The first two children fell ill around June 17, 1894, their legs suddenly unwilling to cooperate. The disease spread from there, striking at random as it swept through Rutland County: a 6-year-old girl paralyzed in all extremities; a 2-year-old boy unable to move his legs; a 3-year-old boy who seemed to get better, until he fell into a coma and died.

"Many of these [children] were taken sick without apparent cause," Charles Caverly, a 37-year-old Rutland doctor, wrote in the Yale Medicine Journal later that year. "After a few weeks deaths were heard of, and during the latter part of July everyone was discussing 'the new disease.'"

Other instances of "infantile paralysis" — or polio, as it later became known — had been documented long before this, but cases were few and far between. Most physicians had never encountered it.

As president of the Vermont State Board of Health, Caverly felt a duty to investigate. He surveyed his Rutland County colleagues and found that, by summer's end, there had been 132 suspected cases of the malady. Most were children younger than the age of 6, but roughly a dozen teenagers and adults fell sick, too, including a 70-year-old woman. More than 50 cases resulted in paralysis; 18 people died. 

Caverly effectively documented the first major polio outbreak in history. In doing so, he debunked the prevailing belief that only children could be stricken, and he became one of the first physicians to recognize that polio could occur with or without paralysis. He provided the clearest evidence to date of the disease's potential to become an epidemic. 

Now, as the world stands on the brink of eradicating polio more than a century later, the Green Mountain State may once again make a difference. 

Researchers at the University of Vermont Larner College of Medicine's Vaccine Testing Center are conducting a pair of trials using new polio vaccines to determine whether the modernized cocktails can replace existing ones and better protect children. If the results are promising, the drugs could eventually be added to the global arsenal and, experts hope, eradicate the disease once and for all. 

"Vermont had a seat at the very beginning of the history of polio in this country, if not worldwide," said Jessica Crothers, a UVM pathologist who's leading one of the two trials. "And now, we're in the position to play this important, starring role in what is hopefully the last chapter of polio." 

It may surprise Americans to learn that there's a need for new polio vaccines, given that the disease was eradicated in this country in 1979. The World Health Organization declared war on polio a decade later, and billions of dollars have been spent on eliminating it since — with much success. Incidences of polio have since dropped by 99 percent, and the disease has disappeared from most countries. In 2016, only 42 cases were reported worldwide.

But polio has maintained a foothold in parts of Africa and the Middle East, infecting a small but growing number of children in recent years. These outbreaks now rarely involve the "wild" forms of the polio virus; only two nations — Afghanistan and Pakistan — have reported such cases this year. Instead, most modern outbreaks are caused by mutations in one of two existing vaccines. 

That vaccine, named after Albert Sabin, a Polish American medical researcher who developed it in the 1950s, is administered orally and has been a mainstay of the global vaccination effort for decades. It contains a weakened strain of the virus that immunized children can pass through their feces — the same way wild polio spreads. 

If the weakened form of the virus spreads to enough unvaccinated people, it can regain its strength over time and eventually resemble the wild kind, sometimes causing paralysis. While very rare, these so-called vaccine-induced polio outbreaks have become more prevalent as of late, causing nearly 1,000 cases across 27 countries in 2020. 

Most wealthy countries, including the U.S., stopped using the oral vaccine years ago because of this risk, instead relying on the injectable vaccine, which is named after Jonas Salk, the American virologist and medical researcher who developed it in the 1950s. That injectable vaccine remains a staple in the American childhood immunization regimen: 93 percent of U.S. children get jabbed by the age of 2, according to the Centers for Disease Control and Prevention.

But poorer countries have stuck with the oral vaccine for mass immunizations because it is easier to administer — just two drops in a child's mouth.

For more than a decade, researchers have searched for a safer alternative. They secured emergency approval from the World Health Organization last November to begin distributing a new version of the vaccine that's more stable and less likely to mutate. Tens of millions of doses have been distributed.

But that vaccine targets only one of the three main polio strains, type 2, while versions targeting the other two strains are still being studied.

That's where UVM comes in. The university's Vaccine Testing Center recently launched a trial of type 1 and type 3 oral vaccines through a global effort funded by the Bill & Melinda Gates Foundation. It's one of only three such studies under way in the U.S. The other two are at Dartmouth University and the University of North Carolina at Chapel Hill.

