menu-iconMore mobile-close-icon
Skip Navigation
Skip Navigation
PrintDownload PDFGet Adobe ReaderDownload to WordDownload as HTMLDownload as XMLCitation Manager
Save to Favorites
Guideline Summary
Guideline Title
Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices (ACIP).
Bibliographic Source(s)
Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, Lett SM, Levis R, Meltzer MI, Schaffner W, Cieslak PR, Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2010 Mar 19;59(RR-2):1-9. [30 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

FDA Warning/Regulatory Alert

Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.

  • November 13, 2013 – Over-the-Counter Topical Antiseptic Products External Web Site Policy: The U.S. Food and Drug Administration (FDA) is requesting label and packaging changes to enhance the safe use of certain over-the-counter (OTC) topical antiseptic products. This request is the result of their ongoing evaluation of infrequent but continuing reports of infections resulting from antiseptic products labeled for preoperative or preinjection skin preparation. When used properly, topical antiseptics are safe and effective products to reduce the number of bacteria on patients' skin prior to surgery or injections. However, most often, contamination of topical antiseptics occurs when organisms are introduced into the product by users. Therefore, health care professionals and patients should follow all label directions to decrease the chances of infection.

Scope

Disease/Condition(s)

Human rabies

Guideline Category
Management
Prevention
Clinical Specialty
Infectious Diseases
Preventive Medicine
Intended Users
Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Health Plans
Hospitals
Nurses
Physician Assistants
Physicians
Public Health Departments
Guideline Objective(s)

To update previous recommendations of the Advisory Committee on Immunization Practices (ACIP) for postexposure prophylaxis (PEP) to prevent human rabies

Target Population

Persons in all age groups exposed to rabies virus

Interventions and Practices Considered
  1. Postexposure prophylaxis of unvaccinated persons
    • Wound cleansing
    • Human rabies immune globulin (HRIG): 20 IU/kg body weight
    • Vaccine: human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL, intramuscular (IM) (deltoid area), 1 each on days 0, 3, 7, and 14
  2. Previously vaccinated
    • Wound cleansing
    • Vaccine: HDCV or PCECV 1.0 mL, IM (deltoid area), 1 each on days 0 and 3
  3. Postvaccination serologic testing
Major Outcomes Considered
  • Prevalence and incidence of rabies in the United States
  • Morbidity
  • Mortality
  • Vaccine efficacy
  • Vaccine coverage levels
  • Cost-effectiveness of rabies vaccination
  • Side effects and adverse reactions of rabies vaccine

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Searches of Unpublished Data
Description of Methods Used to Collect/Select the Evidence

The Advisory Committee on Immunization Practice (ACIP) Rabies Workgroup used an evidence-based process for consideration of a reduced vaccination regimen in human rabies postexposure prophylaxis (PEP). This approach consisted of a review of information available from basic and applied studies of rabies prevention. Because rabies is almost always fatal among immunologically naïve persons once clinical symptoms of rabies occur, randomized, placebo-controlled efficacy studies of vaccine in humans cannot be conducted. The ACIP Rabies Workgroup reviewed six areas: 1) rabies virus pathogenesis, 2) experimental animal models, 3) human immunogenicity studies, 4) prophylaxis effectiveness in humans, 5) documented failures of prophylaxis in humans, and 6) vaccine safety. Studies for review were identified by searching the PubMed database and other relevant references and by consulting subject-matter experts.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Not stated
Rating Scheme for the Strength of the Evidence

Not applicable

Methods Used to Analyze the Evidence
Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup was formed in October 2008 to review 1) previous recommendations; 2) published and unpublished data from both national and global sources regarding rabies postexposure prophylaxis (PEP); and 3) the immunogenicity, effectiveness, and safety of a 4-dose PEP rabies vaccination regimen.

