On May 4, 1837, Francis A. Chardon, the churlish head trader at FortClark, a fur-company outpost on the Upper Missouri River, reported in his journal, “Last night the Cock crowed five times.” The superstitious Chardon then added: “Bad News from some quarter is expected.”

But with the severe winter over, and the ice-clogged river finally thawed, Chardon’s mood inched toward optimism. The nearby Mandan and Hidatsa tribes had gathered hundreds of packs of bison robes. Traders and Indians alike were eagerly awaiting the arrival of the steamboat St. Peters, churning upriver from St. Louis to pick up the furs and drop off its annual load of supplies from Pratte, Chouteau & Company, the western branch of John Jacob Astor’s former American Fur Company.

The St. Peters, a 119-ton side-wheeler, docked at FortClark on June 19 and unloaded trade goods and Indian provisions. Also aboard was Chardon’s 2-year-old son, Andrew Jackson Chardon, whom he had fathered with a handsome Lakota Sioux woman, Tchon-su-mons-ka. That night the crew members of the St. Petersjoined in a boisterous “frolick,” singing and dancing with the men and women at the Mandan’s bustling village of Mit-tutta-hang-kush.

The next day the St. Petersheaded upstream toward FortUnion, at the mouth of the Yellowstone. But in its wake it left a ticking time bomb. In addition to its cargo of supplies, the steamboat had been carrying several passengers and crewmen infected with variola major, the lethal virus feared for thousands of years by its better-known name: smallpox.

Smallpox had previously swept across the high plains from Mexico in the late 18th century, ravaging the Mandan and other tribes such as the Ojibwa, Pawnee and Arikara, whose population fell by as much as two-thirds. But by the 1830s the Mandan and the other tribes of the Upper Missouri had largely outlived their acquired immunity to the disease, and none had been inoculated or vaccinated. As a result, the voyage of the St. Peterstriggered one of the most catastrophic epidemics recorded on the North American continent. “There is nothing in our experience we can compare it to,” says W. Raymond Wood, an anthropologist who has studied Plains Indian cultures. “It was completely devastating.”

The disease had announced itself when a St. Peterscrew member had showed symptoms on May 2, two weeks after the boat left St. Louis. Ignoring suggestions that the man be put ashore, the 33-year-old captain, Bernard Pratte Jr., said he needed every available hand to bring back to St. Louis the packs of profitable furs his company was expecting.

Chardon reported the first Mandan death from smallpox on July 14, less than a month after the side-wheeler left FortClark. Then Indians began dying at an accelerating rate—at first, two or three a day; later, entire families of eight or ten persons at once. “I Keep no a/c of the dead, as they die so fast that it is impossible,” Chardon wrote. Soon his young son Andrew would join them.

The deaths were as horrifying as they were numerous. Victims experienced high fever, chills and excruciating pain. With blood pouring from their mouths and ears, they often died even before the appearance of smallpox’s characteristic pustules. In a futile effort to find relief, sufferers threw themselves into water and rolled in hot ashes. Husbands and wives committed mutual suicide, stabbing themselves with arrows and knives, or leaping off cliffs. Chardon reported that one Mandan woman, after watching her husband die, killed her two children and “to complete the affair she hung herself.”

In scenes that might have been painted by Goya, bodies piled up in the village too rapidly to be buried and were dumped into the river. “This Morning two dead bodies, wrapped in a White skin, and laid on a raft passed by the Fort, on their way to the regions below,” Chardon reported, adding sardonically, “May success attend them.” After estimating that 800 Mandan had died by mid-September, Chardon—who never concealed his contempt for Indians—commented, “What a bande of RASCALS has been used up.”

The pandemic was no less terrifying elsewhere along the river. At FortUnion, the post at the junction of the Missouri and Yellowstone rivers, traders bungled an attempt to inoculate Indian women living there with scabs taken from a victim. Dozens of Indians died, as did whites who had not been inoculated, and the stench of decaying bodies inside the post was palpable 300 yards away. When one party of Assiniboine arrived outside the post’s walls, they were persuaded to leave only after the traders lifted an infected boy above the pickets, displaying for the visitors his ghastly face that “was still one solid scab,” as one of the traders later wrote.

Reports of the immensity of the horror on the Upper Missouri soon began to trickle eastward. William Fulkerson, who oversaw local Indian affairs from his base at Fort Clark, wrote to the explorer William Clark, at the time Indian superintendent in St. Louis, that “the small pox has broke out in this country and is sweeping all before it—unless it be checked in its mad career I would not be surprised if it wiped the Mandans and Rickaree [Arikara] tribes clean from the face of the earth.”

Clark forwarded Fulkerson’s letter to his superiors at the War Department back in Washington, D.C. But most of the federal government appeared to shrug off the impending disaster, following a familiar pattern: five years earlier, Secretary of War Lewis Cass had cut off funding of a vaccination program for the Indians in the Upper Missouri, apparently not wishing the doctors to proceed as far upriver as the pro-British Blackfeet. The powerful Chouteau family, which controlled fur trade on the Missouri, had likewise blocked a vaccination program because it would have delayed Indian hunting parties from leaving for their profitable trips to the high plains.

But this time, in the face of widespread administrative indifference, one U.S. official finally decided to take action. Joshua Pilcher, a 47-year-old Virginian, had just been appointed to take charge of the Sioux Agency at Fort Kiowa, north of today’s Chamberlain, South Dakota. Traveling to his new post on board the St. Petersduring its fateful trip, Pilcher had observed the disease spreading among passengers on the ship before he disembarked at his post, downriver from FortClark. Quickly realizing the nature of the unfolding calamity, Pilcher sent out messengers from FortKiowa to warn the nomadic Lakota and Nakota Sioux still hunting on the plains to stay away from the river in order to avoid contagion.

By the time he returned to St. Louis that winter, Pilcher had pieced together the first overall estimate of the extent of the tragedy. In just seven months since the first death, the Mandan had been reduced from 1,600 people “to thirty-one persons,” he wrote to Clark in February 1838. (Scholars now believe that there were 100 to 200 actual survivors.) Half of the Hidatsa had died, as had half of the Arikara. “The great band of [Assiniboine], say ten thousand strong, and the Crees numbering about three thousand have been almost annihilated. . . . The disease had reached the Blackfeet of the Rocky Mountains. . . . All the Indians on the Columbia River as far as the Pacific Ocean will share the fate of those before alluded to.” In short, Pilcher told Clark, the Great Plains were being “literally depopulated and converted into one great grave yard.”

But what to do? Pilcher reasoned that it was not too late to save the bands of nomadic Sioux whom he had warned away from “the fatal destroyer” over the summer—and were still on the plains. He proposed going upriver with a doctor and $2,000 in presents. They would try to locate the Sioux and persuade them to accept vaccination with the milder form of variola called cowpox. This vaccine, developed by the Englishman Edward Jenner in the 1790s, had proved so effective that Jefferson had urged Lewis and Clark to carry it with them on their historic expedition. (Their supply was damaged in transit and never used.)

As Pilcher observed, “It is a very delicate experiment among those wild Indians, because death from any other cause, while under the influence of vaccination, would be attributed to that and no other cause.” Nevertheless, he wrote to Clark, “If furnished with the means, I will cheerfully risk an experiment which may preserve the lives of fifteen or twenty thousand Indians.”

It was a bold and seemingly quixotic undertaking. The Indians were profoundly embittered toward the white traders who had inflicted the malady upon them, and some sought revenge. Chardon himself received several death threats and narrowly escaped an assassination attempt at FortClark. In a speech found among Chardon’s papers— the authenticity of which is doubted by some scholars—the dying Mandan chief Four Bears denounced the whites as “a set of Black harted Dogs, they have deceived Me, them that I always considered as Brothers, has turned Out to be My Worst enemies.” Four Bears allegedly went on to say that “my face is so rotten” that “even the Wolves will shrink in horror at seeing me,” and urged his warriors to “rise all together and Not leave one of them alive.”

The War Department, feeling pressure from church groups to take action to relieve the Indians’ suffering, approved Pilcher’s plan. But the agent needed to locate a doctor willing to enter the dangerous borderlands on the Middle and Upper Missouri, at a wage of $6 a day, to vaccinate the Indians. Who would risk such a perilous trip?

Pilcher would find his man in an unlikely spot: the roughhouse streets and saloons of St. Louis. Dr. Joseph DePrefontaine, who was apparently having little success in medicine, had started a new career in theatrical management—and had become notorious for his barroom carousing. In March 1838, DePrefontaine had been ordered out of his employer’s theater for rolling on the floor and singing during a performance of Hamlet. Undeterred, DePrefontaine took his revenge by writing newspaper articles attacking the theater.

Swallowing whatever doubts he may have harbored, and with no other applicants breaking down his door, Pilcher hired DePrefontaine. By April 1838, ten months after smallpox first hit the Mandan, the two men were ready to head up the Missouri to look for Sioux. At the St. Louis levee, they boarded the steamboat Antelope and proceeded upriver, making the usual stops at FortLeavenworth and the Black Snake Hills near present-day St. Joseph, Missouri.

Once past Council Bluffs, in what is now Iowa, Pilcher and DePrefontaine prepared to face tribes angry at whites and suspicious of vaccinations. Instead, they were astonished to find that the Indians had not only lost their fear of vaccinations but were eagerly seeking them. The two men stopped to vaccinate the Oto, Omaha and Santee Sioux. Just below the Sioux Agency at the mouth of the White River, they found “three or four thousand” Sioux who had gathered for the annual distribution of presents and annuities mandated by the Indians’ treaties with the U.S. government. “Having explained to the Indians the object of the physician, he commenced vaccinating,” Pilcher reported later in a letter to Clark. DePrefontaine soon found himself so inundated by “the mass of men, women and children that crowded around me” that he gave up any effort “to keep an account of ages, sexes, etc.” Working rapidly, he ran out of the vaccine supplied by the War Department and was forced to acquire more on his own, presumably from traders.

After the food and supplies were distributed to the hungry tribes, the Indians quickly departed, Pilcher wrote, like “a flock of Crows rising from a dead carcass—they are suddenly gone, and in a few hours are spread over the Country in every direction, in numerous small bands.” The two men continued upriver, vaccinating isolated bands of Yankton, Oglala and Saone. By the time the Antelope reached FortPierre, 1,500 miles above St. Louis, DePrefontaine estimated he had given 3,000 vaccinations, though Pilcher believed the actual total was far larger.

But DePrefontaine had not yet located several large bands of nomadic Lakota still hunting somewhere in the vast plains between the Missouri River and Rocky Mountains. Pilcher furnished him with more vaccine and sent him overland on horseback. His instructions were to find the Sioux, or to return to FortPierre in three weeks.

Unfortunately, the mission was only a partial success. De- Prefontaine himself fell ill from an unnamed malady “in the Prairies and was not so successful in finding the Indians as I anticipated,” Pilcher reported. Still, DePrefontaine located “several small bands, and operated on all that he found.”

A few months later, Pilcher was able to tell his superiors that the epidemic had finally subsided. He returned to St. Louis and eventually went on to serve as Clark’s replacement as superintendent of Indians. DePrefontaine continued to vaccinate tribes on the Missouri for at least two more years. But as often on the frontier, there was a fine line between humanitarian and rogue. In the 1840s, the mercurial doctor was identified as a member of a gang that robbed and murdered a Spanish merchant on the Santa Fe Trail. He later was reported to have been involved in an attempt to assassinate Frank P. Blair Jr., a prominent antislavery activist and future U.S. senator.

Pilcher and DePrefontaine may well have felt that their efforts did not make much difference in the end. The vaccination campaign saved thousands of lives—but as many as 20,000 Indians had perished across the high plains. Ninety percent of the Mandan died. “In human terms, their culture was massively impoverished,” says anthropologist W. Raymond Wood. “The epidemic ravaged their economy, their arts, their social systems and their kinship systems.” And the epidemic had a monumental effect on the destiny of the West: “By reducing the number of Native Americans,” Wood says, “it made settlement simpler for whites.”

While many Native Americans today are descended in part from the Mandan, there are no full-blooded Mandan left. Only a handful of teachers still know the Mandan language. “When those people leave us, they are going to take the language with them,” says Amy Mossett, a Mandan-Hidatsa educator and interpreter of the life of Sacagawea, the famed Indian woman who helped guide Lewis and Clark. Mossett lives in North Dakota, not far from the site of the old FortClark and Four Bears’ village. “I go out to that site every now and then,” she says. “It’s usually real quiet, and I remember one July walking through the depressions left by earth lodges that stood there. It was searing hot, and I could see the heat waves dancing on the prairie. I remember wondering if our ancestors saw those heat waves before they slipped into delirium, then death.” Now, she says, “for our people this is hallowed ground, a sacred spot. We must treat it with reverence.”

This month marks the 25th anniversary of the World Health Organization’s official declaration of the elimination of smallpox from the earth. It’s been even longer, since 1949, that a single case was reported in the United States. But the variola virus itself still exists in the form of samples retained for research in Siberia and at the Centers for Disease Control and Prevention in Atlanta—leading scientists and homeland security officials to raise the specter of other samples potentially finding their way into the hands of bioterrorists. If that were to happen, the human population would be susceptible to a resurgence of smallpox. Without acquired immunities or widespread vaccinations, “to some extent we’re in the same boat Native Americans were in before 1492,” points out DukeUniversity professor Elizabeth Fenn, author of Pox Americana, a history of the disease. “We’re approaching 100 percent vulnerability.”