ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for 2-dose Rabies Vaccination Schedule

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

*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Appendix 1: Studies Included in the Review of Evidence

¹Observational studies may have been originally designed as randomized trials but, in this meta-analysis we broke the randomization to extract pertinent data.

²Age for total study population was not reported in this paper. Numbers in this cell are from the study arm from which data were extracted.

Table 3a: Summary of Randomized Control Trial Studies Reporting Outcome

¹Allocation concealment not reported. Study did not blind participants or healthcare personnel; however, unlikely that co-interventions would have influenced the outcome.

²Method of randomization and allocation not reported. Study did not blind participants or healthcare personnel; however, unlikely that co-interventions would have influenced the outcome.

Table 3b: Summary of Observational Studies Reporting Outcome

¹Data from observational studies, where intervention and comparison data were taken from the same people at different time points, were analyzed using M-H Risk Ratio random effects procedure. Due to unavailable raw data on pairing, a matched analysis was not possible.

²Study quality for observational studies was assessed using the Newcastle Ottawa Scale.

³Age for total study population was not reported in this paper. Numbers in this cell are from the study arm from which data were extracted.

⁴Studies contained multiple arms relative to the analysis. Risk ratio reflects pooled analysis from eligible arms.

Table 4: Grade Summary of Findings Table

CI: Confidence interval; RR: Risk ratio

Explanations

a. Method of randomization and allocation not reported in Soentjens 2019 and allocation concealment not reported in Endy 2019. Neither study blinded participants or healthcare personnel; however, unlikely that co-interventions would have influenced the outcome.

b. Sabchareon 1999 study was conducted among children and the response may be more robust than in adults, which would potentially overestimate the immune response.

Table 5: Summary of Evidence for Outcomes of Interest

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