https://www.nytimes.com/2020/04/21/magazine/pandemic-vaccine.html
How Scientists Could Stop the Next Pandemic Before It Starts
On a cold morning in February 2018, a group of 30 microbiologists, zoologists and public-health experts from around the world met at the headquarters of the World Health Organization in Geneva. The group was established by the W.H.O. in 2015 to create a priority list of dangerous viruses — specifically, those for which no vaccines or drugs were already in development. The consensus, at least among those in the room, was that as populations and global travel continued to grow and development increasingly pushed into wild areas, it was almost inevitable that once-containable local outbreaks, like SARS or Ebola, could become global disasters.
“The meeting was in a big room, with all the tables arranged around the edge, facing each other,” one of the group’s members, Peter Daszak, recalled recently. “It was a very formal process. Each person was asked to present the case for including a particular disease on the list of top threats. And everything you say is being taken down, and checked factually, and recorded.”
Daszak, who directs the pandemic-prevention group EcoHealth Alliance and is also chairman of the Forum on Microbial Threats at the National Academies of Sciences, Engineering and Medicine, had been given the task of presenting on SARS, a lethal coronavirus that killed roughly 800 people after it emerged in 2002. (SARS stands for Severe Acute Respiratory Syndrome and is officially known as SARS-CoV-1.) “We’d done a lot of research on coronaviruses, so we knew they were a clear and present danger,” he told me. “High mortality, no drugs or vaccines in the pipeline, with new variants that could still be emerging.”
The discussion, he said, was intense. “Everyone else in the room knows the facts already — they’ve read all the research,” Daszak said. But for each pathogen, the speaker had to convince the room that it presented a significant threat — “that this disease really could take off, and that we should concentrate on it rather than on Lassa fever or something else. So, you argue the case, and then people vote. And sometimes it gets quite heated. I remember that monkey pox was an issue, because there are outbreaks, but there’s really nothing we can do about them. It was a really rigorous, really excellent debate — and then afterward, we went and had fondue.”
The final list — which did contain SARS and MERS, along with seven other respiratory, hemorrhagic or otherwise-lethal viruses — also included something the W.H.O. dubbed “Disease X”: a stand-in for all the unknown pathogens, or devastating variations on existing pathogens, that had yet to emerge. Daszak describes Covid-19, the disease caused by the virus SARS-CoV-2, as exactly the kind of threat that Disease X was meant to represent: a novel, highly infectious coronavirus, with a high mortality rate, and no existing treatment or prevention. “The problem isn’t that prevention was impossible,” Daszak told me. “It was very possible. But we didn’t do it. Governments thought it was too expensive. Pharmaceutical companies operate for profit.” And the W.H.O., for the most part, had neither the funding nor the power to enforce the large-scale global collaboration necessary to combat it.
As Covid-19 has spread around the world, overwhelming hospitals and even mortuaries, there has been widespread consternation over how we could have been caught so flat-footed by a virus. Given all the shining advances of high-tech medicine — computer-controlled surgery, unprecedented immunotherapies, artificial-intelligence programs for assessing heart-disease risk — this failure feels utterly baffling. How could the entire world remain so powerless? More important, what could be different next time?
According to some infectious-disease experts, the scientific tools already exist to create a kind of viral-defense department — one that would allow us to pursue a broad range of vital global projects, from developing vaccines and drugs that work against a wide range of pathogens to monitoring disease hot spots and identifying potential high-risk viruses, both known and unknown. What’s lacking is resources. “We really did miss the wake-up call,” Daszak says. “The alarm went off with SARS, and we hit the snooze button. And then we hit it again with Ebola, with MERS, with Zika. Now that we’re awake, we should think about where to go from here.”
In late March, Vincent Racaniello, host of the podcast “This Week in Virology” and a professor at Columbia University, conducted an interview with the pediatric infectious-disease expert Mark Denison. Denison, who teaches at Vanderbilt University Medical Center, led a team that developed one of the most promising current treatments for Covid-19: the drug remdesivir, currently being tested by the pharmaceutical company Gilead Sciences.
On the show, Denison noted that because it is almost impossible to predict which virus might cause the next pandemic, researchers had long argued that it was essential to design panviral drugs and vaccines that would be effective against a wide range of strains: all types of influenza, for instance, or a substantial group of coronaviruses rather than just one. When his lab was first applying for a grant to study remdesivir, Denison recalled, that was already the goal. “We don’t want to work with a compound unless it inhibits every coronavirus we test,” Denison said. “Because we’re worried about MERS, we’re worried about SARS-1, but they’re not really our problem. The future is the problem.”
