Occasionally on the news you hear journalists call vaccine research a “cat-and-mouse” game. That’s only partially true. It misses the point that, if the cat doesn’t get its claws into the mouse, sometimes the mouse turns around and kills the cat. This game has been going on for most of recorded history and, as we have become better-educated about the nature of viruses and vaccines over the last 18 months, it’s safe to say that we have gained a greater respect for both the cat and the mouse.

Thankfully, in 2021, the cat seems to have gained the upper hand. Because, for most of human history, let’s face it: The mouse was winning. Until relatively recently, in fact, unchecked viruses, diseases, infections and a fundamental misunderstanding of how the body works doomed most people to an early grave.

Which explains why the idea that human beings might somehow create resistance or immunity to serious illness stretches back centuries—and how we arrived at the current state of vaccine technology. Long before scientists understood how epidemics spread, or even what they were, many cultures in Europe, Asia and Africa subscribed to the belief that exposure to a small amount of virus could boost immune response and prevent large-scale deaths. As the vaccines developed in late 2020 and early 2021 helped us turn the corner on COVID-19, it is worth a look back at how we got to where we are today.

The Scourge of Smallpox

The initial breakthrough dates back more than 1,000 years to China, where we find the first mention of variolation experiments. Variolation takes its name from the scientific name for smallpox, variola. Smallpox killed an estimated one-third of the individuals who contracted the disease, and left its survivors hideously scarred and often sterile or blind. A ship entering an ancient harbor with reports of smallpox aboard was often quarantined until the disease had run its course. The root of the word quarantine, with which we are now all too familiar, is quarantena. It originated with the policy in Venice during the bubonic plague of the 1300s and 1400s, when all ships arriving at the Italian port were compelled to anchor for 40 days before sailors could come ashore. For the record, the “quarantine” imposed on travelers during the coronavirus pandemic isn’t a quarantine at all; technically it is medical isolation.

Variolation involved various methods of introducing a small amount of biological material taken from an infected patient into an uninfected person. Among the ways this was accomplished was with a needle piercing a smallpox pustule and then being scraped across the skin of a healthy individual. Another was the collection of scabs from a smallpox victim, which were then ground up and rubbed into an incision in the skin—or blown up the healthy person’s nose. Sometimes a needle and thread that had been pulled through a smallpox pustule were pulled through a small scratch in the uninfected patient’s skin. The goal was to induce a very mild version of the infection, which (fingers-crossed) would subside in a few weeks and create a strong resistance to smallpox.
Early adopters of variolation did not include England, which considered itself the world leader in medical expertise, which it wasn’t. However, enough prominent physicians had used it effectively in the 1600s and early 1700s to finally convince the government to approve its use against smallpox in the early 1720s, with the full support of the Royal Family. Remember, at this point scientists had almost no understanding of how viruses and bacteria caused disease. Predictably, there was public outcry against variolation—the precursor to today’s anti-vaxers—not just in Great Britain, but in the American colonies, as well. To many, giving someone a dreaded disease they didn’t have seemed crazy and dangerous. In Boston, clergyman Cotton Mather was the target of a bomb for his advocation of variolation. The explosive hurled through his window contained a note that read You dog, dam [sic] you; I’ll inoculate you with this; with a pox to you.

Mather was a controversial public figure who had his hands in just about everything in the Massachusetts colony and was nothing if not a paradox. For example, he was devoted to importing Newtonian science to the American wilderness on the one hand while, on the other, he was the guy who set up the Salem Witch Trials. Mather learned of variolation not from Newton or other British scientists but from a Libyan slave he received in 1703 as a gift, who he rechristened Onesimus (his real name is lost to history). Curious about the scars on the man’s body, Mather listened as Onesimus explained how North African cultures dealt with smallpox. He then spearheaded a variolation campaign during an outbreak in Boston that yielded spectacular results. And took all the credit, of course.

