Recommendation of the Immunization Practices Advisory Committee (ACIP) Rabies Prevention -- United States, 1984

These revised recommendations of the Immunization Practices Advisory Committee (ACIP) on rabies prevention update the previous recommendations (MMWR 1980;29:65-72,277-80) to reflect the current status of rabies and antirabies biologics in the United States. For assistance on problems or questions about rabies prophylaxis, call local or state health departments.*

INTRODUCTION

Although rabies rarely affects humans in the United States, every year, approximately 25,000 persons receive rabies prophylaxis. Appropriate managment of those who may have been exposed to rabies infection depends on the interpretation of the risk of infection and the efficacy and risk of prophylactic treatment. All available methods of systemic prophylactic treatment are complicated by instances of adverse reactions. These are rarely severe. Decisions on management must be made immediately; the longer treatment is postponed, the less likely it is to be effective.

Data on the efficacy of active and passive immunization after rabies exposure have come from both human and animal studies. Evidence from laboratory and field experience in many areas of the world indicates that postexposure prophylaxis combining local wound treatment, vaccine, and rabies immune globulin, is uniformly effective when appropriately used. However, rabies has occasionally developed in humans who had received postexposure antirabies prophylaxis with vaccine alone.

In the United States, rabies in humans has decreased from an average of 22 cases per year in 1946-1950 to zero to five cases per year since 1960. The number of rabies cases among domestic animals has decreased similarly. In 1946, more than 8,000 rabies cases were reported among dogs; 153 cases were reported in 1982. Thus, the likelihood of human exposure to rabies in domestic animals has decreased greatly, although bites by dogs and cats continue to be the principal reasons given for antirabies treatments.

The disease in wildlife--especially skunks, foxes, raccoons, and bats-- has become more prevalent in recent years, accounting for approximately 85% of all reported cases of animal rabies every year since 1976. Wild animals now constitute the most important potential source of infection for both humans and domestic animals in the United States. Rabies among animals is present throughout the United States; only Hawaii remains consistently rabies-free.

Four of the six rabies fatalities in U.S. citizens occurring between 1980 and 1983 were related to exposure to rabid dogs outside the United States. In much of the world, including most of Asia and all of Africa and Latin America, the dog remains the major source of human exposure.

RABIES IMMUNIZING PRODUCTS

There are two types of immunizing products: (1) vaccines that induce an active immune response, which requires about 7-10 days to develop but may persist for as long as a year or more, and (2) globulins that provide rapid passive immune protection, which persists for a short period of time, with a half-life of about 21 days. Both types of products should be used concur- rently for rabies postexposure prophylaxis.

Vaccines for Use in the United States

Human diploid cell rabies vaccine (HDCV)**: HDCV is an inactivated virus vaccine prepared from fixed rabies virus grown in WI-38 or MRC-5 human diploid cell culture. The vaccine grown on WI-38 cells and developed in the United States is inactivated with tri-n-butyl phosphate and B-propiolactone (Wyeth Laboratories' WYVAC(R)), while that grown in MRC-5 cells and developed in Europe is inactivated with B-propiolactone (Merieux Institute's RABIES VACCINE(R)). Both vaccines are supplied as 1.0 ml, single-dose vials of lyophilized vaccine with accompanying diluent.

Globulins

Rabies Immune Globulin, Human (RIG): RIG (Cutter Laboratories' HYPERAB(R) and Merieux Institutes' IMOGAM(R)) is antirabies gamma globulin concentrated by cold ethanol fractionation from plasma of hyperimmunized human donors. Rabies neutralizing antibody content is standardized to contain 150 inter- national units (IU) per ml. It is supplied in 2-ml (300 IU) and 10-ml (1,500 IU) vials for pediatric and adult use, respectively.

Antirabies Serum, Equine (ARS): ANTIRABIES SERUM(R) (Sclavo) is a refined, concentrated serum obtained from hyperimmunized horses. Neutralizing antibody content is standardized to contain 1,000 IU per vial. Volume is adjusted by the manufacturer on the basis of antibody potency in each lot. Currently, a 1,000-IU vial contains approximately 5 ml.

RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS

Both types of HDCV rabies vaccines are considered equally efficacious and safe when used as indicated on the labels. Only the Merieux Institute vaccine has been evaluated by the intradermal (ID) dose/route for preexposure immuni- zation. No data are available on ID use with the Wyeth Laboratories vaccine. RIG is preferred over ARS, because the latter has a much higher risk of adverse reactions.

Vaccines

The effectiveness of rabies vaccines is measured by their ability to protect persons exposed to rabies and to induce antibodies to rabies virus. HDCV has been used concurrently with RIG or ARS to treat 45 persons bitten by rabid dogs or wolves in Iran, 31 persons bitten by a variety of rabid animals in Germany, and 511 persons bitten by a variety of rabid animals in the United States. In these studies, no person contracted rabies after receiving HDCV in combination with RIG.

All persons treated with RIG and five 1.0-ml intramuscular (IM) doses of HDCV and tested have developed a rabies antibody titer. The definition of a minimally acceptable antibody titer varies between laboratories and is influenced by the type of test conducted. CDC currently specifies a 1:5 titer by the rapid fluorescent-focus inhibition test (RFFIT) as acceptable. The World Health Organization (WHO) specifies a titer of 0.5 I.U.

Serious adverse reactions associated with rabies vaccines include systemic, anaphylactic, and neuroparalytic reactions. Serious adverse reactions occur at lower rates in the HDCV vaccine than with previously available types of rabies vaccine.

Globulins

RIG and ARS are both effective; however, ARS causes serum sickness in over 40% of adult recipients. RIG rarely causes adverse reactions and should be the product of choice when available.

RATIONALE OF TREATMENT

Physicians must evaluate each possible rabies exposure. Local or state public health officials should be consulted if questions arise about the need for prophylaxis.

In the United States, the following factors should be considered before specific antirabies treatment is initiated:

Species of Biting Animal

Carnivorous wild animals (especially skunks, raccoons, foxes, coyotes, and bobcats) and bats are the animals most commonly infected with rabies and have caused most of the indigenous cases of human rabies in the United States since 1960. Unless an animal is tested and shown not to be rabid, post- exposure prophylaxis should be initiated upon bite or nonbite exposure to the animals. (See definition in "Type of Exposure" below.) If treatment has been initiated and subsequent testing in a competent laboratory shows the exposing animal is not rabid, treatment can be discontinued.

The likelihood that a domestic dog or cat is infected with rabies varies from region to region; hence, the need for postexposure prophylaxis also varies.

Rodents (such as squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (including rabbits and hares) are rarely found to be infected with rabies and have not been known to cause human rabies in the United States. In these cases, the state or local health department should be consulted before a decision is made to initiate postexposure antirabies prophylaxis.

Circumstances of Biting Incident

An unprovoked attack is more likely than a provoked attack to indicate the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked.

Type of Exposure

Rabies is transmitted by introducing the virus into open cuts or wounds in skin or via mucous membranes. The likelihood of rabies infection varies with the nature and extent of exposure. Two categories of exposure should be considered.

Bite: Any penetration of the skin by teeth.

Nonbite: Scratches, abrasions, open wounds, or mucous membranes contam- inated with saliva or other potentially infectious material, such as brain tissue, from a rabid animal. Casual contact, such as petting a rabid animal (without a bite or nonbite exposure as described above), does not constitute an exposure and is not an indication for prophylaxis. There have been two instances of airborne rabies acquired in laboratories and two probable airborne rabies cases acquired in a bat-infested cave in Texas.

The only documented cases of rabies from human-to-human transmission occurred in four patients in the United States and overseas who received corneas transplanted from persons who died of rabies undiagnosed at the time of death. Stringent guidelines for acceptance of donor corneas should reduce this risk.

Bite and nonbite exposures from humans with rabies theoretically could transmit rabies, although no cases of rabies acquired this way have been documented. Each potential exposure to human rabies should be carefully evaluated to minimize unnecessary rabies prophylaxis.

