A Pandemic Playbook

We don’t always know where pandemic threats come from, but we do know that, with nearly eight billion people on the planet, they're always somewhere just beyond sight. We also know that not all germs are created equal. No matter where they come from, what counts is how they behave once they enter human populations: how sick they make us (virulence), how easily they spread (transmission), and whether they spread silently, without warning (stealth). Calculating the threat is something that even infectious-disease experts find tough, however. H5N1 avian flu, hantavirus, Ebola, West Nile, SARS-CoV-1, H1N1 swine flu, Covid-19, monkeypox. Which diseases have pandemic potential, and which are likely to sputter and die?

Some infections are truly limited—dangerous under local circumstances but unlikely to cause shutdowns or massive death. However ominous West Nile and Zika initially seemed, they’re mosquito-borne diseases whose scope is restricted by the availability of screens and air-conditioning. Spillovers from animal populations, such as the bat coronavirus that killed three cave miners in China in 2012, generally go nowhere because they’re ultimately adapted to animals, not us. SARS-Cov-2, the virus that causes Covid and can be transmitted through the air, is one kind of threat. Monkeypox, a rodent disease that, in the past, only sporadically infected people in West and Central Africa and that spreads only through direct contact, is quite another.

The ur-text for the worst kind of pandemic is the Black Death, the fourteenth-century outbreak caused by the plague germ Yersinia pestis. Everything else, even Covid, pales in comparison: Covid has slain its millions, the Black Death its tens of millions. The death rate from Covid hovers between 1 and 2 percent in the United States and in some nations is as high as 5.6 percent. But the Black Death, uniquely virulent and transmissible, burned across Europe, eastern and central Asia, the Muslim world, North Africa, and Russia for seven years. At least 25 million died in Europe alone.

Without antibiotics, Yersinia pestis kills 60 to 100 percent of its victims, depending on how it spreads. Untreated pneumonic plague transmitted by aerosol is always fatal; flea-borne bubonic plague, the mild form, kills “only” 60 percent of victims without access to the antibiotics of today. Much of the Black Death was pneumonic. When the outbreak subsided, in 1353, perhaps 30 to 50 percent of those in Europe and other afflicted regions lay dead. The Black Death shows us just how bad things can get.

The Black Death gives us a helpful context for understanding novel infectious threats. From HIV and the AIDS pandemic to Ebola and Zika and now Covid-19 and monkeypox, how do we think about a new disease when we suddenly face it? Is it really a Black Death–level threat, or more like another flu—or something in between?

To evaluate how dangerous a novel disease can be, look to the three factors mentioned earlier: virulence (deadliness), transmission (how a disease spreads), and, for an extra garnish of horror, stealth (the ability to spread silently from host to host).

Transmission is the major factor determining whether the disease it causes can become pandemic. Some diseases spread sluggishly, some explosively, and some (like tetanus, rabies, or anthrax) don’t spread from human to human at all. With the outbreak of a novel coronavirus in 2003, later called SARS, it soon became evident that because the disease spread late in the course of infection, and mostly in hospitals, it would never explode out of control. Enabled by modern transport, it popped up in scattershot fashion around the world, infecting around 8,000 people and killing 774. But its inefficient spread allowed the ancient tools of isolation and ultimately quarantine to drive it off the earth.

Other new pathogens spread in still more limiting ways, using insects—fleas, ticks, mosquitoes—as vectors (carriers). The vector must get from one host to another, and in the Western world, well protected in general by screens and air-conditioning, that’s not so easy to do. This is why malaria, dengue, yellow fever, and Zika, despite how deadly they can be, have never found a foothold in modern Europe or North America. Other diseases, like cholera, are waterborne, and their spread is limited by modern sanitation. The real threat to the developed world is from lung-borne diseases, those spread by respiration, because you can’t stop people from talking, coughing, or breathing.

But transmissibility itself isn’t enough to bring the world to its knees. The rhinoviruses, adenoviruses, and human-adapted coronaviruses are all highly transmissible, but they don’t shut societies down. Something else is needed, something the Black Death had to the maximum: virulence, or lethality. Deadly diseases abound in the world: Rabies, Hendra, Nipah, leptospirosis, Legionnaires’ disease, and tetanus are all virulent and may kill many or, in the case of rabies, virtually all their victims. But their assaults generally either end with the victim, like anthrax or rabies, or spread sluggishly at best.

The Black Death was different. It was both highly transmissible and lethal, which is why it remains engraved in history as a single, traumatic, fracturing event, a pandemic that broke the world. Virulence and transmissibility must both be relatively high for a pathogen to emerge as a powerful threat. Fortunately, high virulence and high transmissibility very seldom coexist, and only once in as hideous and destructive a way as our medieval ancestors experienced in the mid-fourteenth century.

Diseases that are virulent but not transmitted efficiently can, however, become deadly local threats, as virologist Angela Rasmussen of the University of Saskatchewan points out. Ebola, a deadly virus spread by exposure to blood and other bodily fluids, isn’t a pandemic threat because it doesn’t have the capacity to spread via respiratory transmission. Yet it has caused thousands of deaths locally in West Africa because of the intimate way that people in Sierra Leone and other countries in the region care for their sick and their dead, whom they carefully wash, exposing themselves to infected bodily fluids and keeping chains of infection going. Ebola is a highly virulent disease with tremendous capacity for local disruption, and it shouldn’t be minimized simply because it’s not highly transmissible. Still, the American panic over Ebola in recent years has been totally misplaced; despite hysterical articles warning that the virus could “go airborne,” diseases have never been known to change their mode of transmission, as Columbia University virologist Vincent Racaniello points out. The real concern should have been for the people of West Africa, facing a deadly threat and dying by the thousands, not for the Western world.

