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Gavin: Hello, and welcome to a special episode of The Lancet Voice. It's November 30th, 2021, and I'm Gavin Cleaver. The discovery last week of the highly mutated Omicron variant of the SARS CoV 2 virus made headlines around the world. South Africa's genetic sequencing of Omicron revealed a virus with mutations both familiar and unfamiliar.

So how was Omicron discovered? What do its mutations mean? And how does South Africa feel about the global response over the last few days? There's no better person to answer these questions than Professor Salim Abdul Karim, leader of the South African Ministerial Advisory Committee on COVID 19, making him the South African government's top advisor throughout the COVID 19 pandemic.

We spoke to Salim at the start of 2021 to discuss the beta variant, and we welcome him back here to discuss the very early days of Omicron. In this interview with Salim, you'll hear first from my co host, Jessamy Bagelal.

Jessamy: Thank you so much for joining us at such short notice, and I was just reflecting with Gavin how it was about a year ago that you told us the story of the discovery of the beta variant, and here we are again can you tell us the story of the last couple of weeks? 

Salim: Oh, where does it all begin?

Okay, so let's start. The first case of a patient with this new variant was described in Botswana. It was just over a week ago that particular sequence was uploaded onto GISAID. Not much notice was taken of it. But then we had a small outbreak, and that outbreak occurred at a university just outside of Pretoria.

And among these students who were infected, they were tested at a private laboratory. And the laboratory noticed that in the PCR test, that one of the three genes Reflected that this look like an alpha variant because the alpha variant doesn't respond to the S gene in the kit, the PCR kit. So based on that, they sequenced it and they sent it across to the genome sequencing group that does sequencing in South Africa and when they did the sequencing, that's when they realized that this was a new variant.

It didn't look like anything else we know and when they looked at it, they realized it's similar to what was already reported from Botswana. Initially, it wasn't clear as to what this entailed. I was brought in when the first sequences from the Pretoria group became available. So that's how I got roped in, because Professor de Oliveira's His office is one floor below mine, so he shouts and I went down to look at the data and I said, wow, there's a lot of mutations here.

I had no idea. Actually, it turned out there were more than 50 new mutations. That was quite something. Now, what happened was that the next step was undertaken immediately. to collect several more samples where they were SG in target failures. In order to assess whether we had more of these or was it just, a once off kind of result.

And that's when we realized within a matter of, what, two or three days, no, two days, we realized that actually we've got several more cases now. Now this is not just a once off, this is real. So the data was shared immediately with the WHO, a meeting was called and all of the data was shared. And the next day we went public and shared it with the world.

And the WHO met the next day after the announcement. And we learned two days later that they were skipping two Greek letters. Because the last letter that has been used was mu. And the next one that was supposed to be used was nu. But they decided nu would be confusing because people would keep referring to it as nu when, even when it's a very old variant.

So they chose to go with Omicron. And what was striking to us? It's not just the number of mutations, but the fact that it drew on some of the most important mutations in each of the four variants. It has the same deletions that the alpha variant has that leads to the S gene target failure. It has the same three key mutations that beta and gamma have that confer immune escape.

And then finally, it has all, it has a whole range of mutations close to the furin cleavage site, including those that are present in the Delta variant. In a way, this variant has copied, the other variants of concern. And so we were concerned that actually had characteristics of all of these variants.

And so that's what led to our initial concern, that this was going to be something new. It is going to be something that you know, was in a different situation. 

Jessamy: I just wanted to ask if you could, I think we're all aware of it, but maybe you could just briefly summarize what we don't know about this still, and when we might know it.

Salim: As far as Omicron is concerned, it is still too early. We've only known about this virus for just about a week. It's too early to have any reliable, empiric, scientific data to assess, the three key questions everybody wants to know. Is it more infectious? Do our vaccines work? Is the disease more severe?

I know those questions are important, I share them with you, but we don't have data. What we do have is we can make some deductions. We can extrapolate what the likely answers are to those questions based on the mutations. So let's explore that. What we have seen in this variant Is that given the mutations it has acquired that mimic many of the mutations in Delta plus a few more that it is quite likely to be a highly infectious variant.

