About
The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.
Summary
Question: Should TBE vaccine be recommended for use in laboratory staff working with TBE virus?
Population: Laboratory staff working with TBE virus
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
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, but other modes of transmission have been documented including through exposure to the virus in the laboratory. Currently, fewer than 10 U.S. laboratories work with TBE virus for diagnostic or research purposes; however, research activity might increase with the availability of a vaccine in the United States.
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.1
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 years. 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. Pfizer has marketed a TBE vaccine in Europe for more than 40 years. The current formulation of the vaccine became available in 2001, and more than 75 million doses have been administered in Europe.
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
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the problem of public health importance? | No | Four cases of TBE virus infection have been reported among US laboratorians working with TBE virus. Among them, three were cases of overt disease, and one case was an asymptomatic infection. There were two deaths. All cases occurred prior to 1979. Based on these data, TBE cannot be considered a problem of public health importance overall. However, for laboratorians working with TBE virus the disease is a concern because of the risk of a potentially severe disease that can result in death or permanent sequelae. |
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./div> 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./div>
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| 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 | 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. | To ensure appropriate laboratory staff are vaccinated, a local institutional biosafety committee should undertake a risk assessment of the potential for exposure to TBE virus considering the type of work to be performed and the biosafety level at which work is being conducted. |
| 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
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Does the target population feel that the desirable effects are large relative to undesirable effects? | Yes | There is no published information on how much laboratorians might value TBE vaccination. However scientists who understand the risks of disease and are aware of the good immunogenicity and safety profile of the vaccine are likely to value a preventive measure for a potentially severe disease with possibly serious outcomes. | Shortly after the announcement of licensure of a TBE vaccine, laboratory managers reported inquiries from staff about vaccine availability, suggesting interest in the vaccine. |
| Is there important uncertainty about or variability in how much people value the main outcomes? | No important uncertainty or variability | Although there are always a very small number of individuals who refuse vaccination, most laboratory staff working with TBE virus are likely to understand the risks and benefits and place value on availability of a vaccine. |
Acceptability
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention acceptable to key stakehold-ers? | Yes | Key stakeholders were considered to be individuals who make decisions on institutional vaccination policies (e.g., biosafety committee members, occupational health directors) and laboratorians in research and diagnostic laboratories. Vaccine availability will improve safety. When vaccines for other flaviviral diseases are available (e.g., yellow fever and Japanese encephalitis vaccines), vaccine policy usually encourages vaccination. Vaccine availability will also remove a barrier to research. |
Resource Use
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention a reasonable and efficient allocation of resources? | Yes | A cost-effectiveness analysis has not been conducted, but vaccination recommendations will be for a small number of staff undertaking diagnostic or research work with TBE virus. Currently, fewer than 10 laboratories in the United States work with TBE virus.
Vaccination is likely to be considered by management officials to be a reasonable use of resources to improve safety and reduce the risk of an adverse outcome among staff working with TBE virus. Vaccination is a small cost for administrators to pay to avoid the impact and costs of a worker being infected with TBE virus in the event of a laboratory accident.
|
Equity
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| What would be the impact of the intervention on health equity? | Probably increased | TBE vaccine will likely be paid for by employers. Equity will be increased as it will improve safety for those staff who are at occupational risk of a potentially severe disease. |
Feasibility
| Criteria | Work Group Judgements | Evidence | Additional Information |
|---|---|---|---|
| Is the intervention feasible to implement? | Yes | There are no special requirements for storage or administration of this inactivated vaccine, and vaccination is likely to build on routine mechanisms for vaccination of laboratory workers against other occupationally-related vaccine-preventable diseases. |
Balance of consequences
Desirable consequences clearly outweigh undesirable consequences in most settings.
Is there sufficient information to move forward with a recommendation? Yes.
Draft recommendation (text)
TBE vaccine is recommended for laboratory workers with a potential for exposure to TBE virus.
Additional considerations (optional)
The recommendations will be presented with additional text to provide clear information and allow appropriate interpretation (see MMWR Recommendations and Reports document).
- Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet 2008;371:1861–71.
- Avsic-Zupanc T, Poljak M, Maticic M, et al. Laboratory acquired tick-borne meningoencephalitis: characterisation of virus strains. Clin Diagn Virol 1995;4:51–59.
- The Subcommittee on Arbovirus Laboratory Safety of the American Committee on Arthropod-Borne Viruses. Laboratory safety for arboviruses and certain other viruses of vertebrates. Am J Trop Med Hyg 1980;29:1359–81.
- Heinz FX, Holzmann H, Essl A, Kundi M. Field effectiveness of vaccination against tick-borne encephalitis. Vaccine. 2007 Oct 23;25):7559–67.