Part of Pandemic-Proof, Future Perfect’s series on the upgrades we can make to prepare for the next pandemic.

The Covid-19 pandemic has given the world a painful primer on the power of exponential growth.

On December 30, 2019, per the World Health Organization, there were two confirmed cases of what would become known as Covid-19. One week later, there were 46. A week after that, 134. A week after that, 2,028. A week after that, 14,565. By the beginning of March, the cumulative global caseload had hit six digits, and by the end of March it was over a million.

Exact numbers that early in the pandemic — when tests were often hard to obtain — are shaky, but the picture is clear: Covid-19 went from being a very small problem affecting a handful of patients to a widespread pandemic at alarming speed.

That’s the particular danger of a contagious respiratory pandemic — the more time that passes before you can mount an effective response, the faster outbreaks will get out of hand and the more painful it will be to bring it back under control.

But the flip side of exponential growth is that being able to intervene early gives us the opportunity to prevent the next pathogen with the pandemic potential of SARS-CoV-2 from wreaking the same kind of havoc on the world. That, more than anything else, is the key lesson from Covid: We need to go faster. One estimate in May 2020 found that instituting social distancing policies just one week earlier in March of that year could have prevented about 83 percent of deaths in the US up to that point, potentially saving tens of thousands of people.

Speed mattered for more than social distancing. Vaccines saved 1.1 million lives by the end of November 2021, according to one estimate, and effective Covid-19 treatments have saved many others. But while the Covid-19 vaccines were developed in record time — Moderna’s mRNA shot took just a weekend for its initial design — and extraordinary, innovative studies found effective treatments quickly as well, neither was fast enough to outrun the virus’s exponential growth.

Covid-19 will not be the last disease with the potential to grow into a pandemic. To fight the next one, we need to have a game plan to speed up the search for and deployment of vaccines and treatments. Such a plan would launch research and development efforts targeting pathogens with pandemic potential, stand up an infrastructure to accelerate the testing of candidate vaccines and antivirals, and pump funding into both.

The virus next time will require a faster response from governments and a longer view from policymakers, who need to see that a dollar spent on prevention today will save many more dollars and lives in the future. Speed and time are of the essence. The reality, as we see this pandemic fade in the rear view, is that the fight against the next one begins now.

We have some idea of what diseases will cause the next pandemic

Before Covid-19, the world had received several warnings that a coronavirus could cause a brutal pandemic.

There was the 2002-2003 emergence of severe acute respiratory syndrome, or SARS, which killed 774 people by December 2003. Another warning came with the Middle East respiratory syndrome (MERS) in 2012, a slower-moving outbreak that has killed 890 people thus far, the vast majority in Saudi Arabia.

In response, vaccine researchers created candidates to vaccinate against SARS and MERS, and began testing them in phase 1 trials. Researchers published a phase 1 study in 2007 showing that a SARS vaccine candidate from the Chinese firm Sinovac was safe and generated an immune response in a small sample of patients.

A year later, a phase 1 trial at the US National Institutes of Health’s (NIH) Vaccine Research Center found that a different SARS vaccine, from the US company Vical, was safe and produced immune responses in a small sample of participants. In 2019, a phase 1 study confirmed safety and immune response for a proposed MERS vaccine from South Korea’s GeneOne Life Science.

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Phase 1 trials are just a first step. Larger, costlier phase 2 trials are necessary to confirm safety and immune response among a broader range of people. But SARS/MERS vaccine research never got to that stage, and some researchers put the blame on a lack of funder interest.

Peter Hotez and Maria Elena Bottazzi at Texas Children’s Hospital have said they had a SARS vaccine candidate ready for trials but “ran out of money before they could test it on people,” per Politico. After a MERS outbreak in South Korea in 2015, Oxford professor Adrian Hill told Reuters, “Should we have made a MERS vaccine? Yes. Could anyone have afforded it? Yes, the government of Saudi Arabia. So should something be done? Yes, someone should go and develop a MERS vaccine sooner rather than later.”

Hill and colleagues finally launched a MERS vaccine trial in Saudi Arabia years later in December 2019, right before Covid-19 hit. Hill would go on to help create the Oxford/AstraZeneca vaccine for Covid-19, and Hotez and Bottazzi announced their own vaccine for the disease earlier this year.

