Figure 1.5 Characteristic smallpox lesions in a young victim. Illustrations like these were used as examples to track down individuals infected with the smallpox virus (variola virus) during the World Health Organization campaign to eradicate the disease. Courtesy of CDC/Dr. Robinson (CDC PHIL ID#10398). See also the interview with Dr. Donald Henderson: http://bit.ly/Virology_Henderson.

In the 1790s, Edward Jenner, an English country physician, established the principle on which modern methods of viral immunization are based, even though viruses themselves were not to be identified for another 100 years. Jenner himself was variolated with smallpox as a young boy and was undoubtedly familiar with its effects and risks. Perhaps this experience spurred his abiding interest in this method. Although it is commonly asserted that Jenner’s development of the smallpox vaccine was inspired by his observations of milkmaids, the reality is more prosaic. As a physician’s apprentice at age 13, Jenner learned about a curious observation of local practitioners who had been variolating farmers with smallpox. No expected skin rash or disease appeared in farmers who had previously suffered a bout with cowpox. This lack of response was typical of individuals who had survived earlier infection with smallpox and were known to be immune to the disease. It was supposed therefore that, like smallpox survivors, these non-responding farmers must somehow be immune to smallpox. Although the phenomenon was first observed and later reported by others, Jenner was the first to appreciate its significance fully and to follow up with direct experiments. From 1794 to 1796, he demonstrated that inoculation with material from cowpox lesions induced only mild symptoms in the recipient but protected against the far more dangerous disease. It is from these experiments that we derive the term vaccination (vacca = “cow” in Latin); Louis Pasteur coined this term in 1881 to honor Jenner’s accomplishments.

Initially, the only way to propagate and maintain the cow-pox-derived vaccine was by serial infection of human subjects. This method was eventually banned, as it was often associated with transmission of other diseases such as syphilis and hepatitis. By 1860, the vaccine had been passaged in cows; later, horses, sheep, and water buffaloes were also used. The origin of the current vaccine virus, vaccinia virus, is now thought to be horsepox virus (Box 1.3).

      The first rabies vaccine was made by Louis Pasteur, although he had no idea at the time that the relevant agent was a virus. In 1885, he inoculated rabbits with material from the brain of a cow suffering from rabies and then used aqueous suspensions of dried spinal cords from these animals to infect other rabbits. After several such passages, the resulting preparations were administered to human subjects, where they produced mild disease but effective immunity against rabies.

      Today, viral vaccine strains selected for reduced virulence are called attenuated, a term derived from the Latin prefix ad, meaning “to,” and tenuis, meaning “weak.” Safer and more efficient methods for the production of larger quantities of these first vaccines awaited the recognition of viruses as distinctive biological entities and parasites of cells in their hosts. Indeed, it took almost 50 years to discover the next antiviral vaccines: a vaccine for yellow fever virus was developed in 1935, and an influenza vaccine was available in 1936. These advances became possible only with radical changes in our knowledge of living organisms and of the causes of disease.

Microorganisms as Pathogenic Agents

      The 19th century was a period of revolution in scientific thought, particularly in ideas about the origins of living things. The publication of Charles Darwin’s The Origin of Species in 1859 crystallized startling (and, to many people, shocking) new ideas about the origin of diversity in plants and animals, until then generally attributed directly to the hand of God. These insights permanently undermined the perception that humans were somehow set apart from all other members of the animal kingdom. From the point of view of the science of virology, the most important changes were in ideas about the causes of disease.

The diversity of macroscopic organisms has been appreciated and cataloged since the dawn of recorded human history. However, a vast new world of organisms too small to be visible to the naked eye was revealed through the microscopes of Antony van Leeuwenhoek (1632–1723). Van Leeuwenhoek’s vivid and exciting descriptions of living microorganisms, the “wee animalcules” present in such ordinary materials as rain or seawater, included examples of protozoa, algae, and bacteria. By the early 19th century, the scientific community had accepted the existence of microorganisms and turned to the question of their origin, a topic of fierce debate. Some believed that microorganisms arose spontaneously, for example, in decomposing matter, where they were especially abundant. Others held the view that all were generated by their reproduction, as are macroscopic organisms. The death knell of the spontaneous-generation hypothesis was sounded with the famous experiments of Pasteur. He demonstrated that boiled (i.e., sterilized) medium remained free of microorganisms as long as it was maintained in special flasks with curved, narrow necks designed to prevent entry of airborne microbes (Fig. 1.6). Pasteur also established that distinct microorganisms were associated with specific processes, such as fermentation, an idea that was crucial in the development of modern explanations for the causes of disease.