It's not clear if it's more infectious than Delta, probably will be given the rate at which it's spreading in a population that has Delta circulating. But the early evidence. certainly points to a highly transmissible virus, more so than Delta. That means that even if it's not more clinically severe, hospitals will fill up fast.

That's what it basically means. That's what it translates to. The second question is, does it cause more severe infection? Now, to gain evolutionary advantage, a virus needs to enhance its transmissibility, and it needs to develop some immune escape, but it needs to become less lethal. It needs to become less severe, because the more severe it becomes, the less it's able to spread.

If you get more severe disease, you stay at home or you stay in the hospital, you don't spread the disease. So the more people that can, are perfectly fine walking around spreading the disease, it carries a big evolutionary advantage. So we're not expecting it to be more severe, but we'll wait to see what the data looks like.

We do, we have spoken, this morning I spoke to several of our clinicians, general practitioners and hospital doctors. And they all said the same thing. They're not seeing any difference clinically. That it looks like COVID, like any other COVID. So there's no alarm bells. But I have to tell you that's just anecdotal and, it should be taken with two bags of salt because it's just what the clinicians are seeing.

And the reality is that in COVID, the more severe cases will become apparent with time because they're not evident very early on, they get evident later. I wouldn't want to go on that at all. And then finally, what do we know about vaccine escape? Based on what we have seen in this particular variant, it's quite likely that this variant will be able to escape several antibodies.

Now, in natural immunity, the level of antibodies generated are sufficiently low and they dissipate quite fast. that it's quite likely we are going to see more reinfections. So people who are not vaccinated, naturally infected, we're likely to see more reinfections. An early indication, and again, take this, with all the caveats, early indications are that we are seeing more reinfections.

We're not, it's not confirmed data, but it certainly is suggestive. What about vaccines? The mutations suggest that we may see at least partial immune escape from vaccines. So when the vaccines generate a whole array of antibodies, we expect that this virus will be able to escape some of them, probably not all.

So we will see some protection in all likelihood. against this variant, but it'll be lower in all likelihood compared to what we're seeing in against other variants. So that's what we think is the likely scenario. Should be pointed out. That the vaccines, almost all of them, do pretty well in preventing severe disease and hospitalization, regardless of variant.

Even the worst of the variants, like the Delta variant, or even the Beta variant. The vaccines still do pretty well in preventing hospitalization and severe disease. And that's probably because that's largely mediated through T cell immunity. And it's more difficult to escape T cell responses. And so it's quite likely that in this particular instance, if I was a betting man, I would bet that it would behave similarly.

That we will see breakthrough infections, they will be mostly mild, and we will still see pretty high levels of protection for severe disease and, hospitalization. Now, I, this is just a deduction, it's just an extrapolation. I might be completely wrong. That's as best as I can tell from the mutations.

I want to make one caveat, and that is that this variant has over 50 mutations. About a dozen or just over a dozen of them are variants are mutations that we know. They are mutations that come from the other variants of concern. There's about another, I don't know how many, close to a dozen, that are not in the other variants of concern, but we know about them.

We know something about them. Not a lot, but we know something about them. But there's a whole lot of other mutations we know nothing about. So I might be proven to be completely off beat and off target in my comments. But I think we can make some assumptions in how we move forward. If my assumptions prove to be wrong, we can make a course correction as evidence becomes available.

But it gives us a starting point. to plan. And so that's why the overreaction and the panic, especially in the UK, to, to believe that the best thing to do is to ban travel. That is going to harm science. It's going to harm transparency, because the message it gives If you do a lot of sequencing and you identify new variants, whatever you don't tell the rest of the world.

Certainly don't tell Britain because they are going to isolate you. They're going to punish you for having made this discovery. And for me, I think what really hurt Is that when the world is faced with a threat, a global threat, like Omicron, the way you defeat a threat like this is to stand together, is to work together, to join hands and deal with the threat and take it head on.

What you should be doing is building bridges, not building barriers, not building fences. That defeats the very thing we need to do, and that's part of the reasons why we have all this vaccine inequity, why we are battling to protect Africa. It's because so many countries are so concerned about, stockpiling vaccines for themselves, why should they care about poor Africa?

