Virtual Harper Lecture: COVID & Beyond: Understanding Vaccine Adjuvants, with Aaron Esser-Kahn
Today you will hear from our world class faculty and enjoy stimulating conversations on critical topics, all in the comfort of your home. We extend our appreciation in advance to our global university community for their collective efforts and supporting the mission of the university in today's deeply challenging environment. Technology has allowed us to remain connected and engaged and tonight YouTube will be part of the conversations, a couple of notes. All participants will be muted. However, we do encourage you to ask questions, we will have plenty of time for questions at the end of the presentation.
If you have issues with audio, you may want to shut down your programs running in the background or dial in from your phone. Hi, I'm calling on behalf of everyone at the you Chicago alumni office we offer our deepest gratitude and appreciation for your continued support. We're proud to be part of this community, as it has come together during these trying times to invest in our students empower our faculty and scientists and extend care and connection. And now it's my pleasure to welcome you to the 41st season of the University of Chicago's Harper lecture series. Thank you for being with us enjoy Professor Jeffrey A. Hubbell: Good evening,
pleased to welcome you this evening to this so Harper lecture and that would be on the topic of covered 19 and beyond. Professor Jeffrey A. Hubbell: Understanding Vaccine Adverse events and innate immune responses with Professor Aaron Astrakhan I'll introduce him in a moment to you.
Professor Jeffrey A. Hubbell: So we're also appreciative for alumni relations and development for inviting us to to be with you this evening in this hard production. Professor Jeffrey A. Hubbell: Aaron, if you could bring up the slides. I'd like to begin by introducing you to an aspect of the University of Chicago's Pritzker schools and molecular engineering Professor Jeffrey A. Hubbell: Called the Chicago and you know engineering Innovation Center.
My name is Jeff Hubble. I am a Eugene Bell, professor of tissue engineering Professor Jeffrey A. Hubbell: In the Pritzker schools and molecular engineering and also one of the co leads of the Chicago, Illinois engineering Innovation Center. Professor Jeffrey A. Hubbell: As we've built up the Pritzker school molecular engineering we focused our hiring and the biological domain. Professor Jeffrey A. Hubbell: On immunology, the immunology engineering interface which
includes the cancer engineering interface as well. I just like to introduce that center to you briefly. Professor Jeffrey A. Hubbell: Before we move on to the the main show tonight which is Aaron is recon so here we develop engineering approaches to address both basic and translational immunology. Next slide. Professor Jeffrey A. Hubbell: What does this mean so from basic immunology engineering
can contribute directly to even basic immunology. Professor Jeffrey A. Hubbell: Through engineering systems to quantitative systems systems physiology systems to address basic unknown questions and immunology. Professor Jeffrey A. Hubbell: Using cell and tissue engineering approaches developing micro
device tools to address questions that could not be addressed. Professor Jeffrey A. Hubbell: Other ones. So, for example, how do you do not just one experiment, but how do you do 1000 experiments all at the same time using microfluidic devices. Professor Jeffrey A. Hubbell: How do we apply computational approaches to immunological data to understand data sets. They're so complicated that they really can't be understood by the human in the absence of a computational framework.
Professor Jeffrey A. Hubbell: And what Aaron will discuss with you tonight engineering molecules. Molecules as both tools to probe immunology.
Professor Jeffrey A. Hubbell: And molecules as translational aspects that could potentially be drugs good turn them into drugs. Professor Jeffrey A. Hubbell: So this is being addressed in our center in the context of cancer immunology autoimmune diseases in the asthma and allergy. Professor Jeffrey A. Hubbell: In engineering the microbiome in the garden, the skin and
the mouth to provide for human health and then the topic of tonight's session infectious diseases translation immunology to address infectious diseases. Professor Jeffrey A. Hubbell: So without brief introduction to the Center for that I want to describe, I'd like to introduce to you, Aaron s or con Aaron joined us. Professor Jeffrey A. Hubbell: In the Pritzker school molecular engineering, he's trained as a chemist, so he he grew up in in Michigan and the Bloomfield Hills area of Michigan.
Professor Jeffrey A. Hubbell: Took his so bachelor's degree at the California Institute of Technology in chemistry from there moved up for his PhD at the University of California, Berkeley. Professor Jeffrey A. Hubbell: Also in in chemistry. And so he joined us a couple of years ago, three years ago from the University of California, Irvine.
Professor Jeffrey A. Hubbell: To bring his unique capabilities in synthesis and design of novel molecules in the context of vaccines and other aspects. So translation, you know, G. So with that, Aaron, the floor is yours. Thank you very much.
Professor Aaron Esser-Kahn: Oh, thank you, Jeff. And thanks for the introduction and thank you all for coming and listening. I think this is an exciting time. Professor Aaron Esser-Kahn: For vaccination, even if it's sort of a scary time in the world.
We're at a really Professor Aaron Esser-Kahn: major turning point in the world of vaccination. So I'm excited. I get to share some of that with you all, and tell you a little bit about what my lab is doing. Professor Aaron Esser-Kahn: In the context of vaccines as well and motivate that with some of what's going on with coven right now. Professor Aaron Esser-Kahn: So I'm going to talk a little bit tonight about vaccines.
