Dec 3, 2020 7:00 AM

The NIH’s Top Vaccine Maker Wants Warp Speed to Be the New Normal

John Mascola, who worked on the research that led to the Moderna shot, thinks Covid-19 proves we have to prep for the next virus, too.

If the first vaccines against Covid-19 really do start coming online in a couple of weeks, that’ll be a blazingly fast scientific achievement—from new virus to new vaccine in just about 12 months, faster than ever before, and using a new vaccine technology, too. Amazing! And also only sort of true, because the path of the two vaccines likeliest to become available first, one from the pharmaceutical companies Pfizer and BioNTech and one from Moderna, began long before people started getting sick in Wuhan in December 2019.

Courtesy of NIAID

Like all scientific discoveries, that path has many trailheads. One of them is the lab of John Mascola, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. He didn’t come up with the idea of using genetic material to make vaccines, but he and collaborators around the US spent years trying to direct those efforts against coronaviruses, the family that includes SARS-CoV-2, the cause of Covid-19. Most vaccines against the disease clue the immune system into seeing a specific protein on the surface of the virus; it was Mascola’s VRC that brought the mRNA for that “spike protein” to Moderna.

Mascola and his colleagues correctly foresaw what was coming and figured out how to get ready for it. And as an adviser to Operation Warp Speed, the US government’s vaccine-funding program, Mascola has been one of the voices helping to determine whether the new vaccines work, and how to get them to people. In this conversation, edited for length and clarity, WIRED talks with Mascola about the path that brought these vaccines to the cusp of distribution, what their warp-speed progress has taught people about Covid-19 and vaccinology, and what science knows (and doesn’t know) about what’ll happen next.

WIRED: You advocated for developing new vaccines and new ways to make them—and basing them on mRNA—long before Covid-19 was a thing. These last few weeks must feel like something of a vindication.

John Mascola: I would say it’s gratifying for sure, more than a vindication. We had a belief that these new technologies, DNA and RNA vaccines, could play a major role in vaccinology and in responding to a pandemic. So it’s really nice to see that come true.

How did the VRC’s work on mRNA and the spike protein end up being developed by Moderna, a relatively small and inexperienced pharmaceutical company?

Our partnership started probably with working on the disease Zika in 2017, or maybe even before. We looked at a number of companies who were doing RNA vaccines, and we came to have a good working relationship with Moderna because we had a strong mutual interest in infectious disease vaccines. So it was a very good fit, and we were pretty convinced that they had a very robust, strong scientific capability to make RNA vaccines. Moderna was interested in working on Zika, they had some funding from Barda—the Biomedical Advanced Research and Development Authority—and they wanted a scientific partnership to work on the design of the vaccine. So we had a collaboration going back to Zika, and then after that passed, we talked to them about other areas of mutual interest. We proposed that coronaviruses would be a fruitful area for both of us.

That was a really good—well, not “guess,” I suppose, but a good hypothesis, right? That a coronavirus was going to be a problem?

We were hedging our bets. No one knew what the next outbreak would be. It could have been a variant of influenza; it could have been one of a number of pathogens. But yeah, the short answer is, if you look at a list of outbreaks over the last 20 years, if two of the viruses on the list are in the coronavirus family, then you shouldn’t be shocked that it comes up again. SARS was 2002. MERS was 2012. In pandemic history, that’s a pretty short timeframe.

So we did some work with Moderna on designing MERS vaccines—all early, preclinical—so we were able to test how our mRNA worked, and we could test some designs on what the RNA should teach the body to make an immune response against. We had a lot of groundwork already laid when we found out the new virus was a coronavirus.

That groundwork focused on the spike protein, the protein on the surface of coronaviruses that they use to infect other cells. Did you worry that the spike protein work on MERS wouldn’t translate to the Covid-19 virus, to SARS-CoV-2?

