“While there are effective injectable vaccines to fight covid-19, drug makers are creating vaccines that will be easier to store, transport, and administer. Currently, Mayo Clinic is developing a new nasal vaccine platform that may have advantages in blocking the coronavirus. 

The goal is to make protein from the coronavirus, to have the immune system see it, and then, if you actually got infected, to reject the virus. 

I'm Dr. Harlena Gazelka. The covid-19 pandemic has brought public awareness to vaccines and how vaccines work in a way that we've never seen before. A vaccine is an agent that causes the immune system to remember a specific disease-causing entity. In the case of covid-19, that's a virus, of course. And then, when the body sees that entity again or that virus, it remembers it and helps to prevent future infection. 

At Mayo Clinic, decades of research have led to the development of a new vaccine platform–a single cycle adenovirus nasal vaccine. This is now being tested in phase one clinical trials for covid-19. 

–– MAYO CLINIC Q&A ––

Dr. Halena M. Gazelka: Dr. Michael A. Barry is the director of Mayo Clinic's Vector and Vaccine Engineering Laboratory, and he's going to explain to us these vaccines. Thanks for being here today. 

Dr. Michael A. Barry: Thank you. It's great to be with you, and I'll do my best to try to explain and translate from scientists to everyone else. 

WHAT IS THE SINGLE-CYCLE ADENOVIRUS VACCINE? 

Dr. Barry: Most of us are made up of proteins, and the same thing goes for the virus. So actually, for most of the vaccines that are being deployed, and many of you have gotten, the goal is to make protein from the coronavirus, to have the immune system see it, and then, when or if you actually got infected, to reject the virus. 

Dr. Gazelka: That's really interesting, Mike. So the concept is that our body should know what belongs to us, and when it sees things that don't belong to us, it will recognize it as something that's bad. So having more of that protein isn't a bad thing, in that it makes the body recognize it better and mount a better response. Would that be fair to say? 

Dr. Barry: Yeah. So in theory, and at least in practice, when we test these, if we put equal amounts of our vaccine versus the regular adenovirus vaccine, that same amount will drive a much stronger immune response. And so the level of protection is higher. 

The other potentially cool thing is that if ours is really a hundred times more potent, then maybe, if we make a batch of an adenovirus vaccine and a batch of the ones that are out there, we might be able to squeeze a hundred times more doses out of the same batch. So that could be very important on a global scale for covid or for other sorts of pathogens. 

WHAT DOES A "SINGLE-CYCLE" MEAN?

Dr. Barry: It basically has to do with multiplication. 

So, when the adenovirus puts the gene in the cell, the ones like the Johnson and Johnson or Oxford one, that one gene goes in and just remains in that state, and it makes a lot of the spike protein. But ours will go in, and it will copy that gene many times, so that the more copies of the gene, the more protein you produce off of it. The single-cycle means it's basically going through part of its cycle and making a lot more protein. 

PLATFORMS V. VACCINES–ARE THEY THE SAME?

Dr. Barry: Well, so you made a vaccine that was what one might call a one-off, where you made it once, and it only applies to that pathogen. A platform means that you can kind of plug-and-play or cut and paste. 

Before we did the SARS virus, we actually did a bunch of others like HIV, influenza, Zika, Ebola, Clostridium difficile, etc. That's pretty simple because you just basically cut and paste the gene for the protein you want to target into the virus, and then you can target different pathogens. 

Dr. Gazelka: That's really interesting, so this has to be specific to the virus or to the pathogen that you're trying to fight. You can make this specific to different uses. 

Dr. Barry:  Right? And years ago, when I was a baby scientist about 30 years ago, we used things called gene guns. It was literally something you would shoot the genes in, and you could plug-and-play whatever you wanted with that. But it was not very efficient. 

And so we evolved over the past few decades, moving towards these adenoviruses because they're very robust evolutions, doing all the heavy lifting for us to be efficient and have good genes in there. 

WHY DOES THE ADENOVIRUS WORK BETTER THAN THE INITIAL COVID VACCINE?

Dr. Barry: But also, as you mentioned, one of the strategies is to actually try to vaccinate not in your muscle, but intranasally because almost never does a virus enter your body through your muscle. And so one would say that maybe that's not the place you should put your vaccines. 

It ends up that your body is well evolved to try and repel things that come up your nose or in your eye or what are called mucosal surfaces. So it's engineered all these cells and antibodies to be up at that mucosal barrier to try to protect you. And so there's data even with our vaccine that there is an advantage to actually vaccinating not in the muscle, but intranasally, and particularly, when you're talking about a respiratory virus like SARS, that's a good strategy. 

