Preparing for the Pandemic We Haven't Seen Yet w/ Dr. Dan Barouch & Kris Brown, Vector Sciences

The COVID-19 pandemic proved that vaccine platforms can move at unprecedented speed, but it also exposed how much of the world's response rested on a narrow set of technologies. mRNA dominated the headlines, but what happens next time when the threat is a hemorrhagic fever, a respiratory virus that spreads before symptoms appear, or a deliberate biological attack? Dr. Dan Barouch and Chris Brown have built Vector Sciences around a different concept that durable preparedness depends on optionality, multiple modalities, mucosal immunity that can block transmission, and a platform built for the threats we don't know yet.

Welcome to CareTalk Executive Features, where we host leaders of innovative healthcare organizations. I'm David Williams, president of Health Business Group, and host of CareTalk. Today's guest, Dr. Dan Barouch, is a virologist and vaccine researcher whose work spans HIV, adenovirus- adenoviral vector platforms, and the COVID-19 vaccine effort, including the science underlying the single-dose Ad26 approach.

He's co-founder of Vector Sciences and a developer of the Reovax platform, which is built on rhesus adenovirus vectors. Chris Brown, he's co-founder of Vector Sciences as well. He's an angel investor, senior law partner in the life sciences and technology practice group at Goodwin Procter LLP. He's advised on more than 250 life sciences transactions spanning M&A, public offerings, licensing, royalty monetizations, and strategic alliances, and he counsels investors, executives, and boards on governance and securities matters.

Dan and Chris, welcome to CareTalk. Thank you. Thank you, David. So Dan, you spent your career in virology, and I wonder what did you see that convinced you the world still needs a new vaccine platform, and so what problem was Vector Sciences funded and founded to solve?

The pandemic led to the emergence of novel vac- novel vaccine technologies, including mRNA vaccines, viral vector vaccines, and other vaccine platforms. These proved incredibly effective. However, no vaccine platform that we have today is perfect. They all have strengths and limitations.

And so the rhesus Ad platform is intended to capitalize on a number of the positive features of prior adenovirus platforms, but with added efficacy and safety features So mRNA was certainly the story of the pandemic, and I think probably the, uh, recognition of that term went from 1% to 99% pretty quickly. Um, but you are both talking about its limitations as much as its strengths. So I'm wondering, what did COVID teach us about the strengths and the limits of mRNA, and why does relying on a single modality, no mat- no matter how good, concern you?

mRNA vaccines have tremendous benefits. They're simple to make. They can be manufactured rapidly. They're flexible.

They induce high titer antibody responses, at least in the short term. And they're easily deployable. However, they also have some limitations. Uh, they require a cold chain.

Uh, in some cases, the durability has been limited, um, as well as, uh, the biophysical stability. And it's been known to be associated with certain, uh, cardiac toxicities in small numbers of cases as well. So while mRNA vaccines have tremendous benefits, then, uh, there is also a number of drawbacks. And so having a portfolio, having a variety of different vaccine platforms is beneficial, because ultimately, different vaccine platforms may be more useful in different settings.

Okay, so you talk about optionality, and that's the idea of having, you know, multiple vaccine modalities in the toolkit, and I'm wondering, you know, why does that diversification matter, and what do we lose by consolidating around a single approach? You know, why not just consolidate around, like, the best approach? I think what we saw with COVID is that there was a, a, a belief that vaccines were what we'd receive when we were kids. You know, a single shot would protect us against mumps, rubella, you know, the other, the other childhood diseases that we were used to, um, getting vac- vaccinated against, and that that would have, uh, a lasting, almost lifetime, um, effect on our, on our ability to stave off those diseases.

When COVID came along, we used this term vaccine to describe what really were immune boosters, temporary reprieves or the ability to kind of increase antibody, uh, antibody levels in the body to stave off the disease for short periods of time. We also found they were very, very expensive. They had to be delivered via needle, and if you get jabbed, you know, f- three or four times a year, that's pretty tough. So, um Coming up with a, a different modality that could give long-term effect, actually be a vaccine where you were protected for years, not months, and something that, in the case of Rheovax, the platform that we've developed, can be delivered mucosally, for example, through a, an inhalation to, you know, through the nose versus a jab to the arm, was, was something that we felt was needed to kind of bring trust back to the world of vaccines.

