-borne encephalitis surveillance in U.S. military service members and beneficiaries, 2006-2018. MSMR 2019; 26:4–10.
  4. Mease LE, Maddox SA, Noss MR, et al. Case report: tickborne encephalitis virus infection in beneficiaries of the U.S. military healthcare system in southern Germany. MSMR 2019; 26:12–5.
  5. Tickborne encephalitis among U.S. travelers to Europe and Asia — 2000–2009. MMWR Morb Mortal Wkly Rep 2010; 59:335–8.
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  16. Haglund M, Forsgren M, Lindh G, et al. A 10-year follow-up study of tick-borne encephalitis in the Stockholm area and a review of the literature: need for a vaccination strategy. Scand J Infect Dis 1996;28:217–24.
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