Rabies Vaccine (Monograph)

Brand names: Imovax, RabAvert
Drug class: Vaccines

Introduction

Inactivated virus vaccine. Rabies vaccine contains rabies virus antigens and is used to stimulate active immunity to rabies infection. Commercially available in the US as human diploid-cell rabies vaccine (HDCV; Imovax) and purified chick embryo cell culture rabies vaccine (PCECV; RabAvert).

Uses for Rabies Vaccine

Prevention of Rabies

Prevention of rabies in children, adolescents, and adults exposed to or at increased risk of exposure to rabies disease or virus.

Rabies is a viral infection transmitted by saliva of infected mammals, most commonly wild, terrestrial carnivores (e.g., skunks, raccoons, foxes, coyotes) or bats. In the US, the greatest risk for naturally acquired rabies is from contact with and bites from insectivorous bats. Following exposure and infection, rabies virus usually moves along a neural pathway and enters the CNS. After entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and encephalomyelitis usually develops and almost always is fatal.

During January 2000 to December 2020, 52 cases of human rabies were diagnosed in the US, 38 were indigenously acquired. None of these infections were in individuals who had previously received preexposure prophylaxis. Rabies prevention and control strategies and elimination of canine rabies virus variants and enzootic transmission among dogs have lowered the number of rabies cases in the US to an average of 1–2 per year. However, worldwide, rabies is much more common and at least 59,000 rabies-related deaths occur each year.

USPHS Advisory Committee on Immunization Practices (ACIP) recommends preexposure vaccination with rabies vaccine (series of 2 doses with booster doses when indicated) in individuals who are or will be at increased risk of exposure to the virus.

Postexposure prophylaxis with a regimen that includes local wound treatment, rabies vaccine (series of 4 or 5 doses), and a single dose of rabies immune globulin (RIG) is recommend for previously unvaccinated children, adolescents, and adults following potential rabies exposure. Postexposure prophylaxis with a regimen that includes local wound treatment and a series of 2 booster doses of rabies vaccine (without RIG) is recommended for previously vaccinated children, adolescents, and adults following potential rabies exposure.

Preexposure Vaccination Against Rabies in High-risk Groups

Preexposure vaccination in children, adolescents, and adults who are or will be at risk of exposure to rabies virus.

Preexposure vaccination does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.

Need for rabies preexposure vaccination depends on the nature of risk and associated level of potential exposure. Consider preexposure vaccination for individuals whose risk of rabies exposure is greater than that of the general population (e.g., veterinarians and their staff, animal-control and wildlife workers, field biologists, spelunkers, missionaries, rabies researchers, certain laboratory workers). Also consider preexposure vaccination for individuals 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. (For ACIP revised risk categories and recommendations regarding preexposure vaccination for each category, see Table 1.)

Travelers to areas where rabies is endemic may be at risk, especially 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 RIG) is unlikely. Canine rabies remains highly endemic in certain areas of the world (e.g., parts of Africa, Asia, Central and South America). CDC recommends preexposure vaccination based on local incidence of rabies in the country to be visited, availability of appropriate agents for rabies postexposure prophylaxis in that country, and intended activity and duration of stay.

Unrecognized exposures are those that recipients might not know occurred. Recognized exposures are bites, scratches, and splashes that are usually identified by the individual because the exposure is unusual. When antibody titers <0.5 IU/mL, a booster vaccination should be provided. There is no need to verify booster response in immunocompetent individuals. For immunocompromised individuals, the antibody titer should be verified ≥1 week (ideally, 2-4 weeks) after booster administration. Sustained risk is elevated risk for rabies >3 years after completion of the primary rabies preexposure prophylaxis vaccination schedule.

Adapted from the Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2022; 71(18):619-26.

Postexposure Prophylaxis of Rabies

Postexposure prophylaxis of rabies in previously vaccinated and unvaccinated children, adolescents, and adults following exposure to rabies disease or virus.

History of previous vaccination against rabies simplifies the postexposure prophylaxis regimen, but does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.

Whenever a possible human exposure to rabies occurs, the risk of infection must be accurately assessed to determine the need for postexposure prophylaxis. Base decisions regarding the need for postexposure prophylaxis on vaccination status of exposed individual (see Table 2), type of exposure (bite, nonbite), information about the animal involved (type, vaccination status, condition at time of attack) (see Table 3), and rabies epidemiology in the specific geographic region. Consult local or state public health officials for assistance when evaluating rabies exposures and the need for postexposure prophylaxis.

Any person with a history of a complete preexposure or postexposure vaccination regimen with HDCV, PCECV, or rabies vaccine adsorbed (RVA; not commercially available in the US), or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination

Individuals with immunosuppression should receive a 5-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IM once on days 0, 3, 7, 14, and 28.

Deltoid area is the preferred site for IM administration of rabies vaccine in adults, adolescents, and older children (3 to 10 years of age). For younger children, the anterolateral thigh is preferred. Never administer in gluteal area.

Day 0 is the day the first dose of rabies vaccine is administered.

Adapted from Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010; 59 (RR-2):1-9.

