Raphael ThysCredit...Harry Campbell
The Covid-19 pandemic would look very different if scientists had been able to develop a treatment sooner. The death rates are likely to have been far lower, and it may have been harder for myths and misinformation to spread the way they did.
In the early days of the pandemic, I expected a treatment to come along well before any vaccines were available. I wasn’t alone: Most people I know in the public health community felt the same way. Unfortunately, that’s not what happened. Safe, effective Covid vaccines were available within a year — a historic feat — but treatments that could keep large numbers of people out of the hospital were surprisingly slow out of the gate.
It wasn’t for lack of trying. As soon as the coronavirus was identified, researchers started looking for the holy grail of treatments: an antiviral drug that’s cheap, easy to administer, effective for different variants and capable of helping people before they get too sick. Scientists explored dozens of potential treatments, including hydroxychloroquine, dexamethasone, remdesivir and convalescent plasma. Some showed promise, but all had drawbacks.
In late 2021, a few of their efforts paid off — not as soon as would have been ideal, but still in time to have a big impact. Merck and its partners developed an antiviral called molnupiravir, which was shown to significantly reduce the risk of hospitalization or death for people at high risk. Soon after, another oral antiviral, Paxlovid, made by Pfizer, also proved to be very effective, reducing the risk of severe illness or death by nearly 90 percent among high-risk, unvaccinated adults. These drugs are useful tools for combating the pandemic, but they arrived much later than they should have and, for many, they are still difficult to access.
By the time these treatments were available, a large share of the world’s population had received at least one dose of a vaccine. But just because there is a vaccine doesn’t mean therapeutics aren’t important, in Covid or any other outbreak. It’s a mistake to think of vaccines as the star of the show and therapeutics as the opening act you would just as soon skip.
We’re lucky that scientists made Covid vaccines as quickly as they did — if they hadn’t, the death toll would be far worse. But in the event of another pandemic, even if the world is able to develop a vaccine for a new pathogen in 100 days, it will still take a long time to get the vaccine to most of the population. This is especially true if you need two or more doses for full and continued protection. If the pathogen is especially transmissible and deadly, a therapeutic drug could save tens of thousands or more.
Even once there is a vaccine, we’ll still need good therapeutics. As we’ve seen with Covid, not everyone who can take a vaccine will choose to do so. And, along with non-pharmaceutical interventions, therapeutics can reduce the strain on hospitals, which would prevent the overcrowding that ultimately means that some patients die who otherwise wouldn’t.
With good therapeutics, the risk of severe illness and death could drop significantly, and countries could decide to loosen restrictions on schools and businesses, reducing the disruption to education and the economy. What’s more, imagine how people’s lives would change if we’re able to take the next step by linking testing and treatment. Anyone with early symptoms that might indicate Covid (or any other viral disease) could walk into a pharmacy or clinic anywhere in the world, get tested and, if positive for the virus, walk out with antivirals to take at home.
All of which is to say: Therapeutics are fundamentally important in an outbreak. To understand what caused the delay in drugs and how we can avoid such delays in the future, we need to take a tour through the world of therapeutics: what they are, how they get from the lab to the market, why they didn’t fare better early in this pandemic and how innovation can set the stage for a better response in the future.
Treating disease is nothing new to humans. The practice of using roots, herbs and other natural ingredients as healing agents dates to ancient times. Some 9,000 years ago, Stone Age dentists in modern-day Pakistan drilled into their patients’ teeth with pieces of flint. The ancient Egyptian architect and physician Imhotep cataloged treatments for 200 diseases nearly 5,000 years ago, and the Greek physician Hippocrates prescribed a form of aspirin — extracted from the bark of the willow tree — more than 2,000 years ago. But it’s only in the past couple of centuries that we’ve been able to synthesize medicines in the lab rather than by extracting them from things we found in nature.
While some of the drugs we rely on today were invented intentionally through painstaking research, others are products of pure accident. In the 1880s, for instance, two chemistry students at the University of Strasbourg were testing whether a substance called naphthalene — a byproduct of making tar — could be used to cure intestinal worms when they stumbled upon a solution to a problem they weren’t even looking to solve. Naphthalene didn’t get rid of worms — but to the students’ surprise, it did break the person’s fever. After further investigation, they realized they hadn’t even administered naphthalene at all, but rather a then-obscure drug called acetanilide, which the pharmacist had given them by mistake. Soon, acetanilide was on the market as a cure for fevers, but doctors found that it had an unfortunate side effect: It made some patients’ skin turn blue. Eventually, they derived a substance from acetanilide that had all the benefits without the blue hue. It was called paracetamol, which Americans know as acetaminophen, a.k.a. Tylenol.