Dr. Gazelka: Isn't that interesting, Mike? I had literally never thought of that. I'm a pain physician, so I think of things in terms of how the body absorbs them, or how you can make it bioavailable to them, like a drug. But with a vaccine, maybe it's more about targeting the area where that virus or the pathogen would live. 

Dr. Barry: Yeah, and it's like that sort of comes down to sort of trafficking. You know, if you learn and if you grew up in your neighborhood, you're going to tend to come back to your neighborhood. 

The same thing goes with your immune system. Maybe if you learned in your nose or your lungs, you're probably going to come back there more often. And so, therefore, if you get exposed to a respiratory pathogen, the likelihood of you seeing it and doing something about it is much higher if you're constantly driving by the old neighborhood. 

Dr. Gazelka: Mike, one of the things that has been astounding, I think, to anyone who works in a science or any research area is how quickly science has changed over the course of covid-19 and how fast information has been shared, et cetera. When you talk about this vaccine platform and about plug-and-playing with different pathogens in the future, as we see new pathogens, does that mean it will be much faster to develop vaccines in the future?

WILL THE VACCINE PROCESS BECOME MUCH FASTER IN THE FUTURE?

Dr. Barry: I think we're seeing that with the messenger RNA vaccines, and to some degree, the adenovirus vaccines. The fastest vaccines you can make are DNA vaccines. And every other vaccine technology, including ours, at some point, starts off with DNA. And so, if you want to make a messenger RNA vaccine, you first make the DNA, and then you use it to make the messenger RNA. And then we also use DNA to make our virus. 

So the fastest ones can be DNA and messenger RNA. The viral ones are a little slower because you have to make the viral vector, but the payoff is a lot more potent. Generally, when you run them head to head against each other. 

So I think the response rate is really fast, technologically. The slower part is the regulatory process of how long you have to do the clinical testing to make sure things are safe. And I think some of the groups that went forward like Moderna and some of the other ones had some advantages because they already worked on SARS-1, the original. They could kind of use that to give them a foundation and jumpstart quickly. 

Dr. Gazelka: We have talked quite a lot about covid vaccines in the past, and how those who are immunocompromised may not respond as robustly to them. And there are some vaccines, I think, that are not necessarily safe for those who are immunocompromised (perhaps the vaccine is with live pathogens, etc.). Is there any reason that this sort of platform would work better for those who are immunocompromised? 

COULD THIS PLATFORM WORK BETTER FOR THOSE WHO ARE IMMUNOCOMPROMISED? 

Dr. Barry: Yeah, I think they will just because they're more potent. It's pound for pound. But we haven't tested that in particular. I think it will be interesting to see how well they do in older people. 

As you get older, your immune system becomes a little bit less robust, and it might take a harder pope to activate it. And so you see that, with the current flu vaccines, they tend to give higher doses, more protein, in older patients to try to get the immune system up. So they know the immunocompromised people depend on exactly how they were compromised. But our vaccine and the others are engineered to not cause problems. So I think they should be more potent. 

Dr. Gazelka: But are they intended to cause a more intense response of the immune system, hopefully overcoming that, if there was just a minimal response, you may not be covered against the pathogen?

A LONGER RESPONSE AND EASIER INJECTION 

Dr. Barry: Yeah, I mean, the other thing we've tried, to make it hard on ourselves, was to see how good we could do if we just immunize once. And that's a measure of potency–if you have to come in and boost with your vaccine, then it’s probably not as potent as one that you come in once for. 

And so we just are completing a study in experiments where we immunized once and then challenged the SARS virus ten and a half months after that one immunization. And we had good protection after that very long period of one immunization. 

Dr. Gazelka: And besides the fact that the immunization response is more robust, think of the global improvements in being able to administer vaccines if you only had to reach each individual in the world once. 

Dr. Barry:  Yeah, and actually that's a whole other thing that we could talk about, some of the things that we work on is how can you make these easier to deliver. At certain times, we've done things like take the vaccine and put it into capsules so you just swallow it and then be immunized. The idea would be you could potentially ship the vaccine off to other countries, and it should be pretty stable, normal room temperature. But then rather than have needles and syringes all over the place, something you put on your tongue could be quite good, 

Dr. Gazelka: Not to mention those medical-grade freezers that have been needed for some of the vaccines that we're using now. 

Dr. Barry: Yeah, I mean, that's the adenovirus vaccines of actually, I think something on the order of a half million people, particularly military people, have gotten adenoviruses vaccines that were freeze-dried and then given as a pill ingested to protect against adenovirus itself. So there's really no harm. 

IS THE ADENOVIRUS CLOSE TO BEING AVAILABLE TO USE?

Dr. Barry: Technology was licensed to a company, and they are taking it into humans. And so the first thing you have to do is make sure it's safe. So this is the first time the single-cycle platform has been tested. Phase one is the first test. 