On their own, it might seem as though more advanced trials to produce a SARS or MERS vaccine wouldn’t have been a good use of funds. The diseases were not highly contagious and only killed a few hundred people over a period of years, while outbreaks were halted with infection control methods. A disease like HIV, by contrast, killed about 680,000 people in 2020 alone. Intuitively, HIV — which drew nearly $15 billion in research funding between 2000 and 2018 — deserves more research attention.

But funders, including pharmaceutical companies, governments, and philanthropies, failed to consider not just what SARS and MERS were, but what they were foreshadowing — closely related viruses that, with a few genetic changes, could bring the whole world to its knees. It’s impossible to know for sure, but approved SARS or MERS vaccines might have been able to at least partially protect people from Covid-19 early on, before a targeted vaccine was developed, or at least get us further along the track of developing a Covid-19 vaccine.

That possibility has led to growing interest among vaccinologists in funding the development and testing of candidate vaccines against dozens of viruses that could one day cause a pandemic. Most of these diseases never will, of course. But as it happens, it’s far cheaper to prepare vaccines for, say, 100 viruses that could potentially mutate into a pandemic pathogen than it is to let any one of those pathogens run rampant for a year or longer until we can design and fully test a new vaccine.

Here’s how we’d go about it.

Why testing drugs and vaccines before a pandemic matters

Generally speaking, drugs and vaccines undergo three phases of testing before going to market.

Phase 1 trials involve 20 to 80 people and ensure, first, that the drug or vaccine is safe. These trials also are used to determine proper dosage.

Phase 2 trials are larger (100 to 300 subjects) and test effectiveness. For vaccines, this often means “correlates of protection”: signs in patients, like antibody production, that suggest the vaccine is successfully priming the immune system against infection.

Phase 3 trials are larger still (several hundred to 3,000 subjects) and ensure effectiveness and safety in a larger sample, as well as in sub-samples of particular concern, like the very old or the very young, or women versus men.

Phase 4 trials occur once the treatment or vaccine is already on the market, and capture rarer side effects and measure effectiveness in even more specific populations. The length of each phase varies wildly for different therapeutics, so it’s hard to make any generalizations, but the Pfizer/BioNTech SARS-CoV-2 vaccine entered phase 1 trials in May 2020, with a joint phase 2/3 trial starting two months later, and the FDA authorizing the vaccine for emergency use five months after that.

Here’s the crux: For vaccines and antivirals targeting hypothetical future pandemic pathogens, we can absolutely do phase 1 and 2 trials years in advance. Doing so means being able to dive right into phase 3 at the emergence of the next pandemic, saving humanity precious months.

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Florian Krammer, a virology professor at Icahn School of Medicine at Mount Sinai, laid out in a December 2020 commentary in the journal Med how a large-scale program to develop vaccines for potential pandemic pathogens could work.

1. Researchers curate a list of up to 100 viruses to prepare against.
2. Teams produce candidate vaccines for each of these pathogens.
3. Those teams then conduct phase 1 and 2 trials for each vaccine.
4. Once a viral pandemic emerges, researchers pick the vaccine candidate closest to the pandemic strain, adjust it to more closely target the new threat, then initiate phase 3 trials to show the vaccine is effective.
5. The vaccine gets emergency use authorization a few months after the trial begins, once it shows efficacy.

While Krammer’s piece is focused on vaccines, the same kind of process could work for producing antivirals. In fact, antivirals may be an even more tractable target for such an approach than vaccines are. “Broad spectrum” antivirals can target a range of viruses, just as penicillin is useful against a range of bacteria. Molnupiravir, the recently approved anti-Covid pill, is a broad-spectrum antiviral that began life as a treatment for the flu before it was shifted to target Covid-19.

This approach could also involve the development of so-called “universal” vaccines for certain families of viruses. For decades, researchers have sought a “universal flu vaccine” that could work against all influenza strains, not just the handful targeted by each seasonal vaccine. (A main reason the annual flu shot is rarely more than 50 percent effective is that the virus present in the population often mutates and ends up being quite different from the strains selected months earlier for the vaccine.)

Since Covid-19, many experts, including National Institute of Allergy and Infectious Diseases (NIAID) researchers David Morens, Jeffery Taubenberger, and Anthony Fauci, have called for the development of universal coronavirus vaccines. Such vaccines probably won’t be truly universal (we can’t predict every possible mutation of these viruses, as Covid-19 has amply demonstrated), but they would provide broad-based protection and reduce the odds of outbreaks or pandemics coming from influenzas or coronaviruses.

