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Zoonotic Infections

Rabies

• Disease Burden
• Virology
• Vaccine
• WHO Rabies Factsheet
• WHO Rabies homepage
• Rabies Vaccine Information
• WHO Immunization, Vaccines and Biologicals web Site on human and animal rabies

Disease Burden

Rabies is a viral encephalitis transmitted from animal to animal and from animal to man through saliva. Animal bites introduce the virus into muscle and nerve ending-rich tissues from which it penetrates into nerve cells where it replicates and progressively travels through the spinal cord to the brain. This process usually requires weeks or even months, depending upon the distance from the bite site to the brain. Replication of the virus in the brain causes hydrophobia, hallucinations, aggressive behavior, and paralysis, eventually leading to coma and death. The virus also spreads to salivary glands and the skin, cornea, nasal and intestinal mucosa and other organs including kidneys. The disease thrived from most ancient times (its first written description can be found in the Babylon Codex, 23 centuries BC) to the end of the 19th century when, in 1885, Louis Pasteur and collaborators succeeded in the first cure of human rabies through post-exposure vaccination [170] . More than 120 years later, however, the disease still continues to affect mankind, especially in developing countries in Africa, in South and South-East Asia, and to a lesser extent Latin America.

In nature, rabies is a disease of wild carnivores, involving dogs, cats, wolves, foxes, coyotes, jackals, raccoons, skunks and also bats as reservoirs and vectors. All mammalian species are believed to be susceptible, including nonhuman primates. Human infection almost always results from the bite of an infected animal, although transmission of the virus through transplantation of infected corneas and other organs (heart, liver and kidney) has been reported. On rare occasions, the virus was also reported to be transmitted by aerosols in caves populated by rabies-infected bats. According to WHO, more than 3.3 billion people are at risk for rabies in over 85 countries worldwide [171] [172] . About 55 000 deaths from rabies are estimated to occur every year, 99% of which are the consequence of dog bites [173] [174] . Of these 55 000 deaths, 31 000 are estimated to occur in Asia (20 000 in India alone) and 24 000 in Africa. The annual incidence of animal bites in many countries can be as high as 100-200 bites per 100 000 population. In 2005, more than 12 million individuals received a post-exposure prophylaxis (PEP) treatment against rabies, preventing an estimated 280 000 deaths [175].

Canine rabies is still widespread in stray dogs in Asia, Africa and parts of Latin America. Control of rabies in these countries is often hampered by religious beliefs and cultural habits. For example, Buddhist and Hindu ethics restrain culling of the canine population. India and Thailand have prohibited the euthanasia of stray dogs by municipalities. In these countries, stray dogs account for >90% of human rabies exposures, especially among 5-14 years old children in rural or peri-urban areas. Human rabies has been endemic in India for immemorial times, but the actual incidence of the disease never had been carefully studied. A recent survey on 10.8 million persons in mainland India led to conclude that the annual incidence of rabies was 2 per 100 000 population [176] . In most developing countries, however, the true incidence of rabies is largely underestimated, due to poor reporting.

In countries where an effective rabies control has been implemented, various wildlife species including bats have become the main reservoir of rabies and most human cases are secondary to bites by rabid bats [177] [178] . In the USA, the predominant vectors for rabies are skunks in the western and central states, raccoons in the eastern states, coyotes in the far south and foxes at the Canadian border and in Alaska. In Western Europe, prior to the implementation of wildlife vaccination, 83% of rabid animals were foxes. Most of Western Europe is now rabies-free, and several countries in Central and Eastern Europe are almost rabies-free, but rabies is still a problem in the Baltic countries, Ukraine, Russia and Independent States of former USSR.

Virology

Rabies virus is an enveloped, bullet-shaped virus which belongs to the genus Lyssavirus in the family Rhabdoviridae. The negative sense viral RNA genome encodes five viral proteins, the N (nucleocapsid), P, M (membrane), G (envelope glycoprotein) and L (replicase) proteins. Seven virus genotypes have been described, genotype 1 corresponding to the rabies virus and genotypes 2 to 7 to bat lyssaviruses. These are: genotype 2 (Lagos bat virus), genotype 3 (Central Africa Mokola virus), genotype 4 (South Africa Duvenhage virus), genotypes 5 and 6 (European bat lyssaviruses) and genotype 7 (Australian bat virus). New Lyssaviruses have been identified (e.g. central Asia) and the addition of new genotypes is under consideration. All these viruses can be pathogenic for humans.

The G protein, which forms spikes at the surface of the virion, is responsible for the attachment of the virus to virus receptors and bears the neutralization epitopes. There seems to be little cross neutralization between genotype 1 (rabies virus) and genotypes 2 (Lagos bat virus) and 3 (Mokola virus).

Vaccine

For more than 70 years after Pasteur's original work, inactivated vaccines were produced from sheep, goat or rabbit brains and contained nerve tissue, a cause of severe neurological adverse events. The Semple vaccine, which was produced on sheep or goat brains and inactivated with phenol was until recently commonly used in humans in many countries in Africa and Asia. The first rabies vaccine produced in animal tissues with low myelin content was prepared in the 1960s by Fuenzalida and colleagues [179] starting from infected suckling mouse brains, again using phenol as the inactivating agent. Suckling mouse brain vaccines (SMBV) were the most frequently used vaccines for many years, until their production started being discontinued a few years ago, especially in major SMBV producing countries such as Brazil and Mexico, to be replaced by a number of inactivated rabies vaccines produced on either primary or continuous cell lines or embryonated eggs.

