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Volume 31 • ACS-5
1 June 2005
An Advisory Committee Statement
National Advisory Committee on Immunization (NACI)*?
For readers interested in the PDF version, the document is available for downloading or viewing: Update on Rabiesl Vaccines (PDF document 8 Pages - 233 KB)
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada?s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
Since the publication of the 6th edition of the Canadian Immunization Guide(1), a new rabies vaccine (RabAvert®, Chiron Corporation) has been approved for use in Canada. While the two approved vaccines (Imovax® and RabAvert®) both protect against rabies, they differ in their composition. The recommendations in this statement focus on the new vaccine, interchange- ability of the currently approved products, and intradermal vaccine administration. They are based on currently available scientific data and the experiences of other countries. For more detailed information related to the use of rabies vaccines, the epidemiology of rabies in Canada, and use of rabies vaccine in international travellers, readers are referred to the 6th edition of the Canadian Immunization Guide, 2002(1), the Committee to Advise on Tropical Medicine and Travel (CATMAT) statement on travellers and rabies vaccine(2), and the most recent rabies surveillance report(3).
RabAvert®, manufactured by Chiron Corporation, is a sterile, freeze-dried vaccine produced by growing the fixed-virus strain Flury low egg passage (LEP) in primary cultures of chicken fibroblasts. The virus is inactivated with beta-propiolactone and processed by zonal centrifugation. It is lyophilized after the addition of buffered polygeline (processed bovine gelatin) and potassium glutamate as a stabilizer solution. The reconstituted vaccine contains polygeline, human serum albumin (< 0.3 mg), potassium glutamate, and sodium EDTA, as well as traces of bovine serum (which originates from source countries known to be free of bovine spongiform encephalopathy), chicken protein, ovalbumin (< 3 ng), neomycin, chlortetracycline, and amphotericin B. The vaccine has no preservative. Sterile diluent for RabAvert® is supplied for reconstitution. The reconstituted vaccine is a clear to slightly opaque colourless solution. The potency of one dose (1.0 mL) is at least 2.5 IU of rabies antigen. RabAvert® is approved for intramuscular use in Canada. It should be stored, protected from light, at 2oC to 8o C.
The dosage schedule for RabAvert® is similar to that of
Imovax® Rabies. For pre-exposure immunization, three 1.0 mL
doses of RabAvert® should be given intramuscularly (deltoid
muscle or the anterolateral upper thigh in infants) on days 0, 7,
and 21. For post-exposure prophylaxis of previously unimmunized
individuals, five 1.0 mL doses of RabAvert® should be given on
days 0, 3, 7, 14, and 28 by the intramuscular route (deltoid muscle
or the anterolateral upper thigh in infants), in conjunction with
rabies immune globulin (RIG) administered once on the first day
(day 0). For post-exposure prophylaxis of previously immunized
individuals, two 1.0 mL doses of RabAvert® should be given
intramuscularly (deltoid muscle or the anterolateral upper thigh in
infants) on days 0 and 3, without RIG. Readers are referred to the
Canadian Immunization Guide, 2002(1), for further
Local reactions commonly reported (i.e.> 10% of recipients) after RabAvert® administration consist of pain, tenderness, and induration at the injection site, which last for 2 to 3 days(4-6). Other local reactions, including erythema, itching, and swelling, have also been reported(5,6). Systemic reactions are generally less common (i.e. 1% to 10% of recipients) and may consist of malaise, myalgia, arthralgia, headache, and fever(7). Lymphadenopathy, nausea, and rash have been reported occasionally(5,6,8). Temporally associated neurologic and anaphylactic events have been very rarely reported following the administration of RabAvert®.
As rabies is a fatal disease, any contraindication to vaccine should be carefully re-considered before withholding post-exposure immunization. Although not contraindicated in pregnant and nursing women, it may be prudent to delay pre-exposure immunization in such women unless there is a substantial risk of exposure. Persons with a history of hypersensitivity to the vaccine or any of its components should not be given the vaccine for pre-exposure immunization. Persons with egg allergies are not necessarily at increased risk of a hypersensitivity reaction to RabAvert®. However, for pre-exposure vaccination, the vaccine should not 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 reaction should be available.
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(9). Antibody titre determination may also be advisable after pre-exposure immunization in these populations(1). Neutralizing antibodies develop 7 days after immunization and persist for at least 2 years. The Canadian National Reference Service for Rabies Serology considers an acceptable antibody response to be a titre of>= 0.5 IU/mL by the rapid fluorescent-focus inhibition test. Those with inadequate titres should be given a booster dose of RabAvert®.
Vaccine interchangeability should be considered when a new vaccine is approved, in situations of vaccine shortages or if an individual is immunized outside of Canada with a product not approved for use in Canada. When vaccines are examined for potential interchangeability, factors including indications for use, safety, reactogenicity, immunogenicity, and efficacy should be taken into account. Different production methods, antigen concentrations, stabilizers and preservatives, which could affect the immunogenicity, safety, or efficacy profile of the product, should be considered. In addition, immunization regimens should be equally acceptable from the perspective of safety, efficacy, and scheduling.
