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Canadian Immunization Guide
Seventh Edition - 2006
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Part 4
Active Immunizing Agents
Rabies Vaccine
Rabies is a neurotropic viral infection that has two clinical presentations and is a fatal disease. After infection, the usual incubation period is 20 to 60 days, although it may vary from several days to years. The more common, agitated (furious) form presents with the classic symptoms of hydrophobia or aerophobia with a rapidly progressing encephalitis and death. The paralytic form of the disease manifests as progressive flaccid paralysis, has a more protracted course and is more difficult to diagnose.
Since the publication of the 2002 Canadian Immunization Guide, a new rabies vaccine product has become available, and new recommendations have been made regarding the intradermal administration of rabies vaccine in certain pre-exposure situations.
Epidemiology
Human rabies
In 2000 and 2003, two people in Canada died of rabies infection, one in Quebec (2000) and one in British Columbia (2003). These were the first cases of human rabies in Canada since 1985. The most likely sources of infection for both of these people were unrecognized bat exposures. Since 1924, a total of 23 people in six provinces have died of rabies in Canada (Figure 14): Quebec (12), Ontario (6), Saskatchewan (2) and Alberta, British Columbia and Nova Scotia (1 case each). In 2004, the US Centers for Disease Control and Prevention confirmed the first reported case of rabies following solid organ transplantation.
Animal rabies
The rabies virus can infect any mammal. In North America, it
occurs mainly in certain wild terrestrial carnivore species and
can spread to domestic livestock and pets. Over the past few
years the overall number of animal rabies cases in Canada has
been steadily decreasing. There remain regional differences in
the prevalence of animal rabies across the country, and the
specific species infected in each region vary over time.
For up-to-date details on animal rabies activity in Canada,
please see the Canadian Food Inspection Agency (CFIA) Web site:
http://www.inspection.gc.ca/english/anima/heasan/disemala/rabrag/statse.shtml
During the past 6 years (2000-2005) a total of 2,238 cases of confirmed animal rabies were reported in Canada (average: 373 per year). Skunks accounted for 40% of the total cases, followed by bats (26%), foxes (11%) and raccoons (8%). Bat rabies was detected in most regions across Canada, except the three territories and Prince Edward Island (PEI). Three provinces accounted for the majority of cases: Ontario (43%), Manitoba (24%) and Saskatchewan (14%). The species most affected, by region, during the 6-year period were as follows: skunks in Manitoba (434/540 or 80%) and Saskatchewan (243/316 or 77%); bats in British Columbia (91/95 or 96%), Alberta (20/21 or 95%) and Quebec (66/118 or 56%); foxes in the Northwest Territories/Nunavut (57/74 or 77%) and Newfoundland/Labrador (33/44 or 75%); and raccoons in New Brunswick (55/70 or 79%). In Ontario the most affected species were bats (356/956 or 37%) and skunks (226/ 956 or 24%). Over the past 6 years, PEI reported one case of animal rabies (cat), and Nova Scotia reported three. Yukon had no reported cases of animal rabies. Spread to domestic species of animals, such as pets (e.g., cats and dogs) and livestock (horses and cows) has occurred. Dogs and cats accounted for 4.5% of animal rabies cases.
Bat rabies has accounted for 58% of the human rabies cases in the United States since 1980 and appears to be increasing in frequency. The increased incidence is due, in part, to the failure to recognize the small wound inflicted by a biting bat and thus omission of post-exposure prophylaxis. In most of the recently reported cases, there has not been a history of a bat bite although there has been contact, either recognized or unrecognized at the onset of the illness, with infected colonies. In the past, four cases were thought to have been acquired through aerosolized virus across mucous membranes.
Preparations approved for use in Canada
This chapter will deal only with vaccines that are currently marketed in Canada.
