If the first vaccines against COVID-19 actually go online in a few weeks, it will be a lightning-fast scientific achievement – from new virus to new vaccine in just about 12 months, faster than ever and using a new vaccine technology too. Amazing! And just kind of true, because the journey of the two vaccines likely to become available first, one from pharmaceutical companies Pfizer and BioNTech and one from Moderna, began long before the people of Wuhan got sick in December 2019.
Like all scientific discoveries, this path has many starting points. One of these is the laboratory of John Mascola, director of the Vaccine Research Center at the National Institute for Allergies and Infectious Diseases. He didn't have the idea of using genetic material to make vaccines, but he and coworkers in the US have tried for years to steer these efforts against coronavirus, the family to which SARS-CoV-2, the cause of COVID-19 , heard . Most vaccines for the disease tell the immune system to see a specific protein on the surface of the virus. It was Mascolas VRC who brought the mRNA for this “spike protein” to Moderna.
Mascola and his colleagues correctly anticipated what was to come and figured out how to prepare for it. As an advisor to Operation Warp Speed, the US government's vaccine funding program, Mascola was one of the voices that helped determine whether the new vaccines would work and how they could be brought to people. In this conversation, edited for length and clarity, WIRED talks to Mascola about the path that brought these vaccines to the cusp of proliferation, what their advancements in warp speed are showing people about COVID-19 and Taught vaccinology and what science knows (and doesn't know) I don't know what's going to happen next.
WIRED: They advocated 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 a justification.
John Mascola: I would say it's certainly gratifying, more than a justification. We believed that these new technologies, DNA and RNA vaccines, could play an important role in vaccination science and in responding to a pandemic. It is really nice to see this come true.
How did the VRC work on mRNA and the spike protein come about by Moderna, a relatively small and inexperienced pharmaceutical company?
Our partnership probably started working on Zika in 2017 or maybe even before that. We looked at a number of companies that make RNA vaccines and we built a good working relationship with Moderna because we had a strong mutual interest in infectious disease vaccines. So it fitted very well, and we were pretty sure they had a very robust, strong scientific ability to make RNA vaccines. Moderna was interested in doing work on Zika, they had some funding from Barda – the Biomedical Advanced Research and Development Authority – and they wanted a scientific partnership to work on developing the vaccine. So we had a collaboration that went back to Zika and after that we talked to them about other areas of mutual interest. We suggested that coronavirus would be fertile territory for both of us.
That was really good – well, I suppose not "guessing" it was a good hypothesis, right? That coronavirus would be a problem?
We have hedged our bets. Nobody knew what the next outbreak would be. It could have been a variant of influenza; it could have been one of several pathogens. But yes, the short answer is, if you're looking at a list of outbreaks over the past 20 years and two of the viruses on the list belong to the coronavirus family, you shouldn't be shocked to find them recurring. SARS was 2002. MERS was 2012. That is a fairly short period of time in the history of the pandemic.
So we worked with Moderna to develop MERS vaccines – all early, preclinical – so we could test how our mRNA works, and we were able to test some designs of how RNA should teach the body to respond to it develop. We had already laid a lot of groundwork when we found out the new virus was a coronavirus.
Those basics centered 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 in MERS does not lead to the COVID-19 virus, SARS-CoV-2?
For both the original SARS and MERS, we were able to manipulate the spike protein to make a good vaccine. To do this, you had to understand what the tip looks like atomically – how it's actually built – and then make some tweaks to keep it in the correct configuration so that the immune system is seeing the right thing. This worked for both SARS and MERS, so we were confident but not sure that if another coronavirus emerged we could apply the same structure-based stabilizing mutations. That was Barney Graham's work in our center. We could just look at the genetic sequence of the virus and the genetic sequence of the spike protein and then move what we did from the original SARS into this new SARS-CoV-2. These mutations worked immediately. So we were way ahead of the game.
There was some luck here too.
Scientifically, we were fortunate that we understood coronaviruses well. And it turned out that the first design the scientific community came up with for the spike protein worked. But let's play it. Let's say we made a design that didn't work that well and we had to go back and make a second generation design. Now we've lost three or four months. Think about where the world would be. For Zika, our center, in collaboration with Moderna, created two designs of the analog protein – not the spike protein, but a surface protein of the virus. The first one we took to the clinic didn't work well and didn't trigger a very good immune response. The second did. This is common in science.
A shakier question. Why an Operation Warp Speed at all? Its mission seems to be what your PRC should already be doing.
It's an important distinction. I spoke out in favor of getting up for Operation Warp Speed. As the director of the vaccine center, I know what we can do, but I also know what the restrictions are. The National Institutes of Health can develop and early-stage a vaccine, but NIH does not commercialize a vaccine or manufacture it on a large scale. That needs a private sector partner. In addition, NIH does not fund product advancement like Barda does. Many of us who have been in government for a long time and have seen epidemics before have recognized that when an epidemic is this severe, the response should be integrated across governments.
But why then involve an industry leader rather than government or academia?
The recommendation to use an outside advisor also came from some of us in the government. My experience working with companies in the PRC is that if you want to work with a company you need to understand their incentives. I am a government researcher. I know what my incentives are. What is the incentive for Moderna to work with us? Pfizer said they wouldn't do it, they would do it alone. What if everyone said that? Bringing in someone from Big Pharma to run the program gives you their perspective. That is an added value for the public.
You wrote an article in Science magazine – with Anthony Fauci, director of the National Institute for Allergies and Infectious Diseases – that provided a rationale for testing many different types of vaccines against COVID-19 at the same time. But they also said that the way these tests are carried out and the type of data they collect should be harmonized. It didn't happen to me. Different clinical endpoints are assessed in the studies, and no one is testing vaccines directly. The pharmaceutical companies do their own studies instead of having them done by independent researchers. Are you convinced of this setup?
There has been an enormous amount of discussion on this point. OK, as you know, the funding unit is Barda. When Barda finances in a more traditional way, it generally says, "We want you to develop a coronavirus vaccine. So here's some contract money. You need to get in touch with us and hit milestones." That means every company does its own thing. Nothing would be coordinated. Of course nobody spoke out in favor of it.
On the other hand, the government could control everything and say, "It will be a log and you will all deliver your vaccine." That was discussed. It's called the master protocol and is a good idea in some situations. But with COVID-19, number one, the vaccines came at different times. So you can never really test them out directly. And your control group, which is crucial, changes because the epidemic changes. So your control group really has to be at the same time as your vaccine. Second, as you know, the vaccine trials are huge – 30,000, 40,000, 60,000 people. Multiplied by five, that's really bigger than an entity can coordinate. And the third reason is that the data that must be submitted to the Food and Drug Administration in order to obtain a license must be submitted by a company to market the vaccine. For speed and efficiency, it is better to have a company recognized by the FDA as being responsible for the product in the study.
Operation Warp Speed, however, places strict requirements on the implementation of the experiment. So it's not a master protocol, but the protocols are what we call harmonized. They're not exactly alike, but if you 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 conduct the study together. The oversight group, the Data Safety Monitoring Board, was set up by the NIH and had to be the same for all experiments funded by Operation Warp Speed. So there were these harmonizing elements that were ultimately our approach.