Regardless of rabies immunization status, ACIP and AAP recommend that postexposure prophylaxis of rabies begin immediately with thorough cleansing of all bite wounds and scratches using soap and water and, if available, irrigation with a virucidal agent such as povidone-iodine solution. Local wound treatment is an essential initial step in rabies postexposure prophylaxis in all individuals.

In previously unvaccinatedchildren, adolescents, and adults following potential rabies exposure, a postexposure prophylaxis regimen of active immunization with a 4- or 5-dose regimen of rabies vaccine and passive immunization with a single dose of RIG is recommended as soon as possible. The ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for postexposure prophylaxis in previously unvaccinated individuals who are immunocompetent; however, a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.

In previously vaccinated children, adolescents, and adults following potential rabies exposure, a 2-dose booster regimen of rabies vaccine (without RIG) is recommended as soon as possible.

During the 10-day observation period, begin postexposure prophylaxis in the exposed individual at the first sign of rabies in a dog, cat, or ferret that has bitten them. If the animal exhibits clinical signs of rabies, euthanize it immediately and perform appropriate testing.

Initiate postexposure prophylaxis as soon as possible following exposure to such wildlife, unless animal is available for testing and public health authorities are facilitating expeditious laboratory testing or it is already known that brain material from the animal has tested negative. Other factors that might influence urgency of decision-making regarding initiation of postexposure prophylaxis before diagnostic results are known include the animal species, general appearance and behavior of the animal, whether encounter was provoked by a human, and the severity and location of bites. Discontinue postexposure prophylaxis if appropriate laboratory tests (i.e., direct fluorescent antibody test) are negative.

Euthanize the animal and test as soon as possible. Holding for observation is not recommended.

Adapted from the Recommendations of the Advisory Committee on Immunization Practices (ACIP) on Human Rabies Prevention. MMWR Recomm Rep. 2008; 57 (RR-3):1-28.

Bite exposures include any skin penetration by teeth; all bite exposures from an animal known or suspected to be rabid, regardless of bite location, pose a potential risk of rabies transmission and require postexposure prophylaxis. Risk of transmission varies in part based on species of biting animal, anatomic site of bite, and severity of wound. Rabies transmission can occur from bites of some animals (e.g., bats) that inflict rather minor injury and wounds that are difficult to detect.

Any potential exposure to a bat requires thorough evaluation. If possible, the bat should be submitted for rabies diagnosis. Postexposure prophylaxis is not necessary if the individual can be reasonably certain a bite, scratch, or mucous membrane exposure did not occur or if the bat is available for testing and is negative for rabies virus. Situations that might qualify as exposures include finding a bat in the same room as a person who might be unaware that a bite or direct contact occurred (e.g., a deeply sleeping individual awakened to find a bat in the room or an adult observes a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person). Other household members who did not have direct contact with the bat or were awake and aware when in the room with the bat should not be considered as having exposure to rabies.

Nonbite exposures include contamination of preexisting open wounds, abrasions, mucous membranes, or scratches with saliva or other potentially infectious material (e.g., neural tissue) from an animal known or suspected to be rabid. Although nonbite exposures only rarely cause rabies, such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis. Nonbite exposures of highest risk occur in surgical recipients of corneas, solid organs, and vascular tissue transplanted from patients who died of rabies and individuals exposed to large amounts of aerosolized rabies virus.

Transmission of rabies to individuals performing autopsies not reported to date; no confirmed cases of rabies reported in individuals performing postmortem examinations of humans or animals. CDC recommends that personnel performing autopsies on decedents with confirmed or suspected rabies use appropriate personal protective equipment, wear heavy or chain mail gloves, minimize aerosol generation by using a handsaw rather than oscillating saw, limit the number of individuals participating in the procedure and collection of specimens, and use ample amounts of 10% sodium hypochlorite solution during and after the procedure to ensure decontamination of all exposed surfaces. CDC states that preexposure vaccination against rabies usually is not required for individuals performing autopsies and that rabies postexposure prophylaxis is recommended in autopsy personnel only if a wound or mucous membrane gets contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue) during the procedure.

Other forms of contact in the absence of a bite or nonbite exposure (e.g., petting a rabid animal or contact with blood, urine, or feces of a rabid animal, contact of saliva with intact skin) are not considered exposure and postexposure prophylaxis is not necessary.

In health-care personnel, routine delivery of health care to a patient with rabies is not an indication for postexposure rabies prophylaxis; postexposure prophylaxis in such personnel is indicated if they have been bitten by the patient or if they have mucous membranes or nonintact skin (e.g., open wounds) that were contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue).

Because the rabies incubation period in humans can range from days to years (usually 1–3 months), initiate rabies postexposure prophylaxis (regardless of the length of delay) if a documented or likely exposure has occurred and clinical signs of rabies have not appeared in the exposed individual.

