Rabies - Treatment Review

All human cases of rabies were fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux. Their original vaccine was harvested from infected rabbits, from which the nerve tissue was weakened by allowing it to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines. The human diploid cell rabies vaccine was started in 1967; however, a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. A recombinant vaccine called V-RG has been successfully used in Belgium, France, Germany and the United States to prevent outbreaks of rabies in wildlife. Currently pre-exposure immunization has been used in both human and non-human populations, whereas in many jurisdictions domesticated animals are required to be vaccinated. In the U.S., since the widespread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments, the number of recorded deaths from rabies has dropped from one hundred or more annually in the early twentieth century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated. September 28 is World Rabies Day, which promotes information on, and prevention and elimination of the disease.

Treat Rabies

There is no cure for rabies once symptoms of the disease develop, making prevention and control extremely important. Human deaths from rabies can effectively be prevented by vaccination. Rabies vaccine (pre-exposure vaccination) is given to people at high risk of being infected by rabies to protect them if they are exposed to the virus. The vaccine (post-exposure treatment) can also prevent the disease if it is given to a person after they have been exposed to the virus if treatment occurs fairly soon after exposure.

Pre-Exposure vaccination

Pre-Exposure rabies vaccination is usually recommended for those who do certain kinds of work or activities with a high risk of rabies exposure, such as:

• veterinarians
• lab workers who regularly handle rabies specimens
• hunters and trappers in high-risk areas
• animal control and wildlife workers
• spelunkers (cave explorers)

travellers in areas of high rabies activity where there is limited access to post-exposure treatment

Post-Exposure Treatment

Post-Exposure rabies treatment is given depending upon your risk of exposure to a rabid animal. Factors involved in determining this risk include the type of exposure and the type of animal involved. Your doctor or your local public health unit can help determine your risk of rabies exposure from animals in your area.

Soon after an exposure

Rabies vaccination should be obtained as soon as possible after an exposure. After you get any immunization, make sure your doctor updates your personal immunization record, such as your Yellow Immunization Card. Keep it in a safe place.

Vaccine Types

Four formulations of three inactivated rabies virus vaccines are licensed for use by the U.S. Food and Drug Administration (FDA). Two RIG formulations are also FDA-licensed.

HUMAN DIPLOID CELL VACCINE (HDCV).

Human diploid cell vaccines (HDCVs) use inactivated rabies viruses. HDCV comes in two formulations: one for intramuscular (IM) injection and one for intradermal (ID) injection into a deep layer of skin.

PURIFIED CHICK EMBRYO CELL VACCINE (PCEC).

Purified chick embryo cell (PCEC) vaccine became available in the United States in 1997. PCEC is made from rabies virus grown in cultures of chicken embryos and then inactivated. The drug is formulated for IM administration only.

RABIES VACCINE ADSORBED (RVA).

Rabies vaccine adsorbed (RVA) is manufactured from virus grown in cell cultures of fetal rhesus monkey lung cells and then inactivated.

RABIES IMMUNE GLOBULIN (RIG).

Human rabies immune globulin (RIG, HRIG) is a vaccine made from human serum that contains high levels of antibodies against rabies. It is used in conjunction with an inactivated-rabies vaccine for post-exposure prophylaxis. RIG provides immediate but short-lived protection against rabies. Approximately one-half of the antibodies are lost within 21 days after administration. RIG is separated from the blood plasma of hyperimmunized human donors. Numerous procedures are used to clear the serum of rabies virus.

OTHER VACCINES.

Although the four types of inactivated-rabies vaccines and the two RIGs are the only rabies vaccines available in the United States, various other rabies vaccines are produced throughout the world. Although inactivated-rabies vaccines from diploid cell cultures are safe and effective, they are expensive. In developing countries, rabies vaccines often contain nerve tissue which can cause adverse effects. Various less expensive but safe and effective vaccines are under development.

General Use

Inactivated-rabies vaccines are injected, either before or after exposure to the virus, in 1.0-ml. doses containing at least 2.5 IU/ml. of rabies virus antigen. This is the recommended standard of the World Health Organization (WHO). The size and number of vaccine doses are the same for children and adults. Although the same rabies vaccine usually is used throughout an immunization series, there is no evidence of adverse reactions or loss of effectiveness when two different vaccines are used in the same series. Modern rabies vaccines are relatively painless.

Side Effects

Side effects from the rabies vaccines currently used in the United States are much less common and less severe than the side effects of earlier rabies vaccines. However side effects may vary with the brand of vaccine and adverse reactions to rabies vaccines used in some other countries are quite common. The risk of side effects also increases with the number of vaccine doses. However a vaccination series should not be interrupted because of localized or mild side effects.

