Vaccine Information: IMOVAX RABIES

IMOVAX RABIES- rabies virus strain pm-1503-3m antigen (propiolactone inactivated) and water
Sanofi Pasteur Inc.

WISTAR RABIES VIRUS STRAIN PM-1503-3M GROWN IN HUMAN DIPLOID CELL CULTURES

DESCRIPTION

The Imovax® Rabies Vaccine produced by Sanofi Pasteur SA is a sterile, stable, freeze-dried suspension of rabies virus prepared from strain PM-1503-3M obtained from the Wistar Institute, Philadelphia, PA.

The virus is harvested from infected human diploid cells, MRC-5 strain, concentrated by ultrafiltration and is inactivated by beta-propiolactone. One dose of reconstituted vaccine contains less than 100 mg human albumin, less than 150 mcg neomycin sulfate and 20 mcg of phenol red indicator. Beta-propiolactone, a residual component of the manufacturing process, is present in less than 50 parts per million.

The finished, freeze-dried vaccine is provided for intramuscular administration in a single dose vial containing no preservative. After reconstitution, immediately administer the full 1.0 mL amount of vaccine. If it cannot be administered promptly, discard.

The potency of one dose (1.0 mL) of Imovax Rabies vaccine is equal to or greater than 2.5 international units of rabies antigen.

CLINICAL PHARMACOLOGY

Pre-exposure immunization

High titer antibody responses to the Imovax Rabies vaccine made in human diploid cells have been demonstrated in trials conducted in England (1), Germany (2) (3), France (4) and Belgium. (5) Seroconversion was often obtained with only one dose. With two doses one month apart, 100% of the recipients developed specific antibody, and the geometric mean titer of the group was approximately 10 international units. In the US, Imovax Rabies vaccine resulted in geometric mean titers (GMT) of 12.9 IU/mL at Day 49 and 5.1 IU/mL at Day 90 when three doses were given intramuscularly during the course of one month. The range of antibody responses was 2.8 to 55.0 IU/mL at Day 49 and 1.8 to 12.4 IU at Day 90. (6) The definition of a minimally accepted antibody titer varies among laboratories and is influenced by the type of test conducted. CDC currently specifies a 1:5 titer (complete inhibition) by the rapid fluorescent focus inhibition test (RFFIT) as acceptable. The World Health Organization (WHO) specifies a titer of 0.5 IU.

Post-exposure immunization

Post-exposure efficacy of Imovax Rabies vaccine was successfully proven during clinical experience in Iran in which six 1.0 mL doses were given on days 0, 3, 7, 14, 30, and 90, in conjunction with antirabies serum. Forty-five persons severely bitten by rabid dogs and wolves received Imovax Rabies vaccine within hours of and up to 14 days after the bites. All individuals were fully protected against rabies. (7)

Studies conducted by the United States Centers for Disease Control and Prevention (CDC) have shown that a regimen of 1 dose of Rabies Immune Globulin (RIG) and 5 doses of HDCV induced an excellent antibody response in all recipients. Of 511 persons bitten by proven rabid animals and so treated, none developed rabies. (8)

Do not inject Imovax Rabies vaccine in the gluteal area as there have been reports of possible vaccine failure when the vaccine has been administered in this area. Presumably, subcutaneous fat in the gluteal area may interfere with the immune response to human diploid cell rabies vaccine (HDCV). (9) (10)

For adults and older children, Imovax Rabies vaccine should be administered in the deltoid muscle. For infants and younger children, the anterolateral aspect of the thigh is also acceptable, depending on age and body mass (see DOSAGE AND ADMINISTRATION).

IMOVAX RABIES Indications and Usage

Imovax Rabies is a vaccine indicated for pre-exposure and post-exposure prophylaxis against rabies. Imovax Rabies vaccine is approved for use in all age groups.

1. 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. (11)

The following factors should be considered before antirabies prophylaxis is initiated.

Species of biting animal

Bats

Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important wildlife reservoirs for variants of rabies virus transmitted to humans. Transmission of rabies virus can occur from minor, seemingly underappreciated or unrecognized bites from bats (see Table 2). (11)

Wild Terrestrial Carnivores

Raccoons, skunks, and foxes are the terrestrial carnivores most often infected with rabies in the United States. Suggestive clinical signs of rabies among wildlife cannot be interpreted reliably. All bites by such wildlife should be considered possible exposures to rabies virus. Post-exposure prophylaxis should be initiated as soon as possible following exposure to such wildlife, unless the animal is available for diagnosis and public health authorities are facilitating expeditious laboratory testing, or if the brain tissue from the animal has already tested negative (see Table 2). (11)

Other Wild Animals

Small rodents (eg, squirrels, chipmunks, rats, mice, hamsters, guinea pigs, and gerbils) and lagomorphs (including rabbits and hares) are rarely infected with rabies and have not been known to transmit rabies to humans. In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate post-exposure prophylaxis (see Table 2). (11)

Domestic Dogs, Cats, and Ferrets

The likelihood of rabies in a domestic animal varies regionally, and the need for post-exposure prophylaxis also varies on the basis of regional epidemiology (see Table 2). (11)

Circumstances of biting incident

An unprovoked attack might be 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. Consult the local or state health department following a provoked or unprovoked exposure to determine the best course of action based on current public health recommendations.