Postexposure prophylaxis failures have not been reported in the US when recommended wound management and postexposure regimens were followed using commercially available rabies vaccines and RIG. ACIP states that rabies pathogenesis data, animal data, clinical studies, and epidemiologic surveillance indicate that a 4-dose vaccine series is as effective as a 5-dose vaccine series when used in conjunction with wound management and RIG. Rare reports of postexposure prophylaxis failures in other countries usually involved some deviation from recommended procedures (e.g., postexposure prophylaxis not given or substantially delayed, wounds not adequately cleansed, rabies vaccine given IM into the gluteal rather than deltoid region, failure to passively immunize with RIG by infiltrating the wound site, use of less than the recommended dose of RIG, use of less than the recommended number of vaccine doses).

Travelers to rabies-endemic countries should be warned about the risk of acquiring rabies and educated in bite prevention strategies (e.g., avoiding contact with bats, avoiding stray dogs, monkeys, or cats). Because appropriate preparations of RIG or rabies vaccine may be not available for postexposure prophylaxis in the destination country, CDC recommends that travelers to such countries have a preplanned strategy in place that may involve identifying a different country where appropriate postexposure prophylaxis can be obtained if necessary. CDC states that rabies vaccines grown in animal brains (nerve tissue vaccines; NTV) may still be used in some developing countries; if offered such a vaccine (identified by a regimen that requires 5-mL injections once daily for 14–21 days), travelers should refuse the vaccine and travel to a country where an acceptable rabies vaccine and RIG are available. If travelers in other countries receive postexposure prophylaxis with regimens and/or preparations not recommended by ACIP (or not used in the US), additional therapy may be necessary following return to the US. In such cases, consult state and local health authorities for advice regarding the need for additional postexposure prophylaxis. Consider serologic testing in these travelers to verify efficacy of the regimen used and to ensure an adequate immune response.

Rabies Vaccine Dosage and Administration

General

• Rabies postexposure prophylaxis in previously unvaccinated individuals involves thorough cleansing of all bite and nonbite wounds followed by active immunization with rabies vaccine and passive immunization with RIG.

• Rabies postexposure prophylaxis in previously vaccinated individuals involves thorough cleansing of all bite and nonbite wounds followed by booster doses of rabies vaccine (without RIG).

• Because rabies virus may remain localized at the site of inoculation for a variable time before entering neural tissue, immediately wash all bites and scratches with soap and water; if available, irrigate with a virucidal agent (e.g., povidone-iodine solution). Institute tetanus prophylaxis and measures to control secondary infection as indicated. Consider cosmetic factors and the potential for bacterial infection before deciding to suture large wounds. AAP states that, if possible, the wound should not be sutured.

Administration

IM Administration

Administer only by IM injection.

Depending on patient age, administer IM into the deltoid muscle or anterolateral thigh.

For adults, adolescents, and older children (3 to 10 years of age), the deltoid is the preferred IM injection site; for younger children, the anterolateral thigh is preferred.

Avoid use of the gluteal area as a possible IM injection site.

Avoid injection into or near blood vessels or nerves.

To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin using a needle length appropriate for the individual's age and body mass, thickness of adipose tissue and muscle at the injection site, and injection technique.

Administer immediately after reconstitution. Use entire volume of reconstituted single-dose vaccine vial.

Use separate needles for reconstitution and administration.

Do not administer rabies vaccine in the same syringe or simultaneously at the same injection site as RIG.

Do not mix with any other vaccine or solution.

Syncope may occur following vaccination; may be accompanied by transient neurologic symptoms (e.g., visual disturbances, paresthesia, tonic-clonic movements). Take appropriate measures to decrease risk of injury if patient becomes weak or dizzy or loses consciousness (e. g., have vaccinees sit or lie down during and for 15 minutes after vaccination). If syncope occurs, observe patient until symptoms resolve.

Reconstitution (HDCV; Imovax)

To reconstitute, add entire contents of syringe containing diluent provided by the manufacturer to the single-dose vial of lyophilized vaccine to provide a solution containing at least 2.5 international units per mL of rabies antigen. Use only the diluent supplied by the manufacturer.

Attach reconstitution needle and plunger to the syringe and inject diluent into vaccine vial. Gently swirl until completely dissolved. The lyophilized vaccine is creamy white to orange; reconstituted suspension is pink to red.

The vaccine vial contains negative pressure that may impede withdrawal of the full dose of reconstituted vaccine. The manufacturer recommends that the syringe be disconnected from the needle after reconstitution to allow any remaining vacuum to exhaust.

Remove reconstitution needle and discard. Use a suitable needle for IM administration. Use immediately after reconstitution.

Reconstitution (PCECV; RabAvert)

To reconstitute, add entire contents of syringe containing diluent provided by the manufacturer to the single-dose vial of lyophilized vaccine to provide a suspension containing at least 2.5 international units per mL of rabies antigen. Use only the diluent supplied by the manufacturer.

Attach the longer of the 2 needles provided by the manufacturer to the syringe. Insert the needle at a 45° angle into the vaccine vial; slowly inject entire contents of diluent vial into the vaccine vial. Mix gently to avoid foaming. Lyophilized vaccine is white; reconstituted suspension is clear to slightly opalescent, colorless to slightly pink.

Withdraw entire amount of dissolved vaccine into the syringe and replace the long needle with the smaller one for IM injection. Use immediately after reconstitution.