For both the original SARS and for MERS, we were able to manipulate the spike protein to make it into a good vaccine. That required understanding how the spike looks atomically—what its actual structure is—and then making some changes to hold it into the right configuration, so the immune system sees the right thing. That worked for both SARS and for MERS, so we were confident, but not sure, that if another coronavirus came we could apply the same structure-based stabilizing mutations. That was work led by Barney Graham at our center. We were able to look just at the genetic sequence of the virus and the genetic sequence of the spike protein, and then transfer what we did from the original SARS into this new SARS-CoV-2. Those mutations worked right out of the box. So we were way ahead of the game.

Again, there was some luck there.

We actually were fortunate, scientifically, that we understood coronaviruses well. And it turned out the very first design the scientific community made for the spike protein worked. But let’s play it out. Let’s say we made a design, and it didn’t work out too well, and we had to go back and do a second-generation design. Now we’ve lost three or four months. Think of where the world would be. For Zika, our center, working with Moderna, made two designs of the analogous protein—not the spike protein, but a surface protein on the virus. The first one we took to the clinic didn’t work too well, didn’t induce a very good immune response. The second one did. That’s common in science.

A more wonkish question. Why have an Operation Warp Speed at all? Its mission seems like what your VRC is already supposed to do.

It’s an important distinction. I argued for standing up Operation Warp Speed. Because I’m director of the vaccine center, I know what we can do, but I also know what the limitations are. The National Institutes of Health can develop a vaccine and bring it to early phase testing, but NIH doesn’t commercialize a vaccine or produce it in mass scale. That takes a private sector partner. Also NIH doesn’t fund the advanced development of products the way Barda does. Many of us who have been in government a long time and seen epidemics before realized that when you have such a serious epidemic, the response should be integrated across government.

But then why bring in a leader from industry rather than government or academia?

The recommendation to bring in an outside adviser also came from a number of us in government. My experience in the VRC working with companies is, if you want to partner with a company, you need to understand their incentives. I’m a government researcher; I know what my incentives are. What’s the incentive for Moderna to come work with us? Pfizer said they wouldn’t, that they’d do it on their own. What if everyone said that? When you bring someone in from Big Pharma to run the program, you gain their perspective. That’s value added to the public.

You cowrote an article in the journal Science—with Anthony Fauci, the head of the National Institute for Allergy and Infectious Diseases—that laid out a rationale for the simultaneous testing of lots of different kinds of vaccines against Covid-19, which happened. But you also said that the ways those trials are conducted and the kind of data they collect should be harmonized. To my eye, that didn’t happen. The trials assess different clinical endpoints, and no one is testing vaccines head to head. The drug companies are running their own trials rather than having independent researchers conduct them. Are you confident in that setup?

There was an enormous amount of discussion about that point. OK, so as you know, the funding entity is Barda. Generally speaking, when Barda funds in more traditional ways, they say, “We would like you to develop a coronavirus vaccine, and so here’s some contractual money, and you have to report to us and you have to meet milestones.” So that would be, every company does its own thing. Nothing would be coordinated. Of course, nobody espoused that.

And on the other side, you could have the government control everything and say, “It’s going to be one protocol, and you all supply your vaccine.” That was discussed. It’s called a master protocol, and it is a good idea for some situations. But with Covid-19, number one, the vaccines were coming in at different times. So you can never really test them head to head. And your control group, which is pivotal, changes, because the epidemic changes. So your control group really has to be contemporaneous with your vaccine. Two, the vaccine trials are enormously large, as you know—30,000, 40,000, 60,000 people. Multiplied by five, that’s larger really than any one entity can coordinate. And the third reason is, the data that are required to submit to the Food and Drug Administration to get a license have to be submitted by a company, to commercialize the vaccine. So for speed and efficiency, it’s better to have a company recognized by the FDA as the responsible entity for the product in the trial.