What we know about them what important questions remain. I'm going to give a brief primer on on coven and where the vaccine world stands right now, which is changing, literally, every day I woke up this morning that new news. Professor Aaron Esser-Kahn: And, you know, maybe some some stuff that will be good for your turkey days zoom conversations, you know, and then I'm going to talk about our work understanding, you know. Can we count. Professor Aaron Esser-Kahn: Different types of immune responses. Can we see how the cells respond to a vaccination and then I'll tell you a little story about how can we change the conversation between vaccines and the immune system to shape it to be more safer and more efficacious.
Professor Aaron Esser-Kahn: I get probably is obvious to everybody here but it sort of bears repeating that vaccines are still one of the most effective cheapest Professor Aaron Esser-Kahn: Public health interventions ever and really nothing sums up better than this infographic developed by the CDC. Professor Aaron Esser-Kahn: These are the pre and post morbidity rates. After the introduction of a vaccination.
Professor Aaron Esser-Kahn: And you can see that really vaccines are one of the only ways we can wipe this disease literally off of the face of the earth. In some cases, which has been true of smallpox, so far, but really you can reduce the prevalence of a disease, almost nothing with the introduction of vaccination. Professor Aaron Esser-Kahn: So, but there are still many diseases on the planet and and one that's really on everybody's mind this year that Professor Aaron Esser-Kahn: Don't have effective vaccinations.
And the question is, what is different about some diseases and others. And how do we develop vaccines against these sort of harder to vaccinate Professor Aaron Esser-Kahn: Diseases and and just, you know, a point here is that, you know, while we are really focused on Cobra, this year, I think it's important to bear in mind you know just how many people Professor Aaron Esser-Kahn: Suffer from some of these other diseases, particularly tuberculosis, which in many ways has all of the same challenges as coven Professor Aaron Esser-Kahn: You know, but still results in a very large number of deaths every year and has for the last hundred years. Professor Aaron Esser-Kahn: So I think it's important to bear in mind that this is these are problems that the world has been dealing with for a long time. Um, Professor Aaron Esser-Kahn: So there are many challenges and vaccines and I really only work on the development of the molecular side of things. So I'm going to try and get some of the stuff out of the way. Professor Aaron Esser-Kahn: Before we go along.
Because I'm not really equipped to talk about the public health parts of this and I'm also not really a person who can proselytize about all the things Professor Aaron Esser-Kahn: About vaccines, but I'll just give you some basic facts and figures that I think will help so Professor Aaron Esser-Kahn: First of all, there's this sort of myth that vaccines are somehow driving a large part of the profit. In fact, Professor Aaron Esser-Kahn: One of the main problems with oxidation is that they're the least profitable part of the biotech industry they routinely make pennies per administration. Professor Aaron Esser-Kahn: And we'll talk about exactly why they take so long to develop. It's because nobody wants to risk the cost of development.
Professor Aaron Esser-Kahn: approved vaccines are extremely safe, you know, they're safer than driving your car. In fact, they're actually safer than taking Tylenol. Professor Aaron Esser-Kahn: Which probably you don't really think about, but there are more result deaths from Tylenol every year, other than there are from vaccination. Professor Aaron Esser-Kahn: And vaccine development, as we'll see a little bit later is all about ensuring safety a herd immunity is incredibly difficult to achieve without vaccination.
I'll show an example of that later. And then I'll talk a little bit about Professor Aaron Esser-Kahn: I'll talk about. I'm sorry. I was looking at the chat there. Um, I'll talk about covert vaccines in particular as as motivation.
Professor Aaron Esser-Kahn: So this is just a great example from the website 538 and it's actually the work of Emily Auster at Brown University. If any of you guys have read crib sheet. She's the author of that book. I chose correlation between Professor Aaron Esser-Kahn: The number of cases and the percentage of people are particularly children in this case age 19 to 35 months who've been vaccinated Professor Aaron Esser-Kahn: And and so really, you know, in order to achieve something like herd immunity. You need extremely high vaccination rates upwards of 95 to 99% Professor Aaron Esser-Kahn: For something like whooping cough, even to lower the rates down to this one to 2% so it's it's really hard to achieve without Professor Aaron Esser-Kahn: Complete vaccination in a population. So just bear that in mind when you're listening to people in the news right now talk about herd immunity.
It's very difficult to achieve. Professor Aaron Esser-Kahn: Everywhere else, Professor Aaron Esser-Kahn: Is it somebody seen caption somewhere. I don't have captions on the screen, so I'm Professor Aaron Esser-Kahn: A oh that that unfortunately the margins are simply because of the way the screen is projected that it's just 16 by nine.
So there's not much I can can do about that. Professor Aaron Esser-Kahn: So the other great news that's been coming up recently people have probably seen the cover of The New York Times is and other things is that Professor Aaron Esser-Kahn: I think Professor Aaron Esser-Kahn: We've seen really effective vaccination against coven and reason weeks of course the Asterix right now is that the data needs to be reviewed. People need to take a really good look at it, but all signs point to the fact Professor Aaron Esser-Kahn: That these are going to be extremely effective vaccinate Professor Aaron Esser-Kahn: Vaccination approaches and we're really excited about that. So I wanted to talk a little bit about Professor Aaron Esser-Kahn: That and then dive into the details of how these things work. So you guys have probably heard this term warp speed bandied about I just wanted to talk a little bit about what that meant.