Panviral drugs — ones that work broadly within or across virus families — are harder to make than broad-spectrum antibiotics, largely because viruses work by hijacking the machinery of our cells, harnessing their key functions in order to replicate. A drug that blocks one of those functions (e.g., the production of a particular protein) is often also disrupting something that our own cells need to survive. Researchers have begun to find ways around that problem, in part by refining which process a drug targets. But they’ve also begun to test existing drugs against a wider array of viruses. It was in just such a follow-up screen that Gilead discovered that remdesivir, originally developed to treat hepatitis C and later tried against Ebola, might be effective against coronaviruses. (Favipiravir, an influenza drug developed in Japan, is another broad-spectrum candidate.) The reason drugs sometimes work in extremely different diseases — in, say, Ebola and coronaviruses and flu — is that they block some common mechanism. Remdesivir and favipiravir, for instance, each mimics a key building block in a virus’s RNA, which, when inserted, keeps the virus from replicating. “It’s definitely possible to make a drug that would work across a good range of coronaviruses,” Racaniello says. “We honestly should have had one long ago, since SARS in 2003. It would have taken care of this outbreak in China before it got out. And the only reason we didn’t is because there wasn’t enough financial backing.”
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Panviral vaccines are also becoming a real possibility. In recent years, a number of prospective universal flu vaccines have been developed that work by targeting not the virus’s globular head, which mutates easily, but its stalk, which barely mutates at all. (As Daszak noted, if this outbreak had been a flu rather than a coronavirus, we’d be in much better shape.) Another new approach, mRNA vaccines, works by exploiting messenger RNA — a kind of courier that communicates the genetic instructions for making proteins — to drive an immune response. The advantages of mRNA vaccines are potentially enormous, in part because they can be made very quickly (one month instead of six for a known strain; two to three months for a novel virus) but also because they can be made on a vast scale (billions of doses, compared with the 100,000 doses that were needed for the Ebola epidemic). They’re extremely adaptable too: If a researcher can develop a platform that works with this coronavirus, it’s easy to redesign it for the next one. (One mRNA start-up, Moderna, set a drug-industry record by creating a prospective Covid-19 vaccine, mRNA-1273, in just 42 days, using the virus’s genetic sequence. The drug is currently in Phase 1 clinical trials to be safety-tested on healthy volunteers.) And while no mRNA vaccines have yet received F.D.A. approval, Covid-19 will almost certainly change that.
But for years, Racaniello notes, the real obstacle to making panviral drugs or vaccines has been that no one was willing to pay for their development. For pharmaceutical companies, he points out, panviral vaccines are simply a terrible business proposition: Companies have to spend hundreds of millions of dollars to develop a shot that people will get once a year at most — and not at all in years when no particular disease is ascendant.
Panviral drug treatments are unprofitable for similar reasons. For one, the course of treatment is short, usually just a few weeks; for chronic diseases (diabetes, high blood pressure), patients take regimens of pills daily, often for years. (One person noted that Gilead’s stock price actually dropped after the company produced a revolutionary hepatitis C drug. Because the treatment completely cured patients, the market for it started to shrink, undermining the company’s bottom line.)
The other problem is that there’s currently no way to quickly test for most viruses, which is essential if a doctor wants to establish a diagnosis and prescribe the right drug. As a result, Racaniello says, it’s “a chicken-and-egg situation: No one is developing drugs for these viruses because there’s no way to test for them. And no one is developing tests, because there aren’t any drugs to prescribe.”
Governments, meanwhile, have been reluctant to fund panviral development — both because it’s expensive and because the rewards can feel remote, especially as many diseases originate in other countries. “We don’t prevent well; we respond well,” Daszak notes. “Remember when Obama got $5 billion for the Ebola outbreak in West Africa, and U.S. troops went to help fix the problem? That’s heroic. How heroic is it, three years before Ebola, to say, ‘We’re going to fund a massive program in West Africa to help these poor countries get ready in case an outbreak happens?’ He’d be laughed out of the room!”
Global nonprofits like the Gates Foundation have tried to step into this funding void. The foundation has supported GAVI, an international alliance that helps vaccinate children in poor countries and spearheaded a fund to fight H.I.V., tuberculosis and malaria worldwide. Mark Suzman, the chief executive of the Gates Foundation, says that when governments and companies do pull together, the focus is often on projects like these rather than “forward-looking” issues like pandemics or climate change. One exception, he says, has been CEPI, the Coalition for Epidemic Preparedness Innovations, an NGO that was founded in 2017 to coordinate and finance the development of new vaccines for diseases that might lead to a pandemic. When it started, Suzman told me, CEPI was a low-profile project: “It was really a response to the Ebola epidemic of 2014 and 2015. Now, of course, it looks incredibly farsighted.”
