Watch the replay of this event held on November 17, 2021. (Transcript below.)

New variants of the coronavirus behind the Covid-19 pandemic arise constantly, with some, such as Delta, driving new waves of infections and subsequent deaths. What kinds of genetic changes make some variants of SARS-CoV-2 more dangerous and why have virologists long been concerned about coronaviruses in particular? And what do studies of old foes such as influenza, HIV and SARS tell us about the course that SARS-CoV-2 may take and how we might prepare for the changes ahead? 


Edward Holmes headshot

Edward Holmes, Virologist, University of Sydney

Renowned for his work on the emergence and evolution of infectious diseases, Edward Holmes’ research focuses on the ecological and genetic factors that enable RNA viruses to jump between species and to cause disease outbreaks. He is the coauthored of a recent Cell review on the origins of the SARS-CoV-2 virus, and has published many studies on influenza and other pathogens. A fellow of the Australian Academy of Science and of the Royal Society, Holmes is an ARC Australian Laureate Fellow at the University of Sydney, holds a faculty appointment in the medical school, and is a member of the Charles Perkins Centre and Marie Bashir Institute for Infectious Diseases and Biosecurity.

Lisa Gralinski headshot

Lisa Gralinski,  Virologist, University of North Carolina, Chapel Hill

Lisa Gralinski studies disease-causing coronaviruses, how they interact with the human immune system, and how those interactions can result in a wide range of outcomes, from overcoming the viral infection to more serious, virus-induced, immune-mediated disease. An assistant professor in the Department of Epidemiology in the Gillings School of Global Public Health at University of North Carolina, she also studies how genetics of the host influences the severity of respiratory virus infection. Her goal is to discover targets for antiviral and immune modulatory drugs that lessen the burden of respiratory virus disease.


Eva Emerson headshot

Eva Emerson, Editor in Chief, Knowable Magazine from Annual Reviews

Eva Emerson is the founding editor of Knowable Magazine. Previously, she was Editor in Chief of Science News magazine.


This event is part of Reset: The Science of Crisis & Recovery, an ongoing series of live events and science journalism exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation. 

Knowable Magazine is a product of Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Major funding for Knowable comes from the Gordon and Betty Moore Foundation.


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Eva Emerson: Hi. Welcome. I’m Eva Emerson, the editor in chief of Knowable Magazine, and I’m so pleased that you could all join us today, as well as our guests. This is “Viral Variants: From Covid to the Flu,” and the 13th event in “Reset,” which is a series of events that looks to discuss the pandemic, its consequences, and the way forward. I also just wanted to let everyone know that our next “Reset” event will be in January. There will be a link to register in the chat, and it will focus on sleep, why it’s so important for health, and why sleep inequity is now a challenge for public health researchers.

OK, so today, I’m excited to talk about variants in viruses, both because I love the biology and because, unfortunately, even though I did think maybe delta would be less in the news, it still seems to be able to be a topic of conversation. I think everybody has been... well, I’ve been surprised by delta. I thought we were kind of coming out of things, and then it reared its head, and I’m not sure it’s completely gone away, but we’ll find out today.

We have two amazing scientists here today, both of whom have been doing hands-on work with various versions of the coronavirus for more than two years, but actually, I know it’s been for more than two years. Eddie Holmes studies the evolution of viruses at the University of Sydney in Australia, and just this month received Australia’s highest scientific prize — the top prime minister’s prize for science — for his work on how viruses evolve, including key work on SARS-CoV-2, so it’s a great honor. He and his colleagues released the first genetic sequence data on SARS-CoV-2 in January of 2020, enabling other scientists to begin work on what would become a pandemic that as of today has killed more than 5 million people worldwide. Thanks, Eddie, for joining us today.

Edward Holmes: My pleasure.

Eva Emerson: I’m also very excited to have Lisa Gralinski here. Lisa has worked on coronaviruses since, as she said on her Twitter, I think, “before it was cool,” which is very true. A virologist at the University of North Carolina in Chapel Hill, Lisa focuses on studies of what exactly happens when viruses infect cells and people, although mostly she works in mice, I think. Looking at the details of how the virus causes disease, the interactions between the body’s efforts to defend itself and the virus, as well as why some people might be more susceptible. She is actively looking at emerging variants to see how they may affect us, and she’s often bundled up in protective gear, jockeying for room in the biosafety lab. Lisa, thank you and welcome.

Lisa Gralinski: Thanks for having me.

Eva Emerson: Let’s start with the delta variant, which I’m sure a lot of people are curious about. What has enabled it to spread so fast, so far? Lisa, would you like to start?

Lisa Gralinski: Sure. The delta variant is named as kind of the fourth big variant of concern that has taken over globally. What’s really notable about this one, what’s been studied the most with it, are some key mutations in the spike gene, which result in some critical coding changes, changes in the amino acids, where the virus spike protein binds to the host receptor, ACE2. What’s really notable here in the delta variant is that it has an improved cleavage site, so that the virus that comes out of people is more poised and ready to infect the next round of virus victims. It really has a head start. It’s much faster, so that’s why this virus variant is so much more transmissible than the original virus we saw coming out of Wuhan, and even more transmissible than the alpha variant, which was the first one to really catch the world’s attention as being a variant of concern, and a significant change from the original virus. Delta took off even further from there.

Eva Emerson: Eddie, do you have anything to add?

Edward Holmes: No, I think Lisa explained that beautifully. Just to go back to one of your opening remarks though, back to “surprised by delta.” I think we all knew evolution was going to happen. I mean, that was, every virologist who works knows that viruses mutate, which we’ll actually discuss this more shortly, mutate their genetic variation all the time. They evolve all the time. It’s kind of what they do. It’s the kind of humdrum part of virus life, but as we knew there were variants would appear, but the sheer increase in infectivity of delta was certainly a surprise to me, and I think it surprised a lot of people.

