Have a long post on the variants in the main COVID thread last night. I would argue that whether or not this virus becomes endemic is an open question. If enough people get vaccinated before the virus mutates enough, via antigenic drift, to "escape" the vaccine, then transmission rates could go to zero and the virus could be stamped out (this would need to happen worldwide, though), like SARS/MERS were. Length of immunity/effectiveness of the vaccines (and infection/immunity) is also key here.
I don't think anyone knows, though, how quickly we can get transmission rates to be very low, and when/if the virus will mutate enough to render the current vaccines ineffective. It's doubtful that happens in the next year, though, which will hopefully give us enough time to get transmission rates to very low levels. Also, at least with the mRNA vaccines, they're easy to "retool" to provide efficacy against a virus mutated enough to escape the current vaccines (would take a month or two), which might allow us to keep ahead of new variants. Much of this was discussed in the post below, with the ScienceMag article being a very good one on this.
A New Problem: Virus Variants
Topol: Now we have a new problem, not that we've gotten this virus squashed in any respect outside of countries like yours, continents like yours. This variant in the United Kingdom — not necessarily born in the United Kingdom — but this B117 variant has cropped up in recent weeks. It's led to a big surge in spread, not only in parts of the United Kingdom; I understand that there's at least one case in Australia, the Netherlands, Italy, and Denmark. It's gotten around a bit. Obviously, there may be other countries that aren't doing sequencing that may have it there. In the United States, we haven't seen that yet or the South African variant, N501Y, which seems to have some thread as far as an important spike mutation. [Editor's note: A patient with the B117 variant was identified in the United States after this interview was recorded.]
What's your sense about this? Where are we headed now?
Holmes: It's obviously the question of the moment. I'm not directly involved in the UK works. I'm seeing it kind of secondhand. From the body of data that I've seen, there are definitely concerns here. I think there are a number of things that are acting as the links in the chain.
We start with the epidemiology. As you've mentioned, this variant does appear to be growing very rapidly in the United Kingdom. That's not just because the south of England had fewer restrictions, because if that was the case, then all the variants would increase in frequency. It's a particular variant, one lineage, that's increasing compared with any others. It's growing quite, quite quickly. The same appears to be true in South Africa. It's a different lineage, but it has at least one of the same mutations. That's a worry.
The second is they're reporting now that the virus has evidence of a higher viral load of infection, measured by lower-on-average cycle threshold (Ct) values and more sequence reads on sequencing. That's saying there's more virus, which would explain the faster growth rate.
If you boil down to the actual biology, the virus, as you mentioned, has this mutation in amino acid 501 in the spike protein in the receptor binding domain, which is one that we'd already flagged as being a really key site. Other labs have shown that this mutation is critical for receptor binding. That's the same mutation that's come in South Africa as well. That would be the molecular explanation for the higher viral load, which then explains the growth rates. All those things move together.
I think what they felt they had to do in the United Kingdom, because they've had a very difficult epidemic, was to act sooner rather than later. Even though not all of the I's have been dotted and the T's crossed on the biology of this virus, it's important to act now to stop it spreading. That was what made the UK government do what it did.
Obviously, we're still waiting a little bit on complete functional characterization. We want to know exactly what's going on. I think the interesting thing about South Africa and the United Kingdom is that it's not just this one mutation — the amino acid 501 change; it's that those lineages have a huge number of changes compared with other ones, which is really fascinating.
There's one suggestion that makes a lot of sense, which is that they evolved in somebody who may be immunocompromised, because you have chronic infection for a much longer time in a single individual. You have a partial kind of immune response there. Maybe that's allowed this virus to evolve and select in an unusual way. It's a very unique set of selective pressures on the virus in a patient like that that's led to these changes. That's not proven by any means at all, but it's an interesting theory.
Topol: There have been a few cases of immunocompromised patients in which they showed rapid evolution, so your point there is well taken.
The other question, Eddie, is that in the United States, convalescent plasma is being used highly without the evidence in hundreds of thousands of people. Could that also lead to more evolution of the virus?
Holmes: I think it depends on the number of people being used relative to the proportion of the population. Selection is kind of a numbers game. There needs to be selection pressure for the virus to evolve in that way. If most people in the population are using convalescent plasma, then you see a selection pressure. If it's only a small proportion, I don't think it would select that much.
This case is different, though, because it's in a single individual. A single patient has a chronic infection with a lot of viral replication. So you're replicating a whole population's worth of evolution in a single patient. That's why it's so unusual. As you mentioned, in some other SARS-CoV-2 cases within immunocompromised hosts, you see mutations, as you also do in norovirus infections and influenza virus infections. I've seen it in my past work. It's certainly a very interesting theory.
