ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for 2-dose Rabies Vaccination Schedule
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.
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.
|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§|
§Purified chick embryo cell vaccine
|Outcome||Importance*||Included in evidence profile|
|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,
|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
|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|
|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,
|242||240||HDCV, ID||Some concerns2|
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.
|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,
|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|
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.
|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
|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)
|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)
CI: Confidence interval; RR: Risk ratio
- 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.
|Outcome||Importance||Included in profile||Certainty|
|Primary immunogenicity||Critical||Yes||Level 2, Moderate|
- 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.