Radiation oncologist at Washington University, Dr. David Curiel talks about a new COVID vaccine that doesn’t require a needle.
Interview conducted by Ivanhoe Broadcast News in 2023.
Why did you start focusing on a nasal vaccine?
Curiel: Because I think that there had been interest in intranasal vaccines previously and there wasn’t a reason why they weren’t pursued other than physician preference. So when COVID came and it was clear it was a respiratory transmitted virus, it seemed a time to revisit the nasal route.
Why did it come out as a shot first? Why not nasal?
Curiel: Well, for two reasons. One is that one of the leading vaccines was mRNA, and mRNA has many, many values, but it can’t be given by the mucosal route. All of the various lipid nanoparticles and other devices can’t accomplish vaccination by mucosal routes. So all the benefits of mucosal immunization that we’re going to talk about, mRNA vaccines cannot accrue that. So one of the reasons the nose wasn’t used first was the companies were aware that you couldn’t use mRNA in a mucosal delivery route. And the other reason was just for the reason that it was a backwater. There was an approved intranasal vaccine, FluMist. It had excellent efficacy, but pediatricians who are at the frontline of giving it just didn’t have a high comfort level with it. So it remained a backorder. One of the themes, I think, that came out of COVID was this old saying by Julius Caesar. And that was, everything useful comes from war. And so in 1995, I was actually the first person to show mRNA could be used as a vaccine. And at the time that I tried to engage pharmacy partners to address the technical issue of upscale, no one was interested.
What was the connection with the war?
Curiel: That everything useful comes from war. So that RNA languished for 30 years and then with COVID, there was the need to make a vaccine quickly and people saw that the value of mRNA warranted overcoming the technical barriers. So that’s war Story 1. So war Story 2 is I’ve worked principally in the area of adenovirus. And there was a gene therapy death in 1989, the so-called Jesse Gelsinger death. And that caused big pharm to view adenovirus cautiously. And so it remained a backorder for 20 years. And then once COVID hit, people revisited the idea, this was actually quite a good vaccine. So here’s two stories of something useful that languished that the demands of COVID, the war as you will, brought it to usefulness.
Why was mRNA the way they chose though, instead of nasal?
Curiel: So, around 30 years ago, an investigator named Jon Wolff showed that you can inject DNA into the muscle, plasma DNA, and it would express genes and it can be used as a vaccine. But the thing that was recognized was muscle was unique at having this ability to take up the DNA and express it. No other tissue did it. You could inject it anywhere, you could spray it anywhere, it didn’t work. So the investigators with RNA capitalized on that. They gave it to the place that it worked; the muscle. And even to this day, there’s a very limited repertoire of ways and sites that mRNA can be delivered. It works great in the muscle, and that subserves the goal of one kind of vaccination, but it doesn’t work in a lot of other contexts.
Why did you say nasal is the way we need to go?
Curiel: Because of the recognition that this was a respiratory transmitted disease. We needed to augment the respiratory defenses and it was well-recognized that mucosal vaccination, I’m using those words interchangeably. Nasal immunization is one form of mucosal vaccination. Other forms are in the lung or in the gut. So I’m using the words interchangeably. So it was known that mucosal vaccination generated augmented immunity at mucosal sites. So it seemed logical with such a threatening respiratory pathogen. And remember, three years ago everybody was dying of lung disease that was being transmitted through the air. So it seemed like the occasion to revisit, how can we best augment lung defenses?
How does your vaccine work?
Curiel: So, we’re taking advantage of adenovirus, which is a virus that normally infects via the airway, and we’re engineering it to encode the genes for the SARS-CoV-2 virus, the virus that causes COVID. And we even go one step further. We’re using an adenovirus that’s derived from a chimpanzee. So this is similar to the human adenovirus, but different enough that it will traverse any immunity to the human adenovirus.