This current variant, we need to monitor it closely. We need to see more on the basic functional biology. We need to see how the vaccines will cope with this. That is a key question. That work is being done at the moment in the United Kingdom, I think, and fingers crossed that the vaccines are still going to be tip-top. If they are, we can breathe a small sigh of relief, I think.
A Need for Booster Shots in the Future
Topol: Let's say the virus variant is not a problem for this vaccine, but it shows you that while the virus was so slow in evolving in terms of any meaningful functional variant except for this D614G, that became the dominant one. Now we have a different look at this virus.
Does that make you think that even if the current vaccines hold up well, we're going to be looking at booster shots adjusted to the continued evolution of the virus for the years ahead?
Holmes: That's a great question. We need to think about evolution in different phases. During the first phase, basically most of this year, what you've had is a virus spreading in a population where there's no immunity. That's been the key marker of this outbreak, really, because everyone is susceptible. In those circumstances, there's no immune selection pressure on the virus whatsoever. Any lineage can find a susceptible host to infect; it's actually really easy. The virus spreads, and it just infects people. It's kind of a free-for-all.
As immunity rises in the population, hopefully by vaccination — although some countries, such as the United States and the United Kingdom, are really trying hard to do this without vaccination — as immunity rises in the population, that's going to change the selective landscape.
You will see that the virus will evolve away from that. I think that's an absolute certainty. Now, it does evolve a little bit more slowly than some RNA viruses — maybe three times more slowly than the influenza virus. It's not an abnormally low rate of evolution; it's actually pretty average, but lower than flu.
My guess is that as immunity rises in the population, hopefully by vaccination, you will start to see immune escape gradually. That will happen. That's an inevitable consequence of natural selection. It's been played out for millennia, and it's going to happen again. We will very likely need to update these vaccines at some point. That may take 2 years or 5 years or 1 year; I don't know.
To me, it's a racing certainty that immune selection pressure is going to push the virus in a certain way. You'll probably start to see more direct evolution than you have done in the past, because now it's harder for the virus to find a susceptible host because people are immune. Only the fittest strain is going to make it through, and that fitness is going to depend on a particular antigenic configuration.
Rising immunity will completely change selection pressure. I think it'll become even more seasonal, too. Early on, the virus didn't need to be seasonal because everyone was certainly susceptible to any lineage at any time. As immunity rises and susceptible persons become fewer in the population, the right kinds of conditions for spread become more important. The virus will change in its behavior because of rising immunity.
Topol: This is a central point you're making, in that the race toward population-level herd immunity, vaccine-induced, is countered by the virus evolving. We're not seeing the end of this virus just because you get 80% of the world vaccinated. This is an endemic story, would you say?
Holmes: I would put money on this being an endemic respiratory virus. Absolutely. Even if we rolled out the best vaccine coverage program ever, we're not going to vaccinate everybody. We can't do it simultaneously. The virus will evolve fast enough to keep itself going, and they'll reenter the susceptible class. I think it's endemic. Absolutely.
Topol: Well, that's exciting, isn't it? It's kind of interesting to speak to a leading evolutionary virologist because you get a different perspective about it. This is what you spend your whole life on, and you really understand the context of what we're looking at right now.
Holmes: It's also thinking comparatively. Talking about evolution, I work on many different viruses, and I see the patterns between them. SARS-CoV-2, in a comparative way, is not mysterious. It's not a magical virus. It has the standard properties that respiratory viruses do, and it's subject to the same rules of epidemiology and evolution. They work pretty well.
I can't predict what mutations will appear in what order or at what time, but I think I can make a pretty strong prediction that it is going to evolve and is going to escape immunity like everything always does. I think that's a pretty safe prediction.
Topol: Would you say it's fortunate that the spike protein gave us this ability to get a potent vaccine? Would you have predicted, for example, this 95% efficacy?
Holmes: No. I was optimistic that we would get a vaccine. I was thinking more around 60%, maybe 70% if we were lucky. Certainly not 95%, which is absolutely spectacular. And more than once — multiple vaccines can do the same thing. Some months ago, I did a little exercise with the Wellcome Trust, which was very interesting, on horizon scanning, playing out what the future might be like in 5-10 years' time.
We've looked at vaccination, immunity, and antivirals. In our vaccine horizon scanning future predictions, a vaccine of this efficacy was our absolute best-case scenario. Our middle-case, most likely scenario was much worse. I think with the vaccinations, we're in a very good place, with incredible speed. These people did an amazing job.
Topol: Well, you helped them — you and Professor Zhang.
Monitoring the Fault Lines
Topol: How do we get smarter for the next pandemic? We're going to have another one. Your friends, these viruses, are going to haunt us in the future. How do we avoid having the toll here of harm, of deaths, and long COVID? How can we be smarter?
