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Louis Pasteur and the Development of the Attenuated Vaccine

By November 23, 2016eVLP Platform

Since their earliest and most rudimentary introduction in the late 18th century, vaccines have fundamentally changed the way modern medicine is practiced and have eliminated or managed the incidence of some of the most devastating human diseases. Humankind has benefited from vaccines for more than two centuries, but the path to discovering effective vaccines was long and difficult. The work required a number of brave research pioneers and clinicians.

In this spirit of giving thanks this holiday season, we will explore the history of vaccines and the work of the 19th century pioneer Louis Pasteur, who was the first scientist to create a vaccine in a laboratory setting.

Born in 1822 to humble beginnings in Dole, France, Louis Pasteur was a hard-working, serious child, who at a young age demonstrated a greater interest in the arts than the sciences. Few would have predicted that he would grow up to be one of the most important scientific figures of the 19th century.

During the course of his career, Pasteur made crucial discoveries in chemistry, biology, and medicine. He was the first to discover molecular chirality and spontaneous resolution while studying crystallography. He studied fermentation, demonstrating that it is a chemical process carried out by microscopic organisms. These findings gave him the information necessary to disprove the myth of spontaneous generation and to propose methods for preventing the growth of bacteria in food items. His name quickly became a household word for food safety, e.g. “pasteurization”.

Louis Pasteur in 1857. Source: National Library of Medicine

Pasteur’s studies on microorganisms inspired him to pursue the study of infectious diseases. While studying an epidemic in silkworms that was disrupting France’s silk industry, he isolated the microorganisms causing the disease. This finding led him to propose the germ theory, which simplistically states that many diseases are caused by microorganisms too small to see without magnification. The germ theory would revolutionize the medical world and have a number of important practical consequences, including increased hygiene standards in the medical community and a newfound interest in disease-causing bacteria in the research community.

By the early 1870s, Pasteur had already established himself as a renowned leader in research, and in 1877 Pasteur began to fully immerse himself in the study of disease. At the time, Pasteur was studying chicken cholera (Pasteurella multocida), a diarrhoeal disease that was destroying the breeding chicken population. Influenced by Edward Jenner, Pasteur reasoned that if a vaccine could be found for smallpox, vaccines could be found for all diseases.

By 1878, Pasteur had succeeded in culturing the causative virulent bacteria of chicken cholera and began inoculating chickens. However, many chickens died after the procedure so Pasteur continued to study the disease, looking for safer inoculation methods. It was during this study that Pasteur changed the field of virology forever.

In 1879, Pasteur observed, by chance, that old bacterial cultures lost their virulence. He had instructed an assistant to inject the chickens with a fresh culture of the viral bacteria before a holiday. The assistant, however, forgot and went on vacation. When he returned a month later, he performed the procedure using the old cultures. Unexpectedly, the chickens only showed mild signs of the disease and survived. When they were healthy again, Pasteur, intrigued by the results, injected them with fresh bacteria. The chickens did not become ill. Pasteur reasoned the factor that made the bacteria less deadly was exposure to oxygen.

The discovery of the chicken cholera vaccine by Louis Pasteur revolutionized work in infectious diseases and can be considered the birth of immunology. The notion of using a weakened form of the disease to provide immunity was not new, but Pasteur was the first to take the process to the laboratory, impacting all virologists who followed after him.

The microbe, weakened in the lab, had taught the chicken immune system to fight the infection without causing any serious harm to the chicken. This type of vaccine is called a live, attenuated vaccine. Hypothesizing the technique could be extended to other diseases, Louis Pasteur continued to explore illnesses in the pursuit of new vaccines. In 1881, he helped develop a vaccine for anthrax, which was used successfully in sheep, goats and cows. Then, in 1885, while studying rabies, Pasteur tested his first human vaccine. Pasteur produced the vaccine by attenuating the virus in rabbits and subsequently harvesting it from their spinal cords.

Louis Pasteur performing an experiment.

Rabies had presented a new obstacle for Pasteur in the development of a successful vaccine. Unlike chicken cholera and anthrax, both caused by bacterium, the microorganism causing the disease could not be specifically identified, meaning Pasteur would not be able to develop the vaccine in vitro (in the laboratory).

Pasteur did not know this at the time, but the reason he could not find the microorganism is because rabies is a viral disease. Viruses are small infectious agents that replicate quickly and have a high mutation rate. These rapid mutations can be used to the benefit of researchers in the development of an attenuated vaccine. By serial passage of a virus through a different species, the virus becomes more adapted to that species, and less adapted to its original host, deceasing virulence with respect to the original host (e.g. it is “attenuated”). By passing the virus through rabbits, Pasteur made the virus less dangerous to human hosts, while still giving the body enough information to recognize the antigen and develop immunity to the “wild” version of the disease.

Louis Pasteur in his laboratory, painting by Albert Edelfeldt in 1885.

After successfully protecting dogs from the disease, Pasteur agreed to treat his first human patient, a nine-year-old boy who had been so severely attacked by feral dogs there was little doubt he would die if nothing was done. Pasteur injected the boy with a daily series of progressively more virulent doses of the vaccine from the rabies-infected rabbits. The boy never developed symptoms and Pasteur became an international hero.

Until Louis Pasteur developed the rabies vaccine, “vaccines” had referred only to the cowpox inoculation for smallpox. His procedure was originally called “Pasteur’s treatment”, but Pasteur decided to honor the 18th century virology pioneer Edward Jenner, who publicized the cure for smallpox, and give these artificially weakened diseases the generic name of “vaccines”. Thus, we largely have Pasteur to thank for today’s definition of a vaccine as a “suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce immunity and prevent infectious disease or its sequelae.”

Louis Pasteur’s work advanced the nascent field of virology and served to spur vaccine research all over the globe. In subsequent decades, live, attenuated vaccines were developed and introduced against a number of the world’s most deadly diseases including diphtheria (1888), plague (1897), tuberculosis (1927), yellow fever (1936), measles (1963), mumps (1967), rubella (1969), varicella (1995), and rotavirus (1998).

While the variety of vaccine types has increased over the years, many of the vaccines used today are still live, attenuated viruses. In fact, among the list of recommended vaccines for U.S. children are a number of live, attenuated vaccines, including those for measles, mumps, rubella, varicella (chickenpox), and some type of influenza. Vaccination has substantially reduced morbidity and mortality from infectious diseases in much of the developed world. This result was ignited, in a large part, by the efforts of Louis Pasteur.

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