MANAGEMENT OF BITING ANIMALS

A healthy domestic dog or cat that bites a person should be confined and observed for 10 days and evaluated by a veterinarian at the first sign of illness during confinement or before release. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be humanely killed and its head removed and shipped, under refrigeration, for examination by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog or cat that bites a person should be killed immediately and the head submitted, as described above, for rabies examination.

Signs of rabies in wild animals cannot be interpreted reliably; there- fore, any wild animal that bites or scratches a person should be killed at once (without unnecessary damage to the head) and the brain submitted, as described above, for examination for evidence of rabies. If the brain is negative by fluorescent-antibody examination for rabies, the saliva can be assumed to contain no virus, and the bitten person need not be treated. If the biting animal is a particularly rare or valuable specimen and the risk of rabies small, consideration may be given to initiating postexposure treatment to the bitten person and delaying killing the animal for rabies testing.

POSTEXPOSURE PROPHYLAXIS

The essential components of rabies postexposure prophylaxis are local treatment of wounds and immunization, including administration, in most instances, of both globulin and vaccine (Tables 1 and 2).

Local Treatment of Wounds

Immediate and thorough washing of all bite wounds and scratches with soap and water is perhaps the most effective measure for preventing rabies. In experimental animals, simple local wound cleansing has been shown to reduce markedly the likelihood of rabies.

Tetanus prophylaxis and measures to control bacterial infection should be given as indicated.

Immunization

Postexposure antirabies immunization should always include administration of both antibody (preferably RIG) and vaccine, with one exception: persons who have been previously immunized with the recommended preexposure or postexposure regimens with HDCV or who have been immunized with other types of vaccines and have a history of documented adequate rabies antibody titer (See "RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS") should receive only vaccine. The combination of globulin and vaccine is recommended for both bite exposures and nonbite exposures (as described under "RATIONALE OF TREATMENT"), regardless of the interval between exposure and treatment. The sooner treatment is begun after exposure, the better. However, there have been instances in which the decision to begin treatment was made as late as 6 months or longer after the exposure due to delay in recognition that an exposure had occurred.

HDCV: HDCV is the only type of vaccine currently available in the United States and should be administered in conjunction with RIG at the beginning of postexposure therapy, as described below. In 1977, WHO established a recom- mendation for six IM doses of HDCV based on studies in Germany and Iran of a regimen of RIG or ARS and six doses of HDCV. When used in this way, the vaccine was safe and effective in protecting 76 persons bitten by proven rabid animals. The vaccine also induced an excellent antibody response in all recipients. Studies conducted by CDC in the United States have shown that a regimen of one dose of RIG and five doses of HDCV was safe and induced an excellent antibody response in all recipients. Of 511 persons bitten by proven rabid animals and so treated, none developed rabies.

Five 1-ml doses of HDCV should be given intramuscularly (for example, in the deltoid region). Other routes of administration, such as the ID route, have not been adequately evaluated for postexposure prophylaxis and should not be used. The first dose should be given as soon as possible after exposure; an additional dose should be given on days 3, 7, 14, and 28 after the first dose. (WHO currently recommends a sixth dose 90 days after the first dose.) Because the antibody response following the recommended vaccination regimen with HDCV has been so satisfactory, routine postvac- cination serologic testing is not recommended. In unusual instances, as when the patient is known to be immunosuppressed, serologic testing is indicated. Contact state health department or CDC for recommendations.

RIG (or ARS if RIG is not available): RIG is administered only once, at the beginning of antirabies prophylaxis, to provide immediate antibodies until the patient responds to HDCV by active production of antibodies. If RIG was not given when vaccination was begun, it can be given up to the eighth day after the first dose of vaccine was given. From about the eighth day on, RIG is not indicated, since an antibody response to the vaccine is presumed to have occurred. The recommended dose of RIG is 20 IU/kg or approximately 9 IU/lb of body weight. (When ARS must be used, the recommended dose is 40 IU/kg, approximately 18 IU/lb or 1,000 IU/55 lb body weight.) If anatomically feasible, up to half the dose of RIG should be thoroughly infiltrated in the area around the wound, the rest should be administered intramuscularly. Because RIG may partially suppress active production of antibody, no more than the recommended dose of RIG should be given.

