I’ve had a lot of questions from people about the prospects for monoclonal antibodies and vaccines against the coronavirus, and I thought that it might be helpful to answer them in this format. Let’s start the press conference!
We’ll start with monoclonal antibodies. Why are you so optimistic that this technology will work?
Two big reasons: one is that mAbs are already extremely successful drugs. If you look at the best-selling drugs from last year, 11 of the top 25 are monoclonal antibodies (and one other is a fusion protein with an antibody side chain). We know a lot about producing these things on scale (through several different routes) and a lot about evaluating their effects in human patients. The second reason is even more salient: the great majority of people who have recovered during the COVID-19 pandemic did so because they raised their own neutralizing antibodies to the virus. We know, then, that neutralizing antibodies to the virus really exist and that they are effective. In fact, many of the mAb candidates that are being developed have been isolated via the immune cells of just such human patients (the others are generally raised from the same sorts of cells from humanized mouse models). And remember, it takes some time before an infected person’s immune system can mount a full antibody response, so giving the neutralizing ones in quantity, right at the start, should have a strong effect.
Those things on that linked chart are all for arthritis, cancer, and other diseases. Are there any against infectious diseases like the virus?
There are, but that’s been more of a specialty area. Antibodies have to be given by injection, so it’s not as easy as making (and taking) a pill, but for serious infections it’s a real option. Here’s a recent review on what’s out there now, but it’s important to realize that in recent years we’ve gotten a lot better at discovering and developing mAbs. It’s become more feasible to think about mAbs for other indications, and people have actually been gearing up for their use in the case of an emerging epidemic. Here, in fact, is a 2018 article by an obscure physician named Tony Fauci on just that topic. Monoclonals have turned out to be very useful in the treatment of Ebola (a totally different kind of virus, but one that’s
even more infectious and more fatal than SARS-CoV-2). Interestingly, one good source of antibodies for that one could be people who have participated in vaccine trials against it.
OK, fine. But that chart of yours is for best-selling drugs, and the reason the mAbs are so high on it is because they’re so damn expensive, right? What are they going to cost in this case?
Yeah, that’s a big one. That lands us right into the drug-pricing debate, and it’s important to realize that the existing mAbs, like pretty much every other drug, are priced at what payers are willing to pay. And that is tied to the value of the drug, of course. But all these calculations are pushed aside in the current situation: the value of a drug that will keep health care workers and other front-line people from coming down with coronavirus is clearly huge, but at the same time you’re not going to see companies scooping up billions of dollars, either. They’re very aware of how that would look, and frankly, the industry has been hoping that this whole pandemic might lead to some more goodwill. But that will go right out the window if someone looks like they’re profiteering. You’ll note that J&J has explicitly stated that they’re doing their vaccine work on a not-for-profit basis. I’m sure that there will be arguing about recovering costs, but I would expect that being the company that helps knock down the pandemic is a pretty big gain all by itself. We shall see.
And as for those internal costs themselves, it’s going to be hard to estimate, because we’ve never tried to do a mAb under these time constraints. I would be very interested in estimates from people who know better than I do.
On to vaccines, then. What do you say to people who say that there’s no such thing as a coronavirus vaccine?
Well, that’s not quite the case. There is, for example, a canine coronavirus vaccine available, although one has to note immediately that it’s for an enteric virus, not a respiratory one, and that it itself is of no use whatsoever (in dogs or in people) against the COVID-19 epidemic. But one big reason that there’s no human coronavirus vaccine is that we haven’t needed one. SARS was the first time there was a major coronavirus problem in humans (otherwise there are some that cause a portion of the common colds every year). And it disappeared before a full-scale vaccine effort could come to fruition.
How about the claim that developing one may be impossible, then?
There certainly are diseases for which vaccine development has (so far) been impossible. Some of these are nonviral (tuberculosis, malaria) and in those cases the organisms themselves are very hard to get an immunological handle on. But there are also viral diseases that we can’t yet vaccinate for, the biggest example being HIV. But remember, that one is specifically targeting the human immune response, which makes it a bigger challenge right from the start. Among the more common types of viral attack, hepatitis C comes to mind as one where a vaccine approach has never succeeded. That’s largely because there are a lot of different strains, and it has a high mutation rate. That’s similar to the problem with influenza viruses, which notoriously mix-and-match components to produce a different blend every time around. This coronavirus, though, is in a different family than any of these – fortunately – and while we’ve seen mutations, they are not occurring at a particularly rapid rate and do not look (so far) like they would limit the usefulness of any of the vaccines under development. In short, there’s no reason to think that the SARS-CoV-2 virus is going to be “unvaccinateable”. The opposite, in fact: it has an excellent target (the Spike protein), and many effective antibodies from recovered patients turn out to be hitting it.
So if we can probably get a vaccine that raises immunity to the virus, what’s the biggest worry?
Safety, as usual. We’re stipulating for now that one way or another we can make enough of the vaccine, but that is of course another problem entirely, albeit one that responds fairly well to having enormous amounts of money thrown at it. But any time you’re messing with the immune system you have to be concerned about safety. There can be bad reactions in small numbers of patients that are difficult to catch in clinical trials, and we’re going to be doing a lot fewer of those this time around than we have been for the marketed vaccines. I’m sure that we’re going to be doing as much as possible given the timelines, but there’s really no way to work something out as thoroughly as usual if we don’t want to wait for a few more years.
What happened with the SARS vaccines, anyway?
That’s very much worth studying. Here’s a look from during the original epidemic, and you’ll note that the landscape is pretty similar to what we’re seeing now (attenuated viruses, inactivated ones, virus-like particles, recombinant protein antigens). One thing that didn’t feature the first time around was the mRNA vaccines, which have been getting a lot of attention now, of course, but we don’t know yet if those are going to work. As you’ll see from this WHO list, though, DNA vaccines were indeed in the mix. Several of these went into clinical trials, but the problem was that the disease itself disappeared during this process, so none of these got the full investigation. There are, though, some of these that are being looked at now for cross-reactivity to the current coronavirus, which is quite similar.
So the SARS story is incomplete, but the good news is that the the lessons learned from it are generally applicable to the current epidemic – things like zeroing in on the spike protein and its receptor-binding domain, being alert to antibody-dependent enhancement, etc. We actually have much more of a head start on SARS-CoV-2 thanks to version 1.
How long is it going to take?
And that’s the big question that none of us can answer. We’ve got a lot of different mechanisms heading into humans, with no good way to be sure which will be more effective. And safety is, as always, a hold-your-breath-and-find-out process, as it is for every investigational therapy, vaccine or not. Then there’s the manufacturing and scaleup – these different technologies can call for very different sorts of manufacturing processes, so we’re probably going to spend bushels of money to push more than one at the same time (as we should). There will be problems there, too, most likely (aren’t there always?) So after you’ve run your time estimates through three fan blades like this, what’s left? The timelines you see about having one early next year, it’s safe to say, are for a candidate for which everything works perfectly the first time. If we take enough simultaneous shots, we could have one of those. Or not.