Transcript of interview with Professor Andrew Ward* by Lara Marks, 21 June 2021

(this transcript has been edited for clarity and brevity)

* Department of Integrative Structural and Computational Biology, The Scripps Research Institute

Andrew

My lab is interested in structure based vaccine design or rational vaccine design. That just means that if you can look at the atomic structure of a protein, you can further engineer it. In this case, we look at the proteins on the surface of viruses to understand how antibodies bind to them and neutralise and attack them. Then we go back and design on the computer more stable or more preferable proteins that when presented to the immune system will give a stronger immune response.

Since 2010 my lab has really been working with Cryo EM, which is a structural tool that we use to generate atomic level pictures of pieces of virus. We started really doing a lot of work on HIV and influenza which have analogous spike proteins on their surface. They have related problems in terms of stability and eliciting the correct types of antibodies. That field has really exploded in the last 10 to 15 years. In part because there's new structural techniques like Cryo EM that allow you to do this work, and because the traditional empirical approaches of just heat inactivating a virus and injecting it don't work that well for a number of pathogens. Even when they work there's issues: they can be heterogeneous over different batches, they can have different effects on different people. You're also vaccinating with a lot more pieces of the virus, instead of the key antigen that you want to focus on.

So as a result of work in HIV, influenza, which has driven the field, there's a lot of pre-existing knowledge. On the other side of things, Jason McClellan, who we collaborate with, was doing a parallel approach, but for RSV [Respiratory Syncytial Virus]. When he left the NIH to start his own lab, I was five years into my lab, and he reached out and asked if I'd like to join up and work together on coronaviruses.

Lara

Why did you pick coronaviruses to work on?

Andrew

Yeah, so it's interesting. At that time we had seen MERS and SARS and had some appreciation that there would be a periodic [outbreak] every 10 years or so of a coronavirus like pathogen. And because of the [ongoing research] in the large franchises of HIV and influenza, it was also an opportunity to look where other people were not looking at the time. Also for myself, we were developing this technology platform that can work on anything, any pathogen. Jason was also interested, because Barney Graham, who he had been working with, had a historical interest in respiratory viruses. Lastly, the formation of CEPI [Coalition for Epidemic Preparedness Innovations] in 2015 and the attention that was given to potential pandemic outbreak viruses was an opportunity. [So] one it was awareness and two there was an opportunity for funding. Whenever you do scientific research, you have to connect the dots and make sure it's fundable. The irony is that it was difficult for Jason and I to get funding at the time, and now it's quite trivial to get funding for coronavirus research.

Lara

You must have woken up in 2020 and thought 'good grief'.

Andrew

There are some famous lines from our grant and paper reviews that, in retrospect, were incredibly naive, but that's just how science works. And really MERS and SARS were not spreading rapidly and they were contained. To be honest I don't think anybody expected a virus like this that wasn't influenza. There's always the looming threat of pandemic influenza. It you look back historically pandemic influenza kills a lot more people on an annual basis really than anything else. And [in terms of] the morbidity and effect on work and everything else it’s had a huge impact. That's why people were really focused on influenza and why we're returning to do more work on flu.

Lara

When you started working on the structural design for looking at the receptors on the virus, could you have done that without Cryo EM?

Andrew

At the time, no. Even now, nobody has used another structural technique to generate that information. With Cryo EM the timing was beautiful, because it was just starting to emerge as a technique.

My lab was one of the very few in the world that had the technology to do it. I had an interest in vaccine design, and had trained and was looking in that space. Jason is a structural biologist and he was using something called X-ray crystallography which was, and still is, severely limited for large viral antigens. It's very difficult, if not impossible [to do with smaller viral antigens]. Cryo EM really opened up the door for HIV and other pathogens as well. I had also hired a postdoc, a PhD level scientist, who was excited about Cryo EM and he also had an interest in coronaviruses. It was just this beautiful congruence, like I said, this unique timing to pull it all off as we did.

Lara

Was Richard Henderson the guy who developed Cryo EM?

Andrew

The 2017 Nobel Prize was given to Richard Henderson, Jacques Dubochet and Joachim Frank for Cryo EM. So you could see the fast ramp up of the technology. They got the Nobel Prize for all the pioneering work, but it was actually the detectors, these very high end atomic level cameras, essentially, that you could put on the microscopes that really opened up the doors. They became available in 2010, 2011. That's really why Cryo EM has enjoyed so much success since then is because these cameras are just amazing. And at Scripps, where I work, we made one of the first investments in one of those instruments.

