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Information pertaining only to rabies preexposure prophylaxis has been excerpted from the Centers for Disease Control document entitled "Rabies Prevention - United States, 1999, Recommendations of the Advisory Committee on Immunization Practices (ACIP)," published in the Morbidity and Mortality Weekly Report, January 8, 1999/Vol.48/No. RR-1. For information on postexposure prophylaxis, please refer to the original published document at www.cdc.gov.
The following information serves as a reference for veterinarians. Individuals contemplating preexposure prophylaxis should consult with their physician.
Centers for Disease Control. Rabies Prevention - United States, 1999: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1999; (RR-1); [1-21]. These revised recommendations of the Immunization Practices Advisory Committee (ACIP) on rabies prevention update the previous recommendations (MMWR 1999;33:393-402,407-8) to reflect the current status of rabies and antirabies biologics in the United States. The use of trade names and commercial sources is for identification purposes only and does not constitute endorsement by the Public Health Service, the U.S. Department of Health and Human Services, or the American Veterinary Medical Association. For assistance with problems or questions about rabies prophylaxis, contact your local or state health department. If local or state health department personnel are unavailable, call the Division of Viral and Rickettsial Diseases, Center for Infectious Diseases, CDC ([404]639-1075 during working hours or [404]639-2888 nights, weekends, and holidays). |
Summary
These revised recommendations of the Advisory Committee on Immunization Practices update the previous recommendations on rabies prevention (MMWR 1991;40{No.RR-3}:1-14) to reflect the current status of rabies and antirabies biologics in the United States. This report includes new information about a human rabies vaccine approved for U.S. use in 1997, recommendations regarding exposure to bats, recommendations regarding an observation period for domestic ferrets, and changes in the local administration of rabies immune globulin.*
RABIES IMMUNIZING PRODUCTS
Two types of rabies immunizing products are available in the United States (Table 1):
Vaccines Licensed for Use in the United States
Four formulations of three inactivated rabies vaccines are currently licensed for preexposure and postexposure prophylaxis in the United States (Table_1). When used as indicated, all three types of rabies vaccines are considered equally safe and efficacious. The potency of one dose is greater than or equal to 2.5 international units (IU) per 1.0 mL of rabies virus antigen, which is the World Health Organization recommended standard (20). A full 1.0-mL dose can be used for both preexposure and postexposure prophylaxis. However, only the Imovax Rabies I.D. vaccine (human diploid cell vaccine {HDCV}) has been evaluated and approved by the Food and Drug Administration (FDA) for the intradermal dose and route for preexposure vaccination (21-24). Therefore, rabies vaccine adsorbed (RVA) and purified chick embryo cell vaccine (PCEC) should not be used intradermally. Usually, an immunization series is initiated and completed with one vaccine product. No clinical studies have been conducted that document a change in efficacy or the frequency of adverse reactions when the series is completed with a second vaccine product.
Human Diploid Cell Vaccine (HDCV)
HDCV is prepared from the Pitman-Moore strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration, and inactivated with beta-propiolactone (16). It is supplied in two forms:
Rabies Vaccine Adsorbed (RVA)
RVA was developed and is currently manufactured and distributed in the state of Michigan by BioPort Corporation. The vaccine is prepared from the Kissling strain of Challenge Virus Standard (CVS) rabies virus adapted to fetal rhesus lung diploid cell culture (26-31). The vaccine virus is inactivated with betapropiolactone and concentrated by adsorption to aluminum phosphate. Because RVA is adsorbed to aluminum phosphate, it is liquid rather than lyophilized. It is approved for IM administration only as a 1.0-mL dose.
Purified Chick Embryo Cell Vaccine (PCEC)
PCEC became available in the United States in autumn 1997 (32). It is prepared from the fixed rabies virus strain Flury LEP grown in primary cultures of chicken fibroblasts. The virus is inactivated with betapropiolactone and further processed by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration only. PCEC is available in a single-dose vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying diluent to a final volume of 1.0 mL just before administration.
| Human Rabies Vaccine | Product Name | Manufacturer |
| Human diploid cell vaccine (HFCV) Intramuscular Intradermal |
Imovax Rabies Imovax Rabies I.D. |
Pastur-Meriux Serum et Vaccins, Connaught Laboratories Inc. Phone: (800) VACCINE (882-2463) |
| Rabies Vaccine absorbed (RVA) Intramuscular |
Rabies Vaccine Absorbed (RVA) |
BioPort Corporation Phone: (517) 335-8120 |
| Purified chick embryo cell vaccine (PCEC) Intramuscular |
RabAvert |
Chiron Corporation Phone: CHIRON8 (800) 244-7668 |
PRIMARY OR PREEXPOSURE VACCINATION
Preexposure vaccination should be offered to persons in high-risk groups, such as veterinarians, animal handlers, and certain laboratory workers. Preexposure vaccination also should be considered for other persons whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies. In addition, international travelers might be candidates for preexposure vaccination if they are likely to come in contact with animals in areas where dog rabies is enzootic and immediate access to appropriate medical care, including biologics, might be limited. Routine preexposure prophylaxis for other situations might not be indicated (33,34).
