 Hi, I'm Jay Fidel. This is St. Tech, Hawaii, and we're talking about much more on medicine. This is a show I've been waiting to do for, I don't know, a week at least. Very important show involving two researchers here in Hawaii. There's Axel Lara. He's with the John A. Burns School of Medicine, and Dave Clemens. He's with Hawaii Biotech, and they are collaborating on some very important vaccine research right here in Hawaii. Now, you see, we do this. We are world-class. Welcome to the show, Axel. Welcome to the show, Dave. Thank you, Jay. Thank you. Yeah, I'm so excited to be able to talk to you. So this is a collaboration between an academic researcher and Hawaii Biotech, which has its own researchers in their alien part. And we want to examine how that works. We want to examine what you're looking at and how well it's going, what your anticipation is, and how this is going to fit in the global effort to do something on vaccines. So let's see. Axel, why don't you begin? It's only because he's younger, Dave, you know? Okay. What are you working on? Tell us about your research on vaccines. Well, maybe I should go and pull this closure and say that actually my post-doctoral career in research started at Hawaii Biotech. This was quite a few years ago. We're not going to talk about how many. And so that is actually one of the things why, of course, collaborations here. But then Honolulu are kind of a natural thing for us. So what I do mainly here at the John A. Byrd School of Medicine is develop vaccines. So I have, many years ago, started to work on filovirus vaccines, which is a very exciting topic. Now a lot of people are going to say, oh, what are filoviruses? I have not heard about those too much. But when I say the Ebola is one of them, that is actually what got us started on this. And the Ebola virus, as we all know, is a very formidable enemy of human life. And so through this project, what we're doing is we're developing vaccines for both the developing and developed world where we try to have a solution that can help everyone on the globe. And of course, as you were saying, well, we all were thrown into into a world that is a bit different these days. And so, of course, coronaviruses came up earlier this year. And that is also part of our ongoing collaborations. Well, you say that, you know, you're doing research in generally in vaccines, but isn't the coronavirus like different? It's different from other viruses. It's more challenging in some ways. Am I right about that? Coronaviruses are a little bit difficult because we all come from fields where we have viruses that are a little bit more exotic or vector born. Here we have a virus that is respiratory, the route of transmission is respiratory. And therefore, protection against it is a little more difficult. And we need to prevent the transmission also from person to person, which is, I think, the biggest public health impact that a successful vaccine will have. So how do you do that? You take an attenuated version of the virus and you inject it into somebody and let us, I know this sounds oversimplistic, doesn't it? And let his immune system, you know, find defenses. Is it as simple as that? It is as simple as that, Jay. But if we were doing this, then the vaccine would be about 10 to 15 years away. It's a conventional way of making vaccines. So a live attenuated vaccine would be wonderful, but I don't think any of us has the time to wait for that long of a development. So how do you speed it up? The speed that we build into our platform is by recombinant technology. So basically what we do today is modern vaccinology. That is where you very quickly analyze the sequence of the bug and then you identify the part that will most likely protect you. Now, we all were blessed in some ways that a lot of people before us have done the research on SARS coronavirus, the kind of original bad boy in the family of coronavirus. And basically we learned what the key antigen would be. Antigen is that protein that will make you immune. And based on this is where, well, I would say 95 to 99% of all vaccines right now are based on various versions of just this protein. So we don't need to grow the virus for that. That's what is really important. We can just take the genetic makeup of the virus. We can make recombinant proteins just using cell culture. Is that CRISPR? No, CRISPR isn't part of that. CRISPR would be more used for specific targeting where we might want to change the genome. We just use conventional technologies where we put a transgene into the cell line that is, let's say, is friendly to that new building. So is this safer than the classical way of developing vaccines? It is clearly safer because classical ways, you've described one of them. One is making an attenuated virus that would be making the bug less virulent. And that is, of course, going to give you very good protection. And the other classical way is to basically just kill the pathogen. What you do for that is you use a chemical like formaldehyde to inactivate the virus and then you immunize the person with that. So these are kind of the classic ways. The safety aspect that we have is that we only package the component of the virus that will make you immune without having all the other proteins and all the RNA and all the cell culture byproducts that you would get. Like as a good example, when you read the insert for a flu vaccine, you'll see that flu vaccines are typically made in chicken eggs. So there's always some certain components of that that may remain in a vaccine. Our approach is a very clean approach where we really just put the protein of interest into the product. Okay, last question before we move on to David. What's special sauce have you got? I mean, there's a worldwide competition going on. What is special about what you're doing there in Kakaako as opposed to all these other people around the world who are racing for the big bucks on a vaccine? Well, we're all racing for the same. And some people may be in a slightly more advantageous position for that race. But we have actually, this was really fortunate that we just over the last few years in this collaboration on our filovirus vaccine, we actually identified a almost ideal combination where we use this like a protein from a virus, in that case, for Ebola or Marburg virus. But you know, it's the same