When definitive research evidence was lacking, the recommendations incorporated the expert opinion of the ACIP Rabies Workgroup members. The ACIP Rabies Workgroup also sought advice and comment from representatives of the vaccine industry, the National Association of State Public Health Veterinarians, the Council of State and Territorial Epidemiologists, state and local public health officials, additional national stakeholder groups, and other national and international experts.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

Preliminary economic assessments support the cost savings associated with a reduced schedule of vaccination. The Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup has estimated that, assuming 100% compliance with a recommended vaccine regimen, a change in recommendation from a 5-dose schedule to a 4-dose schedule would save approximately $16.6 million in costs to the U.S. health-care system. Persons who receive rabies vaccination might see some savings related to deletion of the fifth recommended dose of vaccine, measured in both the cost of the vaccine and the costs associated with the additional medical visit.

Method of Guideline Validation
Internal Peer Review
Description of Method of Guideline Validation

The proposed revised recommendations and a draft statement from the Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup were presented to the full ACIP during February 2009. After review and comment by ACIP, a revised draft, recommending a reduced regimen of 4 1-mL doses of rabies vaccine for PEP in previously unvaccinated persons, was prepared for consideration. These recommendations were discussed and accepted by ACIP at the June 2009 meeting.

Recommendations

Major Recommendations

Revised Rabies Postexposure Prophylaxis Recommendations

Rabies Postexposure Prophylaxis (PEP) Schedule — United States, 2010

Vaccination Status Intervention Regimen*
Not previously vaccinated Wound cleansing PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent (e.g., povidine-iodine solution) should be used to irrigate the wounds.
  Human rabies immune globulin (HRIG) Administer 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around and into the wound(s), and any remaining volume should be administered at an anatomical site (intramuscular [IM]) distant from vaccine administration. Also, HRIG should not be administered in the same syringe as vaccine. Because RIG might partially suppress active production of rabies virus antibody, no more than the recommended dose should be administered.
  Vaccine Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid area†), 1 each on days 0,§ 3, 7 and 14.
Previously vaccinated** Wound cleansing All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidine-iodine solution should be used to irrigate the wounds.
  HRIG HRIG should not be administered.
  Vaccine HDCV or PCECV 1.0 mL, IM (deltoid area), 1 each on days 0§ and 3.

* These regimens are applicable for persons in all age groups, including children.
† The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area.
§ Day 0 is the day dose 1 of vaccine is administered.
¶ For persons with immunosuppression, rabies PEP should be administered using all 5 doses of vaccine on days 0, 3, 7, 14, and 28.
** Any person with a history of pre-exposure vaccination with HDCV, PCECV, or rabies vaccine adsorbed (RVA); prior PEP with HDCV, PCECV or RVA; or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination.

Postexposure Prophylaxis for Unvaccinated Persons

For unvaccinated persons, the combination of RIG and 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 appropriate laboratory diagnostic testing (i.e., the direct fluorescent antibody test) indicates that the animal that caused the exposure was not rabid, PEP may be discontinued.

Vaccine Use

A regimen of 4 1-mL vaccine doses of HDCV or PCECV should be administered intramuscularly to previously unvaccinated persons (see Table above). The first dose of the 4-dose regimen should be administered as soon as possible after exposure. The date of the first dose is considered to be day 0 of the PEP series. Additional doses then should be administered on days 3, 7, and 14 after the first vaccination. Recommendations for the site of the intramuscular vaccination remain unchanged (e.g., for adults, the deltoid area; for children, the anterolateral aspect of the thigh also is acceptable). The gluteal area should not be used because administration of vaccine in this area might result in a diminished immunologic response. Children should receive the same vaccine dose (i.e., vaccine volume) as recommended for adults.

