The deadliest viruses in human history, from COVID to smallpox

Over the first two years of the COVID-19 pandemic, the coronavirus directly or indirectly killed about 15 million people worldwide, according to estimates from the World Health Organization. In the United States, more people died in 2020 and 2021 than during the 1918 influenza pandemic, which was widely called the most deadly in recorded history. 

The word “deadly” certainly applies to the virus that causes COVID-19. And yet, epidemiologists hesitate to give SARS-CoV-2 the superlative of deadliest virus in human history. To them, the raw number of mortalities caused by a given virus doesn’t always paint the full picture of a pathogen’s danger—especially when comparing viral outbreaks across time.

Raw mortality numbers have to be taken in the context of the world’s total population, says Jennifer Nuzzo, professor of epidemiology and director of the Pandemic Center at Brown University School of Public Health. “A lot of people talk about how COVID deaths eclipsed what we saw in 1918,” she says. “It’s really important to remember that the population of 1918 was a fraction of what it is today.” In that context, the flu of 1918 rises back up in the ranks in terms of deadliness.

Using the “case fatality rate” metric to determine what virus is the deadliest, rabies would likely come out on top. That’s because, if an infection becomes symptomatic, rabies is fatal to humans in more than 99 percent of cases. Globally, approximately 59,000 people die from rabies every year. Very few of those deaths—an average of two in the US—occur in the developed world because of rabies vaccines for household pets and swift medical interventions after bites.

But “a virus doesn’t have to have a very high case fatality ratio to cause a tremendous amount of death and disruption,” Nuzzo says. “It’s more about looking at the environments in which the viruses are spreading, and our social and human vulnerabilities to it.” 

A virus with a lower case fatality rate can kill more people if it’s highly transmissible, with a long period of time before severe or obvious symptoms set in. This allows an infected person to expose many others. That’s why SARS-CoV-2 caused such a rapid and devastating outbreak around the globe. It’s easily transmitted via airborne droplets, and doesn’t always or immediately cause severe illness. 

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Globalization sped it along, too. “When a virus spreads at the pace of a human being walking, that’s very different than when you can hop on an airplane and be anywhere in the world in 36 hours,” Nuzzo says. 

During large outbreaks such as epidemics or pandemics, epidemiologists look at another metric, called excess deaths: how many more people died during a period of time than typically do over that same window. Excess deaths can account for other indirect ways that a virus causes death, Nuzzo says, such as patients who need critical care but can’t get it in overburdened hospitals.

Here’s how some of the most devastating viruses in human history tell different stories of how high a death toll can rise:

Influenza

The 1918 influenza pandemic still far and away ranks as the deadliest global outbreak of the 20th century. Thought to be caused by an H1N1 virus, it spread globally in 1918 and 1919. An estimated 500 million people were infected (approximately a third of the global population) and 50 million people died worldwide, about 675,000 of whom were in the United States, according to the Centers for Disease Control and Prevention. 

Without sophisticated testing and tracking, death toll estimates rely heavily on excess death calculations. Some suggest the true toll was closer to 17 million, while others set it much higher at 100 million. William Schaffner, professor of preventive medicine and professor of medicine in the division of infectious diseases at the Vanderbilt University School of Medicine, cautions against over-interpreting comparisons between the historic flu data and modern viral outbreaks.

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 “We are determining cases and even counting deaths with much more precision now than we did then,” he says. At the time, there were also no flu vaccines and no antibiotics to treat secondary bacterial infections, which likely drove the excess death toll higher.

Today, the youngest and oldest people are most likely to die from influenza. But during the pandemic over 100 years ago, Schaffner says, deaths bore a different signature: mortality peaked among young and middle-aged adults, too. Why that happened is still unclear, he says, but it contributed to the historic toll of that pandemic.

Influenza continues to hold its place as one of the deadliest viruses, despite the availability of vaccines. Variants of the influenza virus have led to other pandemic-level events, such as the 2009 outbreak colloquially called the swine flu pandemic. But the virus is also endemic in our society, and infects an estimated 1 billion people globally every year, according to the World Health Organization. Of those cases, the WHO reported in 2019, somewhere between 290,000 to 650,000 result directly or indirectly in deaths. 

An estimated 40.1 million people have died from AIDS-related illnesses since the start of the epidemic, according to the Joint United Nations Program on HIV and AIDS. That is nearly half of the number of people estimated to have become infected with HIV since the start of the epidemic, at an estimated 84.2 million. 

The case fatality rate of HIV/AIDS was historically quite high. Some estimates put it around 80 percent without treatment. But much has changed since the 1980s. Today, there are ways to manage HIV and mitigate the immunodeficiencies associated with an infection, and most patients are diagnosed sooner after an infection. In the United States, the rate of HIV-related deaths fell by nearly half from 2010 to 2017, according to the CDC. 

That excess deaths metric likely reached a much higher number by the time officials declared the public health emergency over in early May. The Omicron wave that swept around the globe in late 2021 and early 2022 saw one of the largest surges in cases of COVID-19 and, although the variant didn’t seem to be more deadly than previous variants, with millions of people infected, a high death toll in the hundreds of thousands was inevitable. 

Early in the pandemic, the case fatality rates calculated for SARS-Cov-2 varied considerably. Many estimates were likely higher than the true number, as researchers scrambled to devise tests for the virus and milder cases slipped through the cracks. In early 2020, estimates of the case fatality rate by country ranged as high as 25 percent or more. Since then, case fatality rates have dropped, and now, according to Johns Hopkins University, they are as high as 4.9 percent. In the US, the case fatality rate is 1.1 percent. 

Mortalities continued to stack up into the 20th century, with an average of three out of every 10 people infected dying. The disease, which is caused by variola virus, is estimated to have killed more than 300 million people from 1900, until a global vaccination campaign halted its path of devastation in 1977. It was the first disease ever to be eradicated. 

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But it was the very thing that made it particularly fearsome that was its downfall, Schaffner says. “It created such a distinctive rash that people could identify it and fear it. And that was one of its Achilles heels,” he says. Because it was so easily identifiable, and spread so slowly, vaccinating the local population near an outbreak swiftly curtailed transmission. Such an approach, he says, was part of the vaccination strategy that eradicated the great pestilence.