kind of class of proteins, those proteins form trimmers on the surface of the virus. We know how to make those proteins. What we also do is we combine it with an adjuvant, which is a kind of a that's the special sauce that you're talking about, basically, that will enhance the immune response. And then as a third component, we're actually also trying to lyophilize the whole mixture at the end, so that then the product will be thermostable. I told you earlier, we're trying to have products that could be used everywhere in the world, whether you have a refrigerator or not available. So this is I think that combination of three things, high quality proteins that we make here together with the technology that actually then give you a good immune response and stability of the product. Okay, David, turning to you, you've been with White Biotech before you, actually both of you guys were there at the same time. So what is the nature of the collaboration now? The thing that strikes me is that White Biotech has the ability to get intellectual property rights that is patents on things and also market them, you know, perhaps in a more leveraged way than Japson would. But what is the nature of your collaboration relationship with Axel and with Japson? Well, as Axel has already stated, you know, we're working on, you know, expressing proteins which represent the viruses of interest and that we take these proteins and we make vaccines. And as Axel has worked on his filovirus program over the years, which actually originated from Hawaii Biotech once upon a time, it shares a common platform. And that common platform is something that, you know, we work together on to further develop and to refine so that, you know, we have the potential to either react quickly to whatever the current outbreak is. And that allows us to move forward and to, you know, get into these, I guess you could say these races for various vaccines. And just as an example, when Zika came out in 2016, we were able to take our initial efforts and ramp that up and get all of our parts in place so that we could go to the FDA to ask for initial allowance to begin the process of going to clinical trials. We did not go there at that time, but it demonstrated the speed at which we could go from, you know, as Axel said, from the initial gene sequence to be ready to, you know, be able to go into clinical trials, you know, and there's a lot of moving parts in that. And so over the years, it's something that we've worked out and we've collaborated with the University of Hawaii and others to be able to put together this package that allows us to identify new targets, you know, whatever the virus is in this case, the coronavirus, and to move those quickly into a process that allows us to, excuse me, get to the FDA. In a sense, part of our secret sauce is that we have put together a package which the FDA is familiar with. So when we ramp something up very quickly, we can go to the FDA, we can say, look, this is sort of what we've done before. Everything's the same. The only thing we've swapped out are the genes. We have a different protein, but by and large, our process is the same. And they tend to like that approach. It helps to smooth things out because when they see something completely brand new, they want to dig down deep and make sure everything's right. But we've been to them on other programs such as Dengue and West Nile, so they're familiar with it. So that gives us some leverage when we get to that stage of having our vaccine ready to go to clinical trials. I read recently that the Chinese in Wuhan, same place, working on a vaccine, and they believe they have a vaccine. And in China, you don't have the FDA, not even close. And so they're actually skipping phase three trials. They're deploying the vaccine right now or soon. Yeah. So one of the key questions that is out there, we have these vaccines that are in the clinic, the warp speed process right now, but there's a lot of issues related to safety. These has actually alluded to, there's been previous work done on coronaviruses on the original SARS back in 2003 and moving forward. And there were safety signals that came up regarding what happens when you give different forms of vaccines to test subjects, in this case mostly animals, obviously, because none of those went to humans. And there's things that need to be caution, there needs to be caution about and, you know, how this all plays out. And, you know, when, when we, will we might see that something falls out because something pops up all of a sudden. And so, you know, talking about the different types of vaccines that can be used, each technology that use has its own set of risks to it. And so coming back to again, our collaboration, our platform, we think that we have quite a bit of a safety advantage over many of the other platforms that are out there. So, you know, that's something that keeps us moving forward. You know, you look at the field, the last number I heard that there's over 200 different vaccine approaches right now for a coronavirus. So, you know, it's a very crowded field. But, you know, you have to carve out, you know, some way in which you're going to navigate through this process. And, you know, safety is one of the things that we think we have going for us, you know, in our approach to tackling this particular viral threat. I want to be clear, we are all so totally happy you're doing this. You know, it's world-class work needed by the world and you're doing it right here, right here in Hawaii. That is, it makes us also so damn proud if you want to know. Whatever happens, we care about. Thank you. Yeah. So, what is left to happen here? Put us on the time continuum, David. So, I mean, currently, you know, we're evaluating the products that we've produced. We're very happy with our current expression and the current candidates that we have developed thus far. We're in a stage right now where we're trying to sort through a whole lot of data. You know, we have to look at, you know, the quality of the protein. We have to look at the stability of the protein. We have to do initial evaluations on the immune response of the protein. And there's a lot of comparisons that you have to make. You have to ask, you know, what you see right now is when humans are currently infected, they have certain antibody titers. So, we have