Medication Summary
Before the onset of rabies symptoms, passive and active immunizations are effective in preventing progression to full-blown rabies.
If the patient has had no prior rabies vaccination, if they are of unknown status, rabies vaccine and immunoglobulin should be administered as follows (these dosages being applicable to products available in the United States):
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Rabies vaccine IM (deltoid) - 1 mL on Days 0, 3, 7, and 14 (if immunocompromised, add an additional dose: 1 mL IM deltoid on days 0, 3, 7, 14, and 28)
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Rabies immunoglobulin - 20 IU/kg infiltrated as much as feasible around and under the bite wound; if any is left over, give IM at a site distant from vaccine administration
If the patient has had prior rabies vaccination, vaccine should be administered as follows (this dosage again being applicable to US vaccine): Rabies vaccine IM (deltoid) 1 mL on Days 0 and 3.
Passive Immunizing Agents
Class Summary
Rabies immunoglobulin is recommended as part of the rabies postexposure regimen for persons not previously immunized against rabies. Vaccine and antiserum should never be mixed or injected in the same limb.
In the United States, passive immunization consists of administration of HRIG pooled from the sera of immunized human donors. In developing countries, equine rabies immunoglobulin (ERIG) is sometimes used but has a higher incidence of adverse effects. ERIG is no longer produced by large pharmaceutical companies. When produced by smaller pharmaceutical firms, its quality cannot be assured. New-generation purified ERIG preparations are under investigation.
Human rabies virus–specific monoclonal antibody preparations are in development, theoretically to decrease the possibility of anaphylaxis. [63, 64, 65]
Because of cost, ERIG and HRIG are not readily available throughout much of the developing world, areas in which rabies is more common than in the United States. If HRIG is available only after more than a week after vaccination has started, then it is probably unnecessary, because an active antibody response has already begun.
Rabies immune globulin, human (RIG) (HyperRAB S/D, KedRab, Imogam Rabies-HT)
HRIG has been licensed since 1975, and unlike its predecessor, ERIG, it is not associated with significant adverse reactions, anaphylaxis, or serum sickness. Purified ERIG is still used in some developing nations because of cost or availability and is associated with an adverse effect rate of 0.8-6%, which usually involves minor reactions. HRIG is not associated with transmission of viral hepatitis or HIV. Experimentally, infiltration of HRIG at the site of exposure is more protective than IM administration. The current recommendation is that the entire dose be infiltrated, if possible, in and around the site, with any remaining solution administered IM at a site distant from vaccine administration.
Heat-treated and cold alcohol–fractionated immunoglobulin is derived from pooled human plasma from individuals immunized with human diploid cell rabies vaccine.
A stabilized, ready-to-use solution for injection (KedRab) is also available.
Rabies Vaccines (United States)
Class Summary
These agents promote immunity by inducing an active immune response. Two types of rabies vaccines have been produced: cell-cultured vaccines and nerve tissue vaccines.
In developing countries worldwide, nerve tissue vaccines have been the most widely used type for prophylaxis of rabies. They are dangerous because they may induce autoimmune CNS disease and may produce neurologic reactions; they also require multiple injections and are not always effective. WHO has advised discontinuation of nerve tissue rabies vaccines. [3]
Two types of nerve tissue vaccine exist: the Semple type (STV) and the suckling mouse brain vaccine (SMBV). STV is obtained from inactivated virus prepared on adult animal nerve tissue. It is inexpensive and relatively easy to produce. In India, 3 million people receive postexposure courses of STV each year. STV may produce neurologic reactions, including postvaccination encephalomyelitis, in up to 1 in 220 courses, with a 3% mortality rate.
SMBV is cultured on immature mouse brain tissue, which contains little myelin. It is the most widely used rabies postexposure vaccine in Vietnam. Rare neurologic reactions occur, with complications in 1 in 27,000 treated people, with a 22% mortality rate.
Because SMBV and STV are widely used throughout the developing world, they are the vaccines that are administered to US travelers exposed to animal bites in some countries. It is advisable that US travelers to endemic areas receive pretravel rabies immunization with a cell-cultured vaccine if the itinerary suggests sufficient risk.