On the other hand, influenza, which is only moderately virulent (common strains have a mortality rate of 0.1 percent), causes tens of thousands of deaths worldwide each year because flu spreads effectively through airborne transmission. The reason the 1918 flu rivaled the Black Death in its destructive force was that, despite a mortality rate of “only” 2.5 percent, it infected virtually the entire planet, leaving 20 million to 50 million dead.

Covid-19, the pandemic disease caused by the novel coronavirus SARS-CoV-2, is both virulent and explosively transmissible, making it the deadliest pandemic in living memory. While it doesn’t approach the mortality of Ebola or the plague, it still has an approximate case fatality rate of about 1 to 2 percent, depending to some extent on the strain, on local conditions, on the age and health of the patient, and on whether people are vaccinated. Worse, people can be infected more than once. Worse still, perhaps 20 percent of survivors, according to some estimates, suffer long-term effects—cardiac, vascular, neurological, renal, pulmonary—for months or years.

But the real accelerant, the singular weapon, that has turned Covid into an uncontrollable pandemic is something it shares with the Black Death (and, incidentally, with polio): the ability to spread by stealth—that is, by people who carry the infection while appearing well. Those who fled the Black Death spread it while asymptomatic, and presymptomatic people spread SARS-CoV-2. Stealthy transmission is another pandemic danger signal, Louisiana State University virologist Jeremy Kamil says.

Stealthy, virulent, and transmissible, Covid still affects our lives. But more than two and a half years since its appearance, another disease has sprung up in its shadow: monkeypox. This well-known rodent virus, misnamed because its true reservoirs are likely small rodents like rats and squirrels, used to be confined largely to West and Central Africa. It was first recognized as a human disease in 1970, though it is certainly much older. The blisters and pustules that characterize monkeypox look like smallpox, though monkeypox patients also have swollen glands. Unlike smallpox, however, monkeypox has never spread efficiently.

Notably, victims of monkeypox have traditionally been children surreptitiously hunting small animals like squirrels and rats, according to John Huggins, who studied the disease for many years while at the U.S. Army Medical Research Institute of Infectious Diseases. “Young children catch small rodents and eat them out in the jungle,” he explains.

There are two clades, or distinct genetic lines, of monkeypox. The one we are seeing in the United States and Europe now is known as the “West African” clade, which has a mortality rate of around 1 percent, comparable to variola minor, a mild strain of smallpox that has been eradicated. The so-called “Congo Basin” or “Central African” clade, which Huggins studied, kills about 10 percent, comparable to most African outbreaks of smallpox.

That’s where the similarity to smallpox ends because monkeypox, which is a spillover from rodents, is not a human-adapted disease. Where monkeypox spreads within a single household, the first case, caught directly from an animal, has the highest level of virus. That gradually drops off as the virus spreads within the family. Unlike smallpox, monkeypox seems to spread not via aerosol but in large respiratory droplets, so transmission requires close contact.

Huggins has always worried about what would happen if monkeypox entered a large, crowded city where a dense population might allow the evolution of more effective transmission. Is that what we’re seeing now? Probably not just yet.

Monkey pox is no Covid, and it is certainly no Black Death. More than 22,000 cases have been reported worldwide, and there’s no evidence to date of significant change toward greater virulence or transmissibility. While monkeypox doesn’t appear to be sexually transmissible like HIV or syphilis, it clearly spreads through intimate contact via skin and large respiratory droplets. Despite a lot of speculation to the contrary, monkeypox virus has not been shown to float or hang suspended in the air like SARS-CoV-2.

Where does that leave us with this disturbing disease? Monkeypox is frightening and painful. While the outbreak in the West is hardly as virulent or transmissible as Covid, let alone the Black Death, it is stealthy: People may have nonspecific flulike symptoms, fevers, swollen glands, and lesions in the throat (which appear before the skin pustules erupt) without realizing they have monkeypox, and in this early phase they can already transmit it to someone else.

Monkeypox may not be a second Covid, but governments and public health officials are not reacting swiftly enough to break the chains of human transmission. We can never eliminate monkeypox, but we can drive the pathogen back into its animal reservoir in the wild. As with Covid, public health messaging has not been informative or simple enough; testing widespread or accessible enough; vaccines available enough. The chains of transmission go on.

We haven’t seen the last of pandemic diseases because the conditions that give rise to them remain. In the wake of global warming, animal species are pried from their usual niches and carry infections elsewhere. Insect vectors expand their ranges and the reach of the pathogens they carry. We are knit together as a global community, and the monkeypox that once intermittently plagued Central Africa has reached out to us in the West. Worse, we’ve created conditions that forge new, deadly livestock diseases, like African swine fever, Newcastle disease, foot-and-mouth disease. The wild animal markets found in Southeast Asia spawned both SARS-1 and SARS-2 and remain ongoing threats for the adaptation and evolution of more pathogens.

Whatever the source of a new disease, our response is at least as important as the disease itself. We should reject blind panic over threats that aren’t virulent, transmissible, or stealthy enough to cause a deadly outbreak. There’s no point in panicking over monkeypox; it won’t force the planet into lockdown, though it stands to make many lives miserable. But if scientists find another new disease that transmits explosively, kills a significant percentage of people who contract it, and—worst of all—spreads from asymptomatic people, we’re in for another world of trouble. We would do well to recognize the danger signs and prepare now.