to ask, you know, the antibody titers that we generate, how do those compare to what you typically see in humans? Or the type of vaccine technology that we're using, we want to see stronger responses than natural responses. We think that gives us a comfort level to say that, you know, we're on the right track. So, we're sorting through all that data right now, trying to make sure that all the logic fits together. And once we have that in parallel, we're working to develop the manufacturing methods that are necessary to be able to take this forward. Again, you have to put your whole package together so that when you're ready to go, you go to the FDA and say, here's all the pieces I have. This is how I'm going to do it. You know, is this acceptable? And can you do a phase one trial before that, or you have to wait for that? If you're doing it in the U.S., you have to take your package to the FDA and have, they have to grant you allowance to move into clinical trials. You know, there are people who are out there actually doing, going into phase three. I don't know exactly what their approach is, but they, you know, there's been discussion from the White House, that doesn't mean it's correct, but there has been discussion about, you know, people who are ready to move into phase three soon. When does that put you in juxtaposition? And there are people for that matter that are apparently ready to manufacture the devices by which this would be injected and have virtually billions of them ready. Where does that put you? And can you, should you do the same thing? So, I mean, it's incredibly complicated at this point. I mean, this is totally unprecedented. I mean, nothing like this has ever happened. So it's hard to put everything into perspective. But one thing that I think that we have to accept at this stage of the game, you know, being that, you know, we're not a big company, we're not, you know, heavily funded at this point in time, is that what we're really looking at is second generation vaccines, because the ones that are in the clinic way ahead of us, those are going to be the primary out there. And as I said earlier, you know, whether they're all going to make it forward, you know, what are the complications that are going to come up? And, you know, generally, safety is a key component of that. And so until they move along, we don't know. So we're looking to the fact that we can come in and, you know, potentially deliver a safer vaccine. And where that's really key is when you start looking at the elderly population. So all of these trials that are being done right now are what we call healthy adults, meaning 18 to 59. And so that's, you know, your healthy population. You don't get generally as good immune responses in the people over 60. So with our secret sauces, as you said earlier, we hope that that's an avenue that we can approach. And, you know, just for parallels, we have another program for alpha viruses, particularly chicken gunia. And again, it's kind of a crowded field there too. But again, we're bringing something that's different. We think that, you know, we can come into these populations that are either elderly or immunocompromised, where a lot of these traditional vaccines may not be applicable. So we're trying to carve out, you know, our own little piece of this big pie that's out there right now, and to offer something that's a little bit different, you know, primarily in the area of safety. Well, I think that's really important for people to understand. At the end of the day, this is not going to be one vaccine. There'll be a number of vaccines and we'll need a number of vaccines. Absolutely. Let me turn to you, Axel, and ask you this. What is your target? Now, there have been various remarks. And again, who's to say whether they're accurate or not, because what the public hears is different than what you do and what you hear. But for the proposition that no vaccine is going to last that long, in other words, whatever immunity we can develop out of the vaccine, it's not going to be, we don't know how long it's going to be. We don't know if it's a year or six months or three months, you may have to be. In fact, I think people generally say you'll have to be vaccinated a couple of times for it to have any significant effect. What target are you looking for? What would you like to achieve? I know it's impossible to say exactly how this is going to work, but what are you shooting for on this? Well, as David has described so nicely already, I mean, so one of the things that we have to look at is that there are different populations that will get different vaccine candidates. That is the same in the field of the coronavirus vaccines as it is here with the coronavirus vaccines. About one third of the population in the US, for example, is pre-diabetic or diabetic. We know that those individuals are of particular accessibility for severe COVID-19 disease. So, you have a different population that you need to vaccinate. You may have to specifically focus that immune response to be as protective as a vaccine in the normal healthy adult that will and is the current subject of all the clinical trials that we're talking about. So, when we are talking about durability, that is a very important thing. So, we don't want a vaccine where you basically have to go back every few months to get revaccinated. So, I would say an ideal schedule here would be similar as for the flu vaccine with an annual booster vaccine. That is based on reality, on the reality that the immune response is waning and that we do need relatively tight immune control in this case. Coronaviruses are, like you said earlier, a little bit more of a different beast from other diseases. So, while a lifelong vaccination, like we could get, for example, with the yellow fever vaccine, which is an ideal life-attenuated vaccine, that lifelong protection is not something that seems achievable here. However, another marker that we need to look for and that we are actually very happy about is a very quick onset of immunity. So, let me give you an example here where, you know, the, of course, front runner in the vaccine development right now is Moderna, but their mRNA vaccine. This genetic vaccine does seem to actually raise the proper type of immunity. However, it needs for sure two doses at a minimum. We are trying to minimize