Current strategies for human rabies pre and post-exposure prophylaxis


Guide for post-exposure prophylaxis (PEP)

PEP which consists of local treatment of the wound, followed by vaccine therapy (with or without rabies immunoglobulin) should be initiated immediately following a transdermal bite or scratch by an animal suspected of being rabid or when possibly infectious material, usually saliva comes into direct contact with the victim’s mucosa or with fresh skin wounds (see full definitions of categories of exposure below). Prompt post-exposure use of CCVs combined with proper wound management and simultaneous administration of rabies immunoglobulin is almost invariably effective in preventing rabies, even following high-risk exposure However, delays in starting or failure to complete correct prophylaxis may result in death, particularly following bites in highly innervated regions, such as the head, neck or hands, or following multiple wounds. Rarely, true failures have been reported after patients received state-of- the-art treatment. Treatment should be started as early as possible after exposure, but in no case should it be denied to exposed persons whatever time interval has elapsed.

Treatment may be discontinued if the animal involved (dog or cat) remains healthy throughout an observation period of 10 days; or if the animal is killed humanely and found to be negative for rabies by laboratory examination. Any biting animal suspected of being rabid should be immediately killed humanely and tissues examined using appropriate laboratory technique(s). In areas where canine or wildlife rabies is epizootic, adequate laboratory and field experience, indicating that there is no infection in the species involved, may justify local health authorities in not recommending specific anti-rabies treatment. Obviously modification of the recommended procedures would be indicated in a rabies-free area where animal bites are encountered.

The indication for PEP with or without rabies immune globulin depends on the type of contact with the rabid animal.

Types of contact and categories of exposure are: category I – touching or feeding animals, licks on intact skin category II - nibbling of uncovered skin, minor scratches or abrasions without bleeding, category III – single or multiple transdermal bites or scratches, licks on broken skin, contamination of mucous membrane with saliva from licks; exposure to bat bites or scratches For category I no treatment is required, whereas for category II immediate vaccination and for category III immediate vaccination and administration of rabies immune globulin are recommended in addition to immediate washing and flushing of all bite wounds and scratches. All intramuscular injections must be given into the deltoid region or, in small children, into the anterolateral area of the thigh muscle. Vaccine should never be administered in the gluteal region. In order to reduce the cost of post-exposure treatment, intradermal multi-site regimens using a fraction of the intramuscular volume per intradermal inoculation site have been developed.

Tissue-culture or purified duck-embryo vaccines of potency at least 2.5 IU per single intramuscular immunizing dose should be applied according to the following schedules:

Intramuscular administration for PEP
- In the Essen regimen one dose of the vaccine should be administered on days 0, 3, 7, 14 and 30. - In the abbreviated multisite schedule, the 2-1-1 regimen, one dose is given in the right arm and one dose in the left arm at day 0, and one dose applied in the deltoid muscle on days 7 and 21. - An alternative for healthy, fully immunocompetent, exposed people who receive wound care plus high quality rabies immunoglobulin plus WHO-prequalified rabies vaccines, is a PEP regimen consisting of 4 doses administered intramuscularly on days 0, 3, 7 and 14.

Intradermal administration for PEP
The 2-site regimen prescribes injection of 0.1 mL at 2 sites (1 in each of the deltoid and thigh) on days 0, 3, 7 and 28. This regimen can be used for people with category II and category III exposures in countries where the intradermal route has been endorsed by national health authorities. Only vaccines that have been demonstrated to be safe and efficacious should be used by the intradermal route (currently PVRV (Verorab TM, Imovax TM, Rabies vero TM, TRC Verorab TM) and PCECV (Rabipur TM).

PEP in already immunized people
For rabies-exposed patients who have previously undergone complete pre-exposure vaccination or post-exposure treatment with cell-derived rabies vaccines, two intramuscular or intradermal doses of a cell-derived vaccine separated by three days are sufficient. As an alternative to this regimen, the patient may be offered a single-visit 4-site intradermal regimen consisting of 4 injections of 0.1 mL equally distributed over left and right deltoids and tights. Rabies immune globulin treatment is not necessary in such cases. The same rules apply to persons vaccinated against rabies who have demonstrated neutralizing antibody titres of at least 0.5 IU/ml.

Combined immunoglobulin-vaccine

Combined immunoglobulin-vaccine treatment is the best specific systemic treatment available for the post-exposure prophylaxis of rabies in humans, although experience indicated that vaccine alone was sufficient for minor exposures (category II). Rabies immunoglobulin for passive immunization is administered only once, preferably at, or as soon as possible after, the initiation of post-exposure vaccination. Beyond the seventh day after rabies immunoglobulin is not indicated because an active antibody response to the CCV is presumed to have occurred. The dose of human rabies immunoglobulin is 20 IU/kg body weight; for equine immunoglobulin and F(ab’)2 products it is 40 IU/kg body weight. All of the rabies immunoglobulin, or as much as anatomically possible to avoid possible compartment syndrome, should be administered into or around the wound site or sites. The remaining immunoglobulin, if any, should be injected intramuscularly at a site distant from the site of vaccine administration. Rabies immunoglobulin may be diluted to a volume sufficient for all wounds to be effectively and safely infiltrated. Most of the new equine immunoglobulin preparations are potent, highly purified, safe and considerably less expensive than human rabies immunoglobulin. However they are of heterologous origin and carry a small risk of anaphylactic reaction (1/45 000 cases). There are no scientific grounds for performing a skin test prior to administering equine immunoglobulin because testing does not predict reactions, and it should be given whatever the result of the test. The treating physician should be prepared to manage anaphylaxis which, although rare, could occur during any stage of administration.

Local treatment of wounds

Elimination of rabies virus at the site of the infection by chemical or physical means is an effective mechanism of protection. Local treatment of wounds involving possible exposure to rabies is recommended in all exposures. Recommended first-aid procedures include immediate and thorough flushing and washing of the wound for a minimum of 15 minutes with soap and water, detergent, povidone iodine or other substances of proven lethal effect on rabies virus. If soap or an antiviral agent is not available, the wound should be thoroughly and extensively washed with water. If suturing after wound cleansing cannot be avoided, the wound should first be infiltrated with passive rabies immunization products and suturing delayed for several hours. Other treatments, such as the administration of antibiotics and tetanus prophylaxis, should be applied as appropriate for other bite wounds.

The recommendations given here are intended as a general guide. It is recognized that, in certain situations, modifications of the procedures laid down may be warranted. Such situations include exposure of infants or mentally disabled persons and other circumstances where a reliable history cannot be obtained, particularly in areas where rabies is enzootic, even though the animal is considered to be healthy at the time of exposure. Such cases may be treated as category II or III.