How to design COVID-19 vaccine? ‘First vaccines will not be very effective.’6

What are the major approaches to design vaccines against COVID-19? What approaches are more promising or more risky?

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As a prominent immunologist, you study the best way to design vaccines. And there are reports of about 70 different vaccines against COVID-19 coronavirus now in development around the world. What are the different major approaches to design vaccines against COVID-19? And what approaches do you think are more promising, and which approaches are more risky? Because vaccines are being developed against different proteins on the virus. Some of them could actually make things worse. There is a view that it is a possibility. When we think about vaccines, we might want to divide that into the antigen that we’re presenting – the piece of the virus that we’re presenting to the immune system, and how we present it. And so we’re especially working hard on the first part, the antigen that’s being presented. Then there are many options for presenting that antigen. Just to give some examples of how to deliver that antigen. You can make it as a protein and inject it. You can make it as an mRNA, messenger RNA, and allow your own body to make the protein version of that. You can deliver it as a viral vector, for example, without adenovirus. So there’s many ways to deliver proteins. The question we have been focused a lot on is, what is the best form, what is the best piece of the virus? And, in particular, what is the best piece of the viral spike or S protein to present to the immune system? So we have to focus on the S protein because that’s the only protein that’s really visible to the antibody response. And the thought is – our thought included – is that some regions of that S protein are especially good to focus an immune response on. And some regions are not useful, and as you suggest, they may even be harmful. And the possibility of this being harmful is something that’s in the literature. It’s not clear that this will be the case. But in any case, I think because certain epitopes are less likely to be harmful, and those same epitopes are the ones that are most likely to be useful. We should focus on those. And when I say epitopes, I mean the piece on the S protein that we want the immune system to focus on. So we’ve been focusing on something, a piece of the protein that we were aware of from SARS-1 from the original SARS outbreak. We call that the receptor-binding domain. This is a small, less than – to throw some numbers here – less than 200 amino acids, piece of the protein of the 3600 amino acids-long spike protein. And that is the piece that has to bind the receptor. And if an antibody binds and blocks that [part of viral S protein], the virus cannot bind this receptor and cannot get into cells. So it is the best-defined region or the molecule that will neutralize the virus. That will prevent the virus from getting into the cell. Because it’s the best-defined, we think it should be part of most vaccine strategies. And the vaccine strategies that focus on larger pieces of the molecule should at least be supplemented by a reminder to the immune system to focus on, to put more emphasis on this important region of the S protein. So, I think I didn’t directly answer the question. The direct answer to the question is that people are using larger forms of this protein, trimeric forms of this protein or smaller pieces such as what I have just described, including pieces like the receptor-binding domain. And perhaps ultimately, a combination of those two will be the most effective. So I see that some clinical trials will start very soon or have already started, but we won’t see the vaccine in about a year or so. But there’s also a view that it might be up to three years until we know that the vaccine is safe and effective. You know, it seems like a large gap. Well, I don’t think it’s three years. I think three years is too long. What I think will happen is we will be getting soon vaccines on the order of six months – between six months and a year – that early reports will suggest are moderately effective. That is to say, they could be useful in protecting healthy individuals. For example, perhaps a healthcare worker. But early vaccines may not be as effective for a broader range of individuals, including especially individuals that are most susceptible to the virus. So it’s entirely possible that there’ll be a second set of vaccines that are more effective, and some of those may even be designed to boost the efficacy of that first set of vaccines. So, again, this first set of vaccines will focus probably on the full trimeric S protein, a full soluble piece of the primary S protein, and a very large piece. And I would expect that one would wish to boost that with a [vaccine that focuses on] a smaller piece, that’s more focused. And that’s what I expect to happen as individuals notice that the first set of vaccines are not sufficiently effective for all individuals. So that probably kind of doubles the time [to effective vaccine]. You try the first vaccine in about six months to a year, you see what the responses are. And then you boost it with another vaccine potentially. That’s another year. Again, I’m a little bit more optimistic. And the reason is that we can measure very quickly in individuals their antibody response. And their antibody responses are very predictive of their ability to control the infection. So if you receive a vaccine, and a month later I draw your blood and measure your ability to stop the virus or a [animal] model of your virus, I can know pretty well how protected you are going to be from that virus. So as a consequence, we can know pretty soon whether a particular vaccine is effective and how effective it is in a range of individuals. The worry is that many of these, the newest vaccines, the easiest to produce, the fastest to produce, are also novel technologies. And we know in the laboratory that any novel technology takes a while to iron out some of the difficulties. Which is the primary basis for my expectation that the first set of vaccines will not be effective enough.