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

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

*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
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

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 3a: Summary of Studies Reporting Outcome

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

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

Table 4: Grade Summary of Findings Table
Certainty assessment							Impact	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Impact	Certainty	Importance
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

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.

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