An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT) *†

STATEMENT ON TRAVELLERS AND RABIES VACCINE

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Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to tropical infectious disease and health risks associated with international travel. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

Rabies is a vaccine-preventable neurotropic viral disease. In humans there are two clinical presentations, furious (agitated) and paralytic (dumb) rabies. The former is more common and associated with the classical presentation that includes hydrophobia and/or aerophobia. Most patients die within a few days of the onset of symptoms. Paralytic rabies is less distinctive with a more protracted clinical course, associated with local paresthesia and progressive flaccid paralysis. Regardless of the clinical presentation, once manifest, rabies is almost invariably fatal⁽¹⁾.

Canada and the United States (U.S.) have both witnessed a substantial decrease in the incidence of human rabies, corresponding to the dramatic decrease in rabies among domestic animals⁽²⁾. Concurrently, rabies among wildlife - especially raccoons, skunks and bats - has become more prevalent. Since 1980 more than half of the human cases of rabies in the U.S. have been associated with bat variants.

World Health Organization (WHO) reports indicate that more deaths occur worldwide from rabies than from other common infections including: dengue fever, polio, meningococcal meningitis or Japanese encephalitis. Of the 50,000 human rabies deaths reported annually, it is estimated > 30,000 deaths occur in the Indian sub-continent with the majority of the remainder occurring in Southeast Asia, (particularly the Philippines), Oceania, Africa, and Latin America^(1-3).

The vast majority of cases with a defined source are due to dog bites^(1,4). India boasts a dog population of about 50 million^(4,5). In Bangalore, postmortem examination of suspected rabid animals confirmed the presence of the rabies virus in 50% of stray dogs and 11% of stray cats⁽³⁾, however there was only one reported case of rabies associated with a bat variant in 1974. Sporadic case-reports cite bites from tigers, camels and the Indian civet as the source of infection⁽⁵⁾. Among foreign travellers in Nepal, dog bites accounted for 76% of reported exposure, 20% were due to monkey bites and a mere 2% from cats and squirrels⁽⁶⁾.

Thailand has approximately 10 million dogs for its human population of 58 million. In Bangkok it is estimated that one in 10 stray dogs is infected, and one in three dogs suspected of being rabid are confirmed to have the virus⁽⁷⁾. A study of 20,000 Thai school children <= 15 years of age revealed that 25% had experienced a dog or cat bite and that 7% had received postexposure rabies treatment⁽⁸⁾.

The risk of acquiring rabies subsequent to exposure to a rabid animal is approximately 15%, ranging from as low as 0.1% in persons experiencing nonbite exposures to as high as 60% in persons with deep wounds or severe injuries⁽⁹⁾. Injury to the upper body, or face, and injuries in close proximity to, or within, peripheral nerves pose the greatest risk. The usual incubation period ranges from 20 to 60 days, although onset can occur as soon as 1 week to as long as several years^(10,11).

Risk to international travellers

It is difficult to assess the risk of exposure to rabies among travellers, given the varied incidence of rabies and dog-bites. A questionnaire survey of 1,882 foreign tourists staying in Thailand for an average of 17 days revealed that 13 per 1,000 tourists experienced dog bites⁽¹²⁾. Steffen reported an incidence of 1.7 animal bites per 1,000/month in a general survey of travellers⁽¹³⁾. Shlim reported that 0.15 per 1,000 travellers to Nepal presented for post-exposure rabies immunoprophylaxis⁽⁶⁾. The Peace Corps Volunteers initiated postexposure treatment in 1.4 per 1,000 volunteers per month and 3.6 per 1,000/month in 1978 and 1988 respectively^(14,15).

The risk of children being bitten is conservatively estimated to be 4 times greater than that of adults in both developed and developing countries, accounting for 35 % to 40% of those who receive post-exposure vaccination in India⁽²⁾. Boys may be at greater risk than girls⁽¹⁶⁾. Furthermore, the bites in children are usually higher on the trunk or face and are more severe.