The vaccine vial contains negative pressure that may impede withdrawal of the full dose of reconstituted vaccine. The manufacturer recommends that the syringe be disconnected from the needle after reconstitution to allow any remaining vacuum to exhaust; however, creating positive pressure (e.g., by injecting air into the vial) is not recommended since over-pressurization may interfere with withdrawal of the proper vaccine dose.

Dosage

Whenever possible, the rabies vaccine (HDCV [Imovax], PCECV [RabAvert]) used for the initial dose should be used for subsequent doses in the vaccine series in the same individual. Although only limited data available to date, most experts state that rabies vaccines currently available in the US may be considered interchangeable. ACIP states clinical studies not available to date showing differences in efficacy or safety if the vaccine series is completed with a different preparation.

Adhere to the recommended vaccination schedule as closely as possible. If a minor deviation from the schedule occurs (e.g., a dose is delayed by a few days), give the dose and resume the vaccination schedule using the same interval between doses. If a substantial deviation from the schedule occurs, perform serologic testing 7–14 days after the final vaccine dose to assess immune status. For the 2-dose preexposure prophylaxis vaccine series, when substantial delays occur (2 weeks or more) from the recommended date of the second dose, local and state public health authorities should be consulted for guidance.

Pediatric Patients

Preexposure Vaccination Against Rabies in High-risk Groups

Primary Immunization in Children and Adolescents

IM

Primary immunization consists of a series of 2 doses. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give first dose on a selected date; give the second dose 7 days later.

Completion of the recommended 2-dose primary series before an expected exposure to rabies virus ensures the highest level of protection.

Serologic confirmation of rabies immunity following the 2-dose primary series is not necessary in most individuals.

Booster Doses in Children and Adolescents

IM

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give a booster dose if indicated to maintain adequate levels of antirabies antibody. (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1 under Uses.)

Postexposure Prophylaxis of Rabies

Previously Unvaccinated Children and Adolescents

IM

Postexposure prophylaxis in previously unvaccinated individuals consists of active immunization with a series of 4 or 5 doses of rabies vaccine in conjunction with passive immunization with a single dose of RIG.

Although the manufacturers recommend a 5-dose regimen of rabies vaccine in conjunction with RIG for postexposure prophylaxis in all previously unvaccinated individuals, the ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for previously unvaccinated individuals who are immunocompetent and that a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.

Immunocompetent children and adolescents: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 3 remaining doses on days 3, 7, and 14, respectively, after first dose. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Immunocompromised children and adolescents: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 4 remaining doses on days 3, 7, 14, and 28, respectively, after first dose. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Administer RIG dose preferably at the time of the first dose of rabies vaccine. If rabies vaccine is not immediately available, administer RIG dose and start the vaccine series as soon as possible. If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose. RIG is not necessary after day 7 since sufficient vaccine-induced rabies antibody will be present in most vaccine recipients.

Previously Vaccinated Children and Adolescents

IM

Postexposure prophylaxis in previously vaccinated individuals consists of a series of 2 booster doses of rabies vaccine (without RIG).

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give first dose as soon as possible after exposure (day 0); give second dose 3 days later.

This 2-dose regimen can be used in those who previously received a preexposure or postexposure vaccination regimen with HDCV (Imovax), PCECV (RabAvert), Imovax Rabies I.D. (no longer commercially available in the US), or rabies vaccine adsorbed (RVA; no longer commercially available in the US) or those who previously received preexposure vaccination with some other vaccine and had documented levels of antirabies antibody considered adequate.

Adults

Preexposure Vaccination Against Rabies in High-risk Groups

Primary Immunization in Adults

IM

Primary immunization consists of a series of 2 doses. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give first dose on a selected date; give the second dose 7 days later.

Completion of the 2-dose primary series before an expected exposure to rabies virus ensures the highest level of protection.

Serologic confirmation of rabies immunity following the 2-dose primary series is not necessary in most individuals.

Booster Doses in Adults

IM

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give a booster dose if indicated to maintain adequate levels of antirabies antibody. (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1 under Uses.)

Postexposure Prophylaxis of Rabies

Previously Unvaccinated Adults

IM

Postexposure prophylaxis in previously unvaccinated individuals consists of active immunization with a series of 4 or 5 doses of rabies vaccine in conjunction with passive immunization with a single dose of RIG.

Although the manufacturers recommend a 5-dose regimen of rabies vaccine in conjunction with RIG for postexposure prophylaxis in all previously unvaccinated individuals, the ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for previously unvaccinated individuals who are immunocompetent and that a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.

Immunocompetent adults: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 3 remaining doses on days 3, 7, and 14, respectively, after first dose. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Immunocompromised adults: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 4 remaining doses on days 3, 7, 14, and 28, respectively, after first dose. Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Administer RIG dose preferably at the time of the first dose of rabies vaccine. If rabies vaccine is not immediately available, administer RIG dose and start the vaccine series as soon as possible. If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose. RIG is not necessary after day 7 since sufficient vaccine-induced rabies antibody will be present in most vaccine recipients.

