番茄社区

番茄社区 spoke with Warner Greene, MD, PhD, of the Gladstone Institutes' Center for HIV Cure Research and a professor at the University of California San Francisco, during a about what the new COVID-19 variants mean about the course of the pandemic, and what impact they could have on vaccines and treatments.

Greene addressed potential modifications to booster doses to combat these variants, how much they may resist antibodies and compromise immune responses, and whether we'll have to cope with new "escape variants" forever.

Following is a transcript of the interview; note that errors are possible.

We are honored to be joined once again by Dr. Warner Greene. He's senior investigator at Gladstone Institutes and a professor at University of California San Francisco. As we've discussed, COVID-19 variants are very much in the news. Can we go over what is the latest news about the variants, even today? What do we know about them and what's the latest that's been happening?

Variants are very much in the news. What we're seeing is the slow but steady evolution of the coronavirus. There are now four major variants that are of concern. And, in fact, they call them variants of concern. The first recognized was the U.K. variant, recognized in the south of the United Kingdom. It has an increased transmission efficiency. And there are some reports that it may be somewhat more virulent, particularly in men over the age of 60.

Of even greater concern is the South African variant, which contains mutations that confer resistance to certain monoclonal antibodies, like one of the two monoclonal antibodies developed by Regeneron. The Eli Lily monoclonal antibody doesn't seem to work against the South African variant and vaccine efficiency is also reduced with the South African variant.

Similarly, the Brazilian variant has basically the same set of mutations that are conferring antibody resistance, causing real concern. What it means for the vaccines, etc.: I think that both the South African and the Brazilian variants are a major concern. And it is possible that those variants as they spread, and they are in the United States now, we may need to revise the vaccines to account for these types of variants. That's not clear yet, but better to be prepared, in case we do need to revise the vaccine.

And then there's a fourth type of variant, which is just kind of emerging, less well-studied at this point, but out of California. So clearly there, the virus is searching for a lock and key mechanism trying to search for ways to allow itself to replicate better. We're applying immune pressure. So it's mutating away from some of that immune pressure, and that's why this antibody resistance is emerging.

So what types of mutations does the SARS-CoV-2 virus have to go through to make it a variant?

Well, for example, the South African variant has 27 mutations, nine of which occur in the spike protein. The spike is the protein on the surface that binds to the ACE2 receptor and allows entry and fusion into the host cell. And, of course, that's where most of the vaccines are focused, is on the spike. That's where the monoclonal antibody therapeutics are focused, on the spike. And so the virus is looking for ways to avoid these types of immune pressures and it's making mutations in its receptor binding domain and the internal domain that confer resistance to certain types of neutralizing antibodies.

Given that recent studies from Novavax and Johnson & Johnson last week found somewhat reduced clinical efficacy of vaccines against these variants, what type of booster modification is required for vaccines in order to better combat them with the mRNA and the viral vector vaccines? Is it different, is it the same?

I think the booster that, for example, Moderna and Pfizer are now working on is to take the genetic sequence of the variant and use that as the immunogen. So, there is a mutation at position 484 that is absolutely key for this loss of antibody protection. You would introduce an RNA that now has that same mutation at position 484 into the vaccine to create a vaccine that is really tailored to take that particular type of virus out. And that mutation is shared between the South African and the Brazilian variants.

And so it wouldn't require a different type, depending on the type of vaccine, it would just be the same type of reformulation. It wouldn't be mRNA, different than a viral vector, it would just be a different formula. It's not anything to do with the type of vaccine. It still would be an mRNA-based vaccine. It would just contain a different RNA or more likely it will be a multi-valent vaccine that would be original virus, as well as a new virus.

It's not clear exactly how that would be administered. It may be that we want to boost immunity against the old virus, as well as the new virus, so we would use a multi-valent approach in that case. But the mRNA vaccine platform is quite amenable to this type of updating. That's a real advantage, much more so than the adenoviral vectors, the virus-delivered vaccines. It's a more complicated process there.

If we could just look at the vaccines as we have them now against this wild-type strain, if for some reason we didn't have any boosters, what type of progress could we make against the pandemic? Can we vaccinate our way out of the pandemic, even if we don't have these boosters? Have these variants prevented that?

To be clear, these variants, the Brazilian and the South African variants, are only compromising the neutralizing antibody response against the coronavirus. The T-cell immune response presumably is fully intact and remains unevaluated. So it's quite possible that these vaccines will stand up better than we expect or predict. Clearly the U.K. variant does not appear to be a threat, although the recent acquisition of the neutralizing mutation at 484 causes concern that the virus is evolving. Even the U.K. variant is evolving.

I would say that the one thing that is disturbing to me, or that causes me pause is the story in Manaus, Brazil. Manaus is in the Amazon basin, they had a huge outbreak in the spring. It was thought, as reported, that there would probably be herd immunity within the community up to about 75%. Then this variant comes in to the community and it's just sweeping through, causing re-infection or what appears to be re-infection.

Now did the original immunity wane and these people were all sensitive? Is it just that the variant is able to avoid both the T-cell and the antibody response that was present in the herd in Manaus? That kind of real-time experiment is concerning in terms of the spread of this virus. And I think data like that and what's going on in South Africa is what's really prompting the vaccine companies to get prepared now. We don't know the full dimensions of the problem, but better to overprepare at this point in time.

So, given what happened in Brazil, do you think that's evidence of viral escape?

