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

Clinical Guidance

The Work Group identified additional considerations that are essential to effective administration of rabies PrEP. These include coadministration of PrEP and chloroquine (or drugs related to chloroquine), the approach to PrEP in special populations, and management of deviations from the ACIP recommendations.

Coadministration of IM Rabies PrEP and Chloroquine or Drugs Related to Chloroquine

Recent data show that although concomitant administration of chloroquine and IM rabies PrEP is associated with a significant reduction in rabies antibody titer, the reduced levels remain >0.5 IU/mL.[14] This finding is of uncertain clinical significance because immunocompetent persons who receive chloroquine and rabies vaccines would presumably mount rabies antibody titer levels ≥0.5 IU/mL and therefore not require management that differs from that for persons who did not receive concomitant rabies vaccine. However, out of an abundance of caution and because rabies is nearly always fatal, clinicians might consider avoiding chloroquine when rabies vaccine is being administered. If avoidance is not possible, ensuring that a patient's rabies antibody titer is ≥0.5 IU/mL no sooner than 1 week (preferably 2–4 weeks) after completion of the series will confirm that vaccination was effective. No impact on efficacy was observed in the same study when other antimalarials (i.e., Malarone [atovaquone plus proguanil] and doxycycline) were administered with IM rabies PrEP. Limited anecdotal reports suggest mefloquine does not impair rabies vaccine effectiveness;[15] however, large-scale trials are needed to evaluate this hypothesis.

Approach to PrEP in Special Populations, Including Persons Suspected or Confirmed to be Immunocompromised

Modern rabies vaccines are inactivated and have been safely administered to persons of all ages, including pregnant women and immunocompromised persons. An adequate immune response is anticipated among all immunocompetent persons (including elderly immunocompetent persons) who receive rabies vaccines in accordance with the ACIP recommendations. For this reason, proof of primary immunogenicity through laboratory confirmation is not advised for immunocompetent persons after the following actions: completion of the 2-dose primary series; administration of booster doses for serial titers <0.5 IU/mL (risk categories 1 and 2) or the one-time titer <0.5 IU/mL (risk category 3); and administration of a one-time booster dose (risk category 3).

However, among persons with primary or secondary immunodeficiencies, the immune response to vaccines, including rabies vaccines, can be suboptimal. ACIP recommends that, when possible, vaccination be delayed until a temporary immunocompromising condition has resolved or immunosuppressive medications can be withheld.¶¶ If an immunocompromising condition cannot be temporarily reversed, rabies vaccines can be administered, but antibody titer should be checked no sooner than 1 week (preferably 2–4 weeks)[10] after completion of the 2-dose PrEP series and all booster doses (including those administered within 3 years of the primary series and in response to a low titer during the serial titer checks recommended for risk categories 1 and 2). If the titer is <0.5 IU/mL, a booster dose should be administered, followed by a subsequent titer check. If two such booster doses fail to elicit an acceptable antibody titer, local or state public health authorities should be consulted for case-specific guidance. Participation in high-risk activities by persons confirmed or suspected to be immunocompromised should be avoided until the laboratory-confirmed minimum acceptable antibody titer is achieved or until public health authorities provide alternative guidance. Of note, if deviations in the ACIP recommendations occur as described in management of deviation section below, a titer check is recommended regardless of immune status.

Management of Deviations From the Recommendations

Unavoidable delays of a few days from the recommended date of the second dose of the 2-dose primary series are clinically inconsequential. The effect of longer lapses of 2 weeks or more is unknown. When substantial delays occur, local and state public health authorities should be consulted for guidance. The second dose of the primary series should not be administered before the recommended interval between doses has elapsed; if it is inadvertently administered earlier, local and state public health authorities should be consulted for guidance.

Persons who have not previously received rabies PrEP should identify the risk category based on their activities. If their activities change over time, the recommendations of the new risk category should be followed to ensure long-term immunogenicity. Persons in risk category 3 who do not obtain the titer check or booster dose recommended by ACIP within the specified interval can be realigned with the ACIP recommendations (i.e., they should first have a random titer checked regardless of their immune status); for some, titers remain ≥0.5 IU/mL[16] and a booster dose is not required. However, for those whose titer is <0.5 IU/mL, a booster should be administered and then titers checked no sooner than 1 week (preferably 2–4 weeks) later. Once a titer of 0.5 IU/mL is achieved, these persons should be managed the same as persons who, consistent with the ACIP recommendations, had the recommended titer or booster within 3 years of the 2-dose primary vaccination series vaccine (Figure).

Persons who have not realigned with the ACIP recommendations and have a rabies exposure require the same PEP that is recommended for persons who did not receive PrEP (i.e., rabies immunoglobulin and 4 IM doses of rabies vaccine on days 0, 3, 7, and 14).[17] After this, they are considered to have been previously vaccinated, and in response to any subsequent exposure, only require 2 doses of rabies vaccine on days 0 and 3. Similarly, persons whose risk was categorized as category 4 (e.g., because of short-term animal care work), might later in life shift to risk category 3 (e.g., because they are pursuing a veterinary career). Shifts from risk category 4 to risk category 3 should be managed through realignment with the ACIP recommendations described; if realignment is not done, an exposure to rabies virus should be managed with rabies immunoglobulin and the 4-dose rabies vaccine series (doses administered on days 0, 3, 7, and 14)