But Operation Warp Speed imposes a stringent set of requirements on how they conduct the trial. So it’s not a master protocol, but the protocols are what we call harmonized. They’re not exactly the same, but if you take a step back and look, they all had a very similar design. The protocols and the primary and secondary endpoints were approved by Operation Warp Speed, and each sponsor had to work with the NIH to co-conduct the study. And the oversight group, the Data Safety Monitoring Board, was established by NIH and had to be the same for each of the trials that was funded by Operation Warp Speed. So there were those harmonizing elements that ended up being the way we proceeded.

OK, but Pfizer and BioNTech aren’t funded by Operation Warp Speed, so they now have a different DSMB. Doesn’t that pose problems for approval, or for comparisons going forward?

A couple of things to say that I think you already know, but are important: Even if they’re funded by Operation Warp Speed, when the companies submit a license, or an Emergency Use Application before license, that submission goes to the FDA. Operation Warp Speed does not have any sway over the FDA role here.

What I would say is that Pfizer kept in close touch with Operation Warp Speed. So I think there was a good sense that what they were doing in their trial was actually very similar to the Moderna trial and the other trials, and that will make it a little easier for the FDA. The other part of that answer is, aside from Pfizer, that important part of having all the other companies part of one Data Safety Monitoring Board is that they also agreed to share their data with a shared biostatistical group. So we can look at the data of all the trials together. And so there may be a lot we learn in the next few months, not from one individual trial versus another. You can learn that information if you combine trials, and look across trials.

You can do that with just the Phase 3 data? Even though Pfizer and Moderna weren’t regularly testing people until they had symptoms? Are they collecting the kind of data you’ll need to do that, or does that have to happen in the aftermarket?

No, the Phase 3 trials are ongoing. Pfizer and AstraZeneca are all collecting a substantial amount of samples and information on what’s called a case—a person who volunteers for the trial becomes a case if they become Covid-infected. And there is a lot of detailed laboratory and medical information collected on people who unfortunately become cases in the study. All that becomes part of the record of the Phase 3 trial.

But you want the people who aren’t cases, too, don’t you? Maybe not, if you’re just looking for the duration of immunity. But if you’re worried about asymptomatic transmission, you’d want more.

So you do what’s called a substudy, where you study a number of cases in detail and a number of non-cases, people who are vaccinated and don’t become cases, to compare their immune responses. And so you can understand correlates of immunity by doing that, and that is planned for each of the studies. Each company has agreed to do that.

And then what happens after the vaccines get into the broader population? Will there be a registry for longer-term safety issues, or to keep looking at duration of immunity?

It’s really the responsibility of the FDA to specify what’s called post-marketing surveillance, and they’ve also said in their guidance that volunteers in these Phase 3 trials need to be followed for a period of time. I think the FDA specified two years. But also, an Emergency Use Authorization for the FDA is not a license. The product remains investigational until it has a full license. And there will be responsibilities that the company has to the FDA to fulfill their EUA, which would mean a detailed follow-up. And the FDA can require post-marketing, post-licensure data collection. I think that’s likely.

Putting your vaccinologist hat back on, what kinds of data would you want to see? What do you want to know about any of the new vaccines?

Well, there’s lots of key data. We know, broadly speaking, that the vaccines are very effective at preventing symptomatic Covid. Most of us would have only in our dreams hoped for 94 or 95 percent efficacy. Honestly, I had in my head that I’d be excited if it was above 80, a little disappointed if it was lower. I set myself a parameter. So that’s incredibly good news. It means that the virus is vulnerable to the immune system and that we will control this pandemic.

But think of all the things we don’t know. We don’t really know how well the vaccine works in elderly populations or people who are elderly and more frail, or have an imperfect immune system. We don’t know the duration of immunity. Will it last a year, two years? We don’t know. We know that the vaccine prevents symptomatic Covid, and we actually know that it prevents severe cases of Covid, which is very important. But we don’t know, for example, if it’s possible that someone gets infected and is shedding virus but has no symptoms, right? They would never be called a case. So there’s a lot we need to learn, and this first set of studies is the key time to learn it.

