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Covid. Ebola. Influenza.

There are, as American Public Health Association Executive Director Dr. Georges Benjamin puts it, “a lot of bad bugs out there.”

And as a nation still reeling from a deadly pandemic that killed more than 1 million Americans, those in the infectious disease realm are contemplating what the next pandemic might be.

Experts differ on which pathogen might cause the next global outbreak. But they agree there will be one – and probably sooner than later.  

A recent survey of 187 infectious disease experts from around the world ranks influenza as the most likely bug to cause another pandemic.  

Disease X – described as an illness caused by an as-yet-unknown pathogen – came in second, followed by Covid, according to the survey published in the January-February 2024 issue of the Elsevier Journal ScienceDirect.  

While there are dozens of possibilities, Benjamin says influenza is still probably the best bet for the next pandemic.

“Influenza sticks around. It circulates. It mutates. It’s easy to catch. And on a periodic basis, the genetic structure of this virus makes a major shift and becomes a lot more lethal or infectious – or sometimes both,” he said.

“There are lots of other infectious agents out there,” he added, “but none have been as durable as influenza.”

Influenza is also at the top of the list for Dr. Michael Sweat, faculty director at the Medical University of South Carolina Center for Global Health.

“Of particular note right now is bird flu,” said Sweat, also director of the Division of Global and Community Health in the Department of Psychiatry. 

Indeed, the World Health Organization says avian flu viruses are “a significant public health risk due to their widespread circulation in animals and potential to cause a future pandemic.” 

Avian flu has had a terrible impact on the bird population, resulting in the deaths of millions of birds, Sweat said.

“But it’s begun to leap over into mammals, and most recently dairy production cattle have been infected, and that’s led to some infections in humans,” he added. “It’s been quite limited. But it’s concerning because as it spreads, influenza virus is known to mutate heavily.”

And the more it mutates, he said, the more likely it is that it could evolve into a strain that is transmissible between humans.

But Dr. Helmut Albrecht, medical director of the Center of Infectious Diseases Research and Policy at Prisma Health, has another take on what might cause the next pandemic.  

“I would go with Disease X,” he said. “Influenza is so much more manageable. We have the tools to stop the flu much quicker.”

Disease X typically originates in bats or some other animal and crosses over to humans, who have no natural immunity to it, he said. And the rate and volume of worldwide travel can cause it to spread quickly, he said.   

“You can now get around the globe in hours,” he said. “And how many planes land in the U.S. every day?”

“We have a hugely integrated jet-based lifestyle with much more migration and leisure travel to remote parts of the world,” Sweat agrees. “That allows things to transmit much faster than in the past.”

Still, he added, while a Disease X is always a worry, they don’t tend to emerge that frequently.

All the doctors agree that if the next pandemic is caused by influenza, the world will be better able to tackle it than a Disease X.

As a result, they say, it would never result in an outbreak like the one in 1918, which caused 50 million deaths worldwide, according to the National Archives.

“The difference is that then they didn’t know what they had, they didn’t know about viruses,” said Benjamin. “We have antiviral agents, and we have vaccines against influenza which we did not have then. And while we have had outbreaks of influenza since, we have been able to control them because we have these therapeutic agents.”

In addition to vaccines, antivirals, and increased knowledge, Sweat said, there is a well-established surveillance system for influenza that could pick up a particularly virulent strain early.

“There’s a lot of (avian flu) monitoring going on,” he said. “And it’s not currently a major threat to human health.”

Albrecht agrees that there are helpful interventions for the flu, even avian flu, that mean medicine is much more prepared to react than if something like Ebola becomes more transmissible.

So far, at least, the few cases of avian influenza in humans have been through occupational exposures among people who worked in poultry factories or around cows, Benjamin said, adding that so far it’s not spread by respiratory routes.

The challenge is when these viruses spread to other species, the doctors said. 

“It’s a sign that that virus is adapting to other animals, and that enhances its ability to mutate,” Benjamin said. “And a big concern with avian influenza – just like human flu we see every year – is as it goes through various species it affects, it’s only a few mutations away from being more infectious or more lethal.”

While there is some concern about avian flu spreading through milk, he said studies show that routine pasteurization done in the U.S. reduces infectivity. And to limit the spread between cows, he said, dairy farmers may have to sterilize the milking equipment as opposed to the cleaning process they use now.

When a flock of chickens is infected, historically farmers cull the herd to try to control the spread, which is a big economic loss, Benjamin said. But while there are ways to vaccinate flocks, it’s expensive, he added. 