Eva Emerson: Yeah, Eddie, let’s follow up on that. What is a variant exactly, and how often do they arise? And kind of a related question is can one person have multiple variants within themselves, if they’re infected?

Edward Holmes: Yeah, so the thing to think about viruses, RNA viruses, right? So you have DNA viruses and RNA viruses, and they differ in the nucleic acid that makes up their genome. RNA viruses, like coronaviruses, and influenza, and measles, and things like that, the way they’ve chosen to live, if you’d like, if I can anthropomorphize it, is they just make lots and lots of mutations. Humans and things have DNA. We can normally repair our genomes. So when the replication takes place, there are enzymes that comes along and correct if an error is made. Often, errors are made, but they’re corrected.

RNA viruses just don’t do that. Coronavirus has made it a little bit more than the other ones, but generally, the errors, every time the virus replicates, it makes an error. Because the enzymes are a little bit sloppy. So, in the general lifecycle of a virus, when it gets into a host cell, gets into your body, it will replicate, and it will make errors all the time. So if you had SARS-CoV-2, and people took a sample of viruses from your body, you would see that they would differ by mutations, because this ongoing mutation happens all the time.

Most of these mutations go nowhere. Most of them are actually kind of bad for the virus, some maybe do very little, and a very small number may be advantageous. And delta’s in that advantageous class. So, this process of generating mutations is an ongoing thing, happens every day in every single person who is infected globally, and that’s true of every RNA virus. What then happens is, once those mutations take place, very few of them may increase fitness, make it a better virus. And the vast majority won’t. A very small percentage will do. Delta just happens to have the right combination of mutations that make it super fit.

So then natural selection, the other key part of evolution takes over, so the mutations are made, you make this new virus. It’s fitter, and then it has a reproductive advantage, like standard natural selection, so it produces more offspring, and it can kind of spread faster. That’s how variants are produced, and they will continually occur. Can you be infected by more than one variant? Again, variants, mutations occur all the single time. I think what the question actually means is can you get more of these variants of concern infecting you?

And the answer is yes, it does happen. I mean, we know it happens for it, because we can actually see a clear signal of that is the process of recombination, which is kind of a genetic exchange. If two different coronaviruses get into a single cell, the enzymes, the replication enzymes kind of jump between them, and you get a kind of hybrid. For that to happen, you have to have a mixed infection, of different viruses in a single cell. Over the last couple of years, we have seen cases of this recombination taking place, of mixed infections.

And that occurs because immunity is pretty good when you get infected. You’re are immune, but it’s not perfect. It’s leaky, so you can be reinfected more than once. Simultaneously, with two different variants. So again, there’s nothing unusual about this process. It’s true of all viruses. Mutations occur on a daily basis. They’re made. Most of them go nowhere. Very few get spread. Very, very few are super fit like delta. And they can recombine to make new variants by recombination.

Eva Emerson: And do I understand that’s kind of a numbers game, that I mean, it’s making a lot of bad mutations, but it makes so many of itself that…

Edward Holmes: Yeah. I like to think of it as humans and RNA viruses are the complete opposite kind of life strategies, right? If you’re a big human, like I am, I mean you carry it, our life strategy is we don’t... We make very few offspring, but they’re very accurate copies. We invest a lot into making good copies of ourselves. If you’re an RNA virus, you have the complete opposite kind of life strategy. That’s that you produce an enormous number of offspring. Most of them are defective, probably. They’ve got mutations somewhere that disables them, disables some key function, and just not working, but there’s enough, because you can produce so many offspring, there’s enough that gets you through to the next generation. So they’re like the complete opposite kind of life history strategy to a human.

Eva Emerson: Lisa, I wondered how do we know if a variant might be a threat to us? Is this something that’s clear just from looking at the genetic code?

Lisa Gralinski: It’s not completely clear-cut just from the genetic code. There are multiple stages of assessing a variant. The first is really surveillance. We need to be tracking cases, we need to be sequencing as many isolates as we can, so that we know what viruses are circulating, and if we see the numbers, the percentage of one variant increasing, then it might become a variant of interest, or eventually a variant of concern. That’s the most clear-cut way to know if something is worrisome.

A lot of different laboratories, though, have been doing either laboratory studies looking at the spike protein and how it binds to the human receptor, ACE2, and varying different amino acids to see if that improves binding, if it changes in any way. Then there are also a lot of different computer modeling groups that have been looking at the same question, and we can get a lot of predictive information from these, but when people make kind of artificial dead-end virus particles to do a lot of these studies, they’re good mimics of the live virus, but they’re not exact mimics of the live virus, so sometimes, all the pieces don’t come together in exactly the same way as they would in real life, with actual, replicating SARS-CoV-2, so ultimately, especially as a virologist, my opinion is that you need the live virus experiment. You need that isolate in a head-to-head comparison, in cells, to be able to determine if a new variant has a competitive advantage.

And it might have a transmission advantage, as we’ve seen with delta, and then the other concern that people are always talking about is what we’ve seen with beta a lot, which was originally called the South African variant, is is there a change in immunogenicity? Is there maybe an advantage in evading the host immune response with a variant? Luckily, we don’t see that with delta, but that’s something that a lot of groups are concerned about and monitoring for.

Eva Emerson: Lisa, tell us a little bit about what you do. I mean, do you hear about a new variant and somehow get a sample, or how does that work?

