Toyota, we set our sights on creating a car that looks good, feels good, but does even more good when that feels even more exciting, even more energetic, even more electric without ever needing to be plugged in. Challenge accepted. The all new self charging hybrid electric Yaris contact your dealer today about flexible payment options and see just how affordable the new Yaris is.

Toyota built for a better world.

If you're looking for a better tomorrow, start heading for it today at Toyota. We started to look ahead over 20 years ago when we built our first self charging hybrid electric cars. Now the Toyota hybrid drivers are reducing harmful emissions and making a real difference, thanks to them. The best selling car in Ireland today is a Toyota hybrid and has more drivers. Join us. We'll all help to shape a brighter future together. Toyota built for a better world.

Nobody could have been more skeptical about Operation Warp speed than I was Operation Warp Speed. That's the name given to the U.S. government's 18 billion dollar program to try to fast track a covid-19 vaccine. Look, I'm just not a big believer in government, especially when it comes to doing things quickly and innovatively, and particularly the Trump administration, which has been nothing but anti science from the very beginning. And yet here we are seven months later, and we've already got two remarkably effective vaccines that are not only developed, but they're ready for mass distribution.

All I can say is that this is a massive victory for mankind and for science.

Welcome to people I mostly admire with Steve Levitt. My guest today is Moncef Slaoui, who spearheaded that operation. I'm so curious to get an inside look at how they pulled it off.

I'm also really interested to learn more about him. He has an amazing back story. He was born poor in Morocco. His father died at an early age and his mother was left to raise five children on her own. And somehow, from those humble beginnings, he's risen to be one of the most influential scientists in the world. He spent three decades at pharmaceutical giant GlaxoSmithKline, first as a vaccine researcher and eventually as head of research and development to develop vaccines for Ebola, cervical cancer and malaria.

And he was also a board member at Maidana, one of the first companies to develop a successful covid-19 vaccination. But I'm also nervous about the interview.

I've never spoken with him before when I watch TV interviews that he's done.

He seems pretty serious, maybe not that much fun, and also worry that because he's in a political position, he won't be very candid.

So here's my strategy.

I'm going to start off the interview by asking him a kind of question he would never get from a TV interviewer.

And I'm hoping that that's going to loosen him up and lead to a really fruitful conversation.

So I have to say, I can think of a thousand reasons why any sensible person would have declined to take your current job. I mean, you were given what seemed to be an unrealistically optimistic timeline for disease we knew almost nothing about in a highly politicized environment for an administration that was actively trying to convince the public that covid wasn't really that big a deal. Did you not have friends and family members who could save you?

Well, I agree with most of the things you said except for one. And I'll tell you which one again.

So, yes, this clearly was a very big challenge, however. I was on the board of Moderna and I was chairing the product development committee of the board and therefore fully aware of the potential of the technology in general. We were already in a number of clinical trials for seven vaccines, if I remember, and covid-19 was the eighth one or something like that. So I knew that we could be very fast and that the technology was surprisingly effective in inducing an immune response.

And that, frankly, is what made me think, you know what, it's not crazy. There is some credibility to it with the right resources. Second, regarding the administration, clearly I'm not aligned with the political position of the administration. However, this is about people's life and our livelihood. And the one thing I was frankly very naive to and is the only thing that made me twice or three times tell myself, oh, my God, why did I do this was the incredible politicization of what was going on.

I was aware that the pandemic was political, but I thought, OK, if we're trying to make vaccines and medicines, how on earth would come to interfere with it? And I do have to say that, frankly, the current administration did not interfere with it.

It strikes me that one of the things that makes your job quite unattractive is that so many people despise Trump and the administration so much. Therefore, they don't want to acknowledge under any circumstances that anything good could have come out of it. It sounds like you've experienced a little bit of that.

I think that was the case and that's been very disappointing to me. But I got used to it and it just melted away. I'm so happy I've done this.

I can't tell you how rewarding it is to with all the teams and the companies. The tens of thousands of volunteers have participated in a trial has all coalesced towards the outcome. And the outcome will have such an enormous impact on this pandemic and on our society and frankly, on the globe.

