Lessons for a future pandemic

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

University of Melbourne Laureate Professor Peter Doherty is the Patron and namesake of the Doherty Institute and has been involved in research on infection and immunity for 50 years. He shared the Nobel Prize in Physiology or Medicine in 1996 with Swiss colleague Rolf Zinkernagel for their discovery of how the immune system recognises virus-infected cells.

He was Australian of the Year in 1997, and has since been commuting between St Jude Children’s Research Hospital in Memphis and the Department of Microbiology and Immunology at the University of Melbourne. He often devotes time to delivering public lectures, writing articles for newspapers and magazines and participating in chats like the one you're about to hear. Dr Andi Horvath sat down for a Zoom chat with Professor Peter Doherty to talk about viruses, COVID-19, infections, treatments, antiviral drugs and vaccines.

ANDI HORVATH
So, Peter, tell us, what exactly is a virus? It lives inside cells, that's what I do know and that it infects cells in animals. But what exactly is it?

PETER DOHERTY
Well, a virus is basically some genetic information. It could be DNA, the nucleic acid information that we use, or it could be RNA. No other cellular organisms, even bacteria, use RNA as their information system. What they are is a bit of that genetic information, wrapped in some protein and some fat or lipid to protect it, that is out there and gets into our cells and to some extents takes over the machinery of our cells, to turn, say, a cell in our respiratory tract, in our throat, our breathing apparatus, into a factory that will produce more virus particles. It can't reproduce on its own. It has no capacity to move around on its own. It's pretty inert, until it gets into our cells.

ANDI HORVATH
So, how does it get about? I mean, how come it stays on surfaces that we touch? Doesn't it dry up?



PETER DOHERTY
The way it gets about, I mean, this particular virus, the SARS Coronavirus 2, gets around by being protected, to some extent, by mucus, by the stuff that we cough up. So, the virus particles are surrounded with this. That will protect it for a time. If, for instance, someone who coughs, they've got this mucus on their hand, touches a door handle, or an elevator button, it can survive there maybe three days or more. But it's just surviving passively. Some viruses survive a lot, lot better than that. I mean, influenza virus will survive, for instance, in fresh water very well and so forth. It's not a particularly tough virus, but it can survive for a time.

So, otherwise, it survives in us, or whatever species is transmitting it. That's why it has to transmit, because if it doesn't transmit to other individuals and multiply in other individuals, once a person becomes immune, they'll stop making new virus and it will die out. So, the strategy of this virus is to keep transmitting to more and more people and just keep itself going.

ANDI HORVATH
So, it's all that invisible mucus that we sneeze out, or even just breathe out as we're talking. In fact, you can probably even see the speckles on our own computer screens…

PETER DOHERTY
Yes.

ANDI HORVATH
…to realise how much droplets carry to a surface. So, where do these viruses come from? We've heard of things like bird flu, which comes from birds obviously and swine flu, into the mammalian sector. I guess, could we call COVID-19 a bat flu, because there seems to be some suggestion it's come from bats? So, how does this all progress?

PETER DOHERTY
Well, it's highly likely it's come from bats. There have been Chinese scientists studying these viruses in bats very intensively. They've got a whole lot of viruses like this. So, it's almost certainly it's come from a bat. What's not so clear is how it got into us. The initial thinking was that the bat infected an animal that ended up in one of these wet markets in Wuhan. The animal suggested was a pangolin. Then that transmitted to us by people coming into the wet market and being exposed. A lot of doubt has been thrown on that. It's likely, I think, it's gone through another species. I noticed one of the European virologists was suggesting he'd look very hard in raccoon dogs in China, if he had the opportunity to be there and had the funding to do it.

We also know that it infects mink. That seems pretty unlikely as a transmission mechanism, because I don't know if there's a lot of mink in that part of the world. Maybe it can infect cats a bit too. So, it's almost certainly what happens with these viruses is they go from bats, to another species, to us. So, the original SARS virus we do know went from bats to a little animal called the civet cat, which was sold in live markets in China, then jumped into us. But there's another one, the Middle Eastern respiratory syncytial virus, same thing, bats. But we think it went into camels and then went from camels to us. So, one of the bits of advice there is never kiss a camel.