Within a generation, our Founding Fathers had all hopped on the variolation stagecoach. Benjamin Franklin convinced English physician William Heberden to produce a pamphlet touting the success of smallpox inoculation (a word borrowed from horticulture, originally related to the grafting of plants) and distributed it free of charge throughout the 13 colonies. Two decades earlier, Franklin had lost a son at age four to smallpox. The pamphlet included do-it-yourself instruction for home inoculations—a forerunner of YouTube videos for DIYers. George Washington contracted smallpox as a young man, which some have theorized was responsible for his inability to produce offspring with Martha. True or not, it did make him immune to the smallpox outbreaks that would ravage military camps during the American Revolution. One of Washington’s lesser known edicts as commander of the Continental Army was that his soldiers had to be variolated. During Thomas Jefferson’s presidency, he personally conducted inoculation experiments on his slaves at Monticello, demonstrating both his enlightened approach to science and his unenlightened regard for human freedom and dignity.

Vaccines Arrive

There were worse jobs for young ladies in 18th century Europe than being a milkmaid, but like most occupations it came with its own set of risks. Repeated contact with a cow’s udder, especially by someone with broken or abrased skin common to farm work, was an invitation to contract cowpox, which produced pustules on the hands and forearms. The disease was considered an occupational hazard—rarely serious and, once a girl got it, she didn’t get it again. And, farmers began to notice, those girls didn’t contract smallpox, either—even after close contact with workers or family members who did. In 1774, smallpox began tearing through the county of Dorset in the south of England. A farmer named Benjamin Jesty used fluid from cowpox lesions to successfully inoculate his wife and children against smallpox. Over the next 20 years, similar stories caught the attention of scientists. Another piece of the puzzle was that British cavalry officers tended to dodge smallpox outbreaks, presumably from exposure to horsepox, a close relative of cowpox.

In 1796, English scientists Edward Jenner made the big breakthrough. He took a sample of pus from the lesion of a cowpox-infected milkmaid and injected it into an 8-year-old boy who had never had smallpox. Six weeks later he injected smallpox into the boy, who was the son of his gardener—which poses some uncomfortable questions about Jenner’s moral compass—but lo and behold, there was no reaction! Jenner called this process vaccination, from vacca, the Latin word for cow. Recent DNA research suggests that the disease Jenner was working with may have been transferred from horses to cow, possibly through farriers, whose farm duties often involved shoeing horses and milking cows. In which case you could say that we are all getting equivaccinations this year.

Vaccinations caught on quickly in the United States and, in 1813, President James Madison signed a bill creating the National Vaccine Agency. Part of that bill waived postage fees for vaccine material. England went one better, making vaccination of infants mandatory; if parents refused, they faced possible imprisonment. In 1863, little more than halfway through Abraham Lincoln’s first term as President, he contracted smallpox and was desperately ill for a month before recovering. His valet, William Henry Johnson, was not so lucky. He caught smallpox from Lincoln and was dead by the end of January. He had worked with Lincoln going back to his Springfield days. Some historians posit that the president contracted the disease around the time he delivered his Gettysburg Address, which in retrospect had all the earmarks of a textbook super-spreader event.

The next breakthrough in vaccines was discovered, somewhat accidentally, by Louis Pasteur in 1879. The French biologist was the first person to create a vaccine in a lab. An oversight by an assistant during an experiment with chicken cholera demonstrated that exposure to oxygen makes bacteria less deadly. This led the way to several more discoveries, including the rabies vaccine in 1885. By the turn of the century, researchers in the U.S. and Europe were beginning to get the upper hand on typhoid and cholera and, by World War I, the first vaccines for these diseases were becoming available.