Lisa Gralinski: We are in communication mostly with scientists at the CDC, through official channels, and that’s where we would be most likely to get a new variant from. A vial would come in the mail on dry ice, in special infectious-shipping packages, and be handled very carefully, and taken into the high-containment facilities. But also, communication happens so rapidly these days that honestly, Twitter is a great place to find out new information, or get a report up to the minute of someone saying, “We have new sequences that are coming from the UK.” We get a lot of data from the UK, because they have really great public health monitoring there. Or is something happening in Israel? I know people who do sequencing at the University of Michigan. There are groups at Yale who are really excellent, so I regularly know what’s happening in Connecticut, even though I’m not in Connecticut.

Eva Emerson: I had read that the alpha variant, which I think was found first in the UK, actually has some of the same genetic changes on the spike protein that the delta does, and yet, I guess I’m wondering why would that one not be as spreading as much, whereas the delta has?

Lisa Gralinski: The critical, critical change that delta has that the other variants of concern haven’t had to date is the amino acid change in that furin cleavage site, and that’s really what pre-poises this virus to be ready to infect the next round of cells in the next host and give it such a transmission advantage, and why we see so many more breakthrough cases in vaccinated people. The virus is just so much more fit and ready to infect, so exposure takes much less when we’re dealing with delta than when we were dealing with the original Wuhan isolates.

Eva Emerson: Eddie, I just wanted to bring in the flu for a second too, which I know people are kind of gearing up around here — you probably are done with your flu season in Australia — but we’re just gearing up for it. I wonder if all of the same kind of system of surveillance and worrying about new variants also applies to flu.

Edward Holmes: Yes, it does. Yeah, we’ve had our flu season here in Australia, a very low flu season. Last year was even lower I think, so globally, we’ve had a suppression of flu, partly because of the population lockdown measures that have taken place and lack of travel. With flu, the key issue is that we have a vaccine, as we all know, which everyone should take, and that vaccine is... The virus evolves, again, like coronaviruses, continually. And as it evolves globally each year, it picks up mutations in the hemagglutinin protein. It’s kind of the equivalent of the spike protein of influenza viruses, kind of surface protein that kind of interacts with a host cell. The virus, every year, it picks up mutations in there, and occasionally, those mutations allow it to evade the immunity in the population, rather like we think the beta variant of SARS-CoV-2 may have done.

Edward Holmes: So what people do with flu, there’s a kind of global network of surveillance laboratories, that monitor the spread of these flu viruses, to see, can you see new variants coming that are antigenically different, that might cause immune escape. That’s critically important, because in flu what happens is they make a vaccine. They update the vaccines every so often, and they’re scanning for these mutations that they might need to make the vaccine. And the vaccines are made in chicken eggs, so we’ve basically got to take these viruses and grow them in these chicken eggs, to get enough vaccine to produce.

The problem is, that takes sort of six months to do that process, from identifying the strain to producing the vaccine. So they have to predict, six months in advance, which strain is going to be the one they’ll need for the forthcoming vaccine. So every year, there’s a meeting in the Northern Hemisphere and the Southern Hemisphere, to see what... They monitor the strains and those variations, in those regions, for each strains, to see what ones are dominant, to then predict what they need for their vaccine six months later.

For Covid, for SARS-CoV-2, the question is will we do the same thing? We’ve got two options. One is we try and predict what’s going to happen, rather like flu, so we monitor, we make some predictions and, “I think the virus is going to do this,” and then make our vaccines. That’s one way we could do it. The other way, which I think is actually more realistic, is that we have a really good network of sequence surveillance now, globally, which we can discuss that shortly. We need to kind of improve that, a global sequence surveillance network, that watches these variants appear, and then rather than just trying to predict it six months in advance, we try and make the vaccine as quick as we possibly can, and some of the biotech companies are saying now, if they found a new variant that was an immune escape variation, variant, they can actually make, design, and test the vaccine in 100 days. That’s their kind of timeframe to do that.

So, hopefully, the Covid, our way of... And I think the vaccine companies are testing on the variants that we have at the moment, so for the future, the way is we need to build some surveillance, rather than like flu, so we can kind of track the immune escape mutations if they appear, and then hopefully quickly design vaccines.

Eva Emerson: Lisa, I wondered, when you’re evaluating delta, are you looking at how well the vaccines are still working? Maybe you could just describe how you’re doing that.

Lisa Gralinski: Sure. In the laboratory, we will get serum from participants in the different vaccine trials, or sometimes from volunteers for different studies, and then we do what’s called neutralization assays in the laboratory. We do this with live virus, and we dilute the sera from different patients in known concentrations across a 96-well plate, so if you imagine a laboratory worker just moving through stacks of 96-well plates and wishing they had a robot to do it, that is where we’re at right now. We’re trying to get more automated.

But what we’re looking for is to see if the sera from these people who have been vaccinated is able to block replication of the virus, and we do this one of two ways, either with a virus that encodes a protein called luciferase, which glows really brightly. In that case, we can look for the brightness, or hopefully the absence of brightness, after a serum has been incubated with these cells in the virus, looking to see if there’s a change in replication. Or you can look actually, microscopically, and try and see, have the cells actually been infected and been destroyed, looking at what we call cytopathic effect, or CPE, to assess if the sera was able to protect these cells, whether it was able to bind to the virus and stop it from replicating.

These are really standard assays that are done for all sorts of different viruses, so they were techniques that we had in the laboratory before the Covid-19 pandemic started, and then we ramped them up. So we’ll do this type of assay with the original Wuhan, and then summer of 2020, there was a lot of fuss about a D614G virus that swept the globe, but didn’t really change things too much, so we have that virus, and then we have alpha, beta, delta. I don’t think gamma is as much of a concern these days, but we’ll look with all of these different variants, to assess and say is the serum from the person who is vaccinated with a strain matching the original Wuhan isolate able to still recognize all of these different viruses? And so far, generally speaking, the answer is that it recognizes and blocks quite well. The only significant outlier has been beta, but that hasn’t taken off globally. It didn’t have the transmission advantage, so delta has out-competed it, and that’s really the one that all of us are at risk for right now.

