Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Tick-Borne Encephalitis (TBE) Vaccine

Summary

On August 13, 2021, the Food & Drug Administration (FDA) approved an inactivated TBE vaccine (manufactured by Pfizer as TICOVAC) for use in persons aged ≥1 year. A TBE Vaccine Work Group was formed in September 2020 to discuss use of TBE vaccine in U.S. adults and children. The policy question developed by the Work Group was “Should TBE vaccine be recommended for use in persons aged ≥1 year traveling to or residing in TBE risk areas and in laboratory staff working with TBE virus?” The critical outcomes were considered to be protection from disease after the 3-dose primary series and after the booster dose administered at 3 years after the primary series, and serious adverse events following vaccination. A systematic review of evidence was conducted as described in the methods section below. For protection after the primary series, findings were based on 10 observational studies and for protection after the booster dose, on two observational studies. Seropositivity within approximately 1 month of the primary series in adults and children was high with seropositivity rates ≥96% in all but one study. Similarly, seropositivity was high (100%) at one month after a booster dose and remained high (≥85%) in adults and children through 10 years after the booster dose. The evidence for both outcome measures was certainty level 3 (low) with indirectness a limitation but the magnitude of effect being a strength of the evidence. Findings for vaccine-related serious adverse events were based on results from four randomized controlled trials, nine observational studies, and three post-marketing surveillance studies. Vaccine-related serious adverse events were rarely reported. For this outcome measure, the certainty was level 2 (moderate); the evidence available from randomized controlled trials was downgraded because of risk of bias from inadequate blinding. The Work Group presented the GRADE assessment to the Advisory Committee on Immunization Practices (ACIP) as part of the Evidence to Recommendations (EtR) Framework at the January 12, 2022 ACIP meeting.

Introduction

On August 13, 2021, the FDA approved a TBE vaccine (manufactured by Pfizer as TICOVAC) for use in persons aged ≥1 years. This inactivated TBE vaccine is the first TBE vaccine to be licensed in the United States; other TBE vaccines are available internationally, but are not licensed in the United States. As Pfizer’s TBE vaccine is the only currently-available TBE vaccine in the United States, it will be referred to in this document as “the TBE vaccine” (or when necessary, “the FDA-approved TBE vaccine”).

The TBE vaccine has an adult formulation for individuals aged ≥16 years and a pediatric formulation for children and adolescents aged 1–15 years. The vaccination schedule includes 3 primary doses and 1 booster dose at ≥3 years after the primary series. The only difference between the adult and pediatric schedules is the interval between doses 1 and 2 which for adults is 14 days–3 months and for children and adolescents is 1–3 months. Dose 3 of the primary  schedule is delivered at 5–12 months after dose 2 for both adults and children.

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. Clinical manifestations of TBE can include febrile illness or neurologic disease, including meningitis, encephalitis, or meningoencephalomyelitis. Since 2001, 20 TBE cases have been diagnosed among U.S. residents who traveled abroad to parts of Europe, Russia and China [1].

An earlier formulation of Pfizer’s TBE vaccine was first licensed in Austria in 1976. Changes to the formulation over time have included removal of thimerosal and a transition of the production virus seed from mouse brain suspension to chick embryo fibroblast cells. The current adult (0.5mL) and pediatric (0.25mL) formulations became available in 2001 and 2003, respectively. Because of the manufacturing changes that have occurred, only the current formulation of the vaccine was considered in this GRADE assessment. TBE vaccine currently is marketed in about 30 countries, primarily in Europe. Since 2001, >75 million doses have been administered in Europe, about two-thirds of those to adults and one-third to children.

There are no efficacy data for the TBE vaccine and low TBE incidence would make such trials infeasible. There also are no field effectiveness studies for the FDA-approved TBE vaccine alone. One study from Austria showed a vaccine effectiveness estimate of 99%  during a period when 90%–95% of the vaccine in use was the FDA-approved TBE vaccine, but the data were not considered in the GRADE assessment as other limitations included that subjects were vaccinated according to the Austrian schedule and many persons would have received the older TBE vaccine formulation [2]. In the absence of relevant data on vaccine protection against TBE disease, this GRADE assessment considered immunogenicity data. Anti-TBE virus neutralizing antibodies are believed to confer protection against disease in humans, and a 50% neutralizing antibody titer of ≥10 is generally used in studies for other flavivirus vaccines to indicate protection [3]. However, no formal correlate of protection has been established and no international reference reagents are available.