Lara

Why did these cameras make a difference?

Andrew

Richard was the thought leader in the field, had done all the math and physics and said it's theoretically possible, given the wavelength of electrons to recover atomic level information, analogous to how X ray crystallography works. But with older detectors there's [some] corruption and blurring of images. Detecting a single electron, which is what these cameras do, is a pretty remarkable feat. If you just look at how your iPhone camera has changed, or, any digital camera has changed, you can appreciate what the cameras do now. One of the tricks is that, in addition to the pixel size, they actually are recording movies, just like a modern camera does. Then they're able to combine all the images together and average them so that they're not a blurred movie, but they're a very well aligned movie.

Lara

So that gave you the atomic structure of what you wanted to look for in terms of the protein receptor. Is that right?

Andrew

Yeah. In fact, we started looking at MERS and SARS, because those were the big news getters. Those didn't work actually. Oftentimes the target you want to look at doesn't work for a number of reasons. So we actually started broadening and looking at the seasonal coronaviruses that were related in the beta coronavirus family. The one that worked biochemically and in the lab was HKU1, which causes mild to moderate seasonal colds and there's some higher risk for immunocompromised or elderly people. We were able to make enough of the protein, put it in the microscope and solve its atomic structure, which at the time happened very quickly (Kirchdoerfer et al).

It's funny, I talk about how quickly things moved and how successful we were, but it took us six to eight months. It now takes us less than a week to do these things. So once we had that image and structure, we could then model it based on the sequence of SARS or MERS, and look at where in the protein they were similar or not similar. You do this all the time on a computer. If you have a related thing, you can then layer on the sequence.

What I like to say is if you have all the schematic drawings of a car, let's say a Toyota or whatever, and I give you the sequence of all the parts of a Ford, you're going to be able to say, okay, the muffler goes here, the engine goes here, and whatever goes here. [So you can] put together a pretty good approximation of what that car should [like like], even though you don't have the Ford plans in front of you.

And that's what we did. We went through and reconstructed on a computer what the MERS and SARS [viruses] would look like. Then we used the lessons that my lab and others had for HIV, Jason for RSV, to make mutations in very strategic places where we basically were preventing these molecules from being unstable. So we were stabilising them, using worn ideas from other viruses. By putting [mutations] in strategic places and then testing, I think we tested 50 or 75 of them, we [eventually determined that we could stabilise the molecule's structure] by adding two prolines [2-P] which is a type of amino acids. The nice thing is the P is it can also be inserted into the HIV envelope which is the spike protein on HIV. We solved the first structure [HIV] in 2013 (Lyumkis et al).

That technology was sort of plug and play for coronavirus as it is for many other viruses that undergo these structural transitions and are unstable. So we got the 2P and and all of a sudden we could make the protein. [Before that] we had tried to make it and couldn't. Now we were able to make a lot of it [which meant we could] solve its structures. Then we showed that it could work across all the betacoronavirus. Every time we put the 2P in that analogous location we could make the protein and proceed (Kirchdoerfer et al).

Lara

Can I just ask, to make the protein, is that to educate the immune system to attack that part of the virus. Was that the idea?

Andrew

Yeah, exactly. So in a lab you're usually making these proteins with cells. You introduce DNA into cells, they can be insect cells or they can be human or mammalian cells. There's different immortalised cell lines that can be turned into production factories for the protein that you're interested in. Then you purify the protein you're interested in, away from all the rest of the cells and debris. That's what we use for structure studies. But that also is what Novavax uses in their protein subunit vaccine. It's also what mRNA vaccines produce in your own body using your own cells. It's introducing these messenger RNAs to tell your body to make the antigen.

Lara

So the key thing is to know the structure of the antigen so that you can then encourage the body to recognise that antigen to then attack it. Is that the point?

Andrew

Yeah. In the case of the SARS-CoV-2 spike the prefusion stabilised form is the key state of the molecule that you want your antibodies and immune system to recognise. Having the structure enables you to add the 2P mutations and other mutations, so that when you do make it, it really stays in that state and is stable. Most of the vaccine platforms that came out tested non-mutated, or wild type versus 2P versus maybe some other strategies to stabilise. When they tested [that] in small animals, they found that the 2P gave them the best immune responses so they quickly down selected [to that].