Eva Emerson: Thanks, Lisa.

Edward Holmes: Can I add a point?

Eva Emerson: Yes.

Edward Holmes: Great. Yeah, what I think Lisa’s doing is the kind of second step, the critical step, because that’s assessing these viruses for their different immune escape behavior. Prior to that, we need to do this kind of global surveillance of genomics, to see what strains are spreading. If you actually look at the pandemic as a whole, one of the great things that’s happened is the science of viral genomics has really come of age. It’s quite extraordinary. We now have... Talking to us now, we have something like 5 million-plus genome sequences of SARS-CoV-2, 5 million, which is just extraordinary. That’s it, there is lots of sequencing being done, but the problem is, that sequencing is very much localized to particular countries. The USA, as you might expect, and the UK particularly, have done the bulk of the genomic surveillance of the virus, which is great, but what that means is there are patchy... There are gaps in our global surveillance of the virus. Some countries are just far less well surveyed for virus genomically.

So, one slight concern… a major concern is that we may miss a new variant for a while, because it appears in a place where the genomic sequencing surveillance is not quite at the capacities as in some nations. Going forward, a critical thing to do is to enhance this kind of global sort of genomic surveillance, like we do for flu, but probably more so, to try and really track, in real time, how these variants are spreading, because if one then does start to spread genomically, we can track it, we can isolate it, and then people like Lisa, in the laboratory, can then really do some very careful analytical work, say, “OK, this virus really is going to be a problem. We need to update the vaccines now.” It’s a kind of multistep process in doing this.

Lisa Gralinski: I just want to say I can’t agree with that too much at all. Like, I agree so heavily, that everything that we talk about in terms of vaccines and treatments all comes down to knowing what’s happening with the virus in as close to real time as possible, and that means testing and that means sequencing. Without that working at high capacity globally, almost nothing else we do is going to have a fighting chance of intervening in this pandemic.

Edward Holmes: And the good thing is, we have, the whole landscape of how we sequence viruses and analyze them in real time globally has changed with Covid. It’s a completely new game now. So that’s actually worked very well, and like I said, there’s just some gaps in where surveillance is taking place and may need to be filled. But I think we have the tools in place to respond very, very quickly, if this thing does come up.

Eva Emerson: Eddie, is that a matter of kind of developing the capability in places? I mean, obviously, there’s a lot of really great labs in the US, the UK, the government’s kind of sponsoring a lot of genomic surveillance. Is there any movement to push kind of for local capacity to do that?

Edward Holmes: Yeah. And I think that’s, you’ve hit the nail on the head there. I think the technology’s actually very straightforward now. The cost is actually not that much. I mean, the UK did not actually need to invest an awful lot of money to make them one of the world’s leading Covid genomics countries. It’s actually pretty cheap, relatively. The problem is, is infrastructure and training in locations, so it’s capacity building in countries that are kind of low income, low resources, that may not do this on a regular basis. That’s the critical thing.

And the great thing is, if we can do it, if we can do that capacity building, that training, the infrastructure — there’s also kind of IP issues to deal with as well —if we can do that in places, lower-income countries, not only will that help protect us against Covid. It will help protect against the next pandemic. I think we’re at a really key moment here, that if we do invest in this globally, we can really do a... We can help protect our species from whatever may appear next.

Eva Emerson: Eddie, beyond delta, are there any other SARS-CoV-2 variants — and, Lisa, feel free to jump in too — that are out there right now that you’re concerned about?

Edward Holmes: No, not in particular. I think what we’re seeing now, and people shouldn’t get complacent, is we’re at a little bit of an evolutionary respite. Because delta’s kind of swept the world. It’s taken over, and that’s the one that’s kind of dominant. We all know about delta. I actually called it Pandemic 2.0, because it was like a completely new thing almost. It was so much more infectious. So we’re in a little bit of a respite, but the virus is continually... As we’re talking, the virus is evolving. Mutations are happening every day, there are variations being generated, mutations are being produced. Some of those may enhance fitness, so it’s an absolute racing certainty that we will get new variants in the near future. It’s going to happen. That’s what viruses do, and I think it’s a racing certainty also, that some of these variants will ultimately evade aspects of immunity. Beta showed, Lisa mentioned beta was the one that was kind of most antigenically diverse. The virus has the capacity to make those. So it will happen. When? Who knows, but it’s a racing certainty that that will take place at some point. The critical thing now is we’re able to track them when they do appear quickly, do the necessary lab tests quickly, and then redesign the vaccines quickly.

Eva Emerson: Lisa, you said a scientist initially made some assumptions about SARS-CoV-2 based on SARS1, that later turned out to be a bit wrong. What’s different about SARS and SARS-CoV-2?

Lisa Gralinski: The viruses are really quite similar on a nucleotide level. If we compare the sequences, they’re both coronaviruses. They have about 30,000 nucleotides. They’re RNA viruses. The structure is quite similar. But there are some really critical changes. A lot of them are in that spike protein, which is, as we mentioned, what allows the virus to attach to the host receptor, bind to cells, and enter them for infection. One thing that’s really striking about SARS-CoV-2 is that it’s very much a generalist. It’s able to recognize the ACE2 protein on many, many species. We’ve heard a lot over the past year-and-a-half about cats being infected, or somebody’s pet dog being infected, or gorillas in the zoo being infected, or I think recently, we had some tigers die at a zoo somewhere in the United States.