ANDI HORVATH
How often does a virus, like say the influenza virus, mutate? We have a vaccine for that every year, in fact I just got my flu shot today. Does the COVID-19 and these other SARS-related viruses also mutate?

PETER DOHERTY
The influenza virus, like the COVID-19 virus, is an RNA virus. It's about a third the size of the SARS corona 2, which is the COVID-19 cause. Influenza viruses mutate at a very high rate all the time. We had a young person who was persistently infected with flu, the person in question had a defective immune system, so they had a persistent influenza virus infection. They were throwing off enormous numbers of mutants. That's what influenza does, it throws off enormous numbers of mutants. But most of them would be mutants that would compromise fitness. That is, they would not favour better growth by the virus or they would be mutants that are just irrelevant and might just get carried along. It's only every year or so that we see a new variant selected of the enormous numbers of mutations that are out there.

Now, the coronavirus, on the other hand, is much bigger. It does have a protein that's involved in what we call proof reading. So, though it does have mutations and you can follow some of the lineages of these viruses by following these mutations, it's regarded as a virus that has a pretty high fidelity. That is in actual fact, though it may carry little mutations with it, it doesn't really change much what the virus does, how it grows, or even what the specificity of it is. So, flu and the human immunodeficiency viruses are really high-mutation viruses. The COVID viruses are not.



ANDI HORVATH

Let's talk about infection rates and fatality rates. Because some viruses are highly infectious and some viruses have fatality rates that are higher and some are low. So, let's do a little bit of comparative virology.

PETER DOHERTY
Well, if we just look at the coronaviruses that we think have come across from bats, the first one, the SARS virus, killed about 10 per cent of the people it infected. It was fairly infectious, but it didn't ever really get out of Asia, except to Toronto. We had a few people that we call super spreaders, who seem to infect a lot of other people. One of those super spreaders went to Toronto. But it never went further than Toronto. The Middle Eastern virus is more lethal than the original SARS. It kills about 30 per cent that it infects. It doesn't look to be as infectious, but it's hung around for longer. For instance, it first emerged about 2012 and we were still getting cases last year and I expect probably this year, as well. It went from the Middle East to Asia, but I don't think it went to any western countries.

Whereas this one, the SARS coronavirus 2, is highly infectious. It's at least as infectious as influenza. We don't know exactly what percentage of people it's killing, because we're still unclear about the background infection rates. Most of us think it's somewhere around one to 1.5 per cent of people. But we're not sure of that, it could be lower, it could be higher.

ANDI HORVATH

People seem to respond to the virus in different ways. Why is there such a variation in people's immune responses?

PETER DOHERTY
There's always a difference in people's immune responses to viruses. That's true of influenza, as well. Basically, the main problem with this one, we think, is that older people are not responding particularly well to it. Some older people aren't. Of course, that variation in how well you respond becomes greater as you get older, because what happens is we lose what's called the naive immune response, the capacity to respond to something new. That varies a lot between people as they get older. So that, we think, is the main reason why older people are so much more susceptible. But we do know that a lot of young people particularly may have totally inapparent infection. We don't know much about how good their immune response is. We do know that a lot of younger people, and older people too, who've made quite strong responses to this and been sick, maybe not in the hospital, but also in hospital, we know that some of the older people have made very strong immune responses.
You can make a very, what looks like a really pretty normal immune response, though we're still studying that. We now can study that in enormous detail with modern technology, much more so than, say, was available back when SARS, the original one, came along in 2002.

From what I've seen so far of the detailed studies, and they're very limited, this virus is making a fairly normal immune response. I'd expect that people would be protected at least for a year against being reinfected. Or, if they did get a second infection, it would be very, very mild and you wouldn't notice it. But we're still not clear about that either. When you think about it, we've only known about this virus for a few months. So, there's still an enormous amount of work to understand what the infection's actually like.