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 and nonbite.

Bite

Any penetration of the skin by teeth.

Nonbite

Scratches, abrasions, open wounds, or mucous membranes contaminated 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. Rare reports of airborne rabies have been received from laboratory and bat-infested cave settings. (11)

Rare cases of rabies from human-to-human transmission have occurred in patients in the US and overseas who received organs transplanted from persons who died of rabies undiagnosed at the time of death. No documented laboratory-diagnosed cases of human-to-human rabies transmission have been documented from a bite or nonbite exposure other than the transplant cases. At least two cases of human-to-human rabies transmission in Ethiopia have been suggested, but rabies as the cause of death was not confirmed by laboratory testing. The reported route of exposure in both cases was direct salivary contact from another human (ie, a bite and a kiss). Routine delivery of health care to a patient with rabies is not an indication for post-exposure prophylaxis unless the healthcare worker is reasonably certain that he or she was bitten by the patient or that his or her mucous membranes or nonintact skin was exposed directly to potentially infectious saliva or neural tissue. (11)

2. Pre- and post-exposure prophylaxis of rabies

A. Pre-exposure

Pre-exposure immunization should be offered to rabies researchers, certain laboratory workers and other persons in high-risk groups, such as veterinarians and their staff, and animal handlers. Pre-exposure vaccination also should be considered for 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, some international travelers might be candidates for pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care, including rabies vaccine and immune globulin, might be limited. (11)

Vaccination is recommended for children living in or visiting countries where exposure to rabid animals is a constant threat. Worldwide statistics indicate children are more at risk than adults.

Pre-exposure prophylaxis is administered for several reasons. First, although pre-exposure vaccination does not eliminate the need for additional medical evaluation after a rabies exposure, it simplifies management by eliminating the need for Rabies Immune Globulin (RIG) and decreases the number of doses of vaccine needed. This is particularly important for persons at high risk for being exposed to rabies in areas where modern immunizing products might not be available or where cruder, less safe biologics might be used, placing the exposed person at increased risk for adverse events. Second, pre-exposure prophylaxis might offer partial immunity to persons whose post-exposure prophylaxis is delayed. Finally, pre-exposure prophylaxis might provide some protection to persons at risk for unrecognized exposures to rabies. (11)

PRE-EXPOSURE RABIES PROPHYLAXIS GUIDE

Pre-exposure prophylaxis consists of three 1.0 mL doses of Imovax Rabies vaccine administered intramuscularly, using a sterile needle and syringe, one injection per day on Days 0, 7, and 21 or 28. In adults and older children, the vaccine should be administered in the deltoid muscle. In infants and small children, the anterolateral aspect of the thigh may be preferable, depending on age and body mass.

Administration of booster doses of vaccine depends on exposure risk category and serologic testing as noted in Table 1.

Immunosuppressed persons should postpone pre-exposure vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies should have their viral neutralizing antibody titers checked after completing the pre-exposure series. If no acceptable antibody response is detected, the patient should be managed in consultation with their physician and appropriate public health officials. (11)

Table 1: Rabies Pre-exposure Prophylaxis Guide (11)
Risk category Nature of risk Typical populations Pre-exposure recommendations
*
Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level.
Continuous Virus present continuously and often in high concentrations. Specific exposures likely to go unrecognized. Bite, nonbite, or aerosol exposure. Rabies research laboratory workers; rabies biologics production workers. Primary course.Serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level.*
Frequent Exposure usually episodic, with source recognized, but exposure also might be unrecognized. Bite, nonbite, or aerosol exposure. Rabies diagnostic laboratory workers, cavers, veterinarians and staff, and animal-control and wildlife workers in areas where rabies is enzootic. All persons who frequently handle bats. Primary course.Serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level.*
Infrequent (greater than population at large) Exposure nearly always episodic with source recognized. Bite or nonbite exposure. Veterinarians and animal-control staff working with terrestrial animals in areas where rabies is uncommon to rare. Veterinary students. Travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care including biologics is limited. Primary course.No serologic testing or booster vaccination.
Rare (population at large) Exposure always episodic with source recognized. Bite or nonbite exposure. US population at large, including persons in areas where rabies is epizootic. No vaccination necessary.
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