Preexposure prophylaxis is administered for several reasons. First, although pre-exposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies therapy by eliminating the need for RIG and decreasing the number of doses of vaccine needed -- a point of particular importance for persons at high risk for being exposed to rabies in areas where immunizing products might not be available or where they might be at high risk for adverse reactions. Second, pre- exposure prophylaxis might protect persons whose postexposure therapy is delayed. Finally, it might provide protection to persons at risk for inapparent exposures to rabies.
Intramuscular Primary Vaccination
Three 1.0-mL injections of HDCV, RVA, or PCEC should be administered intramuscularly (deltoid area) -- one injection per day on days 0, 7, and 21 or 28 (Table 2). In a study in the United States, greater than 1,000 persons received HDCV according to this regimen. Antibody was found in serum samples of all subjects when tested by the rapid fluorescent focus inhibition test (RFFIT). Studies with other products have produced comparable results (21,35-39).
Intradermal Primary Vaccination
A regimen of three 0.1-mL ID doses of HDCV, one each on days 0, 7, and 21 or 28, is also used for preexposure vaccination (Table 2) as an alternative to the 1.0-mL IM regimen for rabies preexposure prophylaxis with HDCV (8,21,22,24,35-37,40). A single dose of lyophilized HDCV (Imovax Rabies I.D.) is available prepackaged for reconstitution in the syringe just before administration. The syringe is designed to deliver 0.1 mL of HDCV reliably and has been approved by the FDA since 1986 (25). The 0.1-mL ID doses, administered in the area over the deltoid (lateral aspect of the upper arm) on days 0, 7, and 21 or 28, are used for primary preexposure vaccination. One 0.1-mL ID dose is used for routine preexposure booster vaccination (Table 2). The 1.0-mL vial is not approved for multidose ID use. RVA and PCEC are not approved for and should not be administered intradermally (26).
When chloroquine phosphate was used routinely for malaria prophylaxis, investigators discovered that the drug decreased the antibody response to concomitantly administered HDCV (41). Although interference with the immune response to rabies vaccine by other antimalarials structurally related to chloroquine (e.g., mefloquine) has not been evaluated, precautions for persons receiving these drugs should be followed. Accordingly, HDCV should not be administered intradermally to a person traveling to malaria-endemic countries while the person is receiving one of these antimalarials (42). The IM administration of three doses of 1.0 mL of vaccine for preexposure prophylaxis provides a sufficient margin of safety in this situation (42). For persons who will be receiving both rabies preexposure prophylaxis and antimalarial chemoprophylaxis in preparation for travel to a rabies-enzootic area, the ID regimen should be initiated at least 1 month before travel to allow for completion of the full three-dose vaccine series before antimalarial prophylaxis begins. If this schedule is not possible, the IM regimen should be used.
Preexposure Booster Doses of Vaccine
Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category (Table 3) {43}) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies antibody every 6 months. Booster doses (IM or ID (Table 2)) of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT. The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), spelunkers, veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic. Persons in this group should have a serum sample tested for rabies antibody every 2 years; if the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and animal-control and wildlife officers working in areas with low rabies rates (infrequent exposure group) and at-risk international travelers do not require routine preexposure booster doses of vaccine after completion of primary preexposure vaccination.
Preexposure Vaccination and Serologic Testing
Because the antibody response has been satisfactory after these recommended preexposure prophylaxis vaccine regimens, routine serologic testing to confirm seroconversion is not necessary except for persons suspected of being immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When that is not possible, immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their antibody titers checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public health officials.