The Coalition for Epidemic Preparedness Innovations (CEPI), arguably the leading international pandemic prevention organization, is focusing its work on roughly 25 “viral families” with pandemic potential, while NIAID maintains a priority list of organisms or biological agents that pose a biodefense threat. In 2015, the World Health Organization made a shortened list of six known virus types to work on, and NIAID has targeted seven viral families for antiviral drug development.

“There is a growing consensus that these families of viruses should be priority targets for research and countermeasure development because their transmission modes, severity, and demonstrated pandemic potential make them major threats,” Judith Wasserheit, a professor of global health and medicine and co-director of the University of Washington’s Alliance for Pandemic Preparedness, told me in an email.

Having a candidate in hand for a family of viruses allows us to skip some steps in developing specific vaccines during a pandemic. If we had entered January 2020 with a SARS or MERS vaccine that had proven safe and provoked immune response, we could’ve launched a clinical trial that month to see if a tweaked version was effective against SARS-CoV-2, the virus that causes Covid-19. That might have bought us precious months.

Phil Krause, a former deputy director of the FDA’s Office of Vaccine Research and Review, told me that in such a scenario, “it’s conceivable that [a phase 3] trial could’ve been done a few months earlier,” and a vaccine could’ve been authorized in the summer of 2020. Vaccines would have been available in the months leading up to winter 2021, when the daily US death toll from Covid-19 was at its highest. It’s not a guarantee, but we would’ve had a significant leg up.

The same approach could also be applied to the development of treatments. Having more effective therapies for coronaviruses generally would have saved still more lives during this pandemic.

That’s the kind of work that the Rapidly Emerging Antiviral Drug Development Initiative (READDI) at the University of North Carolina is doing.

Think of READDI as the antiviral equivalent of what CEPI does for vaccines. Its focus is developing “small-molecule antiviral drugs that work against entire families of viruses with high pandemic potential.” These are treatments that, according to READDI, will be “highly likely to be effective against the next virus in that family to emerge, providing ‘on the shelf’ protection from future viral pandemics.”

That’s a noble goal, one that could use more than one research group pursuing it — and that could also benefit from an accelerated development program.

Building the infrastructure for clinical trials

That takes us to the next big upgrade we can push now: setting up the infrastructure at the National Institutes of Health for a pandemic treatment study before the next pandemic comes. That means enrolling participants for trials during normal pre-pandemic times, establishing data-sharing with their hospitals, and preparing to jump into action once a pandemic strikes.

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The best, fastest research on Covid-19 treatments has come from the UK RECOVERY study, which was up and running within six weeks of its announcement in March 2020 and was able to quickly collect data from National Health Service hospitals.

The study identified effective treatments like the steroid dexamethasone and the monoclonal antibody treatment REGEN-Cov faster than some research from more established sources; while RECOVERY quickly learned hydroxychloroquine was not effective at fighting Covid-19, a much bigger study by the company Novartis was canceled before it could even get results.

Some of RECOVERY’s success was due to the centralized UK health care system; most hospitals are run by the national government and have a shared data system, making collecting information about patients much simpler. That is far from the case in the mostly privatized US system.

But there’s no reason the NIH couldn’t copy the RECOVERY model of standing up a large-sample study quickly by relying on hospital health records to make collecting data on patients easier and faster.

“If you’re struggling to set up the infrastructure from scratch, it’s very hard,” Joshua Sharfstein, a professor at the Johns Hopkins Bloomberg School of Public Health and former deputy head of the FDA, told me. “But if you already have the study ready to go, then you get higher-quality data to the FDA faster.” And faster data means faster drug approvals and deployment.

We can also learn from RECOVERY’s methods. Doctors in the study randomly determined who received which treatments. That produces more reliable data more rapidly than large-scale observational studies, where treatments are not randomized and researchers sift through results after the fact to try to determine what worked and what didn’t.

The team behind the RECOVERY trial recently launched a nonprofit called Protas, which aims to spread the model of low-cost, high-enrollment, fast-to-launch clinical trials. Funding work like that should be a no-brainer for the US pandemic preparedness budget.

More ambitiously, NIH could invest in setting up the infrastructure for challenge trials, in which healthy volunteers would be infected with the pathogen in question, enabling faster testing of treatments and vaccines.