You know, people were being told they were getting a vaccine, and again, they were used to something that would last a long time. That wasn't happening, and they were getting sick. And, you know, what really should've been said, first by the, you know, first administration, then by the administration, in my opinion, was you're not really getting a vaccine so much as you're getting, um, a, a way of being protected against death from this virus. Uh, you may get sick, but you won't die.

That would've been better messaging perhaps to a community of, of, of people who are already a little bit skeptical of vaccines. And then you bring into the mix, um, the leadership in, in this HHS and FDA that are already somewhat skeptical of vaccines generally, and it was kind of adding fuel to the fire of that skepticism. So we think that we need to bring kind of honesty about what's going on and an approach that's simple and understandable to people to treat infectious diseases which have been with mankind and plaguing mankind since the beginning of time.

Okay, so adenoviral v- vaccines also have been around for a bit, and I think even for COVID, J&J's vaccine and then the Ebola vaccine are proof points that people may be, may be at least somewhat familiar with. But as I understand it, the Rheovax platform is using rhesus, uh, vectors specifically. So I'm wondering what makes those vectors different, and why does that difference matter? So the rhesus adenoviral platform is related to the human and the chimp adenoviral platforms that were used in the pandemic, uh, but has, uh, several advantages.

One is, uh, likely efficacy advantage, uh, because there is no baseline immunity in the human population to the vectors themselves, whereas human adenoviruses are the common cold, and so everybody has had the common cold before. And perhaps more importantly, uh, there is a potential safety advantage as well. Uh, one of the limitations of the AstraZeneca and J&J vaccines, uh, despite their durable protective immunity, uh, is that in very, very rare cases, about three in a million, then they caused a thrombosis side effect, uh, which in some cases was very serious.

Uh, and recently The molecular basis of this thrombosis effect has been reported, and is believed to be the, uh, cross-reactivity of an adenovirus protein called P7, uh, that led to antibodies that bound to a human coagulation protein called platelet factor 4, and is believed to, uh, trigger this cascade in very, very rare cases that lead- leads to thrombosis. So a key feature of the adenovirus platform is it does not have the key epitopes in the P7 protein that, uh, have been linked to this thrombosis effect.

So, so our belief is that the rhesus Ad platform, uh, will likely have both efficacy advantages and safety advantages compared with the existing Ad platforms. So one of the interesting parts of the work is the focus on the mucosal intranasal immunity. And as I understand it, you know, respiratory viruses are typically entering through mucosal surfaces, but most of the vaccines are designed to generate systemic immunity. So can you help me understand the difference between systemic and mucosal immunity, and why that matters here?

Sure, absolutely. So when we think of the immune system, we typically think of antibodies or T cells in the bloodstream that help fight off infections that are distributing throughout the body. And one of the best ways of inducing immune responses systemically in the bloodstream is through an intramuscular shot. However, there's another component of the immune system, which is the immune system on mucosal surfaces, such as antibodies in the, um, upper and lower respiratory tract.

Turns out that antibodies in the bloodstream don't move very well to the mucosa and vice versa. So an intramuscular shot, even if it raises high antibody titers in the bloodstream, it really doesn't raise high antibody titers in the respiratory tract, particularly not the key antibodies known for mucosal immunity, which is called IgA. The way that we know can induce mucosal antibodies is by a viral infection, uh, delivered to the respiratory tract, for example, a native influenza or COVID-19 infection.

So we had a hypothesis that The respiratory vaccines are often lower efficacy than other vaccines because the intramuscular shot does not optimally induce mucosal immunity. And an example is the influenza vaccine. It's known by the CDC to have about 19 to 60% effectiveness over the last 20 years. Uh, this year, uh, was one of the lower, on the lower end of that.