And how vaccine development worked Professor Aaron Esser-Kahn: So, you know, it's not really a pace so much as it is a massive public and private partnership. Professor Aaron Esser-Kahn: And speed and vaccination is not really about how fast you can do the experiments. It's mostly a financial and logistical challenge.
Professor Aaron Esser-Kahn: So you can think of speed in terms of development of a vaccine as really about taking into account safety and that adding basically unlimited resources and the difference is that Professor Aaron Esser-Kahn: This has never happened before. There's never been people willing to supply essentially unlimited resources. Professor Aaron Esser-Kahn: Associated with a vaccination, because as I mentioned before, nobody is willing to take the risk Professor Aaron Esser-Kahn: To develop vaccines, because they yield such low amounts of profit.
Nobody wants to develop them at risk. And so this is what operation warp speed really is about. It's not about Professor Aaron Esser-Kahn: Taking the timeline and compressing it.
It's about de risking the timeline by dumping money into each element of the Professor Aaron Esser-Kahn: Timeline. So there's a couple of things that have allowed this to happen. One of them that really doesn't get enough mentioned is the amount of legwork that went into developing all of these technologies. Professor Aaron Esser-Kahn: So it's not like these technologies just simply sprung into existence in March and April, all of these vaccine platforms as they've been mentioned already existed and had been well vetted and developed Professor Aaron Esser-Kahn: Previously using several different systems and so they could, they were basically plug and play technologies that could be used with these new antigens and then developed very rapidly, and then really the key thing is that by combining the different phases of the process. Professor Aaron Esser-Kahn: And and essentially what you're doing there is basically just paying people to Professor Aaron Esser-Kahn: De risk each step of the process you can basically move everything along quite quickly.
And so I'll talk a little bit more about that. Professor Aaron Esser-Kahn: Just so that you can think about it and really what this is, is basically like a Manhattan Project approach to vaccines. I think that's something Professor Aaron Esser-Kahn: That at this campus and and historically, we're all quite familiar with the idea of Grand Challenges built on the back of large government intervention. So in a traditional development, you have one to two years where you develop all of the initial work. Professor Aaron Esser-Kahn: Around this. The difference here is that all of that initial work had already been done.
Professor Aaron Esser-Kahn: For analogous diseases. In this case, the original SARS and mers. So all of that was already eliminated, because those two diseases had very close similarity in terms of the proteins. Professor Aaron Esser-Kahn: That were born out on the on the structure of the coronavirus so that that basically chopped out those first couple of years. So again, built on the back of many years of hard labor. Professor Aaron Esser-Kahn: In national are in in the NIH and many labs across the country.
Then the other thing that's different is that normally in a vaccine development. You do phase one, phase two and phase three, and the real reason you do it this way is not because you Professor Aaron Esser-Kahn: Need to, but because at each point here. The company is unwilling to put more money into the process until they're absolutely certain that phase one works. Professor Aaron Esser-Kahn: And then absolutely certain that phase two works and that absolutely certain that phase three works because each of these is basically an exponential amount of more money that the company has to dump in Professor Aaron Esser-Kahn: And the difference here is that now the government has stepped in and basically said, hey, we're willing to front you all of the cost of running all of these trials.
Why don't you just do them all stacked on top of each other. Professor Aaron Esser-Kahn: And and as long as they work we'll still know the same results in the same amount of time. Professor Aaron Esser-Kahn: And we'll still mo will add in production to will begin producing things in tandem. Professor Aaron Esser-Kahn: And if they and if things work.
Then we'll already have things rolling off the production line at the same time. So all of this has always been possible. Professor Aaron Esser-Kahn: I shouldn't say it's always been possible.
What I should say is that it's been possible in the last 10 to 15 years to do this but no one's had the guts or the Professor Aaron Esser-Kahn: The capital, basically, to make this happen until there was this sort of Professor Aaron Esser-Kahn: Emergency and necessitated this. So I think you can think of operation warp speed as the world and the United States government rising to the challenge, much like they did in the Manhattan Project to muster scientific and intellectual capabilities to produce something Professor Aaron Esser-Kahn: That has that is possible with human capability and understanding Professor Aaron Esser-Kahn: It just wasn't happening before due to the fact that the right people weren't in the right room at the right time and the right amount of Professor Aaron Esser-Kahn: Money wasn't placed before them. So that's really the difference in terms of warp speed. It's really just about de risking the process that already existed.
Professor Aaron Esser-Kahn: And moving it into it into compress timeframes for people like me who develop Professor Aaron Esser-Kahn: Or think about this early stage process out here that's mostly where I focus my time and energy. What's really exciting about this is that you know when you hear people who've gone through this for their entire lives. Professor Aaron Esser-Kahn: They're talking about this as the question is, will this be the future of vaccine development or will we go back to this for every new vaccine. Professor Aaron Esser-Kahn: And if we can do this for every new disease.