Previously Vaccinated Adults

IM

Postexposure prophylaxis in previously vaccinated individuals consists of a series of 2 booster doses of rabies vaccine (without RIG).

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.

Give first dose as soon as possible after exposure (day 0); give second dose 3 days later.

This 2-dose regimen can be used in those who previously received a preexposure or postexposure vaccination regimen with HDCV (Imovax), PCECV (RabAvert), Imovax Rabies I.D. (no longer commercially available in the US), or rabies vaccine adsorbed (RVA; no longer commercially available in the US) or those who previously received preexposure vaccination with some other vaccine and had documented titers of antirabies antibody considered adequate.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Rabies Vaccine

Contraindications

• HDCV (Imovax) for preexposure vaccination: history of life-threatening systemic hypersensitivity reactions to the vaccine or any vaccine component.

• PCECV (RabAvert) for preexposure vaccination: History of anaphylactic reactions to the vaccine or any component.

• HDCV (Imovax) and PCECV (RabAvert) for postexposure prophylaxis: No known contraindications, including pregnancy, because of the almost invariably fatal outcome of rabies infection.

Warnings/Precautions

Warnings

Nervous System Effects

Neurologic effects, sometimes serious (e.g., Guillain-Barré syndrome, transient neuroparalysis, myelitis, retrobulbar neuritis, multiple sclerosis, subacute peripheral and focal CNS disorders) temporally associated with HDCV (Imovax) and PCECV (RabAvert).

If neurologic effects occur, carefully consider the individual's risk of acquiring rabies when deciding whether to discontinue the vaccination series. Contact state health departments or CDC for advice and assistance regarding management of these individuals.

Use of corticosteroids to treat life-threatening neuroparalytic reactions may interfere with the immune response to rabies vaccine. Perform serologic testing in individuals receiving corticosteroids to verify seroconversion following vaccination.

Immediately report all serious vaccine-associated neuroparalytic reactions to the manufacturer and to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].

Administration Precautions

Administer IM preferably into the deltoid for adults, adolescents, and older children (3 to 10 years of age); for younger children, the anterolateral thigh is preferred.

Do not administer into gluteal muscle; suboptimal immunologic response may occur. Reason for suboptimal response unclear; may occur because of inadvertent sub-Q injection or administration into fatty tissue instead of muscle. Fatal rabies paralysis and encephalitis reported in several individuals who received HDCV (Imovax) by IM injection into the gluteal area.

Inadvertent intravascular injection of PCECV (RabAvert) may result in systemic reactions (e.g., shock).

Do not administer RIG in the same syringe or simultaneously at the same injection site as rabies vaccine.

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy. Consider possibility that the immune response to rabies vaccine and efficacy may be reduced in these individuals.

ACIP states that recommendations concerning use of rabies vaccine in individuals with altered immunocompetence (e.g., patients with HIV infection, congenital immunodeficiency, leukemia, lymphoma, aplastic anemia, generalized malignancy, solid organ transplant, asplenia, renal failure, diabetes, alcoholism, or alcoholic cirrhosis, or in those receiving therapy with alkylating agents, antimetabolites, radiation, corticosteroids, or other chronic immunosuppressive therapy) generally are the same as those for patients who are not immunocompromised. However, the ACIP states that a 5-dose vaccine series (not a 4-dose series) of HDCV (Imovax) or PCECV (RabAvert) should be used when rabies postexposure prophylaxis is indicated in previously unvaccinated individuals with altered immunocompetence.

Postpone preexposure vaccination (2-dose primary series) in immunocompromised individuals and advise them to avoid activities for which rabies preexposure vaccination is indicated.

If this is not possible, administer the rabies vaccine but check the antibody titer no sooner than 1 week (ideally, 2 to 4 weeks) after comopletion of the 2-dose preexposure series and all appropriate booster doses (including those given within 3 years of the primary series and in response to a low titer during the serial titer checks recommended for risk categories 1 and 2). If the titer is <0.5 IU/mL, administer a booster dose and perform a subsequent titer check. If 2 such booster doses fail to elicit an appropriate antibody response, consult local or state public health authorities for guidance.

Avoid use of immunosuppressive agents during rabies postexposure prophylaxis, unless considered essential for the treatment of other conditions.

If rabies postexposure prophylaxis is indicated in an immunocompromised individual, serologic testing is considered essential after completion of the postexposure prophylaxis regimen to confirm than an adequate antibody response is obtained. If an acceptable antibody response is not detected after the final vaccine dose of the postexposure prophylaxis series, the patient should be managed in consultation with their clinician and appropriate public health officials.

Risk of Transmissible Agents in Preparations Containing Albumin

HDCV (Imovax) and PCECV (RabAvert) contain albumin human.

Since albumin is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).

Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and/or filtration procedures have reduced, but not completely eliminated, risk of pathogen transmission with plasma-derived preparations.

Sensitivity Reactions

Hypersensitivity Reactions

Allergic reactions, including anaphylaxis and immune complex-like reactions, reported in association with HDCV (Imovax) or PCECV (RabAvert). Bronchospasm, edema, pruritus, and urticaria also reported during postmarketing surveillance.