We didn’t hear about that type of thing with the original SARS-CoV, back in 2002 and 2003. SARS-CoV-2 binds more tightly to the ACE2 receptor. It’s really good at replicating in the upper respiratory tract, which is part of why it’s also really good at spreading to other people. With original SARS-CoV, it didn’t bind as tightly. It tended to cause more severe disease, which was really easy to identify in those people who had been infected, which let us isolate them, do contact tracing, and really stop that epidemic through basic public health measures, which SARS-CoV-2, since it so frequently causes a more mild disease, just in the upper respiratory tract tissues, we’re not able to do that.

We also assumed, based on SARS-CoV and MERS-CoV, both of which caused really obvious, severe infections in the majority of people, that it would be the same type of thing with SARS-CoV-2, and it’s not. Instead, we had a lot of asymptomatic people. We had people who are transmitting when they’re asymptomatic or presymptomatic, and that wasn’t something that had been observed with these highly pathogenic human coronaviruses before.

So while we had a lot of knowledge from these previous viruses, laboratories that were set up doing this type of high-containment research, that had animal systems in place, had cell culture systems in place, and were ready to go. And a lot of that is what allowed the vaccines to be produced so quickly, so our previous knowledge gave us a giant head start, but it also allowed for a couple of, I think, critical misconceptions that tricked a lot of us at the beginning of what we now know as the Covid-19 pandemic, where we weren’t concerned about the asymptomatic infection possibility.

We weren’t really thinking as much about presymptomatic transmission as we should have been, and hindsight is 20-20. If I could have told, 20 or 22 months ago, public health officials that this was going to be a problem, I would love to be able to do that, but we just didn’t know yet, because this, while similar to viruses that we had encountered before, is also a totally unique beast, and something that we just needed time to learn about.

Eva Emerson: Eddie, I wonder if you could tell us a little bit about your experience right at the beginning, in January 2020. Were you surprised? Maybe just tell us about that experience of sequencing, helping to sequence that initial version, and that you’d already been working with bat coronaviruses?

Edward Holmes: Well, we’d been working with... I had a long collaboration, I still do, with people in China. Professor Yong-Zhen Zhang is in Fudan. What we normally do, we’re interested in actually virus evolution and ecology more than anything else, so we were actually sequencing viruses from everything, shrimps, worms, fish, you know? Mainly non-mammals actually, and occasionally some mammals. So we had this going on, and in particularly in Wuhan, we sampled a lot around... I’ve been to Wuhan a few times. We sampled around Hubei Province, around Wuhan, and animals, and also by complete coincidence, we actually had a project in Wuhan’s central hospital. That’s the one you’ve seen in your TV screens at the start of last year. It’s kind of the big one of the epicenters for the outbreak.

We had a project prior to Covid, looking at people who were being, going into hospital with pneumonia and acute respiratory disease. That was the kind of syndrome they had. And of course, SARS, and Covid is very much like... is pneumonia, acute respiratory disease. So we were looking at these patients, and using our genomic technology to work out what microbes were giving them pneumonia and acute respiratory disease. Is it viruses, bacteria, fungi, parasites, whatever.

We were doing that, and we were taking this what’s called a lung wash, or the technical name’s a bronchoalveolar lavage sample, so kind of deep lung sample, sequence them to see what kind of microbes were causing this disease. We were in the right place, using the right technique on the right sample and the right patients, at the right time, or actually a little bit before Covid. So when the first Covid patients came into that hospital, Professor Zhang was one of the first people to get the samples.

When he first sequenced it, he called me on the 5th of January. In fact, he emailed me and said, “Please call me immediately,” so I called him back, and we were sort of chatting about this. We looked at... They’d just done the first sequence. We had a quick evolutionary tree. It looked just like SARS. It was very close to SARS. It was obvious at that point, and in January 2020, there weren’t all these other viruses... We didn’t have a whole bunch of bat viruses and pangolin viruses to compare it to. They weren’t really there at the time, so it looked even kind of closer to SARS1.

The assumption was, as Lisa mentioned, that this was really very much like SARS1. It was obvious to us that this was going to be a respiratory pathogen, absolutely blindingly obvious, because coronaviruses are respiratory, and it was like SARS1. So Professor Zhang wrote to the ministry of health in China on January 5th, the day that we sequenced the virus, and he said, “This is a respiratory infection. It’s like SARS1. People should take precautions.” Because it was obvious to us this was going to be a problem.

What the assumption was made, and I mean, Lisa’s already touched on this, is that because it was like SARS1, the assumption I think that was going around was it’s going to be... We can deal with this in the same way that we dealt with SARS1, and that based on the fact that people would only transmit when they were symptomatic. So you could actually quite easily spot someone who was infected. You could kind of ring fence those people, quarantine them, and that’ll be enough to shut down the next set of transmissions. That was the kind of assumption that was made.

And of course initially, I think they actually didn’t even... It took a long time in China to actually agree that there was actually human-to-human transmission. I think that was actually quite obvious from the sequence data. The assumption was that if there was human transmission, it was only through symptomatic transmission. It turned out that was the wrong call. I think it was understandable, and again, Lisa’s already mentioned the benefit of hindsight, but clearly, the big difference is this virus is much more infectious, and is much more able to transmit between this asymptomatic route, this silent spread. It’s actually kind of the worst nightmare if you’re in infectious disease control.

You know, it’s very hard to kind of judge this. There were missteps made. Clearly, I think there were some mistakes made. I think some of those were kind of reasonable, based on prior assumptions and what the virus looked like, and the others were more questionable. They’ve been discussed already. It was a very difficult time.

Eva Emerson: Thanks, Eddie. I guess the question is, are we going to be prepared for a SARS-CoV-3, and will there be a SARS-CoV-3, or a MERS2,? If either of you, if both of you want to answer that? Lisa, why don’t you start?