the number of doses that are required, and even if you may not have full protection, if you have a significant level of protection already after a single dose, and that may actually start rising after maybe a week or two already, then that is an important marker that we're looking for. So, we're looking at these specific special needs and other vaccines that are front runners, like the Oxford vaccine approach also requires two doses. And one of the problems with that platform is that they just also happen to be in the Ebola field with that same platform is that immunity vanes very quickly. So, while we see partial protection in monkeys after one year after the last dose of our Ebola vaccine that we developed together with Hawaii Biotech, we are these, these adenovirus-vectored vaccines, you know, show a waning immunity and require another booster at about six months, I would say. So, it is that those are those kind of markers. It's great that you asked that question because this is one of the true benefits of the platform that we have developed, that we can fine-tune the response to that extent. So, Axel, what do you say to those people? And the last poll I saw was something in the order of 20, 24 percent of the people in this country, I think the results are different in Europe and Asia who are anti-vaxxers and would not be interested in taking any vaccine. What do you say to them about this vaccine, about COVID, about public health? Well, I mean, as I told you earlier, vaccinology is my area of specialty. So, of course, this is a topic that we discuss a lot with our students or in my classes. So, it's a very, very important topic. Public health is not something that others do. Public health is something that starts at home. So, I can understand when people are afraid of certain vaccinations that may be painful or may have other side effects that are risky. But we are, and we're not alone in that because it is especially the FDA's role to make sure that the vaccines that reach the US customer are perfectly safe. And that is, I think, the biggest message out there. If you get a vaccine in this country, you can be sure that it has been fully vetted. Of course, in the history, you know, there have been other examples, but this is the 21st century. Technologies have advanced to a point that you are definitely going to be safe. And so, my message is, you know, get your vaccines, discuss it with your doctor, discuss it with your pharmacist. You have questions. This is the way how you learn about it. It is not about looking at some things in social media. The most important thing is to talk to your experts and learn about what it can do for you and what it can do for others. Yes, others especially. So, David, you know, it has become clear that humanity lives in a world of viruses. And for hundreds of thousands of years at least, we have to share the planet with them. And they come for us from time to time. I'm not sure I should limit that to viruses either, remembering the Black Death and the plague in the 6th century and the 14th century, which continues in some places even today, you know, even with antibiotics. So, what you guys are doing, diseases you dealt with, is something that you're going to have to continue dealing with. And so, it's wonderful to have Hawaii Biotech and Japsum collaborating and working on diseases. But I have to say, my reaction is that you're going to have to keep on doing that. There'll be more coming down the road. You will be busy for a lifetime and a lifetime of lifetimes trying to save humanity. Am I right about that? How do you feel about that? No, I think you're absolutely right. I mean, you know, the viruses aren't going to go away. There's been so many programs over the last, you know, decade of identifying more viruses. So, we're aware of even more than that we knew that was out there to begin with, or knew 10 years ago. And so, this is something that's going to be coming at us. The real key and the lesson I think learned here is we have to do a lot more to be prepared for these. We can't do this on a reactionary level. And, you know, this has been an argument that's been, you know, gone over many times in the last 10 years or more about we have to be more prepared. And yet again, we're unprepared. And I think, you know, what we like to believe with this platform that we're working with is we're trying to refine it and make it as plug and play as possible. And I think that's what everybody has to realize at some level is we have to have a way that when the next thing shows up, you can, to the extent possible, just plug it in and run with it and ramp it up. And so, having all of the safety features built into it that you can, having all of the manufacturing modules built in it that you can to allow you to just, dare I say, keep it as simple as possible so that you can move as quickly as possible. But also to, you know, look at these viruses that we know that are out there and to develop, start developing those in advance and having all the pieces in place so that, again, we can move with them much faster. And that's something that as a company we've been arguing for it's hard to get traction over the years. We kind of have some of that in play right now. And we're hoping that we can take advantage of that. You think Hawaii can be a significant player in this even beyond Hawaii biotech going forward? It's always something that we hope for. We've been trying to do this for many years. The people at the university have been trying to do this for many years. And, you know, it's something that we need to keep, you know, driving forward and doing our best to put our best foot forward and to be a force within the vaccine field out there to be able to put new products out there that can help us all. Thank you. David Clements Hawaii Biotech, working with Elliot Parks there, a wonderful company, doing wonderful work for a long time. We have followed you for, oh gosh, it must be 15 years at least. A little bit more than that. Sorry, I don't want to understate. And Axel, they're working at Japsum and the two collaborating on the most important medical and public health issue of our time and our generation, maybe for 100 years going forward, the coronavirus. Thank you, Axel. Thank you, David. It's been wonderful to talk to you. Thank you, Jay. Appreciate it. Thanks, Dave.