Human Rabies Immune Globulin (HRIG) Use

The recommendations for use of immune globulin in rabies prophylaxis remain unchanged by the revised recommendation of a reduced rabies vaccine schedule. HRIG is administered once to previously unvaccinated persons to provide rabies virus-neutralizing antibody coverage until the patient responds to vaccination by actively producing virus-neutralizing antibodies. HRIG is administered once on day 0 at the time PEP is initiated, in conjunction with human rabies vaccines available for use in the United States. If HRIG was not administered when vaccination was begun on day 0, it can be administered up to and including day 7 of the PEP series. If anatomically feasible, the full dose of HRIG is infiltrated around and into any wounds. Any remaining volume is injected intramuscularly at a site distant from vaccine administration. HRIG is not administered in the same syringe or at the same anatomic site as the first vaccine dose. However, subsequent doses (i.e., on days 3, 7, and 14) of vaccine in the 4-dose vaccine series can be administered in the same anatomic location in which HRIG was administered.

Postexposure Prophylaxis for Previously Vaccinated Persons

Recommendations for PEP have not changed for persons who were vaccinated previously. Previously vaccinated persons are those who have received one of the ACIP-recommended pre- or postexposure prophylaxis regimens (with cell-culture vaccines) or those who received another vaccine regimen (or vaccines other than cell-culture vaccine) and had a documented adequate rabies virus-neutralizing antibody response. Previously vaccinated persons, as defined above, should receive 2 vaccine doses (1.0 mL each in the deltoid), the first dose immediately and the second dose 3 days later. Administration of HRIG is unnecessary, and HRIG should not be administered to previously vaccinated persons to avoid possible inhibition of the relative strength or rapidity of an expected anamnestic response. Local wound care remains an important part of rabies PEP for any previously vaccinated persons.

Vaccination and Serologic Testing

Postvaccination Serologic Testing

All healthy persons tested in accordance with Advisory Committee on Immunization Practices (ACIP) guidelines after completion of at least a 4-dose regimen of rabies PEP should demonstrate an adequate antibody response against rabies virus. Therefore, no routine testing of healthy patients completing PEP is necessary to document seroconversion. When titers are obtained, serum specimens collected 1–2 weeks after prophylaxis (after last dose of vaccine) should completely neutralize challenge virus at least at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT). The rabies virus-neutralizing antibody titers will decline gradually since the last vaccination. Minimal differences (i.e., within one dilution of sera) in the reported values of rabies virus-neutralizing antibody results might occur between laboratories that provide antibody determination using the recommended RFFIT. Commercial rabies virus antibody titer determination kits that are not approved by the Food and Drug Administration are not appropriate for use as a substitute for the RFFIT. Discrepant results might occur after the use of such tests, and actual virus-neutralizing activity in clinical specimens cannot be measured.

Management of Adverse Reactions, Precautions, and Contraindications

Management of Adverse Reactions

Recommendations for management and reporting of vaccine adverse events have not changed. These recommendations have been described in detail previously.

Immunosuppression

Recommendations for rabies pre- and postexposure prophylaxis for persons with immunosuppression have not changed. General recommendations for active and passive immunization in persons with altered immunocompetence have been summarized previously. This updated report discusses specific recommendations for patients with altered immunocompetence who require rabies pre- and postexposure prophylaxis. All rabies vaccines licensed in the United States are inactivated cell-culture vaccines that can be administered safely to persons with altered immunocompetence. Because corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses might reduce immune responses to rabies vaccines substantially, for persons with immunosuppression, rabies PEP should be administered using a 5-dose vaccine regimen (i.e., 1 dose of vaccine on days 0, 3, 7, 14, and 28), with the understanding that the immune response still might be inadequate. Immunosuppressive agents should not be administered during rabies PEP unless essential for the treatment of other conditions. If possible, immunosuppressed patients should postpone rabies preexposure prophylaxis until the immunocompromising condition is resolved. When postponement is not possible, immunosuppressed persons who are at risk for rabies should have their virus-neutralizing antibody responses checked after completing the preexposure series. Postvaccination rabies virus-neutralizing antibody values might be less than adequate among immunosuppressed persons with HIV or other infections. When rabies pre- or postexposure prophylaxis is administered to an immunosuppressed person, one or more serum samples should be tested for rabies virus-neutralizing antibody by the RFFIT to ensure that an acceptable antibody response has developed after completing the series. If no acceptable antibody response is detected after the final dose in the pre- or postexposure prophylaxis series, the patient should be managed in consultation with their physician and appropriate public health officials.