CEPI works by identifying the most promising research, and then connecting it to industry and government resources, in order to bring multiple sets of “candidate” vaccines through initial clinical trials. The goal is to create a stockpile of potential treatments for known coronaviruses, hemorrhagic fevers and other global threats that could quickly go into production in the event of an epidemic. Daszak noted that CEPI is running a trial for a vaccine against Nipah virus, a zoonotic virus — one that exists in animals but can infect people — which can cause acute respiratory illness and fatal encephalitis. “This is the classic example,” Daszak says. “So far, there have been only a few outbreaks, so the market is minuscule: a few thousand people a year get it, in Malaysia or Bangladesh. But it infects a wide range of animals, and that means it’s likely to keep crossing over into people. And if it ever broke out, it could be a pandemic with very lethal consequences.”
The group also funds technologies aimed at “Disease X” (the potentially pandemic viruses that we have yet to discover) with the goal of faster vaccine development should a totally new threat emerge. As Jake Glanville, whose company, Distributed Bio, received a grant from Gates Foundation to create a universal flu vaccine, told me, “This is how we win the forever war, and not just battles against these pathogens.”
CEPI isn’t the only group trying to find solutions to the drug and vaccine problems. In the United States, a federally funded university collective called the Antiviral Drug Discovery and Development Center (AD3C) was created in 2014, with the goal of developing drugs for influenza, flaviviruses (including West Nile), coronaviruses and alphaviruses. Like CEPI, AD3C partners with pharmaceutical companies but focuses on salvaging and reformulating promising drugs that might be valuable but that the company isn’t interested in pursuing. (When Gilead discovered that remdesivir worked on coronaviruses, for instance, the treatment was routed to AD3C, which enlisted scientists at Vanderbilt University and the University of North Carolina to repurpose it.)
Amesh Adalja, a senior scholar who specializes in infectious-disease and pandemic preparedness at the Johns Hopkins University Center for Health Security, told me that approaches like these are going to be “instrumental” in preventing whatever comes after Covid-19. “In the wake of this pandemic, people are going to realize that spending money on organizations like CEPI is a good investment — especially when you realize how much having a vaccine against the coronavirus would have offset the damage and destruction and disruption that we’ve seen.”
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Credit...Illustration by Tim Enthoven
Despite these efforts, there is still one overarching problem: how little is known about the planet’s viral threats. Viruses make up roughly two-thirds of all newly discovered human pathogens — far more than either bacteria or fungi. Over the course of human evolution, we’ve been exposed to so many that about 8 percent of the human genome is made up of retroviral DNA sequences that have inserted themselves into the human germ line, often to our benefit. (An ancient virus is thought to be responsible for the development of the human placenta, for example.)
Perversely, viruses get no advantage from making people seriously ill; it’s simply a byproduct of the encounter. Over the years, or sometimes centuries, viruses and hosts usually reach an accommodation: They coexist. Typically, the most dangerous viruses are those that have jumped into humans from other species, as happened with Covid-19. That’s partly because the disease is new, so our immune system hasn’t had a chance to create antibodies. But it’s also because an unfamiliar virus is more likely to throw our immune system into overdrive, potentially fatally.
For anyone hoping to identify where the next pandemic is coming from, the difficulty is that there are literally millions of viruses to analyze. One paper recently estimated that there were 1.6 million potentially zoonotic viruses, of which fewer than 1 percent have even been identified. “One thing we definitely need is better diagnostic testing where we’re actually looking for these emerging pathogens in people,” Adalja says. “Because there are already many, many one-off cases that no one ever diagnoses, but which could be the first sign of a new virus jumping into a human species.” While influenza and coronaviruses are known pandemic threats, they’re far from the only ones. Nipah and Hendra viruses are deadly paramyxoviruses that have emerged from bats within the past three decades. Marburg is a highly lethal hemorrhagic fever like Ebola, but without any vaccine or treatment in the pipeline. (Dozens of other hemorrhagic viruses also exist, but so far haven’t made the jump to humans.)