Although rabies infection is rare in international travellers, a significant proportion of rabies deaths are reported in the developed world among travellers who contracted the disease in developing countries. Over a period of 17 years 33% of rabies cases reported in the U.S. acquired their infection in other countries⁽¹⁷⁾, while the United Kingdom reported 12 cases over 20 years, 10 of which came from the Indian sub-continent⁽¹⁶⁾. Likewise, 18 of the 19 cases of rabies reported in France over a 20-year period were acquired abroad, the vast majority in Africa. There has been one Canadian case acquired abroad in the 7 decades since statistics have been kept⁽¹⁸⁾.

Rabies biologics

Rabies Immune Globulin

Human Rabies Immune Globulin (HRIG) is the only biologic available in Canada for passive immunization. The recommended dose of 20 IU/kg has been carefully calculated so as not to interfere with the development of active immunity from simultaneous vaccination with a tissue culture vaccine. It is utilized exclusively for post-exposure immunization, providing for prompt levels of neutralizing antibodies in the wound during the initial phase of management. Rabies Immune Globulin (RIG) has a relatively short half-life of approximately 21 days.

Two other forms of Rabies Immunoglobulin, non-pepsin-digested (non-purified) Equine Rabies Immune Globulin (ERIG) and ammonium-sulfate-precipitated (purified) ERIG may be available in international settings. The latter is the safer of the two preparations with only 0.0025% experiencing a nonfatal anaphylactic reaction⁽¹⁹⁾ compared with 3.8% of persons receiving non-purified ERIG⁽²⁰⁾. The calculated dose of ERIG is 40 IU/kg.

Rabies vaccines

Human Diploid Cell Vaccine (HDCV) (Imovax® Rabies, Aventis Pasteur SA) is the only rabies vaccine available in Canada. Neutralizing antibodies, which develop 7 to 10 days after the initial dose, persist for at least 2 years. Other varieties of tissue culture and avian culture vaccines are available in other countries and are considered to be interchangeable (Appendix 2).

Prevention

Primary prevention, domestic animals

Although there has been a concerted effort by WHO to reduce the risk of animal rabies through mass immunization programs, the widely recommended single injection of rabies vaccine administered to canines as pre-exposure prophylaxis does not always result in long lasting (> 3 months) antibody titres. In Thailand 3% to 6% of dogs found rabid by fluorescent antibody testing had reliable histories of rabies vaccination within 2 years of death⁽²¹⁾. Pets and guard dogs are frequently challenged by contact with infected strays. Of persons treated for dog bites in a hospital setting in Bangkok, 8.5% occurred inside homes from "owned" dogs⁽²²⁾.

Pet owners scratched or bitten while separating their pets from another animal may underestimate their risk of contracting rabies, considering their exposure to be secondary to a "provoked" attack. One study in a high-risk community noted that a "provoked" dog bite is only 38% less likely to come from a rabid animal than one that has not been considered as provoked⁽²³⁾. Therefore, the behavior of the biting dog and whether the attack was provoked or unprovoked should not be emphasized in areas where rabies is en demic^(17,23). Likewise, the practice of quarantine and observation is rarely of practical benefit in that setting⁽¹⁷⁾.

There is no standard post-exposure immunization protocol established for dogs and the WHO officially discourages the practice. Canadian expatriates should use caution when keeping pets by preventing them from having contact with other animals. All pets, especially guard dogs, should be vaccinated according to North American standards. Given the unpredictable nature of exposure, travellers should be warned to consider all stray animals to be infected with rabies.

Pre-exposure immunization

Cell culture vaccine is administered intramuscularly (IM) in three doses on days 0, 7 and 21 or 28⁽²⁴⁾. Because of the high cost of the vaccine, intradermal (ID) vaccination, using one-tenth the dose, has been used in the U.S. and throughout the developing world. A licensed ID vaccine is not available in Canada.

