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.

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. travellers.^[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.

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*https://www.fda.gov/media/75709/download
^† https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert-RabAvert.pdf

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.