An ACIP TBE Vaccine Work Group was formed in September 2020 to discuss use of TBE vaccine among U.S. adults and children. The Work Group developed the following policy question “Should TBE vaccine be recommended for use in persons aged ≥1 year traveling to or residing in TBE risk areas and in laboratory staff working with TBE virus?” The components of the question (i.e., population, intervention, comparison, and outcomes [PICO]) are presented in Table 1. The outcomes that were considered for the TBE vaccine GRADE assessment and their rankings are presented in Table 2. A systematic review of evidence on vaccine safety and immunogenicity was conducted and the results are presented below. The GRADE assessment was summarized for ACIP at the January 12, 2022 ACIP meeting as part of the EtR Framework for TBE vaccine.

Methods

A systematic review was conducted for evidence for TBE vaccine for the pre-specified outcomes. To identify published literature that contained relevant evidence, we conducted a search of Medline, Embase, CINAHL, Scopus, and Cochrane Library databases for papers published from January 1995 through September 21, 2021. We used the following search strategy and terms: “Encephalitis, Tick-borne and (vaccin* or immunization* or Immuno AG or Baxter* or Pfizer*)” OR “(Tick-borne encephalitis OR TBE) and (vaccin* or immunization* or Immuno AG or Baxter* or Pfizer*)” OR “FSME-Immun*” OR “TICOVAC” (Appendix 1). Duplicate publications were identified and removed. We reviewed the title, abstract, or complete paper to identify relevant articles.

Published articles were included if they met the following criteria: 1) Involved human subjects; 2) Reported primary data; 3) Included data relevant to the outcome measures being assessed (i.e., vaccine efficacy, effectiveness, immunogenicity, or serious adverse events); 4) Included data for an FDA-approved dose and schedule; 5) Included data where all doses administered were with the current formulation of the vaccine; and 6) Reported results based on neutralizing antibody testing (for immunogenicity outcomes). Publications or data within publications were excluded if they represented a single case report, related to investigation of subjects with a medical condition which could affect safety or immunogenicity results (e.g., immunosuppression, post-thymectomy), or were only available in a non-English language.

We identified 1,737 unique publications using the search strategy. Among these publications, 1,717 were excluded as they did not meet one or more of the inclusion criteria, leaving 20 publications with relevant data [4–23](Appendix 1). In addition to published studies we also searched the ClinicalTrials.gov website, reviewed FDA documents related to licensure of TBE vaccine (https://www.fda.gov/vaccines-blood-biologics/ticovac), and requested unpublished or other relevant data from the manufacturer. Evidence type was assessed through a review of the studies and their design, risk of bias, inconsistency, indirectness, imprecision, and other considerations (i.e., publication bias, strength of association, dose response, or opposing plausible residual confounding).

Results

Among the 20 publications, nine were included for evidence of protection and serious adverse events [5,6,7,9–12,14,16], three were included for protection alone [8,18,22], and eight were included for serious adverse events alone [4,13,15,17,19–21,23] (Appendix 1)

Protection after the 3-dose primary series

The evidence used to evaluate protection from disease after the 3-dose primary series was from 11 publications describing 10 studies [5–7,9–12,14,16,18,22] (Tables 3a and 3b). All were observational studies and all measured seropositivity after a primary series and not prevention of disease. Among 1,951 adult and pediatric subjects in 10 studies from whom seropositivity data were available after a primary series, 1,911 (98%) were seropositive at approximately 1 month (range: 1–6 weeks) after the primary series (Table 3a). The only study with a seropositivity rate <96% was a small study in which 35 subjects had testing conducted with a non-standard diagnostic test (i.e., neutralizing antibodies were measured with a rapid fluorescent focus inhibition test that used a non-vaccine-type TBE virus). Among 595 adult and pediatric subjects in two of the studies from whom seropositivity data were available at 3 years after the primary series [11,16], immediately prior to a booster dose, 574 (96%) were seropositive; seropositivity was 94% for adults and 98% for children (Table 3b).

Protection after the booster dose

The evidence used to evaluate protection from disease after the booster dose was from two studies described in  three publications [8,11,16](Tables 3c, 3d, and 3e). Both studies were observational and measured seropositivity and not prevention of disease. At 1 month, 5 years, and 10 years after a booster dose, the percentage of adults seropositive was 100% (240 of 240), 94% (209 of 222), and 85% (189 of 222), respectively. For children at the same time points, seropositivity rates were 100% (172 of 172), 99% (155 of 156), and 90% (140 of 155).

