Immune Response
A limited natural human immune response to rabies does exist, but without the amplification provided by vaccination the infection will ultimately be fatal. Infection usually begins with the bite of a rabid animal which breaks the skin. The saliva containing virus first comes in contact with muscle cells, and a viral glycoprotein attaches to the nicotinic acetylcholine receptor. An article published in 1998 announced that rabies binds the neural cell adhesion molecule (NCAM) as a receptor also. For a detailed description of the infection process, click here.Rabies virus replicates in these cells until enough of a concentration exists in the region of the bite that some viral particles come in contact with sensory or motor nerve cells. Viruses enter the axons where they are not myelinated, and move up towards the neuron's nucleus by retrograde axoplasmic flow. Retrograde transport is a natural function of nerve cells to transport messenger molecules from axon to nucleus, where dynein molecules move along the microtubules of the axon. Rabies virus capitalizes on this mechanism to reach the spinal cord, moving at 8 to 20mm per day. Oral herpesvirus also takes advantage of retrograde axoplasmic flow.
Once rabies spreads to the central nervous system it is isolated from immune recognition. It spreads through the CNS and into the peripheral nerves, which bring it to the skin, intestines, and salivary glands. In order to prevent infection of the CNS, wounds must be thoroughly cleaned and vaccination given as soon after the bite as possible. The time in which the virus is replicating in the muscle cells is the infection's incubation period, which can be as short as 4 days or greater than a year, by some reports. The average time frame is 20 days to 3 months. Most prophylactic vaccination programs involve multiple shots spread out over this time period. Once in the CNS, the virus spreads rapidly in the brain and spinal cord, causing the symptoms of the disease.
Clinical Rabies
There are two clinical types of rabies, furious and paralytic. The virus's replication in neuronal cells causes inflammatory reactions, encephalatis and myelitis. Virus that is more prevalent in the brain results in the furious form. The symptoms of this type are more familiar than the paralytic form. They include hydrophobia and foaming at the mouth, as well as aerophobia, behavioral changes, andeventual paralysis. The symptoms of the paralytic type are fever, headache, sore throat, fatigue, behavioral changes, pain or tingling at the wound site, delirium, and of course, paralysis. In order to test if a patient showing some of these symptoms has rabies, assays are performed on CSF, neck skin biopsys, serum and saliva. In the symptomatic stage of rabies the probablility of survival, even with vaccine and immune globuline, is slim. However, in one of the five famous cases of infection caused by corneal transplants, survival depended on vaccination, and other treatments after an assay of the donor corpse detected rabies.
Immune Response to Vaccination
Today's standard rabies vaccines consist of inactivated viral particles. They induce a mostly humoral response, the strength of which can be measured by monoclonal antibody assays. The older attenuated virus vaccines produced both humoral and cell mediated immunity, but could revert to virulent forms and produced other undesirable side effects. Direct administration of rabies specific antibody augments the initial humoral response produced by vaccination, and this is highly effective, so that the cell mediated response is not necessary. By the time the effects of the RIG (Rabies Immune Globulin) would begin to fade, B cells specific to rabies are producing more antibody, which continues reducing the viral load. Antibody binds viruses and inhibit their binding to infect cells. Memory B cells form, but they do not confer lifetime immunity, which is why people likely to be exposed to rabies need boosters in order to retain the benefits of prophylactic vaccination. The same is true in animals, which is why laws exist concerning keeping pet vaccinations current.
References:
Kaplan C, Turner GS, Warrell DA. Rabies: The Facts. Oxford University Press. 1986
Bear MF, Connors BW, Paradiso MA. Neuroscience:Exploring the Brain.Williams & Wilkins. 1996
Kuby J. Immunology. WH Freeman & Co. 1997.
Thoulouze, MI et al. The Neural Cell Adhesion Molecule is a Receptor for Rabies Virus. J. Virology. Vol.72,No.9, p7181-7190, Sept.1998.
CDC Rabies Information Page: http://www.cdc.gov/ncidod/dvrd/rabies/
