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Rabies

Rabies is a viral infection transmitted in the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost always fatal. Definitive diagnosis of rabies infection in humans or suspected animal vectors depends on the detection in infected brain tissue of specific rabies antigen, inclusions (Negri bodies), or of rabies nucleic acid by the PCR reaction, on the presence of antibodies in th CSF, and on the isolation and identification of the virus from the brain or the saliva (1). The infection is widely distributed throughout the world and present in all continents. The number and size of rabies-free countries, territories or areas are small compared to those of rabies affected areas. Only 46 out of 153 countries and territories reported no cases of rabies in 1996. World-wide, a large number of mammalian animal species are involved in rabies maintenance and transmission. In a given area, one animal species is usually both host and transmitter of the disease. The rabies host species consists mainly of wild terrestrial animals (e.g. red, arctic and grey foxes, racoons skunks, coyotes, mongooses). Also many bat species are involved either as hosts, transmitters or victims of rabies (e.g. in the USA, certain South American countries, some European countries, and more recently Australia). Dogs, however, remain the principal host and transmitter of rabies to humans. It is estimated that more than 2.4 billion people, about half the world's population, are living in countries/territories where dog rabies still exists and are potentially exposed to rabies.

Epidemiology

Most of the 33,209 human deaths reported to WHO for the year 1996 occurred in Asian countries: India officially reports 30,000 deaths and Bangladesh, 2,000. On that basis and considering the level of under-reporting (e.g. in Pakistan estimates range from 2,000 to 10,000 deaths annually), it is estimated that 40,000 rabies deaths are occurring in Asia alone. Therefore between 35,000 and 50,000 persons may die of rabies each year and most of these deaths are taking place in developing countries (2). In addition to mortality due to rabies, some 50 million doses of vaccines are used in 10 million human post-exposure treatments world-wide. About 8 million people receive rabies vaccine in developing countries annually and again most of these treatments are administered in Asia (e.g. 1 million in India, 5 million in China) and Latin America (2, 3).

In countries such as China and Thailand, an improved post-exposure treatment and a vaccine delivery system, associated with a major shift in the type of vaccine produced from brain tissue towards cell culture based products, has played a major role in drastically reducing the number of human deaths due to rabies.

Prompt and thorough cleansing of the wound, together with administration of purified equine or human rabies immunoglobulin (ERIG or HRIG) and modern vaccines immediately after exposure virtually guarantee complete protection, and the risk of post-exposure treatment complications is much lower than with brain tissue vaccines.

Vaccines

There are two main types of vaccine:

i) brain-tissue vaccines. First used by Pasteur in 1885, they are prepared from the nerve tissue of adult or neonate animals, inactivated by phenol, ultraviolet radiation or, more recently, betapropiolactone (BPL) and at best purified by centrifugation. Repeated inoculation of homogenates of brain tissue may induce immune responses to some neural antigens. In the case of sheep-brain-tissue vaccine (Semple vaccine), these neurological complications are attributed to myelin basic protein and some of the ganglioside and phospholipid constituents. Though properly prepared suckling-mouse brain vaccines contain virtually no myelin, neurological complications still occur, but at much lower rates than with adult nerve-tissue vaccines.

ii) modern vaccines. These second-generation vaccines consisting of highly purified vaccines prepared on primary and continuous cell lines, and in embryonating eggs (4).

Only the following vaccines meet WHO's safety, potency and efficacy requirements when used for post-exposure intradermal treatment of rabies: - 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 duck embryo vaccine (PDEV): Lyssavac N ™

The quantity of vaccine produced on nerve tissue and administered to patients is still much higher than that of modern vaccine produced on cells or embryonating eggs. There is however a tendency to replace the former with cell-culture vaccines, partly from public demand, partly from a public health point of view and partly from commercial interests.

For all modern vaccines that meet WHO requirements, the Essen regimen consists of five injections of one dose intramuscularly on days 0, 3, 7, 14 and 28. In addition, three reduced-treatment regimens have been developed to reduce the cost of rabies post-exposure treatment:

· the "2.1.1." regimen, consists of two intramuscular doses on day 1, and a single-dose booster on days 7 and 21. This regimen is particularly recommended when no immunoglobulin is required i.e. when contact consists in nibbling of uncovered skin, minor scratches or abrasions without bleeding, licks on broken skin. 

