As the pandemic set in, and the death toll rose, there were very few things we could be certain about. That the coronavirus mutated slowly, however, seemed to be one of them. That was until September last year, when a variant now known as 501Y.V2 was first described in South Africa.
That variant went on to cause major delays in the country’s vaccine rollout and has become the dominant form of the virus here. It has shown up, along with a growing list of others, all over the globe.
These new variants, which are popping up from Manaus to New York, and the threats they pose to vaccinating the world against Covid-19 are at the tip of our collective tongue. We spoke to Penny Moore – one of South Africa’s leading virologists – about why 501Y.V2 is just the beginning of our fight against them.
Dennis Webster: Hi Penny. I wanted to talk to you about the 501Y.V2 variant of Covid-19. I hear that some virologists are starting to describe these emerging variants with nicknames based on mutations to the spike protein. Do you have a favourite nickname yet for 501Y.V2?
Penny Moore: Yes! “Eek” and “Doug”. We’ve got one in our lab called “Miscreant”, and we have “Nicky” and “Ticky”. But not for 501Y.V2. For that one I’m well behaved, and I stick to “the variant previously isolated in South Africa”, which makes it very hard to have conversations, unfortunately. So “Eek” and “Nicky” and “Ticky” and all of those things are generally names that are given based on individual mutations, and that makes it easier. So, “Eek”, for example, is a mutation of position 484 that goes from an “E” to a “K”, and that’s why it’s “Eek”. But 501Y.V2 has this whole suite of mutations across the entire spike protein, which makes it hard to come up with a name that describes it.
DW: Of those key mutations that define this variant, one increases transmission. Another, which seems to be making vaccines less effective, neutralises antibodies, and is being seen in different variants around the world. The virus had been mutating for so long without concern, and then suddenly, around September last year, this. What happened?
PM: You’re right, we’ve been seeing mutations pop up all over the place. I mean, it’s a virus, it mutates, that’s kind of expected. But what defined this was that there was a whole suite of mutations. So it’s almost like the virus found a combination of mutations that all come together in a way that enables the virus to have some sort of, what we call, selective advantage. And all that means is that the virus is fitter in the environment it’s in. In South Africa, it’s a fitter virus that can kind of outrun all the other viruses. And that’s why it comes to dominate, and that’s why it’s responsible for more than 90% of infections in the places where we’re looking.
DW: We’ve all become lay virologists over the last year. But reiterating the basics is important. So, can you break down, from you the virologist proper to me the virologist pretender, just what the spike protein is? And what did it go through to change into something even more dangerous – into this fitter virus you’re talking about?
PM: So, if you imagine a virus, it’s kind of studded by what we call spike proteins, right on the outside of the virus. Now, they’re the bits of the virus that enable it to bind to the host receptor, and then you have that interaction between the virus and what’s called “ACE-2”, which everybody has also heard of by now. And it’s that interaction that enables the virus to infect cells. That spike is also the target of the immune system. So that’s how the immune system tries to prevent the virus from infecting cells, essentially by messing with that interaction between the spike and ACE-2. It does that by kind of swooping in and sending antibodies to the top of the spike, to a region often called the RBD, or the Receptor Binding Domain, or to a region a little lower called the N-Terminal Domain. And the whole point of the immune system is to send antibodies to bind to those two regions, which are kind of red flags to the immune system.
The reason antibodies to those sites are particularly effective is because they’re really good at preventing that interaction between the spike protein on the outside of the virus and the ACE-2 host receptor. So what’s happened in the last few months, essentially, is that the virus has picked up a whole collection of mutations that are predominantly based in those two hotspots that the immune system loves to target. And it’s because of that that many of the antibodies can no longer bind to the spike on the new variant.
DW: From what I understand, this variant comes out of a vicious second wave of infections in South Africa. Was it this that allowed the variant to develop?
PM: Yes, and not just here. I think it’s important to point out that, although we were one of the first to pick up on the variant, it’s because we have such great sequencing. So, the harder you look, the more you find. Basically, these variants have popped up because there are so many infections across the world. So, all viruses engage in this kind of cat-and-mouse game where they are the focus of the immune system and they tweak their spikes, and most viruses have a spike of some sort that is able to mutate to get away from the immune response. And this is what viruses do, this is what they are absolutely brilliant at. With the coronavirus, we kind of hoped that it wouldn’t have that much wiggle-room to get away from the immune system, because, unlike HIV, where you have years and years and years of infection where the antibodies and the virus keep messing with one another, in coronaviruses it’s what we call an acute infection. So, it’s a very short infection and then the virus is gone, we think. So we kind of hoped that wouldn’t give the virus too many opportunities to mutate. But, if you have enough infections, and we have millions across the world, and enough people whose immune systems are not quite as robust as they should be and don’t quite clear the virus as quickly as possible, then that is like the perfect storm. That is everything that the virus needs to have enough wiggle room to try out various mutations on the spike and see what works for it.