Pre-exposure immunization: vaccine efficacy

Virtually 100% of healthy individuals will mount an adequate immune response with appropriate administration of IM or ID cell culture rabies vaccines. Concern has been raised with respect to the adequacy of long-term protection. Studies among veterinary students established that viral neutralizing antibodies (VNA) are present 2 to 3 years after vaccination. When studying the effect of a booster dose 1 year following two and three dose pre-exposure regimens, Strady et al. noted that 100% of both groups had VNA > 0.5 IU/mL on day 42. However, by day 365 only 38.5% of persons with the two-dose regimen had adequate levels of neutralizing antibodies compared with 100% of those with the three-dose regimen. Following the booster dose, all had a booster effect and 97% of those in the three-dose group continued to demonstrate protective levels of neutralizing antibodies at 10 years⁽²⁵⁾.

Briggs observed that only 79% of Peace Corps Volunteers who received IM rabies vaccine and 51% of those who received ID vaccine had protective levels of VNA between 2 and 2.5 years following their initial dose⁽²⁴⁾. Wilde et al., studied subjects who had post-exposure treatment with a tissue culture vaccine > 5 years earlier and noted that only 75% of the subjects had adequate VNA levels (> 0.5 IU/mL). However, 7 days after a booster dose 100% were adequately protected, thus demonstrating that although a significant proportion had inadequate immunity by measurable standards, all experienced a brisk anamnestic response⁽²⁵⁾.

In contrast, 20% of nerve tissue-derived vaccine recipients re-exposed to rabies failed to demonstrate an anamnestic response. Thus, unless VNA titres > 0.5 IU/mL have been documented, recipients of nerve tissue derived vaccine must be considered immunologically naive⁽²⁶⁾.

With ID administration, there is a risk of failure due to the administration of vaccine into adipose tissue and, in the absence of an approved pre-loaded preparation for ID administration in Canada, there is the added risk of administering a sub-optimal dose⁽²⁷⁾. Furthermore, in one randomized control study, subjects given pre-exposure rabies vaccine ID had lower neutralizing antibody titres 5 days following a simulated post-exposure ID booster⁽²⁸⁾. An unreliable immune response has also been documented in immune compromised individuals and in persons concurrently taking chloroquine when they received ID rabies vaccine^(29,30).

Published data on the immune response to ID rabies vaccine in persons taking mefloquine is limited. Four case reports were published where documented immunity was established. Although preliminary data support the hypothesis that concurrent use of mefloquine does not compromise the effectiveness of a primary course of ID HDCV, data from large-scale randomized clinical trials are not available⁽³¹⁾.

Pre-exposure immunization: vaccine safety

Risk of vaccination is estimated to be minor; pain, erythema, swelling and itching at the injections site have been reported among 30% to 74% of recipients; mild systemic reactions such as headache, nausea, abdominal pain and dizziness may occur in about 20%⁽³²⁾. Immune complex-like allergic reactions have been reported in up to 6% of persons receiving booster doses of HDCV. There were few hospitalizations and no deaths⁽³³⁾.

Pre-exposure immunization: strategy

Pre-exposure immunization does not eliminate the need for careful wound management and post-exposure immunization; it obviates the need for RIG and simplifies the vaccine schedule by reducing the number of doses. This is particularly important for travellers to rabies enzootic countries where there is limited access to potent tissue culture vaccines and RIG.

Pre-exposure boosters and serologic testing

The goal to maintain the level of rabies antibodies >= 0.5 IU/mL was initially developed primarily to ensure adequate protection for those who may be continuously at risk (e.g., rabies research laboratory workers) or frequently at risk (e.g., veterinarians, speleologists/spelunkers).

However, since travellers are at infrequent risk of inadvertent exposure - and if previously immunized with a cell culture vaccine, they uniformly develop an anamnestic response to post-exposure immunization regardless of their antibody status - it is not necessary to routinely boost such individuals, or to determine their serologic status at regular intervals.

In settings where one of the potent tissue culture vaccines is not readily available, travellers should be managed as those who are frequently at risk.