· the "2.2.2.0.1.1." regimen for use with purified vero cell vaccine (PVRV), purified primary chick embryo cell vaccine (PCEC) and purified duck embryo vaccine (PDEV). It consists of intradermal injections of one fifth of the intramuscular dose (0.1 to 0,2 ml according to vaccine type) at two locations on days 0, 3 and 7, and at one location on days 30 and 90. 

· the "8.0.4.0.1.1." regimen for use with human diploid cell vaccine (HDCV) and purified primary chick embryo cell vaccine (PCEC). ) It consists of an injection of 0.1 ml intradermally at 8 different intradermal sites on day 0, four sites on day 7, and one site on days 28 and 90. This regimen is particularly recommended for severe exposure (single or multiple transdermal bites or scratches, contamination of mucous membranes with saliva) when no immunoglobulin is available (5).

When vaccine is administered intradermally, proper staff training is needed in correct storage, reconstitution and administration of the vaccine. A 1ml syringe and short hypodermic needle are used. If proper sterile technique is used in drawing the vaccine up from the vial, the remainingdoses may be kept in the vial in a refrigerator at 4-8°C for another patient within 6 to 8 hours after reconstitution if there is no preservative (6).

Public health strategies

The three principal control strategies for the prevention of rabies in humans are the increased supply and administration of appropriate vaccine for pre and post-exposure use; and the elimination of rabies in its animal host(s). Due to increasing awareness and a subsequent increasing trend in demand for safer and efficacious products from exposed people, there is a tendency to favor the first strategy over the second. This is in spite of relatively high costs of human biological products, and despite the indication in developing countries where most human cases result from contact with rabid dogs, that rabies elimination by vaccination of the dogs might be the most cost-beneficial strategy in the long term.

WHO policy

Each of the following strategy has its place in the prevention and control of rabies in humans and animals: · Vaccination of humans before exposure. Pre-exposure prophylaxis is currently mainly recommended for those individuals at increased risk of infection by nature of their occupation. · Post exposure treatment: the combination of local treatment of wounds, passive immunization with rabies immunoglobulins (RIG) and vaccination is recommended for all severe exposures to rabies. New recommendations on the use of immunoglobulin were issued by WHO in 1996 and supplement/supersede the relevant recommendations of the 8th report of the Expert Committee on Rabies published in 1992 (5).

Factors that should be taken into consideration when deciding whether or not to initiate post-exposure treatment are:

· the nature of the contact, 

· the presence of rabies in the area where the contact occurred or from which the animal came from, 

· the species of the animal involved; 

· the vaccination and clinical status of the animal involved, the type of vaccine used and the availability of the animal for observation; 

· the results of laboratory testing of the animal for rabies, if available.

In areas where either wildlife or dog rabies prevails, dogs should be vaccinated. WHO promotes the implementation of mass vaccination campaigns for dogs using inactivated potent veterinary vaccines injectable by the subcutaneous or intramuscular routes. For dog sub-populations that are difficult or impossible to reach, WHO promotes research on (live) vaccines for use in bait. In areas where there is wildlife rabies, in those animal species host for which oral vaccines have been shown to be safe and efficacious, WHO promotes the use of rabies vaccine-loaded bait for oral immunization (8). Such techniques have led to the elimination of fox rabies in many areas in Western Europe.

Special issues

Cost: Reduction in the cost of each effective course of treatment remains an essential objective. Costs of a full rabies post-exposure treatment (currently US$ 30 to 35 on average for vaccine and US$ 50 to 160 for immunoglobulin) remains prohibitive for most people particularly those living in countries affected with canine rabies.

Supply of vaccine: A significant reduction in the price of these would help reduce the cost of treatment and make it more acceptable to poor people who are often the most at risk. Rabies vaccines have been added to the WHO list of essential drugs and should be made available at the lowest price possible within a country.

Supply of immunoglobulins: The current WHO definitions for certain categories of exposure call for more frequent passive immunization in association with vaccination. The increased production and use of highly purified horse immunoglobulins that are safer than the heterologous products of the previous generation should be promoted to provide at least a partial solution to the problems of supplies of human immunoglobulin and the cost involved.

New post-exposure regimens: None of the existing regimens is entirely satisfactory. As no new vaccine or delivery system will be available soon, continued research into new vaccines and reduced regimens and associations with other EPI vaccines (9) is a priority.