麻豆传媒

What's it like in a New York lab working with Omicron right now? 麻豆传媒 spoke with Benjamin tenOever, PhD, a virologist at NYU Langone Health, for an inside look at sequencing efforts to track down Omicron.

The conversation also touched on Omicron origins (it's not from the Delta lineage); why kids haven't been as affected and why Omicron could change that (it's about ACE2 receptors and puberty); why live-attenuated boosters may be a good idea (the virus makes a lot of nucleocapsid protein); and why tenOever isn't too concerned about this variant ("What Omicron represents is scary, but Omicron itself is not scary").

An edited transcript of the conversation follows.

What is your lab working on right now regarding SARS-CoV-2 and the Omicron variant?

tenOever: We've been studying how viruses interact with their hosts for 20 years now. In the beginning of the pandemic, the lab shut down all ongoing research and everybody transitioned to working with SARS-CoV-2. At that time, it was the Washington strain.

Initially, we worked with ferrets and organoids. We were characterizing how the virus interacted with the host, what the inflammation looked like. Then we transitioned to the hamster, probably about 6 months in, when it became clear that the hamster was a better model for COVID-19 than the ferret.

Pre-Omicron, we were studying long COVID in hamsters, and we have a manuscript under review. However, with Omicron surfacing, the World Health Organization quickly banded together the community again -- because we were slowly fading away from our weekly calls -- and said, it's really unclear whether Omicron is something we need to worry about, but we do need to get this answer quickly.

They wanted us to view this as a rehearsal for the next pandemic. The idea was, let's pretend this is a whole new virus. What can we do in 100 days? Have we learned anything from our past experience to do this faster and better?

In some ways, that kind of worked. It did rally the community a little bit. I now have Omicron in my lab so we can do tests. Right now, we have hamsters that have been either vaccinated or previously infected, and we challenge them with Omicron so that we can answer these questions about whether the way you taught your immune system -- either via vaccine or infection -- will still protect you from Omicron. My guess is the answer to that is going to be, yes.

Why do you suspect that?

tenOever: Yesterday there was a paper from South Africa and it appears that people who have been vaccinated and have antibodies can neutralize it. It's the same kind of data that Pfizer published today.

The proteases and the replication machinery of Omicron has not changed compared to Beta or Delta, so it's also clear that drugs like Pfizer's drug and Merck's drug are still going to be equally effective against Omicron.

The truth is that I'm not overly concerned about Omicron at all. All the cases have been very mild and I don't actually understand where the hysteria is coming from. There have been a couple of people loudly saying on Twitter that this new virus is 20 times less affected by the way you taught your immune system, but the truth is that's really hard to predict that computationally.

Two, it throws out all the other dynamics that are in place. It's not just about the antibodies you make, you also have a T-cell response, you also have a response at the cellular level. Those things all contribute to our ability to fight off an infection.

To do something, either by modeling, or based on the serum of one individual and see the antibodies in that individual, and how well they can neutralize the virus, is really only a tiny piece of the overall picture. It has created a bit of hysteria that is really unjustified, because the data we really need that nobody has, is where you take an animal and you actually infect it. Or you look at humans who were infected.

Is there anything notable about Omicron compared with other variants?

tenOever: The one thing about Omicron that is noteworthy is that the lineages have thus far built on the one before it. They are improving in their ability to bind to ACE2 very incrementally. So the difference between Beta and Delta was a few incremental changes in spike protein to increase its ability to engage this receptor.

That has consequences not just for transmission, but it probably also is allowing the virus to get into younger populations, because it does seem like the expression of ACE2, which is part of your angiotensin system, does turn up with puberty. That's probably why this virus has largely spared kids, because they don't have a lot of ACE2 in their system. As the virus gets better and better at binding ACE2, it also gets more and more capable of infecting people with less ACE2. So that's a little bit worrisome.

But the real weird part about Omicron is that it doesn't come from Delta. You would expect the next variant to be an incremental change that builds on Delta, but Omicron's closest relative is actually from mid-2020. The reason why that's fascinating is that it means that somewhere in mid-2020, the virus that was then circulating the planet jumped somewhere different, and has been hanging out in that different place for over a year now. That explains how it could have ever developed 35 amino acid changes in spike and a protein that's actually better and can outcompete Delta. So it's not from the Delta lineage at all.