| Table 2. Rabies preexposure prophylaxis schedule, United States, 1999 | ||
|---|---|---|
| Type of vaccination | Route | Regimen |
| Primary | Intramuscular Intradermal |
HDCV,PCEC, or RVA; 1.0 mL (deltoid area), one each on days 0*, 7, and 21 or 28
HDCV; 0.1 mL, one each on days 0*, 7, and 21 or 28 |
| Booster | Intramuscular Intradermal |
HDCV,PCEC, or RVA; 1.0 mL (deltoid area), day 0* only
HDCV; 0.1 mL, day 0* only |
| HDCV=human diploid cell vaccine; PCEC=purified chick embryo cell vaccine; RVA=rabies vaccine absorbed. | ||
| * Day 0 is the day the first dose of vaccine is administered. | ||
| Table 3. Rabies preexposure prophylaxis guide, United States, 1999 | |||
|---|---|---|---|
| Risk Category | Nature of risk | Typical populations | Preexposure recommendations |
| Continuous | Virus present continuously, often in high concentrations. Specific exposures likely to go unrecognized. Bite, nonbite, or aerosol exposure. | Rabies research lab worker,* rabies biologics production workers. | Primary course. Serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level.+ |
| Frequent | Exposure usually episodic, with source recognized, but exposure may also be unrecognized. Bite, nonbite, or aerosol exposure. | Rabies diagnostic lab workers,* spelunkers, veterinarians and staff, and animal-control and wildlife workers in rabies enzootic areas. Travelers visiting foreign areas of enzootic rabies for more than 30 days. | Primary course. Serologic testing or booster vaccination every 2 years.+ |
| Infrequent greater than population at large) | Exposure nearly always episodic with source recognized. Bite, or nonbite exposure. | Veterinarians and animal-control and wildlife workers in areas of low rabies enzooticity. Veterinary students. | Primary course; no serologic testing or booster vaccination. |
| Rare (population at large) | Exposures always episodic with source recognized. Bite or nonbite exposure. | U.S. population at large, including persons in rabies epizootic areas. | No vaccination necessary. |
| *Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor. | |||
| +Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by RFFIT. Booster dose should be administered if the titer falls below this level. | |||
| Note: To print large tables and graphs users may have to chang their printer settings to landscape and use a small font size. | |||
VACCINATION AND SEROLOGIC TESTING
Serologic Response Shortly After Vaccination
All persons tested during several CDC studies 2-4 weeks after completion of preexposure and postexposure rabies prophylaxis in accordance with ACIP guidelines have demonstrated an antibody response to rabies (13,38,101,102). Therefore, serum samples from patients completing preexposure or postexposure prophylaxis do not need to be tested to document seroconversion unless the person is immunosuppressed (see Precautions and Contraindications). If titers are obtained, specimens collected 2-4 weeks after preexposure or postexposure prophylaxis should completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. In animal studies, neutralizing antibody titers have been shown to be imperfect markers of protection. Antibody titers will vary with time since the last vaccination. Differences among laboratories that test blood samples also can influence the results.
Serologic Response and Preexposure Booster Doses of Vaccine
Although antibody levels do not define a person's immune status, they are a marker of continuing immune response (103). To ensure the continuity of an immune response, titers should be checked periodically, with booster doses administered as needed. Two years after primary preexposure vaccination, a 1:5 serum dilution will neutralize challenge virus completely (by the RFFIT) among 93%-98% of persons who received the three-dose preexposure series intramuscularly and 83%-95% of persons who received the three-dose series intradermally (104). If the titer falls below the minimum acceptable antibody level, a preexposure booster dose of vaccine is recommended for a person at continuous or frequent risk for exposure to rabies (Table 3). The following guidelines are recommended for determining when serum testing should be performed after primary preexposure vaccination:
ADVERSE REACTIONS HDCV, RVA, and PCEC
Reactions after vaccination with HDCV, RVA, and PCEC are less serious and less common than with previously available vaccines (74,106,107). In previous studies with HDCV, local reactions (e.g., pain, erythema, and swelling or itching at the injection site) have been reported among 30%-74% of recipients (108). Systemic reactions (e.g., headache, nausea, abdominal pain, muscle aches, and dizziness) have been reported among 5%-40% of recipients. Three cases of neurologic illness resembling Guillain-Barre syndrome that resolved without sequelae in 12 weeks have been reported (8,109,110). In addition, other central and peripheral nervous system disorders have been temporally associated with HDCV vaccine, but a causal relationship has not been established in these rare reports (111).
An immune complex-like reaction occurred among approximately 6% of persons who received booster doses of HDCV 2-21 days after administration of the booster dose (9,10). The patients developed generalized urticaria, sometimes accompanied by arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise. In no cases have these reactions been life-threatening. This reaction occurred less frequently among persons receiving primary vaccination. The reactions have been associated with the presence of betapropiolactone-altered human albumin in the HDCV and the development of immunoglobulin E (IgE) antibodies to this allergen (112-114).
PRECAUTIONS AND CONTRAINDICATIONS
Immunosuppression
Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination (41,116). For persons with immunosuppression, preexposure prophylaxis should be administered with the awareness that the immune response might be inadequate (see Primary or Preexposure Vaccination). Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should be vaccinated by the IM route and their antibody titers checked. Failure to seroconvert after the third dose should be managed in consultation with appropriate public health officials (see Preexposure Vaccination and Serologic Testing).
Immunosuppressive agents should not be administered during postexposure therapy unless essential for the treatment of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, it is especially important that a serum sample be tested for rabies antibody to ensure that an acceptable antibody response has developed.
Pregnancy
Because of the potential consequences of inadequately treated rabies exposure, and because there is no indication that fetal abnormalities have been associated with rabies vaccination, pregnancy is not considered a contraindication to postexposure prophylaxis (117,118). If the risk of exposure to rabies is substantial, preexposure prophylaxis might also be indicated during pregnancy.
Allergies
Persons who have a history of serious hypersensitivity to rabies vaccine should be revaccinated with caution (see Management of Adverse Reactions).
