Over 100 years ago, in 1885, Louis Pasteur developed a crude nerve tissue vaccine for the postexposure treatment of rabies. This form of vaccination used dessicated infected tissue and was found to prevent rabies infection in a 9 year old boy named Joseph Meister. Following Pasteur's initial vaccine, inactivated vaccines were developed. This inactivated form of vaccine was produced by serial dilutions followed by sterilization with chemical agents that inactivated the virus. Further improvements to the inactivated virus vaccine developed through growing virus in various animal tissues and inactivation by UV light or phenol. Semple (derived from sheep or goat brain) vaccines examples of inactivated virus and are still used throughout the world today. They are poorly efficacious and poorly tolerated. Side-effects include the demyelination of central or peripheral nervous system in 1 out of 3000, and is occasionally fatal.
Today human diploid cell vaccines(HDCV), also an inactivated virus vaccine, are used almost exclusively by the developed world for pre and post vaccination of Rabies. In the 1950's methods for preparing embryonated tissue vaccines appeared lead by the pioneering work of the Wistar Institute. Using this process, virus can be harvested from infected human diploid cells, concentrated by ultrafiltration and is inactivated by chemicals such as beta propiolactone. The vaccine product consists of a sterile, stable, freeze-dried suspension of rabies virus. HDCV is the benchmark prodect, by which the efficacy of all new vacines are measured. Human diploid cell vaccine gives high neutralizing antibody after 10 days, and carry a lower burden of side-effects as those derrived frrom neuronal tissue. When used appropriately can confer 100% protection. They are widely used in North America and Western Europe, however use is scarce in Latin America, Africa and the western Pacific. WHO reccommends that cell culure vaccines should replace brain tissue derrived vaccines as soon as possible. Current human diploid cell vaccines (HDCV) on the market include Rabipur (PCEC) from chicken embryos and PVRV from Vero cells, and PDEV from duck embyos. PDEV was used extensively for 25 years in the US, despite eliciting a poor antigenic response in some people and severe adverse reations. Rabipur was first intrdoduced in 1984 in Germany. On October 20, 1997, the Food and Drug Administration licensed a new rabies vaccine for both pre-exposure and postexposure prophylactic use in humans. Rabipur is safe and as effective as HDCV yet lacks the immune related hypersensitivity that occurs in 6% of those receiving HDCV boosters. Because the product contains trace amounts of animal by-products, antibiotics, and human serum albumin, systemic allergic reactions are possible such as local reactions such as swelling, induration, and reddening and have been reported. The cost of nationwide rabies prevention efforts estimated to cost $230 million to $1 billion per year in the United States.
For individuals considered to have frequent exposure to Rabies such as veternarians and spelunkers, pre-exposure immunization is recommended. This consists of the three doses of HDCV, 1.0 ml, intramuscularly (deltoid area), one each on Days 0, 7 and 21 or 28. Administration of routine booster doses of vaccine depends on exposure risk category. For individuals with high risk, booster immunization or serology testing for titers of neutralizing antibody are required every 2 years. For the population at large, no pre-exposure immunization is called for.
For individuals who have been bitten or scratched by wild or domestic animals, local treatment of wounds is an important method of disease prevention. Experiments have shown that an effective measure to prevent rabies post exposure is washing the wound and scratches with soap and water. In the United States post-exposure anti-rabies immunization always includes a combination of active and passive immunization. Administration of both antibody (preferably human RIG) and vaccine is standard procedure, except for persons who have been previously immunized with the recommended pre-exposure or post-exposure regimens with HDCV or who have been immunized with other types of vaccines and have a history of documented adequate rabies antibody titer should receive only vaccine. Antibodies are given to reduce the viral burden and enhance the effectiveness of treatment since it has been documented that vaccination alone may not be enough to prevent rabies.
