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) (https://www.cdc.gov/vaccines/acip/recs/index.html). Summary evidence for primary immunogenicity was determined and discussed.

Table 1: Policy Question and PICO

Table 1: Policy Question and PICO
Policy question: Should a 2-dose pre-exposure prophylaxis (PrEP) series involving HDCV* or PCECV§ IM [0, 7 days] replace the 3-dose series IM [0, 7, 21/28 days] for all those for whom rabies vaccine PrEP is recommended?
Population Persons for whom rabies vaccine PrEP is recommended
Intervention [0, 7 days] rabies vaccine PrEP schedule with HDCV* or PCECV§
Comparison [0, 7, 21/28 days] rabies vaccine PrEP schedule with HDCV* or PCECV§
Outcomes Primary immunogenicity
*Human diploid cell culture vaccine
§Purified chick embryo cell vaccine

Table 2: Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome Importance* Included in evidence profile
Primary 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

Appendix 1: Studies Included in the Review of Evidence
Last name first author, Publication year Study design1 Country Age (years) Total population N Intervention N comparison Outcomes Funding source
Ajjan, 1989 Observational France Mean 22, Range 19-41 144 72 69 adverse events and immunogenicity NR
Arora, 2004 Observational USA Mean 26.2 135 44 44 safety and immunogenicity Aventis Pasteur
Briggs, 1996 Observational USA NR 318 146 146 safety and immunogenicity Swiss Serum and Vaccine Institute, Bern, Switzerland
Cramer, 2016 Observational Austria, Germany,
Switzerland
Mean 36.7, SD 12.9 661 371 364 safety and immunogenicity Novartis Vaccines
Endy, 2019 RCT USA Mean 32.4, Range 18 – 59 59 22 24 serologic immune response, adverse events US Department of Defense, Defense Health Agency through the Medical Research and Development Command
Hacibektasoglu, 1992 Observational Appears to be Turkey Mean 20, Range 18 – 24 90 30 30 safety and immunogenicity NR
Jaijaroensup, 1999 Observational Thailand Range 17 – 22 138 138 129 Immunogenicity NR
Kitala, 1990 Observational Kenya NR 80 37 37 Immune response NR
Recuenco, 2017 Observational USA Median 41.0, Range 20 – 62 130 60 59 immunogenicity and adverse effects CDC
Sabchareon, 1999 Observational Thailand Mean 10
SD 1.32
400 190 190 immunogenicity and safety Pasteur Merieux Connaught, Lyon, France
Soentjens, 2019 RCT Belgium Median 29.0, NR 500 242 240 safety and immunogenicity Institute of Tropical Medicine, Belgium
Vodopija, 1986 Observational Appears to be Croatia NR 185 49 46 Immunogenicity NR
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

Table 3a: Summary of Randomized Control Trial Studies Reporting Outcome
Authors last name, pub year Age (years) N intervention N comparison Vaccine Risk Ratio [95% CI] Study limitations (Risk of Bias)
Endy, 2019 Mean 32.4,
Range 18 – 59
22 24 PCEC, IM, ID 1.00 [0.89, 1.12] Some concerns1
Soentjens, 2019 Median 29.0,
Range NR
242 240 HDCV, ID Some concerns2
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

Table 3b: Summary of Observational Studies Reporting Outcome
Authors last name, pub year Age (years) N intervention N comparison Vaccine Risk Ratio [95% CI]1 Study limitations (Study quality2)
Ajjan, 1989 Mean 22, Range 19-41 72 69 HDCV, IM 1.00 [0.97, 1.03] 9/9 No concerns
Arora, 2004 Mean 26.2 44 44 HDCV, IM  1.00 [0.96, 1.04] 9/9 No concerns
Briggs, 1996 NR 146 146 HDCV, IM  1.00 [0.99, 1.01] 9/9 No concerns
Cramer 2016 Mean 36.7, SD 12.9 371 364 PCEC, IM  0.99 [0.98, 1.01]4 7/9 Minimal concerns
Hacibektasoglu, 1992 Mean 20, Range 18 – 24 30 30 HDCV, IM 0.90 [0.79, 1.03] 9/9 No concerns
Jaijaroensup, 1999 NR, Range 17 – 22 138 129 PCEC, IM, ID 0.94 [0.87, 1.02]4 9/9 No concerns
Kitala, 1990 NR 37 37 HDCV, IM  1.00 [0.95, 1.05] 8/9 Minimal concerns
Recuenco, 2017 Median 41.0, Range 20 – 62 60 59 PCEC, IM, ID 1.00 [0.96, 1.05]4 9/9 No concerns
Sabchareon, 1999 Mean 10,
SD 1.33
190 190 HDCV, IM  1.00 [0.99, 1.01] 7/9 Minimal concerns
Vodopija, 1986 NR 49 46 HDCV, PCEC, IM 1.00 [0.94, 1.06]4 9/9 No concerns
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

Table 4: Grade Summary of Findings Table
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations [0, 7 days] rabies vaccine PrEP schedule [0, 7, 21/28 days] rabies vaccine PrEP schedule Relative
(95% CI)
Absolute
(95% CI)
Immunogenicity (RCTs) (follow up: range 2 weeks to 3 weeks; assessed with: titer level above 0.5 IU/mL)
2 1,2 randomized trials serious a not serious not serious not serious none 264/264 (100.0%) 264/264 (100.0%) RR 1.00
(0.99 to 1.01)
0 fewer per 1,000
(from 10 fewer to 10 more)
Level 2
Moderate
CRITICAL
Immunogenicity (observational studies) (follow up range: 2 to 3 weeks, assessed with titer level above 0.5 IU/mL)
10 3,4,5,6,7,8,9,10,11,12 observational studies not serious not serious not serious b not serious none 1090/1137 (95.9%) 1081/1114 (97.0%) RR 1.00
(0.99 to 1.00)
0 fewer per 1,000
(from 10 fewer to 0 fewer)
Level 3
Low
CRITICAL

CI: Confidence interval; RR: Risk ratio

Explanations

  1. 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.
  2. 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

Table 5: Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
Primary immunogenicity Critical Yes Level 2, Moderate

References

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