Rabies-Prevention Policy Update: New Reduced-Dose Schedule

Rabies is a rapidly progressive encephalomyelitis with a very high case fatality rate. Approximately 55 000 people worldwide, nearly half of whom are children, die annually of rabies. Rabies is caused by RNA viruses in the family Rhabdoviridae, genus lyssavirus. In the Americas, only type 1 lyssavirus (rabies virus) circulates and is common in wild animals, particularly bats, coyotes, foxes, raccoons, and skunks, in the United States. Virus is transmitted in the saliva of rabid mammals after a bite or through contamination of an open wound or mucous membrane. The incubation period (1–3 months) is long enough to render immunization a highly effective strategy for postexposure prophylaxis (PEP). Approximately 20 000 to 30 000 persons receive PEP in the United States each year, and 1 to 3 cases of human rabies occurs annually. Between 2000 and 2007, 20 of 25 cases of human rabies reported in the United States were acquired within the United States. Among the 20 indigenously acquired cases, 17 were associated with bat rabies virus variants.

In the United States, animal rabies is common. Education of children to avoid contact with stray or wild animals is of primary importance. PEP is indicated once an exposure has occurred. PEP has never failed in the United States since the introduction of modern cell-derived vaccines in the 1970s. Keys to effective PEP have included prompt washing of the wound with copious amounts of soap and water, infiltration of human rabies immunoglobulin into and around the wound, and a 5-dose schedule of intramuscular vaccine administered over 28 days.

In 2007, when human rabies vaccine was in limited supply, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention formed a rabies work group to review rabies vaccine options and then accepted its recommendations to adopt a 4-dose vaccination regimen. The recommendation was published in Morbidity and Mortality Weekly Report: Recommendations and Reports on March 19, 2010.¹ 

A detailed review of the evidence in support of a reduced, 4-dose schedule for human PEP has been published.² 

• The induction of rabies-neutralizing antibody is a surrogate for an adequate immune response to vaccination and was achieved in all subjects (∼1000) by day 14, when the fourth dose of cell-derived rabies vaccine was given.

• From observational studies that included persons likely exposed to confirmed rabid animals and with imperfect adherence to the 5-dose vaccine schedule, the Rabies Working Group estimated that more than 300 persons in the United States received only 3 or 4 doses annually, and there were no resulting cases of human rabies. Although human PEP failures do occur rarely worldwide, no cases have been attributed to the lack of receipt of the fifth rabies vaccine dose on day 28.

• In animal models ranging from rodents to nonhuman primates, timely PEP was important, but the absolute number of vaccine doses did not contribute to significant differences in survival rates.

• Adverse reactions to the modern cell-derived rabies vaccines are uncommon in children and, theoretically, will be the same or less common with 1 less vaccine dose.

• Preliminary economic assessments indicate that there would be a $16 million cost savings to the United States health care system by using the reduced-dose schedule.

1. Unchanged: For unvaccinated persons, the combination of rabies immunoglobulin and rabies vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of PEP. If PEP has been initiated and results of appropriate laboratory testing (ie, the direct fluorescent antibody test) indicate that the animal that caused the exposure was not rabid, PEP may be discontinued.

2. New: A regimen of four 1-mL vaccine doses of human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) should be administered intramuscularly to previously unvaccinated, immunocompetent persons (Table 1). The first dose of the 4-dose regimen should be administered as soon as possible after exposure. However, the vaccine regimen may be started weeks to months after the exposure if signs and symptoms of rabies are not present. The date of the first dose is considered to be day 0 of the PEP series. Doses should then be administered on days 3, 7, and 14 after the first vaccination.

3. Unchanged: For persons with immunosuppression (see “Immunocompromised Children” in Red Book⁴ ), rabies PEP should be administered by using the 5-dose vaccine regimen (ie, 1 dose of vaccine on days 0, 3, 7, 14, and 28). The immunosuppressed patient should be tested for rabies virus–neutralizing antibody with the rapid fluorescent focus inhibition test 1 to 2 weeks after the fifth dose of vaccine. If an acceptable antibody response is not detected, the patient should be managed in consultation with an expert in rabies. Commercial rabies virus antibody tests that are not approved by the US Food and Drug Administration are not appropriate for use as a substitute for the rapid fluorescent focus inhibition test.

4. Unchanged: Sites of intramuscular vaccination remain unchanged (deltoid area in adults; anterolateral aspect of thigh or deltoid in children). The gluteal area should not be used.

5. Unchanged: Recommendations for rabies immunoglobulin use and PEP of previously vaccinated persons have not changed.³ 

6. Unchanged: No routine testing to document seroconversion in healthy patients who have completed PEP is necessary.

7. Unchanged: Recommendations for management and reporting of vaccine adverse events have not changed.

8. Unchanged: Pregnancy and breastfeeding are not contraindications to PEP.

Michael T. Brady, MD, Chairperson

Henry H. Bernstein, DO

Carrie L. Byington, MD

Kathryn M. Edwards, MD

Margaret C. Fisher, MD

Mary P. Glode, MD

Mary Anne Jackson, MD

Harry L. Keyserling, MD

David W. Kimberlin, MD

Yvonne A. Maldonado, MD

Walter A. Orenstein, MD

Gordon E. Schutze, MD

Rodney E. Willoughby, MD

Robert Bortolussi, MD

Canadian Paediatric Society

Marc A. Fischer, MD

Centers for Disease Control and Prevention

Bruce Gellin, MD

National Vaccine Program Office

Richard L. Gorman, MD

National Institutes of Health

Lucia Lee, MD

Food and Drug Administration

R. Douglas Pratt, MD

Food and Drug Administration

Jennifer S. Read, MD

National Institutes of Health

Jane Seward, MBBS, MPH

Centers for Disease Control and Prevention

Jeffrey R. Starke, MD

American Thoracic Society

Jack Swanson, MD

Committee on Practice Ambulatory Medicine

Tina Q. Tan, MD

Pediatric Infectious Diseases Society

Carol J. Baker, MD

Red Book Associate Editor

Sarah S. Long, MD

Red Book Associate Editor

H. Cody Meissner, MD

Red Book Associate Editor

Larry K. Pickering, MD

Red Book Editor

Lorry G. Rubin, MD

Jennifer Frantz, MPH

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