Two rabies vaccines are currently marketed for active immunization of humans in Canada:
- Imovax® Rabies, Sanofi Pasteur Ltd
- RabAvert®, Merck Frosst (distributor)
Both products may be used for pre-exposure and post-exposure prophylaxis. Imovax® Rabies is prepared from rabies virus grown in human diploid cell culture (HDCV), concentrated by ultrafiltration and then inactivated with beta-propiolactone. Sterile diluent is supplied for reconstitution into a single 1.0 mL dose. RabAvert is a purified chick embryo cell vaccine (PCECV) produced by growing the fixed-virus strain Flury low egg passage in primary cultures of chicken fibroblasts. The virus is inactivated with beta-propiolactone and processed by zonal centrifugation. The vaccine has no preservative. Sterile diluent is supplied for reconstitution into a single 1.0 mL dose.
Two human rabies immune globulin (RabIg) products are approved in Canada for passive immunization. RabIg is concentrated by cold ethanol fractionation from the plasma of hyperimmunized donors and undergoes multiple procedures for human viral pathogen clearance during preparation. It is supplied at a standardized concentration of 150 IU per mL. Please refer to the Passive Immunizing Agents chapter for more information on immune globulin products.
For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.
Pre-exposure management
Pre-exposure rabies immunization with either HDCV or PCECV should be offered to people at potentially high risk of contact with rabid animals, e.g., certain laboratory workers, veterinarians, animal control and wildlife workers, spelunkers, and persons hunting and trapping in high-risk areas. Travellers to endemic areas where there is poor access to adequate and safe post-exposure management should consider pre-travel immunization. As well, children who are too young to understand either the need to avoid animals or to report a traumatic contact are considered at greater risk of rabid animal exposure and should be offered pre-exposure immunization when travelling to endemic areas (please refer to the Immunization of Travellers chapter for more information).
Post-exposure management
HDCV or PCECV together with RabIg and local treatment are highly effective in preventing rabies in exposed individuals. No post-exposure failures have occurred in Canada or the United States. The few reported failures else where in the world have been attributed to delay in treatment, lack of appropriate cleansing of wounds, suboptimal methods of immunization or omission of passive immunization. Responses to vaccines received in other countries may be less predictable.
Rabies prophylaxis must be considered in every incident in which potential animal exposure to rabies virus has occurred, unless rabies is known to be absent from the local animal population. In evaluating each case, local public health officials should be consulted. If there has been no exposure, as described below, post-exposure treatment is not indicated.
1. Species of animal
The animals in Canada most often proven rabid are wild terrestrial carnivores (skunks, foxes and raccoons), bats, cattle, and stray dogs and cats. As the distribution of animal rabies and the species involved vary considerably across Canada it is important to consult the local medical officer of health or government veterinarian in cases of possible exposure. Human exposures to livestock are usually confined to salivary contamination, with the exception of horses and swine, from which bites have been reported. The risk of infection after exposure to rabid cattle is low. Squirrels, hamsters, guinea-pigs, gerbils, chipmunks, rats, mice or other rodents, rabbits and hares are only rarely found to be infected with rabies and are not known to have caused human rabies in North America; post-exposure prophylaxis should be considered only if the animal's behaviour was highly unusual.
The manifestations of rabies and the incubation periods vary in different species. The length of time virus may be excreted in saliva before the development of symptoms has not been determined for the purpose of defining rabies exposure except in domestic dogs, cats and ferrets. In these animals, rabies virus excretion does not generally precede symptom development beyond 10 days. It remains unclear as to whether asymptomatic carriage of rabies virus in wild animals is possible.
2. Type of exposure
Rabies is transmitted when the virus is inoculated into tissues. This occurs most commonly through bites, although when cuts or wounds are contaminated by rabies virus from saliva or infected tissue, transmission is possible. Rarely, transmission has been recorded when virus was inhaled, or infected grafts/organs were transplanted into patients. Thus, three broad categories of exposure are recognized as warranting post-exposure prophylaxis: bite, non-bite and bat exposures.
Bite: This is defined as any penetration of the skin by teeth. Bites inflicted by most animals are readily apparent with the exception of bats (see below). Wild or stray animals, or any domestic animal behaving unusually should never be handled by untrained individuals. Children should be taught this.