There are the naysayers of the vaccine. We don’t condone that. But they were like it’s mRNA, it’s going to kill you. You don’t know what it’s going to do to you. You’re the man behind that, but you know the naysayers, what they say. They spout this off. Does this shut them down because it’s not mRNA?
Curiel: You’ve made a really good point. It’s important to remember that when mRNA was applied for COVID, there was a good deal of interest in the biotech community and people imagined this was a medical revolution and that it was going to be used for everything. Well, in fact, it can be used for some things really well. It can be used for those contexts where you need to make a vaccine quickly. A pandemic, or this new field that we call personalized cancer vaccines, where we take a patient’s tumor DNA, find the antigen and put that antigen into a vaccine. Those are two instances where you have to make the vaccine quickly and in which the unique ability of mRNA to be rendered into a vaccine quickly give an advantage. But for many other diseases that’s been proposed, cystic fibrosis, or inherited genetic disease, mRNA has difficulty being delivered into many places. It’s a short-term expression vector. So it’s clearly not going to have value for every single possible application where you need gene transfer.
But for your vaccine it doesn’t use mRNA, right?
Curiel: And so I’m really hammering on this important point. What our work showed was that mucosal immunization gives you superior immunity in the airways, which is of a special utility for respiratory diseases like COVID.
Especially because that’s where you’re killing it before it gets a chance.
Curiel: Bingo. So presently, the available mRNA species and their vectors are not effective delivering mucosally. So at the present time, whatever are the advantages of mRNA, they can’t be applied to mucosal route. And therefore you can’t get the airway immunization that our vector can give. I can talk a little bit about another piece of this that’s really interesting about the White House Summit. So, Mike Diamond and I, who developed this approach, we can’t claim to be nose biologists or legitimate mucosal immunologists. We’re vaccinologists who recognized an opportunity. But once we saw the value for COVID, we also recognized we had tools that can make it even better. That our virus wasn’t engineered specifically for the nose, it was just a respiratory virus, but we have the ability to engineer the virus very profoundly. So our studies provoked interest at the NIH and the NIH provoked interest at the White House. And the White House, about four months ago, had a summit where they brought in all the biomedical leaders who highlighted the value of intranasal approach and proposed something like a moonshot initiative; resources and effort directed to make this new and exciting approach even better. And then nothing happened. And it turns out that the COVID vaccine, for whatever reason, is still fairly political. So the NIH having a su- provoking the White House to have a summit, the White House having a summit to try to engender public support and investment, that’s how things are normally done. That’s how the NIH gets what we call a set-aside for an area of importance. And I always highlight the government can move really fast, like when there was a Zika outbreak. Does anybody remember Zika anymore? Money moved very fast from the public sector to the laboratories. So here’s an example of something even more supremely important in which the White House did everything they were supposed to do to engender interest, and it died on the vine. So it has been- as somebody who knows how to make these vectors even better, it has been frustrating. Waiting for NIH support to underwrite that.
Now, tell me why you started it in India.
Curiel: So, India, it turned out and it was surprise to us, as a really, really well-developed infrastructure to do large-scale production of viruses. Two of the biggest vaccine producers in the world are in India, Serum Institute of India, and Bharat Biotech who we work with. And number 2, is they have an incredible ability to do clinical trials because of the public health structure there are public health nurses in each and every little Indian village. So it’s easy to set up a trial and monitor it. So quickly after our study was published, Bharat Biotech came to Warsu and sought to license the technology. And we saw their ability to make the virus quickly, and we saw their ability to trials quickly as real value-added. So even though we started later than the big companies, they accomplished in no time validating trials and they gained approval in India. So this is now a drug that’s approved. And there are flower covered buses driving around villages distributing it.
Is this the number 1 way to get a vaccine in India?
Curiel: Presently, yes. And now we’ve licensed it to an American company AquaGen, and we’re in the process of mentoring them through their FDA approval.
So, could we see it this year?
Curiel: Yeah, I think the company is targeted to go to the FDA by the end of this year.