DW: So, the variants are coming from this perfect storm. Does that mean that the slow rollout of vaccines, here and in other poorer countries, along with the looming threat of third and even fourth waves of infection, mean we might see further variants of concern emerging?
PM: Yes. Yes. I mean, I think, as a hardcore virologist, that it’s inevitable that we’re going to see more variants coming out. And, to be honest, wherever we look now we are seeing more variants. I mean, Texas has more variants than I ever thought possible for one little area. So, it’s not just us. It’s everywhere where we are not able to control the virus for whatever reason. And, you’re right – the very slow rollout of vaccines in South Africa didn’t help that. And also the incredibly high force of infection. There are some studies that suggest that, in some areas, as many as 40% of people were infected during the first wave. In the coming months and weeks, I think there are going to be lots of opportunities for that virus to mutate further. And until we get good enough vaccine coverage to reduce the numbers of infections to virtually zero, then we’re still going to have new variants coming out.
DW: And how concerned should we be by that?
PM: You know, I think it poses a challenge to us as we try to design vaccines. What we want, ideally, is a vaccine that can deal with all the new variants. And, at the moment, it seems like these variants are quite good at escaping from existing immune responses. But there are lots of clever people out there coming up with clever ways of tweaking the vaccines. I mean, we have cool data that kind of suggests that people who are infected with the new variant [501Y.V2] somehow have better antibodies that are able to recognise the old variant and the Brazilian variant, even though they have never seen those viruses. And that suggests that if you make vaccines that are based on 501Y.V2, then that vaccine might intrinsically be able to elicit better antibodies.
DW: So, do your findings suggest that people who have been infected with 501Y.V2 are not only protected against further reinfection, but are protected from other variants as well? Even other variants we might not yet know about?
PM: Yes, exactly. That’s kind of the hope. Certainly what I would say – because I am a very conservative scientist and I stick to what I know – is that the antibodies that are triggered by 501Y.V2 are somehow better than the antibodies that were triggered by the original variant. What we don’t know yet is how that translates into reinfection and how that then translates into vaccine efficacy. We kind of hope that people who were infected with 501Y.V2 might be better protected against reinfection. But we’re measuring one aspect of a multifactorial response to SARS-CoV-2. That one aspect seems to be better. But we’re only just beginning to delve into things like T-cell immunity and other complex parts of the immune system. And, realistically, immunity against reinfection comes from all of those parts of the immune system working together.
DW: From what I understand, all of the variants so far involve changes to the spike protein, which I guess means that spike variants are the main thing we must look out for. But is it possible we will see variants emerge with mutations in other parts of the virus?
PM: They already exist. So we tend to talk a lot about the spike variants because they affect antibodies, and that’s really the focus of vaccine designs. So every vaccine that is out there at the moment is based on the spike. And so, when we’re talking about mutations we really focus on the spike. But that’s not to say that other parts of the virus are not mutating. If you look at enough sequences, you’ll find mutations across the entire genome. It’s everywhere.
DW: You called yourself a conservative scientist for sticking to what you know. But I wonder if we can talk about an area that may be outside of what we know. If the virus were to ever escape vaccines completely, I imagine it would need to evolve a variety of mutations that block multiple different antibodies, all at the same time. And, from what I understand, with every new infection there is another chance that might happen. Do you think that is likely at all?
PM: I don’t. Let me go back to what I know, and then I’ll come to what I think. So, what we know is that the immune response to a virus is very complex. Our immune systems throw everything they can at a virus. Often the responses to a vaccine are what we would call much more narrow. What happens during infection is that there are millions of different viral particles. So, there are lots of opportunities for the immune system to engage and to learn. And, as much as the virus is changing, the immune system is also changing. It’s really a cat-and-mouse game. In a vaccine situation, generally you get one or two shots. So there is much less opportunity for the immune system to mature compared to an infection. And even in an infection, where the immune system has a much more complex response, there’s plenty of evidence to show that there are parts of the virus that simply can’t change fast enough to get away from the immune response. And that’s not just on the antibody side, but also on the T-cell side. And all of that pressure on a virus keeps it contained and keeps it on the straight and narrow and makes it very difficult for a virus to escape completely. I think what people often don’t appreciate is how much the immune system changes too. We always think that viruses are these crazy things that mutate so fast that we can’t keep up with them. But if you look at our antibodies – they mutate just as fast. And our antibodies have the coolest, most funky, most amazing ways of generating diversity. I always get more excited by antibodies than I do about viruses because the way our bodies are built, we produce millions and millions of antibodies every day. So, it’s really difficult for a virus to get away from that.
