“In any crisis, leaders have two equally important responsibilities: solve the immediate problem and keep it from happening again... The first point is more pressing, but the second has crucial long-term consequences.”

So wrote Bill Gates in a February editorial in The New England Journal of Medicine about COVID-19, which “has started behaving a lot like the once-in-a-century pathogen we’ve been worried about.”

Those long-term consequences are even more crucial considering the modern realities of a “once-in-a-century” event.

Driven by climate change and urbanization, century pandemics look set to increase in frequency, much like “century floods” have already occurred twice in Europe in the first 20 years of the 21st century. And while century pandemics, even if they occur several times in a century, are rare by their nature, spillovers are not. Zoonotic diseases emerge, on average, three times every year.

Given those realities, even as the world grapples with the current emergency, researchers and public health officials are trying to apply its lessons to future outbreaks. What sorts of surveillance gives the best shot at early detection? Can rapid vaccine technologies be developed for deployment in future outbreaks? What are the fastest ways to get effective therapeutics for future threats whose exact nature remains unknown until they surface?

Surveillance: crime families

“Surveillance is one of the most important aspects of a public health system,” Ralph Cordell, epidemiologist at the CDC, told his audience in an introductory webinar. “Surveillance data drives our actions, informs our decisions, and like the proverbial dog in the night, informs us of potential threats to the health of those we serve.”

In humans, pandemic surveillance starts with symptoms. COVID-19 was first identified by Chinese public health authorities of Hubei province as an unusual cluster of influenza-like illnesses, much like what was to become known as HIV was first reported as a cluster of five pneumonia cases in young healthy men.

Viruses and animal populations are also surveilled directly. The global virome project, for example, is a 10-year effort to create a catalog of viruses belonging to 25 viral families that could pose human health threats.

The project was part of the now-shuttered PREDICT program at the Agency for International Development (USAID), and continues to operate independently of USAID.

It is likely that more than 300,000 viruses exist in mammalian hosts. A combined estimate of mammalian and bird viruses, which are the two animal groups that are the most likely sources of emerging infections, suggests that there are somewhere between 630,000 and 830,000 viruses that pose a potential risk to humans.

SARS-CoV-2 is what the WHO’s blueprint for pandemic preparedness calls a Disease X, “representing the awareness that a previously unknown pathogen could cause a major public health emergency,” as WHO researchers wrote in the 2018 WHO R&D Blueprint, which is a review of “emerging infectious diseases requiring urgent research and development efforts.”

However, certain viral families are more likely to spill over into human populations, and more likely to spread rapidly if they do spill over.

SARS-CoV-2 is a Disease X, but it has two relatives – SARS and MERS – on the WHO watchlist. The 2009 H1N1 influenza pandemic, too, was a surprise in its specifics, with public health surveillance more focused on H5N1 avian influenza at the time. But no one was surprised to see influenza, which caused three pandemics in the 20th century, be the cause of the 21st century’s first pandemic as well.

In general, Rino Rappuoli, told BioWorld, “We know that something is going to come, but we don’t know exactly what. But you can make some scientific guesses that have some kind of scientific bases.”

Several features make a pathogen more likely to go from a rapidly extinguished spillover to a large-scale epidemic or pandemic.

“Viruses are the ones that can emerge quickly and spread globally in a very short time,” said Rappuoli, who is chief scientist at the GSK Vaccines arm of Glaxosmithkline plc. “And among the viruses, the ones that we worry the most about are RNA viruses, because they mutate faster than the others.”

Although Ebola and HIV show that viruses that transmit via blood and bodily fluids can lead to epidemics and pandemics under certain conditions, by and large, it is respiratory infections propagated by droplet or airborne transmission that set off pandemics and large-scale epidemics.

Different animal hosts, too, differ in their ability to harbor pathogens with pandemic potential. Bats, along with different intermediates hosts, have been the source of repeated outbreaks, including the COVID-19 pandemic, the 2004/2005 SARS epidemic, and the largest Ebola virus outbreak to date, which infected nearly 30,000 and killed more than 11,000 people in multiple West African nations from 2014 to 2016.

Bats are likely to harbor viruses because they live the animal equivalent of an urban lifestyle, in large social groups with high population densities. In the largest urban bat colony in North America, located in Austin, Texas, 1.5 million bats live together in the 945-foot-by-60-foot space underneath the Ann W. Richards Congress Avenue bridge.

There is research suggesting that bats also appear to have evolved metabolic adaptations that mean they remain relatively unfazed by viruses that set off strong inflammatory responses. If such a virus then jumps species, it may be relatively unfazed by the immune response those other species can throw at it.

Such species jumping has become more likely as humans have increasingly encroached on bat habitat. The 2014-2016 Ebola epidemic started with a toddler playing in a hollow tree that was home to a bat colony.

Bats have shone a spotlight on the risks of increased interfacing between human and wildlife habitats. But domesticated farm animals, too, pose risks.

Like bats, farmed chickens live in large groups in crowded conditions, which has repeatedly led to concerns with respect to various strains of avian influenza.

In 1997, Hong Kong officials ordered the killing of millions of chickens in its poultry markets after an outbreak of H5N1 avian influenza, and there has been the need for smaller-scale culling on several occasions since. Those responses may have prevented an H5N1 pandemic. Other avian influenza strains, too, have been a source of concern to public health officials – sometimes more so than H5N1, which is relatively conspicuous because it kills birds as well as humans.

Another avian flu strain, H7N9, has a 25% mortality rate in humans but is mostly harmless in birds, which makes it easier for the H7N9 strain to spread undetected in poultry farms and markets.

While some strains of influenza can jump species directly from birds to humans, the most frequent jump happens via pigs as intermediate hosts. Pigs can also give rise to influenza strains directly, including the 2009 H1N1 pandemic.

Researchers at the Robert Koch Institute and the Max Planck Institute for Evolutionary Anthropology approach the question of which pathogens are most likely to cause trouble for humans from the other end. They have a project surveilling chimpanzees that live in tropical forests in the Ivory Coast, which is a high-risk area for the emergence of zoonotic diseases, for infectious deaths that cannot be explained by human-chimpanzee contact.

By looking at our closest evolutionary relatives, Fabian Leendertz and his colleagues hope to be able to see the viruses that pose the greatest threat to humans.

“If you go sequence bats, you can find plenty of new viruses,” Leendertz, group leader at the Robert Koch Institute, explained in a podcast research update. “But which are relevant?”

Editor’s note: Pandemics come and go, but they keep coming. And so, even as the world grapples with COVID-19, researchers and public health officials are trying to apply its lessons to future outbreaks. What kind of surveillance gives the best shot at early detection? What are key diagnostic tests necessary during different phases of a pandemic? What are the fastest ways to get effective therapeutics for future threats whose exact nature remains unknown until they surface? What technologies could speed up the availability of vaccines in future outbreaks? Part 2 in tomorrow’s issue will look at diagnostics: The logistics side of diagnostics rollout during COVD-19 has been its very own disaster. But on the technology side, there is a dizzying range of technologies that test for a pathogen by a variety of features, such as surface antigens and nucleic acids. In addition, the more than 11,000 clinical labs in the U.S. that are authorized to perform lab-developed tests do not deploy an identical set of technologies, another testament to the incredibly complex world of diagnostic testing for communicable diseases. Parts 3 and 4 will explore drugs and vaccines, respectively.