Serious anaphylactic reactions during rabies vaccination pose a serious therapeutic dilemma. Carefully consider the individual's risk of acquiring rabies when deciding whether to discontinue the vaccination series. Contact state health departments or CDC for advice and assistance regarding management of these individuals.

When rabies vaccine is indicated in an individual with a history of hypersensitivity to the vaccine or any ingredient, observe patient closely following each dose and ensure that appropriate therapy (e.g., epinephrine, corticosteroids, oxygen) is readily available to treat a reaction if it occurs. Use of prophylactic antihistamines is acceptable.

Immediately report all serious anaphylactic reactions associated with rabies vaccine to the manufacturer and the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].

Immune Complex-like Reactions

Immune complex (serum sickness)-like (type III hypersensitivity) reactions reported in up to 7% of individuals 2–21 days following booster doses of HDCV (Imovax). Similar reactions also reported following primary immunization with HDCV (Imovax), but much less frequently.

These reactions were not life-threatening; they involved generalized urticaria with or without arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise.

Type III hypersensitivity reactions have been reported during postmarketing surveillance in individuals receiving PCECV (RabAvert).

May be caused by β-propiolactone-altered albumin human formed as a result of the manufacturing process for HDCV (Imovax); β-propiolactone is thought to render the albumin allergenic resulting in development of IgE antibodies to the allergen.

Each dose of HDCV (Imovax ) contains <100 mg of human albumin. Each dose of PCECV (RabAvert) contains ≤0.3 mg of human albumin.

Do not administer additional doses of HDCV (Imovax) in individuals who experienced immune complex-like reactions to a previous dose, unless postexposure prophylaxis with the vaccine is considered necessary.

Allergy to Neomycin or Other Anti-infectives

Each dose of HDCV (Imovax) contains <150 mcg of neomycin sulfate. Each dose of PCECV (RabAvert) contains ≤10 mcg of neomycin and trace amounts of chlortetracycline (≤200 ng) and amphotericin B (≤20 ng).

Use caution in individuals sensitive to these antibiotics. Weigh possibility of an allergic reaction against the potential risk of contracting rabies if the vaccine is not given.

Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis. ACIP states that a history of delayed-type allergic reaction to neomycin is not a contraindication to use of vaccines containing trace amounts of neomycin. However, before giving a neomycin-containing vaccine to an individual with a history of anaphylactic reaction to neomycin, have patient evaluated by an allergist.

Gelatin Allergy

PCECV (RabAvert) contains <12 mg of polygeline (bovine gelatin). Consider possibility of allergic reactions in individuals sensitive to bovine gelatin. Bovine components of the vaccine originate only in the US, Australia, and New Zealand. ACIP states that individuals with a history of anaphylactic reaction to gelatin should be evaluated by an allergist before receiving a gelatin-containing vaccine.

Allergy to Egg-related Antigens

PCECV (RabAvert) is produced in chick embryo cell culture and may contain minimal amounts of chicken protein (ovalbumin). HDCV (Imovax) is produced in human diploid cells and does not contain chicken protein.

Manufacturer of PCECV (RabAvert ) rabies vaccine states that individuals with a history of anaphylaxis (e.g., urticaria, angioedema, swelling, brochospasm, lightheadedness, hypotension, shock) following exposure to egg or chicken protein should receive the vaccine in an inpatient or outpatient medical setting (including but not necessarily limited to hospitals, clinics, health departments, and physician offices) under supervision of a health-care provider able to recognize and manage severe allergic reactions.

General Precautions

Local or Systemic Adverse Effects

Once initiated, postexposure prophylaxis for rabies should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. These reactions generally can be managed with NSAIAs or antipyretic agents (e.g., ibuprofen, acetaminophen).

Serious systemic, anaphylactic, or neuroparalytic reactions pose a therapeutic dilemma. Contact state health departments or CDC for advice and assistance regarding management of these individuals.

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against rabies.

May not prevent rabies in individuals who do not achieve adequate antibody titers.

Duration of Immunity

Duration of immunity following the recommended 2-dose preexposure vaccine series (primary immunization) of HDCV (Imovax) or PCECV (RabAvert) is unclear. Clinical data show that an anamnestic response after the 2-dose series occurs at 3 years; however, such a response >3 years after the series has not been evaluated.

Need for additional (booster) doses after primary immunization depends on the nature and category of risk associated with the potential exposure.

Concomitant Illness

A decision to administer or delay vaccination in an individual with current or recent febrile illness depends on the severity of symptoms and etiology of the illness.

ACIP states that minor acute illness, such as mild diarrhea or mild upper respiratory tract infection (with or without fever) generally does not preclude vaccination.

The manufacturers and ACIP state that preexposure rabies vaccination (but not postexposure prophylaxis) with HDCV (Imovax) or PCECV (RabAvert) generally should be deferred in individuals with moderate or severe acute illness until improvement of the condition is noted.

Individuals with Bleeding Disorders

Because bleeding may occur following IM administration in individuals with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or in those receiving anticoagulant therapy, use caution in such individuals.

