#10 Ravi Gupta - The Omicron Variant

Ravindra Gupta, MA, MPH, BMBCh, PhD, FRCP, FRCPath, FMedSci
University of Cambridge,
United Kingdom

Transcript

Anton: [00:00:06] Hello and welcome to this new podcast for science and society, and I'm Anton Posniak. And I'm talking today to Professor Ravi Gupta, who's a professor of virology at Cambridge University and an expert in COVID. So Ravi, welcome to the program. 

Ravi: Thank you. 

Anton: Right. So we're going to talk today about the hot news in COVID, which is this Omicron variant. And I just wanted to ask, can you describe how genetically different this variant is from the others that we know well, the Delta and the beta variant?

Ravi: [00:00:43] It's got some similarities between other variants, but it really has more mutations than we've ever seen before on one virus. It's got sort of something like 50 across its genome and 30 of them are in that spike protein that we always hear about. And that spike protein is the bit that latches onto our cells and enables the virus to get in. And that bit of the virus is also the bit that our antibodies are largely targeted at. And therefore when the spike protein changes, it makes our antibodies less effective often, you know, after vaccination or previous infection. So that's how it's genetically different in some ways on spike. The other bits, it does have some other changes in the bits of the spike protein that's responsible for generating a mature or really infectious form. So this is the cleavage site and that's also mutated with three different mutations, and we've seen that before. We've seen signatures like that before in the in the Delta and the Alpha variants. So it's doing things that make it more infectious likely, and it's also doing things that make it less visible to our immune system.

Anton: [00:01:45] Wow. And the sort of Delta beta variants, they don't have 50 mutations, do they? This is quite extraordinary.

Ravi: [00:01:53] Yes, that's right, so the other variants of concern have had up to sort of 20 odd mutations and you know, most you'd see sort of up to 10 in the spike protein, but not 30.

Anton: [00:02:06] So it's an interesting thing that I heard, which is that this variant doesn't seem to have evolved out of Delta or beta. Where do you think it evolved from or have I got that wrong?

Ravi: [00:02:20] Yes. I mean, if you look at the ancestry of this virus and you look at on phylogenetic tree, its root is traced back to viruses that were circulating in 2020 after the virus emerged out of Wuhan. You might you might remember that it acquired this mutation D614G, and that became the globally dominant virus. It wasn't called a variant back then because it was just three different mutations. And that was again the result of the virus trying to get more infectious. So it evolved from something circulating in mid-2020 and my view on this is that it's probably been sort of incubating or sitting in a single person for over a year to acquire that many mutations. And it may have gone from one person to another and done and through chronic infection over many months, it may have happened in two individuals.

Anton: [00:03:12] Even so, these are these are individuals that we've heard about that it could be immune suppressed and therefore not being able to clear the virus, you know, it stays sort of in some sort of symbiotic relationship with it.

Ravi: [00:03:25] Yes, that's right. In mid-2020, it is becoming clear that, you know, this virus didn't just cause an infection and either kill you or you recovered from it. There was this sort of no man's land where you could end up being infected for quite some time, shedding virus. And for a while, people thought that virus was kind of dead. But actually, we and we and others showed quite convincingly that the mutations could occur on top of the original virus and quite some large number could be acquired and selected for. And sometimes if you gave people convalescent plasma, you could drive Darwinian selection or evolutionary selection of these mutations that the virus can use to escape from the antibodies or make antibodies less effective.

Anton: [00:04:11] And presumably, if you give these people monoclonal antibodies, you could do the same thing.

Ravi: [00:04:17] Yes. Yes, that's right. You could. Theoretically, you could. The monoclonal that we use are given a very high dose. So there are a lot of them, and since that can partially overcome any resistance. But yes, under certain circumstances where there isn't enough antibody around or the virus has already started mutating, then then you can drive further kind of selection of resistance mutations to the antibodies.

Anton: [00:04:44] But at the moment, I'm going to talk about treatment later. But at the moment, we don't know about the effect of any of these monoclonals on this virus at the moment.