Some, like AstraZeneca, didn't include 2P. And, I think they've had problems partially because of that, and also for a variety of other reasons. But some of the other ones that took a classical approach of making a bunch of viruses and inactivating it, like some of the Chinese ones, don't have 2P. They have some efficacy, but they don’t appear as good as these vaccines that are really presenting the idealised stabilised form of the molecule.

Lara

So it's the stable part of the virus that it's targeting? And can that then go across the different coronavirus variants as well?

Andrew

Yeah, so that's the interesting thing. Even though your immunity starts to wane over time, that's a natural phenomenon, I think we're all surprised at how well a lot of these vaccines are holding up against the variants. That's good news in the sense that the variants aren't escaping some of the antibody pressure or the immune pressure that's being put on them. But they can't really escape far because then they're not able to bind the ACE2 receptor. So it's a balance that they have to maintain in order to still infect cells. Because they still need to be able to recognise them, which means they can't change that spike too much. Therefore antibodies can still get in there and recognise them.

Lara

And they need the spike in order to enter the host cell anyway. So it's always going to be an issue.

Andrew

Correct. That’s why it is the key target. They need that to recognise the host cell. It also provides the energy and machinery to get into the cell. So if you knock that out in some way, they're just dead.

Lara

So going forward, given we're seeing all these variants around the world popping up and we're likely to see them coming out constantly, do you think these vaccines will help us combat that problem?

Andrew

I think so. I think the real big question out there is whether this turns into a seasonal type of coronavirus given how many people are infected. We're probably at the hundreds of millions to billion level right now. That's a pretty big incubator space for the virus to sample different mutations. The vast majority of them are non productive. There are a few that, you know the UK and Delta variants, have emerged that seem to escape some antibodies, but also the viruses that infect better and faster are taking over.

All this is to say there's going to be a level of pre-existing immunity, either through vaccines or infection. And then as the virus circulates back through the world, it's potentially just like influenza, that there's a variant that pops up that will come back into the population, especially as people's immunity wanes, a year or two years out, that can have some traction and then start another outbreak. I don't want to say pandemic, because I think all the data points to the fact that if you have any pre-existing immunity you're going to be protected from severe and moderate, or severe indications. That's why it's so important that we get everybody in the world vaccinated, and even those that have been infected, the data shows that vaccinating them really boosts their immune system up and pushes them over the top too.

I think there's the potential for seasonality, but probably not with the same level of devastation we've seen. And then we need to calibrate that based on the flu. That brings up a good parallel with the flu vaccine. It is between 10 and 60% effective on average, which isn't great. Also, of course, the whole world doesn't get vaccinated. So again, there's this large incubator space, not to mention all the animal reservoirs, which are constantly incubating.

With flu, you boost a little bit of immunity here and there. But a lot of populations don't respond well. With the elderly it certainly doesn't work. And this is known, they have antigenic sin [which is where the immune system preferentially relies on its memory for a previous infection when it encounters a second slightly different pathogen]. They've been exposed so many times that their immune system is trained, and flu can take advantage of that, and come in with a new strategy that then becomes problematic for infecting them. So, I think ultimately things might go in that direction. I just don't know how proactive we necessarily need to get to have an all in one pan-coronavirus [vaccine].

Vaccine hesitancy is going to always remain a problem. It's even more problematic given the side effects that people experience. Motivating people to take an additional vaccine when there's no imminent threat is going to be a hard challenge.

The coverage of how broad the vaccine should be is another important question. Should it be SARS CoV-2 and variants? Should it be SARS-1 and SARS-2? Should it be SARS, all sarbeco or SARS like viruses? That's unknown. We know that SARS viruses exist in bats and pangolins and they've never been as big of a problem as now. But it's one of those things, that if it's not really a problem do we go after it and try to proactively get vaccine programmes deployed and get people either vaccinated or stockpile vaccines?

We have a short memory. You know with Ebola, which is another field I worked in, everybody was interested in it and then once that outbreak died off the funding was gone. Zika same story. So I think we have some sociological and other pressures that are important. I would say scientifically, we should try to figure out as much as we can now so we can be prepared. Like we were doing when we saw the first structures to say, 'hey, if this is ever a problem, we're gonna have some information for you'.