Both human diploid cell vaccines (HDCV) and purified chick embryo cell vaccines (PCECV) are approved for use in many other parts of the world and are used interchangeably. Of the vaccines approved for use in Canada, Imovax® is an HDCV and RabAvert® is a PCECV.
For pre-exposure, three doses of either HDCV or PCECV given over 21 to 28 days have produced protective antibodies in 100% of individuals in all age groups(9,10). 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(5,7,8).
Throughout the world, both HDCV and PCECV have been used effectively with RIG or equine rabies immune globulin for post-exposure prophylaxis(9). PCECV, like other cell culture vaccines, has been consistently shown to induce virus-neutralizing antibodies(10). Bijok and coauthors concluded from the results of a multi-centre trial that for post-exposure prophylaxis the vaccine is comparable to HDCV in terms of antibody induction and efficacy(6). Sehgal and coauthors found the vaccine to be effective for post-exposure prophylaxis for all age groups, with no vaccine failures, in a 10-year study in the Indian population(4). Failures are mainly attributed to failure to follow the recommended post-exposure prophylaxis protocol. There have been at least two published cases, both with severe facial bite injuries, that can be considered true treatment failures(9).
Both RabAvert® and Imovax® have been shown to be effective in boosting immunity in previously immunized individuals (both pre-exposure booster and post-exposure prophylaxis)(9). A rapid anamnestic response is obtained regardless of whether the primary vaccine is PCECV or HDCV(6-8).
Both PCECV and HDCV are comparable in terms of side effects and are well tolerated and safe. Local reactions are the most commonly reported side effect and are similar with both vaccines(5). Systemic reactions are infrequent and are also similar with both products(5,7,8). Boosters of both vaccines have been documented to be safe(7,10).
In summary, Imovax® and RabAvert® should be considered interchangeable in terms of indications for use, immunogenicity, efficacy, and safety. Readers are referred to the Canadian Immunization Guide, 2002, for further details.
While intramuscular (IM) administration of rabies vaccine is the gold standard, the World Health Organization (WHO) considers the intradermal (ID) regimen an acceptable alternative as it uses less vaccine to produce a comparable degree of protection against rabies(9,11). In a number of countries throughout the world, ID administration has become standard practice. Although not recommended by the manufacturer in Canada, ID vaccination with rabies cell culture vaccines is an economical and widely accepted alternative to IM vaccination and uses one-tenth of the IM dose.
For pre-exposure vaccination three 0.1 mL doses of rabies cell culture vaccine 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(1).
In Canada, cell culture rabies vaccines are supplied as a 1.0 mL dose for IM use. For ID use, the WHO recommends storage at +4oC to +8o C for up to 6 to 8 hours after reconstitution, provided proper aseptic precautions have been taken(11). PCECV has been shown to be safe and immunogenic 7 days after reconstitution in a large Thai study using clinical sterility precautions and proper storage in a clinic refrigerator(12).
With both HDCV and PCECV, Nicholson and coauthors found the neutralizing antibody titres after the 0, 7, and 21 day regimen with ID vaccinations to be lower than those with IM vaccination but adequate in terms of protection(5). Dreesen and coauthors also found the antibody levels after day 50, 92, and 365 with intradermal HDCV and PCECV to be similar to each other but lower than those after IM vaccination; this finding was not felt to affect the level of protection(8). Two years after vaccination, the antibody titres in the ID groups were similar to each other but lower than those in the IM groups; however, the level of antibodies was found to be protective in all except one subject. A 2 years ID booster produced a high anamnestic response regardless of the primary vaccination (intradermal PCECV, intradermal HDCV, and intramuscular HDCV did not differ from each other; intramuscular PCECV produced the greatest response). In one randomized controlled trial involving 138 subjects, those given ID pre-exposure vaccination had lower protective antibody levels 5 days after a simulated post-exposure booster than those given the IM pre-exposure series. However, all subjects developed adequate protective titres by day 14(13). Briggs showed that after 2 to 2.5 years, 79% of IM vs. 51% of ID vaccinees had protective antibody levels(2). According to the Advisory Committee on Immunization Practices, 2 years after primary pre-exposure immunization, 93% to 98% of persons who receive the series IM and 83% to 95% of those who receive the series ID will have protective antibody levels(9).
In Canada, some provinces have been using the ID route of administration for rabies pre-exposure immunization. Since 1978, 488 healthy individuals in Manitoba have received primary pre-exposure prophylaxis with three doses of 0.1 mL of human diploid cell-culture strain vaccine at 1-week intervals. The median concentration of rabies neutralizing antibody in serum 6 to 12 months after the third dose was 2.7 IU/mL; 95% had levels> 0.5 IU/mL, which the Canadian National Reference Laboratory specifies as acceptable (Greg W. Hammond, MD, and Fred Y. Aoki, MD: personal communication, March 2005).
In Ontario, ID pre-exposure rabies vaccination has been given to 100 travelers and ex-patriots since 2000. All of the 45 subjects who returned for post-immunization serology had developed adequate protective antibody titres (Ken Gamble, MD: personal communication, March 2005).