Now, I suspect that most people don't know much about operation warp speed actually does how much I really know. So the first task that you faced was deciding which particular vaccine candidates to support, because when you launched, if I understand, there were already over 100 vaccines in development and your team ultimately picked 14 candidate vaccines to support.

How did you decide who the likely winners would be?

In fact, we went from ninety something to actually six. The way we decided it was to say first we should have a portfolio of product, not just one or two. Second, we should diversify the biological risk by using different platform technologies, different approach to designing a vaccine because we are not sure which one is going to work. Third, we're going to also diversify the execution risk and the much more granular details within each one of the technologies selected by making sure we have two representatives of each technology.

And frankly, once you take that very rational and logical approach and overlay on it what we thought was the kind of immune response needed to tackle this virus and overlaid on it the speed with which we needed to execute, overlaid on it the collateral risk. For instance, if you needed to also design a completely new way of injecting or inoculating that has completely independent risk on its own, then why do that if I can avoid it? And then also a good understanding of the companies that were the holders of the examples we selected knowing a company is able to execute with us.

So they were either pretty large players that are very experienced in developing vaccines or Pfizer JNJ and Sanofi GSK are very experienced or we said we're going to take companies whose existence in itself will depend on the success of this endeavor because they are working on a platform technology. And I knew, for instance, in the case of Moderna and similarly in the case of Novavax, if this works, it will change the company's faith and future. And if it fails, it will change it the other way around.

So the commitment to execute will be maximalists with super high priority for them. And this is how we ended up selecting the six when Operation WebSphere was announced back in.

May of 2020, I will admit that I and honestly, everybody intelligent that I knew predicted it would be a complete disaster, that there's no way you would hit your timeline of January twenty one.

I am so delighted to be sitting here today. Completely wrong in my predictions. Yes.

Frankly, it is amazing. There are great learnings out of it. For me, one of the learnings is science can help humanity. This is the most stringent demonstration of it. This one is very dramatic because the impact happens on a short period of time that we can see it and live it. But if I take global warming where we impact our livelihood but on a much slower pace and science tells us it's going in the wrong direction, we should be listening to it.

I hope it's one of the lessons from this.

I have been arguing for years that what we need on climate change is something very much like the exercise we just did with Operation Warp Speed, where we take the best scientists in the world and we devote them to tackling climate change.

There's been very few problems that mankind has put its scientific might towards and not been able to solve. So are you willing to volunteer for the job of running the exercise when you're finished with this one?

If I had expertise, I would definitely consider it. But I do think one of the ingredients that is very important, particularly when timelines are fast and therefore decreasing attrition and failures is very important is what I call educated intuition, which is really anchored in knowledge and experience. You don't know the answer to the question, but somehow your instincts drive you in a particular direction and it turns out to be the right direction. And the other thing that's really important and it's unfortunate that it takes a crisis for that to happen is the intrinsic alignment of all the players that rather than spending whatever percentage of our time arguing for the last five percent of alignment, everybody's aligned.

We don't have to repeat the same conversation twice. And that does happen when you're in a crisis setting and everybody is clearly aware of it, that global warming, unfortunately, not everybody is.

What's odd is if you took the top one thousand scientists in the world right now, defined in whatever way you want to define that, and you ask how many of them are focused on global warming, it's an extremely small number and many of the people who are working are working on it within the private sector, where the intellectual capital is carefully guarded and kept secret from everyone else.

When it seems like a global problem. What you really want to do is you want to share intellectual capital as much as possible and figure out how to get the financial incentives aligned in some other dimension. I mean, I love capitalism, but it seems like capitalism is often the wrong model for trying to solve these big social problems.

Yeah, except in this case, frankly, it's very interesting because each company has maintained their intellectual property very, very close to their chest. Yet everything else was shared in how you conduct a clinical trial, how you build up a manufacturing site, how you recruit more subjects of this type or that type of how you measure the immune response to everything that wasn't in the product itself. The collaboration and openness was maximal between all the companies that have been involved in the operation.

So it is possible actually to maintain the area that's competitive and then identify everything else that's not.

The first two big successes, the Fizer and the Moderne, they both use this new approach with messenger RNA, is it possible to explain to lay people like myself in simple terms how that differs from the typical vaccine approach?

Yes.

