Trevor Mundel, president of global health at the Gates Foundation, talks to Scientific American Editor in Chief Mariette DiChristina about the Coalition for Epidemic Preparedness Innovations (CEPI) and the efforts to create vaccine platforms for rapid responses to epidemics.

Steve Mirsky: Welcome to Scientific American Science Talk posted on January 30, 2017. I’m Steve Mirsky. On January 18^th at the World Economic Forum in Davos, Switzerland, the Coalition for Epidemic Preparedness Innovations also known as C-E-P-I or CEPI announced that it had raised an initial $460 million backing from Norway, Germany. Japan, the Welcome Trust and the Bill and Melinda Gates Foundation. The organization expects to raise the $1 billion that it needs for the next five years by the end of this year. As the journal Nature put it, CEPI is thus the largest vaccine development initiative ever against viruses that are potential epidemic threats.

Scientific American Editor in Chief Mariette DiChristina was at Davos and spoke briefly with Trevor Mundel. He’s the president of global health at the Gates Foundation. They talked mostly about what’s ahead for vaccine platforms. That’s the thing that’s going to carry the antigen which is what will get the immune system to spring into action. What is sounds like they are hoping to do is get one or a few vaccine platforms especially using nucleic acids that could code for whatever antigen you need. So that if you have for example malaria in this part of the world, you pop in the malaria antigen and start vaccinating. If you have Ebola in another part of the work, you take the same platform but switch in the Ebola antigen instead of the malaria one.

Obviously, that’s a gross oversimplification but that’s the general idea. According to Nature the first targets for CEPI are vaccines against the Nipah virus and those that cause Middle East Respiratory Syndrome MIRS and Lasa Fever. Here’s Trevor Mundel and Mariette DiChristina. Mundel by the way has a medical degree and a doctorate in mathematics and he was a Rhodes scholar. The conversation is just over eleven minutes.

Mariette DiChristina: The one thing I really would love to follow up on with you is about vaccine platforms and your view of the future on that because it’s something people are very excited about.

Trevor Mundel: So as much as we have the couple of example of pathogens which are a set of experts’ best guess from a list of 20 or 30 options what could be the likely next outbreak, the truth of the matter is the likely next outbreak is probably unknown as we learned from Zika. So that’s the number one likelihood. So what we see with this construct, this investment in vaccine R&D is that as much as we could produce vaccines against these pathogens and it might even be the ______ which is a rapidly mutating virus. We can produce a vaccine and then the strain that actually emerges will not be the same one.

And vaccines are very selective so that it would not be helpful against the new virus. So the greatest utility is to do two things at once. At the same time as we need a virus to work on, we work on it with a new platform so that we have two things. We have validated a new platform and we have a vaccine just in case that turns out to be the pathogen. So it’s kind of a two for one.

DiChristina: And can you speak to me a little bit about which platforms seem particularly promising to you and why that might be the case.

Mundel: We are tracking this pretty intensively. So the platforms that we are excited about right now are some of the vectored, nucleic acid vector platforms. So there’s one set of platforms around RNA. So where you code the antigens in RNA. And then you deliver them into muscular. They get taken up by largely the muscle cells. And that nucleic acid is then translated into protein and that’s going to be the antigen.

So the advantages of this is that you can inoculate very small amounts and because you rely on the body cells to actually be their own vaccine factory, you amplify tremendously. So a small amount of vaccine and then you have the flexibility that if you have the new antigen, the new protein all you need to do is recode it and just change the sequence. So there’s a hope that these platforms are going to be somewhat modular. It’s going to be a type of plug and play that you can go from yellow fever to Zika or yellow fever to Ebola.

You just change the surface protein and the code and then all the axillary things that you have to do in vaccine development like the toxicology if you do animal toxicology. You have to do kinetic studies to see what the resistance is. All of that additional work and even the manufacturing quality work would be done once up front and then the regulators would then accept a very attenuated rapid package for the next one because of the belief that you didn’t change much. You just changed the sequence. So we have to convince our self that just changing the sequence doesn’t change things that much. It would be difficult to imagine how it does but you never know. So we’ll see that with the first couple of examples.

Once you’ve got that somewhat antigen independent platform, then as has once been done we believe from industry that would be compounded with this. But there was one case for a fairly recent flu vaccine, a flu virus that spread where the company didn’t have the strain as they normally have it. They just had the sequence and they were able to go from sequence to a usable vaccine in six months which is the fastest we’ve ever got. Well, we believe that we can do even better than that. And if you saw the full demonstration that I did. So what that shows is it takes something to the 1917 – ‘18 flu epidemic and we just assume 30 million people died although many more people died.

And the parameter that we changed was how soon do you introduce an effective vaccine? What happens if you do it in 30 weeks or 22 weeks or 6 weeks? And it is astonishing actually. I was surprised by the audience reaction. I didn’t anticipate it because I’ve seen it so many times but when I flipped by 30 weeks where you get 2 million lives saved out of 30 million to 22 weeks and suddenly you’re saving 17 million lives. And there was a sort of gossip.