Non-bite: This category includes contamination of scratches, abrasions or cuts of the skin or mucous membranes by saliva or other potentially infectious material, such as the brain tissue of a rabid animal. Petting a rabid animal or handling its blood, urine or feces is not considered to be an exposure, but such contact should be avoided. Being sprayed by a skunk is also not considered an exposure. These incidents do not warrant post-exposure prophylaxis.
Exposures incurred in the course of caring for humans with rabies could theoretically transmit the infection. No case of rabies acquired in this way has been documented, but post-exposure prophylaxis should be considered for exposed individuals.
Bat exposures: Recently, the majority of individuals who have died in North America from bat rabies have not had a bite history or even, in several situations, a known bat exposure history. In addition, bites inflicted by bats to a sleeping person may not be felt, and may leave no visible bite marks. Hence, when people are sleeping unattended in a room where a bat is found, when there has been close contact with bats or when the possibility of a bite cannot be reasonably excluded - e.g., if a bat is discovered in proximity to an individual who is cognitively impaired or near a young child - post-exposure prophylaxis should be initiated. Bats should never be handled with bare hands.
Four cases of rabies were thought to have been acquired through aerosolized virus across mucous membranes. However, each of these likely had exposure to large quantities of aerosolized virus, as two were spelunkers and two laboratory workers. Post-exposure prophylaxis is therefore warranted and recommended in rare instances of non-bite exposure, such as inhalation of aerosolized virus by spelunkers exploring caves inhabited by infected bats or by laboratory technicians homogenizing tissues infected with rabies virus; however, the efficacy of prophylaxis after such exposures is unknown.
3. Investigation of the incident
Each incident of possible exposure requires a full investigation. This should include an assessment of the risk of rabies in the animal species involved and, in a low prevalence area such as Canada, the behaviour of the particular domestic animal implicated. An unprovoked attack is more likely to indicate that the animal is rabid. Nevertheless, rabid cats and dogs may become uncharacteristically quiet. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked.
Domestic pets with up-to-date rabies vaccination are unlikely to become infected with rabies. If vaccinated animals exhibit signs suggestive of rabies they must be carefully evaluated by a veterinarian.
Any animal that has bitten a human and/or is suspected of
being rabid should be reported to the local medical officer
of health and to the nearest CFIA veterinarian. These
veterinarians are familiar with the regulations concerning rabies
and, if necessary, will collect and ship appropriate specimens
to a federal laboratory for diagnosis. Further information and
advice is obtainable from the CFIA regional offices or
local district office on the CFIA Web site or by
consulting the blue pages of the local telephone directory.
If the animal escapes during the 10-day observation period, the need for post-exposure prophylaxis should be carefully re-assessed. Exotic pets (other than ferrets) should be treated as wild animals because the incubation period and period of rabies virus shedding in these animals are unknown. Recent information regarding the pathogenesis of rabies in domestic ferrets has prompted them to be considered in the same category as domestic dogs and cats rather than wild carnivores.
Management of people after possible exposure to rabies
Table 12 outlines the recommendations for the management of people after possible exposure to rabies. These recommendations are intended as a guide and may need to be modified in accordance with the specific circumstances of the exposure.
Immediate washing and flushing of the wound with soap and water is imperative and is probably the most effective procedure in the prevention of rabies. Suturing the wound should be avoided if possible. Tetanus prophylaxis and antibacterial drugs should be given as required.
If a rabies exposure is considered likely then post-exposure prophylaxis should never be delayed. If an observed animal such as a cat, dog or domestic ferret remains asymptomatic over a 10-day period or the animal is tested and there is no pathologic evidence of rabies, the course can be discontinued.