The COVID-19 vaccines, although, uh, they do a very good job at preventing severe disease and hospitalization and death, which is incredibly important, they actually don't do a very good job at blocking acquisition of infection Um, so, so the, so the contrast is, uh, measles and polio and other classic vaccines that have 90, 99% efficacy. So we had a hypothesis that the difference between respiratory vaccine efficacy and other classic vaccines was because respiratory vaccines given by the intramuscular route failed to raise sufficient antibody and T-cell responses on mucosal surfaces.

Essentially, that's the portal of entry of the virus, and then the virus can enter the respiratory tract, replicate unimpeded, causing, you know, mild but still troublesome, um, uh, upper and lower respiratory disease. And only once it distributes further out, uh, and goes systemically does the immune system really kick in. So we showed in a series of publications over this past year that the, uh, ResusAd platform can be delivered through, uh, the respiratory tract, intranasal, intratracheal, et cetera, and can raise robust responses on the mucosal surface, and that leads to, uh, in experimental models, leads to substantially improved protection against pathogens such as COVID-19 and influenza.

Chris, before, um, you know, you had talked about some of the practical advantages. So Dan just explained some of the scientific advantages assuming a person gets the vaccine. But let's talk about some of the practical elements. So you mentioned, uh, you know, you don't need a needle.

Uh, it's probably easier for someone to administer it as well, not just to, to receive it. The cold chain. You know, I remember when the, the Pfizer vaccine came out, and people needed these, you know, special freezers, and how are you gonna make sure it stays cold all the way through, and to be able to scale up, uh, quickly. So how much… If you look at this case for intranasal, how much is it about better immunity versus better deployment?

And what are the, you know, what are the overall, uh, applications of it, if so? Well, it's - the good news is, is it's really both. That's the beauty of this platform. You do not need a cold chain.

In fact, you can p- lyophilize. You can, you can put this in a powder form and, and re-administer it, um, so it's much easier to store at almost any temperature for much longer periods of time. And of course, you don't need all the equipment associated with injections and new needles, et cetera, so you remove that element. And again, um, as Dan mentioned, if you create a mucosal immunity, remember these, these- bugs are coming at us through the air, right?

So it kinda makes sense we would wanna stop them at the place where we first experience air in our lungs and in the mucosal system. And if you do that, you actually wind up reducing what's called viral load in the body, which means that a person who has this mucosal immunity is not just not getting systemic, you know, um, uh, infections, but they're also not transmitting, uh, because they don't have a high viral load to third parties. Remember, a big part of this was that you, you may have gotten your shot, your, your Pfizer, your Moderna, et cetera, but you still didn't want… couldn't be around people or had to wear a mask because despite the fact you might not be getting sick, you were still infecting other people.

We're able to eliminate that as well with this approach So I'll, I'll add one other, one other feature that, um, uh, many people are hesitant to get vaccines because they're needle phobic. They really just don't like needles. Uh, and so a vaccine that can be delivered as a spray in the nose or maybe a puff, um, uh, potentially could reach a group of people who otherwise, um, may be less enthusiastic to get vaccines if they don't like needles. So we think that's an additional practical deployment advantage.

That makes sense. You know, I just tell people just, like, tough it out, but, uh, some- somehow that doesn't work as a public health message when you're trying to get someone to, to take your friend's medicine. It's not g- it's not good when you're telling kids to, to, to get a needle, does it? I, uh, what about- Um, I also want to just echo, uh, the, the, the study that was done.

Actually, it was done with, uh, in collaboration with Pfizer, where they compared… Or one of the studies was done in collaboration with Pfizer, where they compared their, their phase three, uh, uh, stage, uh, mRNA platform for influenza against ours. Um, we delivered ours both, uh, intramuscularly to compare it directly to how they do, and then also mucosally, and we compared that to the marketed, um, currently available, uh, flu vaccines, and ours was significantly superior both to what's marketed, but also to Pfizer's.

Um, again, Pfizer's is, is more advanced. It's been through human clinical trials, and they have a lot invested in getting that out there. But it was significant to, to, for us to show that ours was superior to even theirs. We have a little more work to do, right, to get into humans, et cetera.