Think about all of the lives that we could save if we simply turn this into the new paradigm for vaccine development, rather than going back to this. Professor Aaron Esser-Kahn: In the future, so I wanted to give a little bit of a primer about how vaccines work. Professor Aaron Esser-Kahn: And what's important and what you need to know about them. Professor Aaron Esser-Kahn: And so I'll start with sort of a very simple version and then build up in complexity as we talk about them. Professor Aaron Esser-Kahn: So how do you fight a disease. I have sort of a simple version of this, and then we'll, we'll get into the molecular scale first.
So you have a pathogen you're trying to fight it. So how do you fight a disease. Well, what you try and do is cheap, right, you try and figure out how you can Professor Aaron Esser-Kahn: Give yourself an advantage. So what do drugs and antibiotics do well. They basically figure out how to cripple disease in some way.
You know, they remove so important enzyme they they damage the disease in some way. The other approach is to Professor Aaron Esser-Kahn: All the problem with that, in general, is that the disease usually figures out a way around that it mutates or grows in some fashion and then you end up with a tougher enemy because it usually has a way around your drug Professor Aaron Esser-Kahn: In vaccination. What you do is basically you try and make your immune system smarter.
So you're trying to educate yourself in ways to Professor Aaron Esser-Kahn: combat the problem. So you make yourself smarter. You also generally make yourself tougher. Professor Aaron Esser-Kahn: These are the two basic principles of vaccination. So how do you do this. How do you educate the immune system.
Well, basically you need to give it a set of information you give an information about how to find and target the pathogen of interest and Professor Aaron Esser-Kahn: So I have a metaphor for this that I use to explain this idea and then we'll get into sort of the details so Professor Aaron Esser-Kahn: I think this is very similar to sort of the wanted poster that you use for you know in the in the Old West basically Professor Aaron Esser-Kahn: You give the immune system kind of the same information that you put on a wanted poster. You have the name some sort of identifying information. Professor Aaron Esser-Kahn: Then you have kind of the last known places that you look for and then you have kind of a method that the immune system uses to find and identify the pathogen. Professor Aaron Esser-Kahn: So method of apprehension dead and alive.
So obviously this is different than the immune system uses different information. Professor Aaron Esser-Kahn: Than you would for apprehending. Say, Billy the Kid. Professor Aaron Esser-Kahn: But it's, it's still pretty similar. You have the problem you have a code name of some kind.
You have a method of identification and a method of capture those are basically the key principles you need Professor Aaron Esser-Kahn: For an effective vaccine. So let's just go into the coronavirus here to take a look at how that works. So you'll see that the coronavirus Professor Aaron Esser-Kahn: Has this, you know, like most liquid envelope viruses that has proteins on the outside and then genetic information on the inside. And the key. Professor Aaron Esser-Kahn: A protein here to focus on is this spike protein.
And if you guys have been reading about it. You'll often hear this referred to is either the S protein or there's a specific Professor Aaron Esser-Kahn: Portion of this protein called the OBD that's the part that binds to this as to receptor that allows the virus entry into the cell. Professor Aaron Esser-Kahn: Then what happens is once that virus replicates in the cell. It'll eventually bump into one of these things called an antigen presenting cell that's basically your Sheriff or the thing that's going to be alerted to the presence of the Professor Aaron Esser-Kahn: Virus, it's going to then grab onto the virus and begin to process that information alert, say, a T helper cell which is going to educate a B cell and a side of toxic T cell and then that's going to develop antibodies and then start Professor Aaron Esser-Kahn: Also alerting T cells which are then going to start destroying the buyers. So that's sort of the process that happens, the key thing here is the antigen Professor Aaron Esser-Kahn: Which is that method of identification.
That's how you know how to Professor Aaron Esser-Kahn: Tag and identify the virus. And the other thing you need is a way to alert the antigen presenting cell to the fact that this is a virus and not something that actually came from the cell and that sort of this code name. Professor Aaron Esser-Kahn: Of some kind, so this is basically what you have in the case of coven you have some sort of alias basically Professor Aaron Esser-Kahn: So the way the immune system actually determines that this is a virus is it looks for a series of chemical signatures in the virus, which it then uses to turn on.
Professor Aaron Esser-Kahn: The immune response. And these have different code names. They're generally called pathogen associated molecular patterns which is a real mouthful. Professor Aaron Esser-Kahn: And and they activate these things called total like receptors, but you can just out for the sake of the talk, I'll just call them receptors, they get activated. Professor Aaron Esser-Kahn: And then there are specific sequences of the protein that it develops antibodies against these are you typically called episodes or antigens.
Professor Aaron Esser-Kahn: And that's what it uses to identify them and then it uses this method of apprehension, which is a combination of antibodies and T cell responses in balance here that Professor Aaron Esser-Kahn: So you you use it to alert each other. So there's a good question there, which I think I can address immediately, which is that how do you keep it from identifying Professor Aaron Esser-Kahn: How do you make sure that it doesn't attack itself. Professor Aaron Esser-Kahn: And so that's because only viruses contain this chemical information. Professor Aaron Esser-Kahn: And and not the rest of your body. So that's how it knows not to generate antibodies against itself. There's also some other, more complicated systems called T regulatory cells that make sure you don't attack.