ACIP states that vaccines may be given IM to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the vaccine can be administered with reasonable safety. In these cases, use a fine needle (23 gauge) to administer the vaccine and apply firm pressure to the injection site (without rubbing) for ≥2 minutes. If patient is receiving antihemophilia therapy, administer the IM vaccine shortly after a scheduled dose of such therapy.

Advise the individual and/or their family about the risk of hematoma from IM injections.

Pre- and Postvaccination Serologic Testing

The minimum antibody level historically recommended by ACIP is one that results in complete neutralization of rabies virus at a 1:5 serum dilution by the rapid fluorescent focus inhibition test. This is approximately equivalent to a titer of 0.1 to 0.3 IU/mL. Most published studies use 0.5 IU/mL as a correlate of protection; therefore, this level is now endorsed by ACIP and replaces the previous minimum acceptable rabies antibody titer.

Serologic confirmation of rabies immunity following preexposure vaccination (2-dose primary series) is not necessary in most individuals because of the high rate of response in immunocompetent adults, adolescents, and children when the recommended vaccine regimen is used.

Postvaccination serologic testing may be particularly important in immunocompromised individuals who receive preexposure vaccination since these individuals may have impaired immune response to vaccination.

To determine the need for preexposure booster doses of rabies vaccine in individuals who received preexposure vaccination with a primary vaccine series, see Table 1 under Uses.)

Serologic testing is not indicated prior to postexposure prophylaxis in previously vaccinated individuals who are exposed to rabies. Such testing is inappropriate because it would delay postexposure prophylaxis and, although antirabies neutralizing antibodies are an important component of immunity, other immune effectors also play a role in disease prevention.

Serologic confirmation of rabies immunity following postexposure prophylaxis is not necessary in most individuals because of the high rate of vaccine response among immunocompetent adults, adolescents, and children when the recommended rabies postexposure prophylaxis regimen is used (i.e., proper wound care followed by a single dose of RIG and a 4- or 5-dose regimen of a cell culture-derived rabies vaccine).

When postexposure prophylaxis against rabies is indicated in an immunocompromised individual, serologic testing is considered essential after completion of the postexposure prophylaxis regimen to confirm that an adequate antibody response was obtained. This includes individuals receiving immunosuppressive agents (e.g., those receiving corticosteroids for the treatment of life-threatening neuroparalytic reactions to rabies vaccine).

Consider serologic testing to confirm that an adequate antibody response was obtained in travelers who received rabies postexposure prophylaxis with regimens and/or preparations not currently recommended by ACIP.

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.

Do not administer HDCV (Imovax) or PCECV (RabAvert) that has been mishandled or has not been stored at the recommended temperature.

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained. If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether the vaccine is usable.

Specific Populations

Pregnancy

Manufacturers state that HDCV (Imovax) and PCECV (RabAvert) should be given to pregnant females only if clearly needed.

However, ACIP, CDC, AAP, American College of Obstetricians and Gynecologists (ACOG), and the manufacturers state that pregnancy is not considered a contraindication for postexposure prophylaxis with rabies vaccine because of the potential risks of inadequately treated rabies exposure and because there is no evidence of an association between fetal abnormalities and rabies vaccine. ACOG recommends that each pregnant woman be considered individually and that public health authorities be consulted.

Preexposure vaccination may also be indicated during pregnancy when a substantial risk of rabies exposure is present.

Lactation

Not known whether antigens contained in rabies vaccine are distributed into milk. CDC states that use of rabies vaccine in nursing females should follow the same guidelines as other adults.

Because inactivated vaccines do not multiply within the body, the ACIP states that they should not pose any unusual problems for nursing females or their infants.

PCECV (RabAvert): Manufacturer states nursing is not considered a contraindication when the vaccine is indicated for postexposure prophylaxis because of the possible risks of inadequately treated rabies exposure. In addition, use of the vaccine for preexposure vaccination may be indicated in nursing females when a substantial risk of rabies exposure is present.

Pediatric Use

HDCV (Imovax): Safety and efficacy in children established.

PCECV (RabAvert): Limited data available regarding safety and efficacy in children. Used effectively for preexposure vaccination in children ≥2 years of age and for postexposure prophylaxis in children ≥1 year of age. At least 1 neonate received 5 doses of RabAvertrabies vaccine (given on days 0, 3, 7, 14, and 30) without unusual adverse effects.

Children are at higher risk of rabies exposure compared with adults because of increased potential for animal contact and because they are more likely to be bitten on the head, face, and neck leading to more severe injuries.

Geriatric Use

PCECV (RabAvert): Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently to the vaccine than younger adults. Clinical experience with PCECV (RabAvert) reveals that there are no overall differences in safety between geriatric and younger individuals.

Common Adverse Effects

HDCV (Imovax): Local effects at injection site (pain, swelling, erythema, itching), mild systemic reactions (headache, nausea, abdominal pain, muscle aches, dizziness).

PCECV (RabAvert): Local effects at injection site (pain, swelling, erythema, itching), influenza-like symptoms (mild to moderate asthenia, fatigue, fever, myalgia, malaise, headache).