So a typical vaccine approach would be one where you look at the virus, it has those spikes coming out. You identify the gene, which is a template that helps make that spike. And you take that gene and you put it in a cell that is able to grow in a fermenter. In a big tank, ultimately on an industrial scale, and you make that sell produce just that spike. And then you spend enormous effort to purify that spy from all the rest of the proteins that are into the cell, and once you have done that, you need to make sure that the structure of that spy is still as similar as can be to the shape it has when it's on the virus.

And that would be your vaccine that you then inject inside people and they see something that looks like the virus but isn't the virus. And that's how you make an immune response against it. That's the last three to four decades way of making safe grade vaccines.

OK, so the old way involves this messy process of growing something inside a fermenter, which honestly, I had no idea. Then what's the new way using messenger RNA?

The messenger RNA doesn't take the gene. It takes the intermediary that the gene uses to make a protein when we want to make a protein. What happens is our genes, which are made in DNA, actually make a kind of a carbon copy of themselves, but it's slightly different chemically. And that's called the messenger RNA. And that messenger RNA actually goes into the machinery that makes proteins for us in our cells and it gets into that machinery. And as a carbon copy of the original template, which is a DNA, we have now a carbon copy of it.

It's used to make the protein, but after a limited period of time, that carbon copy actually disintegrates and disappears. And if you wanted to make more of the protein, you have to make a new carbon copy, a new messenger RNA. The genius in the approach is to use that carbon copy and to design it in such a way that it will get inside my cells. It will trick myself to think, oh, this is messenger RNA coming from a virus that tells me make the spike.

My cells will make the spikes exactly as if the virus was there making them. I don't have to purify the spike. I don't have to make sure it has the right structure. I don't have to go through a zillion things because now the factory is not a big tank. It's each one of the cells in my body that has received that particular messenger RNA. It stays with the machinery that makes protein, helps make the protein and then disappears. So it's safe and the rest of the immune response happens exactly as if I had injected the protein that I made in a fermenter.

Except here. And this is why we went so fast. The fidelity of the structure, etc. of the spike is perfect and the data show it works superbly well, very fast.

And you think that the fidelity of the shape is the reason that it's proven so effective? Two reasons, and one is exactly that. It's exquisitely, appropriately structured. You know, if you make it in your own cells, you do it exactly as if the virus was making it worthwhile. If you make it in a fermenter, you make it into a cell that grows in the fermenter, etc. That's one half of the story, or maybe even more than a half.

The other half of the story is that our immune system has evolved to recognize two worlds of aggressor's, either those aggressor's that stay outside of our cells. And we make antibodies against them. However, some viruses get inside our cells and that's where they hide. And what the immune system has evolved is a second strategy where the immune system can now recognize a cell that's infected with the virus and kills that cell before the cell makes 10000 or 100000 new viruses.

So it kills the virus by killing the cell. It's called cellular immunity or t cell responses. And the beauty of the messenger RNA. It's good as making the right antibodies that are best fit to kill the virus when it's outside of a cell, but because the protein is made inside cells as if they were infected with the virus. It also is very, very good at making t cell responses. And those two arms of the immune response, the antibody arm and the T cell response arm are very, very important for protection against viral infections.

And I think this is why the vaccine has 95 percent efficacy or even 100 percent efficacy against severe disease. And this is why I feel confident that these vaccines will have a long lasting immunity. This is not going to be a short lived immunity.

The one piece that I still don't understand is why when you give us in two doses, when you give the second dose to, people often feel really sick because there's no actual virus associated with. I wouldn't think that people would feel so sick.

OK, so first, it's in fact a minority of people that feel pain in the injection site, redness and then some chills and a little bit of fever and headache. It's about 10, 15 percent of people. What those are, it's actually your immune response at work. Fever is an immune mechanism.

Chill's is an immune mechanism. Pain and redness is the damage that your immune system does by creating inflammation, that inflammation is an immune mechanism and the way our immune system works is that the first time you show its something, its main objective is to learn it. So the response is subdued when you give the second dose. Now the immune system has learned the response is enormously faster than the first time, at least ten times stronger. Often times a hundred times stronger.