Travellers working in animal control or as wildlife workers in rabies enzootic regions should follow the standard guidelines which include serologic testing every 2 years and the administration of a booster dose when VNA fall below 0.5 IU/mL.

Pre-exposure vs. post-exposure vaccination

All travellers who would otherwise qualify for pre-exposure immunization programs should be vaccinated, including veterinarians, animal handlers and persons involved in high-risk adventures such as cave exploration (i.e., speleologist)⁽³⁴⁾.

For other travellers, attempts have been made to develop a policy based on cost/benefit outcomes because pre-exposure prophylaxis is very expensive and post-exposure treatment has proven to be extremely effective. Routine pre-exposure prophylaxis for all Canadian travellers to enzootic areas would prevent 0.6 cases per million travellers with an estimated cost of $5 billion and
$3.3 million per adult and child's life saved respectively⁽¹⁶⁾.

Rabies deaths invariably relate to a failure to comply with the WHO guidelines for post-exposure therapy or occur when there was a significant delay in treatment⁽¹¹⁾. Both of these issues are relevant in countries where the risk of contracting rabies is the greatest and RIG is in short supply⁽³⁵⁾. In addition, in many countries with limited financial resources, the potentially dangerous and poorly efficacious brain tissue-derived Semple vaccine is still the most widely available vaccine.

For post-exposure vaccination to work and be cost-effective, it is essential that medical expertise be available on an urgent basis and that there be access to potent tissue culture or avian culture vaccines and either HRIG or purified ERIG.

Post-exposure management

Post-exposure management of potential rabies contact is an urgent medical problem. Local treatment of wounds is crucial and recommended in all cases.

First-aid treatment

Elimination of rabies virus at the site of infection by immediate vigorous washing and flushing with soap and water is the most effective mechanism of protection. Following thorough wound irrigation apply 70% ethanol, tincture or aqueous solution of iodine or povidone iodine. Delayed wound closure is recommended⁽³⁵⁾.

Post-exposure immunization: vaccinated

For post-exposure vaccination, two doses of a tissue culture vaccine are administered IM on days 0 and 3. This regimen is recommended for individuals who have a history of appropriate pre-exposure immunization, post-exposure treatment with a tissue or avian culture vaccine and persons with evidence of seroprotec tive antibody levels in the past⁽³⁶⁾. RIG is not routinely administered.

Post-exposure immunization: unvaccinated

Post-exposure prophylaxis should begin as soon as possible after exposure and should be offered to exposed persons regardless of the elapsed interval (e.g., even several months after exposure). Persons without pre-exposure immunization require RIG in conjunction with a tissue culture vaccine on day 0, followed by additional doses of vaccine on each of days 3, 7, 14 and 28.

Persons who have received post-exposure treatment with nerve tissue derived vaccine should be managed as though they were immunologically naive unless there is a history of documented immunity⁽²⁷⁾.

Rabies immunoglobulin

Persons who have not had pre-exposure immunization should have RIG as a single dose on day 0. The dose has been carefully calculated (20 IU/kg HRIG or 40 IU/kg ERIG) so as to provide local protection without interfering with the immune response to the vaccine⁽³⁶⁾. RIG and the vaccine must not be administered with the same syringe.

The entire calculated dose of HRIG or ERIG should be administered by careful instillation into the depth of the wound and by infiltration around the wound^(37,38). In cases where the calculated dose is insufficient to infiltrate all wounds, the vaccine is to be diluted two- or three-fold with normal saline⁽³⁶⁾. Care must be taken when injecting into tissue compartments. If the full dose
of RIG cannot be safely administered into the site of injury, the remainder should be injected into a muscle distant from the site of vaccine inoculation⁽³⁸⁾.

If RIG is not available for immediate administration, it may be given up to and including day 7 following the administration of the first dose of a tissue culture vaccine⁽³⁶⁾.

If there has been a delay of > 7 days and the vaccine used was not given in accordance to current WHO recommendations, or if the vaccine was a nerve tissue vaccine (Semple vaccine), RIG should be administered in conjunction with the initiation of another full course of rabies vaccine.