But, um, I think that's, that's quite exciting to think that, that we're outperforming even the, the, the, the latest versions of these mRNA drugs. And, and one thing Dan alluded to, but just to be clear, the, the current - with the current technologies, the lipid nanoparticles or the, the s- systems by which the, uh, mRNA medicines are delivered, the vaccines are delivered are, are… They, they can't get across the mucosal barrier. The, it's just not possible. So they can't be delivered, at least in current forms, mucosally.

So that's a limitation to mRNA vaccines full stop Got it. So I'm hearing about, you know, we've been talking about COVID, but also hearing recently about things like Ebola in particular, uh, Bundibugyo, if I'm saying that right, uh, hemorrhagic fever, and preparedness on the vaccine side, you know, is, is flagged as a gap. I think there's a, a lot of concerns about how we can actually handle such outbreaks, and especially, you know, with the US stepping back from its traditional role in global public health.

So why is it so hard to establish a rapid re- a rapid response vaccine infrastructure for these viruses, and are you hoping to play in that area as well? So for Ebola, there are several licensed vaccines already. One is based on a VSV vector, the vesiculostomatitis virus vector, and a second one is based on an adenovirus vector, Ad26. Um, and there are funded efforts to bring, um- VSV-based vaccines, um, adenovirus vaccines, as well as mRNA vaccines forward for the Bundibugyo outbreak.

Uh, the current vaccines against the traditional Ebola virus Zaire strain are believed to be less effective or maybe not effective against Bundibugyo because of strain differences. So the, the idea is that, that dedicated vaccines are likely gonna be needed. One of the problems with pandemic preparedness is that we don't know which is going to be the next outbreak. So the current, um, vaccines would've been immediately deployable if this were an Ebola virus Zaire strain outbreak.

Uh, but it was a rare strain called Ebola virus Bundibugyo. So, so when a new vaccine needs to be made, we can do that now faster than ever before, as evidenced first by mRNA and second by adenoviral vaccines during the COVID-19 pandemic. But still, that still takes, um, uh, months, not days or weeks. And so that process is underway now to create new vaccines for the Bundibugyo outbreak.

So I guess the answer to your question is really twofold. First, um, it still takes months to make a new vaccine and, uh, at least it's not years anymore, but it's, it is a number of months. And, and second, um, uh, the vaccines tend to be strain specific, so we need to invest in more, uh, vaccine platforms, and we also need to invest in vaccine antigens that are cross-reactive that could lead to reactivity against multiple strains of Ebola, not just one single, because the next Ebola outbreak might be even yet a new strain.

So we've been talking about vaccines, and we've only kind of, uh, indirectly discussed, uh, the HHS, HHS Secretary Jr., who has notably strong views on this topic. I'm curious how you think that your platform will be viewed or has been viewed by him, uh, and his team. Take a, take a stab at this.

I, I, I believe that, um, Junior is most concerned with safety. Um, he is, uh, very concerned about often the adjuvants, the mercury and other additives that are put into the suspension to keep the vaccines stable. Um, and I think frankly, he's concerned by the terminology again, that was used in describing these as vaccine to a popu- a population, which, which, you know, he's close with that are suspicious of, of the side effects and other things that come, that have come along with some of these medicines.

So I think what something like the Riovax platform will do and, and, and can do to, to someone like Junior, who's somewhat skeptical, is address each of those concerns in the sense it is a real vaccine creating durable long-term immunity. It is safe, meaning it's addressed the known side effects. Um, it is easy to manufacture and, uh, not expensive and so can be delivered quickly. And it again, creates this, um, durable long-term, uh, uh, immunity that, you know, puts trust back into the, the word vaccine.

So I think someone like , um, is particularly interested in this. We know this because a similar platform that's based upon a gorilla form of the adenovirus was approved this past August to treat a type of, um, it's called, uh, papillomavirus. It's a, it's a treatment for a form of respiratory human papilloma, papillomavirus, which is HPV essentially, which you may know is quite a common, uh, type of, uh, infection that occurs in women and often leads to cancer, uh, cervical cancers in women and, and throat cancers in men.