Drug Interactions

Other Vaccines

HDCV (Imovax) and PCECV (RabAvert) rabies vaccines are inactivated viral vaccines; interactions with other inactivated vaccines, live virus vaccines, recombinant vaccines, or toxoids are unlikely. Inactivated vaccines can be administered either simultaneously with or at any time before or after inactivated or live vaccines. However, each vaccine should be administered using a different syringe and a different injection site.

Specific Drugs

Stability

Storage

Parenteral

Suspension for IM Injection

HDCV (Imovax): Prior to reconstitution, 2–8°C; avoid freezing.

PCECV (RabAvert): Prior to reconstitution, 2–8°C; protect from light.

Must be used immediately after reconstitution; discard if not used immediately.

HDCV (Imovax) and PCECV (RabAvert) do not contain thimerosal or any other preservatives.

Actions

• Rabies vaccine is a sterile, freeze-dried vaccine containing inactivated rabies virus antigen (≥2.5 international units/mL).

• Commercially available as human diploid-cell rabies vaccine (HDCV; Imovax) or purified chick embryo cell culture rabies vaccine (PCECV; RabAvert).

• HDCV (Imovax) contains antigen prepared from the Wistar Institute Pitman-Moore strain (PM-1503-3M) of rabies virus propagated in MRC-5 strain of human diploid-cell tissue culture. PCECV (RabAvert) contains antigens prepared from the fixed-virus strain Flury low egg passage (LEP) of rabies virus propagated in primary cultures of chicken fibroblasts.

• Stimulates active immunity to rabies by inducing production of antirabies neutralizing antibodies. Antirabies antibodies neutralize rabies virus and are believed to have a primary role in preventing rabies infection.

• HDCV (Imovax) and PCECV (RabAvert) are highly immunogenic in immunocompetent children, adolescents, and adults. When administered according to the recommended preexposure immunization schedule in clinical studies, 100% of vaccinees achieved protective levels of antirabies antibody.

• Following IM administration of rabies vaccine, antirabies antibody levels are detectable in serum within 7–10 days and persist for several years.

• Following rabies exposure and inoculation, the virus remains close to the wound for an indeterminate time and can be partially neutralized with RIG while at this site. In susceptible individuals, the virus is transported to the CNS via the peripheral nerves. Following entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and a fatal encephalomyelitis almost always develops.

• Incubation period for rabies infection in humans can range from days to years (usually 1–3 months). After severe bites to the face, neck, or arms, the incubation period may be as short as 10 days.

• Common prodromal symptoms of rabies infection include malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure. Anxiety, agitation, and irritability may also occur during the prodromal stage followed by hyperactivity, disorientation, seizures, aerophobia, hydrophobia, hypersalivation, and eventually paralysis, coma, and death. Following appearance of clinical symptoms of rabies, use of rabies vaccine or RIG will not improve the prognosis and may be detrimental; there is no specific proven effective treatment for rabies once symptoms develop.

• There have been no cases of rabies in the US in previously unvaccinated individuals who received the recommended postexposure prophylaxis regimen (i.e., proper wound care followed by a single dose of RIG and a 4- or 5-dose regimen of HDCV [Imovax] or PCECV [RabAvert] rabies vaccine).

Advice to Patients

• Prior to administration of each vaccine dose, provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient's legal representative as required by the National Childhood Vaccine Injury Act (VISs are available at [Web]).

• Advise the patient and/or patient's parent or guardian of the risks and benefits of vaccination with rabies vaccine.

• Advise the patient and/or patient's parent or guardian that rabies vaccine is used to prevent rabies and is given to persons at high risk of exposure to rabies as a result of employment, travel, or hobbies (e.g., certain laboratory workers, veterinarians, animal control and wildlife workers, spelunkers, hunters).

• Advise the patient and/or patient's parent or guardian that rabies vaccine is also used to prevent rabies in individuals who have been bitten, scratched, or licked on an open wound by an animal known or suspected of having rabies.

• When rabies preexposure vaccination is indicated, importance of completing the 2-dose primary vaccination series.

• When rabies postexposure prophylaxis is indicated in previously unvaccinated individuals, importance of completing a 4- or 5-dose series of rabies vaccine and receiving a single dose of RIG as soon as possible following rabies exposure.

• When rabies postexposure prophylaxis is indicated in previously vaccinated individuals, importance of receiving a 2-dose regimen of rabies vaccine as soon as possible following rabies exposure.

• Importance of informing clinicians if the patient has a weakened immune system (e.g., cancer, HIV/AIDS) or receives treatment that may weaken the immune system (e.g., corticosteroids, cancer treatment).

• Importance of informing clinicians if a patient has a fever or serious illness. Advise patient that preexposure vaccination may be deferred if they are moderately or severely ill, but that rabies postexposure prophylaxis will still be administered, regardless of any other illness they may have.

• Importance of informing clinicians if any serious adverse reactions (e.g., hypersensitivity, neurologic reactions) occur. Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.

• Importance of females informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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