Rabies immunization in the immune-compromised host

Corticosteroids, other immunosuppressive agents and immuno suppressive illnesses will interfere with the development of an acceptable immune response to the rabies vaccine. If possible, serological response to the vaccine should be measured following administration of the vaccine⁽³⁴⁾. Otherwise, pre-exposure immunization should be postponed until course of immune suppressive therapy is completed, and those who cannot mount an immune response should be encouraged to avoid exposures that will put them at risk. In this population the ID route should not be used⁽³⁰⁾.

Post-exposure treatment in pregnancy

A study of the outcomes of post-exposure treatment administered to 202 pregnant women in Thailand concluded that tissue culture derived rabies vaccines as well as immune globulin are safe to use for post-exposure prophylaxis during pregnancy. Such treatment should never be withheld or delayed if the patient possibly was exposed to rabies⁽⁴⁰⁾.

Recommendations

Rabies pre-exposure prophylaxis is not routinely recommended to the general population of travellers to prevent rabies. Vaccination is usually recommended to specific risk groups. However, travel medicine advisors must recognize that post-exposure guidelines in Canada were based on an assumption that there is ready access to potent cell culture vaccines and HRIG. The limited availability of HRIG and purified ERIG invalidates this assumption in many rabies enzootic areas⁽³⁴⁾. The itinerary, purpose, lifestyles, activities and duration of the trip should be carefully evaluated in the context of the risk of contracting rabies and the availability of rabies biologics. Table 1 presents evidence-based medicine categories for the strength and quality of evidence for the recommendations that follow.

• Recommended pre-exposure regimen: The recommended pre exposure immunization series includes three doses of HDCV or equivalent administered IM on days 0,7 and 21 or 28. (AI)
• ID preparations are not licensed in Canada but could be utilized in accordance with the normal schedule provided the traveller has ample time to assess the antibody titres at least 1 month after administration to ensure that they have achieved an adequate immune response. (CIII)
  

The following travellers from Canada should receive pre-exposure vaccine:

• Persons with frequent risk of rabies exposure, (e.g., veterinarians, farm workers, and spelunkers) when travelling to rabies enzootic areas⁽³⁴⁾. (CIII)
• Children in rabies enzootic areas who are too young to understand their need to avoid animals or to report an animal bite⁽³⁴⁾. (CIII)
• Persons in rabies enzootic areas where there is limited access to tissue or avian culture vaccines and or HRIG and purified ERIG^{(11,12,14-16)}. (BIII)
  
• Persons in rabies enzootic areas where ready transportation to an appropriate health care facility cannot be assured^{(11,12,14-16)}. (BIII)

Serologic testing

• Serologic testing is recommended every 2 years for those in the frequent-risk category (e.g., veterinarians, animal control workers and spelunkers)⁽²⁵⁾. (BII)
• Serologic testing is not routinely recommended for inter national travellers who are likely to be infrequently exposed^(24-26). (BIII)

Special risk groups

• Pregnant women can be vaccinated without concern for the fetus⁽⁴⁰⁾. (BII)
• Immune-compromised individuals should receive vaccine by the IM route, and have serological testing following the administration of the vaccine^{(30, 34)}. (CII)
• Persons prescribed chloroquine should receive vaccine by the IM route or be vaccinated by the ID route at least 1 month prior to their taking chloroquine⁽²⁹⁾. (BIII)
• There are insufficient data regarding concurrent use of mefloquine with rabies immunization⁽³¹⁾. (CIII)

Post-exposure guidelines

• All wounds must be thoroughly cleansed with soap and rinsed with 70% alcohol or poviodine⁽³⁶⁾. (AII)
• Primary wound closure should be avoided, but if it is necessary immunoglobulin must first be applied⁽³⁶⁾. (BIII)
  