The first modern rabies vaccine (Human diploid cell vaccine, HDCV) was developed at the Wistar Institute in Philadelphia by propagating the rabies virus on the human diploid cell line WI-38 and using beta-propiolactone for its inactivation [180] . This was followed by a purified vaccine produced in Vero cell cultures (PVRV), and also inactivated by beta-propiolactone, which was developed by Sanofi Pasteur [181] [182] ; and a purified vaccine produced on primary chick embryo cells (PCECV), developed by Novartis. The three vaccines show comparable tolerance and immunogenicity and their efficacy was demonstrated in several PEP clinical trials. In addition, a primary baby hamster kidney cell culture vaccine (PHKCV), a purified duck embryo vaccine (PDEV), three Vero cell-based vaccines and one HDCV have been developed in China and India.

These vaccines can be used either for preventive immunization or for PEP. Preventive immunization is recommended for certain professional groups such as veterinarians and for travelers to rabies-endemic countries. There is no doubt that preventive vaccination of children in areas where rabies is endemic should also be given thorough consideration. The recommended preventive immunization regimen consists in three IM doses at 0, 7, and 21 or 28 days. The longevity of rabies neutralizing antibody anamnestic response in vaccinated persons was examined on 118 Thai volunteers who had received a cell culture vaccine 5 to 20 years previously and who each received a booster ID injection of 0.1 mL PVRV. All volunteers except one had detectable neutralizing antibody titers on day 0 and responded to the ID booster immunization with an accelerated antibody response, indicative of a long-lasting immune memory conferred by the vaccine [183].

Rabies vaccines are mostly used for PEP after bites from suspect rabid animals, as the time the virus takes to travel to the brain can be up to 2 months, which allows the immune system to mount an immune barrier in response to PEP before symptoms occur. The recommended schedule for PEP is five doses at 0, 3, 7, 14 and 28 days, often coupled to passive immunization with rabies immunoglobulins (RIGs). Two types of RIG are currently available, human IgGs (HRIGs) and highly purified equine IgGs (ERIGs). The overall shortage of RIGs and their current cost however represent a real public health threat in many countries. The use of rabies monoclonal antibodies (MRIGs) to replace RIG in PEP has been studied by various groups [184] and one such cocktail of two human monoclonals was recently tested in a Phase I study [185].

The relatively high cost of a full PEP regimen using IM immunizations also prompted attempts at using a reduced dose of vaccine for PEP, replacing IM by ID inoculations and using 0.1 mL (1/5th of a dose) of vaccine [186] [187] . Various ID post-exposure regimens (PEP) have undergone extensive evaluation, especially by the Thai Red Cross (TRC) in Thailand, using two ID injections on days 0, 3 and 7 followed by two injections day 28 [188] [189] [190] . The immunogenicity, tolerance and efficacy of PEP using either PCECV or PVRV administered ID at 0.1 mL per site according to the WHO recommended protocols [191] have been well documented [192] [193] [194] . Post-exposure ID vaccination is also routinely practiced in India, the Philippines and Sri Lanka, where it reduced the cost of PEP intervention by about 80% [175] [195].

The possibility of using the ID route of immunization for rabies pre-exposure vaccination was eventually tested in a randomized, open-label Phase II trial in schoolchildren in Thailand using 1/5th of a dose of purified chick embryo cell vaccine (PCECV) on days 0, 7, and 28 or 0, 7 and 21: 100% of the children developed protective rabies-neutralizing antibody titers [196] [197] . An abbreviated pre-exposure vaccination schedule using two ID injections at two sites on day 0 was found to lead to persistence of neutralizing antibodies one year later [198] . The possibility of routinely immunizing children in rabies-endemic countries using a simplified ID vaccination regimen is being explored in Thailand, again showing that a two-site ID immunization done on the same day using 0.1 mL of vaccine in each site could prime the human host immune memory for at least one to three years [199] [200].

It should be realized, however, that there will not be any easy solution to the problem of rabies in rabies-endemic countries if no attempt is made at eliminating the virus from its animal reservoirs. Vaccinating dogs against rabies has already been demonstrated as a highly efficacious preventive measure [174][174] [201] . Similarly, oral vaccination of foxes and other wildlife using either live attenuated rabies virus mutants or a live vaccinia virus recombinant that expressed the rabies G glycoprotein (RaboralTM) was highly successful at eliminating rabies from Western Europe. Different strategies, kinds and shapes of baits have been developed for targeting the major wild rabies reservoirs: stray dogs, foxes, coyotes and raccoon dogs [202] [203] [204] [205].

No disease exceeds the case fatality rate of rabies. Progress must continue towards the elimination of human rabies, itself depending on wildlife rabies control and canine rabies elimination [206] . The declaration of an Annual World Rabies Day, September 8, should hopefully raise public awareness of the severity of the disease [207].