And, with the pandemic, you know that when all the already pretty good vaccines that we have, how far are we going too far along we get with the testing and the phase one, two, and beyond is hard to say. But now with the new variants popping up, you know, it's kind of persisting in the pandemic, I think. And so there maybe we may be able to get pretty far along with testing it, but that's sort of up to the company that's licensed to. 

HOW FAR HAVE WE COME, AND HOW FAR DO WE STILL HAVE TO GO?

Dr. Gazelka: Wow, that's great. Mike, we talk so much about how in the silver lining of covid has been this rapid dissemination of research and information, but actually these vaccines, not just the one that you and I are talking about today, but the ones that are in emergency use authorization now, were decades in the making. Would that be correct? How long does it take to work on this, and how long have you been working on this project? 

Dr. Barry: Well, as I said, I think 28 years ago, I was shooting vaccines with gene guns. And this particular platform has since evolved. I think we've been working on it for about 13 years or so. And this was work done by really talented graduate students and technicians at Mayo Clinic. 

So these things may benefit people, but we're also educating and building up the people for the next generation. If there are people out there who have an interest in pursuing higher degrees or PhDs or M.D. or master's program degrees in the area of gene therapy, vaccines, or oncolytic viruses is a great place to come. I would encourage you to check it out. 

Dr. Gazelka: So, Mike, I have a question for you. We've heard so much about vaccine hesitancy, some people are saying, “Oh, they just cranked this vaccine out too quickly. We don't know if it's safe.” 

What would you say to that? Have the vaccines that we are seeing in use now for covid-19 really been put forth that quickly, that they haven't been tested properly? Would you have concerns about that? 

WERE THE VACCINES PRODUCED TOO QUICKLY?

Dr. Barry: No, and I've been vaccinated, so I think the cost-benefit is huge. I don't want to end up in the hospital with SARS. So I definitely think it's worth it to do. I mean, as I said, I've been doing this stuff for almost 30 years. And some of these vaccines have been around even longer than that. 

They have been tested in a number of different diseases like in, 2014, when Ebola was a potential pandemic that was percolating in Africa. One of the two vaccines that went into human testing was an adenovirus vaccine. And so these have been around. 

It's just we've never immunized so many people with them. And about a half million people have gotten the military vaccine. This is an oral vaccine, so it's a little different. We're talking about the intranasal and, I mean, your body's engineered to deal with viruses, your respiratory surfaces. And so that may be the know those types of routes of oral or intranasal may have some safety advantages as well, but we won't know until we test. 

Dr. Gazelka: So basically, we could say they've been decades in the making of these vaccines. 

Dr. Barry: Yes, exactly. 

Dr. Gazelka: I find this conversation with you absolutely fascinating, and one of the thoughts that I have had because you know that I've done some work with Dr. Greg Poland, who also works and has worked in vaccine research, et cetera, and also works at Mayo Clinic. 

But, you know, vaccines are something that we take for granted. I have adult children now. I have grandchildren. We just expect that kids get vaccinated and that we don't have some of the horrible diseases that plagued our forefathers and the generations that came before us. What is it like, as a vaccine researcher, to finally see people excited about vaccines and talking about vaccines?

WHAT IS IT LIKE TO BE A VACCINE RESEARCHER IN COVID?

Dr. Barry: Well, it's great. I mean, as you said, when vaccines work, they're kind of boring. I mean, so it's kind of very interesting that, like, I teach in our virology and gene therapy courses. And so now the vaccines have become a big chunk of those lectures. So that's very exciting. And, you know, the vaccine hesitancy is I think it's a matter of what information people are consuming. 

And, you know, Dr. Poland is a great communicator on this topic. Many of us scientists are not that good at talking to the public because we sort of exist in the state of, you know, we have facts now, and then we were wishy-washy. 

We almost never like to say always, and that doesn't help us. But if you talk to most scientists, they will have been vaccinated. There's a good reason for that. 

And actually, I've been at Mayo for 15 years and Dr. Poland recruited me because I try to make vaccines, and he does a lot of the testing actually in patients. And it’s a nice bridge there. So it's just wonderful but nice to not have a pandemic drive at all. 

Dr. Gazelka: That's right. We can do without that, can't we? But it certainly has gotten you working hard over time, I'm sure. 

Dr. Barry: Oh, yeah. 

Dr. Gazelka: So any last words you'd like to share with us. What else would you like our listeners to know? 

Dr. Barry: Today might well be great if we want to get vaccinated, and I think being vaccinated is the best way to be protected. I don't think any of us want to end up in the hospital with this disease, so it's just a good way to go. 
Dr. Gazelka: I couldn't think of a better ending myself. Thank you so much.”

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