At War with Disease

There were setbacks, of course, including a terrible story here in New Jersey, where nine children died from tainted smallpox vaccines. That incident led to the Biologics Control Act, which was passed in 1902. However, then as now, the increasing involvement of the government in public health was not always appreciated. In England and America, there was small but vocal opposition to vaccinations, mostly citing an infringement on personal freedom. Massachusetts was the first state to make smallpox vaccinations mandatory and the resulting lawsuit went all the way to the Supreme Court. In 1905, the court upheld the constitutionality of the program in Jacobson v. Massachusetts. In 1909, Americans learned the story of Mary Mallon, the woman dubbed “Typhoid Mary” by the press. She was what we now call an asymptomatic spreader of the disease, who worked as a cook for several wealthy families and, later, for hospitals, hotels and restaurants. Everywhere she worked (often gaining employment under a fake name) a typhoid outbreak soon followed. Mallon finally had to be quarantined on North Brother Island, near Riker’s Island in New York’s East River.

The need for further progress on the vaccine front was made particularly clear in the waning days of the First World War, when the Spanish Flu—which probably originated in a U.S. Army camp in Kansas—spread across the planet and killed tens of millions people. It was a particularly powerful version of the H1N1 influenza virus; it took a particularly high toll on young, healthy adults, who normally weathered the flu without incident. It spread fast, killed quickly and if a patient’s lungs filled with fluid, there was nothing doctors could do. If you got it, you went to bed and waited:
On the last day of that year, 1918, I went up to the shop with a bad cold. Influenza had been raging in [Norwood, MA], the hospital was crowded, and there were deaths almost daily. About two hours after going to work, I collapsed. It had got me. I was taken home, went to bed and a doctor was summoned. I was past 70, but he was the first doctor since my birth who had ever been called to treat me. He found me in great pain, temperature 104, but said my lungs were not affected. For several days as I lay in bed, I did a deal of thinking. I thought it was probable that I was near the end of the race, but I had no dread. I was comforted that I had been able to keep up the payments on my life insurance, and that my wife would have the use of it in her old age.
This patient, my great-grandfather George Stewart, survived to write this account before he died, in 1925. He was never the same, however. George was unable to walk more than a short distance or do anything that required strength, including ascending the flight of stairs leading to the second floor of his home. In his defense, I know those stairs. They are weirdly steep and are available if a movie company is interested in remaking the Hitchcock classic Vertigo. The point here is that the world became fixated on understanding how the influenza virus mutates and spreads, the long-term impact for survivors, and what could be done to give humans a fighting chance. A century has passed and we are still addressing these challenges.

How To Make a Vaccine

The first important step in creating an effective, mass-produced flu vaccine was to develop a process for growing (or culturing) viruses in large quantities. Scientists already knew how to culture bacteria—give them a comfy medium and they’re off to the races—which was the key to making vaccines for bacterial illnesses. However, viruses don’t reproduce on their own. A virus must first infect a cell before using the cell to make copies of itself, and at the time of the Spanish Flu there was no method for growing viruses outside of a living host. The breakthrough came in the mid-1930s, when two English researchers discovered separately that the flu virus could be grown on the membranes of fertilized hens’ eggs—and soon after isolated the first neutralized antibodies. One of the U.S. scientists working on the flu vaccine at this time was Dr. Jonas Salk, who used what he’d learned in the 1930s to tackle polio in the 1950s.

The U.S. President during this era was Franklin Roosevelt, who had been stricken with polio as a young man. His inability to walk or stand was the best-kept/worst-kept secret in America. During a 1938 radio broadcast, entertainer Eddie Cantor, whose program had an audience of millions, pitched the idea of sending dimes to the White House to help fund polio research. Listeners sent more than 2 million dimes to Washington, triggering a grassroots effort that involved several more national celebrities and eventually became known as The March of Dimes. A year after FDR passed away, his profile replaced the head of the winged liberty on the silver 10-cent piece, commonly known as the Mercury dime. Reach into your pocket and you’ll notice that this coin still bears his image.

