How Humankind Got Ahead of Infectious Disease

With polio on the verge of eradication, a career immunologist explains the medical marvel of vaccination and the pioneers who made it possible

School girls line up to receive vaccinations between classes. © Paul Chesley/National Geographic Society/Corbis

World health officials and organizations are currently involved in a final push to eradicate polio, the paralyzing disease that was once a crisis in the United States but now remains in just three countries—Pakistan, Nigeria and Afghanistan. If the efforts succeed, polio will join smallpox as one of the only human infectious diseases to have been eliminated, entirely. Such a feat involves cooperation, coordination and determination, but it also rests on one crucial development: vaccines, what career immunologist John Rhodes calls “the most successful medical measure of any.”

Rhodes has spent his life studying how the immune system reacts to first encounters with infectious agents and other fundamental aspects of vaccine development and success. His research interests have included influenza, malaria and HIV/AIDS vaccines, with time at the U.S. National Institutes of Health, the Wellcome Foundation in London and GlaxoSmithKline, where he was the director of strategy in immunology from 2001 until 2007. In his new book, The End of Plagues: The Global Battle Against Infectious Disease (MacSci), Rhodes traces the long road to vaccination and the twists and turns that are still ahead.

Your story begins with smallpox, widely cited as one of the biggest killers in history. How did that disease affect society?

Up until the 17th century, it was the Black Death, or bubonic plague, which had the most impact. The Great Plague of London, which happened in 1666, was the last major visitation, at least in Britain. After that, there was a considerable change in the pattern of disease in that smallpox became the biggest killer. The difference between the plague and smallpox is that smallpox afflicted people across the social scale. Those at the very highest, the very top of society, the highest in the land, seemed equally at risk, whereas in the case of the plague it was just the poor people who tended to die in very large numbers.

How many people were affected?

If you lived in London in the 18th century, then most children would have smallpox during their childhood. The mortality rates were about 20 to 30 percent. It was a common experience in virtually every household in the cities.

Help came from an unlikely source, a woman who was an aristocrat rather than a member of the medical profession. Who was Lady Mary Wortley Montagu, and what role did she play?

She was a remarkable woman and a pioneer of women’s rights. She went in 1717 to Constantinople, modern-day Istanbul, with her husband who was ambassador, where she found out the customs of ordinary people and discovered that the Greek people in Constantinople had this long-standing custom of protecting their children with the forerunner to vaccination, which is called variolation. By giving small amounts of the smallpox germ under the skin, preferably from a non-serious case of smallpox, they could protect their children. When she came back to London, she championed and pioneered this against a good deal of resistance, especially from members of the medical profession, who were still promoting the classical ideas of upsets in the four vital humors as being the cause of disease. Purging, vomiting, bloodletting were the treatments of choice at the time.

Mary was a lone voice. Then she convinced Caroline of Ansbach, the wife of the Prince of Wales, that this was the way to protect aristocratic children who could afford the treatment. Mary and Caroline pioneered it, which led to the first trial in 1721, the so called Royal Experiment in Newgate Prison, where a handful of prisoners were injected with smallpox on the understanding that if they survived they would be pardoned. (They were all due to be hanged.)

Was this approach seen as, well, gross at the time?

You have to remember that this was taking place when disease was rife, sanitation was poor, there was no reliable supply of clean water so diseases like cholera caused epidemics periodically. Inevitably, that is why people tended to drink beer—small beer it was called, with a low level of alcohol—because they knew it was safe. The standards of life were very much different from what they are today. Any sign of some sort of protective measure was seized upon and the standards of proof were very, very low. If it seemed to be safe, then people would adopt it because they hoped it would be lifesaving. That is how half a dozen prisoners came to persuade King George that this should be adopted for the members of his family.

At what point does Edward Jenner, the English doctor credited as the pioneer of vaccination, come into the picture?

