Use of Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies

Background

Transmission of rabies virus occurs when saliva or neural tissue from an infected mammal is introduced into a person or another animal through, for example, a bite or contact with mucous membranes (1). Worldwide, approximately 59,000 human rabies deaths occur each year (2). The canine rabies virus variant (CRVV) is the most common source of human rabies infections, accounting for approximately 98% of cases, including some cases among U.S. travelers (3). In the United States, CRVV has been eliminated (3), but wildlife rabies remains endemic, accounting for approximately 5,000 reported rabid animals each year (4). Specific wildlife rabies virus variants (RVVs) associated with mesocarnivores (small to midsized animals whose diet includes 50%–70% meat) are endemic in distinct geographically confined locations in 42 U.S. states and Puerto Rico (4). In contrast, bat RVVs are widely distributed throughout the United States, with only Hawaii being rabies-free (3). During January 2000–December 2020, 52 cases of human rabies were diagnosed in the United States, 38 of which were indigenously acquired (i.e., from rabies exposures that occurred in the United States) (4); none were in persons who had previously received PrEP.

In the United States, two modern cell culture vaccines are licensed for rabies PrEP and PEP: human diploid cell vaccine (HDCV; Imovax/Sanofi Pasteur)* and purified chick embryo cell vaccine (PCECV; RabAvert/Bavarian Nordic),^† respectively; both are packaged for intramuscular (IM) administration (1). Each IM dose of vaccine consists of 1 mL and should be administered in the deltoid for adults, and in either the deltoid or anterolateral aspect of the thigh for children.

Reasons for Revisions of Recommendations

ACIP has recommended rabies PrEP since 1969 (5). As safe and effective modern cell culture vaccines have replaced those derived from nerve tissue and duck embryo, and as rabies epidemiology has continued to evolve (e.g., elimination of CRVV, emergence and spread of the racoon RVV, and host shifts of bat RVV to mesocarnivores in the southern United States), changes have been made to ACIP recommendations. Since 2008, when the last ACIP rabies PrEP recommendations were published, barriers affecting adherence to the recommendations have been identified, including out-of-pocket costs of rabies biologics (3-dose PrEP vaccination series is currently estimated at ≥$1,100^§), confusion about which activities fall within different risk categories, and noncompliance with recommendations for repeated titer checks (6). In addition, travel medicine providers have indicated that the largest group for which PrEP is recommended (travelers to regions with endemic CRVV) might often be unable to complete the 3-dose series described in the 2008 ACIP recommendations (1) because at least 21 days are required to complete the series before initiation of travel (7).

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. The Work Group comprised experts in diverse disciplines including laboratory, public health, and clinical specialties. Data collected, analyzed, and prepared by the Work Group were deliberated by ACIP during six public meetings. With publication of this report, the recommendations become final and are the official CDC recommendations for rabies PrEP.

Redefined Risk Categories

Recommendations for PrEP depend on the level of a person’s risk for being exposed to rabies. The Work Group redefined risk categories into five groups, with level 1 involving activities with the highest risk and level 5 involving those with the lowest risk (Table). The highest risk categories (levels 1 and 2) include exposures that might be unrecognized (i.e., not perceived by the exposed person); for example, a small scratch to the skin during an inconspicuous personal protective equipment breach might not be noticed by persons testing neural tissue from a rabid animal or conducting ecologic studies on bats in the field. For persons with risk for unrecognized exposures, checking serial titers has historically been advised to ensure maintenance of persistently elevated rabies antibody titers; in its recent discussions, ACIP upheld this guidance because the assumption is that high titers might provide some protection when PEP is not sought for an unrecognized exposure. Recognized exposures, as defined by ACIP, are those bites, scratches, and splashes for which PEP would be sought because the exposures are usually registered by a person as unusual (e.g., contact with a bat) or painful (e.g., bite or scratch from a raccoon). The Work Group concluded that most high-risk activities involving live animals (e.g., providing veterinary health care or participating in outdoor activities in countries with endemic CRVV) are associated with only recognized exposures (risk categories 3 and 4); ACIP concluded that checking serial titers for these persons is unnecessary because recognized exposures should always prompt evaluation for PEP. Rabies vaccination recommendations for each of the redefined risk categories is summarized under Recommendations.

Risk categories might change over a person’s lifetime. Some persons for whom PrEP is indicated might have elevated risk for a limited period (e.g., during a summer internship working with wildlife or a month-long vacation to a rural village where CRVV is enzootic [risk category 4]). After the event has passed, risk level and associated recommendations for such persons will change. Shifts in risk categories are explained in the management of deviations from the recommendations section under Clinical Guidance.

Minimum Acceptable Rabies Antibody Titer Level

A correlate of protection for rabies antibody titers has not been defined. The minimum antibody level historically recommended by ACIP is one that results in complete neutralization of rabies virus at a 1:5 serum dilution by the rapid fluorescent focus inhibition test. This is approximately equivalent to a titer of 0.1–0.3 IU/mL. Stakeholders have advocated for a specific titer value in IU/mL units of measure (rather than a range) and, ideally, one that aligns with current global guidance (i.e., that of the World Health Organization) (8). Although no infections among vaccinated persons occurred with the previous ACIP cut-off titer, most published studies use 0.5 IU/mL as a correlate of protection. This level is now endorsed by ACIP and replaces the previous minimum acceptable rabies antibody titer. The higher value provides a more conservative limit for indicating inadequate response to rabies vaccination and the need for booster doses (9).

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 o