Table 12. Post-exposure Prophylaxis for Persons Not Previously Immunized Against Rabies
| Animal species | Condition of animal at time of exposure | Management of exposed person |
|---|---|---|
| Dog, cat or ferret | Healthy and available for 10 days' observation | |
| Rabid or suspected to be rabid*. Unknown or escaped |
|
|
| Skunk, bat, fox, coyote, raccoon and other carnivores. Includes bat found in room when a person was sleeping unattended. | Regard as rabid* unless geographic area is known to be rabies free |
|
| Livestock, rodents or lagomorphs (hares and rabbits) | Consider individually. Consult appropriate public health and CFIA officials. Bites of squirrels, chipmunks, rats, mice, hamsters, gerbils, other rodents, rabbits and hares may warrant post-exposure rabies prophylaxis if the behaviour of the biting animal was highly unusual. | |
RabIg = (human) rabies immune globulin, HDCV = human diploid cell vaccine, PCECV= purified chick embryo cell culture vaccine * If possible, the animal should be humanely killed and the brain tested for rabies as soon as possible; holding for observation is not recommended. Discontinue vaccine if fluorescent antibody test of animal brain is negative. ** See text for potential bat exposure. |
||
Schedule and dosage
Pre-exposure immunization
Three doses of HDCV or PCECV are required and should be given on days 0, 7 and 21. The vaccine is given as a 1.0 mL dose intramuscularly into the deltoid muscle or the thigh in infants. See discussion on intradermal administration below.
Post-exposure prophylaxis of previously unimmunized individuals
Five doses of 1.0 mL of HDCV or PCECV should be given, the first dose (on day 0) as soon as possible after exposure and additional doses on each of days 3, 7, 14 and 28 after the first dose. Vaccine should be administered intramuscularly into the deltoid muscle (never in the gluteal region) or the anterolateral upper thigh in infants. An appropriate dose of RabIg, as described below, should also be given on day 0.
The vaccine series may be discontinued after consultation with public health/infectious disease experts if the direct fluorescent antibody test of the brain of an animal killed at the time of attack is negative. However, if suspicion of rabies in the animal remains high, even in the presence of a negative test, the immunization series should be continued.
The recommended dose of human RabIg is 20 IU/kg body weight. This formula is applicable to all age groups, including children. Preferably, the full dose of RabIg should be thoroughly infiltrated into the wound and surrounding area. If not anatomically feasible, any remaining volume should be injected intramuscularly at a site distant from vaccine administration. When more than one wound exists, each should be locally infiltrated with a portion of the RabIg using a separate needle and syringe if possible. In such instances, the RabIg may be diluted 2- to 3-fold in a solution of 0.9% sodium chloride in order to provide the full amount of human RabIg required for good infiltration of sites at risk of rabies. If the site of the wound is unknown, the entire dose should be administered intramuscularly. Because of interference with active antibody production, the recommended dose should not be exceeded. Since vaccine-induced antibodies begin to appear within 1 week, there is no value in administering RabIg more than 8 days after initiating an approved vaccine course.
Vaccine and RabIg should be used concurrently for optimum post-exposure prophylaxis against rabies, except in certain previously immunized people, as indicated below. Under no circumstances should vaccine be administered in the same syringe or at the same site as RabIg.
Post-exposure prophylaxis of previously immunized individuals
Post-exposure prophylaxis for people who have previously received rabies vaccine differs according to which preparation of vaccine was received.- Two doses of
HDCV or PCECV, one injected immediately and the other 3 days
later, without RabIg, are recommended for exposed individuals
with the following rabies immunization
history:
- Completion of an approved course of pre-or post-exposure prophylaxis with HDCV or PCECV within the previous 2 years
- Completion of immunization with other types of rabies
vaccine or with HDCV or PCECV according to unapproved schedules
as long as neutralizing rabies anti body has been demonstrated in
serum (see serologic testing below)
- A complete course of HDCV or PCECV plus RabIg is recommended for those who may have received rabies vaccines in the past but do not fulfill the criteria listed in A above. A serum sample may be collected before vaccine is given, and if protective antibody (> 0.5 IU/mL) is demonstrated the course may be discontinued, provided at least two doses of vaccine have been given. If in doubt, consultation with an infectious diseases or public health physician is recommended.
Route of administration
RabIg is always given intramuscularly and preferably directly into the edges surrounding the wound.
Rabies vaccine for post-exposure prophylaxis must be administered intramuscularly. Both HDCV and PCECV are approved in Canada for intramuscular (IM) use.