• Pre-exposure vaccination does not obviate the need for wound care⁽³⁶⁾. (BIII)
• Persons with a history of post-exposure treatment with a tissue or avian culture vaccine and persons with documented evidence of seroprotective antibody levels in the past can be managed as persons with pre-exposure immunization⁽²⁵⁾. (AII)
• Persons with a history of post-exposure treatment with a brain tissue derived vaccine (Semple vaccine) should be considered immunologically naive⁽²⁶⁾. (AII)
• The entire calculated dose of HRIG or ERIG should be ad ministered by careful instillation into the depth of the wound and by infiltration around the wound^(36,37). (AII)
• Care must be taken when injecting into tissue compartments. If the full dose of RIG cannot be safely administered into the site of injury, the remainder should be injected into a muscle distant from the site of vaccine inoculation^(34,38,39). (CIII)
  
• In the event of multiple wounds or in a child where the volume of RIG is limited, the RIG can be diluted two- or three-fold with normal saline to facilitate wound management⁽³⁶⁾. (AIII)
• RIG should be administered as soon as possible and preferably concurrent with the first dose of rabies vaccine^(38,39). (AII)
• RIG or ERIG should not be administered beyond the 7^th day of the active immunization program with a cell culture vaccine⁽³⁹⁾. (AI)
• RIG should be administered along with a complete series of vaccine in the event that the type or quality of vaccine previously utilized does not meet WHO standards (e.g., Semple vaccine was administered)^(38,39). (BIII)
• RIG and active immunization should be initiated regardless of the delay after possible rabies exposure^(38,39). (BIII)

General public health guidelines, primary prevention

• All pets, especially guard dogs, should be vaccinated according to North American standards.
• Pets exposed to rabies where animal quarantine standards cannot be followed should be destroyed.
  
• Travellers should be informed to avoid any stray animals.
• Travellers should be apprised about the risk of contracting rabies and be provided with guidelines regarding appropriate post-exposure management including the names and types of vaccines available.

Appendix 1

The most effective mechanism of protection against rabies is to wash and flush a wound or point of contact with soap and water, detergent or plain water, followed by the application of ethanol, tincture or aqueous solution of iodine. Anti-rabies vaccine should be given for Category II and III exposures (Table 1) as soon as possible according to WHO recognized regimens. Anti-rabies immunoglobulin should be applied for Category III exposures only. Suturing should be postponed, but if it is necessary immunoglobulin must first be applied. Where indicated, anti-tetanus treatment, antimicrobials and drugs should be administered to control infections other than rabies (see categories II and III if suspect animal confirmed as rabies negative).

Appendix 2

The following vaccines meet WHO's safety, potency and efficacy requirements:

• Human diploid cell vaccine (HDCV)
• Rabivac™ - purified vero cell vaccine (PVRV)
• Verorab, Imovax, Rabies vero, TRC Verorab™ - purified chicken embryo cell vaccine (PCECV)
• Rabipur™- purified chicken embryo vaccine ( PCECV)
• Lyssavac N™- purified duck embryo vaccine (PDEV)

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* Members: Dr. B. Ward (Chairman); Dr. K. Kain (Past Chairman); H. Birk;
M. Bodie-Collins (Executive Secretary); Dr. S.E. Boraston; Dr. H.O. Davies;
Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone; Dr. P.J. Plourde; Dr. J.R. Salzman; Dr. D. Tessier.

Liaison Representatives: Dr. R. Birnbaum (CSIH); L. Cobb (CUSO); Dr. V. Marchessault (CPS and NACI); Dr. H. Onyette (CIDS); Dr. R. Saginur (CPHA); Dr. F. Stratton (ACE).

Ex-Officio Representatives: Dr. E. Callary (HC); Dr. M. Cetron (CDC); R. Dewart (CDC); Dr. E. Gadd (HC); Dr. H. Lobel (CDC); Dr. A.E. McCarthy (DND); Dr. M. Parise (CDC).

Member Emeritus: Dr. C.W.L. Jeanes.

† This statement was prepared by Dr. Kenneth Gamble and approved by CATMAT.

[Canada Communicable Disease Report]