Vaccination of wild animals is an necessary strategy to further reduce the number of rabies cases. In 1983, a vaccinia-rabies glycoprotein (V-RG) recombinant virus vaccine was developed that has proven to be an effective oral immunogen in raccoons and various other important reservoir species. Vaccine advantages include improved thermostability and an inability to cause rabies. The first North American V-RG vaccine field trial began on August 20, 1990, on Parramore Island off the eastern shore of Virginia. This limited field trial demonstrated vaccine safety. Oral rabies vaccination of the red fox with vaccine- laden baits is an integral aspect of rabies control throughout southeastern Canada and Europe. Tests by Cornell University veterinarians and biologists proved that oral vaccine, concealed in flavored baits and dropped from aircraft, can immunize most raccoons against rabies. Aerial distribution of oral vaccine is also seen as a less labor-intensive way of immunizing wild animals, compared to the trap-vaccine-release method, The recombinant vaccine, which cannot cause rabies in animals, would be encapsulated in cookie-sized baits made of rancid tallow, food grade wax and marshmallow flavored sugar.
DNA vaccines utilize naked DNA strands alone for immunization, without traditional proteins or carrier viruses. The genes encoding immugeneic proteins are inserted into a circle of bacterial DNA known as a plasmid. DNA vaccine uses just enough genes from the virus to activate the immune system. The plasmids are shot into muscle tissue using a gene gun, where they are taken up and expressed by cells. Surprisingly enough this method of immunization has been shown to work surprisingly well when it comes to eliciting an immune response against pathogens, yet it is still not clear exactly how the DNA vaccines stimulate an immune response. It must be also kept in mind that the response is still not as strong as that seen with traditional vaccines. Recently announced was the first DNA vaccine that was shown to prevent rabies in monkeys. All eight of the monkeys treated with the DNA vaccine before being given a lethal dose of the rabies virus survived. DNA vaccine is very inexpensive to make and it's very stable, so it does not require refrigeration. This makes it useful candidate in developing countries. But the new vaccine can only be used prior to exposure to rabies, and is not a replacement for post-exposure treatment with IgG and HDCV.Researchers said there are no immediate plans to conduct human clinical trials, due to questions concerning whether additional genes must be inserted to offer protection to humans, and whether it would be effective if it were administered after a person contracted rabies.
The essential goals for rabies vaccine development is the development of cheap, safe, and portable vaccines. Although vaccine strategies have greatly reduced the disease burden in developed countries, programs to vaccinate wild and domestic animals are the key to continue these trends. Possibilities for future vaccine now in development include an avirulent escape mutant SAG-2 that may be candidate for animal vaccination. The mutant is avirulent in rodents, cats, dogs, and foxes, yet gives immunological protection from virulet strains. Other possibilities being looked at for cheap and effect means of vaccination include edible plant vaccines expressing rabies antigens. It has been shown that by making transgenic plants that express rabies antigens, one can induce antibody response in mice. In a similar approach recombinant plant bacteria could be constructed which can infect and express rabies proteins. Alternatively, one could construct recombinant plant viruses such as Tobacco Masaic Virus modified to deliver important epitope encoding genes to elicit a protective immune response.
References:
1. Picture of Louis Pasteur Courtesy of The Bettmann Archive. From painting by Edelfeld.
2. DNA Graphics Created with PovChem http://grserv.med.jhmi.edu/~paul/DNA.html
3. The Antibody Resource Page http://www.antibodyresource.com/rot2.html>
4. Rabies.com http://www.rabies.com
5. CDC Rabies Information Page: http://www.cdc.gov/ncidod/dvrd/rabies/
6.Noah, Donald et al. Epidemiology of Human Rabies in the United States, 1980 to 1996. Annals of Internal Medicine. 128:11;922-30
7.Fu, Zhen. Rabies and Rabies Research: Past, Present and Future. Vaccine. 15;S20-24
8.Dreesen, David. A Global Review of Rabies Vaccines for Human Use. Vaccine.15;S2-6
9.Fu, Z.F and Wasi, C. Rabipur Proceedings. Vaccine. 15;S1
10. Cells Alive http://www.cellsalive.com