For pre-exposure prophylaxis, the intradermal (ID) route may be considered in some circumstances: while IM administration of rabies vaccine is the gold standard, the World Health Organization (WHO) considers the ID regimen an acceptable alternative as it uses less vaccine to produce a comparable degree of protection against rabies. The ID route should not be used in all individuals. The immune response to ID vaccination in persons who are immunocompromised or taking steroids or chloroquine has been unreliable. In these individuals vaccine should be administered by the IM route only. It is also important to note that improper administration may cause the vaccine to be injected subcutaneously. In addition, a suboptimal dose of vaccine may be administered. The proper syringe and needle are imperative to ensure that the correct route and dose are used. ID vaccines should therefore only be given by well-trained staff and in situations in which there is a well-established cold chain and preferably when a large group of individuals is being vaccinated at the same time. Post-immunization antibody titres should be determined to ensure that an acceptable level of protection has been achieved at least 1 month after completion.
For pre-exposure vaccination three 0.1 mL doses of HDCV or PCECV can be given on days 0, 7 and 21 or 28 intradermally (on the upper arm, over the deltoid). The WHO recommends that the vaccine should contain at least 2.5 IU per IM dose.
If a decision is made to give pre-exposure prophylaxis by the ID route, then ample time must be available to allow for choloroquine use to be delayed for at least 1 month after vaccination.
Booster doses and re-immunization
Some individuals with ongoing high-risk exposure to rabies may require pre-exposure booster doses if their antibody titres fall below 0.5 IU/mL (see Serologic Testing). People with continuing high risk of exposure, such as certain veterinarians, should have their serum tested for rabies antibodies every 2 years; others working with live rabies virus in laboratories or vaccine-production facilities who are at risk of inapparent exposure should be tested every 6 months. Those with inadequate titres should be given a booster dose of either HDCV or PCECV. People previously immunized with other vaccines should also be tested for evidence of protective antibody, and those with inadequate titres should be given a booster dose of HDCV or PCECV.
Previously immunized individuals must still receive two additional immunizations at 0 and 3 days following a rabies exposure. An incompletely or inadequately immunized individual requires the complete series of active and passive immunization following rabies exposure.
Both RabAvert® and Imovax® Rabies have been shown to be effective in boosting immunity in previously immunized individuals in both the pre-exposure booster and post-exposure prophylaxis settings. A rapid anamnestic response is obtained regardless of whether the primary vaccine was PCECV or HDCV.
Serologic testing
Three doses of either HDCV or PCECV given intramuscularly over 21 to 28 days have produced protective antibodies in 100% of individuals in all age groups. Numerous studies comparing the pre-exposure immunogenic responses to PCECV and HDCV have shown both vaccines to be comparable in terms of antibody induction, and the height and persistence of antibody response. Therefore, healthy people immunized with an appropriate regimen do not require routine post-immunization antibody determinations unless vaccinated by the ID route.
Neutralizing antibodies develop 7 days after immunization and persist for at least 2 years. The Canadian national rabies reference laboratory is the Ontario Provincial Public Health Laboratory, which considers an acceptable antibody response to be a titre of > 0.5 IU/mL by the rapid fluorescent-focus inhibition test. Determination of post-immunization antibody titre may be advisable for those whose immune response may be reduced by illness, medication or advanced age.
Corticosteroids, immunosuppressive agents and immunosuppressive illnesses may interfere with the antibody response. Upon completion of a post-exposure course of vaccine in these populations, antibody titres should be determined to ensure that an acceptable level has been achieved. Antibody titre determination may also be advisable after pre-exposure immunization in these populations.
Protective antibodies are present immediately after passive vaccination with RabIg, but they have a half-life of only approximately 21 days.
Storage requirements
Both HDCV and PCECV must be stored protected from light at +2° to +8° C.
Simultaneous administration with other vaccines
No clinical trial data are available regarding the concurrent administration of rabies vaccines with other vaccines. Other essential inactivated vaccines may be given at the same time as rabies vaccines but at separate sites using a separate needle and syringe.
Adverse reactions
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.
