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Coronapod: Why COVID antibody treatments may not be the answer

Noah Baker and Heidi Ledford discuss COVID-19 antibody treatments.

In the early days of the pandemic, researchers raced to identify the most potent antibodies produced by the immune system in response to SAR-COV-2 infection and produce them in bulk. The resulting ‘monoclonal antibodies’ have since been tested in a variety of settings as treatments for COVID-19.

But despite promising clinical trial results and several therapies having already been approved, antibody therapies have not yet played a large role in the fight against COVID-19. In this episode of Coronapod, we ask why.

News: COVID antibody treatments show promise for preventing severe disease News: Antibody therapies could be a bridge to a coronavirus vaccine — but will the world benefit?

Never miss an episode: Subscribe to the Nature Podcast on Apple Podcasts, Google Podcasts, Spotify or your favourite podcast app. Head here for the Nature Podcast RSS feed.

doi: https://doi.org/10.1038/d41586-021-00766-w

Transcript

Noah Baker and Heidi Ledford discuss COVID-19 antibody treatments.

Benjamin Thompson

Welcome to Coronapod.

Noah Baker

In this show, we’re going to bring you Nature’s take on the latest COVID-19 developments.

Benjamin Thompson

And we’ll be speaking to experts around the world about research during the pandemic.

Amy Maxmen

We’re entering a new era now. We have new COVID strategies, there’s some new unknowns and we’ve got a vaccine.

Noah Baker

Hello and welcome to Coronapod. Ben Thompson is not with us this week but joining me, Noah Baker, is Heidi Ledford. Heidi, how are you?

Heidi Ledford

I’m great, thanks. How are you?

Noah Baker

Yeah, I’m not too bad. I managed to cut my finger open over the weekend but it’s all healed up and so I’m sort of just holding my hand in the air as though I’ve always got a question to ask. So, this week on Coronapod we’re going to talk about a therapy that we have mentioned before. We don’t talk about therapeutics very much and the large reason we don’t talk about therapeutics related to coronavirus is that there aren’t very many of them, to be honest. We’ve got steroid treatments that have been shown to be effective, and outside of that there are very few treatments, but one of those treatment options is monoclonal antibody treatments. Heidi, remind us what do we mean by monoclonal antibodies?

Heidi Ledford

Yeah, so I think by this point in the pandemic we’re all pretty familiar with the idea that antibodies are made by our immune system in response to infection and that they can be very important, particularly in coronavirus infections. Some of them can even bind to the viral proteins and keep the virus from replicating, for example, which is really key to limiting the scope of the infection. But when your body does that, when your body launches that kind of attack, it’s usually not just making one antibody, it makes a whole slew of antibodies against maybe different coronavirus proteins, even against different regions within the same coronavirus protein. A monoclonal antibody, though, is when researchers pick one of those antibodies, they pick one that looks like it’s doing really well at recognising even neutralising the virus and they say, ‘Okay we’re going to make vats of that stuff and we’re going to infuse it into people who are sick and see if it helps them then recover from the illness. These were among the first therapies that they reached for, I think, when the news of the pandemic broke and they were like ‘Okay, what are we going to do.’ Monoclonal antibodies were one of the first, highest priorities.

Noah Baker

So, am I right in thinking that you could think about an antibody therapy a little bit like the temporary version of what a vaccine might do? So, you’re just shoving in the antibodies, the body isn’t making them, which means they won’t be able to make them after the therapy is finished, but you are kind of putting in the end goal of that immune response which gives you a protection for a period of time.

Heidi Ledford

Yes, that’s right, and it’s really important, actually, that you brought up the point that the effects are transient, right. This antibody only works as long as it is in your bloodstream. Once it is broken down and degraded, it’s gone. That’s it. That’s your protection done. So, it’s different from vaccines in that sense but it is similar to a vaccine in the idea that you have this directed response against the virus.

Noah Baker

So, various trials have been ongoing looking at these antibodies, and quite famously these leapt into the news when Donald Trump became infected with SARS-CoV-2 because that was one of the treatments he received. Tell us a little bit about the trials that have been ongoing.