I have to say, if this was intended to be a test for humanity's resolve in being able to face a global threat, we have failed, Dismin. We have failed the test of what it takes.

Gavin: I wanted to ask you if you felt like the travel restrictions, given Omicron's apparent infectiousness, do you think they would make much of a difference? 

Salim: So we learned this through the Delta variant, that if you impose travel restrictions, you will slow the initial seeding of the virus, but it has a very short lived benefit, very short lived.

Because already by today, almost 20 countries are reporting cases. And once this virus is reported, you must know that when you report a virus, it's already been there for two weeks. Because that's how long it takes before you have the sequence. This virus is already spreading in the UK. It's already spreading in several other countries.

You can't, it's not anybody's fault. It's just, this is a virus, this is how it spreads. In my view, what should have been done is that we should have gone on the basis that we have the tools to make travel safe. And those tools are widely used, and they comprise five things. Only the vaccinated get on to planes and ships.

Only, those with a negative PCR result. Only those who are not ill, who are, pass a symptom check. Only those who wear a mask for the entire duration of the journey. And only those who are negative on a test result on arrival. Those five things. Protect any country, they will protect South Africa from any variant in any other part of the world.

Gavin: I wanted to go back a little bit to talk about, as you were talking about, the discovery of Omicron. In the regions where you first discovered Omicron, did this spike come out of the blue? Were there any other kind of changes in policy in South Africa at the time that might have contributed to a sudden rise in cases?

Or was this was this kind of just a surprise that came out of nowhere? 

Salim: So what do we know about how variants develop? So there are now several studies of how SARS CoV 2 creates persistent infection in immunocompromised individuals. Patients with advanced cancer, transplant recipients, advanced uncontrolled HIV.

There's a whole list of immunocompromised individuals. And what happens in these individuals is that, unlike people who are not immunocompromised, where the virus, when a person gets infected, the virus is cleared within a matter of 10 to 14 days. You have no more virus after that, right? Even if have a little bit of a severe infection, it is still cleared within two, three weeks, maybe a month at most.

But in immunocompromised individuals, they have a long term, persistent, replicating, culturable virus. And that virus undergoes multiple mutations, repeatedly. And we know this because we have studied this in one, actually now in two people, over a period of seven to eight months, they acquire from a virus that had, was, had no mutations, they acquired 30 mutations.

So you can't, in a matter of three weeks, develop the T mutation. The virus doesn't work like that. It's got proofreading in the way it replicates, not like HIV or other viruses. And it is only through this long, persistent infection. So it's very likely that some immunocompromised individual had this long, persistent infection that led to this virus.

And from that one person, it has now spread. Now, in, in South Africa, until a week ago, we were in our low transmission. Now we know how the virus works in South Africa. We have roughly a three month low transmission. Our population is about the same as the UK. And, just over a week ago, we were averaging about 200 to 300 cases per day.

I think the UK is averaging like 30 or 40, 000 cases per day compared to what we were. But what has happened is that we also know that after roughly three months of low transmission, we get a new wave. And that new wave is often driven by a new variant. We were anticipating this. In fact, we had already anticipated and had put our plans in place that we would have a fourth wave in December and that it was likely to be driven by a new variant.

And that's the reason why our government invested so heavily in the genome surveillance and the genomic sequencing platforms. To do exactly what was done, which was, and it worked, right? They identified the variant and they identified it quickly. All of that investment paid off. In my mind, what we have done is, we have shown that you can identify the emergence of new variants quickly.

What we haven't worked out, what is the appropriate response? Once identified and there we seem to be unclear in South Africa approach is really based on three things in dealing with this variant. The first is we want to increase vaccinations and we want to restrict particularly indoor environments to vaccinated people only.

Which is something that's already widely implemented in Europe. The second is, we want to reinvigorate the adoption of our public health measures. Because what's happened is because we've had low transmission in very few cases. People put their masks around their necks, not on their mouth. And what happens is social distancing goes.

And all those, and all the good things that they do when the wave is there, we lose all those things. The complacency sets in. I don't blame people. Frankly, people are fed up of this virus. They are sick and tired of this virus. They've had enough of it. But I keep telling them, even though you've had enough of this virus is not done with us.