HDCV: Local reactions such as pain, erythema, swelling and itching at the injection site may occur in 30% to 74% of recipients; mild systemic reactions such as headache, nausea, abdominal pain, muscle aches and dizziness may occur in about 5% to 40%. Systemic allergic reactions characterized by generalized urticaria and accompanied in some cases by arthralgia, angioedema, fever, nausea and vomiting have been reported. These reactions are uncommon in people receiving primary immunization but have occurred in up to 7% of those receiving a booster dose, with onset after 2 to 21 days. Such reactions have been shown to follow the development of IgE antibodies to beta propiolactone-altered human serum albumin in the vaccine. Immediate anaphylactic reactions have occurred in 1 in 10,000 people given HDCV. Neurologic complications are rare, but three cases of neurologic illness resembling Guillain-Barré syndrome, which resolved without sequelae within 12 weeks, were reported in the early 1980s.
PCECV: Local reactions commonly reported (i.e., > 10% of recipients) with RabAvert® consist of pain, tenderness and induration at the injection site, which lasts for 2-3 days. Other local reactions, including erythema, itching and swelling, have also been reported. Systemic reactions are generally less common (i.e., 1%-10% of recipients) and may consist of malaise, myalgia, arthralgia, headache and fever. Lymphadenopathy, nausea and rash have been reported occasionally. Temporally associated neurologic and anaphylactic events have been very rarely reported following the administration of RabAvert®.
RabIg: Local pain and low-grade fever may follow administration of RabIg.
Contraindications and precautions
Contraindications
There are no definite contraindications to the use of rabies vaccine after significant exposure to a proven rabid animal.
Precautions
Persons with egg allergies are not necessarily at increased risk of a hypersensitivity reaction to RabAvert®. However, for pre-exposure vaccination, an alternative vaccine (HDCV) should be given to persons with a history of severe hypersensitivity reactions to egg or egg products. If an alternative vaccine is not available, post-exposure prophylaxis should be administered with strict medical monitoring. Facilities for emergency treatment of anaphylactic reactions should be available. Persons with a history of hypersensitivity to the vaccine or any of its components should not be given the vaccine for pre-exposure immunization if possible. For more specific advice please consult an allergy specialist.
Serious allergic or neuroparalytic reactions occurring during the administration of rabies vaccine in the post-exposure situation pose a serious dilemma. The risk of rabies developing must be carefully considered before a decision is made to discontinue immunization. The use of corticosteroids as a possible treatment may inhibit the immune response. The patient's blood should be tested for rabies antibodies and expert opinion should be sought in the management of these individuals.
Pregnancy is not a contraindication to post-exposure prophylaxis, but it would be prudent to delay pre-exposure immunization of pregnant women unless there is a substantial risk of exposure.
Other considerations
Vaccine interchangeability: wherever possible, an immunization series should be completed with the same product. However, if this is not feasible, RabAvert® and Imovax® Rabies are considered interchangeable in terms of indications for use, immunogenicity, efficacy and safety.
Selected references
Centers for Disease Control and Prevention. Compendium of animal rabies prevention and control, 2005. Morbidity and Mortality Weekly Report 2005;54(RR-3):1-8.
Centers for Disease Control and Prevention. Human rabies prevention - United States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report 1999;48(RR-1):1-21.
National Association of State Public Health Veterinarians. Compendium of animal rabies control, 1998. Morbidity and Mortality Weekly Report 1998;47(RR-9):1-9.
Parker R, McKay D, Hawes C et al. Human rabies, British Columbia - January, 2003. Canada Communicable Disease Report 2003;29(16):137-38.
Plotkin SA. Rabies. Clinical Infectious Diseases 2000;30(1):4-12.
Turgeon N, Tucci M, Deshaies D et al. A case report: human rabies in Montreal, Quebec, October 2000. Canada Communicable Disease Report 2000;26(24):209-10.
Varughese P. Human rabies in Canada - 1924-2000. Canada Communicable Disease Report 2000:26(24):210-11.
World Health Organization. WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva: World Health Organization, 1997. WHO/EMC/Zoo.96.6.
World Health Organization. World survey of rabies -1997. Canada Communicable Disease Report 2000;26(2):13-6.
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