ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for Booster Dose of Rabies Vaccine
Introduction
In February and June 2021, a 2-dose rabies pre-exposure prophylaxis (PrEP) series was recommended for all persons for whom rabies PrEP is recommended. A one-time rabies antibody titer during years 1-3 (and a booster dose if the titer is <0.5 IU/mL) was recommended for persons at sustained risk for only recognized exposures (i.e., risk category 3 of the recommendations of the Advisory Committee on Immunization Practices [ACIP]). During February and June 2021, ACIP recommended a rabies vaccine booster dose as an alternative to the one-time titer check, no sooner than day 21 but no later than 3 years after the 2-dose PrEP series for those in risk category 3.
Methods
During September 2019–November 2021, the ACIP Rabies Work Group participated in monthly or bimonthly teleconferences and considered evidence-based updates to the 2008 ACIP recommendations. As a basis for the GRADE analysis, the policy question about an intramuscular booster dose of rabies vaccine (as an alternative to a titer check) was defined consisting of the population, intervention, comparison, and outcomes of interest (Table 1). The Work Group designated primary immunogenicity a critical outcome (Table 2). Adverse events were not evaluated because the two rabies vaccines recommended in the United States (human diploid cell culture vaccine [HDCV] and purified chick embryo cell vaccine [PCECV]) have shown favorable safety profiles for decades and no new concerns have been identified. A systematic review of the evidence was conducted and observational data identified. A modified GRADE approach was taken where evidence certainty ranges from type 1 (high certainty) to type 4 (very low certainty) (www.cdc.gov/vaccines/acip/recs/index.html). Summary evidence for primary immunogenicity was determined and discussed.
Table 1: Policy Question and PICO
Policy question: | Should an IM booster dose of rabies vaccine (HDCV* or PCECV§) be recommended as an alternative to a titer check no sooner than day 21 and no later than 3 years after the 2-dose pre-exposure prophylaxis (PrEP) series IM [0, 7 days] for those in the #3 risk category of people who receive PrEP? |
---|---|
Population | Persons in the #3 risk category for whom rabies vaccine PrEP is recommended |
Intervention | Day 21 to year 3 rabies vaccine booster after [0, 7 days] rabies vaccine PrEP schedule with HDCV* or PCECV§ |
Comparison | No rabies vaccine booster after [0, 7 days] rabies vaccine PrEP schedule with HDCV* or PCECV§ |
Outcomes | Long-term immunogenicity |
§Purified chick embryo cell vaccine
Table 2: Outcomes and Rankings
Outcome | Importance* | Included in evidence profile |
---|---|---|
Long-term immunogenicity | Critical | Yes |
Appendix 1: Studies Included in the Review of Evidence
Last name first author, Publication year | Study design | Country (or more detail, if needed) | Age (measure central tendency – mean/SD; median/IQR; range) | Total population | N Intervention | N comparison | Outcomes | Funding source |
---|---|---|---|---|---|---|---|---|
Endy, 2019 | RCT | USA | Mean 32.4, Range 18 – 59 | 59 | 20 | No comparison1 | serologic immune response, adverse events | US Department of Defense, Defense Health Agency through the Medical Research and Development Command |
Soentjens, 2019 | RCT | Belgium | Median 29.0, NR | 500 | 183 | No comparison1 | safety and immunogenicity | Institute of Tropical Medicine, Belgium |
Table 3a: Summary of Studies Reporting Outcome
Authors last name, pub year |
Age (years) | N intervention | N comparison | Vaccine | Absolute difference/effect estimate | Study limitations (Risk of Bias) |
---|---|---|---|---|---|---|
Endy, 2019 | Mean 32.4, Range 18 – 59 | 20 | No comparison1 | PCEC, IM | Not able to calculate2 | 8/9 Minimal concerns |
Soentjens, 2019 | Median 29.0, NR | 183 | No comparison1 | HDCV, IM | Not able to calculate2 | 8/9 Minimal concerns |
2No comparison data available to calculate effect estimate.
3Study quality for observational studies was assessed using the Newcastle Ottawa Scale.
Table 4: Grade Summary of Findings Table
Certainty assessment | Impact | Certainty | Importance | ||||||
---|---|---|---|---|---|---|---|---|---|
№ of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | |||
Anamnestic response after booster (follow up: range 1 to 3 weeks) | |||||||||
2 1,2 | observational studies | not serious | not serious | not serious | not serious | none | A historical control of trial participants receiving 2 doses of rabies vaccine resulting in 100% immunogenicity (n=264) at 1-3 weeks following vaccination schedule (Endy 2019, Soentjens 2019) : 410/410 (100%) seroconverstion with booster | Level 3 Low |
CRITICAL |
Table 5: Summary of Evidence for Outcomes of Interest
Outcome | Importance | Included in profile | Certainty |
---|---|---|---|
Long-term immunogenicity | Critical | Yes | Level 3, Low |
References
- Endy, T. P., Keiser, P. B., Wang, D., Jarman, R. G., Cibula, D., Fang, H., Ware, L., Abbott, M., Thomas, S. J., Polhemus, M. E.. Serologic Response of 2 Versus 3 Doses and Intradermal Versus Intramuscular Administration of a Licensed Rabies Vaccine for Preexposure Prophylaxis. J Infect Dis; Apr 7 2020.
- Soentjens, P., Andries, P., Aerssens, A., Tsoumanis, A., Ravinetto, R., Heuninckx, W., van Loen, H., Brochier, B., Van Gucht, S., Van Damme, P., Van Herrewege, Y., Bottieau, E.. Preexposure Intradermal Rabies Vaccination: A Noninferiority Trial in Healthy Adults on Shortening the Vaccination Schedule From 28 to 7 Days. Clin Infect Dis; Feb 1 2019.