One argument against doing this kind of work has been that the risk of any single virus’s causing a pandemic is low. Most viruses simply aren’t equipped to make the jump from animals to humans — and even when they do, most aren’t able to replicate in ways that become dangerous or spread from person to person. The problem, Daszak says, is that when you multiply a 10-million-to-one event by the total number of animal-human interactions, the probability isn’t that low after all. “It’s really easy to scientifically demonstrate that these are rare events and we shouldn’t bother,” he added. H.I.V., for instance, was originally present in primates, and spilled over into the human population only about 10 times in the span of a century; each time, it quickly died out — until it didn’t. “Statistically, when you look at the likelihood that a virus will, first, be able get into a person, and then be able to replicate, and then get transmitted through sex, the probability seems like it should be minuscule! But what we failed to appreciate was both the adaptability of viruses, and the dimensions of the human-wildlife interface.”
Hoping to get a more accurate estimate of which viruses could be a threat, Daszak recently traveled to a rural part of Yunnan province, in China, and took blood samples from people who live there, looking for antibodies that would show how often they had been exposed to bat coronaviruses. (Detectable antibodies typically last two to three years after an infection.) “This was bat coronaviruses alone — not all the other stuff that’s out there,” Daszak said. “And we found that 3 percent of the population had been exposed — which tells me that these things are spilling over at an incredible rate, as part of everyday business in rural China.”
Which means, Daszak says, that between one million and seven million people a year in Southeast Asia pick up bat coronaviruses. “For most of them, it probably doesn’t even cause illness. There may have been some little outbreaks that never got noticed, or cases where people even die, and it gets put down to influenza or something.” He paused. “But that is a huge level of spillover. It’s not difficult to imagine one of those infections mutating a bit and becoming Covid-19.”
Policing points of potential spillover is challenging — and the effort needed to rigorously track and test wildlife even more so. As Racaniello observed, “We’ve known since SARS that bats harbor dangerous coronaviruses. So bats are an obvious place to look. But even then it’s not easy to do. You have to crawl into a bat cave, you have to catch them somehow. It’s tedious, costly work.”
In the United States, for example, some species of mice harbor hantavirus, which periodically infects people, most often when they inhale aerosolized mouse droppings — say, when sweeping out a dusty cabin or garage. Because the infection, which starts like a flu but is fatal in 38 percent of cases, doesn’t spread from person to person (yet), the pandemic risk is currently low, Racaniello says. “A good question is, what would have to happen for that virus to become human-to-human transmissible? And also, what else do mice have that might be a threat to people? But the mice of the United States have barely been sampled, in terms of the viruses they carry.”
During the Obama administration, a U.S.A.I.D. program called PREDICT was created to fill that gap, by using biological surveillance and predictive modeling to identify the most likely sources of zoonotic disease. During the 10 years the program existed, researchers found more than a thousand new potential zoonotic viruses, including an unknown Ebola strain. (Daszak, whose group received financial support from PREDICT, called the project “visionary.”) After the program’s funding ended in September, shortly before the coronavirus outbreak began, the Trump administration authorized two successive six-month extensions. A U.S.A.I.D. spokesperson said that in September, there will be “a planned transition” to a new prevention program, Stop Spillover, with a proposed budget of between $50 million and $100 million over five years. “For these sorts of programs to work, you have to be patient,” Racaniello told me. “But these projects also cost money, and they don’t necessarily seem like they’re producing much in the short term, so they’re the easiest things to cut when you want to cut a budget.”
One challenge for pandemic hunters is understanding which animals are most likely to be the source of viruses. Bats, the original carriers for many zoonotic viruses, rarely pass those diseases to humans directly. (One study found that bats in China harbor more than 500 different coronaviruses, but they also carry paramyxoviruses, influenza and hemorrhagic viruses like Ebola.) More often, Daszak explained, bats infect another animal, which then infects us. “About a fifth of all mammals are bats,” Daszak points out. “And they’re all over the globe. We just don’t realize that, because they fly at night. But they’re out there, pooping all over the place — just like deer and birds, except we don’t see it.” (It’s worth noting that, of the thousands of bat species, only a few — such as the fruit bat and horseshoe bat — are currently thought to be the major reservoirs of zoonotic disease.)
Bats also fly, can live for a long time and thrive across a huge range of habitats, which means that we, and other animals, are more likely to come in contact with them than with other species. Racaniello pointed to an outbreak in Australia in the 1990s that was caused when bats began frequenting a racehorse stable, infecting the horses, which then passed the disease on to their human trainers. In Malaysia, Nipah virus emerged from pigs, on farms in an area that harbored fruit bats. In the Middle East, the MERS coronavirus — which most likely originated in a bat — became endemic in camels, who at some point started passing it on to people.