In Alberta, 39 laboratory workers and veterinarians were given ID rabies vaccines from 1983 to 1993. Post-immunization serology showed that in all except six (15%) adequate protective antibody levels developed (Workplace Health and Safety Program, Alberta/NWT Region, Animal Safety Research Institute, Lethbridge, March 2005.)
ID cell culture rabies vaccines are well tolerated and safe. ID vaccination can be given to people of all ages(11). Local side effects are mild and consist of pain, erythema, irritation, or swelling at the injection site in 13% to 92% of individuals. The most frequent side effect is local irritation, in 7% to 64% of recipients(11). Generalized adverse effects, including headache, fever, and influenza- like illness, are reported by 3% to 14% of vaccinees. Occasionally, a transient maculopapular rash and urticaria may be seen(11). Nicholson and coauthors found that PCECV given ID was less painful than given IM, but a higher incidence of local erythema, swelling, and itching was noted(5).
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. In addition, use of choloroquine should be delayed for at least 1 month after vaccination if the ID route is used(2,11). 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 if the proper syringe and needle are not used. ID vaccines should therefore only be given by well-trained staff and when where there is a well-established cold chain, and preferably when a large group of individuals are being vaccinated at the same time. Post-immunization antibody titres should be determined to ensure that an acceptable level has been achieved. Those with inadequate titres should consult an occupational health, infectious disease or travel medicine specialist for further assessment.
NACI recommends the following:
RabAvert® is safe, effective, and well tolerated for pre-exposure immunization, including boosters, and post-exposure prophlyaxis against rabies.
The immunization series should, whenever possible, be completed with the same product. However, if this is not feasible, RabAvert® and Imovax® are considered interchangeable in terms of indications for use, immunogenicity, efficacy, and safety.
For post-exposure prophylaxis, rabies vaccine should be administered by the IM route.
While NACI considers the IM route of administration as the gold standard, consideration may be given to using the ID route of administration for pre-exposure immunization provided there is an opportunity to asses the neutralizing antibody level at least 1 month after administration, so that adequate protection can be ensured.
Health Canada. Rabies vaccine. In: Canadian immunization guide, 6th ed. Ottawa: Health Canada, 2002:191-99. Cat No. H49-8/2002-E.
Committee to Advise on Tropical Medicine and Travel. Statement on travellers and rabies vaccine. CCDR 2002;28(ACS-4):1-12.
Varughese P. Human rabies in Canada: 1924-2000. CCDR 2000;26(24):210-11.
Sehgal S, Bhattacharva D, Bhardwaj M et al. Ten year longitudinal study of efficacy and safety of purified chick embryo cell vaccine for pre- and post-exposure prophylaxis of rabies in Indian population. J Commun Dis 1995;27(1):36-43.
Nicholson KG, Farrow PR, Bijok U et al. Pre-exposure studies with purified chick embryo cell culture rabies vaccine and human diploid cell vaccine: Serological and clinical responses in man. Vaccine 1987;5:208-10.
Bijok U, Vodopija I, Smerdel S et al. Purified chick embryo cell (PCEC) rabies vaccine for human use: clinical trials. Behring Inst Mitt 1984;76:155-64.
Briggs DB, Dreesen DW, Nicolay U et al. Purified chick embryo cell culture rabies vaccine: interchangeability with human diploid cell culture rabies vaccine and comparison of one versus two-dose post-exposure booster regimen for previously immunized persons. Vaccine 2001;19:1055-60.
Dreesen DW, Fishbein DB, Kemp DT et al. Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for pre-exposure immunization. Vaccine 1989;7:397-400.
Human rabies prevention ? United States, 1999. Recommendations of the Advisory Committee on Immunization Practices. MMWR 1999;48(RR-1):1-7.
Plotkin SA, Orenstein WA (eds). Vaccines. 4th ed. Philadelphia, PA: WB Saunders, 2004:1011-38.
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.
Khawplod P, Wilde H, Tantawichien T et al. Potency, sterility and immunogenicity of rabies tissue culture vaccine after reconstitution and refrigerated storage for 1 week. Vaccine 2002;20(17-18):2240-42.
Jaijaroensup W, Limusanno S, Khawplod D et al. Immunogenicity of rabies post-exposure booster injections in subjects who had previously received intradermal pre-exposure vaccination. J Travel Med 1999;6:234-37.
*Members: Dr. M. Naus (Chairperson), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. M.N. Primeau, Dr. B. Tan, Dr. B. Warshawsky, Ms. A. Zierler.
Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. L. Chapman (CDC), Dr. A. Gruslin (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. M. Salvadori (AMMI Canada), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE).
Ex-Officio Representatives: Dr. S. Deeks (CIDPC), Dr. H. Rode (BREC), Dr. M. Lem (FNIHB), Dr. M. Tepper (DND).
Acknowledgement: NACI greatfully acknowledges the assistance of Drs. Humaira Khan, Lindy Samson and Shelley Deeks in preparation if this statement.
?This statement was approved by NACI and the Public Health Agency of Canada.