Lisa Gralinski: I could jump in to start, yeah. I think we would be incredibly naïve at this point to assume that this is the last emerging human coronavirus that we will see. We had SARS-CoV in 2002, 2003. Then we found out about MERS in 2012, and then the very end of 2019, SARS-CoV-2 emerges. Something could happen once by a fluke, but after MERS happened, within the lab we would talk to each other sometimes and be like, “Well, if it’s happened twice, it’s inevitably going to happen a third time.” We never in a million years would have guessed that it would lead to the situation that we’re in right now. We thought maybe another MERS, something that doesn’t transmit that well, but that pops up and reminds people that coronaviruses are important emerging pathogens that we need to have surveillance for and be prepared for.

But I think, unfortunately, there will definitely be a fourth, and a fifth, and hopefully not too much beyond that emerging human coronavirus, that we need to watch out for, that’s going to be really important for public health, and for doctors and surveillance people to be aware of. I think that’s part of why it’s really important for research to push in the direction of universal coronavirus vaccines, or making drugs that are as broad spectrum as possible, so that we are better prepared for when something like this happens again.

You know, we see flu evolving constantly, and we also have more exotic avian flus, or swine flu, even though now we know it didn’t really come from swine, that make their way into people, and so we’re constantly monitoring and preparing for that type of event with influenza viruses, and coronaviruses are going to be in the same type of situation, where we need constant surveillance, constant preparedness, and we need to be ready for something like this to happen again, because humans and animals are in such close contact now, in regions of the world where we know a lot of these viruses are constantly circulating, in bat species in particular, so it’s really just a matter of time and our awareness for when the next human coronavirus is discovered, I think.

Eva Emerson: Eddie, do you have anything to add?

Edward Holmes: Yeah, no, I completely agree. Whatever you think about the origin of this virus, I mean, it’s a very controversial topic that we won’t get into, but whatever you think about the origin of this virus, we are set. Nature is armed and ready with more of these viruses. That’s absolutely clear, and we can’t ever not think about that. Give you two very quick examples. Just recently, a paper was published. It’s actually online, not peer-reviewed, and they sampled, a team sampled-

Eva Emerson: Eddie, that’s in bioRxiv, right?

Edward Holmes: Yes, in bioRxiv. Yeah.

Eva Emerson: BioRxiv?

Edward Holmes: Actually, no. This is the first one I’m going to talk about. This is actually on ResearchGate, which I think is a Nature prepublication service. This is from a team from Laos, in Southeast Asia. What they did in this particular virus paper was they surveyed these Rhinolophus bats, these horseshoe bats, which are the kind of main bat genus we know carries SARS-like viruses, and they surveyed these bat viruses from Laos, and they contain a lot of viruses that are very close to SARS-CoV-2. In fact, the closest viruses we’ve sampled to date to SARS-CoV-2 in animals come from these bats in Laos.

And the amazing thing is, in the receptor binding domain, which is like the functional core of the virus, if you think of the cell as a kind of lock and the virus as the key. The key has to go into the lock. The kind of tip of the key, the kind of mechanism of the key, that’s receptor binding domain. That receptor binding domain in these bat viruses from Laos is almost identical to the human virus, and it binds to the human ACE2 receptor. Lisa’s already mentioned the host receptor. So this virus in animals is ready to go. It’s locked and loaded, ready to infect humans, and it’s there in nature. That’s the first thing.

The second thing, this is a paper on bioRxiv that was recently posted just a few days ago. I’m an author on this, where with some collaborators in China, they’ve gone to the breeding centers that breed the wildlife, the wildlife farms, that then source these live-animal markets in China. Everyone’s seen on the web, these menu boards, these famous animal menu boards outside markets, like the one in Wuhan, the Huanan market, just selling various wildlife. You’ve got hedgehogs, and porcupines, and marmots, and whatever.

What they’ve done, they’ve gone and sourced the animals that stock these markets, and they’ve surveyed them for viruses, and they contain lots of viruses. And some of these animals are sick. They have respiratory viruses, and they have viruses that are jumping species boundaries, and viruses that could potentially infect humans. So, this wildlife trade, this ecology that’s out there, is full of these viruses, and we are now, humans are now part of the ecology, because we have animal markets, the wildlife trade, all the way humans change their behavior, deforestation. We are putting ourselves in this ecosystem, and we will get more. It’s absolutely clear.

The viruses are there. We’re exposed to them. Are we ready for the next one? You know, I’m kind of... I have good days and bad days about this. And certainly there’s been a lot of talk about improving things. There are two or three things we can do. One, as Lisa’s already mentioned, I mean, this is like the Apollo Project for virology, right? Is we need to have cross-broad-acting vaccines and antivirus, absolutely critical. To date, sadly, the funding in this has been very slim. Look at broad universal flu vaccines, recognize all flu strains, very little funding. Very small number of small groups doing it. That needs to be massively expanded, to get more people involved in making these universal vaccine antivirus. That’s the kind of key thing.

Second thing, which is actually easier, I think, is this kind of global radar system or surveillance system, where we track, globally, in a much more integrated, holistic, open sharing manner, what’s out there, what’s emerging, what outbreaks are going. And everyone’s told immediately that this is going to happen. There’s been talk about this. It was discussed at the G7 conference in the UK a few months ago. The WHO built a new center, I think in Berlin, to kind of help coordinate this. But at the moment, I don’t think that mechanism actually exists, but it’s absolutely critical. I think the technology’s actually quite straightforward. That can be done. The money is expensive, but in the great scheme of things, I think it’s not that expensive. There are IP issues, ethical issues, and most of all, I think there’s political issues now. It really means that countries need to take part in this, and be willing to share their data immediately, globally, openly and freely.