Serious adverse events

The evidence used to evaluate serious adverse events was from 16 studies described in 17 publications, including four randomized, controlled trials, nine observational studies, and three post-marketing surveillance studies [4–7,9,10–14,15–17,19,20,21,23]  (Tables 3f, 3g, and 3h). Studies were conducted in Europe and Russia over a 20-year period, so one general limitation was that a standardized case definition was not used and it was not possible to seek clarification when a case definition was not provided. Among the 3,562 adult and 3,350 pediatric subjects who received ≥1 dose of vaccine in the primary series in four randomized controlled [9,15,21,23] and nine observational studies [4–7,10,12,14,17], there were no serious adverse events considered vaccine-related reported (Table 3f). When data from the four randomized controlled trials were combined and weighted using a random effects model, there was no significant difference in proportions of subjects with serious adverse events within 1 month of a primary series dose of TBE vaccine or the comparator TBE vaccines (Figure 1). Among 240 adult and 202 pediatric subjects who received a booster dose of vaccine in two of the observational studies [11,16], no serious adverse events considered vaccine-related were reported (Table 3g).                             Finally, among 687 adult and 1,992 pediatric subjects who received a primary series dose or booster dose in three active post-marketing surveillance studies with follow-up limited to 4–6 days, there was one serious adverse event considered vaccine-related by study investigators [13,19,20](Table 3h). A child aged 12 months with concomitant rhinopharyngitis, gastroenteritis, and otitis media was hospitalized for fever at 1 day after vaccination and had a febrile convulsion the following day.

Conclusion

Following the GRADE approach, we determined the quality of evidence for the pre-specified outcomes (i.e., protection after a 3-dose primary series and after a booster dose, and serious adverse events). Based on results from 10 observational studies with data at 1 month after the 3-dose primary series, seropositivity was high (≥96%) in all but one study. When subjects in one of adult and one of the pediatric studies were followed up at 3 years after the primary series (i.e., through to the time point when a booster dose is recommended), seropositivity remained high (≥94%). Two observational studies with data after a booster dose administered at 3 years, including one adult and one pediatric cohort, demonstrated that seropositivity rates were high at 1 month (100%), 5 years (≥94%), and 10 years (≥85%) later. For evidence on both outcomes measures of protection after vaccination, the certainty was level 3 (low) based on 1) results being from observational studies only; 2) indirectness because the likelihood of protection from disease was based on seropositivity with no established correlate of protection and there being likely but unconfirmed protection against non-European TBE virus subtypes; and 3) upgrading because of the magnitude of effect (Tables 4 and 5).

Based on results from four randomized controlled trials, nine observational studies, and three post-marketing surveillance studies, vaccine-related serious adverse events were rarely reported. For this outcome measure, the certainty was level 2 (moderate). Data were available from randomized controlled trials which provide a higher quality of evidence but evidence type was downgraded because of the risk of bias from inadequate blinding (Tables 4 and 5).

References

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Table 1: Policy Question and PICO

*With advice on tick bite prevention measures for persons traveling abroad

Table 2: Outcomes considered for TBE vaccine GRADE and rankings

*Indirect evidence for prevention of disease from immunogenicity data as no efficacy or effectiveness data

†Administered at 3 years after a primary series

Table 3a: Summary of studies reporting seropositivity by neutralizing antibody testing at approximately 1 month (range: 1–6 weeks)¹ after a 3-dose primary series of TBE vaccine

FDA=Food & Drug Administration; Obs=Observational study
¹Seropositivity was assessed at 1 month after dose 3 unless specifically indicated
²Anti-TBE virus neutralizing antibody titer ≥10
³Assessed at 21–28 days after dose 3
⁴Testing with a 100% neutralization test and titers >10 considered positive
⁵Publication by Loew-Baselli 2006 supplemented by data from Package Insert (TICOVAC)
⁶Publication by Loew-Baselli 2006(b) supplemented by data from FDA Clinical Review Memo
⁷Data were included in a publication on the clinical development of TBE vaccine but were not available in a separate publication, and results are based on FDA’s Clinical Review Memo of study 690601 (Clinicaltrials.gov: NCT00460486)
⁸Assessed at 21 days after dose 3
⁹Age range of participants not available
¹⁰Results presented are for the subjects in healthy control group and <60 years
¹¹Publication by Pöllabauer 2010 supplemented by data from Package Insert (TICOVAC) and/or FDA Clinical Review Memo
¹²Assessed at 35–42 days after dose 3
¹³Randomized, controlled trial with no valid comparative immunogenicity data as dose 3 for the control group was the FDA-approved TBE vaccine
¹⁴Denominator is based on data from FDA Clinical Review Memo and is for subjects with baseline neutralizing antibody titer ≤10.