Ravi: [00:04:53] Now the predictions are that Regeneron, for example, might be less effective, although we'll have to see whether that translates to a clinical changes in how you know how effective Regeneron is. And there's another monoclonal sotrovimab, which also predicted to have maybe some impact on how effective that monoclonal is. But again, we need clinical data, not just the lab data.

Anton: [00:05:20] Yeah, OK. I mean, I think that's very clear. We need to go down that route. Now I also wondered about with this virus about its transmissibility because it seems to arose out of South Africa. That's where the first case is came. Somebody noticed something on the PCRs. Can you just explain quickly what that was?

Ravi: [00:05:45] Yes. So some labs are using a commercial test for coronavirus that involves looking for three bits of the virus's genetic code in three different places, three different sort of sequences of code. And you do three because of the fact that when you have a virus that's changing that if you only looked at one part, you might stop detecting it if that part changed or became different. So they go for three so that you can get a positive result even if you lose one or two due to mutation or change in the virus. And one particular area that this test goes for is quite prone to being mutated. And in fact, we described this mutation happening in an individual during chronic infection, as we were talking about earlier. So it is something that happens during chronic infection and it enables the virus to get a little bit more infectious. But the interesting thing about that mutation is that it also means you drop one of the, you know, you lose one of the signals in the PCR test for coronavirus, so when the virus mutates. To gain an advantage. It also causes this drop in signal, so only two out of three of tests come up positive. And what they observed in South Africa was the fact that they were seeing increasing numbers of cases of positive people that only had two out of three positive signals. And we saw this with the alpha because the Alpha variant also had this this mutation. And so we were well used to using this test as a way of kind of like a proxy for for particular variants. And now the Alpha variant has disappeared. This new variant, the Omicron, has this same signature, and now we can use the dropout signal as a very quick way of telling how many people have the new variant.

Anton: [00:07:32] Wow, that was very well spotted, I must say. But the other interesting thing that I've heard was that people believe that this is much more widespread than just South Africa. The cases have appeared in other countries without travel history. So obviously, there may have been some travel history and transmission, but do you do you believe it only came out of South Africa and spread everywhere? Or do you think that it's occurred in in many places because they don't do all this gene sequencing in every country in the world?

Ravi: [00:08:06] Yes. I mean, it's difficult to know where the virus arose. It could have arisen in another country and then and then the person traveled to South Africa, for example. So it's very hard to tell. But you know, it's a reasonable probability that that it did arise in South Africa and that's where it's been spreading. And that's why the highest number of cases are in South Africa. I mean, yes, South Africa has very good surveillance, and so things are picked up quickly there. But I think that other countries around in the region have stepped up their sequencing and they don't have the sort of case numbers that South Africa has. And therefore, it's probably originated in South Africa, although, as I said, you can't be a hundred percent sure. But yes, the point is clear that not everyone is using this special test with a drop out signal and actual full genome sequencing is not being done at high scale in many places. And so yes, it's probably circulating in many countries at significant levels undetected

Anton: [00:09:05] And the transmission of this virus. What do we know about that Ravi so far?

Ravi: [00:09:13] Well, we know that it's growing very quickly, so in places where it's been introduced, in South Africa, where things were taking off just a few weeks ago, they'd actually come to the end of their third wave of Delta. So Delta was in decline. They were coming up towards this. They're coming there into the summer now. And so when this new variant came, it really sort of took off on a background of quite low infections in general. And so one of the questions was, well, is it actually competing with Delta or not? And so we've had to wait for it to come here to the UK. And in the UK, we are seeing that the Omicron is competing fairly effectively with Delta, which is at high levels at the moment. So it seems to be getting gaining a greater, greater share of the total infection. So that suggests to us that the transmission potential of the virus is quite high. Now, whether that's due to being able to evade antibodies or just being more infectious due to those changes in the spike protein is unclear at the moment. And we and others are working to try and figure out what exactly is going on.

Anton: [00:10:23] Yeah, because we could get insights into how the mutations increase transmission, if that can be teased apart a bit.