Variation from Human Rabies Vaccine Package Inserts

These new ACIP recommendations differ from current rabies vaccine label instructions, which still list the 5-dose series for PEP. Historically, ACIP review and subsequent public health recommendations for the use of various biologics has occurred after vaccine licensure and generally are in agreement with product labels. However, differences between ACIP recommendations and product labels are not unprecedented. For example, during the early 1980s, ACIP review and recommendations concerning the intradermal use of rabies vaccines occurred well in advance of actual label claims and licensing. On the basis of discussions with industry representatives, alterations of current product labels for HDCV and purified chick embryo cell (PCEC) are not anticipated by the producers of human rabies vaccines licensed for use in the United States.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is not specifically stated for each recommendation.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits
  • Observational studies indicate that postexposure prophylaxis (PEP) is universally effective in preventing human rabies when administered promptly and appropriately.
  • Expected positive national benefits are related to omission of a 5th dose (e.g., minimized travel expenses, reduced time out of work, healthcare workers have more time for other patients, and fewer adverse reactions).
Potential Harms

Not stated

Qualifying Statements

Qualifying Statements
  • Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.
  • References to non-Centers for Disease Control and Prevention (CDC) sites on the Internet are provided as a service to Morbidity and Mortality Weekly Report (MMWR) readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of these sites. URL addresses listed in MMWR were current as of the date of publication.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Staying Healthy
IOM Domain
Effectiveness
Timeliness

Identifying Information and Availability

Bibliographic Source(s)
Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, Lett SM, Levis R, Meltzer MI, Schaffner W, Cieslak PR, Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2010 Mar 19;59(RR-2):1-9. [30 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2010 Mar 19
Guideline Developer(s)
Centers for Disease Control and Prevention - Federal Government Agency [U.S.]
Source(s) of Funding

United States Government

Guideline Committee

Advisory Committee on Immunization Practices (ACIP)

ACIP Rabies Work Group

Composition of Group That Authored the Guideline

Advisory Committee on Immunization Practices

Membership as of June 24, 2009

Chair: Dale Morse, MD, New York State Department of Health, Albany, New York

Executive Secretary: Larry Pickering, MD, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia

Members: Carol Baker, MD, Baylor College of Medicine, Houston, Texas; Robert Beck, JD, Consumer Representative, Palmyra, Virginia; Lance Chilton, MD, University of New Mexico, Albuquerque, New Mexico; Paul Cieslak, MD, Oregon Public Health Division, Portland, Oregon; Kristen Ehresmann, MPH, Minnesota Department of Health, St. Paul, Minnesota; Janet Englund, MD, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, Washington; Franklyn Judson, MD, University of Colorado Health Sciences Center, Denver, Colorado; Susan Lett, MD, Massachusetts Department of Public Health, Boston, Massachusetts; Michael Marcy, MD, UCLA Center for Vaccine Research, Torrance, California; Cody Meissner, MD, Tufts Medical Center, Boston, Massachusetts; Kathleen Neuzil, MD, University of Washington, Seattle, Washington; Mark Sawyer, MD, University of California–San Diego, California; Ciro Valent Sumaya, MD, Texas A&M Health Science Center, College Station, Texas; Jonathan Temte, MD, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Ex Officio Members: James E. Cheek, MD, Indian Health Service, Albuquerque, New Mexico; Wayne Hachey, DO, Department of Defense, Falls Church, Virginia; Geoffrey S. Evans, MD, Health Resources and Services Administration, Rockville, Maryland; Bruce Gellin, MD, National Vaccine Program Office, Washington, District of Columbia; Linda Murphy, Centers for Medicare and Medicaid Services, Baltimore, Maryland; George T. Curlin, MD, National Institutes of Health, Bethesda, Maryland; Norman Baylor, MD, Food and Drug Administration, Bethesda, Maryland; Linda Kinsinger, MD, Department of Veterans Affairs, Durham, North Carolina