Table 3b. Summary of studies reporting seropositivity by neutralizing antibody testing at 3 years after a 3-dose primary series of TBE vaccine

FDA=Food & Drug Administration; Obs=Observational study
¹Anti-TBE virus neutralizing antibody titer ≥10
²Publication by Loew-Baselli 2009 supplemented by data from FDA Clinical Review Memo and manufacturer for subjects who received the FDA-approved TBE vaccine alone

Table 3c. Summary of studies reporting seropositivity by neutralizing antibody testing at 1 month after a booster dose of TBE vaccine administered at 3 years after the primary series

FDA=Food & Drug Administration; Obs=Observational study
¹Anti-TBE virus neutralizing antibody titer ≥10
²Publication by Loew-Baselli 2009 supplemented by data from FDA Clinical Review Memo and manufacturer for subjects who received the FDA-approved TBE vaccine alone
³Serum collected at 21–35 days after booster vaccination
⁴An additional 30 subjects had a booster dose administered at 4 years (n=29) or at 5 years (n=1) and 100% were seropositive at 1 month after the booster

Table 3d. Summary of studies reporting seropositivity by neutralizing antibody testing at 5 years after a booster dose of TBE vaccine

FDA=Food & Drug Administration; Obs=Observational study
¹Anti-TBE virus neutralizing antibody titer ≥10
²Publication by Konior 2017 supplemented by data from Pfizer on subjects who received the FDA-approved TBE vaccine alone
³Booster dose was administered at intervals after the primary series of 3, 4, or 5 years for approximately 85%, 14%, and <1% of children, respectively

Table 3e. Summary of studies reporting seropositivity by neutralizing antibody testing at 10 years after a booster dose of TBE vaccine

FDA=Food & Drug Administration; Obs=Observational study
¹Anti-TBE virus neutralizing antibody titer ≥10
²Publication by Konior 2017 supplemented by data from Pfizer on subjects who received the FDA-approved TBE vaccine alone
³Booster dose was administered at intervals after the primary series of 3, 4, or 5 years for approximately 85%, 14%, and <1% of children, respectively

Table 3f. Summary of studies reporting serious adverse events (SAE)¹ reported within one month after any dose of the primary series of TBE vaccine

FDA=Food & Drug Administration; RCT=Randomized controlled trial; Obs=Observational study
¹SAEs considered vaccine-related by study investigators
²Inactivated TBE vaccine (Encepur with polygeline, which has since been replaced by a polygeline-free formulation) based on European TBE virus strain and licensed by Chiron Behring GmbH, Germany (now Bavarian Nordic)[Loew-Baselli 2006], Inactivated TBE vaccine (Encepur Children) based on European TBE virus strain and licensed by Novartis Vaccines (now Bavarian Nordic)[Wittermann 2009, Pöllabauer 2010(b)], Inactivated TBE vaccine (Tick-E-Vac) based on Far Eastern TBE virus strain and manufactured by Chumakov Federal Scientific Center (Russia)[Vorovitch 2019]
³Publication by Loew-Baselli 2006 supplemented by data from FDA Clinical Review Memo. Two SAEs were considered unrelated by study investigators, who likely had access to additional information, but could not be excluded as possibly related to vaccination based on publicly reported data. An 18-year old female was diagnosed with viral meningitis commencing 9 days after dose 1, and a 32-year old female died an unavailable number of days after receipt of dose 1 from cardiac arrest and at autopsy was shown to have a previously unrecognized congenital heart defect with interstitial pneumonia and myocarditis of probable viral etiology.
⁴Results from adults who received 2.4µg (n=135) dose, but also 0 vaccine-related SAEs among adults who received 0.6µg (n=137) or 1.2µg (n=133) dose
⁵Publication by Loew-Baselli 2006(b) supplemented by data from FDA Clinical Review Memo
⁶Data only in review article and results are supplemented by data from FDA’s Clinical Review Memo (study 690601; Clinicaltrials.gov: NCT00460486)
⁷Data only in review article and results are supplemented by data from FDA Clinical Review Memo (studies 198 and 215)
⁸Results represent children who received the 1.2µg (n=420) dose, but there also were 0 vaccine-related SAEs among children who received a 0.6µg (n=436) or 0.3µg (n=422) dose.