Ravi: [00:10:32] That's right, so we will be doing work on the actual virus and also artificial versions of the virus to kind of figure out how immune evasive the spike protein is and how much more infectious that spike protein is to kind of tease apart what we're seeing in populations. Because when you look across millions of people, the problem with those studies is that everyone has a different history. Some have been infected, some have been infected twice, some have been vaccinated, some have been triple vaccinated. They've had different combinations of vaccine and infection. And of course, you've got age and demographics to factor in. So, to the population level, studies become very, very hard to untangle.

Anton: [00:11:14] So what you're really saying at the moment, until we get more data, it's very difficult to know about the transmissibility in people who are unvaccinated, single vaccine, double vaccine booster vaccine. We really haven't got anything yet to hang our hats on for that data.

Ravi: [00:11:33] Not at the moment.

Anton: [00:11:35] Ok, so because I think there's a lot of stuff out there saying, you know, you'll be OK if you're vaccinated, etc. But we're now talking about transmission. They're not severity, so. All right, but what about severity of disease? Have we got any data on how severe this is if it's transmitted to you?

Ravi: [00:11:54] Well, the indication has been that vaccinated travelers, for example, who have become sick, haven't really progressed to severe disease. Now, of course, that's a selected group of people. You know, they're healthier. They're younger. So, so it's hard to read into that. In South Africa again, they were suggesting that the disease was milder than previous waves. They have started seeing increase in hospitalizations and some deaths, but that's inevitable because they have a lot of unvaccinated individuals in South Africa. So I think that there may be some indications that it's progression to severe disease is slightly better with this virus. We don't know that this could easily be offset population level by it being much more transmissible or spreading very quickly in the population because of the sheer numbers of people who will eventually get sick anyway. Because, you know, because even a small proportion of a large number is a large number. So therefore, this may be a prominent public health level.

Anton: [00:12:51] Yeah, yeah. Ok, so the advice would still be for everybody to continue with the current vaccines, which I really wanted to come round to talk to you about the current vaccines. Do you think that we're heading for a future where the current vaccines need to be modified regularly to cover for these variants that crop up?

Ravi: [00:13:16] Yes, I think inevitably we will need to, and I think people, once we realized variants of concern, were a real thing, you know, as a result of chronic infection, I think many of us knew that the vaccines wouldn't last forever. I mean, you know, they've had a fantastic impact so far. But they will need modifying. We've got a variant of virus now that is very, very different from the one used in the vaccine. So we do need to update vaccines. How they've updated is a sort of long discussion. But certainly we will see new vaccines and we do need them.

Anton: [00:13:48] And it seems to me that the immunity for after a couple of doses of vaccine isn't quite lasting to a year in many people because of reinfections. And I've read that this Omicron has caused reinfections and in people and even mean people who have had Beta and Delta before. So I just wonder what you're maybe impossible to answer what your prognosis is for us as humans on the planet where we'll be having annual vaccines or what do you think now?

Ravi: [00:14:20] Yeah. Well, I think that vaccine waning has started two months after your second dose, it seems, and the risk of severe disease in the older age groups increases after that. Of course, Delta had exacerbated that issue because Delta has partial vaccine escape properties. In other words, it can infect you despite being vaccinated. So. And of course, Omicron likely is doing something similar. So we do need boosting. And you know, I think anticipating yearly boosters is a realistic prospect, at least for the next few years.

Anton: [00:14:56] But the difference for me is that we don't give flu vaccine to absolutely everybody. And yet these variants seem to start in young people, maybe because of their social mixing and habits and because they're not being vaccinated and then spread to older people. So do you see a future with Omicron and other variants of interest where we were having to vaccinate? Quite. I mean, we are doing in many countries vaccinating all the way down to five or six years old.

Ravi: [00:15:22] Yes, I mean, there are some benefits to that, which is that people build up immune memory over time, even from a young age. So yes, we're having to vaccinate large numbers of people to limit the burden of infection and chronic infection and new variants. And really, this is not this is not a paradigm we've ever seen before. So. So that's why it's really hard to we shouldn't really apply anything we know about flu to this disease. And I think that was one of the mistakes we made early on by trying to treat it, thinking we could apply just the same tools and clearly that was left wanting. For example, for a start, this is this disease has a mortality that's 10 times higher than flu. You know, fundamentally. So it is a completely different animal.

