Philadelphia is an excellent place to learn about the history of vaccines, and The Wistar Institute, the country’s first independent biomedical research facility, is in great part responsible for this rich history. On Friday, September 28, Wistar Institute President and CEO Russel E. Kaufman, MD, spoke to a group of Wistar Institute friends and donors at The College of Physicians of Philadelphia. (Wistar is in the midst of a major construction project and has limited meeting space.)
He told that crowd that he wanted us to unlearn some things we think we know about vaccines. In particular, he mentioned that he wanted to draw our attention to the way that scientific advancement truly happens: typically, it doesn’t result from a brilliant insight, followed by a methodical plan of action. Rather, accidents, collaboration, and learning from the context of one’s scientific milieu are important factors that affect scientific progress.
Most histories of vaccination begin with smallpox. To establish the scope of the smallpox threat, Kaufman noted that more than 30% of those infected died from it, and about 80% of infected children died. Mortality from smallpox was devastating:
- During the fall of the Roman Empire, smallpox killed about 7 million people.
- An estimated 400,000 Europeans died from smallpox per year in the closing years of the 18th century.
- During the 20th century, 300-500 million smallpox deaths occurred.
- In 1967, when smallpox had been eliminated from most of the developed world, an estimated 15 million people contracted the disease and 2 million died.
Attempts to induce immunity to smallpox may go back to 10th century China. Early recorded practices are mentioned in the 1742 Chinese medical text The Golden Mirror of Medicine, which described four forms of inoculation for smallpox dating to 1695 in China. Three of the methods involved introducing matter from smallpox sores into a healthy, non-immune person. In these methods – as well as in the variolation method that Lady Mary Montague promoted – a person was infected with the ACTUAL illness. (One method involved the practice of crushing white cow fleas and administering the powder to humans.)
We’re all probably familiar with thinking about Edward Jenner as the originator of vaccination, but Kaufman urged us to consider the role of a much lesser-known person.
Before Jenner conducted his test in 1796, English cattle breeder Benjamin Jesty had conducted his own experiment by vaccinating his wife and children with cowpox as a smallpox epidemic bore down on his village. Had Jesty pursued his ideas and published them, he would have been the first to establish the principle that inoculation with a mild disease could induce immunity to a related, more severe disease. Instead, Jesty suffered the scorn of his neighbors, and Jenner became known as the discoverer of vaccination.
Next Kaufman discussed the development of rabies vaccination. Rabies was not a threat in the same ways smallpox was, but it was particularly a scourge in Europe in the 19th century. And rabies, unlike smallpox, was ALWAYS fatal.
A principle lesson in the history of rabies vaccine is the role serendipity played. During the time that Pasteur’s team was working on chicken cholera, a culture of the bacteria was left out and exposed to air while Pasteur’s team away on holiday. On their return, Pasteur attempted to infect a chicken with the material. And while the injected chicken produced a bit of a reaction, it did not develop the full-blown illness. This, then, was the genesis of the principle of attenuation, or of weakening a disease agent, and it is at the root of all vaccinology. Pasteur’s group would apply principle to their subsequent vaccines.
Young Joseph Meister was the first human to benefit from this concept of attenuation, when Pasteur instructed Dr. Charles Grancher to administer the rabies vaccine to him in summer of 1885. Each day they gave the boy a slightly more virulent version of the vaccine virus. Meister did not develop rabies, in spite of his 14 bites from a rabid dog.
Over the next 80 years, Pasteurian rabies vaccines produced many successes. But the nervous system components in the vaccine were highly reactogenic and in some cases caused serious illness and death.
Wistar’s Leonard Hayflick, PhD, made a key discovery that would provide a solution. Hayflick was vexed with the problem that normal human cells in culture would divide about 50 times and then would die. Cancer cells, such as the well-known cells collected from a tumor from Henrietta Lacks, would grow forever, but they were not a suitable medium for certain uses. Hayflick wanted to see if he could take a cell line that normally stops growing around the 50th generation and make it immortal. On his 38th try, his method worked, and the WI-38 cell line was established. This cell line, originally started with cells taken from the lung of an aborted human fetus, had no abnormalities and continued to grow normally.
Also at Wistar, Tadeusz Wiktor, DVM, and Stanley A. Plotkin, MD, were able to take advantage of Hayflick’s cell line. Wiktor was working on rabies, and Plotkin on rubella, and WI-38 could be infected with many viruses; in fact, it was exceptionally good at staying alive and churning out new copies of virus. Since their pioneering work in the 1960s and 1970s, Wistar has produced three vaccines from WI-38 – rubella, polio, and rabies. More than 1 billion people have received vaccines from this cell line. And in the case of rabies, one advantages of using a human cell line is obvious: eliminating nervous system components greatly reduced the side effect profile of the vaccine.
Today in the United States, 40,000 preventive rabies vaccinations are given each year to people who might be exposed to the virus: farmers, animal control workers, scientists, and even spelunkers (bat guano exposure can lead to rabies).
Kaufman defined a vaccine as “a substance used to stimulate immunity against an offending agent.“ What’s helpful about his definition for a new era of vaccine discovery is that it leaves out the word pathogen or microbe. So many infectious organisms have been the target of vaccines that 21st century vaccinology is turning to targets that are self produced, such as cancer cells or malfunctioning of the body’s own immune system (as in autoimmune diseases like lupus).
Wistar’s future work in vaccine development promises to be wide ranging. Recombinant DNA technology is allowing Trojan horse vaccines to deliver antigens more effectively, and HIV vaccines, universal influenza vaccines, and cancer vaccines are goals.
Kaufman ended his talk with the most important lessons he feels we’ve learned from the history of vaccines: that vaccine risks include serious adverse effects, and that, despite a benefit-to-risk ratio in favor of vaccination, the public remains concerned about adverse effects and coincidental adverse effects. These concerns, he thinks, are best dealt with through engagement to understand the public’s concerns and also with clear risk communication on the part of public health and medical experts.
NOTE: See the rabies section of Kaufman’s talk here: http://vimeo.com/50398465.