Mild side effects from rabies vaccines include:

soreness, redness, swelling, itching, or pain at the site of the injection in 30–74 percent of recipients

headache, nausea, abdominal pain, muscle aches, or dizziness in 5–40 percent of recipients

More serious side effects of rabies vaccines include:

hives, joint pain, or fever in about 6 percent of those receiving a booster vaccination

very rarely, an illness resembling Guillain-Barré syndrome, a disorder of the motor nerves that can result in temporary paralysis, lasting no longer than 12 weeks and resulting in complete recovery Other nervous system disorders occur so rarely following rabies vaccination that they may not be related to the vaccine. However, a physician should be consulted if a high fever or behavioral changes occur following rabies vaccination.

Reported side effects of RIG include:

• local pain
• low-grade fever

Although any vaccine is capable of inducing an allergic reaction, serious reactions to rabies vaccine are very rare. Signs of an allergic reaction include:

• paleness
• weakness
• dizziness
• hoarseness or wheezing
• difficulty breathing
• a fast heartbeat

In case of a serious reaction to a rabies vaccine:

A doctor should be consulted immediately. The date, time, and type of reaction should be recorded. Medical personnel or the local health department should file a Vaccine Adverse Event Report.

Interactions

Immune system-suppressing treatments, including cancer drugs and radiation and steroids, can interfere with the antibody response to rabies vaccination. If possible, immunosuppressive medications should be suspended during the vaccination series, and the vaccine injections should be intramuscularly. Alternatively, the child's serum can be checked for antibody production to determine if the vaccination was successful.

Chloroquine phosphate or similar anti-malarial drugs such as mefloquine may interfere with the response to HDCV. Children who will be taking anti-malarial drugs while traveling in areas with endemic rabies should begin the three-dose regimen of ID vaccine one month prior to travel, before they begin taking drugs to prevent malaria. However, a three-dose, pre-exposure regimen of IM vaccine provides an adequate response even in the presence of anti-malarial drugs.

Replication Of Rabies Viruses

The virus is typically present in the nerves and saliva of a symptomatic rabid animal (Turton and Jenny, 2000). The route of infection is usually, but not always, by a bite. In many cases the infected animal is remarkably aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior. Transmission between humans is extremely rare. A few cases have been recorded through transplant surgery ( Srinivasan et al., 2009). After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels along the nerves towards the central nervous system (Jackson and Wunner, 2002). During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. When the virus reaches the brain, it rapidly causes encephalitis. This is called the prodromal phase, and is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord producing transverse myelitis

The steps in the lytic replication cycle of an enveloped virus are illustrated for rabies virus, which has a single-stranded RNA genome.

step 1

The structural components of this virus are depicted at the top. The nucleocapsid of this virus is helical rather than icosahedral.

step 2

After a virion adsorbs to a specific host membrane protein the cell engulfs it in an endosome

steps 3

A protein in the endosome membrane pumps protons from the cytosol into the endosome interior.

Step 4

The resulting decrease in endosomal pH induces a conformational change in the viral glycoprotein, leading to fusion of the viral envelope with the endosomal lipid bilayer membrane and release of the nucleocapsid into the cytosol

step 5

Viral RNA polymerase uses ribonucleoside triphosphates in the cytosol to replicate the viral RNA genome

step 6

synthesize viral mRNAs One of the viral mRNAs encodes the viral transmembrane glycoprotein (blue), which is inserted into the lumen of the endoplasmic reticulum (ER)

step 7

it is synthesized on ER-bound ribosomes

step 8

Carbohydrate is added to the large folded domain inside the ER lumen and is modified as the membrane and the associated glycoprotein pass through the Golgi apparatus.

step 9

Vesicles with mature glycoprotein fuse with the plasma membrane, depositing viral glycoprotein on the cell surface with the large folded domain outside the cell, the transmembrane α helix spanning the plasma membrane, and the small cytoplasmic domain within the cell

step 10

Meanwhile, other viral mRNAs are translated on host-cell ribosomes into nucleocapsid protein, matrix protein, and viral RNA polymerase

step 11

These proteins are assembled with replicated viral genomic RNA (dark red) into progeny nucleocapsids

step 12

then associate with the viral transmembrane glycoprotein in the plasma membrane

step 13

As additional copies of the matrix protein on a single nucleocapsid associate with the cytoplasmic domain of additional copies of the viral transmembrane glycoprotein, the plasma membrane is folded around the nucleocapsid, forming a “bud” that eventually is released

Human Infected By Rabies Virus

Most of uncontrolled rabies’s outbreaks occur in both Asia and Africa.Approximately about 31,000 people in Asia and 24,000 people in Africa are dead because of rabies infection per year.