TREATMENT OUTSIDE THE UNITED STATES

If postexposure is begun outside the United States with locally produced biologics, it may be desirable to provide additional treatment when the patient reaches the United States. State health departments should be contacted for specific advice in such cases.

PREEXPOSURE IMMUNIZATION

Preexposure immunization may be offered to persons in high-risk groups, such as veterinarians, animal handlers, certain laboratory workers, and persons spending time (e.g., 1 month or more) in foreign countries where rabies is a constant threat. Persons whose vocational or avocational pursuits bring them into contact with potentially rabid dogs, cats, foxes, skunks, bats, or other species at risk of having rabies should also be considered for preexposure prophylaxis.

Preexposure prophylaxis is given for several reasons. First, it may provide protection to persons with inapparent exposures to rabies. Second, it may protect persons whose postexposure therapy might be expected to be delayed. Finally, although it does not eliminate the need for additional therapy after a rabies exposure, it simplifies therapy by eliminating the need for globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk of being exposed in countries where the available rabies immunizing products may carry a higher risk of adverse reactions.

Preexposure immunization does not eliminate the need for prompt postex- posure prophylaxis following an exposure; it only reduces the postexposure regimen.

Human Diploid Cell Rabies Vaccine

Three 1.0 ml injections of HDCV should be given intramuscularly (for example, in the deltoid area), one on each of days O, 7, and 28. In a study in the United States, more than 1,000 persons received HDCV according to this regimen; antibody was demonstrated in the sera of all subjects when tested by the RFFIT. Other studies have produced comparable results. Because the anti- body response following the recommended vaccination regimen with HDCV has been so satisfactory, routine postvaccination serology is not recommended.

Booster Doses of Vaccine

Persons who work with live rabies virus in research laboratories or vaccine production facilities and are at risk of inapparent exposure should have the rabies antibody titer of their serum determined every 6 months; booster doses of vaccine should be given, as needed, to maintain an adequate titer (See "RATIONALE FOR CHOICE OF RABIES IMMUNIZING PRODUCTS"). Other laboratory workers, such as those doing rabies diagnostic tests, spelunkers, and those veterinarians, animal control and wildlife officers in areas where animal rabies is epizootic should have boosters every 2 years or have their serum tested for rabies antibody every 2 years and, if the titer is inade- quate, have a booster dose. Veterinarians and animal control and wildlife officers, if working in areas of low rabies endemicity, do not require rou- tine booster doses of HDCV after completion of primary preexposure immuni- zation (Table 2).

Postexposure Therapy of Previously Immunized Persons

When an immunized person who was vaccinated by the recommended regimen with HDCV or who had previously demonstrated rabies antibody is exposed to rabies, that person should receive two IM doses (1.0 ml each) of HDCV, one immediately and one 3 days later. RIG should not be given in these cases. If the immune status of a previously vaccinated person who did not receive the recommended HDCV regimen is not known, full primary postexposure antirabies treatment (RIG plus five doses of HDCV) may be necessary. In such cases, if antibody can be demonstrated in a serum sample collected before vaccine is given, treatment can be discontinued after at least two doses of HDCV.

Intradermal Use of HDCV

HDCV produced by the Merieux Institute has been used for preexposure immunization in a regimen of three 0.1 ml doses given ID in the lateral aspect of the upper arm over the deltoid area, one dose each on days O, 7, and 28. Experience gained with over 2,000 persons vaccinated in the United States by the ID route has shown that antibody was produced in all recipi- ents, although the mean response was somewhat lower and may be of shorter duration than with comparable IM immunization. Antibody response in some groups vaccinated outside the United States has been found to be inadequate for reasons not yet determined.