What's the most likely origin then?

tenOever: There are three possibilities there. The least likely is that it jumped into another species.

You could imagine that in mid-2020, the virus that was then circulating, the Alpha variant, jumped into a rodent, and then had this playground for a year and a half to basically mutate in every direction and make various improvements. Then it would come back into the human population. It's the least likely because you would expect other changes, not just to spike. And it would demand that whatever the other species was had the exact same ACE2 protein that humans do. That's unlikely.

The other two possibilities are that it happened in humans, either in a community where the virus was asymptomatic and the community was not monitoring, so it just festered for a year and a half until it broke free from that community and got back into the world.

I think the most likely of all of the stories is that somebody who was immunocompromised caught the virus and it had a full year within a single individual to explore all of this space and get to this level. If that's true, it's a bit more worrisome because that really does mean the virus could become endemic. If this happened once, we can certainly expect it to happen again.

So, to me, what Omicron represents is scary, but Omicron itself is not scary.

Going back to the recent South African data: Could there be something else about previous infection -- like having antibodies to other parts of the virus -- that might confer better "booster" protection?

tenOever: There was a really great from Paul Bieniasz's lab where they tried to make a pseudotyped virus that could get past all of the antibodies that the mRNA vaccines make. When they took serum from people who had been infected [and vaccinated], those people still made a greater repertoire of different antibodies that bound to different parts of spike that could still neutralize even that [heavily changed spike]. Being naturally infected and getting the vaccine gives you an amazing coverage on spike itself.

The nucleocapsid protein is a great example. The virus makes a lot of nucleocapsid protein. People definitely drive a very strong antibody response to nucleocapsid, but those antibodies aren't going to bind the virus directly. They are going to help identify dead and dying cells and be able to activate other aspects of your immune component. There are T cells that will now recognize nucleocapsid, so any cell that gets infected, then presents on their surface a piece of nucleocapsid, a CD8 killer T cell will see that infected cell and then immediately kill it. That slows down the infection and the ability of the virus to create more virion, so all of these things are working in concert together.

There's also something to be said for getting a vaccine that is just the dead virus as a booster instead of having more spike, because you could make new antibodies to other components of the virus, N protein being probably the number one to do.

How is your lab involved in genetic sequencing and detection of Omicron?

tenOever: When people show up systemically to a hospital and get a nose swab, that sample can get split into two. One sample goes to a clinical core that does the sequencing. What we do with our sample is we add it to special cells, like African Green Monkey cells, or Vero cells, that have been engineered to be like a beautiful, pleasant breeding ground for the virus. That's because there are so few infectious particles in a nose swab that it takes a really long time to grow the virus out. Once it grows out, we sequence it again, which ends up being a more in-depth sequencing effort that confirms the entire sequence of the whole virus. Usually, the clinical sequencing goes after spike just to see whether it's Omicron or something else.

Is New York state sequencing Omicron in a systematic way?

tenOever: At NYU, [genome sequencing] is not something that the insurance companies pay for. It really is at the discretion of the hospitals or whoever is testing. Historically, [states] haven't invested money in that kind of surveillance.

Is there a need for a more coordinated approach to viral sequencing in the U.S.?

tenOever: It's not inexpensive to do that. What's probably going to happen is -- since it does seem like Omicron is a better transmitter than Delta -- that slowly, we'll have a mixture of Omicron and Delta. But if both are equally susceptible to the vaccine, it no longer becomes the highest priority for the health system to know what strain it is.

There's been a long-standing argument that we need to do better with pathogen surveillance in general. This was even pre-SARS-CoV-2. The truth is this, the money's not there.

There are programs here and there that do things like this. ... Researchers can go into sewage water and perform deep sequencing. In the void of a government program that systematically does it, there are individuals who get access to those samples in an academic setting for their own research.

So we'll have to continue to rely on other systems like the South African system to detect new variants?

tenOever: I think what they're doing is excellent. They followed the protocol, they did everything right, and then they were heavily punished for it. The data suggest that this virus didn't even originate in South Africa. They were just doing their due diligence, like we all should have been doing.

Because of the way the world reacted to their identification and announcement of Omicron, I don't think anyone's ever going to do it again. It's a really bad precedent, and really unfortunate that we immediately started shutting down travel with all these other African countries for no scientific reason whatsoever. Because we did that, I feel like reporting in the future is only going to be less and less free.

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