Rabies viruses belong to the genus Lyssavirus of the Rhabdoviridae family. Rabies is a zoonosis (transmission from animals to humans), and human infection usually occurs following a bite or scratch by an infected animal. About 98% of human rabies occurs in regions with large numbers of stray dogs, although other carnivores such as foxes and bats may transmit rabies to humans. The incubation period following infection is variable, ranging from several weeks to several months. Following the bite, the virus is transported to the central nervous system via the peripheral nerves, where it replicates and disseminates rapidly to many different tissues.
The initial symptoms of rabies are fever and often pain or paraesthesia at the wound site. As rabies virus spreads in the central nervous system, progressive acute inflammation of the brain (encephalitis) develops which is characterized by difficulty in swallowing, and therefore panic when presented with liquids to drink (hydrophobia). Signs of nervous system damage appear, hyperactivity and hypersensitivity, disorientation, hallucinations, seizures, paralysis and within a few days, cardiorespiratory arrest that is invariably fatal.
Since their development more than four decades ago, concentrated and purified cell-culture and embryonated egg based rabies vaccines (CCVs) have proved to be safe and effective in preventing rabies. In a few countries, mainly in Asia and Latin America, populations at high risk of rabies may still depend on rabies vaccines derived from animal nerve tissues for post-exposure prophylaxis. Nerve tissue vaccines induce more severe adverse reactions and are less immunogenic than cell culture derived vaccines and their production and use are therefore not recommended by WHO. Following growth in cell cultures or embryonated eggs, the viral harvest is concentrated, purified, inactivated and lyophilized. Human albumin or processed gelatine is added to some vaccines as a stabilizer.
Pre-exposure prophylaxis is recommended for anyone at continual, frequent or increased risk of exposure to rabies virus, either by nature of their residence or occupation. Recommendations for post-exposure depend on the type of contact with the suspected rabid animal. For category I exposure (touching or feeding animals, licks on intact skin), no prophylaxis is required; for category II (nibbling of uncovered skin, minor scratches or abrasions without bleeding), immediate vaccination; and for category III (single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks, licks on broken skin, exposures to bats), immediate vaccination and administration of rabies immunoglobulin are recommended.
Intradermal immunization using CCVs is an acceptable alternative to standard intramuscular administration. Intradermal vaccination has been shown to be as safe and immunogenic as intramuscular vaccination, yet requires less vaccine, for both pre- and post-exposure prophylaxis, leading to lower direct costs. This alternative should thus be considered in settings constrained by cost and/or supply issues.
Rabies Vaccine Standardization
The revision of the Requirements for rabies vaccines for human use in 1980 covered the use of cell cultures, including human diploid cells and embryonated eggs in addition to neural tissue. An additional document, WHO Requirements for rabies vaccine (inactivated) for human use produced in continuous cell lines was published in 1987 to take into consideration advances in the development of cell culture derived vaccines. An amendment which updated the section on the International Standard for Rabies Vaccine was published in 1994 The WHO Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs were revised in 2005. However, the Requirements for Rabies Vaccine for Human use revised in 1980 remain in force for neural tissue derived vaccines until such time as the production of these vaccines is discontinued.
Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs, TRS 941, 2007, Annex 2
Requirements for Rabies Vaccine for Human use, Revised 1980, TRS No. 658, Annex 2
A WHO reference material for rabies vaccine is available to qualified applicants:
Discussion on WHO requirements for rabies vaccine for human use: potency assay, 2003
Discussion on WHO requirements for Rabies vaccine for human use, 2004
Prequalified Rabies Vaccines
Rabies vaccines are prequalified for procurement by UN organizations: