Everyone knows about the Black Death and the Spanish flu from the devastating impacts they wrought on the world. But there were other epidemics, pandemics, and disease outbreaks that changed history—some for the worse, and some, surprisingly, for the better.

1. Malaria Outbreak in the Vatican // 1623

Location: Rome
Fatalities: Eight cardinals and 30 other church officials
How it changed history: The deaths of around 38 relatively unknown people in the 17th century may have saved the lives of millions. In 1623, Catholic cardinals gathered from all over Christendom to elect a new pope—and soon succumbed to a malaria outbreak. Even the newly elected Pope Urban VIII fell ill and took two months to recover. According to legend, Urban VIII issued a decree to find a cure for the disease.

News of the deaths spread to South America, where Jesuit missionaries observed Indigenous people using the bark of the Andean cinchona tree to treat shivering and fevers, both symptoms of malaria [PDF]. Shipments of the “Peruvian bark” then arrived in Rome, where physicians successfully used it to treat malaria. In 1820, French chemists isolated quinine, its active antiprotozoal compound.

2. New England Smallpox Epidemic // 1721

Location: Boston
Fatalities: 850 people
How it changed history: In the early 18th century, influential Puritan minister Cotton Mather of Boston read a treatise on the novel practice of inoculation against smallpox. He responded to its author with his own thoughts on it. Mather had asked his African slave Onesimus if he’d ever had the disease, and he said Onesimus replied, “both, Yes, and, No; and then he told me, that he had undergone an Operation, which had given him something of the Small-Pox, & would forever praeserve him from it.”

Five years later, smallpox hit Boston. Mather began pushing for an inoculation campaign, but many of the town’s doctors and citizens disagreed on religious grounds, while others argued that it was unethical to treat healthy people with an unknown procedure. One critic even threw a bomb into Mather’s window with a note reading, “Cotton Mather, you dog, dam you! I’ll inoculate you with this; with a pox to you.” (The bomb failed to explode.) Only one physician, Zabdiel Boylston, stood by Mather: Boylston inoculated his own son and hundreds of others. At the end of the outbreak he reported, in the first clinical trial evaluated with hard data, that only 2 percent of inoculated patients died, compared to almost 15 percent of those who weren’t. According to the journal BMJ Quality & Safety, the results would guide Edward Jenner’s experiments in vaccination a few decades later. As for Onesimus, he purchased his freedom in 1716, contingent on his obligation to perform chores for Mather when needed.

3. Saint-Domingue Yellow Fever Epidemic // 1802

Location: Modern-day Haiti
Fatalities: 29,000 to 55,000 people
How it changed history: Like malaria, this mosquito-borne disease had a profound impact on the relationship between the Old and New Worlds. In 1791, slaves and other marginalized groups in the French colony of Saint-Domingue (now Haiti) rose up against the oppressive French government, launching the Haitian Revolution. Eleven years later, Napoleon Bonaparte sent his brother-in-law Charles Leclerc and 60,000 troops to restore order. But the French troops began dying by the thousands from yellow fever, with relatively few ever dying in battle—which may have been by design.

Haitian general Toussaint Louverture, one of the revolutionary leaders, wrote to his lieutenant Jean-Jacques Dessalines, “Do not forget that while waiting for the rainy season, which will rid us of our enemies, we have only destruction and fire as weapons.” He knew the seasonal yellow fever outbreaks would weaken the French army. In fact, yellow fever would kill most of the French soldiers, including Leclerc, and helped ensure Haiti’s independence from France.

However, some historians propose that Haiti was just assembly point for the massive array of French troops. The island could have served as a staging area for an expedition to reassert control over Louisiana, which had been given to Spain in 1762 and reacquired by France between 1800 and 1802. But likely as a result of the French defeat in Haiti, Napoleon proclaimed, “I renounce Louisiana. It is not only New Orleans I will cede,—it is the whole colony without any reservation.” The U.S. purchase of Louisiana in 1803 would double the size of the young nation.

4. Third Cholera Pandemic // Mid-19th Century

Location: Worldwide
Fatalities: Hundreds of thousands to more than a million
How it changed history: The third cholera epidemic (which lasted from 1846-1863 or from 1839-1856, depending on the source) is best remembered for two history-changing events that occurred in 1854.

In London’s Soho neighborhood, the cholera outbreak lead to the deaths of 616 people. At the time, most thought cholera was transmitted by foul air (known as the miasma theory). A local anesthesiologist named John Snow had the then-radical idea that cholera was spread by some microscopic organism. He began mapping the location of the neighborhood’s water pumps and the casualties in the outbreak, and noticed they were centered around a pump on the corner of Broad and Cambridge streets (now Broadwick and Lexington streets). His map convinced the local council to remove the pump’s handle, and the number of deaths plummeted. Snow’s investigation became a pivotal moment in fields ranging from epidemiology to data visualization to urban planning. But Snow was never able to identify what caused the outbreak, and likely remained unaware of someone who did.

That same year, when cholera arrived in Florence, anatomist Filippo Pacini performed autopsies on victims and noticed odd microscopic particles that he called vibrions [PDF]. He published his findings, but they were ignored. In the 1880s, German microbiologist Robert Koch rediscovered that the vibrions, present in the intestines of the cholera victims but not healthy people, were actually bacteria that caused the disease. His research into bacteria overcame intense opposition [PDF] and changed how we diagnose and treat diseases. But Pacini hasn’t been ignored—in 1966 the International Committee on Nomenclature officially recognized Pacini’s prior discovery [PDF].

4. Fijian Measles Outbreak // 1875

Location: Fiji
Fatalities: 40,000 people
How it changed history: In tourism brochures, the South Pacific nation of Fiji seems like a placid paradise—but the islands have been roiled by a series of coups d’état that began in part with a virulent virus. In January 1875, the Royal Navy sloop HMS Dido brought the powerful Fijian chief Cakobau and his family back home from a state visit to Australia. But Cakobau contracted measles, and despite recovering, infected his sons. Authorities failed to securely quarantine the ship, so when the Dido arrived in Fiji, its passengers debarked and met chiefs from surrounding islands, who then returned home and spread the infection with startling rapidity. The population of Fiji before the outbreak was around 150,000; by its conclusion in June 1875, roughly 40,000 people had died.

Many Fijians felt the epidemic was a deliberate act by the British government—Cakobau had agreed to make Fiji a British Crown Colony in 1874—and staged an armed rebellion. Possibly as a result of the population decline, British colonists were able to seize Fijian-owned property and brought in Indian indentured servants, who grew into a sizable minority of the population. Soon after achieving independence from the United Kingdom in 1970, “intra-country clashes between political parties representing the majority ethnic Fijian population and ethnic minority communities, most notably Indo-Fijian, led to a military coup d’état,” according to the U.S. State Department. “This was the beginning of what many now refer to as the ‘coup cycle.’”

5. African Rinderpest Outbreak // 1890s

Location: Eastern Africa
Fatalities: Millions of cattle and an unknown number of people
How it changed history: Not all diseases that affect humanity are human diseases: The livestock infection rinderpest led to war, colonialism, and a permanent change of life for much of Africa.

In cattle and other ungulates, rinderpest can have fatality rates in the 90 percent range. The disease never traveled farther south than Egypt until sometime around 1887 when, according to the most popular theory, infected cattle were sent to Italy’s colony in modern-day Eritrea. Cattle began dying by the thousands, and the price for those that survived soared. Some also traded infected hides for food with the long-distance caravans passing through the area, which might have exposed the population to smallpox.

The outbreak has been called “the most catastrophic natural disaster ever to affect Africa” [PDF]. Rinderpest (and smallpox) nearly destroyed the Maasai way of life, the loss of livestock disrupted the traditional means of agriculture, and economic woes forced African landowners to sell their properties. These forces destabilized eastern Africa and allowed European colonialism to take over. The societal upheaval contributed to the Boer War and Matabele War at the turn of the 20th century, while the decimation of much of the continent’s load-pulling oxen spurred the rate of railway construction.

Eventually, quarantines would contain the worst rinderpest outbreaks, though as recently as the 1980s Nigeria lost $2 billion to the disease. In 2011, after decades of work, rinderpest was declared officially eradicated.

6. U.S. Salmonella Outbreak // 1994

Location: United States
Fatalities: Zero dead, 224,000 people infected
How it changed history: Just 25 years ago, the largest outbreak of food-borne illness in history changed the way manufacturers handled food recalls, potentially saving the lives of millions. In 1994, a tanker truck carried unpasteurized liquid egg to a manufacturing facility, and then returned to its headquarters in Minnesota. Before it picked up its next load—ice cream premix for the food company Schwan’s—the tank should have been completely sanitized. It wasn’t. The truck, and its sweet cargo, were contaminated with Salmonella, which eventually spread throughout the entire ice cream production system. An estimated 224,000 consumers in 35 states were infected.

Perhaps afraid of encountering the same blowback that burger chain Jack in the Box received after its response to the deadly E. coli outbreak in 1993, Schwan’s response was so swift and decisive that it became the textbook example for positive crisis management [PDF]. Schwan’s recalled the ice cream before it was sure the product was at fault, shut down the factory, took out advertising to advise people not to eat the ice cream, instituted a 24-hour consumer hotline, and even offered to pay for diagnostic medical exams. “In the process of managing its way through the outbreak, Schwan’s blazed a new trail for what it takes to be a responsible company with a national recall,” Food Safety News noted in 2009.