To me, of all the things we can do, that, to me, is the No. 1 thing. If you have an outbreak and you don’t tell anyone, whatever you do is kind of pointless. The world has to learn from Covid. Again, noises are being made, but I want to see action.

Eva Emerson: That’s a great place. Let’s stop right now and take some questions from the audience. They’ve been coming in. I think a lot of people are wondering about the vaccine. A, when do we know to change the current Covid vaccines we have, how would we make a universal vaccine, and does the new mRNA technology that’s been successful with the Pfizer-BioNTech and Moderna, is that something we could apply to flu, so we don’t have the eggs that take six months?

Lisa Gralinski: Absolutely. There’s a lot of work being done right now I know, by Moderna in particular, but also lots of other companies, trying to develop a kind of double-hit vaccine, thinking that maybe each fall, you would get one shot that contains half vaccine that’s targeting that year’s flu and half vaccine that is a booster for your SARS-CoV-2 to prevent people from becoming part of the Covid-19 pandemic.

The mRNA technology has really, really taken off. The companies that have used it have shown that you can respond really rapidly to take the sequence information and turn that into a vaccine that gets to production quite quickly. It’s really rapid to update. It’s a newer technology, so not as many countries are poised to take off with this immediately, but a lot of people are devoting resources, in the US and Europe definitely, but also in India, and there’s been a lot of discussion about the need to get some factories that are going to have the technology and have the ability to respond in at least a couple of African nations, so that we’re not forgetting about the entire global south when we’re talking about rapidly vaccinating the world for Covid-19 or some future outbreak that we need to deal with.

For surveillance, thinking about variants and do we need to retarget the vaccine? So far, the original Wuhan sequences are a really good match, and provide great protection for the delta variant, but that’s part of what surveillance is for. When people were worried that beta might become dominant, Moderna, Pfizer were definitely starting trials updating their sequences that they were using, of that spike protein, to generate a more specific immune response to that variant, but because that didn’t take off and become the globally dominant variant, I think those trials are more kind of an academic proof of principle at this point. No one’s really seriously thinking about updating the vaccine to give us all a booster against the beta variant that isn’t so much of a concern anymore. But future updates, as Eddie was discussing, happen for the flu vaccine annually. That’s something that we might be thinking about for Covid-19 going forward.

Eva Emerson: Eddie, I saw you kind of make a face when I mentioned how can we make a universal vaccine.

Edward Holmes: Oh, no, look. It needs to be done, and we need to invest heavily in research to do this. I can’t think of a more important project quite frankly. It’s absolutely critical. Just to follow up on what Lisa said, I think one of the great... You look at the good things and bad things happening with Covid, one of the good things has clearly been mRNA vaccines. Quite extraordinary. I mean, amazing development, technology. One of the bad things, though, at the same time, is Covid’s revealed the lack of surge capacity in vaccine production. I think many countries have been reliant on a small number of countries that produce their vaccines. The US is very lucky, and it’s got extraordinary capability to produce vaccines.

Poorer countries don’t have that. If you actually look at the map of vaccine dose usage uptake globally, you’ll see Africa, there’s hardly any. And it’s partly because there’s no production going on. Even in Australia, we don’t produce that many vaccines. So critically, another thing we need to do is build much more capacity to produce vaccines globally, and clearly investing in mRNA technologies is the key thing to do.

As Lisa said, at the moment, the good news is that all the vaccines that are currently commonly used recognize delta, so that’s kind of we’re in a good place. What we clearly need to do is just keep the surveillance going, and then what we’re looking for, I think, is a reduction in neutralization titer, so how well the virus is protected, by about tenfold. Once you get to that level, that’s where you want to be at. Kind of that’s what flu tells us. That’s when you want to be into updating the vaccine strain. We haven’t got there yet with delta, thankfully. That’s good, but it’s all about keeping the surveillance going. And the vaccine, as Lisa mentioned also, what they’re already doing now is kind of testing, can they quickly... If a variant did come up, can they quickly tweak, tweak their vaccines and make enough, get it through the approval process, which is a long thing now, to get it out there? That’s what’s being, kind of the trial runs are going. And hopefully, and again, I’m pretty optimistic about this, that if something did come up, we would be able to pivot to a new vaccine, an updated vaccine pretty quickly.

Lisa Gralinski: I agree. I just want to go back to that universal vaccine point really quickly. When Eddie was talking before and describing kind of the lock-and-key situation, where you have the spike protein and the human receptor, ACE2, most of the vaccines so far are really targeting that receptor binding domain, and what we’ve learned through studies in the lab over the last year is that there are regions on the stem or the stalk structure that are more conserved between different coronaviruses. They’re not the most obvious region to target with antibodies, but some of them are actually quite highly conserved, and if you get an antibody that recognizes the right region, then it can block original SARS, SARS2 and some of these bat viruses. So what we’re trying to do in the laboratory now is develop vaccines that will elicit this type of antibody response, and then they might be more broadly protective. That’s one of the approaches that’s being taken, as we learn more about the structure of this virus, and more the molecular details, but that was not the type of thing that was going to be a first approach for a vaccine platform at all.

Edward Holmes: And that’s a similar approach for universal flu vaccines as well, actually, looking for these conserved domains that are not the normal ones you think about.

Eva Emerson: One of the questions is how does the number of unvaccinated people affect the changing and spreading of Covid variants? I think we know the answer, but maybe you could just address that question.

Edward Holmes: Shall I have a go? It’s actually really a complicated answer to that, actually, so forgive me. There are kind of two conflicting things going on. Places that are unvaccinated will have high levels of transmission, obviously, because there’s no immune protections. The virus has kind of got a free for all, off it goes. So in the unvaccinated situations, lots of transmission, lots of diversity, lots of mutations are being made. That’s going to happen. It’s like the kind of engine room revolution that’s going to happen.