According to National Institute of Allergy and Infectious Disease, there are 18,000 of Americans received vaccine to cure from rabies virus. However, number of rabies-related human deaths in America decline from more than 100 annually at the turn of the century to one or two per year around 1990’s. In America, beside being bite by dog, most of human infected by rabies through bat. Poor people and children are most exposed to the infection. About 30% to 60% of children below 15 years old are dog’s victim. This is due to children often playing with animals and less likely to be bites and scratches.

Human deaths caused by rabies occur to those people who fail to seek medical assistance because of the unaware of their exposure. WHO recommend victim that had been bite to quickly clean and immunize the wounds. This will help to prevent the virus from spread.

However, the numbers of animals died because of rabies are higher compare to the numbers of human died. The ratio of human death is 1-2 people per year while the ratio of rabies cases are over 8000 cases.

Figure 1.3 Animal Rabies Cases (CDC).

Most of rabies cases are reported before 1960 involved domestic animals such dog. However, amount of domestic animals infected by rabies virus decline from 1960 to 2000. In domestic animals and livestock, the most commonly infected animals are cats while dogs tend to responsible for more bites. Oppositely, wild animals such raccoons skunk and foxes number arises from 1960 till 2000. The increasing numbers of infected wild animals are up to 90% per year.

Diagram below shows the distribution of Major Terrestrial Reservoirs of Rabies in the United States.

Figure 1.4 Rabies Reservoirs in the United States (CDC).

*CDC : Centers for Disease Control and Prevention (CDC)

Symptom of Rabies

There are three main phases of rabies development which are prodromal period, acute neurological period and coma. Below general stages onset those symptoms:

Mammals (especially human) that had been infected by rabies virus will show several illness symptoms that can be divided into early and late stage. List below shows several of early symptoms of infected mammals:

There are several differences between animals and human that had been infected by rabies virus such:

Morphology: Rhabdoviruses

Particles ca. 180 x 70nm with unique bullet-shaped appearance (all rather similar). Enveloped with prominent spikes on surface (G protein - haemagglutinates RBCs), but not very variable in appearance. The envelope is lined by the matrix protein and contains the nucleocapsid (RNA + N protein) wound helically inside the core. Two non-structural proteins, L and NS, are associated with the nucleocapsid and act in concert as the viral polymerase. As with most enveloped viruses, the particle is relatively labile.

Rhabdoviruses - Master of Infection

Rhabdo = Greek. 'rod-shaped'. Rabies has been known for more than 20,000 years, the first description dates from the 23rd century BC in the Mesopotamia (Fu, 1997 Rabies and Rabies research: past, present and future. Vaccine 15, S20-S24).

Genetically, these viruses have non-segmented (-)sense RNA genome reminiscent of Paramyxoviruses. There are >200 Rhabdoviruses known (probably still an underestimate of the total), which infect man (Rabies - the only member of the group to do so 'naturally'), other mammals, fish, insects (some replicate in arthropods and were previously classified as Arboviruses) and plants - versatile! The family is split into six genera.

Rabies is an 'ancient' disease, first shown to be of infectious origin in 1808, shown to be of viral etiology by Pasteur in the 1880's (when Pasteur and Koch were developing the germ theory of disease - prior to the firm modern definition of 'viruses' by Beijerinick (1898)). Over a decade, Pasteur carried out the serial passage of Rabies virus in rabbits, and eventually succeeded in isolating an attenuated preparation which was used to treat patients bitten by mad dogs (not without some risks).

Table 1.1 Group V: (-) sense RNA Viruses

A Brief History of Rabies

Figure 1.1 The way of infection happen

Rabies is an infectious and contagious disease of the central nervous system. It has been known since the ancient days of 2300 B.C. This lethal virus still exists in almost all parts of the world. Once infected, and left untreated, this disease is usually lethal. The rabies virus is concentrated

in the saliva, mucous membranes and central nervous tissue of a rabid animal. Only humans, and other mammals, can become infected through a cut or scratch from an animal with rabies, or if the rabies virus comes in contact with the moist tissues of the mouth, nose or eyes.

There are two ways that rabies symptoms appear, dumb and furious. Both can cause abnormal behavior. Immediately prior to death, animals with furious rabies will appear to be ‘mad’: frothing at the mouth and biting anything that gets in their way. They may show extreme excitement and attack stationary things or animals. Bouts of furious rabies usually alternate with periods of depression. In dumb rabies, there is no ‘mad’ period. With dumb rabies, paralysis, usually of the lower jaw and a drooping head are the first signs of the disease. The paralysis quickly spreads to limbs and vital organs and death quickly follows. Animals with dumb rabies may become depressed and retreat to isolated places. Some may appear ‘tame’, having no fear of humans.

Figure 1.2 Infected Dog