Professor Aaron Esser-Kahn: Other things and we'll get into a little bit more of that here in a minute. Professor Aaron Esser-Kahn: So that sort of the key thing is that you want to produce effective antibodies against your antigen of interest. That's how you target the virus. And you also want to produce T cells, which really go in and kind of mop up and destroy Professor Aaron Esser-Kahn: Things, they're basically like hunter seekers that go out and find everything destroy them. They're also very effective at combating cancer. Professor Aaron Esser-Kahn: And the way that you do that is the view basically prime and program naive T cells to either Professor Aaron Esser-Kahn: Then activate B cells are then become the center toxic T cells that happens by these antigen presenting cells traveling to the lymph node and so creating this sort of complex milieux of different chemical information.
Professor Aaron Esser-Kahn: And the cell decides to do that by getting activated by this set of chemical information which is processed by these receptors and and the most important class of these, are these totally receptors. So, these Professor Aaron Esser-Kahn: Cells. They're called antigen presenting sells the most common version of them is dendritic cells. Professor Aaron Esser-Kahn: They decide whether or not something is foreign or self, basically, is it a virus or is it part of me by looking for these chemical fingerprints. Right. Basically, they say.
Professor Aaron Esser-Kahn: Are these chemicals coming from a virus or are they something that I know already exists, and they use these receptors to determine that they say Professor Aaron Esser-Kahn: These molecules could only be coming from a virus, because only viruses or bacteria or fungus make these things and therefore I know this combination of molecules only exists. Professor Aaron Esser-Kahn: In a virus. And so that's what you really need. You need these two ingredients to identify and activate Professor Aaron Esser-Kahn: Either a virus or if you're trying to develop the vaccine. You can you can sort of intentionally include these Professor Aaron Esser-Kahn: To activate on purpose.
You need some combination of these different molecules. Professor Aaron Esser-Kahn: And then an antigen to ultimately develop the antibody response against. So you need an antigen, which is going to target the protein on the on the virus of surface and then these Professor Aaron Esser-Kahn: Molecules that activate the pattern recognition receptors and this is basically the chemical code that you feed to these cells, which in turn activates them. Professor Aaron Esser-Kahn: So vaccines stimulate a number of these different receptors and basically all vaccines all live attenuated vaccines stimulate a whole host of these Professor Aaron Esser-Kahn: And basically every different bugs stimulates a unique code. And there's many categories of these which I won't go into detail. Professor Aaron Esser-Kahn: But a lot of my research is interested in sort of how do you find the optimal combination of these are understand what's really critical for them.
And with each new pathogen and each new Professor Aaron Esser-Kahn: Disease. You have to find both what the right code is for stimulating them what the native Professor Aaron Esser-Kahn: Disease uses but also what the appropriate methods for activation is and that changes, right. So sometimes you have smarter pathogens. Professor Aaron Esser-Kahn: And they'll either find ways to cover up their antigen or they'll find ways to sort of mask the type of code that will work effectively and so that will depend on on the disease that you're looking for, um, Professor Aaron Esser-Kahn: Eventually, people will usually find effective antigens. One of the things that will be the hardest to do is actually identify the set of chemical codes that elicits effective long term durable immunity. Professor Aaron Esser-Kahn: So the good news is that for covert, it looks like this type of response, the type that you need to induce for protection is going to be relatively easy and many methods of inducing protection are going to work.
Professor Aaron Esser-Kahn: So just to cover a couple of the approaches that people have developed. So the one that has been going the fastest in terms of speed is this method of enveloping a piece of Mr na Professor Aaron Esser-Kahn: Which is the method that Madonna and Pfizer are using that piece of Mr. A, then, is injected into cells and some of them RNA finds its way into the antigen presenting cells and stimulates them directly. And some of it then produces Professor Aaron Esser-Kahn: Copies of that viral protein. The spike protein.
And so then that protein gets presented by those antigen presenting cells and the RNA acts as a native stimulant. Professor Aaron Esser-Kahn: That turns out the liquid coding also acts as one of these codes that stimulates the engine presenting cells as well. And those are the two that we heard about in the last two weeks with these incredible Professor Aaron Esser-Kahn: Advocacy the other four that are really right close behind our development or one by Johnson and Johnson and Astro zenica Oxford Professor Aaron Esser-Kahn: And both of those relying adenovirus, which is a similarly sort of a non native virus that isn't self replicating in this case. Professor Aaron Esser-Kahn: Where you encode the same spike protein.
And then the virus itself already has these Professor Aaron Esser-Kahn: PR is the end and molecules that stimulate because it's a virus. So, it finds its way directly antigen presenting cells that activates them. Professor Aaron Esser-Kahn: And then they present again that spike protein directly to the rest of the immune system and the last version, which takes a little bit longer but is sort of the tried and true method.
Professor Aaron Esser-Kahn: Is to make the spike protein directly and then to add in these molecules directly on these ads events. Professor Aaron Esser-Kahn: In combination. And that's what JFK and Novak's are doing and he usually takes a little bit longer to make the first versions of these, but then they're very, very scalable. And so they usually make a little bit longer.