ANDI HORVATH
For people who do have an infection, is their immune response so that it actually jeopardises their life almost an overreaction to the virus? Can you give us a little insight into what's going on there?

PETER DOHERTY
Well, again, our understanding of this is imperfect, but what we do know is that particularly in some older people who maybe are not getting rid of the virus due to their normal immune response, or are getting rid of it very late, we can get what's called cytokine storm. The cytokine storm is actually a function of a different part of the immune system, not the part of the immune system we call the adaptive immune system, which is what we stimulate when we make a vaccine, but a part of the immune system we call the innate immune system. This is an early response mechanism in the main that's designed to put a lot of rather toxic chemicals in some senses out there, to try and stop an invading bacterium, particularly, but also a virus.

We think what might be happening - and this is kind of just theoretical really, because we don't have proof of it, but it makes sense from what we know about very severe influenza infections, is that people who don't clear the infection, very late when things are kind of failing, this innate immune system turns on very strongly to try and do the job. But it can't do it. In the process of turning on like that, a lot of these toxic molecules will, for instance, cause vascular leakage and oedema of the lung and so forth. We think that might be part of it, because we know there seems to be reasonably good evidence, although we haven't seen great trial data yet, so it's kind of anecdotal, that treating with blocking a molecule called interleukin-6, which is one of these innate immune molecules, seems to help people late in the disease.

So, that may be one way of saving a lot of lives, if that's indeed the case. The blocking molecules for interleukin-6 are in use clinically. They're used with rheumatoid arthritis patients. So, getting them into people is no great problem. In some sort of severe clinical context, you can always get compassionate approval to do that. You don't need a whole lot of trials. But we do need a trial to show that it actually works properly.

ANDI HORVATH
So, let's talk about antivirals and vaccines. Let's distinguish between the two. Well, let's start with antivirals. Because there's no vaccine for HIV/AIDS, but it is treated with antivirals. So, how do they work?

PETER DOHERTY
Well, that's true, there is no vaccine for HIV/AIDS. I'm personally quite dubious we'll ever have one. There are other people that still have got some hopes. The reason for that is the virus changes so much, but also because the virus causes a persistent infection and copies back into the genome, which this virus doesn't do and flu doesn't do, for instance. So, what an antiviral is, is a drug. Now, a vaccine's something that you give to an individual and they make an immune response and then that immune response can be there for life. I mean, we know that some immune responses will last as long as 50 years after the initial infection, or exposure, or whatever. So, it's a very, very long-term thing. A drug, on the other hand, is a treatment that you give and it's a chemical, or something else, that you bring in from outside and it will wash out of the system, of course, rapidly, or slowly.

So, drugs have worked great for HIV. What's worked is what we call designer drugs. What happens here is that people we use to call x-ray crystallographers, we now call them structural biologists, who analyse the structure of proteins. That's what the vulnerable entity is on the surface of the coronavirus, or any virus, is a protein, usually a protein that binds to the receptor that gets into the cell, or something like that. So, what they do is they generate a three-dimensional structure of that protein, by bombarding it with energy in an x-ray initially, now they use the synchrotron, the big gadget we've got out at Monash University. They determine what that protein looks like, in its three-dimensional structure. Then they design a chemical which will fit in to what they think's the really important part of that structure for binding to the cell, for instance. That would be a blocker. That's an effective drug.

So, various types of those drugs were made for HIV and now everybody who's got HIV, if they're fortunate enough to be in a reasonably wealthy country, takes a cocktail of several of these every day I think it is, or maybe it's less frequently now, to keep the virus under control. So, if we had a drug, these antiviral drugs, against the coronavirus, this coronavirus, then we could treat people. It's very likely, I think, that if we had that drug and we treated people very early, we might prevent most of the severe disease even developing. If we could do that, for instance, once you can treat a disease, you don't need to lock down the whole of society, you just treat it like any other disease. So, if we can get to drug treatments, then the problem, in the sort of sense we're dealing with it now, is essentially over. We just treat it like any other disease. If we can cure it, then that's great.