Current data provide a sufficient basis to recommend the 0.1 ml ID dose/route as an alternative to the 1.0 ml IM dose/route for preexposure immunization in the United States. Postvaccination serology is not necessary following ID (or IM) immunization, except for persons suspected of being immunosuppressed. The manufacturer has not yet met the packaging and labeling requirements necessary to obtain approval by the U.S. Food and Drug Adminis- tration for the ID route. Since the 1.0-ml vial presently available is intended for IM use and contains no preservatives, the reconstituted vaccine must be used immediately. Data on ID immunization are not available for Wyeth Laboratories' vaccine, and it should not be used for ID vaccination.

ACCIDENTAL INOCULATION WITH MODIFIED LIVE RABIES VIRUS

Individuals may be accidentally exposed to attenuated rabies virus while administering modified live rabies virus (MLV) vaccines to animals. While there have been no reported human rabies cases resulting from exposure to needlesticks or sprays with licensed MLV vaccines, vaccine-induced rabies has been observed in animals given MLV vaccines. Absolute assurance of a lack of risk for humans, therefore, cannot be given. The best evidence for a low risk, however, is the absence of recognized cases of vaccine-associated disease in humans despite frequent accidental exposures.

Currently available MLV animal vaccines are made with one of two attenu- ated strains of rabies virus: high egg passage (HEP) Flury strain or Street Alabama Dufferin (SAD) strain. The HEP Flury and SAD virus strains have been used in animal vaccines for over 10 years without evidence of associated disease in humans; therefore, postexposure treatment is not recommended following exposure to these types of vaccine by needlesticks or sprays.

Because the data are insufficient to assess the true risk associated with any of the MLV vaccines, preexposure immunization, and periodic boosters are recommended for all persons dealing with potentially rabid animals or frequently handling animal rabies vaccines.

ADVERSE REACTIONS

Human Diploid Cell Rabies Vaccine

Reactions after vaccination with HDCV are less common than with previously available vaccines. In a study using five doses of HDCV, local reactions, such as pain, erythema, and swelling or itching at the injection site, were reported in about 25% of recipients of HDCV, and mild systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizzi- ness were reported in about 20% of recipients. Two cases of neurologic illness resembling Guillain-Barre syndrome that resolved without sequelae in 12 weeks, and a focal subacute central nervous system disorder temporally associated with HDCV vaccine, have been reported.

Recently, a significant increase has been noted in "immune complex-like" reactions in persons receiving booster doses of HDCV. The illness, charac- terized by onset 2-21 days postbooster, presents with a generalized urticaria and may also include arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise. In no cases were the illnesses life-threatening. Preliminary data suggest this "immune complex-like" illness may occur in up to 6% of persons receiving booster vaccines and much less frequently in persons receiving primary immunization. Additional experience with this vaccine is needed to define more clearly the risk of these adverse reactions.

Vaccines in Other Countries

Many developing countries use inactivated nerve tissue vaccines (NTV) or inactivated suckling mouse brain vaccine (SMBV). NTV is reported to provoke neuroparalytic reactions at a rate of about 1/2,000 vaccinees; the rate for SMBV is about 1/8,000.

Rabies Immune Globulin, Human

Local pain and low-grade fever may follow receipt of RIG. Although not reported specifically for RIG, angioneurotic edema, nephrotic syndrome, and anaphylaxis have been reported after injection of immune serum globulin (ISG). These reactions occur so rarely that the causal relationship between ISG and these reactions is not clear.

Antirabies Serum, Equine

ARS produces serum sickness in at least 40% of adult recipients; reaction rates for children are lower. Anaphylactic reactions may occur. When RIG is not available, and ARS must be used, the patient should be tested for sensitivity to equine serum. (See package circular for details.)

Because adverse reactions are associated more frequently with ARS than with RIG, and ARS might sensitize recipients to equine protein, ARS should be used only when RIG cannot be obtained.