And in some individuals, for reasons frankly that we don't fully understand, because it's only 10, 15 percent of people that translate into more significant reactions. Those effects last 24 hours, 36 hours, and they lapse very quickly because you make an immune response and then you're good. The reason you get sick when you have a virus is the virus is running more and you're making more and more of your response. But it's maybe not the right one or it's ineffective to clear the virus out.

So you're sicker and sicker while when you vaccinate with something that's not the virus, you see it. You think it's a virus, you make a big immune response. You destroy that little bit of vaccine that we put in and now you're super equipped. Next time the virus comes, you're going to deal with it. You're listening to people I mostly admire with Steve Levitt and his conversation with the head of Operation Warp Speed, Moncef Slaoui, they'll return after this short break.

All you want to do is sit in a cafe and quietly enjoy this podcast when you can, I have a tall Hemi Demi semi half caf McClarty. Oh, and can you served in a macchiato class?

Oh, give me strength.

Cut the nonsense and keep it real. With Trebor, pick up a refreshing boost of Trebor Extra strongman's for a cherry trees of Trigo soft mints.

If you want a better tomorrow, start heading for it today. Lower your emissions and pay less tax than diesel. With Toyota's incredible range of self charging hybrid electric cars as contributions of up to 3000 euro and now with a two percent rate reduction. There's never been a better time to join the thousands of drivers who've made Ireland's best selling car a Toyota hybrid. Contact your dealer or explore the range at Toyota detail and start your electric journey. Today, Toyota built for a better world.

Terms and conditions apply.

I have to say, this is going much better than I expected. Those were hard scientific topics we just discussed, but I felt like I explained them so well that I understood almost everything.

But I'm ready to move away from the science and start talking about the economics of this program, which I think are at least as interesting. And also, I think they made one big mistake on the program, and I want to challenge him on that. So there's something called a challenge trial where people are given an experimental vaccine and instead of waiting around to see how many people in treatment and control get covid over the ensuing months or years, if they live their life in a trial, you actually intentionally expose people who got the vaccine to covid to see if they get sick.

And the huge benefit of the trial is that it yields the answers quickly. And I suspect that if we don't challenge trials and covid, we probably could have speeded up approval of a vaccine by two to four months. Maybe it would have saved one hundred thousand US lives and 500 billion dollars in government deficit. Why didn't we do chanterelles? And do you regret that choice?

No, because actually, I don't agree with what you said respectfully. And there are many reasons why. The first thing is you cannot take wild type virus and challenge people with it. That's totally unethical. You have to take a virus strain that you kind of attenuate a little bit so that you do not run the risk of killing people. And that's the reason nobody has done yet. That is because the challenge of virus is being prepared to make it less hot.

That's number one.

Let me stop you there, because there's a weird dichotomy for me between what medical ethics believes and what common sense says, which is if you can save one hundred thousand lives by maybe killing 10 volunteers who you could pay very generously a million dollars apiece to take a one in 100 chance to die, I don't understand why that's unethical.

Well, you are going to have to take people with comorbidities, old people, Albie's, et cetera, very complex. And the issue of the ethics, it gets very important. If this was Ebola. Where exposure to the virus means 90 percent chance of death. It's a different story if there is an airborne virus that kills 90 percent of people that it gets in. Yes, challenge trial and volunteer to save the others. But this virus kills. It's horrible to say this way.

It's one in a thousand, maybe two in a thousand. And to counter the ethics balance, there are also scientific arguments that there is a number of layers. The second issue with a challenge trial is that we don't know specifically how the virus infects us in a way where we get sick. Because, as you know, a lot of people get infected and are completely asymptomatic. Part of that is that they are healthy or weak. Some of that has to do with the virus load.

How much virus did you get? But some of that has to do with where does the virus go? Did it go in your nose? Did it go in your eyes? Did it go in your lungs straight away? And I can tell you in flu that have been so many challenges, right? I mean, they never helped us make a vaccine because we're unable to reproduce the natural conditions in which the disease happened.

And then the last point, which is very important also is when you do chance trials, you give vaccine. And 14 days after the second immunization, you challenge people. That, again, is not representative because that's the peak of the immune response. What happens one month after the second dose or two months? So we've seen infection from the month of July through to December, at least five months. So the value of the response isn't the same. So that's the reason we didn't go that way.