Jenner was aware of variolation that had been championed by the Lady Mary and Princess Caroline, and also in the Americas by Cotton Mather. Jenner himself was variolated as a child; it was a horrendous experience. He was very unwell for quite a while. Part of the reason was that members of the medical profession were trying to regain ownership of the process from practitioners who they viewed as breaking from medical tradition, so they added a period of fasting and strange diet in order to remystify the process. Jenner came across the notion that milkmaids were never susceptible to smallpox, and he realized it might be possible to use an innocuous agent, cowpox, in order to do the same thing as the very dangerous variolation. It took him almost three decades before he actually did the experiments, in the late 1790s. It wasn’t a step in the dark. It was an improvement on something that already existed—a pivotal improvement, which relatively quickly spread across the world.

There are stunning stories of how vaccination spread. Can you offer an example?

The King of Spain and others essentially wanted to protect their colonies, which were enormously valuable assets to them. So, in the early 19th century, in what I’ve called “the founding voyages,” chains of children were vaccinated one by one so that the vaccine remained fresh over the course of a sea voyage. By the end of the voyage, the last few children would be vaccinated so there was fresh material, fresh cowpox material in this case, to begin to vaccinate in South America. The Portuguese also championed the same strategy. One of the good things was they didn’t confine it to their own colonies. They went into Asia as well. And that is how the spread of vaccination occurred across the globe.

Was there a backlash from skeptics?

I don’t think it was anything we would recognize as a legitimate reason to concern over safety. It was much more to do with religious and philosophical objections to the introduction of a bestial humor [a vital fluid from a non-human animal] into the human body. The idea of deliberately using a disease from a cow to protect humans against disease was repugnant to a large group of people. There were more reasoned critics who believed there was little benefit from vaccination, and it took a little while for it to convince people. But it was only a matter of five years or so before it was beginning its inexorable spread.

How did vaccination evolve, and eventually move beyond smallpox?

There was a sort of gradual, slowly evolving incremental improvement until the end of the 19th century. When there was an explosion in the field of bacteriology, scientists began to realize that there were many other diseases which could be addressed with vaccines, and that led to widespread attempts to bring about vaccines for other infectious diseases. Louis Pasteur and Robert Koch were the important figures of the late 19th century.

It was germ theory that altered everything. In the 1860s, Pasteur was first to show that germs do not arise spontaneously. They exist pretty much everywhere around us. He did away with the theory of spontaneous germ generation. He also managed to produce a vaccine against rabies and also cholera. And a lot of his discoveries were almost serendipitous. In the case of cholera, the researchers had left a culture of cholera germ out on the bench, so it grew weak. Then, when they injected it into chickens, instead of getting cholera, the chickens were protected against subsequent infection… Pasteur knew all about Jenner’s work, by the way, and he used the term “vaccine,” extending it to all kinds of vaccines in Jenner’s honor.

Thereafter, there were all kinds of exciting stories. One of the most important was the discovery antibodies, or antitoxins as they were then called.

It’s clear that vaccines have brought us a long way. What are the plagues that, contrary to your book’s title, are still threats?

Malaria is a huge killer on a global scale and a lot of the disease burden is in the developing world. There are exciting vaccines in the pipeline for malaria.

And tuberculosis, surprisingly, still produces a huge mortality on the global scale. The BCG vaccine, discovered in the early part of the 20th century, is highly controversial. It is used in Britain and used in Europe and third world countries, but it is not used in the U.S.A. One of the problems is if you vaccinate against TB with BCG, you can’t then screen for whether someone has TB or not. If you have been vaccinated, it looks as though you’ve been exposed.

The third is HIV/AIDs, where there has been so much effort and interest in developing a protective vaccine. It has been hugely frustrating for a decade at least. It is partly because the virus targets the very system you are trying to enhance and strengthen—it targets the immune system and the cells, which normally defend us against infection. Those three I would pick on as the major global targets, together with polio.


Interested in learning more? Read John Rhodes' The End of Plagues: The Global Battle Against Infectious Disease (MacSci).

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