Management of Adverse Reactions

Once initiated, rabies prophylaxis should not be interrupted or discon- tinued because of local or mild systemic adverse reactions to rabies vaccine. Usually such reactions can be successfully managed with anti-inflammatory and antipyretic agents (aspirin, for example).

When a person with a history of hypersensitivity must be given rabies vaccines, antihistamines may be given; epinephrine should be readily avail- able to counteract anaphylactic reactions, and the person should be carefully observed immediately after immunization.

Serious systemic anaphylactic or neuroparalytic reactions occurring during the administration of rabies vaccines pose a serious dilemma for the attending physician. A patient's risk of developing rabies must be carefully considered before deciding to discontinue vaccination. Moreover, the use of corticosteroids to treat life-threatening neuroparalytic reactions carries the risk of inhibiting the development of active immunity to rabies. It is especially important in these cases that the serum of the patient be tested for rabies antibodies. Advice and assistance on the management of serious adverse reactions in persons receiving rabies vaccines may be sought from the state health department or CDC.

All serious systemic neuroparalytic or anaphylactic reactions to a rabies vaccine should be immediately reported to the state health department or the Division of Viral Diseases, Center for Infectious Diseases, CDC ({404} 329-3095 during working hours, or {404} 329-2888 at other times).

PRECAUTIONS AND CONTRAINDICATIONS

Immunosuppression

Corticosteroids, other immunosupressive agents, and immunosuppressive illnesses can interfere with the development of active immunity and predispose the patient to developing rabies. Immunosuppressive agents should not be administered during postexposure therapy, unless essential for the treatment of other conditions. When rabies postexposure prophylaxis is administered to persons receiving steroids or other immunosuppressive therapy, it is especially important that serum be tested for rabies antibody to ensure that an adequate response has developed.

Pregnancy

Because of the potential consequences of inadequately treated rabies exposure and limited data that indicate that fetal abnormalities have not been associated with rabies vaccination, pregnancy is not considered a contraindication to postexpsoure prophylaxis. If there is substantial risk of exposure to rabies, preexposure prophylaxis may also be indicated during pregnancy.

Allergies

Persons with histories of hypersensitivity should be given rabies vaccines with caution. When a patient with a history suggesting hypersen- sitivity to HDCV must be given that vaccine, antihistamines can be given; epinephrine should be readily available to counteract anaphylactic reactions, and the person should be carefully observed.

• If these are unavailable, call the Division of Viral Diseases, Center for

Infectious Diseases, CDC ({404} 329-3095 during working hours, or {404} 329-2888 nights, weekends, and holidays). ** Official name: Rabies Vaccine. The duck embryo vaccine which was used from 1957-1982 is no longer available in the United States.

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diploid cell strain rabies vaccine. J Infect Dis 1980;142:133-8. Baer, GM, ed. The natural history of rabies. New York: Academic Press, 1975. Bahmanyar M, Fayaz A, Nour-Salehi S, Mohammadi M, Koprowski H. Successful

protection of humans exposed to rabies infection: postexposure treatment with the new human diploid cell rabies vaccine and antirabies serum. JAMA 1976;236:2751-4. Bernard KW, Smith PW, Kader FJ, Moran MJ. Neuroparalytic illness and human

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J Lab Clin Med 1955;45:679-83. Rubin RH, Hattwick MAW, Jones S, Gregg MB, Schwartz VD. Adverse reactions to

duck embryo rabies vaccine. Range and incidence. Ann Intern Med 1973;78:643-9. Tierkel ES, Sikes RK. Preexposure prophylaxis against rabies. Comparison of

regimens. JAMA 1967;201:911-4. Tint H, Rosanoff EI. Clinical responses to T(n)BP-disrupted HDCS (WI-38)

rabies vaccine. Dev Biol Stand 1976;37:287-9. Wiktor TJ, Plotkin SA, Koprowski H. Development and clinical trials of the

new human rabies vaccine of tissue culture (human diploid cell) origin. Dev Biol Stand 1978;40:3-9. World Health Organization. Sixth report of the Expert Committee on Rabies.

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