Anton: [00:16:08] And do we think that the Omicron will be susceptible to the small molecules that have been developed recently by Merck and Pfizer?

Ravi: [00:16:17] Yes, we think that the antivirals will be efficacious. However, they may be vulnerable because use of monotherapy in highly mutating viruses such as viruses like this and HIV, for example, are generally recipes for generation of resistance. So whilst they may work in the short term, we do need to get into thinking about combination therapies as we go forward.

Anton: [00:16:43] And these small molecules, though, I mean, I've been thinking that maybe when things like Omicron come and people get sick again, that might they might be used as prophylaxis in high risk people or people on the front line. Do you think that that's anything that could be countenanced?

Ravi: [00:17:02] Well, I think that for people not responding to vaccines, then we do need monoclonal antibodies as prophylaxis. I think they will. They should start being used. Of course, we have a problem now with Omicron because it may be escaping some of those. So the alternative is to use the oral antivirals. But the problem is the Half-Life is quite short and you have to take pills for many days on end, and they're extremely expensive at the moment. So yes, we do need prophylaxis for vulnerable people, but I'm not sure we're there yet.

Anton: [00:17:29] Yeah. And I suppose with the Pfizer drug, there's an inhibitor in there which would also affect any other drugs you're taking if you took it in the long term. So yeah, we we're still in the early phases of drug therapy, I would think for COVID. So I'm I'm now going to end with a philosophical question for you because it seems to me that at the moment there's a lot of unknowns whether you're vaccinated, partially vaccinated or fully vaccinated or had COVID in the past and vaccinated, et cetera, all those mixtures of people that we have. What the effect of this virus is on transmission and progression to disease. So if you were in charge, Ravi. I'm not going to hold you to this in the future. What measures would you put in place to limit its spread and the effect on the population? What can we do?

Ravi: [00:18:21] Yeah, I think the mandatory face coverings in all public places would be it would have been a very good start. And if we had it since July, we may have, you know, lessen the burden of disease that we've had. So. So certainly mandatory mask wearing, I would be suggesting obviously measures in classrooms. So school kids should be wearing masks above a certain age. We should have obviously precautions in place. We should be vaccinating down to children in order to keep societies open. At the moment, we've got a real epidemic of children getting sick and being off school, so that's causing trouble. So those are kind of some of the key things I'd be doing. I would also be introducing vaccine passports. There is no excuse for anyone to be not vaccinated in this day and age, so you shouldn't be allowed to go into a restaurant and or any kind of public place unless you have been vaccinated. And of course, travel testing for travel, I think, could be improved as well as test and trace.

Anton: [00:19:20] Well, yeah, I mean, I must agree with you all of those things and the social measures that we have to do so anyway. Well, we hope that for the holiday season, we'll be able to see our family and friends, but we don't know where all this is all going. I would like to thank you so much, Professor Ravi Gupta from Cambridge University for talking to us today about this Omicron variant and everything that it may or is doing at the moment. And it's goodbye from me Anton Posniak from science and society. Thank you very much for having Gupta.

Ravi: [00:19:54] Thank you very much.

Anton: [00:19:56] As we finished the podcast as news breaking that Pfizer have said that two doses of the vaccine may still offer protection against severe disease caused by the Omicron strain, but their preliminary data on the BioNTech-Pfizer vaccine show that protections maximized with a third dose so we should ensure as many people as possible are fully vaccinated and that they get their booster so that we can prevent the spread of the Omicron strain. And with that, it's a great thanks to all of you for listening to me Anton Posniak from Virology Education on behalf of Science and Society podcast, and I've been speaking to Professor Ravi Gupta, Consultant Virologist at Cambridge University. Thank you. We hope you enjoyed the discussion today. Make sure to check out the notes for any references during the podcast. You can learn more about Virology Education and our other programs at W-w-what Academic Medical Education dot com. Thanks for joining us and see you next time.