DiChristina: That’s amazing.

Mundel: Just the drop down. And six weeks of course you virtually completely abdicate. At six weeks it’s almost inconceivable that we could ever get that. So many things we’d have to do to work. But I think three months. So any case, this is the excitement on platforms. And then you could say well, that’s really exciting but what evidence is there that you can do these things.

DiChristina: Yeah. What I was going to ask you why has it been – I mean a lot of people would like this to work. What are some of the challenges that are facing you? I mean it sounds very good. You could swap in an antigen. Why is it so hard?

Mundel: Well, so administering nucleic acids is a little bit – the body is dealing with nucleic acids, RNA nucleic acids all the time in terms of pathogens. So there are enzymes degrading them so you have to – you can’t – it turns out it’s not – you can’t put in unmodified RNA into someone. It doesn’t exist very long. It’s just got a less than a few minutes half-life in its naïve form so you have to modify it. And you have to find what modifications are still amenable to it being translated in the cells.

So there are a number of different parameters. The cells have to recognize it as RNA that they want to translate into protein. Cells have got a lot of antiviral mechanisms and intrinsic defense mechanisms to recognize foreign RNA and actually not translate it. So you’ve got to slip under the cell’s own internal defense, innate defense mechanisms. As we become so excited with bacteria in CRISPR cells have malignant cells with similar kinds of defense mechanisms. So you’ve got to slip under the cell’s defense mechanism. It’s got to amplify it.

On the other hand, you do want some adjuvating because you want the cell to have some reactivity and to sort of – if it has some danger signals and it starts to act and pull other unit cells in, well, that’s what a vaccine does. So it shouldn’t be completely inert. We have another program where we actually want it to be completely inert because we are introducing the RNA to try and get the muscle cells to make antibodies. This might be even faster. This is sort of now back –

DiChristina: So interesting.

Mundel: In our back pocket, it may be a quicker route to actually getting something like a vaccine is if you have the nucleic acid actually comes from antibody and you’ve identified an antibody from somebody who recovered from the virus. And then we’re looking at this with Ebola but it turns out those recovered antibodies didn’t work that well. But let’s say for flu they should work well. So if you could quickly find someone who didn’t die from the flu virus and within a few days could extract one of the antibodies – and we’ve got super quick ways of panning through millions and millions of antibodies now. We find the antibody, we code the antibody into the RNA.

Now that’s probably in some ways more certain because you know that that antibody is going to be effective in preventing the infection. But now in that case, you want to make a lot of antibody and you don’t want the RNA to provoke any kind of inflammation and reaction. So you want it to be completely inert. And we’ve got these two pathways, one where you want to provoke a reaction like a typical vaccine. The other one where you just want to make a whole bunch of antibody and use your own muscle cells as your production factory. You want to be very inept at it and they – I think this one is probably more difficult actually.

The levels that we’ve got in antibody production are not high enough even in nonhuman primates. But we’re getting there. And the DNA seems to actually be on that antibody side quite promising. And they get higher levels in nonhuman primates than the RNA. So these are the platforms. DNA or RNA, RNA is probably the bigger opportunity now that at least there’s more doing those companies. But they are the two that could be actually up front invested in CureVac in Germany and Moderna in Cambridge. They are competitor companies. You might say why have we invested in both and in some ways, they might ask us that question as well. But we don’t – we’re neutral to – we’d like them both to be extremely successful over time what you ______. It would be nice if they were on different vaccines that you’re not directly competing. But who knows. It could be the same vaccine.

DiChristina: And the last thing I just wanted to ask you if there’s anything about – I mean there’s been a lot of different kinds of talk about vaccines around. I can hardly think of another medical intervention that has saved more lives, prevented more damage. I mean maybe there is one but I can hardly imagine one that’s been more effective than vaccines. Is there anything you might like to add?

Mundel: Absolutely. The dramatic decline that we’ve seen in under five mortality globally. The global health areas coming down from over 12 million to 6 million. Can in large part be ascribed to the roll out of vaccines and coming in with the ability to deliver vaccines at scale to kids in the developing world would be _______. Absolutely. And this is the sort of history of vaccines but I believe that in some areas where we are not going to succeed unless we get a vaccine. Actually, finding and combating HIV and getting rid of that epidemic I think is going to take a vaccine. And we’re going to use the same platforms, the RNA platforms to develop an HIV vaccine. And it may be needed in malaria as well. The problem in malaria for instance similar to in HIV.

We’ve got – we’ve now identified more than 20 different targets, antigens. If we make them by the usual vaccine process, all 20 of them where we test them and we go along we’ll be here for 60 years. With the RNA platform we can in one fell swoop make all 20 of them and test them in one study. So the acceleration that we’ll get from these platforms in these other areas that it’s not what vaccines have just done in the past, what they uniquely have the potential to do in the future in these areas, toughest areas, HIV, TB, malaria. We may not win in those areas without a vaccine.

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