Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies

Recommendations of the Advisory Committee on Immunization Practices -- United States, 2022

Agam K. Rao, MD; Deborah Briggs, PhD; Susan M. Moore, PhD; Florence Whitehill, DVM; Doug Campos-Outcalt, MD; Rebecca L. Morgan, PhD; Ryan M. Wallace, DVM; José R. Romero, MD; Lynn Bahta, MPH; Sharon E. Frey, MD; Jesse D. Blanton, DrPH


Morbidity and Mortality Weekly Report. 2022;71(18):619-627. 

In This Article

Evidence for Updated Vaccine Schedule and Recommendations for Booster Doses and Titer Checks

Although there is no established correlate of protection for rabies, induction of a peak antibody response at or above the minimum acceptable antibody titer level (≥0.5 IU/mL) in response to rabies vaccine is an indirect measure of protection (i.e., immunogenicity). Primary immunogenicity refers to immunogenicity that peaks 2–4 weeks after completing the recommended vaccination or vaccinations and elicits an anamnestic response to rabies virus exposures. Since publication of the 2008 ACIP recommendations,[1] scientists have been evaluating data concerning the efficacy of shorter rabies PrEP dosing regimens.

Subject matter experts performed a systematic review of scientific evidence published during 1965–2019 for a 2-dose primary vaccination series (doses administered on days 0 and 7) compared with the 3-dose series (doses administered on days 0, 7, and 21 or 28), which is indicated in the 2008 ACIP recommendations.[1] Data showed that an anamnestic response after the 2-dose series occurs at 3 years;[10] however, an anamnestic response >3 years after the 2-dose series has not been evaluated. In the absence of data confirming an anamnestic response, the Work Group evaluated methods of inferring long-term immunogenicity (i.e., an anamnestic response >3 years after the 2-dose primary vaccination series). Checking a titer or titers was considered one way of inferring long-term immunogenicity as described in the PrEP schedule and long-term immunogenicity section that follows. As an alternative to a titer check, a second systematic review was conducted to evaluate a booster dose after the 2-dose series compared with no booster dose. The Work Group used an adapted Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine the certainty of evidence for immunogenicity rated on a scale of 1 (high certainty) to 4 (very low certainty). Within the evidence to recommendations (EtR) framework, ACIP considered the importance of rabies as a public health problem; the benefits and harms (including GRADE-assessed evidence); the target populations' values and preferences; and issues of resource use, acceptability to stakeholders, feasibility of implementation, and anticipated impact on health equity.

PrEP Schedule and Primary Immunogenicity

The systematic review identified 12 studies that enrolled a combined total of 1,401 subjects. Studies evaluating both IM and intradermal vaccination were included because primary immunogenicity is similar for both routes of administration.[11] Using the GRADE approach, the Work Group concluded with moderate (level 2) certainty that the primary immunogenicity of the 2-dose (days 0 and 7) IM schedule is comparable to that of the 3-dose (days 0, 7, and 21 or 28) IM schedule (risk ratio = 1.00 [95% CI = 0.99–1.01]). ACIP deliberated whether the 2-dose (days 0 and 7) IM PrEP schedule should replace the 3-dose schedule for all persons for whom rabies PrEP is indicated based on this finding and other findings within the EtR framework**: the target population's acceptability of the 2-dose series, feasibility of implementing the 2-dose series, minimal resource use, and anticipated increase in health equity because the 2-dose series is less expensive than the 3-dose series.

PrEP Schedule and Long-term Immunogenicity

Serial antibody titer checks are recommended for persons at elevated risk for unrecognized exposures. During recent discussions, ACIP upheld this recommendation advising that rabies antibody titers be checked every 6 months for persons in risk category 1 and every 2 years for persons in risk category 2. As previously noted, the main reason to maintain high titers is to provide some protection from unrecognized exposures; however, high titers also ensure an anamnestic response after an exposure (i.e., long-term immunogenicity).

For persons at sustained risk for only recognized exposures (risk category 3), checking serial antibody titers (as recommended for risk groups 1 and 2) was determined unnecessary; a one-time check of rabies antibody titer during years 1–3 after the 2-dose primary series was deemed appropriate assurance of long-term immunogenicity for persons with this risk. The rationale for this conclusion is that data indicate that an antibody titer ≥0.5 IU/mL 1 year after a rabies PrEP schedule is a marker for long-term immunogenicity,[12,13] and the 2-dose series is known to be protective for at least 3 years.[10]

As an alternative to the one-time titer check for risk category 3, the systematic review identified observational data from two studies that showed a booster dose triggered an anamnestic response up to 3 years after the 2-dose series. Because the third dose of the PrEP series recommended in the 2008 ACIP recommendations is given as early as day 21 and is known to provide long-term immunogenicity, a booster dose administered from day 21 to year 3 after the primary series was considered. Using the GRADE methodology, the Work Group concluded with low (level 3) certainty that a one-time booster dose of rabies vaccine during day 21–year 3 after the primary vaccination series provides better long-term immunogenicity than no booster dose; low certainty was determined because the data were not from randomized controlled trials comparing the booster with no booster.†† After evaluating these data, ACIP considered an IM booster dose of rabies vaccine during day 21–year 3 after completing the 2-dose series as an alternative to a titer check, for persons with sustained and elevated risk for recognized rabies exposures (i.e., those in risk category 3) from day 21 to year 3 after completing the 2-dose series. The rationale for the recommendation§§ within the EtR framework included the public health importance of rabies, moderately substantial desirable anticipated effect from administering a booster dose, minimal anticipated undesirable effects, acceptability to stakeholders, and feasibility of implementing the booster dose.