But the other thing you can do with drugs is give them as a preventive, what we call a prophylaxis. What happens in HIV is there are still some people who indulge in high-risk behaviour. Well, telling them not to do that doesn't work. So, what they can do is take a drug called Truvada which has two of these anti-HIV drugs that are used also for treatment, but instead of using them for treatment they take them every day, so that if they're putting themselves at risk they just don't get infected. Now, we could do that, particularly with older people if we needed to, because it may be a problem to get older people particularly to make a decent immune response to any vaccine against this thing. So, the way to protect them might be to use what we'd call in the AIDS world, PrEP, that is, you take a couple of these drugs in single pill each day and you don't get infected.

As most older people in their 70s, late 70s and 80s and so forth are taking three or four tablets a day, adding another one won't make a whole lot of difference and it would get us out of this problem. It's always possible, it's quite possible. We will get to good drugs. I mean, there are already some reports coming in through the literature. I know Mark von Itzstein at the Griffith University in Queensland, the man who made the original Relenza drug against flu, has something he thinks is promising. This will be happening all over the planet. I think it's very likely we'll get to good drugs even quicker than we'll get to a good vaccine.



ANDI HORVATH
Right. So, the antivirals are very important in managing wellbeing in the population. Let's talk about the vaccines then, as well. The vaccines are no doubt being worked on around the world. I mean, once the antiviral's all there, that will be great. But the vaccine is something that is, I guess, long term, future. Tell us about those, because that's a whole different ball game, in terms of our immune system. It's not like the drug, as you described, that sort of latches on to a protein, on to the virus and sort of locks it and disables it. The vaccines work in a different way.

PETER DOHERTY
Well, the vaccines, we give a vaccine and the body responds to it. In the old days, the vaccines often were just the virus itself that had been killed in some way. That's the basis of the polio vaccine for instance. People grew up the polio virus, then they killed it, then they gave it to people and they responded to it. So, it's a safe form of mimicking aspects of the infection. A lot of modern vaccines just take a little bit of the virus and give that in some way. You might have heard of 'virus-like particles'. These are non-infectious particles of the virus. That's the vaccine that's used to prevent human papillomavirus infection, that causes cervical cancer in women. It's given to girls and they make an immune response and to boys too, because of the transmission aspects. They make an immune response and then, of course, if the virus comes in, the antibodies that are already there will grab hold of the virus and they'll block it and that's the end of it.

So, vaccines are what we make a response to. But that's why, of course, there are effects, like some people don't have a good functioning immune system. So, whereas a drug will work pretty much the same in everybody, a vaccine will show quite a bit of variation. Now, because you're going to give a vaccine to large numbers of completely normal people, they have to be completely safe. So, there have been a bit of a few safety concerns due to some experimental work that was done with SARS about these vaccines. So, we have to go a bit carefully. We have to test them in large numbers of people and test them in people who are not likely to be badly affected if something goes a bit wrong. That process is beginning.

One of the very first vaccines, it's a vaccine that's been made by putting a little bit of the SARS coronavirus 2 spike protein, the key protein on the surface of the virus, into another virus called adenovirus. This is actually an adenovirus from a chimpanzee. These are viruses that cause common colds in us. Now, that virus was made at the Jenner Institute at the University of Oxford. It's been tried in experimental animals. You have to do what's called pre-clinical testing. It's been done in ferrets at our CSIRO Geelong Laboratory, which used to be called the AAHL Laboratory, which has a different name. Now that, the first shots of that vaccine, have now gone into people's arms in Oxford. They'll do what's called a phase 1 safety trial to make sure that these people make antibodies and they don't get sick just from the vaccine. Then, of course, the interesting part will be when they vaccinate larger numbers of people and let them mix in society where there's a lot of infection happening, which is still the case in Britain and I think will be case for some time.



ANDI HORVATH
Peter, has this particular incident with COVID brought together the scientists in a universal way of collaboration? Is there danger of large pharma wanting to make profits from this? What's your perspective of the world of research against COVID?

