The three antiviral vaccines discovered in the 18th century (smallpox), 19th century (rabies), and 20th century (polio) share a common feature: none would ever be licensed today for human vaccination. Yet Jenner's smallpox vaccine led to the eradication of smallpox, Pasteur's rabies vaccine represented the first successful post-exposure treatment of people bitten by rabid animals, and polio vaccine administered since its discovery in 1950 is leading to the eradication of polio (in the years 2004-2005) from the earth. However, in the case of rabies, efforts at complete eradication are unrealistic, despite the availability of a very effective vaccine, since rabies, unlike smallpox and polio, is not limited to humans and can infect all domestic and wild mammalian species. Rabies is probably the oldest known infectious disease, yet knowledge of the virus and the disease is far from complete. For instance, the appearance of 24 cases of 'cryptic' rabies in the USA, i.e. cases not associated with any bite or scratch, with an incubation period in humans extending 6-8 years, is a puzzling phenomenon that cannot be readily explained. On the other hand, rabies is one of the few strictly neuronal infections and, as such, is an excellent model for the study of neurotropic virus distribution in the brain. Apoptosis induced by a rabies strain expressing high levels of glycoprotein spreads much more slowly through brain tissue than that induced by strains producing lower glycoprotein levels. Attenuated rabies virus constructed to express twice the normal glycoprotein levels is also an excellent antigen for induction of immune responses in the host. Foreign antigens using this vector may also produce highly immunogenic vaccines. Global Approach to Immunization. Those monitoring the spread of AIDS in many parts of the world know that cost of treatment is one of the major problems in combating the disease. Vaccines against HIV face the same problem. In general, the price of vaccines and sera is exorbitant for the afflicted population in developing countries. In addition, the dearth of syringes, the unavailability of nurses and doctors to administer multiple vaccine injections, and other factors in these countries require a drastic change in current vaccine production approaches. About 12 years ago, plants became vehicles to produce biomedical reagents. Plants can be exposed directly to a construct containing a foreign gene and Agrobacterium to create a transgenic plant that, over several generations, produces the desired product. Alternatively, plants infected with a plant virus (e.g. alfalfa mosaic virus) fused with a foreign gene can propagate the foreign antigen as the virus multiplies. Extraction of the plant virus followed by purification provides the desired biomedical product. Our use of either of these systems has led to the creation of plants producing vaccines, sera, hormones, and other biological reagents. In two clinical trials at the Institute of Bioorganic Chemistry of the Polish Academy of Sciences in Poznan, volunteers who ingested lettuce expressing hepatitis B vaccine showed hepatitis B antibodies in their sera. In another trial carried out at the Biotechnology Foundation Laboratories in Philadelphia, volunteers ingesting a spinach-rabies vaccine showed an immunological priming effect, since only one injection of commercially available rabies vaccine significantly raised the level of rabies-specific antibodies. Vaccines against HIV gp120 and Tat have been produced in spinach, and a construct of gp120 with the CD4 receptor is now being adapted to this plant. Two types of antibodies against rabies and against colorectal cancer are being produced in tobacco and in lettuce. The suboptimal quality of the currently available anthrax vaccine prompted our efforts to produce the anthrax Protective Antigen (PA)in tobacco and lettuce. Quite clearly, plants will play a prominent role in producing a variety of biomedical reagents in the future.