Professor Aaron Esser-Kahn: They are, they usually are able to make them on much larger scale and the response is usually quite durable. Professor Aaron Esser-Kahn: So the last few weeks, as I was preparing this lecture. I've been having to update it. Because we've seen a lot of really good news. Seriously, really, really, really good news about how this is working. Professor Aaron Esser-Kahn: such good news that I read it in the morning and I had a moment like Scrooge has in Professor Aaron Esser-Kahn: I woke up and went out of bed and I was like you know what day is it like I was that excited that level of like my whole life.
And there was like a new lease on life level of good news. Professor Aaron Esser-Kahn: And that's because, you know, in the most recent data reports, it appears that the Mr. And a vaccines. The target despite protein have Professor Aaron Esser-Kahn: Efficacy is that approach 95% and that's really about as good as you can ask for just for comparison.
These are the known efficacy is for all the vaccines that we've ever developed as as a collective human beings. Professor Aaron Esser-Kahn: And what you can see is that basically they're nearing the highest efficacy that anybody's ever approached and what this also means is that because all six of these Professor Aaron Esser-Kahn: Vaccines and development all target the same protein in the same area, it's quite likely that many of these approaches are going to have Professor Aaron Esser-Kahn: Similar things. The other good news is that, you know, one of the questions as well can code mutate around this. The other good news is that coven has this built in mutation. Professor Aaron Esser-Kahn: Check system, meaning that it basically tries to prevent itself from mutating Professor Aaron Esser-Kahn: Based on the way that the virus works.
So unlike the flu it mutates much slower and most of the know mutations. At this point, after almost a year of it being in the wild are not in this RB region. Professor Aaron Esser-Kahn: And so it seems very unlikely that at the rate it's mutating it's going to find a way to mutate around the antibodies that people are developing Professor Aaron Esser-Kahn: So that doesn't mean we're out of the woods in any sense because, of course, there are still many diseases. Professor Aaron Esser-Kahn: That don't have effective vaccines. And again, it's interesting to note that will have a disease likely now. Professor Aaron Esser-Kahn: That appeared in 2020 and we developed a vaccine and 2020 which you can contrast to something like tuberculosis, where it appeared in 1882 Professor Aaron Esser-Kahn: And we still don't have an effects the vaccine for it.
So I think there's a lot still to learn about vaccination and a lot to develop here. Professor Aaron Esser-Kahn: So these are the questions that my lab is interested in is, what can prevents us from completing this list, and how do we develop these things more effectively. Professor Aaron Esser-Kahn: And so that's one of the main questions is not only why is this process along. But why do we need to dump literally billions of dollars into this process in order to de risk it. Why is it so risky each step.
Why don't we know how to make things or ensure Professor Aaron Esser-Kahn: Or guarantee between different elements that things are going to work better. Professor Aaron Esser-Kahn: And I think that's because studying the immune system is a lot like studying the economy. Professor Aaron Esser-Kahn: Which is to say that it's fairly easy to tell you what has has happened, but it's sort of difficult to tell you Professor Aaron Esser-Kahn: To predict what's going to happen, right. So it's difficult to predict an immune response, it's difficult to measure individuals performance. Professor Aaron Esser-Kahn: But it's relatively easy to measure things on aggregate macro scale trends are quite reliable and so at P me as Jeff mentioned, we, we like to study sort of molecular and cellular responses. Professor Aaron Esser-Kahn: And my lab is particularly interested in how to make vaccines and immunology more predictable by looking at molecular patterns.
So that's sort of what we do. Professor Aaron Esser-Kahn: In this immuno engineering approach is that's what engineers are good at. We want to take things disassemble them. Professor Aaron Esser-Kahn: measure them and put them back together so they can be predictable and they can run like a car, right. That's our sort of our goal.
And then we take that understanding and turn it into translation that's really what we're focused on Professor Aaron Esser-Kahn: And so that's what we we take is that at each of these steps we understand what's happening at the basic level by quantifying each piece. Professor Aaron Esser-Kahn: We then take that basic understanding and translate it into, you know, new approaches to a problem and then we take those new approaches and bring them to the clinic as new therapies. Professor Aaron Esser-Kahn: Um, so to sort of bring this back to the cells.
This is really what I'm interested in is, you know what, what are these cells doing and how do they work because what I'm about to tell you will probably surprise you. Professor Aaron Esser-Kahn: Which is despite the fact that we've dumped billions of dollars into this process. Professor Aaron Esser-Kahn: Despite the fact that we've made many vaccines in the world. We don't know how many viruses or vaccines are molecules are needed to activate a single antigen presenting cell or any any if you're interested in presenting itself. Professor Aaron Esser-Kahn: We've never observed what the activation of a cell looks like in real time.
And then the last thing that's come out of our questions in this nature is can we change the conversation. How do we manipulate the cells to induce them to Professor Aaron Esser-Kahn: Make safer and more effective vaccination, we Professor Aaron Esser-Kahn: Had this idea by asking these two questions. First, Professor Aaron Esser-Kahn: So just to point out these are sort of the TL ours and the way they work. You don't need to worry about all the details here, but just the key thing is that they activate by diarization that's important. And then they signal through this master. Professor Aaron Esser-Kahn: Transcription factor called NF kappa B and that NF kappa B has to go from the cytoplasm to the nucleus.
