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Advisory Committee on Immunization Practices (ACIP)








ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for 2-dose Rabies Vaccination Schedule						Print
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										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 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 recommendedIntervention
[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 vaccineTable 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance*
Included in evidence profilePrimary immunogenicity
Critical
Yes
*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision makingAppendix 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 sourceAjjan, 1989
Observational
France
Mean 22, Range 19-41
144
72
69
adverse events and immunogenicity
NRArora, 2004
Observational
USA
Mean 26.2
135
44
44
safety and immunogenicity
Aventis PasteurBriggs, 1996
Observational
USA
NR
318
146
146
safety and immunogenicity
Swiss Serum and Vaccine Institute, Bern, SwitzerlandCramer, 2016
Observational
Austria, Germany,
Switzerland
Mean 36.7, SD 12.9
661
371
364
safety and immunogenicity
Novartis VaccinesEndy, 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 CommandHacibektasoglu, 1992
Observational
Appears to be Turkey
Mean 20, Range 18 – 24
90
30
30
safety and immunogenicity
NRJaijaroensup, 1999
Observational
Thailand
Range 17 – 22
138
138
129
Immunogenicity
NRKitala, 1990
Observational
Kenya
NR
80
37
37
Immune response
NRRecuenco, 2017
Observational
USA
Median 41.0, Range 20 – 62
130
60
59
immunogenicity and adverse effects
CDCSabchareon, 1999
Observational
Thailand
Mean 10
SD 1.32
400
190
190
immunogenicity and safety
Pasteur Merieux Connaught, Lyon, FranceSoentjens, 2019
RCT
Belgium
Median 29.0, NR
500
242
240
safety and immunogenicity
Institute of Tropical Medicine, BelgiumVodopija, 1986
Observational
Appears to be Croatia
NR
185
49
46
Immunogenicity
NR1Observational 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 concerns1Soentjens, 2019
Median 29.0,
Range NR
242
240
HDCV, ID

Some concerns21Allocation 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 concernsArora, 2004
Mean 26.2
44
44
HDCV, IM
1.00 [0.96, 1.04]
9/9 No concernsBriggs, 1996
NR
146
146
HDCV, IM
1.00 [0.99, 1.01]
9/9 No concernsCramer 2016
Mean 36.7, SD 12.9
371
364
PCEC, IM
0.99 [0.98, 1.01]4
7/9 Minimal concernsHacibektasoglu, 1992
Mean 20, Range 18 – 24
30
30
HDCV, IM
0.90 [0.79, 1.03]
9/9 No concernsJaijaroensup, 1999
NR, Range 17 – 22
138
129
PCEC, IM, ID
0.94 [0.87, 1.02]4
9/9 No concernsKitala, 1990
NR
37
37
HDCV, IM
1.00 [0.95, 1.05]
8/9 Minimal concernsRecuenco, 2017
Median 41.0, Range 20 – 62
60
59
PCEC, IM, ID
1.00 [0.96, 1.05]4
9/9 No concernsSabchareon, 1999
Mean 10,
SD 1.33
190
190
HDCV, IM
1.00 [0.99, 1.01]
7/9 Minimal concernsVodopija, 1986
NR
49
46
HDCV, PCEC, IM
1.00 [0.94, 1.06]4
9/9 No concerns1Data 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**
**No of patients**
**Effect**
**Certainty**
**Importance****No 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**
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.
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
CertaintyPrimary immunogenicity
Critical
Yes
Level 2, ModerateReferences
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.
Vodopija, I., Sureau, P., Lafon, M., Baklaic, Z., Ljubicić, M., Svjetlicić, M., Smerdel, S.. An evaluation of second generation tissue culture rabies vaccines for use in man: a four-vaccine comparative immunogenicity study using a pre-exposure vaccination schedule and an abbreviated 2-1-1 postexposure schedule. Vaccine; Dec 1986.
Sabchareon, A., Lang, J., Attanath, P., Sirivichayakul, C., Pengsaa, K., Le Mener, V., Chantavanich, P., Prarinyanuphab, V., Pojjaroen-Anant, C., Nimnual, S., Wood, S. C., Riffard, P.. A new Vero cell rabies vaccine: results of a comparative trial with human diploid cell rabies vaccine in children. Clin Infect Dis; Jul 1999.
Recuenco, S., Warnock, E., Osinubi, M. O. V., Rupprecht, C. E.. A single center, open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults. Vaccine; Aug 3 2017.
Kitala, P. M., Lindqvist, K. J., Koimett, E., Johnson, B. K., Chunge, C. N., Perrin, P., Olsvik, O.. Comparison of human immune responses to purified Vero cell and human diploid cell rabies vaccines by using two different antibody titration methods. J Clin Microbiol; Aug 1990.
Hacibektasoglu, A., Inal, A., Eyigun, C., Barut, A., Turkay, F. A.. Comparison of HDCV vs PVRV pre-exposure immunization, reliability and protective effectiveness. Mikrobiyoloji Bulteni; 1992.
Jaijaroensup, W., Limusanno, S., Khawplod, P., Serikul, K., Chomchay, P., Kaewchomphoo, W., Tantawichien, T., Wilde, H.. Immunogenicity of rabies postexposure booster injections in subjects who had previously received intradermal preexposure vaccination. J Travel Med; Dec 1999.
Cramer, J. P., Jelinek, T., Paulke-Korinek, M., Reisinger, E. C., Dieckmann, S., Alberer, M., Bühler, S., Bosse, D., Meyer, S., Fragapane, E., Costantini, M., Pellegrini, M., Lattanzi, M., Dovali, C.. One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series. J Travel Med; Mar 2016.
Briggs, D. J., Dreesen, D. W., Morgan, P., Chin, J. E., Seedle, C. D., Cryz, L., Glück, R., Cryz, S. J.. Safety and immunogenicity of Lyssavac Berna human diploid cell rabies vaccine in healthy adults. Vaccine; Oct 1996.
Arora, A., Moeller, L., Froeschle, J.. Safety and immunogenicity of a new chromatographically purified rabies vaccine in comparison to the human diploid cell vaccine. J Travel Med; Jul-Aug 2004.
Ajjan, N., Pilet, C.. Comparative study of the safety and protective value, in pre-exposure use, of rabies vaccine cultivated on human diploid cells (HDCV) and of the new vaccine grown on Vero cells. Vaccine; Apr 1989.Top of Page
							
					
							Last Reviewed:  April 27, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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