Sat. Oct 1st, 2022
Stock photo of gloved hand with medical needle.

If the first vaccines against COVID-19 really do come online in a few weeks, it will be a lightning-fast scientific feat – from new virus to new vaccine in just about 12 months, faster than ever before, and using a new vaccine technology too. Astonishing! And also somewhat true, because the path of the two vaccines to become available first, one from the pharmaceutical companies Pfizer and BioNTech and one from Moderna, started long before people got sick in Wuhan in December 2019.

Like all scientific discoveries, that trail has many trailheads. One 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 his collaborators in the US have spent years trying to direct those efforts against coronaviruses, the family that includes SARS-CoV-2, the cause of COVID-19. 19 . Most vaccines against the disease prompt the immune system to see 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 to come and figured out how to prepare for it. And as an advisor to Operation Warp Speed, the US government’s vaccine financing program, Mascola was one of the voices helping determine whether the new vaccines work and how to get them to people. In this conversation, edited for length and clarity, WIRED talks to Mascola about the path these vaccines have taken on the cusp of distribution, what their warp-speed advances have taught people about COVID-19 and vaccinology, and what science knows ( and not not knowing) about what will happen next.

WIRED: You advocated developing new vaccines and new ways to make them — and base them on mRNA — long before COVID-19 was a thing. These last few weeks must feel like some kind of justification.

John Mascola: I’d say it’s certainly gratifying, more than a justification. We were convinced that these new technologies, DNA and RNA vaccines, could play an important role in vaccinology and in responding to a pandemic. So it’s really nice to see it come true.

How was the VRC’s work on mRNA and the spike protein ultimately developed by Moderna, a relatively small and inexperienced pharmaceutical company?

Our collaboration probably started working on Zika in 2017, or maybe even earlier. We looked at a number of companies that made RNA vaccines, and we developed a good working relationship with Moderna because we had a strong mutual interest in infectious disease vaccines. So it was a really good fit, and we were pretty confident that they had a very robust, strong scientific ability to make RNA vaccines. Moderna was interested in working on Zika, they had some money from Barda – the Biomedical Advanced Research and Development Authority – and they wanted a scientific partnership to work on the vaccine design. So we had a partnership going back to Zika, and when that was over, we talked to them about other areas of mutual interest. We suggested that coronaviruses would be fertile territory for both of us.

That was a really good one – well, not a ‘guess’ I guess, but a good hypothesis, right? That a coronavirus would become a problem?

We hedged our bets. No one knew what the next outbreak would be. It could be a variant of the flu; it may have been one of a number of pathogens. But yes, the short answer is, if you look at a list of outbreaks from the past 20 years, if two of the viruses on the list belong to the coronavirus family, then you shouldn’t be shocked to see it resurface. SARS was 2002. MERS was 2012. In the history of the pandemic, that’s a pretty short time frame.

So we did some work with Moderna designing MERS vaccines — all early, preclinical — so we could test how our mRNA worked, and we could test some designs about what the RNA would have to teach the body to trigger an immune response. to make up. We had already laid a lot of foundation when we found out that the new virus was a coronavirus.

That basic work focused on the spike protein, the protein on the surface of coronaviruses that they use to infect other cells. Were you concerned 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 MERS, we were able to manipulate the spike protein to make it into a good vaccine. That required understanding what the spike looks like atomically — what its actual structure is — and then making some changes to keep it in the correct configuration so that the immune system sees the right thing. That worked for both SARS and MERS, so we were confident, but not sure, that if another coronavirus came along, we could apply the same structure-based stabilizing mutations. That was work led by Barney Graham at our center. We were able to just look 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 to this new SARS-CoV-2. Those mutations worked right out of the box. So we were way ahead of the game.

There was some luck again.

We were actually lucky, scientifically speaking, to understand coronaviruses well. And it turned out that the very first design the scientific community created for the spike protein worked. But let’s play it out. Let’s say we made a design, and it didn’t work that well, and we had to go back and do a second-generation design. Now we’ve lost three or four months. Think 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 on the virus. The first one we brought to the clinic didn’t work very well, didn’t elicit a very good immune response. The second did. That is common in science.

A more awkward question. Why have an Operation Warp Speed ​​at all? Its mission is similar to what your license plate should already do.

It’s an important distinction. I advocated raising Operation Warp Speed. Being the 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 test it early on, but NIH does not commercialize a vaccine or manufacture it on a large scale. This requires a partner from the private sector. Also, NIH does not fund the advanced development of products the way Barda does. Many of us who have been in government for a long time and have seen epidemics before realized that when you have an epidemic that serious, the response has to be integrated across the government.

But then why would you take an industry leader instead of government or academia?

The recommendation to engage an outside consultant also came from some of us in government. My experience in the PRC working with companies is that if you want to work with a company you have to understand their incentives. I am a government researcher; I know what my motivations are. What drives Moderna to come and work with us? Pfizer said they wouldn’t do it, they would do it themselves. What if everyone said that? When you bring in someone from Big Pharma to lead the program, you get their perspective. That is an added value for the public.

You contribute to an article in the magazine Science— with Anthony Fauci, the head of the National Institute for Allergy and Infectious Diseases — laying the rationale for testing many different types of vaccines against COVID-19 simultaneously, which happened. But you also said that the ways in which those trials are conducted and the type of data they collect should be harmonized. In my view that has not happened. The studies assess several clinical endpoints and no one tests vaccines directly. The pharmaceutical companies conduct their own trials rather than having them conducted by independent researchers. Do you trust that setup?

There was a lot of discussion about that point. Okay, so as you know, the funding entity is Barda. In general, when Barda funds in more traditional ways, they say, “We’d like you to develop a coronavirus vaccine, so here’s some contract money, and you’ve got to report to us and you’ve got to hit milestones.” So that would be, each company does its own thing. Nothing would be coordinated. Of course nobody took that into account.

And on the other hand, you could have the government check everything and say, “It’s going to be one protocol and you’re all delivering your vaccine.” That was discussed. It’s called a master protocol and it’s a good idea in some situations. But with COVID-19 number one, the vaccines came in at different times. So you can never really test them directly. And your control group, which is crucial, changes, because the epidemic changes. So your control group should really be at the same time as your vaccine. Second, the vaccine trials are huge, as you know: 30,000, 40,000, 60,000 people. Multiplied by five, that’s actually bigger than an entity can coordinate. And the third reason is that the data that must be submitted to the Food and Drug Administration to be licensed must be submitted by a company to market the vaccine. So for speed and efficiency, it is better to have a company recognized by the FDA as the responsible entity for the product in the trial.

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

By akfire1

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