So let me turn this a little bit over to the economics of this, away from the science, one of the key pieces of operation warp speed were the contracts that you signed with companies developing the vaccines. And these were big contracts, sometimes a billion dollars or more in return for those companies prioritizing the U.S. to receive a substantial share of the early vaccine production. But one thing I haven't seen a lot of explanation around is what happens if a particular company's vaccine doesn't end up working or if the company isn't able to recruit enough people in the study.

So we never learn about efficacy and safety. Does that company keep the, say, the billion dollars or do they return some of it? How does that work?

So it's very important first to realize that those contracts were bottom up contracts where we built all the levels of activity needed to discover, develop tests in the clinics, scale of the manufacturing, build the manufacturing site and manufacture vaccine doses, and as a reward for paying in full or substantially in full.

For all of that, we would take the first one hundred million doses produced. But it's saying for R&D and manufacturing it for everything. There was one contract that wasn't that way, I should say, which is Pfizer.

Come back to it in a second, but all the others were pay as you go. In other words, if we do the first three experiments and then the fourth one doesn't work, then the cost to the US government is the cost of the three first experiments, and that's it. So we were effectively financing the R&D and the development and the manufacture in exchange for getting the first hundred million doses, as well as options on, depending on the contract, between three more hundred or up to 500 or even 600 million more doses.

Pfizer said, I don't want the R&D money. I don't want to give some level of control because of course, we were paying for R&D. We were at the table in every detail decision and also the U.S. government then. Effectively, legally, owns the vaccine doses, so it makes sense to me why the small companies would take the government's R&D money. And it also makes sense to me why Pfizer would turn it down. They're big company. They can absorb the risk and they get to keep more of the long term upside.

But why then would big companies like Johnson and Johnson and Sanofi GSK, why did they decide to take the research fund?

From my previous life, we did the Ebola vaccine. We went and did a Zika vaccine because it was very important to save the world. But by the time we made the vaccine, the Ebola outbreaks were extinct and Zika was no more of a problem. And here you are as a company, you spent five hundred million or a billion dollars or three hundred million, whatever it is. And then you're just stuck there with something nobody wants and there is no market for it.

So Pfizer said, listen, let me take the risk.

And what we negotiated, there was a price and we set the price at the level where we had with other companies and knew what the first 100 million doses would cost on a unit basis. And that's why the two companies have similar prices, even if one of them we had to really build everything with them.

For Moderna, I think people are really bad at thinking intelligently about big numbers. And when you say a number like 18 billion dollars to finance this project, that seems like a really big number. So I just went to the data and looked at a little bit to try to understand some of the benefit side. And what surprised me is how expensive it has been for the US federal government. So the budget deficit in the year ending in September, twenty 20 was over three trillion dollars.

So that's eight billion dollars a day in budget deficit. And if you compare it to what we were running a deficit before covid, it's about an extra six billion dollars a day for cover. So essentially, if Operation Warp Speed ends the pandemic three days earlier than it otherwise would have ended, absent your efforts, then we've already gotten a return on that money. And I think every indication is that you're cutting off months, if not years for the pandemic.

Honestly, not to sound like too congratulatory, but this might be one of the highest Arawa projects the US government has ever run. Have you thought about it from that perspective?

Absolutely. From day one at that time, we were in lockdown. The lockdown was estimated to cost between 20 and 23 billion dollars a day to the US economy. And therefore, in my conversations when I was discussing whether I could take this role or not, the points were unlimited budget. What it takes is what it takes. And I added to them and absolutely no political interference and absolutely total empowerment. And it was justified, frankly, from day one, and it goes back to the point you made earlier about the power of science and the thing about science is that this big powerful, it's really cheap in general.

R&D is cheap compared to production and implementation. And I think that sometimes gets lost in the shuffle that people feel like it's too expensive to say, you know, go back to climate change, to spend a lot of resources researching climate change when it really it's so trivial that the scientific but it is always so trivial compared to the other costs. I completely agree. And in fact, two points I'd like to make there. One is so the platform technology that we have used to go so fast, whether it's the messenger RNA or the adenovirus platform or the recombinant platform, has been researched for 10, 15 years and enormous amounts of money have been spent.