And, uh, this was approved and, and under this administration. So we feel that he would probably be quite keen to see this type of platform move forward Great. So if we look at, uh, biodefense in the US right now, you've got a lot of different alphabet soup agencies, BARDA, HHS, NIH, Department of Defense increasingly. So I'm thinking about when you're considering strategy and policy for a, a small company like yours, how do you build these relationships?

How does that really work, and how can you kinda hit on the areas that government's gonna be interested in, uh, so that you actually are, are able to be a rising, you know, to rise with whatever tide may be, may be rising at the time? Well, again, I'll just echo kind of what I said before. I think it's r- super important to be honest about what we've had in the past and what has worked and what has not worked, to be critical of some of the approaches that were taken, frankly, by people on both side of the aisle, and to learn from those lessons and present options that address those limitations and that, that work, again, and that don't require, you know, every three to four months one having to get a, a jab again and again.

Um, I think that, that that is what this administration is looking for. Uh, they put a lot of money into trying f- f- for example, focus on, uh, a, a universal flu influenza vaccine. This is a major focus for this administration. Dan, again, alluded to it somewhat in trying to deal with any infectious disease.

We deal with the various strains that come out. Historically, every season, as you know, there's a different strain of flu. But working to try to find those elements that are kind of conserved or exist year to year that can be presented in a vaccine such that even if the strain varies quite a bit, the, the fundamental or, or basic form of it is being addressed by the vaccine, is something that I think they are… will be very, very, um, likely to support. Um, they wanna keep America healthy.

Um, it's not a situation where, um, they're looking to, you know, uh, not have people be vaccinated. They just don't want people to get vaccinated and have side effects or discomfort associated. So you referred to the RioVax platform, but we're talking about also making individual vaccines. What's the relationship between the platform and a given product, and why is it important to describe yourself as a, you know, platform company as opposed to one that's making a vaccine for a given virus?

So the, the, the rhesus ad vectors are a delivery tool in a similar way that the mRNA lipid nanoparticle is a delivery tool. It's a method of delivering any antigen of choice to the human immune system. So you can add to that any antigen you want, such as COVID spike to make a COVID vaccine, influenza hemagglutinin to make a flu vaccine, and you can go down the list of any pathogen you want. So the platform is really the delivery tool, and when that is coupled with, um, the key piece of a viral target or bacterial target, then that becomes the vaccine.

So in a similar way that the mRNA platform is generalizable but can be deployed for COVID-19, for influenza, for RSV, then similarly, the rhesus ad platform is a general delivery platform and can be utilized for a target of choice. And although we focused here in this conversation on infectious disease, what's really interesting about the rhesus adenovirus platform is that the, the body, we call it the capsid, is actually quite large and can hold quite a lot of genetic information.

So it could also be used for gene therapy, in theory, for cancer vaccine, for CRISPR delivery. It has that potential. Frankly, so does mRNA, in theory, but there's a lot more room and a lot more stability, as we just described to you, by using a, an a- an adenovirus. So we're quite excited because it really is a platform upon which all sorts of infectious diseases could potentially be addressed.

And, um, we have focused for the, for the moment on, uh, on, on flu, um, because that's a, a major, major market. There's a huge unmet need. It's an area that, again, this, this administration is focused on. But we would be able to very quickly, and have done preliminary work to show that it could work with this latest strain of Ebola, for example, if needed.

And others using those analogous platforms, albeit with some of the safety limitations, are also proceeding in that same way. Um, so it - there's just quite a lot of things one can do with this technology, and we'll see, we'll see what, what we wind up focusing on in the end. So if I, um, can add to that, then, you know, coming back to a theme at the earlier part of our conversation is one of diversity and options. That, uh, for, for the country or the world to have a, an arsenal of, of vaccine technologies is very important, and have diversity of platforms is very important because each one will have, uh, strengths and limitations.