Lara

One of the things people are talking about is doing a pan coronavirus and influenza virus vaccine. Do you think that's realistic?

Andrew

Yes, and no. In terms of a pan-influenza vaccine that's a tough challenge because everybody has pre-existing immunity and a different exposure portfolio based on when they're born. I think there's excitement about some of the things we've learned particularly in delivery for influenza. But vaccine uptake for influenza is not great, especially worldwide. And if you add in side effects I think that remains a problem. The side effects are actually a good thing. It means your immune system is working. It's just that some people don't make that connection very effectively. Then there's also the ‘this isn't a real threat to me’ type of attitude.

So, I think it's an admirable goal. But, I would say, on balance, we should understand all of the parameters. We should really have all of the ideas worked out ahead of time. Then, because of how fast we can make RNA vaccines, it's arguably better to just make sure we have the infrastructure, so that when the new variant virus from an animal crosses over, the world can start manufacturing and preparing. And if you look at the timeline, that's actually pretty reasonable. SARS- CoV-2 is a great lesson in airborne [viruses]. It has a high R. It spreads when one person infects multiple people. And it really has the hallmarks of the fastest a thing is going to move or as close.

Lara

Doesn’t Ebola move faster?

Andrew

Yes, locally. But because Ebola relies on contact, really efficient and effective public health measures should shut down Ebola outbreaks immediately. Whereas a novel coronavirus is something where people get on aeroplanes and they don't know [if they have it]. If you get Ebola, you're not getting on an aeroplane or in a car. Hemorrhagic fevers are a different problem that we're interested in. It has a separate type of outlook.

Anyway, if it were me I would build all of the infrastructure and resources worldwide. All the plants should be ready to go instead of trying to predict and create a pan coronavirus vaccine. Because it's very hard to know what corner of the earth it going to come from, or what coronavirus it's going to be, and because they can do things like recombine their genomes and do some funky things. Even with good surveillance that level of prediction is difficult.

So if you set up this network and infrastructure, and then the second the virus is identified, it's sequenced, and we know what the surface proteins are, we start with good public health measures and effective international communication which didn't happen in the case of SARS-CoV-2. Then we start a vaccine programme. I would say, at the rate at which things can go, six months or so, to a vaccine is not unrealistic. The SARS-CoV-2 vaccine broke all the clinical and regulator rules about how long it takes to get through that, so I think we'll be able to do that much quicker in the future.

Six months is actually pretty early in the pandemic if you look at where we were last year. SARS-CoV-2 was identified and acknowledged early, at least, by scientists. This really matters in terms of generating doses in the right places. Arguably, if you’d had the local expertise manufacturing in China, you could have done a mass vaccine campaign where the big source was to stop it spreading. Then you could do what's called 'ring vaccination' where any popped up. This means that if you detect it in San Diego, you vaccinate everybody in San Diego, you don't necessarily vaccinate all of America. That's why the Ebola vaccine from Merck actually works really well, because you identify patient zero, and then vaccinate everyone that could have possibly come in contact with them. So there's a focused effort, where instead of trying to get everybody to come in and missing people, concentrate on the key people that would have likely come in contact with patient zero.

This is more of an infrastructure and planning approach and what I hope comes out of this [pandemic]. But I think science has just blown everyone's doors off. You can do this science. But we really have stumbled at the government and communication and deployment side of things.

Lara

And that's where CEPI comes in. I mean, I know that their strategy is not just about the science, but also about infrastructure and making sure you have systems in place so you can run with this stuff very fast.

Andrew

Exactly.

Lara

But we couldn't be able to do this without the science to be honest with you. It's a two-way process.

Andrew

Yes, they go hand in hand. From my perspective, I'm really encouraged and excited about this. This has really brought to fruition structure based vaccine design in short order. It's something that was my long term career goal which has come to fruition and been basically played out here.

Lara

How did you get involved in this area?