Certainly the South African and Brazilian variants, the mutations they are acquiring in their spike protein are examples of escape from the antibody neutralization. These are mutating principal antibody-binding sites that are responsible for neutralization, so that these variants are emerging under the influence of immune pressure. It's harder to get around the T-cell immunity though, because T-cell immunity differs from person to person based on the composition of our HLA genes and our immune response. And T-cells are really the major defense mechanism against viruses, so let's hope that our T-cells fill in for any gaps that the antibodies might come up a little short on.

I'm not sure exactly what has happened in Manaus, whether there was really ever herd immunity, whether it's waned, but I do know that the variant there is hitting hard. So, that's a big question mark. I think Brazil holds the answers to a lot of the future of this pandemic. We need to understand precisely what is going on there.

What do we need to be studying in Brazil specifically? And what type of data would we need to be looking at and tracking, what types of real-world studies and epidemiological studies would you like to see out of what's happening in Brazil to help us going forward?

I would like to know whether or not there was real herd immunity. Before this new variant began to spread, was there clear evidence of a good antibody response and retention of durable antibody responses against the original strain of "wild-type" virus. So if, in fact, there was an intact immune response, and this virus was able to overwhelm that response, well that's not good news, but if the response had waned or had never really developed fully, then that's a less daunting problem.

Now on the positive side, you look at the Johnson & Johnson vaccine, it's not the world's best at preventing you from becoming infected with or developing minor respiratory symptoms. But even with the South African variant, this vaccine protects you from severe disease, having to go to hospital and dying. And frankly, that's what we want from a vaccine. That is fantastic. You may have a runny nose or a mild upper respiratory tract infection, but you're not going to develop life-threatening pneumonia and require hospitalization, intubation, etc. And I'd sign up for that type of vaccine any day.

All we have from the mRNA vaccines from Pfizer and Moderna are these kinds of in vitro and in lab studies that if you expose them to these variants, this is what they'll do, but do we need some type of clinical efficacy? Would you say at this point that we don't have evidence of clinical efficacy against the variants with these two vaccines that are currently being distributed?

Exactly. The mRNA vaccines are not being tested extensively in areas where the variants are prospering, but one of the trial sites for Johnson & Johnson was in South Africa. So they were able to see how their vaccines stood up against that variant and it fared very well in terms of prevention of serious disease.

When do you think that we are going to get these types of studies? Is that something that we're going to see as the vaccine trials kind of evolve, and are we going to be able to get that from the mRNA vaccines? Are we just going to not know what their clinical efficacy is until we get a booster, we're just going to only have the lab evidence?

It's likely that the virus is probably replicating at higher levels or more virus is replicating in terms of country here in the United States than almost anywhere else in the world, in terms of the breadth of cases that we've had, etc. We just simply do not have the genomic surveillance types of apparatus to necessarily detect these variants. For example, we're just now detecting the California variants. There may be many variants in the United States. We do know that the Brazilian, as well as the South African, variants are in the United States, and it's possible that there is community spread of these variants. So, we just have to really ramp up our sequencing efforts to really track what's happening within our pandemic within the country and what types of viruses that we're dealing with.

And it's in that kind of setting as variants begin to hold sway. For example, it's suggested that the U.K. variant will become dominant in the United States by March. So, our prediction is that the current vaccines will do very well against that variant. Now, if that variant is replaced by, for example, a South African variant, which is more immunologically daunting, well then we're going to have to see how the mRNA vaccines hold up against that. And it's that kind of real-world information that's going to inform whether or not we need to boost the immune system with a third shot.

Are the variants occurring in regions due to the similarities in the genome of the regional population, causing the viral RNA to mutate in a specific direction, and do antigen tests pick up variants?

No, the antigen tests will not pick up the variants. You really have to do the sequencing to find these mutations. So, it's clear that the virus has a set of mutations and it's trying different combinations. All the virus wants to do is to replicate better. The U.K. variant has one mutation in the receptor binding domain, which confers tighter binding to the ACE2 receptor and a higher level of transmission by 40% to 70%. And that's the variant that may become dominant here in the United States by March. In contrast, the South African and the Brazilian variants, they not only have the same mutation that the U.K. variant does, they've added to it. They've added at least two additional mutations that really take out these neutralizing antibodies.

Now, did these two variants arise independently? Some would say yes. I don't think that we know precisely because one person coming from South Africa carrying the virus could seed the virus in Brazil. So we don't know, but there are subtle differences. The virus is working toward a solution here for avoiding the antibodies.

Now, another question is, is the virus throwing everything at us right now that it's got? Is this it and can we expect a pretty much static situation from here on out? And, you know, I don't think so. I think the virus still has tricks up its sleeve, and will continue to evolve as we put additional immune pressures on it. So, that would be my guess, but we're right at the cusp of the evolving science. And to think that where we were a year ago with no defense, no innate or no intrinsic immunity to this virus, and nothing really therapeutic or preventive. And now we're in a situation where we have multiple, highly effective vaccines. It's a true triumph of science.

Can you go into how else the virus could mutate? Is there any way that it could mutate that T-cell immunity that we have that would be compromised? Is that possible or is it just not that complex a virus?

Yeah, there may be the emergence of escape mutations that escape a cytotoxic T-cell, CD8 T-cell responses, or CD4 helper T-cell responses. We could certainly see that and it's much harder to monitor for those types of immune reactions. So, certainly, like you get immune escape against antibodies, you can have immune escape against T-cell immunity as well.

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