The vaccines authorized in the US are amazingly effective at preventing serious COVID-19 infections and death—but only if people get them. Vaccination rates remain stubbornly low in certain areas, and with the more contagious Delta variant sweeping through the population, many experts worry that the country is on the cusp of another deadly wave. An effective antiviral—ideally a cocktail of them—could not only help those still vulnerable to the virus but could be a critical tool if a variant emerges that is better at evading our vaccines.
Despite the gargantuan efforts to test already-approved drugs for their potential to kill the virus, researchers found very few actually worked. Today, the only approved small-molecule antiviral for COVID-19 is Gilead Sciences’ remdesivir. Its efficacy is modest at best, and its intravenous delivery makes it suitable only for people already hospitalized with the virus. A handful of newer drug candidates are currently being tested, but even assuming their success—far from a given considering the challenge of finding good antivirals—researchers would like more options, especially ones that hit different viral targets.
To that end, the Biden-Harris administration last month announced it would invest more than $3 billion in the Antiviral Program for Pandemics, an ambitious collaboration to help find, test, and make treatments for COVID-19. C&EN talked to National Institutes of Health director Francis Collins about that influx of funding, why safe, cheap, and effective antivirals are still badly needed, and how the NIH is trying to accelerate their development. This interview has been edited for length and clarity.
A good swath of the US is vaccinated, but we’re obviously seeing pockets where infections are surging—the Delta variant is now dominant. Has it become more important for us to have better antivirals for COVID-19?
I think it’s been urgent all along; it’s just been difficult to come up with antivirals that were safe and effective and could be administered to outpatients, which is what you’d really like to have. Maybe some people were going to argue, “Well, once we have a vaccine, we aren’t going to have to worry that much about the need for drugs.” But I think that’s turned out not to be true and probably never was true. Certainly with a virus that we know has the capability of changing its spike protein over time, as has been happening now with the Delta variant as the latest example, you really would like to have a therapy that was not going to be affected by changes in the virus that cause the vaccine to be less effective.
The other part of this, of course, is we need to think of the whole planet, and not just our own country, and the availability of vaccines in low- and middle-income countries continues to be extremely low. If we had a safe and effective antiviral that could be offered to people who just tested positive, we could save many lives where the vaccine might not get to them real soon.
Has what we need in an antiviral changed at all as the pandemic has progressed? Could you describe to me what the perfect antiviral might look like?
Well, the holy grail would be an oral agent that has as its target a component of the viral life cycle so that the drug would not be expected, therefore, to have side effects against the host. That drug would need to be affordable. In the ideal world, it would not be a single agent but a combination of maybe two or even three different antivirals that hit different targets, because that will reduce the likelihood of resistance arising. Everything we learned about HIV applies here, too.
Can we talk about the Antiviral Program for Pandemics investment?
The new program, the APP as it’s called, funded by the government to the tune of $3.155 billion, aims to try to provide a real infusion of resources to encourage a lot more activity in this space. This will fund everything from early drug design—which we think a lot of our academic centers are pretty good at, and we can give them the resources to make it go faster—all the way through to preclinical tests of those drugs, ultimately to clinical trials. All of this done in close collaboration and cooperation with industry, where a lot of the skills exist as well. Even including some potential money for manufacturing, because it won’t do to find something works without having doses to give to people.
In the past, it has been really tough to find antivirals that can address acute infections like, for example, the flu. Are you confident in our chances of finding small molecules—hopefully a few—that will work against COVID-19?
It’s clear there are some very good targets in the coronavirus life cycle, particularly these proteases, which are encoded by the viral genome; they’re necessary to process the virus from when it first enters the cell to when it becomes capable of replicating itself. If you can knock out that protease, you’re going to knock out viral replication. Similarly, there are some other targets that are less well worked through. But it’s not as if we’re starting with a complete unknown entity here. We know a lot about the vulnerable spots in this virus’s life experience. That’s a good place to start. It’s kind of where we were with HIV in 1993 or so, and in that case, it took a big, organized push—a collaboration between public and private sectors and a lot of resources—and look where we got to: that is a disease which is compatible essentially with a normal lifespan because of the ability to give people combination therapy of two or three antiretrovirals. That’s what we need. I’m confident we’ll get there.
But people should understand that developing antivirals is harder than antibacterials. Bacteria have this much larger genome, this much more vulnerable life cycle to all kinds of things that you can come up with to interfere with. Viruses are really efficient little engines of destruction. You have fewer opportunities to try to stop the engine. But there’s some. For instance, the protease that I think is particularly appealing, this 3CL protease, we know its three-dimensional structure. We know how its active site is organized, and you can almost start to design on a computer the kind of small molecule that would gum up that site. So, the path here is pretty well worked out and has a very high likelihood of success. But it’s going to take time.