Andrew

Totally by chance. I'm a structural biologist by training, which means I like to look at the atomic structures of proteins and understand how they work. So proteins are machines, they do different jobs, they move around and so on. I started as an undergraduate at Duke University, and just happened to get a work study job in a lab looking at the structure of insect flight muscle. It is this beautiful crystalline lattice of proteins which allows insects to move their wings really fast. It's just a beautiful to go down to that molecular level to see this order and structure and beauty inside the insect. That's how I first got into studying structure. We were using electron microscopes to do this work. These were early days for electron microscopy.

And I worked for a husband and wife that were very inspiring - Michael and Mary Reedy. I really liked them because they took me on like a son. It was one of the things which started out as a job but really became like a personal pursuit. They had a wonderful lifestyle. Every year they would go to Italy for three or two months to work with collaborators and then bring samples back. I would house sit for them and they would call me excited about things they were shipping this back. It was really just like this romantic vision of a lifestyle of what science meant.

Then, because structural biology is so visual and intuitive I was naturally drawn to it. When I graduated, I was still a little bit aimless. I liked science, and I liked medicine. And they [the Reedys] had heard of Ron Milligan, who was at Scripps, and he was really one of the early people developing Cryo EM. He was a student of Jacques Dubochet, Nigel Unwin, and Richard Henderson, you know these early folks. He was getting electron microscopy going at Scripps Research and doing Cryo EM. And [the Reedy's] basically said, ‘You should go out to San Diego, it's beautiful, go see what he's doing. We think that Cryo EM is going to have a bright future and there's potential’. So I said, ‘Sure’, and packed my bags and left school and went there. And, again, fell in love for different reasons. [Milligan] worked on molecular motors, the machines that walk along the tracks inside of cells and deliver cargo and that sort of thing.

It was the early days of Cryo EM, where it was totally unsatisfying. The potential was there but there were technical problems. As I mentioned, the cameras were primitive….Fast forward. When I started my own lab, it was still sort of prior to these cameras coming on board. I was actually working a lot on how molecules cross membranes with a therapeutic bent for multi drug resistance and some other sort of applications. Again, that's well suited for structure because if we understand how molecules move through proteins, you can then intervene.

Then my colleague at the time, Ian Wilson, who is famous for all his work on influenza and things he's been doing for 40 years, [contacted me]. He'd known me as a graduate student at Scripps and I had crossed paths with him a few times. When I started my own lab, he came to me and said, ‘Hey, we can't crystallise this protein. Can you look at it with the electron microscope, and maybe tell me why?’ Because we could take pictures of it directly we could say, ‘Oh, it's flexible here and you should maybe try to do some engineering or whatever, to stabilise it’. So that was my first foray into viral proteins. This was for both influenza and HIV, some of the things he was doing. I immediately saw how electron microscopy could really play a role. Then coincidentally, in 2012, when we got one of these first cameras, it was a no-brainer to say, ‘let's see if we can do the atomic level structure solution that X ray crystallography had been trying to do’. It was a very, very fast transition.

The way I look at science and life is, I just want to keep learning and having fun. And I got to change fields from drug resistance and membrane transport to structure based vaccine design immunology, which is just a fascinating field. And, taking my background saying, ‘we can develop the technology, and then we can make rational changes at the atomic level, and then put things in animals and ask, did that molecular change have the effect that we wanted?’ It's like sci-fi futuristic, but it was so intuitive and just so fun in a way. We still do a little bit of membrane transport, but the large majority is in the vaccine and immunotherapeutic space. So that's the story of how you can accidentally be a little bit lucky, certainly a product of great environments and great mentors, and people just giving you opportunities, and then running with those opportunities.

Ian Wilson, like everybody, once I showed them pictures, it was like a light going off moment of we can really use this to our advantage. Even before these cameras came online we were providing invaluable information.

One of the things that I say to remind people in my lab is that oftentimes, you're taking the first images of something that nobody's ever seen before. And you can have an unknown impact just by endeavouring to do that exercise. Some of the first images for the HIV envelope, for coronavirus and others that we've done, [were done with the kind of cameras] that would come in your back pocket. That's, why we can go much faster. If you look at how long it took to identify the causes of AIDS, HIV, the tools that people had at the time, were primitive, really.

Now imaging is certainly important, but also the sequencing that we can do. It's almost overnight. You get a patient in the hospital and you can [quickly sequence their sample]. That's another important factor, the surveillance. Local hospitals and particularly infectious disease units really need the infrastructure to look at patient zeros, diagnose them and make sure that samples are taken so that you can find these causative agents and run with them from there.