It is coming with new variants and so it has 

Jessamy: now that we've had a scare we'd hope that it was a sort of wake up call But I don't think there can be any more wake up calls particularly to the global leaders or to the multilateral system is there any way of looking at where? variants occur and different population levels about, who who we should be vaccinating first beyond the obvious necessity to vaccinate everyone.

Salim: No, I think the, there've been three lessons I've taken away. The first is. Variants emerge across the globe. We've had the Alpha variant first reported from the UK, we've had the Beta variant reported in South Africa, we've had Gamma variant reported in Brazil, we've had Delta variant reported in India.

There's no one part of the world that's a threat to the rest of the world. Everybody's a threat to everybody here. Second is, I think we haven't fully appreciated the importance of immunocompromised people. Immunocompromised people don't respond well to two doses of the Pfizer vaccine. Up to 40 percent have no immune response, detectable immune response after two doses.

We've got to give them third doses, fourth doses. We've got to keep giving them doses until they are protected because when you've got an immunocompromised person that has even partial immunity from a vaccine, that can be even worse. Because now you are creating conditions for even more escape. So I think we have not fully appreciated the importance of identifying them, vaccinating them, checking that they are vaccinated, that they have a good immune response, because that's what's going to protect them.

And they're going to need boosters too. Then the third thing I think I've learned, and I've pointed this out, that you can't really deal with variants. So pretty much you can't deal with any part of this virus. Unless we learn that we are mutually interdependent. Until we learn, we've got to work together, we've got to solve this together.

It's not helpful that, we end up with a situation where rich countries buy up vaccines and the rest of us are struggling to get vaccines. We've had to always go to the back of the queue. And we're not asking for donation. We're buying the vaccines. There's no donations here. Everybody's buying it.

But We're not a market that drug companies care for. We were always heading for trouble in this model. There is no scenario that sees, a handful of rich countries vaccinating themselves to the hilt and then hoping that's going to protect them and they won't ever have to worry. And if that was not clear, it certainly became clear in the panic that we saw in the UK and the US.

in banning travel. 

Gavin: When you spoke to us earlier in the year, we were talking about what became beta. And, that was quite early days when you were talking to us about that. And as you mentioned earlier, Omicron has quite a few of the same mutations as beta, the vaccine escape ones. So is there anything that you're taking from your experience with beta that you can maybe give advice to the world in terms of Omicron?

I 

Salim: wrote a piece in the Lancet about One of the biggest problems we faced in dealing with beta in South Africa is that we didn't know what the correlate of protection is. If you know what the correlate of protection is, then all you need to do is, for every new variant, is to test it against the correlate.

But because we don't have a correlate, we actually don't know what we're testing it for. So right now, for Omicron, we're just testing it for neutralizing antibodies. But neutralizing antibodies are not really the dominant mechanism by which severe disease is prevented. And antibodies are not a validated correlative protection.

But it's the best we have, and it's a pretty good marker, it is a marker of infection rates. It is a marker of severity. It's a helpful marker and we certainly are using it, but I think more needs to be done to identify a correlate. And the best way to do that is, in the clinical trials, is to look at those who became infected, on the vaccine arm.

Because we need to understand what made them different. From those who didn't get infected, what happened, right? Did they just have low antibodies? What happened? We need to understand that. It's very hard if you don't collate that data. And the problem is that there are too few infections. Because these vaccines are so efficacious.

There are so few breakthrough infections in the individual trials. So we need to get the drug companies to work together and to figure this out and share data. Now, once again, we need the drug companies to come in to, to make some or the WHO or somebody, as an honest broker to look at this data to identify a correlate, which I think is critical, because if we have a correlate, Actually, it becomes quite simple.

Every new variant, we have a biobank of stored sera for all the vaccines. We just test it against the new variant. The answer will be available within two weeks, maybe three, and we can go on and figure this out. 

Gavin: Salim, thank you so much. We really appreciate it. 

Salim: No, no problem.

Gavin: Thanks so much for listening to this special episode of The Lancet Voice. I will be back soon with our regular long form content looking at pressing issues in health around the world. If you're not subscribed, you'll be able to find us on the podcast platform of your choice, and we look forward to seeing you again soon.