About
CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
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) Evidence-Based Recommendations—GRADE | Advisory Committee on Immunization Practices (ACIP) | CDC . Summary evidence for primary immunogenicity was determined and discussed.
Table 1: Policy Question and PICO
*Human diploid cell culture vaccine
§Purified chick embryo cell vaccine
Table 2: Outcomes and Rankings
| Outcome | Importance* | Included in evidence profile |
|---|---|---|
| Long-term immunogenicity | Critical | Yes |
*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
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 |
1No comparison data available for this policy question available in these studies.
Table 3: 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 |
1No comparison data available for this policy question available in these studies.
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.