Heidi Ledford

So, these sorts of antibodies, we know they can be useful but they are a bit finicky, I think, in the sense that you have to kind of pick and choose how and when you use them. So, some of the earliest studies of these monoclonal antibodies were looking at people who were already quite sick with COVID-19 and were in the hospital, and there’s an argument to be made than a monoclonal antibody is not going to be particularly effective at that point and there are a few reasons for that. One is that by the time you’ve been infected for a while, if you’re immune system is functioning, it’s a good chance you made this antibody or something like it already and it just wasn’t enough, it didn’t work. But the other thing too is that by the time you become very sick, it’s not just the virus that’s making you sick, it’s other aspects of your immune response that start to really inflame tissues, cause tissue damage and so on, and getting a monoclonal antibody is not going to treat that. So, some of those early studies that were done in patients that were very sick, they didn’t turn up good results and that was to some extent to be expected. It was worth trying, right? I mean, we really wanted to try. Now, since then, we’ve had some other trials looking at what’s called post-exposure prophylaxis. So, if you had, for instance, if you’re in a nursing home and someone becomes sick with COVID-19 and now, oh no, you may have an outbreak on your hands, if you don’t have a widely vaccinated population there, let’s say, then maybe you want to try to give some of these antibodies to the residents and the staff at the nursing home to see if that helps prevent them from being infected. Or if they are infected then maybe you can limit the scope of that infection and the spread. So, that was another scenario in which they were tested and that one showed a lot of promise but by then we had vaccines, so it still could have a use but the vaccines really kind of eat into the notion of using it for prophylaxis in that sense. And then you’ve got these trials, and some of the ones we wrote about recently, where you’re looking at people who have only recently become infected and are not very sick yet so they have quite mild symptoms, if symptoms at all. There you might see a benefit of using these sorts of monoclonal antibodies, and that’s where they did see it was on the order of about 85% protection from hospitalisation and death when they used monoclonal antibodies in that setting. So, that does look quite promising.

Noah Baker

So, 85% – that seems like quite a high number. We’ve been blessed with high efficacies of various therapies, including vaccines, throughout this pandemic, and those results have come out relatively recently – in March is when we’ve started to see those results coming out – is there going to be an explosion of monoclonal antibody treatments now? Like what’s the response to that?

Heidi Ledford

It is a bit tricky because there is the issue of timing. There’s also the issue of expense. They’re quite expensive and it’s not even just a jab, right, it’s an infusion, so you have to go to a hospital or some sort of specialised outpatient treatment centre. It’s not something that you can really roll out on a huge scale, and it’s a little bit tricky with these trials because they’re not like the big vaccine trials where we had 40,000 people enrolled and beautifully crafted trials looking at a diversity of subjects and so on. The data here is coming out in smaller trials and they haven’t been published, many of them, as well. So, they’ve been press released and regulators in various countries likely have the details of this, but some of the key trials haven’t been published yet so researchers haven’t had chance to really pick through it. But so, for these reasons, I think instead of just sort of ‘wow’ headlines all at once, we’ve had a gradual accrual of evidence in favour of these sorts of treatments. There are several of them that are out there now. Several companies have them, and they’ve moved on from testing just one by itself to testing cocktails of two monoclonal antibodies mixed together, and those are in general looking to be quite promising as well, and it’s just a matter of finding the right way to use them.

Noah Baker

I find it really interesting that one of the things you cite as a potential reason that these therapies might not have been taken up that much yet or that they might not be taken up as quickly as we might expect is that the data hasn’t been published because certainly what we’ve seen throughout the pandemic so far is that countries have not necessarily needed really robust data to make quick decisions about treatments in the past. Is the game just a little bit different now in the context of a world well we have vaccines, in a world where things are little bit more under control perhaps in certain places? I mean, why would people need more than a press release now when in the past they didn’t seem to need more than a press release?

Heidi Ledford

I think it’s a combination of things and I think part of it is that regulators, the FDA for example has already issues several emergency use authorisations for the use of monoclonal antibodies in the Unites States. They’ve had access to this data, they’ve looked at it and said it’s okay. But I think that individual physicians, I think that the standards maybe have risen a bit over the course of the pandemic and some of that may be due to things that we’ve seen – you could call them missteps, right – with hydroxychloroquine, for example, which received an emergency use authorisation from the FDA very early on in the pandemic with very little evidence to support it. We also saw convalescent plasma, for example, being authorised ahead of studies really demonstrating whether or not it would have a benefit. So, I do think there has been a bit of growing scepticism about the EUA process. I do also think the FDA has tightened up some of its EUA processes and it looks to be more transparent about what data its using and why its granting these, but yeah, I do think you may see some more hesitation from individual doctors, basically.

Noah Baker

And I suppose there is also kind of a problem of mixed messages here because there are these various different scenarios in which the monoclonal antibodies or cocktails of antibodies could have varying levels of efficacy, and if the first things you heard about as a clinician when you’re reading the New England Journal of Medicine and you see a study or see a report that comes out saying that it doesn’t really make a difference in people that are severely ill, that’s the thing that sticks in your head and it takes a while to get over that and think about it in a different way and a different context.

Heidi Ledford

Yeah, people are telling me that there’s been a stigma, not a huge stigma, but a bit of a stigma attached, and people will say, ‘Oh, this data has come out suggesting that it works but I already heard that it didn’t work so this is not on my mind anymore, this drug.’ So, there is an element of that as well. There’s been some talk about potentially a kind of information campaign, I guess you could say, to try to make sure that physicians realise that where this state of the data is when it comes to monoclonal antibodies, what’s really going on.