However, because people are not vaccinated, there won’t be selection to evade the vaccine, or evade immunity, because people are not immune. In other places that are vaccinated, although there’s lower transmission, less transmission, because there’s fewer cases, therefore less diversity’s being produced, the selection’s going to be stronger, because people are vaccinated. So any variant that does come up will be challenged by evolution to escape that immune pressure. And they’re the ones that eventually, we need to worry about, because they’ll be the ones that will evade immunity, evade vaccines, and then spread globally.

So, there kind of it’s a very complicated mix. You’ve got one, the unvaccinated. That’s kind of like producing diversity. That’s the engine of diversity, and the vaccinated, that’s going to be where the selection’s going to be strongest. And how they kind of interplay is a very complicated thing that will need some complicated modeling. It’s a little bit out of my pay grade, actually, I would say.

Eva Emerson: I think that relates to one question here, from who asked about the situation in Israel, where it’s highly vaccinated but there’s still spread, and they compare this, and I don’t know what this is, but is this like what researchers have seen with Marek’s disease in chickens?

Edward Holmes: Do you want to go? Do you want to? I know the Marek’s disease example.

Lisa Gralinski: OK, because I don’t. I was only going to be able to comment on Israel.

Edward Holmes: I think the situation in a lot of countries that vaccinated early on is you are seeing waning immunity, which is completely expected, right? If you vaccinated very early in 2020, as Israel did and the UK did for example, what you’re now seeing is after six to eight months, immunity starts to wane. That’s going to increase the rate of transmission, because you’re not protected, so they need to have booster shots. That process is absolutely standard to happen. What’s not going on, I don’t think, is the virus is evolving necessarily to get around the vaccines in places like Israel. It’s more that immunity is declining rather than viruses evolving.

The Marek’s disease case story in chickens, for those that don’t know it, it’s actually very interesting. The idea there was that the virus has increased in virulence through time. Over decades, it’s got worse and worse and worse. The idea is what’s driven that increase in virulence is actually that the vaccination is not that good. The first vaccine they gave the chickens against the virus in fact didn’t protect it sufficiently, and it allowed the virus to kind of get past it and infect the chickens, and that selection to get past the vaccine actually increased the virulence of the virus. They then updated the vaccine, and did the thing again, and again, the vaccine wasn’t perfect, and the virus kind of got through, but it increased in virulence again. So there’s been a trajectory of increased virulence driven by not particularly good vaccination.

Now, before everyone kind of panics, that’s like the one really good example of that process happening. Generally, that hasn’t happened. It’s a kind of interesting bit of evolutionary story. It’s a fascinating story. We can learn a lot from it, but it stands out on its own at the moment, so there’s no particular need to worry about that.

Lisa Gralinski: Yeah, that is a little bit of a horror story, but there’s also... This virus has a lot of capacity to change. It has a lot of coding sequence. There are numerous sites in that receptor binding domain that are important for contact to the receptor, but there’s also a limit to how much the virus can evolve. We have really outstanding vaccines that offer amazing protection, at least shortly after you’ve been vaccinated. Six, eight months, waning immunity does start to become a little bit of an issue, but if we get people well vaccinated, even if we have to update the vaccine, eventually the virus will reach a dead end, where it’s no longer able to bind to the human receptor, if we push it too far, is at least the theory and what we’re able to do in the laboratory, if we go in with multiple vaccines, or if we take multiple monoclonal antibodies, and we can drive the virus in one direction, and then we can drive it in another direction, and then it all kind of dies off. So hopefully, we would be able to do something like that, even worst-case scenario in humans, and block this pandemic.

Edward Holmes: If I could make a general point here, let’s not worry about the virus evolving. It’s going to evolve. Whatever we do, it’s going to evolve, right? If we think we can kind of manage how the virus evolves, I think we’re deluded. Whatever we do, whatever vaccine we do, whatever treatment we do, it’s going to evolve. So let’s not worry about that. Let’s just try and get the best protection we can of our population, and the vaccines do a fantastic... These are great vaccines. They do a fantastic job, particularly in reducing severe disease. That needs to be our mantra from now on. It’s not the number of cases that I’m particularly bothered by. This is an endemic virus now. It’s not going away. It’s the number of people in hospital and dying of the virus that we need to worry about. And the vaccines do a brilliant job at reducing that number. That needs to be our focus. The virus is going to evolve. You know, whatever. Let’s get our populations, globally, not just the US, not just Australia, but globally, because there are millions of people who’ve got no access to vaccines at all at the moment. Let’s get their immunity up and reduce the death toll of this virus.

Lisa Gralinski: Absolutely. Evolution is going to happen, but what we’ve seen in highly vaccinated countries is that we’ve broken the link between surges in cases and surges in hospitalizations, and that is incredibly critical for going forward, having a semi-return to what we remember as a normal-ish life, and being able to push through this and not be in lockdown all the time.

Eva Emerson: Ah, well that’s... I have so many more questions, but our time is up unfortunately, and I just want to thank Lisa and Eddie again, for sharing an hour with us. That was so interesting. I want to thank everyone in the audience for tuning in. If you’re enjoying the event and want to join future ones, please be sure to sign up for the Knowable newsletter. The link should be in the chat, and to follow us on Facebook and Twitter. Both these links are in the chat as well. We offer this event for free thanks to philanthropic support, and if you would like to support us, please head to Thanks again. I think the only other thing I need to say is that our next event will be in January. You can sign up for a spot. This recording will be available on the Knowable Magazine website very shortly, and thanks to the Alfred P. Sloan Foundation, the Gordon & Betty Moore Foundation, and Annual Reviews for the wonderful support of Knowable Magazine. Our mission is to make high-quality science coverage freely accessible to all. Thanks again for joining us.