Table 3g. Summary of studies reporting serious adverse events (SAE)¹ reported within 1 month after a booster dose of TBE vaccine

FDA=Food & Drug Administration; Obs=Observational study
¹SAEs considered vaccine-related by study investigators
²Publication by Loew-Baselli 2009 supplemented by data from FDA Clinical Review Memo for subjects who received the FDA-approved TBE vaccine alone
³Booster dose was administered at intervals after the primary series of 3 years for 85% (n=172), 4 years for 14% (n=29) and 5 years for <1% (n=1)

Table 3h. Summary of post-marketing surveillance (PMS) studies reporting serious adverse events (SAE)

FDA=Food & Drug Administration; Obs=Observational surveillance study; PMS=Post-marketing surveillance; NR=Not relevant
¹Active surveillance conducted at 110 medical centers. The TBE vaccine used for children was half an adult dose (half of the liquid vaccine in the pre-filled syringe was discarded prior to administration) and was identical to the pediatric vaccine subsequently available in 2002. Only dose 1 was administered during the surveillance period and surveillance was conducted on days 0–3 post-vaccination
²Overall, 1,899 doses were administered but 467 doses were administered to children aged 6 months through <1 year which is outside the FDA-approved age range for the vaccine; however, among these 467 infants, 0 SAEs were reported
³The one report considered possibly vaccine-related by the study investigator was for a subject aged 12 months with concomitant rhinopharyngitis, gastroenteritis, and otitis media who was hospitalized for fever (1 day after vaccination) and had a febrile convulsion the following day (2 days after vaccination)
⁴Active surveillance with 560 doses administered to 490 subjects. Data were gathered through telephone interview at 5 days post-vaccination. Publication did not document lack of SAEs but because other local and systemic adverse events were comprehensively documented, lack of SAEs was assumed
⁵Active surveillance conducted at 15 centers. In total, 687 doses were administered to 570 subjects and data were gathered through telephone interview at 5 days post-vaccination

Figure 1. Pooled risk ratio for serious adverse events (SAE)¹ reported within 1 month after any dose of the primary series of TBE vaccine in randomized controlled trials²

¹SAEs considered vaccine-related by study investigators
²Pooled risk ratios computed using the random effects model (Mantel-Haenszel method).  Risk ratio = Proportion with SAE in FDA-approved TBE vaccine group / Proportion with SAE in comparator TBE vaccine group.  Risk ratio <1.0 favors FDA-approved TBE vaccine versus other TBE vaccine

Table 4: Grade Summary of Findings Table

NC=Not calculated (NB. Comparator vaccines included 3 different TBE vaccines or vaccine formulations so extensive statistical comparison of the FDA-approved TBE vaccine with this group of vaccines is not appropriate)
¹Randomized controlled trials start at evidence level 1 and observational studies at level 3
²Other considerations include publication bias, strength of association, dose response, or opposing plausible residual confounding
³10 studies described in 11 publications
⁴Seropositivity and not protection from disease was measured, there is no formal serologic correlate of protection, and there is likely but unconfirmed protection against non-European TBE virus subtypes (i.e., Far Eastern, Siberian)
⁵Magnitude of effect supports upgrading the quality of evidence
⁶Based on number of subjects with immunogenicity data at 1 month after primary series or 1 month after booster dose
⁷2 studies described in 3 publications
⁸Risk of bias due to lack of blinding of study personnel in three of the four studies
⁹12 studies (including observational and post-marketing surveillance studies) described in 13 publications
¹⁰Based on number of subjects with safety data within 1 month after a primary series dose or in a post-marketing surveillance study

Table 5. Summary of Evidence for Outcomes of Interest

Appendix 1. Studies Included in the Review of Evidence

Obs=Observational study; RCT=Randomized, controlled trial; PMS=Post-marketing surveillance
¹Subset of subjects from Loew-Baselli 2006
²Subset of subjects from Pöllabauer 2010 (study 2)