The other part, just the last part of the answer, is what we really would like to know is what’s called a correlate of immunity, which is the key parameter of the immune system, the mechanism of protection. We talk about antibodies or neutralizing antibodies. It’s often not just one part of the immune system, because the immune system works in concert. But oftentimes we can identify a key parameter. So for example, maybe there’s a level of antibody to the spike protein that we know that, if you’re above that level, you’re protected.

Are you concerned about the effect that use of the new vaccines will have on ongoing and future trials? I think the ethics of keeping trials going even when a vaccine is available are probably getting worked out now. But what about simply losing potential volunteers because they’re already getting other shots?

That issue will become front and center in the next few weeks. And I think it is a good problem to have. We have a vaccine that’s more effective than we even hoped for. And that means that we now have these ethical issues to address. How long can you really continue a placebo-controlled study, when you have good evidence that your vaccine works?

So what do I consider good evidence? Not a press release from a company, but the FDA looking at the data and saying, “Yes, we agree you have 95 percent efficacy, because we’ve looked at the primary data”—which the FDA will do—and the FDA granting an Emergency Use Application. Then we have to then confront the questions of: When do we offer that vaccine to the people who are on the placebo arm of the study? And I think that will be part of the discussions in the next few weeks at the FDA’s Vaccines and Related Biological Products Advisory Committee. The idea will be to get most of the population vaccinated, and it will become hard to run studies. Whether it’s January, February, March, April or whatever, we don’t know, but it will happen. That’s a good thing.

Now that you’ve seen this process unfold over the past year, what do you think the implications are for vaccine development—not just for whatever the next pandemic is but infectious disease generally?

If you think back to the beginning, there was a lot of concern that we were using technologies that have never been used before for a licensed vaccine. And now we have validation that mRNA vaccines can work, and they can be brought to bear quickly. I think it’s likely that the adenovirus technology has reasonably good protection. So we have another technology that works, and we have the more traditional technology, proteins, which I think will also work.

The other really encouraging implication is that we’ve proven that scientific structure-based vaccine design works, that knowing how to manipulate a viral protein to make it a good vaccine antigen, that’s worked for Covid. It’s being tested for respiratory viruses and children and other cases, but Covid sort of just came to the front of the line and proved that the concept works.

Now we need a much better global surveillance system that’s worldwide and integrated, and uses modern technologies to do testing, so we know what’s out there. We need better global clinical trials capacity so we can stand up these large trials faster. The United States government can put $10 billion, $12 billion, on the table and incentivize companies. But, you know, what about the rest of the world? And how do we create the infrastructure to be prepared and do clinical trials?

When people say that it only took a year to get a Covid vaccine, I know that’s not exactly right. It took nearly two decades to understand coronaviruses well enough to work on. But what if the next one’s not a coronavirus?

There’s a reasonable possibility that a virus could emerge from a different virus family, and we would not be as prepared. We know that there are about 20 major virus families in the world that infect humans, and almost every outbreak we’ve seen in the past 50 years or more has come from one of those 20 virus families. What if we made a concerted effort to study every family in detail, to make vaccines to every family, and do what we did for coronavirus? Make some prototypes. So that if a cousin in that family emerges, a virus we’ve never seen before, we at least have laid some groundwork for vaccine design. One could do that for what used to be considered a lot of money, but what now would be considered a small investment compared to what happens when you have a pandemic.

If a pandemic costs $16 trillion, you mean?

Exactly. I don’t want to pull a number off the top of my head that’s not completely right, but one could, for $20 million per virus family, make a prototype vaccine and test in the clinic. You’re talking a few billion dollars over five years for that kind of project. That used to seem like it wouldn’t be tenable. But now it’s like, well, if I could be prepared for the next pandemic, that’s probably a really good investment.