Building on a wave of discoveries by virologists and epidemiologists, over the next three decades, life-saving vaccines came fast and furious, including increasingly effective flu vaccines, Diphtheria-Tetanus for infants, and measles and mumps vaccines. The crowning achievement of the post-war era was the creation of an effective injectable polio vaccine by Dr. Salk. Salk’s work followed several research breakthroughs dating back to the 1930s and was ready for testing in 1952, the same year polio cases in the U.S. surged over 50,000. Testing proceeded over the next two years, culminating in the Francis Field Trial, which involved more than 1.8 million schoolchildren. It was the largest medical experiment in history at that time and the results were extremely positive, despite a one-man anti-vax campaign waged by gossip columnist Walter Winchell. Winchell “uncovered” that several monkeys had died during initial testing and labeled the Salk vaccine a killer, likening it to a phony cancer cure—and adding that even if the vaccine were 99% effective, well, that wasn’t good enough. Winchell was what we would now call an “influencer”…more than 150,000 parents pulled their children out of the study.

Nevertheless, the Salk vaccine was licensed in 1955 and, thanks to an ingenious “rocking bottle” manufacturing method developed by a team led by Canadian biochemist Leone Farrell, went instantly into mass production. An interesting sidenote is that when Salk traveled to Toronto to meet with Farrell’s team, she was barred from the reception because it was held in a men’s-only club. Farrell was an astonishing figure in medicine who is largely forgotten today; she later devised a way to accelerate penicillin production.

Where We Are, Where We’re Going

Over the last 30 years, vaccines have successfully tackled countless health issues in the U.S. and around the world, including hepatitis, shingles, cervical cancer and the H5N1 avian flu. However, viruses are nimble and clever. When faced with obstacles, they do what we do: evolve and mutate in order to survive. That’s why we get flu shots every year and why sometimes they are only 50% effective. And that’s why scientists are still looking for ways to eradicate tuberculosis, malaria, Lyme disease and hepatitis C. And HIV. And the common cold.

Keep in mind, too, that it takes a billion or more dollars and a decade of research and testing to develop a viable vaccine, and even with government funding, often private industry and investment funds determine what’s “worth” the time, money, effort and risk…and what’s not.

The arrival of COVID-19 on American shores in the winter of 2019–20 and our less-than-stellar response to the virus (including the politicizing of mask-wearing) will leave a public-health and also a cultural legacy that is certain to be with us for a long time. What we will probably forget pretty quickly is how vaccines were going into arms within a year of the start of the pandemic. That is an insanely short period of time to develop a vaccine for a virus that seemed to have everyone baffled at first.

How did it happen so quickly? The short answer is computers. Once the COVID-19 genome was posted by Chinese researchers, the vaccine could essentially be created on a computer screen and then go right into manufacturing. Also, no one in the vaccine game starts from scratch or goes it alone. The COVID-19 vaccines out there now had a scientific running start, which was further accelerated by Operation Warp Speed. The running start in this case were the multiple safe and effective vaccine platforms created since Edward Jenner started tinkering with cowpox. COVID researchers looked at which ones were most likely to offer the highest level of immunity and produce the least side effects, and then got right into determining which proteins, or viral antigens, would generate an immune response that would protect people from the disease.

As it turned out, the quick-turnaround vaccines used mRNA and vector-based platforms. The vector-based strategy was developed in the fight against SARS. Since the viral enemy is technically SARS-CoV-2, that seems logical. The mRNA platform was utilized in treating Zika a few years ago. What both have in common is that they did not exist in the 20th century. They are relatively new but appear to be safe. What is still in question is how long vaccinations will last—like the flu vaccine, we may need a new one every year—and whether they will be effective against the variants that will almost certainly develop in the coming months.

So is 2021 the Year of the Cat? Did we catch and kill the mouse? It may be too early to claim total victory. The mouse undoubtedly has a few more tricks up its sleeve. Also, human behavior is nothing if not unpredictable; even when Americans are “fully vaccinated,” there will be outliers who refuse the needle. And finally, just because we are vaccinated, that doesn’t mean they are. And by they I mean a billion or more people in developing countries who are unlikely to be offered, or avail themselves of, a vaccine—or who fall prey to supply-chain problems, as happened in India this past spring.

This is where the mouse loves to play. Hopefully the cat is watching. EDGE