And we use that a lot as a key signaling factor. Professor Aaron Esser-Kahn: Um, so these are the sorts of questions. I'm going to go through kind of three vignettes about how we approach these problems. So how many Professor Aaron Esser-Kahn: Viruses in vaccines or molecules are needed to activate a cell. This is one of the fundamental questions by lab is after I think it's very important.
So we call this determining the number of receptors to activate a single APC Professor Aaron Esser-Kahn: When I talked to other scientists about this, especially at the campus I talked about it like my Milliken oil drop experiment. Professor Aaron Esser-Kahn: Because it's very similar in the sense that, you know, Milliken if you guys remember what was after trying to figure out the charge Professor Aaron Esser-Kahn: Of an electron. But what was he was actually doing was measuring the charge on individual oil drops. And what we're doing is measuring the molecules on an individual cells.
Professor Aaron Esser-Kahn: But when I talk about it, informally to my family. And if you're a child like me and you watch this commercial endlessly. I think of it as the.
How many licks does it take Professor Aaron Esser-Kahn: Experiment, which is to say, How many licks does it take to get to the center of a Tootsie Pop, because that is forever burned in my head. Professor Aaron Esser-Kahn: What I was looking at as as a kid on so the experiment is is relatively simple once you understand how to design a molecule to do it. Professor Aaron Esser-Kahn: So what we do is we take this antigen presenting cell and I've Professor Aaron Esser-Kahn: Drawn it as a cartoon here we image this NF kappa B. That's the red in this picture here. We designed a very specific molecule that allows us to observe Professor Aaron Esser-Kahn: Whether or not it's docked on to this toll like receptor, the receptor that were that activates the cell and we stick a bright shiny molecule called the floor for on the outside of it. Professor Aaron Esser-Kahn: And that allows us to count exactly how many molecules are on exactly how many receptors and then when this NF kappa B. Professor Aaron Esser-Kahn: activates it moves from the cytoplasm to the nucleus.
And we can quantify that using a microscope. Professor Aaron Esser-Kahn: And as we do that, we can see a move. And we call this the activation threshold.
And we can do this on 30,000 100,000 cells simultaneously using this thing called an image stream which is basically a way of looking at many, many cells all in Professor Aaron Esser-Kahn: All in sequence. And this is the work of a postdoc in my lab Ethan white and it's, it's, in conjunction with the Professor Aaron Esser-Kahn: flow cell operator here at the University Professor Aaron Esser-Kahn: And so we did this by again looking molecular Lee at exactly how to design something so we looked at the crystal structure. Professor Aaron Esser-Kahn: Of try to figure out exactly how that molecule fit into the groove of the structure Professor Aaron Esser-Kahn: And then found the place where we could stick that floor for so that we knew that it would bind irreversibly meaning that every time one of these molecules bound, we knew it was stuck permanently. Professor Aaron Esser-Kahn: And then we knew that we'd have exactly one floor for on exactly the end of this Professor Aaron Esser-Kahn: Side of the molecule. So we knew there was one molecule per one set of receptors.
So we could count the number of receptors and then we get this plot that looks like this. Professor Aaron Esser-Kahn: Where the brighter the the cell that means there's more molecules. And then we can calibrate that using a calibration curve and the similarity score shows us the number of Professor Aaron Esser-Kahn: The, the amount of NF kappa B, that's been activated.
And so you can see here we have these molecules that stand out. Professor Aaron Esser-Kahn: And these are the molecules that are activated and so we can then go back and calculate and right now we've just started to figure this out. This is sort of fresh data.
Professor Aaron Esser-Kahn: But we now know that it's somewhere between 2006 thousand molecules that are required to activate a cell. And what's interesting about that is that it's much more than the number of molecules that would be on a single virus, for instance. Professor Aaron Esser-Kahn: It's, it's probably much more than than what would be on a single bacteria as well. Professor Aaron Esser-Kahn: And so this is an interesting question because it means that to activate a response, you would need more than then the system would need more than one virus to encounter it. And the question is, why now.
Professor Aaron Esser-Kahn: Why do you need so many viruses are so many molecules to activate an immune response. You would think that it would be much more sensitive Professor Aaron Esser-Kahn: But I think what we're, we're, we're conjecturing is that it has to do with sensitivity that it needs to have redundancy built in so that it doesn't accidentally set itself off. Professor Aaron Esser-Kahn: So that there has to be sort of a signal to noise integration and we're just learning how all of this works and all of the intricacies involved in it. But this is the first time anybody's Professor Aaron Esser-Kahn: ever observed this numbers. So this is the first time anybody's ever measured this and we're just learning exactly what that means. Professor Aaron Esser-Kahn: So, again, to highlight this point, you know what's happening.