Another concern, he said, is that flu vaccine is made by incubating it in eggs, and healthy flocks are needed for that. It’s a time-consuming process that has failed in the past requiring restarts, sometimes delaying vaccine production, he said.  

Covid-19, its precursor SARS-CoV-1 (Severe Acute Respiratory Syndrome), and Middle Eastern Respiratory Syndrome, or MERS, are all coronaviruses responsible for outbreaks that occurred roughly nine years apart, Sweat said.

A SARS-CoV-1 outbreak in Hong Kong and Toronto had a mortality rate of about 20 percent, he said. MERS, which is spread by camels and is circulating at a low level, has a mortality rate of about 60 percent, he said.   

“We’ve been having a serious outbreak almost every decade of a coronavirus,” Sweat said. “So, I would rank another coronavirus high on that list.”

With all the advances made with Covid, though, such as the development of the mRNA vaccines, which he called a real breakthrough, the world should be much better prepared for another coronavirus, he said.  

But vaccine uptake is always key in controlling outbreaks, Benjamin said, noting that some years only 40 percent to 50 percent of the population gets a flu shot. 

“We are still dealing with convincing people that mRNA vaccine is safe and effective,” he said. “And there is still some pushback from people who don’t want to use mRNA vaccine for some reason.”

“It’s a major concern in public health,” he said. “Vaccines are pretty carefully vetted … and on balance, the risk benefit ratio is enormously beneficial.” 

It’s a tough problem, fueled by misinformation and conspiracy theories, Sweat said.

“It’s a shame because if we do have a major outbreak, vaccination is our most potent aspect,” he said. “The alternative is people will get infected, and suffer the consequences.”

A study from The Commonwealth Fund concluded that the Covid vaccines “prevented more than 18.5 million U.S. hospitalizations and 3.2 million deaths, and saved the nation $1.15 trillion” by the end of November 2022.

The doctors say that effective mRNA vaccines are being developed for influenza as well.

“That is really important not only for influenza, but all sorts of other pathogens,” Sweat said, noting that warming global temperatures also have been linked to large outbreaks of mosquito-borne diseases like Zika and Dengue in South Asia and Brazil.

Meanwhile, the World Health Organization is looking to accelerate the development and accessibility of an mRNA vaccine for human avian influenza.  

“This initiative exemplifies why WHO established the mRNA Technology Transfer Programme – to foster greater research, development and production in low- and middle-income countries, so that when the next pandemic arrives, the world will be better prepared to mount a more effective and more equitable response," Dr Tedros Adhanom Ghebreyesus, WHO Director-General, said in a release.

The doctors say there’s no way to know how deadly a new pandemic would be or when it would occur. 

“The risk of a pandemic can be months away or a few years away. It depends on the virus,” said Benjamin. 

“The ideal virus that causes a pandemic is one that makes a lot of people sick and is easily transmissible before you have a lot of symptoms,” he said. “About 50 percent of people were asymptomatic (during the Covid pandemic) and were able to spread it.”

“It’s always hard to know,” Sweat said, “but these are certainly things we worry about.” 

“It’s not a question of if. It’s a question of when,” said Albrecht. “And I think it’ll happen sooner because of our mobility and accessibility to remote regions.” 

But the key, the doctors all agree, is being vigilant and prepared for whatever comes next.

“We need to keep stockpiles of important vaccines available and have a supply of masks and respirators,” Sweat said, adding that was not the case for Covid. 

“My pet peeve is that you have to make public health a first responder,” said Albrecht, who is also the Heyward Gibbes Distinguished Professor of Internal Medicine at the University of South Carolina.

The U.S. is one of the few countries that starts revving up for a public health crisis when it happens rather than maintaining a baseline of readiness, he said. 

He compares it to selling off fire trucks after putting out a blaze only to have to buy them again when the next fire breaks out.

“When we have a disease 90 percent on its knees, we stop funding (public health),” he said. “And if you react to an outbreak when it’s happening, it will kill people. Then, it’s a little late.”

Public health needs to maintain software and hardware, monitor waste water for pathogens, and continue surveillance around the world, among other things, he said.

“For a country like ours, with our ability and financial power, to have over a million dead from Covid … is a horrible result,” he said. “If you can find it early where you can stop it, it will cost a lot less than on the backend – and fewer lives too.”

To read the survey, go to Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics - ScienceDirect