E. Ross Colgate, a UVM researcher leading the trial, cited two objectives. "We need to be absolutely sure that these new, novel vaccines are as safe, if not safer, than the current oral polio vaccine," she said. "And then [we measure] immunogenicity — so, are we getting the level of immune response that we need to protect people?" 

The trial will include roughly 75 participants ages 18 to 45 who have previously been vaccinated against polio. Half will receive the existing oral vaccine while the rest will get the new ones. Blood samples from all participants will be sent to the CDC, where they will be tested for antibodies that are strongly correlated to protection from the disease. The aim is to finish the study by the end of next year. 

If approved, the new vaccines would likely be deployed alongside the updated one already in circulation, Colgate said, though it's possible that the three could eventually be combined into a single regimen. 

The U.S. is not expected to switch to the oral vaccine, Colgate said. But that doesn't mean the researchers' work won't make an impact here. The Vaccine Testing Center is also gearing up for a separate study exploring changes to the injectable vaccine. 

That trial will investigate a potential way to disrupt the transmission cycle. The existing injectable vaccine induces an immune response strong enough to guarantee that recipients won't catch polio, but it's less effective in stopping the spread of it. Vaccinated people could potentially travel to areas where polio still exists in the environment, pick it up without getting ill and shed it in their stool for a couple of weeks.

"You're always going to have some people that are immune suppressed, that either can't vaccinate or won't mount an immune response, and those people will still be at risk because these viruses will still be in circulation," explained Crothers, the UVM pathologist who's leading the second trial. 

Researchers have infused the injectable vaccine with a chemical ingredient known as an "adjuvant" that helps jump-start the immune system. Blood samples from recipients of the boosted version will be tested against those who receive the regular one. The trial is expected to begin in late spring, and the researchers are still seeking volunteers. 

"A lot of us feel a sense of global community, but it's hard to find ways that you feel like you can actually effect change," Crothers said. "But this is a real, tangible action that people here can take to bring a safer vaccine and actually help people in their global community." 

Caverly, the Rutland doctor who documented the first major polio outbreak, spent the rest of his career searching for answers to the disease. He was at the front line when another outbreak struck Montpelier and Barre in 1917, resulting in 171 infections — which led to 103 cases of residual paralysis and 15 deaths. His work was cut short a year later, when he died from another infectious virus in the 1918 influenza pandemic. 

A self-described student of history, Crothers easily draws parallels between the century-plus fight against polio and the current fight against COVID-19. "We're not alone in history," she said. "There have been parents and communities at different times here in Vermont that have lived through quarantines, have lived through unknowns and fears." 

U.S. polio outbreaks became increasingly common in the first half of the 20th century, infecting about 35,000 people annually by the late 1940s before peaking at 57,000 in 1952. 

Few diseases instilled more fear in parents, who became terrified of letting their children out of the house during the summer months, when the virus seemed to peak. Franklin Delano Roosevelt, the nation's president from 1933 to 1945, was thought to have contracted it through swimming.

Images of hospital wards full of children stuck in mechanical respiratory machines known as "iron lungs" were seared into the national consciousness. 

"There was a lot of political and economic will put behind the fight against polio," Crothers said. "Never before was the public so invested, informed and engaged in the scientific process." 

Indeed, roughly 100 million Americans pitched in toward the development of a polio vaccine, donating coins to the private charity March of Dimes to help fund the research. Church bells rang across the country when it was announced on April 12, 1955, that the Salk vaccine worked.

"DOOM OF POLIO IS HAILED WORLDWIDE," shouted the front page of the Caledonian-Record, which featured half a dozen stories on the development, including one announcing that Vermont children could begin getting vaccinated within two weeks. Caverly's hometown paper, the Rutland Daily Herald, ran the headline: "Potent New Salk Vaccine to End Terror of Polio." 

Comparing the public's reaction then with the often charged conversation surrounding immunization now, Crothers opined that vaccines have become a victim of their own success. When the polio vaccine arrived, many parents personally knew kids who had been paralyzed. "They knew the risk of not being vaccinated," Crothers said, "so the risk-benefit analysis that they did in their head was very clear to them.

"People do that analysis now, and it's less clear, because they don't have those personal stories," she said. "I think that's kind of what we're feeling now during COVID: that the risk-benefit-reward analysis is subtler, more complicated and more nuanced."