Tell me about your studies. Is it better than the mRNA when it comes to fighting?
Curiel: I think some of those studies, we’re going to take a long term studies. I think in terms of augmenting the lung immunity and preventing severe disease, it’s as good or better. I think the question people are really now focused on is which vaccine can limit transmission. And that’s what the studies are now being set up to look at.
Why do you think yours will be?
Curiel: Because up for the reason of augmenting respiratory immunity. But if you’re blocking the main site where transmission occurs, it’s logical. A systemic injection like mRNA will augment antibodies in the blood, not so much in the lung. Airway vaccination, nasal vaccination all commands antibodies in the nose and airways, and that’s a better defense. And as example of that, one of the other strategies that’s very exciting is people are trying to deliver antibodies to those directly, to directly augment airway defenses, which is what we’re doing with our vaccine.
Is this vaccine something that can be easily tweaked like the flu vaccine and the COVID vaccine?
Curiel: Yes. I want to make this point so clearly. And this goes back to everything useful derives from war. There was nothing wrong with intranasal vaccines and we were not the discoverer. But we used it in a way that made people take a second look at it. Having said that when the White House have their summit and they had five or six companies who wanted to do intranasal vaccines, none of them were using agents specifically designed for the nose. And my point is, we know enough about the biology of the nose. We know enough about the immunology of the nose that we can make a virus specifically for the nose. And that would have theoretically greater potency. And so that’s what we had hoped the government’s support would provide, is for us to design a new generation of vaccines truly tailored for the noses biology.
And so you talk about the other one, you call it the mRNA vaccine. What do you call this? Like, what is the key agent? What is the thing?
Curiel: So, our adenovirus is naturally a respiratory virus. But one of the things to really highlight is that historically, when biologists were trying to learn the basic rules of biology, how genes are controlled, how proteins assemble. The tool they used was an adenovirus, the very thing we use for our vaccine. And this was such an important agent and meta in scientific history that when you go to Cold Spring Harbor, which is where all this fundamental science was done. The weather vanes on the laboratories are little adenoviruses. So it’s not an exaggeration to say we know more about this virus than any other virus. We know its structure down to the level of electrons so that we can engineer it a lot more rationally, that we can engineer other viruses. So what this leads to is the idea that we can engineer the virus rationally. So it infects the nose better. It’s more potent and even builds upon what we’ve accomplished already in terms of the value of the respiratory route.
So, a lot of the vaccines that we had in our past where we were being given the live virus. So basically this vaccine, again does that?
Curiel: No, this is a replication defective virus. We’ve deleted a portion of its genes so it can’t replicate.
And then, I find you fascinating on several levels, not just the butter sculpture. You were at the very beginning of the mRNA. And now you’re at the very beginning of this four.
Curiel: Right. There’s a middle piece too. We know so much about this virus and this is a three-dimensional structure of the virus. And it just shows how we know all of the atoms that make up the capsid. And this green protein is called fiber. And this is the one that dictates which cell is infected and how, dictates what we call tropism. So we can engineer this fiber protein so it binds to other cells or binds to target cells better. So as an example, there’s the use of this virus as a replicating cancer agent. It’s called virotherapy. And lots of biotech money was being applied to engineering viruses as anticancer agents. And we said, well, wait a minute. It may not be that tumors infected as well as it could be. We can engineer the virus so it’s more infectious. In fact, we made this virus 10,000 fold more potent than what was already going into people with simple engineering of the capsid. So that when Joe Biden son had a brain tumor unfortunately, and they were looking for the best therapy, they used the virus made in my laboratory, this tropism modified virus. And they- Joe Biden wrote a book about it called Promise Me Dad. But that’s an example of how a discreet and targeted change in the virus traumatically enhanced its potency. So all we’re really saying is, now that we know the nose is a good route, we can make similar changes that will make the virus even better for that new application.
END OF INTERVIEW
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