And there's some applications for which, uh, one will just be a better choice than another, and other, o- other targets in which there could be multiple adequate platforms, in which case patient choice is also very important So one technology that's certainly come to the fore since five years or six years ago with COVID is AI. And as I hear you, Chris, talking about, you know, a wide potential range of where this platform could be used, does AI and other technologies like computational biology, did those come into play as you consider how to leverage the platform?

They absolutely do. AI is an incredibly useful tool, including, um, i- i- drug discovery, of course. It's being used for understanding how proteins fold, et cetera. That's made quite a lot of news, but also used in the, in the context of patient selection to see which drugs might work on certain subpopulations based upon the proteomic or multi-omic characteristics.

In, in, in our case, it c- it's a very, very useful tool for trying to best assess what are those antigens or epitopes that should be associated with the vector to induce the immune response. I'm gonna make this really simple. Dan sometimes makes fun of me when I use this example. But think of this delivery system as a bit like a tank which has no ammo on board, no guns, but it looks pretty scary 'cause it's a tank.

And it shows up on the beach, and the Marines, you know, get crazy, and that's sort of your antibodies, and they get really excited. But as we know, the Marines are sort of the, the expeditionary force there to stop things. They can't really hold back the whole army, but they keep it at bay until the full army can arrive. And, and so when you show up with an empty tank, they can't do much fighting, and the Marines keep it at bay.

That gives time for the army or this durable longer term immune system to get activated, so when the real tank with the real armor or the real virus with more than just the spike protein shows up, the body is ready to act and, and kill it, and fight, fight it. And so, you know, AI is enabling us to have a better understanding of what are… what can, what can look like a really scary tank to the body and activate the immune system in the best way so that you create a very long-term durable response.

Dan, I don't see how anybody could quibble with that characterization- and I could see it going right in, right into a GM, uh, abstract. Now that I do, Dan. You okay with it this time ? Dr.

Dan Barouch: Now we'll Good. All right. So maybe a final question is, you know, we've been talking about, you know, how do you, how do you act within the current environment for public health, federal administration, and, and so on. But turn around a little bit and say if instead of trying to build the company and to fit into that, you're an advisor to policymakers, and you're trying to encourage innovation before the next crisis, which is, I think, something that, uh, generally speaking, uh, listeners would like to know about.

You know, how would you advise on balancing speed, safety, public confidence so we get to a more optimal approach? Well, I, I'll take a quick stab at this, but Dan, you should fully answer. I would say, again, restoring trust, communicating to people about y- you know, really speaking the truth. If, if you have to simplify it, that's fine, but, but don't tell people they're getting something that they're not getting.

Be very honest about it. Don't underestimate the ability of people to understand, you know, what we're talking about here. And if you have to use an a- analogy like the tank I did to convey that message, that's what we need to do. We need politicians who are willing to do that.

Don't just tell people to take a shot, trust us, it's gonna work. Explain the, the, the issues, ex- explain the advantages, some of the disadvantages. And a- again, an educated population is going to, you know, make good decisions about protecting their health and the health of their families and communities. So, so I would, I would add that if I were an advisor to current policymakers, I would, I would suggest that, uh, there's investment in a variety of vaccine platforms, uh, each of which may have pros and cons.

Um, I, I think that all the vaccine platforms we discussed today are… can be outstanding choices in certain situations, but may not be outstanding choices for all situations. And so having a diversity of selection is very important. Also, investing in the platforms so that they are ready to go when needed is very important. Um, uh, otherwise, we would only be going back to the same limited platforms.

Um, uh, so, so, so I, I think, um, investing in a variety of platforms, a, a diversity of platforms, to the stage where they are all, uh, rapidly deployable is, uh, uh, would be very much in the public interest. Makes good sense. Well, thanks to Vector Sciences co-founders Dan Barouch and Chris Brown for a conversation that goes well beyond the last pandemic and how - and gets into how we're gonna get ready for the next one. We've been talking about how preparedness means having a deep bench of technologies in place before we need them, rather than waiting and hoping that one breakthrough approach is going to save us.

Well, that's it for this executive feature of Care Talk. I'm your host, David Williams. Thank you for listening, and thank you, Dan, and thank you, Chris. Thank you.

Thank you very much.