Holmes: I think there are three things we can do, each with increasing difficulty. The simplest thing we try to do is to somehow distance ourselves more from the animal world. There are clearly practices that we do today, such as live animal markets, the wildlife trade, not zoning (we build on these wildlife areas where we're exposed) — all those things increase our proximity to wildlife that carry viruses, some of which can infect us. We need to be much smarter in how we regulate our exposure to the natural world. That's a relatively easy thing to do, just to regulate those practices more.
Second, we need much better global surveillance. By that, I think the people who work at the human/animal-level interface are the sentinels. They're the canaries in the coal mine because they're going to get exposed more than anyone else. Those sorts of people maybe will need regular virologic screening, something like VirScan, which is a cool technique. I've heard that there is a global observatory looking at blood samples globally; maybe metagenomics should be performed occasionally of people who work in abattoirs or live animal markets on a regular basis.
They are the front line and are like the fault line. I like to think of it as an earthquake analogy. They are where the tremors take place, so they need to be monitored really closely. Those data have to be shared absolutely freely and as quickly as possible globally. There shouldn't be local governments holding onto it, saying, "We're handling it ourselves." That's a barrier to permanent prevention. We need surveillance of the frontline people at the human-animal interface and data sharing.
Finally — and this is really difficult, like an Apollo project— we need to have stockpiled in our freezers broad-acting antivirals and potentially vaccines that can recognize a whole span of coronaviruses or influenza viruses. I'm not into prediction, but I think it's pretty obvious that there is a set of viruses that are particularly jumpy and that are likely to emerge in the future.
I would say the top three are coronaviruses — this is number five in the past 20 years in humans — so it's coronaviruses, influenza viruses, and paramyxovirus that seem to be the most likely to emerge. For those three, are there ways — this is a really big science project — that we can develop antivirals that can recognize several of these, or vaccines that can recognize multiples, and have those ready rather than having to wait? Even a year is really quick, but it's time. Rather than having to wait for that, we have them there that we can roll out. That requires a massive investment in basic science, with many smart people working on it.
Topol: That's really helpful to kind of get a sense of what lurks ahead, particularly your ranking of the virus families that need special attention. I love the concept of broad preparation with antibodies and structure-based vaccines that have that broad capability.
Holmes: Even now, I think the coronaviruses we know, if you look at the evolution history of coronavirus, you can see that some lineages appear — like in the beta coronaviruses that jump most often — I think we know what they are. I think we can certainly start to plan around the likely ones. If they have any structural features in common that we can now utilize, I think we can start on that now.
Topol: Excellent point. I have to tell you, Eddie, this has been a fascinating discussion. We hadn't met before, but to get your sense of the world is just invaluable. Having seen the historic tweet and some of the story about what all happened back in January, as well as some of your extraordinary work in the past, it's really a privilege to have this conversation with you. Any parting words of wisdom?
Holmes: It's a pleasure to talk to you, because the way you convey the message on Twitter for people to understand is absolutely invaluable. I think that's been a huge thing. That does lead me to one of the things that I have noticed and that you're part of as well: In regard to social media, its power in the pandemic is absolutely amazing because it's so rapid, so immediate. You can get your message out extremely quickly. Unfortunately, sometimes that's led to confusion, but normally it's been a phenomenal way of rapidly passing on what needs to be known.
It's more efficient than the other standard channels that we've built since World War II to convey information about pandemics. It really is. I think in the future, another thing we need to do is to enhance those sorts of social media things because they are so direct and so rapid. Because of the pace of pandemics, that has to be the way. We can't wait for these official committees to meet and have everyone sign off. As valuable as they are, sometimes it's going to be quick. Social media is just fantastic, and that has been an absolute game changer too, I think.
Topol: Well, there's no question about the open science, as well as having that ability to get the word out through Twitter. One of those things, just to mention, is that of all the different parts of life sciences or medicine that I'm familiar with, the genomics community has really led the charge to be open like this.
You have done this, of course, throughout your career, and now we saw how it paid off, because it could have taken a lot longer to get where we are in terms of a remedy. Thank you for that. Thanks for the chance to visit with you. I look forward to following you closely and checking in with you in the times ahead as we deal with this endemic mess.
Holmes: My absolute pleasure. Thank you so much.
Eric J. Topol, MD, is one of the top 10 most cited researchers in medicine and frequently writes about technology in healthcare, including in his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again.
Edward C. Holmes, PhD, is an evolutionary biologist and virologist. Since 2012, he has been a professor at the University of Sydney and a National Health and Medical Research Council Australia Fellow. He also has had an appointment as a guest professor at the Chinese Center for Disease Control and Prevention, Beijing, China, since 2014
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