You know locally in China, they did a good job of identifying a real problem instead of passing it off as flu or something else. I mean, there were obvious differences with flu. The mRNA and lipid nanoparticle technology, which has been developed really for cancer applications and delivery of other things, and then the structural work that we did, really all came together. It's three disparate fields, but when they were combined it enabled this really fast and effective vaccine strategy. But then also, not to disregard mRNA [which I think] is transformative, but other vaccines, adeno delivery, what Novavax is doing with subunit proteins, again, you can apply the 2P mutations there. There are some potential distinctions and advantages for having those platforms too. It's important to not ignore those, because for other viruses, and maybe even for boosting immunity, some of these other ones will be important or to overcome vaccine hesitancy if the side effects are a little bit less drastic.

Lara

And everyone's different in terms of their immune response. So people are going to respond in different ways.

Andrew

Exactly. The good thing is all the good vaccines are greater than 90% effective, which is phenomenal efficacy. So it shows that if you deliver the right form of this antigen, this protein, no matter what your genetic background is, or whatever, you have a very, very good chance of hitting a level of herd immunity in the world.

Lara

The question is also expense and also storage with the mRNA vaccines. Are there other vaccine tech platforms we can be developing that can be more applicable in other areas of the world?

Andrew

True, but there are a lot of people working on mRNA storage. And I think that both Moderna, BioNTech and many other companies are going to have a heat stable version within the next few years. To be honest there was never a need to develop that before, because [they were directed towards] cancer applications for the most part. But it's not a giant leap to actually move to stabilising. So I'm optimistic about that.

Lara

Yeah. I was talking to Pamela Bjorkman who's developing the mosaic nanoparticle platform as well, which also sounds interesting to me.

Andrew

Yeah, that's cool. It's sort of analogous to flu, where you just pick the different strains of the coronavirus that you want immunity to and try to develop multiple parallel immune responses rather than a single unified one. So philosophically [there are] two ways. One is to present a single thing that elicits the antibody that can kill all the viruses or present multiple things so that you have multiple antibody responses. The trick is making sure that they're all equivalent. It's like influenza, oftentimes, you get good immunity against flu A, but not necessarily against flu B and vice versa. Your immune system can have some level of confusion when you do that.

Lara

What's your feeling, is essentially the key to going forward for coronavirus that we have both manufacturing capacities in different parts of the world, as well as the science developing for a broad protective vaccine where the science should be worked on at the same time.

Andrew

Absolutely. Just like any good basic research or science, we should be preparing for any eventuality. Like I said before, I think it's actually not so unreasonable to think, using Pamela's approach, or maybe there's actually so many people working on this now, other approaches that we will have a pan Sarbeco virus vaccine, maybe broadening further than that might be more difficult.

Lara

So what do you mean?

Andrew

Sarbeco virus is the family of SARS-like viruses. So SARS-1, SARS-2, and a lot of things that are being found in wet market animals and other things. While you can make a vaccine for what you know, you can't make a vaccine necessarily for what you don't know. And you can make some predictions, and you can have some hypotheses. But therein lies the challenge.

Like I said, even if we did tomorrow, make a pan Sarbeco or SARS virus vaccine, would we use it and would we stockpile it? Would we just have it ready? One, I think we need to just have it ready, but it's very unlikely that we're ever going to do a worldwide vaccination campaign of something that's not a problem. Two, if you do the vaccination, you actually put additional selective pressure on viruses. The more people that have antibodies that are related to SARS viruses, the more immune pressure, and that comes back to the flu problem.

The other aspect is a completely new version of a SARS virus could come into the population that avoids the vaccine totally. Just like the pandemic flu viruses, right, that's another good important analogy. We do so much flu surveillance and have so much predictive power. But in 2009, and historically, in the bigger outbreaks, these ones that come out of left field, are the ones that are just devastating, and have the biggest impact. And so I think being more open and being naked and honest. I don't think we're sophisticated and smart enough to make a pan coronavirus vaccine that is going to be future proof. We're gonna all try and we're gonna make a big hay out of it, but ultimately, as I said, doing quick surveillance, characterisation, and then using sequencing, all of us in structure based vaccine design, and then delivery, mRNA and otherwise, are the way to really future proof ourselves. Because it really is falling down in the manufacturing.