Cell-cultured rabies vaccines benefit from efficacy demonstrated in trials and a high level of immunogenicity; this permits a rational dosing schedule, and cell-cultured vaccines are considered the reference standard. The disadvantage of these vaccines is the cost of production.
In the United States, the CDC recommends rabies postexposure prophylaxis only with IM cell-cultured vaccines; intradermal (ID) formulations are not FDA approved for use in the United States.
Outside the United States, in areas where cost and vaccine supply are limiting factors, alternatives to the IM regimens may be more feasible. In addition, rabies vaccination may be the norm in some countries where rabies is endemic, and anamnestic response may permit effective alternative dosing.
In 1998, WHO released guidelines for ID use of HDCV, purified chick embryo cell vaccine, and purified duck embryo cell vaccine. [42] WHO published updated postexposure prophylaxis guidelines that included ID regimens often used outside the United States. [43]
In previously vaccinated individuals, studies have shown that single-visit, 4-site ID booster regimens offer satisfactory anamnestic response. A retrospective study at The Queen Saovabha Memorial Institute (QSMI) investigated booster regimens in more than 5000 previously immunized individuals who presented with rabies exposures. The study found that the single-visit, 4-site ID booster regimen using cell-cultured vaccine demonstrated superior anamnestic response, more rapid rise in Nab levels, and more persistently high Nab levels 1 year after prophylaxis than did the standard WHO 2-visit booster regimen. [54] Advantages of the single-visit booster also included reduced time and reduced costs from loss of work or from delayed travel, along with enhanced compliance.
Booster immunization is indicated for individuals at continuous or frequent risk of rabies, who should undergo periodic rabies antibody testing and who have serum rabies titer of less than 1:5 dilution based on RFFIT results.
Rabies vaccine (HDCV, Imovax Rabies, Rabies vaccine human diploid cell culture)
Indicated for preexposure and postexposure. Grown in human diploid cell culture. Contains the inactivated virus that promotes immunity by inducing an active immune response. For IM use only.
Rabies vaccine chick embryo cell derived (RabAvert)
Indicated for preexposure or postexposure. Contains the inactivated virus that promotes immunity by inducing an active immune response. For IM injection.
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Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
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Distribution of the 5 strains of rabies virus and the associated wildlife in the United States.
Tables
Category |
Nature of exposure | Target Population |
Relevant biogeography | Immunization Regimen |
Serologic Testing |
1. Elevated risk for unrecognized and recognized exposures including unusual or high-risk exposures |
High concentration exposure is possible, might be recognized or unrecognized, or might be unusual (eg, aerosolized virus) | Rabies research laboratory workers, vaccine production workers, or diagnostic laboratory workers who may work with live rabies virus |
Laboratories | Primary series: IM rabies vaccine on days 0 and 7 |
Rapid Fluorescent Foci Inhibition Test (RFFIT) titer 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 are unlikely | Persons who frequently 1) handle bats, 2) have contact with bats, 3) enter high-density bat environments, or 4) perform animal necropsies (eg, biologists who frequently enter bat roosts or who collect suspected rabies samples). |
All geographic regions where any rabies reservoir is present, US domestic and international | Primary series: IM rabies vaccine on days 0 and 7 |
RFFIT titer 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 (eg, wildlife biologists, rehabilitators, and trappers); and 3) spelunkers |
All US domestic and international geographic regions where any rabies reservoir is present | Primary series: IM rabies vaccine on days 0 and 7 |
1) One-time RRFIT titer at years 1–3 after primary series; booster if titer < 0.5 IU/mL, OR 2) Booster at at point between day 21 and year 3 after primary series |
4. Elevated risk for recognized exposures, but not sustained or continuous |
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 vaccination series) | Same as for risk category 3, but risk duration ≤3 years (eg, 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 | IM rabies vaccine on days 0 and 7 |
None |
| 5. Low risk for exposure | Uncommon exposure. | Typical person living in the United States. General population. | None | None | None |
