Two hundred years ago Edward Jenner inoculated James Phipps with vaccinia and 181 years later smallpox had disappeared from the surface of the earth as a result of generalized vaccination. Compared to the requirements of modern vaccinology, the procedures used by Jenner and his successors, were extremely primitive because of an almost total lack of knowledge in the field of microbiology and immunology. The active principle of smallpox vaccine is vaccinia virus, which in many respects, differs from that of natural cowpox; the term "cowpox" has been used for more than a century and a half to designate the vaccine; it appears itself to be a misnomer, because it is most probably by a virus of rodents, which only occasionally infects bovines or other species, especially cats. The origin of vaccinia remains doubtful, but a plausible explanation is that it is derived from horse-pox. Jenner was convinced that he was working with a virus of equine origin, which was occasionally transmitted from the horse to the cow by the personnel on the farms. Horse pox has now completely disappeared. Especially during the first years after Jenner's discovery, great confusion was caused by other lesions on the cow's udder, which were called "spurious cowpox". We know today that these lesions could be caused by the viruses of papular stomatitis, pseudo-cowpox or para-vaccinia (milker's nodules), herpes mammilitis and papillomatosis; they could not be differentiated from those of cowpox or vaccinia, in addition lesions due to bacteria or other causes also led to confusion. During the first eighty years the vaccine was being transferred almost exclusively from arm to arm with the risks inherent in this procedure; one of the reasons for applying this method was the fear of "bestialization" thought to be linked with the use of material of animal origin. Several contaminations have been observed as a result of the use of the arm-to-arm procedure: smallpox was transmitted, especially in the beginning, because vaccinations were carried out in a contaminated environment. Syphilis was diagnosed in several countries after the use of vaccine taken from syphilis patients. At least two foci of hepatitis were reported after the use of contaminated human lymph. Transmission of tuberculosis or what was then designated as scrofulosis was unlikely, but was used as one of the main arguments against vaccination by the antivaccinists. Varicella and measles were transmitted from time to time with the vaccine and also bacterial infections, such as staphylococci, streptococci e.a. From the global point of view, however, the number of contaminations remained limited in comparison with the large numbers of vaccinations that were performed. Another problem the early vaccinators were facing, was that of the decline and disappearance of the immunity after a certain number of years. Jenner and his successors believed that the immunity post vaccination would be lifelong as it was after variolation. When in the early part of the 19th century more and more immunity breakdowns occurred, this observation led to total confusion and it took dozens of years of debate and controversy before the only logical and efficacious measure, i.e. revaccination, was generally accepted and implemented. In the last third of the 19th century "human lymph", obtained by arm-to-arm vaccination, was gradually replaced everywhere by animal lymph i.e. vaccine produced on the skin of animals, mainly calves. The determining factor in the switch was the risk of vaccination syphilis. Everywhere vaccine institutes were created, where the vaccinia virus was propagated on the skin of calves. The harvested virus served each time for the inoculation of fresh calves; this resulted in a gradual increase of the number of passages leading to the possible risk of overattenuation. To avoid this risk, passages in man, donkeys, rabbits or other species were performed from time to time.