You mention this idea of a combination approach. The template for this with other viral infections has been: one drug gets approved, then something else gets added on and you start building combinations. Do we have time for that? Is the NIH thinking about ways to creatively test antivirals together?
That will be a high priority. I do think there’s going to be a lot of parallel research going on here trying to develop therapeutic compounds that target different parts of the [viral] life cycle. And of course, initially, you’ll have to see, does each of those compounds seem to have some activity and are they safe? But as soon as you have early evidence of that, the idea of testing combinations will be seen as a very high priority. We’ve all been to this movie before, and we know that if you go after a virus with a single agent, you may have a short-term sense of accomplishment, which is then overtaken very rapidly by resistant strains that emerge. That of course also was the story with HIV. And it will be the story here if we don’t take account of that risk.
Many folks are dealing with long-term effects of their infections. Is there a role for antivirals in addressing long COVID-19?
Long COVID is a source of great concern. People who have had even mild illness are at risk of long symptoms that go on for weeks or months. And that applies to young people as well, with things like brain fog and fatigue and cardiac abnormalities. We don’t understand the mechanism. One possibility is that there is still a reservoir of virus in the system—you can’t detect it by a nasal swab or a blood sample, but maybe it’s hiding somewhere in the system. If that were the case, then an antiviral that had good distribution throughout the body might turn out to be really valuable. But right now, we don’t have those to try.
There is some suggestion that at least some people with long COVID get benefit from vaccination—they get vaccinated and in the space of a few weeks, sometimes even a few days, they seem to have notable improvement. But that’s not true for everybody. I’m not even sure it’s true for most. That would suggest, at least for those people, that maybe there is that reservoir, and you’ve given the immune system a kick to be able to really go and find the culprits and take care of it. If that’s true, for at least some cases of long COVID, then having antivirals would be really useful.
When someone gets the flu, they have to take a drug like Tamiflu very early on for it to make a difference. If the antivirals developed for COVID-19 also need to be given soon after an infection, do we have the culture of testing in the US for them to have an impact?
That is going to be a challenge. If we had now, today, an effective antiviral against COVID-19, we would want to make it available immediately to anybody who is showing signs of being infected—but you’d want to be sure that it was really COVID-19 and not something else. So, testing would need to be even more available, perhaps, than it is right now. The good news is, we’ve got the testing capabilities. NIH invested in this in a big way over the last year. There’s an easy ability now to do 3 million tests a day with a whole variety of technologies, many of which are now point of care, some of which are now home tests. That should not be a barrier. We should have crossed into that territory where rapid testing—getting an answer in minutes—should be accessible in every emergency room, every doctor’s office, every home, every pharmacy. But we would have to motivate the system to embrace that. Having an antiviral that you know is effective but had to be given early would be a pretty good motivation to get that kind of testing out there and accessible to everybody.
We have wonderful vaccines, but we still have a lot of infections and pockets of the country where ICUs are being overwhelmed again. As we head into the fall, what keeps you up at night about this pandemic?
I am being kept up at night looking at those pockets where vaccination rates are below 40% and where Delta variant is now spreading rather quickly, with now over 80% of the isolates in this country being Delta, which we know is highly contagious. And you look at places that thought they were over the worst of it, that are now filling up again with very sick patients, many of whom are quite young. All of the things that we hoped would not happen are coming true.
I am worried about not just the next week or two, but particularly about the fall. Because if we have this kind of risky situation in those hot spots, I don’t see how it’s going to be any different in September—and it may be worse as people start moving around more, going back to school and so on.
I don’t know what to expect also in terms of what other variants may be lurking out there that are even worse than Delta. And nobody can tell you that there isn’t the possibility of a future variant for which the vaccines really don’t work very well and then boosters will be necessary—although they aren’t now. So, we’re trying to be ready for that, and I think we will be. But it will complicate things.
And then the other thing that keeps me awake at night is looking at the whole rest of the world and how incredibly serious this pandemic is in places like South and Central America, like the southern parts of Africa, like Indonesia. It is raging forward with relatively little in the way of vaccine protection being available, and you can just imagine where that is going over the coming months. It is heartbreaking to watch.
Describe what our arsenal—testing, treatments, vaccines—would look like in a perfect world. What would the experience be like for someone who feels under the weather?
I’d love to think about the perfect world. We’re certainly not there at the moment.
So OK, you’ve been vaccinated, you know you’re protected, but you’ve got that first hint that something isn’t quite right. Is it a cold? Is it an allergy? Or is it the first symptom that I’ve got a breakthrough case? You’d want to have immediate access to testing, maybe you’d have a test in your own pantry or call your doc or run to the pharmacy. If it were positive, then you’d want an immediate prescription of an affordable therapeutic, which would probably be a combination of a couple different antivirals that together are extremely effective against that viral life cycle. You might take that for 3 or 4 days, and expect almost always at that point, you’d be better. That would be the perfect world. We have a ways to go to get there.