Science is taking care of itself. But manufacturing, deployment, geopolitics are, and even at the front end just public health measures [is where there are problems]. Asia actually has done a better job of just wearing masks and [taking] simple public health [measures]. Also not going into work when you're sick [is important]. Just the common things that really suppress spread. That's the same thing with flu: if we just didn't go into work when we felt symptoms, it wouldn't be a problem. SARS there's a long incubation time so it's a little bit trickier. But I think that alone would be [good] but preventive medicine is the last thing people want to do, right.

We'd rather have a treatment for cancer than try to prevent it or diabetes drugs. All these things that I think why pharma gets a bad rap is they profit off of these diseases that are preventable in many ways with just lifestyle and preventive measures.

Lara

You must have been despairing with the handling of this pandemic?

Andrew

Yes, and no. Honestly, the vaccine happened faster than I expected and science triumphed in the end. It was a little bit touch and go for a while, whether it would. You know, if some of these early vaccines had only been 30 or 50% effective, I think that would have set the field and science back quite a bit, but for them to be 90% it's unequivocal. You can't argue with those numbers and efficacy.

Lara

And what was your involvement with the Moderna vaccine? Because obviously, you found the 2P, but did they come to you? Or did they just pick it up in the literature and run with it?

Andrew

As far as I know Moderna picked it up in the literature, but also had a relationship with Barney Graham for working on influenza and some other viruses, basically just moving things from proteins into mRNA. And so they worked with Barney. Barney's lab, my lab and Jason's lab are the ones that hold the patent. And the patent actually is owned by the NIH who filed it. But every other company, or mostly other companies, were aware and incorporated 2P without consultation of anybody and tested it alongside wild-type spikes. Novavax contacted me after they made different variants, including the non-mutated, and they said, ‘Hey, you know, the 2P is looking the best’. And they contacted me to do some more structure work and characterisation. But I was actually really impressed with how a couple of our papers in a patent were so widely available and disseminated that people could actually execute them.

Lara

And when you patented that, did you have any idea that this could become important?

Andrew

I think just by virtue of the fact that we patented it.

Lara

Yes, of course. But what about at the time?

Andrew

I honestly didn't think it would have this level of impact. I think we thought that it could [if] another SARS or MERS outbreak happened, that could have like an impact for 10,000 people in that regard. And certainly, with the idea of flu pandemics and with things that it could be much bigger than that. But I think we did not appreciate the scale at which it would have an impact. Again, there are newer strategies for stabilisation and even dispensing with most of the protein and focusing even more on the receptor binding domain, for instance. But having that original 2P allowed all the companies to move very, very quickly and have success early. So I think I realised early on in the pandemic that it was going to have a big impact.

Lara

I'm assuming it was all sort of coming together with understanding how to put mRNA into the liposome to code the right mRNA to code for that protein.

Andrew

Exactly. I mean, we had been collaborating with Moderna and colleagues to use mRNA as a delivery platform for HIV vaccines. The companies were kind of dipping their toe in the water. Actually Moderna has a programme and a lot of different viruses like CMV. But it wasn't the main focus, it was delivery of antibodies or other maybe anti cancer immuno therapeutics. And so, it was again this natural repurposing and refocusing that actually happened because the world shut down. It was like, ‘Well, if you do coronavirus research’. It became a worldwide Manhattan Project where everybody just applied whatever they were doing. Whether you were a small local science lab with expertise in some area or a big pharmaceutical or a startup. So it was an opportunity for both BioNTech and Moderna who were in the realm of the known vaccine thing. They were these smaller companies that really had an opportunity and said, can we apply our tech technology for delivery to this problem.

Lara

Yeah. But it was the years of work on HIV and influenza and other areas that also came to the fore here.

Andrew

Yeah, again, it's beautiful, like standing on the shoulders of giants. Everybody's working on interesting scientific problems, and trying to synthesise bigger, more abstract ideas of how you can have real real world impact. It's just the scientific method played out extraordinarily well.

References

Kirchdoerfer, RN at al(2 March 2016) 'Pre-fusion structure of a human coronavirus spike protein ', Nature,531, 118-21.Back

Lyumkis, L, et al (20 Dec 2013) 'Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer', Science, 342/6165, 1484-90. doi: 10.1126. Back