In traditional studies, you can only measure effectiveness if you have a critical mass of people being exposed to the illness. That makes them harder to conduct during non-pandemic times, or early in an outbreak that’s being well controlled. We only wound up not needing challenge trials for Covid-19 because the disease spread so quickly that many of us were being “challenged” by the virus whether we wanted to be or not.

Challenge trials present a thorny ethical question — doctors are understandably reluctant to expose healthy people to a potentially deadly illness — but the efforts are most helpful early in a pandemic; if they take too long to set up, they don’t save time. Having the infrastructure ready, like a biosecure dormitory to house patients so they don’t expose others to the pathogen, would go a long way. And if a challenge trial is successful, it can produce results that can help prevent far more people from being exposed, unprotected, to the virus down the road.

The big ask: Money to make it all happen

US policymakers seem to understand that a large-scale effort to develop vaccines and treatments for a wide variety of pathogens is necessary to prevent or mitigate the next pandemic.

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In early February, NIAID head Fauci announced a new pandemic preparedness plan that aims to produce more research into both “prototype pathogens” (not-yet-dangerous viruses with the potential to cause an outbreak) and “priority pathogens” that are already harmful but could grow more so, like Zika virus.

The issue is that there simply is not enough money authorized by governments, philanthropies, or private pharmaceutical companies to fund research and vaccine development for each prototype or priority pathogen. Krammer estimated that each phase 1 and 2 trial set for each candidate vaccine would cost around $20-30 million; preclinical work to get to the point of having candidate vaccines costs still more. Assuming one vaccine candidate each for 100 different potential pandemic pathogens, that’s at least $3 billion total.

That seems like a lot, but let’s put it in context: each Virginia-class nuclear submarine the Navy purchases costs about $3.45 billion. The Navy is planning to buy two new ones each year for the next 30 years. Given that some estimates have placed the total cost of Covid-19 at around a year’s worth of global GDP, or roughly $84 trillion, funding vaccine studies would be a comparatively trivial expense; even lower estimates focusing only on economic cost go into the tens of trillions.

The international group that would make sense to lead an effort like this is CEPI. Founded in 2016 and funded by the Bill and Melinda Gates Foundation and a number of governments, the organization deserves huge credit for backing three vaccine projects against Covid-19 before the first month of the pandemic was out in January 2020, including Moderna’s successful effort.

But CEPI isn’t large enough to take on the entire task alone. The group is currently trying to raise $3.5 billion over the next five years, intending to use it to make progress developing prototype vaccines from roughly 25 viral families.

“It’s going to require intense involvement from multiple global organizations, private, academic, government — all types,” In-Kyu Yoon, CEPI’s acting director, told me.

Contrary to what anti-vaxxers may tell you, vaccines are not a highly profitable line of business for pharmaceuticals. There’s much more money to be made in selling daily or weekly treatments for chronic diseases than in a few shots that provide lasting protection. Vaccines for diseases that are not yet widespread, but might be one day, are about as unprofitable as you can get. The same goes for treatments for diseases that may one day threaten us, but don’t threaten us yet.

This is a clear case of market failure: These are products that could save millions of lives and trillions of dollars if they prevent or shorten a future pandemic, and yet they’re not being produced by the private sector. In cases like this, we need large-scale public investment.

Money buys speed. The crucial fact of the Covid-19 crisis was that it took many months from the disease’s emergence to the introduction of effective vaccines and treatments — record speed, yes, but still not fast enough to prevent widespread suffering. We can use money to shorten that time, to buy speed, and to make intervention earlier in an outbreak plausible. At best, we could keep an outbreak an outbreak, and prevent it from becoming a world-crushing pandemic.

Congress has authorized some $5.8 trillion in spending to tackle the Covid-19 crisis, the vast majority of which has gone to cushioning the financial blow of the pandemic. By contrast, a bipartisan group of officials (including noted conservatives like former Homeland Security Secretary Tom Ridge and Lisa Monaco, who served under presidents Bush and Obama as a national security official) has called for a $10 billion annual investment in biodefense over the next decade, or $100 billion over the next 10 years. Biden’s own pandemic preparedness plan calls for $65.3 billion in funding over the next seven to 10 years.

Either plan represents less than 2 percent of Congress’s spending to date to tackle the current pandemic. It’s a very small price to pay to prevent the catastrophes to come.