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

Disclosures

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

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)

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^¶¶ https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html

Table. Rabies preexposure prophylaxis recommendations — United States, 2022
Risk category	Nature of exposure	Typical population*	Relevant disease biogeography^†	Recommendations
Risk category	Nature of exposure	Typical population*	Relevant disease biogeography^†	Primary PrEP^§ immunogenicity	Long-term immunogenicity^¶
1. Elevated risk for unrecognized** and recognized^†† exposures including unusual or high-risk exposures	Exposure, often in high concentrations, might be recognized or unrecognized, might be unusual (e.g., aerosolized virus)	Persons working with live rabies virus in research or vaccine production facilities or performing testing for rabies in diagnostic laboratories	Laboratory	IM rabies vaccine on days 0 and 7	Check titers every 6 months; booster if titer <0.5 IU/mL^§§
2. Elevated risk for unrecognized** and recognized^†† exposures	Exposure typically recognized but could be unrecognized; unusual exposures unlikely	Persons who frequently 1) handle bats, 2) have contact with bats, 3) enter high-density bat environments, or 4) perform animal necropsies (e.g., biologists who frequently enter bat roosts or who collect suspected rabies samples)	All geographic regions where any rabies reservoir is present, both domestic and international	IM rabies vaccine on days 0 and 7	Check titers every 2 years; booster if titer <0.5 IU/mL^§§
3. Elevated risk for recognized^†† exposures, sustained risk^¶¶	Exposure nearly always recognized; risk for recognized exposures higher than that for the general population and duration exceeds 3 years after the primary vaccination	Persons who interact with animals that could be rabid***; occupational or recreational activities that typically involve contact with animals include 1) veterinarians, technicians, animal control officers, and their students or trainees; 2) persons who handle wildlife reservoir species (e.g., wildlife biologists, rehabilitators, and trappers); and 3) spelunkers	All domestic and international geographic regions where any rabies reservoir is present	IM rabies vaccine on days 0 and 7	1) One-time titer check during years 1–3 after 2-dose primary series; booster if titer <0.5 IU/mL,^§§ or 2) booster no sooner than day 21 and no later than year 3 after 2-dose primary series^†††
		Selected travelers. PrEP considerations include whether the travelers 1) will be performing occupational or recreational activities that increase risk for exposure to potentially rabid animals (particularly dogs) and 2) might have difficulty getting prompt access to safe PEP (e.g., rural part of a country or far from closest PEP clinic)	International geographic regions with rabies virus reservoirs, particularly where rabies virus is endemic in dog populations	IM rabies vaccine on days 0 and 7
4. Elevated risk for recognized^†† exposures, risk not sustained^¶¶	Exposure nearly always recognized; risk for exposure higher than for general population but expected to be time-limited (≤3 years from the 2-dose primary PrEP vaccination series)	Same as for risk category 3 (above), but risk duration ≤3 years (e.g., short-term volunteer providing hands-on animal care or infrequent traveler with no expected high-risk travel >3 years after PrEP administration)	Same as for risk category 3 (above)	IM rabies vaccine on days 0 and 7	None
5. Low risk for exposure	Exposure uncommon	Typical person living in the United States	Not applicable	None	None

Abbreviations: IM = intramuscular; IU = international units; PEP = postexposure prophylaxis; PrEP = preexposure prophylaxis.
*Nature of exposure and type of work performed are the most important variables to consider when determining a person's risk category. The examples provided are intended to be a guide, but ultimately categorizations should be done on a case-by-case basis with nature of exposure considered. Some persons might be categorized into a different risk group from those suggested by the provided examples. For example, most veterinarians are in risk category 3 because they are at risk for recognized exposures after direct contact with animals. However, a veterinary pathologist who often performs necropsies on mammals suspected to have had rabies might have risk for rabies virus exposure that is more consistent with risk category 2 than risk category 3; such persons should follow the recommendations for the risk category with which their activities best fit. Similarly, most spelunkers do not often enter high-density bat caves; those who do may follow the recommendations for risk category 2 rather than risk category 3. Persons involved in the diagnosis of rabies virus, but for whom the frequency of handling rabies virus–infected tissues is low, or the procedures performed do not involve contact with neural tissue or opening of a suspected rabid animal's calvarium could consider following the recommendations for risk category 2 rather than those for risk category 1.
^†Local or state health departments should be consulted for questions about local disease biogeography.
^§Primary immunogenicity refers to immunogenicity that peaks 2–4 weeks after completing the recommended primary vaccination schedule. Persons without altered immunity are expected to mount appropriate responses, and checking titers is not routinely recommended. Persons with altered immunity are advised to confirm, through laboratory testing, a rabies antibody titer ≥0.5 IU/mL ≥1 week after booster vaccination (but ideally, 2–4 weeks after completing the recommended schedule) and before participating in high-risk activities. Individual laboratories set facility-specific rules about whether acceptable antibody titers should be laboratory-confirmed for all personnel, regardless of whether personnel have altered immunity.
^¶Long-term immunogenicity refers to the ability to mount an anamnestic response to rabies virus >3 years after completion of the primary rabies vaccination series.
**Unrecognized exposures are those that recipients might not know occurred; for example, a small scratch during an inconspicuous personal protective equipment breach might not be noticed by persons testing neural tissue from a rabid animal or persons conducting ecologic studies on bats in the field.
^††Recognized exposures are bites, scratches, and splashes that are usually registered by a person because the exposure is unusual (e.g., contact with a bat) or painful (e.g., bite or scratch from a raccoon).
^§§When rabies antibody titers are <0.5 IU/mL, a booster vaccination should be provided. Antibody titers to verify booster response need not be checked after these boosters are administered to persons who are immunocompetent. For persons who are immunocompromised, the indicated antibody titer should be verified ≥1 week (ideally, 2–4 weeks) after administration of every booster vaccination.
^¶¶Sustained risk is elevated risk for rabies >3 years after the completion of the primary rabies PrEP vaccination schedule.
***Rabies virus is unlikely to persist outside a deceased animal's body for an extended time because of virus inactivation by desiccation, ultraviolet irradiation, and other factors. Risk from transmission to persons handling animal products (e.g., hunters and taxidermists) is unknown but presumed to be low (risk category 5); direct skin contact with saliva and neural tissue of mammals should be avoided regardless of profession.
^†††Checking titers after recommended booster doses is not indicated unless the recipient has altered immunity.