“Before that outbreak, it wouldn’t have occurred to anyone to look in camels for a pandemic virus,” Racaniello said. “The same is true for a lot of things. For instance, we knew that bats carried SARS-like coronaviruses, but it was only when they started looking for the cause of the first SARS outbreak that they found it had jumped from bats to civet cats, which is how we got it. But as to all the other animals in the world, we pretty much have no idea! So, I think you just need to cast a very wide net.”
To do that, Daszak helped found an ambitious project called the Global Virome Project, which seeks to identify 70 percent of the estimated 1.6 million potentially zoonotic viruses over 10 years, at a cost of $1.2 billion. “We found the closest relative to the current SARS-CoV-2 in a bat in China in 2013,” Daszak told me. “We sequenced a bit of the genome, and then it went in the freezer; because it didn’t look like SARS, we thought it was at a lower risk of emerging. With the Virome project, we could have sequenced the whole genome, discovered that it binds to human cells and upgraded the risk. And maybe then when we were designing vaccines for SARS, those could have targeted this one too, and we would have had something in the freezer ready to go if it emerged.”
Racaniello supports this strategy — “I like the test-every-creature-on-Earth approach, personally” — but acknowledged that there were also ways to narrow the field. Risky zoonotic viruses, he noted, are more likely to be found in mammals or birds; anything else is just too big a genetic jump. Within that group, animals that are evolutionarily closer to us are also higher-risk, because we share more of the receptors that viruses use when they infect a cell.
Another risk factor is simply how likely we are to come into contact with a particular animal, whether from activities like logging, through the wildlife trade or through farming. (Measles is thought to have arisen out of the domestication of cattle, while pigs and chickens carry swine flu and bird flu.) But while vaccines exist for some domesticated animals — there’s a successful one for coronavirus in chickens, and researchers recently created a MERS vaccine for camels — there’s no way to vaccinate wildlife, or even urban animals like mice.
“That’s why we need to be studying these things,” Daszak says. “We’ve shown repeatedly that any disease, once it gets into human-to-human-transmission mode, it’s going to come to the U.S. We’re always in the top five every time we do that analysis. We said, about Ebola, because it’s not respiratory, it’s never going to break out of a village, or a country. And it did! And if you get a version with a longer asymptomatic incubation time, like we have with Covid-19, imagine what that could look like.”
In the wake of the Covid-19 pandemic, more systems of global cooperation and investment have started to emerge. In late March, the Gates Foundation set up a Covid-19 Therapeutic Accelerator to screen a vast number of existing drugs and compounds that hadn’t made it to market, in order to test whether they might work on other diseases.
The screening, done by the Rega Institute in Belgium, will scan and test 14,000 compounds in a Scripps Research Institute library, as well as the proprietary libraries of 15 pharmaceutical companies, including Bristol-Myers Squibb, Eli Lilly, Merck, Novartis and Pfizer, for possible crossover treatments. Because most of the drugs have already been tested for safety, they need to be tested only for efficacy, speeding up the process.
The willingness to share proprietary compounds, says Suzman of the Gates Foundation, is “pretty unprecedented.” And while that collaboration is currently focused on Covid-19, the hope is that, after the current crisis has passed, that same collection could be screened for more ambitious projects — like a broad-spectrum anti-coronavirus drug. “I am optimistic — cautiously optimistic — that this is a kind of precedent,” Suzman said. “And that it will lead to more and better global health collaboration.”
Monalisa Chatterji, a microbiologist who is part of the Gates Foundation’s drug-discovery arm, agrees. “The conversation has started” for future pandemics, she told me. “Should there be a standing shared library of unused drugs that research labs can test? Should similar things be done around diagnostics? Should there at least be an agreement where every company has already agreed to provide access to its library in a pandemic situation?” She added, “That sounds small, but it’s these small things that eat up time when it matters.”
The big question, according to nearly everyone I spoke with, is whether we’ll manage to maintain this political and financial will over time. Racaniello and Daszak both remember being sure that after SARS and Ebola, pandemic prevention would be a priority; instead, each outbreak was quickly forgotten. And while it’s hard to imagine forgetting the current disaster, researchers worry that funding and attention will once again fade in the face of competing pressures. As Rancaniello observed, the combined 2019 budgets for the National Institutes of Health and the National Science Foundation was $47 billion — less than 7 percent of the $686 billion allocated to defense. “I would argue that viruses are just as much a threat as a bad nation would be to the military,” Racaniello said.
Or as Daszak put it: “We don’t think twice about the cost of protecting against terrorism. We go out there, we listen to the whispers, we send out the drones — we have a whole array of approaches. We need to start thinking about pandemics the same way.”