DW: Penny, can we step away from the science for a second? In the AstraZeneca trials that showed the vaccine was not effective enough against minor symptoms of 501Y.V2, the numbers were small and there was quite a wide margin of uncertainty. Do you think we should have sent the million doses of the vaccine back?
PM: There’s a lot we don’t know from that trial. It was a small trial, and it was not powered to detect severe disease. And actually that’s my major concern – that we don’t know how well the AstraZeneca vaccine protects against severe disease that is caused by 501Y.V2. And that is no fault of the trialists, and no fault of the people who led that trial. It simply wasn’t designed to test that question. It was designed to ask the question about mild and moderate disease. And so they targeted that vaccine against relatively healthy people. They specifically didn’t target that vaccine trial against older folks with comorbidities. And that’s where the severe disease happens. So it was never designed to test that particular question. So, in a country like ours, where our health systems are overburdened, and our hospitals are drowning during the waves, and our nurses and our doctors are exhausted, then actually the thing we need to be protecting against is severe disease. We need to stop people from becoming ill and dying. That’s our first priority. Then we can work backwards from that place and try to protect people from mild to moderate disease. And the major problem is that there is no evidence, one way or the other, about whether the AstraZeneca vaccine does protect against severe disease. I would love to see a way in which we could understand whether that vaccine can protect against severe disease, in which case it should be rolled out immediately to people who are at risk. But the problem is we don’t have that information. And it’s very difficult to make the call without having the right information, and balancing a fear of vaccine hesitancy. It’s a difficult thing to ask people to take a vaccine that you don’t have evidence for, one way or another. I’m deeply grateful I’m not one of the people who has to make that call.
DW: This is outside of the data as well, but our scientists in South Africa have, in many ways, been on the frontline of the pandemic. As a closing thought, what was the significance of our scientific community’s experience with HIV and TB?
PM: You know it’s not just the South Africans. If you look at the really fantastic science that’s being done on SARS-CoV-2 across the world, it’s often the HIV virologists who’ve kind of pivoted, like we did, and moved across. I think a lot of it is because the platforms and technologies and skills and expertise were so immediately translatable to SARS-CoV-2 that, from a technological point of view, it was a very easy thing to pivot. We have all the platforms in place. And it was a really meaningful, helpful thing to do, and I think from that point of view it appealed to many people. Then, in terms of the collaborations, in South Africa particularly, there’s a really wonderful network of HIV scientists. And I’m by no means saying it is only the HIV scientists who are doing this work, but I think, as an example, the HIV scientists have been doing this work for so many years in this country that it was easy for all of us to then have the networks and the relationships and the existing collaborations. And I’m sure it’s the same in the TB field. You know, collaborations take years to build. And so when you have an existing set of collaborations with people you know you can work with, it’s fast. And I think that was really powerful for us: we can move fast, and we have moved really fast.
DW: Right, interesting. So, that pivot was made easy by these technical factors. Was there also a degree of social urgency in these collaborations you’re talking about, similar to when TB and HIV posed such monumental risks to society?
PM: I think often people who sign up for HIV and TB and that kind of science are the kind of people who want to be able to improve public health. And this was a really immediate opportunity to help people. It’s what we are all trained for, it’s why we’re in science, it’s why we’re addicted. And I will use that word. Addicted to science. I mean, I’m completely addicted to science, as my partner and family will tell you. And here is something where we have the skills and we have the knowledge and we have the friends and we have the networks to really be able to do something incredibly useful. I think it’s wonderful that we have been able to do that. But what I would do is flip your question on its head, actually, and say that when we have this thing under control – which I hope will be soon – what we need to do, right now actually, what we need to do is translate the sense of urgency that we have all had for SARS-CoV-2 back to HIV and back to TB. You know, the way we do science now has changed completely. The way we communicate science has changed. The way we work together, the way we share things, the way we publish – everything, everything has changed. And now what we need to do – and I really feel strongly about this – is take that new mode of working, and turn it back to HIV and TB, which we kind of started moving too slowly on, I think. I mean, think of how many discoveries have been made, think of how many papers are out there, and how many new collaborations exist around SARS-CoV-2. It happened really flipping fast. And now we need to start working that fast on all the other bugs, including the new ones that are coming our way, because this ain’t the last, unfortunately.