PETER DOHERTY
I think everybody just wants to get this problem solved and get society back to normal. I think that's as true of big pharma as anybody else. I don't think anyone's trying to gouge large amounts of money out of this. We just want to get it behind us and get society back to normal functioning. In fact, there was a drug that some people thought was promising. Doesn't look as though it is very promising, made by the American Gilead company. Some of the activities of the Trump administration would have actually allowed that company to charge a lot of money for it. The company completely rejected it. So, I don't think you want to paint big pharma, or anybody wants to paint big pharma in an unfavourable light. I think they're like everybody else, they're trying to solve this problem. I can tell you what's happened in our own Institute. Everyone's working together across the planet.

So, normally this would be a subject for immunologists and virologists, okay. But if you look at our Institute, the bacteriologists have come into it. They're helping to develop tests. They're doing a lot of sequencing of the genome and all sorts of things. Everybody has come in on this from across the planet. Everybody's talking to each other, sharing reagent and sharing information and so forth. That's one of the reasons I think we want to do everything, both at the level of the science, which of course works that way anyway, but also at the level of government policy to promote a general global amity and not try and play blame games, or any other stupid games around this. We need to solve this problem. That's the only motivation at this stage. Getting a solution, making sure people aren't dying and getting us out of this social situation which is so economically and in some ways psychologically damaging.

ANDI HORVATH
So, Peter, what has the history of pandemics been able to teach us about how we can move forward?

PETER DOHERTY
Well, we've always thought - I mean, I wrote a little book about pandemics back in 2013, called Pandemics: What Everyone Needs To Know. It's a general interest book for the broader community. But we've always thought that the real danger is from a respiratory virus. I mean, we understand infections pretty quickly now. I mean, the plague used to be the terrible pathogen. Firstly, it’s not a virus, it's a bacterium. We worked out - by the end of the nineteenth century, people had worked out this is caused by a bacterium that's transmitted by a flea that's on rats. So, that sort of thing we understand very quickly. So, we've always thought influenza was the main risk. We do get serial influenza pandemics and, of course, we had the terrible 1918/19 pandemic, where at least 50 million people died worldwide.

But now, we're hit with another respiratory infection and just as infectious as influenza, or maybe even a little more so. That was completely unpredicted. But we always knew that there was a chance we'd be hit with something that came from completely out of left field and we wouldn't know about it until it hit us. But the one thing I will say is that the technology is improved massively, even since 2002 when SARS hit. We knew what this thing was pretty quickly, the Chinese got to it very quickly. There was some initial confusion on the part of local authorities that behaved very stupidly, but apart from that, once it really got into the lab context, people sorted it out very fast. I think they had their first cases around, I guess, November or something like that. They were putting out the sequence of the virus in January. We're moving incredibly fast. I mean, with AIDS, when it hit in 1981, it took about three or four years to actually find the virus. Now we know that straight away. We're making candidate vaccines within weeks, basically, of knowing what the sequence is.

ANDI HORVATH

We certainly are in a better position in the twenty-first century. So, Peter, is there something we should do about future pandemics and is there something that Australia could do?

PETER DOHERTY
I think there are two parts to that question, Andi. The first thing I think, globally, what we need to do about not going through this again with a future possible pandemic virus that's completely unknown and that is, we should copy what was done by an organisation called CEPI, which is an internationally-funded group. I think it was largely funded with some government money, but a lot of philanthropic money from people like the Gates Foundation, to develop vaccine strategies that could be used in the face of a novel pandemic. That funded the research of Paul Young and his group at the University of Queensland, who've developed the primary Australian COVID-19 vaccine candidate. What they developed was a platform technology called the protein clamp technology. When this new virus came along, they were just able to slot in those new virus genes and move down that road. So, their vaccine, I think, already has been in test in ferrets in the Netherlands. So, we'll see whether that one goes into people pretty soon, I would think, if it's giving promising results, it probably will.