Noah Baker

I mean, it’s interesting as well that you mention a kind of an information campaign because I can’t really think of a bigger advertisement for using an antibody cocktail than the President of the United States being infected and then attributing his recovery to a monoclonal antibody cocktail. It feels like that would be a big highlight of these drugs but that’s maybe not the case?

Heidi Ledford

I don’t know, I mean did you have that reaction? There is, I’m sure, some segment of the population that did see that as a meaningful endorsement, and that’s good, but former President Trump also really pushed hydroxychloroquine And then of course, when it comes to his treatment, I mean he was one person who received lots of different treatments and may never have progressed on to worse disease anyway. It was impossible to draw any conclusions. So, I think he did, I’m sure that he got the word out there to some segments of the general population at that time during the pandemic, but whether or not most physicians would… to be honest, I don’t know if it hurt or helped. I think it probably depends on what part of the country you were living in and what part of the world you were living in for that matter. I do remember during the hydroxychloroquine mess talking to physicians who said it was almost like they had to have two different treatment plans – one for Republicans and one for Democrats – because they would come in demanding different things. One would want the hydroxychloroquine and the other one did not want to go anywhere near the hydroxychloroquine, so yeah, these political messages certainly kind of muddle things a little bit.

Noah Baker

So, I’m really interested in what the role of monoclonal antibody treatments could be going forward. So, we know that they’re not necessarily very effective once someone has severe disease. At that point there’s not much point in using them. But given that we know that monoclonal antibodies do seem to be quite effective at early stages of infection, they could work as a post-exposure prophylactic, but also they’re very expensive, they need to be given in these specific environments and we’ve got vaccines, what is the role of an antibody therapy at this point?

Heidi Ledford

It’s looking quite niche, isn’t it? But they still could be useful and in some ways, given how expensive and difficult they are to administer, it’s nice to be able to narrow down that pool a bit. There is the point that it’s going to take us a while to vaccinate everybody so if we have a way to help prevent serious illness in people prior to their being vaccinated then that’s useful. The other thing is that there are some people that will not be able to mount a good immune response on their own for whatever reason – they may have an immunodeficiency or what have you – in response to vaccination, so they may benefit from this kind of treatment. It’s called passive vaccination. After that, the vaccines are not always 100% effective so if you have these breakthrough cases come through, there is a chance that maybe giving these monoclonal antibodies will help. We don’t know that yet because we haven’t obviously tested in that population, but that’s a possibility. And I think one thing maybe that I should have mentioned earlier is that some of these trials, for example, that are testing in mild disease, it’s not just people who have mild disease or are early in infection but also they are, for some reason, at high risk for developing severe illness, and so in those people in particular, this may be useful. Because it is so expensive and difficult to administer, you don’t want to really give it to just everyone who tests positive. But for those people who do have reason because of their age, maybe because they’re obese, maybe because of some other existing condition, diabetes for example, this could be something that could help.

Noah Baker

And I guess the other key question that people will be asking now because there are concerns with the vaccines is about variants. They’re concerned that the vaccines may become less effective. Where do monoclonal antibodies stand in this environment?

Heidi Ledford

Well, I mean, there are some people who are quite concerned that if you start rolling out individual, single monoclonal antibody therapies on a wide scale that you’re going to encourage the development of resistance against that antibody because you don’t have the breadth of a response like you do in a natural infection. It’s really just that one antibody that the virus needs to evolve to evade, and it might be relatively simple for it to do so. That’s one of the arguments for combining two antibodies together into one cocktail, preferably if they target different regions of a protein or different proteins. So, that is a concern. There was an interesting development in that case, I guess, with one of the antibodies that had clinical trial results announced last week, and that was an antibody made by a company called Vir Biotech and GSK (GlaxoSmithKline). That antibody was actually isolated against SARS-CoV-1 from someone who was recovering from SARS during the outbreak in 2002-2003, and happened to have it on hand and tested it against SARS-CoV-2 and found that it was also effective, and that particular antibody targets a bit of a protein that tends to not mutate. It tends to stay very stable and there’s evidence, I guess, of that because you see its stability between SARS-CoV-1 and SARS-CoV-2. So, there’s some hope that might be a little bit less susceptible to resistance because that region of the protein seems to be so important for the virus. It doesn’t tend to accumulate mutations. As far as the variants that are already out there, I’d have to go back and look to see the data for sure. I think there’s been some patchy lab results from these antibodies. I think some of the monoclonal antibodies, when tested on their own against the variants, didn’t perform very well but when you looked at the cocktail, I think the cocktail did much better. But I would have to go back and look at the numbers on that.

Noah Baker

I feel like the future of monoclonal antibody therapies could be a little bit unknown for us. I’m really interested to see what place they take in the sort of annals of when we read the history books of how this was tackled. In the meantime, Heidi, thank you so much for joining us this week. I hope you have a good, virus-free week coming up.

Heidi Ledford

Thanks, you too. I hope your finger gets better.

Noah Baker

Thank you very much.

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