Today, drug discovery still relies on a mixture of good science and good luck. Unfortunately, when an outbreak appears to be headed toward a pandemic, there’s no time to count on luck. The next time we’re faced with a contagion, scientists will need to develop treatments as fast as possible, much faster than they did for Covid.
So let’s suppose we’re in that situation: There’s a new virus that looks like it could go global, and we need a treatment. How will scientists go about making an antiviral?
The first step is to map the virus’s genetic code and figure out which proteins are most important to it. These essential proteins are known as the “targets,” and the search for a treatment essentially boils down to defeating the virus by finding things that will keep the targets from working the way they should.
Until the 1980s, researchers trying to identify promising compounds had to rely on slow trial and error to identify the right ones. Today, using 3-D modeling and robotic machines that run thousands of experiments at a time, companies can test millions of compounds in a matter of weeks — a task that would otherwise take a team of humans years to complete.
Once a promising compound is identified, the scientific teams will analyze it to determine whether it’s worth further exploration. Once they’ve found a good candidate, they will typically spend several years in the “preclinical” phase, studying it to determine whether it is safe and triggers the desired response. The first studies will be done in animals. (Finding the right animal is not easy. Researchers have a saying: “Mice lie, monkeys exaggerate and ferrets are weasels.”)
If all goes well in the preclinical phase, the drug will move into the riskiest and most expensive part of the process: clinical trials in humans. With permission from a government regulator — in the United States, it’s the Food and Drug Administration — scientists will start a small trial involving a few dozen healthy adult volunteers. They will be looking to see whether the drug causes any adverse effects and to zero in on a dosage that’s high enough to be beneficial but not so high that it makes the patient sick.
Assuming all goes well once again, it will move on to larger and larger trials. Finally, after three phases, if they believe the drug is safe and effective, the scientists will go back to the regulatory agency and apply for approval. Then — assuming they get the green light — it’s time to start manufacturing.
At this point, a team of chemists will work on finding a consistent way to produce the key part of the drug, known as the “active ingredient.” Then, the scientific team will address the next big question: How to make sure it actually reaches everyone who needs it. Not at all an easy problem to solve.
As you can see, drug development is a complex and labor-intensive science, and each step is fraught with scientific and logistical obstacles — but we need to accelerate the process. The faster researchers are able to produce safe, effective drugs for quick-spreading pathogens like Covid, the more lives will be saved and the more we can reduce the burden on health care systems. Fortunately, there are ways to speed up and streamline the process without sacrificing safety.
One of the keys to ensuring that health care workers have better treatment options in the next big outbreak than they did for Covid will be investing in large libraries of drug compounds that researchers can quickly scan to see whether existing therapies work against new pathogens. Some of these libraries exist already, but the world needs more. We need libraries that cover many types of drugs, but the most promising, in my view, are those known as pan-family and broad-spectrum therapies — either antibodies or drugs that can treat a wide range of viral infections, especially those that are likely to cause a pandemic.
Researchers could also find better ways of activating what’s known as “innate immunity,” which is the part of your immune system that kicks in just minutes or hours after it detects any foreign invader — it’s your body’s first line of defense. By boosting your innate immune response, a drug could help your body stop an infection before it takes hold.
To deliver on these promising approaches, the world needs to invest more into understanding how various dangerous pathogens interact with our cells. Scientists are working on ways to mimic these interactions so that they can quickly figure out which drugs might work in an outbreak.
A few years ago, I saw a demonstration of a “lung on a chip,” an experimental device you could hold in your hand that operated just like a lung, allowing researchers to study how different drugs, pathogens and human cells affect one another. With advances in artificial intelligence and machine learning, it’s now possible to use computers to identify weak spots on pathogens that we already know about, and we’ll be able to do the same when new pathogens arise. These technologies are also speeding up the search for new compounds that will attack those weak spots.
With adequate funding, various groups could take the most promising new compounds through Phase 1 studies even before there’s an epidemic, or at least have several leads that can be turned into a product quickly once we know what the target looks like.
In short, although therapeutics didn’t rescue us from Covid, they hold a lot of promise for saving lives and preventing future outbreaks from crippling health systems. But to make the most of that promise, the world needs to invest in the research and systems we’ll need to find treatments much faster. That’s why my foundation has supported a therapeutics accelerator at Duke University, but broader initiatives will be necessary to make lasting change. This will require substantial investment to bring together academia, industry and the latest software tools. But if we succeed, the next time the world faces an outbreak, we’ll save millions more lives.
Bill Gates is an American businessman, software developer and philanthropist. This essay is adapted from his book “How to Prevent the Next Pandemic,” which comes out next month.
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