So, that's great that we had CEPI. But what we needed out there and I sort of mentioned this a few times, but I didn't jump up and down and shout about it, was an equivalent organisation which was making antiviral drugs. Because a lot of these antiviral drugs will go right across a whole class of viruses. The anti-influenza drugs block both what we call the influenza A and influenza B viruses. If we we'd gone on pursuing antiviral drugs against SARS, the original SARS, antiviral drugs that affect its replication strategies, not so much the surface protein, then I think we might have already had drugs that would have worked against this one. So, I think we need an equivalent of the CEPI organisation that's involved in developing drugs against all the major classes of virus that could be a potential threat to us.

Some of those are the paramyxoviruses, the ones that cause Hendra virus, or Nipah virus, which have transmitted to humans and cause severe disease. Another class of drugs would be against the filoviruses, the Ebola-type viruses. I'd include the noroviruses, like the ones that cause diarrhea. I think we should have drug candidates in place that will counter any possible threat from the virus world. Bacteria aren't so much a problem for us, because as they're cells and separate cells, broad-spectrum antibiotics tend to work against most of them. But viruses are specific to themselves and we need that group-specific therapy. So, I think a drug development program for all the potentially threatening viruses, that we take these drugs through to at least a phase 1 safety trial and through experimental animal tests. So, that's one thing I think we should do.

Specifically, from the point of view of Australia, it worries me that we don't have a resource in Australia that could make enormous amounts of what we call GMP-grade protein. This is a protein and you think most of these vaccines would be proteins. If we made monoclonal antibodies that are things that can be used in place of drugs, we don't have a resource in this country which would allow us to make enormous amounts of those sorts of products. I think we should think about putting that in place in Australia, have some sort of agency, or facility that is able to make enormous amounts of these GMP-grade proteins. It could be used for other things in peace time. It can be used to make therapeutics under licence, or various other things. But I think we need to have that resource that makes us independent. What worries me in all this is if even when a successful vaccine is made, if it's a protein vaccine, are we going to be the link at the end of the supply chain? I think we don't want to be in that position.

ANDI HORVATH
Professor, what would you like us to think about as we go to our phones and our devices to read about a COVID-19 story, just to update ourselves, what would you like us to have in the back of our minds?

PETER DOHERTY

In the back of our minds, I think we need to think in terms of - this has shown us what happens when humanity suddenly is faced with an enormous crisis. We've reacted well to it, because human beings, I think, are programmed to react well to acute threats. I think that's what we've done through our whole evolution. There's an acute threat, we all come together, we all work together, we all do our utmost to solve the problem. Societies that are a bit more collectivist in some sense, as many Asian societies are for instance and more accustomed to working together, in some cases have done rather better than this. I mean, the United States, that great bastion of freedom and individual liberty and everybody doing their own thing, some of them don't even believe they should all be forced to drive on the same side of the road, they've not done well with this, at all. So, it's taught us something there.

The other thing is, I think, that this isn't the biggest threat facing humanity, this is something we'll be through in 12 to 18 months. The biggest threat facing humanity is clearly climate change and we all understand that if we've got any sense at all. Yet, we're almost paralysed when it comes to that. I think, personally, that what should come out of this is we need to rethink some of the ways we do things. Some of the values we put on different things in society. Australia, particularly, needs to think, do we really want to be at the end of every supply chain in a globalised market place? I think that's not working all that well for us, though we've done well in the sense of responding. That's another thing that's made me feel very good about Australia, is that I've been worried that the more right-wing aspect of our politics was going too far down the American road. We were aping their love affair with every individual should be able to do exactly what he or she wants.

I think now we've shown, through the actions of the government, that basically we are capable of thinking in terms of the general good and acting accordingly. I'm very, very, very heartened by that and by the strong response the present Prime Minister and the present government have made. I don’t think if the opposition had been in place it would have been any different, but it's great to see that side of politics really stepping up to the plate.

ANDI HORVATH

Professor Peter Doherty. Thank you for your insights and your inspiration.

PETER DOHERTY
You're welcome.

CHRIS HATZIS
Thank you to Professor Peter Doherty, Patron and namesake of the Peter Doherty Institute for Infection and Immunity. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on April 22, 2020. You’ll find a full transcript on the Pursuit website. Production, audio engineering and editing by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis. Join us again next time for another Eavesdrop on Experts.