Liaison Representatives: American Academy of Family Physicians, Doug Campos-Outcalt, MD, Phoenix, Arizona; American Academy of Pediatrics, Joseph Bocchini, MD, Shreveport, Louisiana, David Kimberlin, MD, Birmingham, Alabama; American College Health Association, James C. Turner, MD, Charlottesville, Virginia; American College of Obstetricians and Gynecologists, Stanley Gall, MD, Louisville, Kentucky; American College of Physicians, Gregory Poland, MD, Rochester, Minnesota; American Geriatrics Society, Kenneth Schmader, MD, Durham, North Carolina; America's Health Insurance Plans, Tamara Lewis, MD, Salt Lake City, Utah; American Medical Association, Litjen Tan, PhD, Chicago, Illinois; American Osteopathic Association, Stanley Grogg, DO, Tulsa, Oklahoma; American Pharmacists Association, Stephan L. Foster, PharmD, Memphis, Tennessee; Association for Prevention Teaching and Research, W. Paul McKinney, MD, Louisville, Kentucky; Biotechnology Industry Organization, Clement Lewin, PhD, Cambridge, Massachusetts; Canadian National Advisory Committee on Immunization, Joanne Langley, MD, Halifax, Nova Scotia, Canada; Department of Health, United Kingdom, David M. Salisbury, MD, London, United Kingdom; Healthcare Infection Control Practices Advisory Committee, Alexis Elward, MD, St Louis, Missouri; Infectious Diseases Society of America, Samuel L. Katz, MD, Durham, North Carolina; National Association of County and City Health Officials, Jeff Duchin, MD, Seattle, Washington; National Association of Pediatric Nurse Practitioners, Patricia Stinchfield, MPH; National Foundation for Infectious Diseases, William Schaffner, MD, Nashville, Tennessee; National Immunization Council and Child Health Program, Mexico, Vesta Richardson, MD, Mexico City, Mexico; National Medical Association, Patricia Whitley-Williams, MD, New Brunswick, New Jersey; National Vaccine Advisory Committee, Guthrie Birkhead, MD, Albany, New York; Pharmaceutical Research and Manufacturers of America, Damian A. Braga, Swiftwater, Pennsylvania; Peter Paradiso, PhD, Collegeville, Pennsylvania; Society for Adolescent Medicine, Amy Middleman, MD, Houston, Texas; Society for Healthcare Epidemiology of America, Harry Keyserling, MD, Atlanta, Georgia

ACIP Rabies Workgroup

Membership as of June 24, 2009

Chair: Paul Cieslak, MD, Oregon Department of Public Health, Corvallis, Oregon

Members: Deborah Briggs, PhD, Kansas State University, Manhattan, Kansas; Catherine Brown, DVM, Massachusetts Department of Public Health, Jamaica Plain, Massachusetts; Samuel L. Katz, MD, Duke University Medical Center, Durham, North Carolina; Harry D. Kerr, MD, American College of Emergency Physicians, Dallas, Texas; Susan M. Lett, MD, Massachusetts Department of Public Health, Jamaica Plain, Massachusetts; Robin Levis, PhD, Food and Drug Administration, Washington, District of Columbia; William Schaffner, MD, Vanderbilt University School of Medicine, Nashville, Tennessee; Charles E. Rupprecht, VMD, PhD, Richard Franka, DVM, PhD, Martin I. Meltzer, PhD, CDC, Atlanta, Georgia

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the Centers for Disease Control and Prevention (CDC) Web site External Web Site Policy.

Print copies: Available from the Centers for Disease Control and Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402-9325; (202) 783-3238.

Availability of Companion Documents

None available

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on January 13, 2011. This summary was updated by ECRI Institute on March 6, 2014 following the U.S. Food and Drug Administration advisory on Over-the-Counter Topical Antiseptic Products.

Copyright Statement

No copyright restrictions apply.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

Read full disclaimer...