Short of having done that, we would never, of course, have had them ready to run with like we have done no one. Therefore, R&D is obviously important and huge return on investment. The second point that I'd like to make, and I really hope this carries the message in 2015 or 16, after the Ebola and Zika crisis, I put together a proposal. I was still at GlaxoSmithKline at the time and I came to the government either here in the US or in Europe and said.

Why do we each time have to act after the fact, we spend enormous resources, have lots of people die. To deal with a pandemic, why don't we create an organization that would be a permanent organization that access those platform technologies, four or five of them, that has maybe 150 or 200 scientists and industrialists, and that research develop and manufacture at scale. But in small, no small being one or two million doses, vaccines against a list of more than 50 agents known to be potential pandemic viruses.

Why don't we go through that list one by one? And every six months or every nine months make a vaccine tested just for phase one, phase two studies, and then stockpile one million doses of that vaccine and move to the next one and the next one and the next one. And after each vaccine, that organization would be better and better at designing and developing vaccines. And we will have stockpiled doses of vaccine and the knowledge of immediately beefing up the manufacturing of that particular vaccine, if we're lucky, quote unquote, lucky and in a pandemic happens because of an agent that we had already tackled.

Here we are. We have a vaccine tomorrow. And if it happens with the pathogen we did not yet tackle, we have an organization ready to run, dedicated, hyper expert and trained that will go much faster than than the warp speed has been, but also will cost 10 times less. And I really think this is worth doing. It's prevention and preparedness rather than a reaction and repair. And I hope this time we learn the lesson that we need to be prepared and that the cost of that organization at that time, I think it was a hundred fifty or two hundred million dollars a year.

Even if it cost 500 million, it will be worth every penny. And remember, one military aircraft cost more than that.

So I would like to ask my guests to give listeners some advice.

And with you, I'm really curious if you have any advice as someone who obviously thinks logically and scientifically about how to change the minds of people who don't think logically and scientifically. When you run into people who are ideological or anti science or conspiracy believers, do you have strategies for being persuasive?

That's a very good question. I would say my first advice, which is slightly tangential to what you said, I always say I'm not going to spend a lot of my time describing the problem. I quite quickly, once I, I have somewhat described the problem, I need to start thinking about solutions because that's how you move forward. Otherwise, if you continue describing the problem, you stay still. I use somewhat of a similar strategy of building up an argument and engagement where people understand that I'm genuine and authentic and I'm not at any cost trying to change their mind.

I'm actually mostly trying to understand how they think and start from there, because in order to really convince somebody of something, you need to truly exchange views, which means active listening and understanding why they say something. Some people it's impossible, but otherwise that would be my starting point. And my advice is A, active listening.

And B, once you have some grasp of the problem, think of solutions that also creates energy and momentum to move forward. There was so much more I wanted to ask him, but we ran out of time, if he didn't have to go back to saving the world, I probably could have filled at least another hour with all my questions.

I definitely did not win that debate until those trials.

But I stand by my position.

I still believe that thoughtfully, creatively design challenge trials could both be morally sound and shave months after the vaccine development timeline. And here's something to ponder.

If they had done challenge trials, I suspect we would have had a vaccine by the presidential election. Would that have been a Trump victory? Almost certainly. How ironic would that have been? The antiscience president rescued by science. People I mostly admire is part of the Freakonomics Radio Network and is produced by Freakonomics Radio and Stitcher Not Hecky is the producer Dan Zula and Greg Rippin were the engineers on this episode. Our staff also includes Allison Craig Lowe and Mark McCluskey.

Our intern is immaterial. All of the music you heard on the show was composed by Luis Scarra to listen ad free subscribe to Stitcher Premium. We can also be reached at radio at Freakonomics dot com. Thanks for listening.

If you want a better tomorrow, start heading for it today, lower your emissions and pay less tax than diesel with Toyota's incredible range of self charging hybrid electric cars as contributions of up to 3000 euro and now with a two percent rate reduction. There's never been a better time to join the thousands of drivers who've made Ireland's best selling car a Toyota hybrid. Contact your dealer or explore the range at Toyota detail and start your electric journey. Today, Toyota built for a better world.

Terms and conditions apply.