So when this vaccine actually encounters. Professor Aaron Esser-Kahn: A cell. What actually happens to these receptors right again really nobody knows. Um, Professor Aaron Esser-Kahn: What do they look like when you activate them. So this is another question that we've been interested in because of course Professor Aaron Esser-Kahn: If you wanted to make something round or you wanted the RNA to be in a different place or you wanted to, you know, if you want to design something, you would think, one of the first things you would want to know is, where are the receptors actually live and how do you interact with them.
Professor Aaron Esser-Kahn: Yet nobody has ever tried to image these things before. And so again we picked this to our to system because we we like it and it's easy to work with. Professor Aaron Esser-Kahn: And so we started making movies have an innate immune responses, we've been watching to ours move Professor Aaron Esser-Kahn: On cells, and this has been done in collaboration with my colleague, June Huang. And really, this is something that could only be birthed out of the the CIC Professor Aaron Esser-Kahn: Because June and I otherwise would be in different departments and there would be no way that we would talk, but now we have a joint students Professor Aaron Esser-Kahn: And so, June is sort of a master of this, he's been doing it since his postdoc, but he's never done it on this type of cell.
And so what he did is Professor Aaron Esser-Kahn: He developed these Professor Aaron Esser-Kahn: It's a special type of antibody where you chip cut a very specific part of the antibody. It's called the fab fragment to you then stick a floor for on it that again means that you can image just a very specific part of the receptor. Professor Aaron Esser-Kahn: And then he used a very new technique that's only been developed in the last five years.
It's called Lattice light sheet microscopy. What it allows you to do is like a regular microscope scans, a single beam of light through Professor Aaron Esser-Kahn: Through a cell, but a lattice basically moves the cell through a sheet of light. This allows you to take many more images much faster than normal, which means you can now take basically real time movies. Professor Aaron Esser-Kahn: Have an entire cell as things are moving on. And so these are some of the first images, we've generated each of these yellow dots. Professor Aaron Esser-Kahn: Is a cluster of individual receptors on the surface of cells, and you can sort of see the outline of several of these individual cells here.
This is a 3D Professor Aaron Esser-Kahn: Video what you're about to see is them moving in real time. So that's an immune cell oscillating and pulsing as it begins to look for and detect Professor Aaron Esser-Kahn: Pathogens and what we're finding is that Professor Aaron Esser-Kahn: As we look at these, we can track in real time in in seconds. Exactly where each of these little clusters goes Professor Aaron Esser-Kahn: Using the same type of motion tracking and capture software that you would use for that performers use to sort of do motion tracking so you can sort of Professor Aaron Esser-Kahn: Create trajectories, you can calculate average and mean velocities.
You can look at if these things merged together or come apart and what you can find from that is that as these Professor Aaron Esser-Kahn: Cells encounter a pathogen. They beat these things basically act like a set of grappling hooks, almost like you know Professor Aaron Esser-Kahn: When a ship comes ashore, they cast outlines and basically grab onto this thing and and begin to assemble onto its surface and sift out the information Professor Aaron Esser-Kahn: As its as in real time as the thing is docking with the cell. And so exactly how those molecules are arranged and exactly how they're interfacing is critical for how the cell understands and then processes, the information and so Professor Aaron Esser-Kahn: It shows us exactly how you want to design a vaccine, um, with the last minute here. I'll tell you one vignette about how these understandings have been leading us to then translate these ideas to Professor Aaron Esser-Kahn: improve and change vaccine safety and efficacy Professor Aaron Esser-Kahn: So we were looking at NF kappa B. And we had this idea about how we can change and manipulate the way that it worked.
Professor Aaron Esser-Kahn: Which could then help us improve safety and efficacy. So again, remember I talked about how these covert vaccines. We're activating Andrew presenting cells in particular, these adverse events. Professor Aaron Esser-Kahn: Some of these later stage development were used to activate these cells and Professor Aaron Esser-Kahn: People often talk about these two important elements of Agence which are that they hold great promise, because you can reduce the amount of vaccine that you add Professor Aaron Esser-Kahn: So they're very important they boost the amount of antibody that you get, which means that you reduce the amount of protein that you add Professor Aaron Esser-Kahn: But then the other problem is that you often get excess inflammation from these so you can get sort of side effects, which can include headaches, you know, fever, Professor Aaron Esser-Kahn: flu like symptoms. We've all experienced these at some point where we've been vaccinated Professor Aaron Esser-Kahn: Most of these are attributed to a couple of systemic cytokines that come out of the injection site, notably I'll six and TNF are the two that people mostly regard as as as Professor Aaron Esser-Kahn: Influencing the side effects. And so the question is, how much are each of these going to have side effects.
Professor Aaron Esser-Kahn: And so what we found in studying NF kappa B and reading about it as we were looking at some of these traditional methods. Professor Aaron Esser-Kahn: Is that interestingly the individual subunits that make up this protein seem to have sort of disproportionate. Professor Aaron Esser-Kahn: ways of influencing this process. And so there's sort of one sub unit that seems to do all the good stuff. Professor Aaron Esser-Kahn: Basically that leads to protection and what some unit that seems to do kind of the stuff you don't need as much of you need a little bit of this.
But you don't need that much. And so we had this sort of thought, well, what if we kind of put in a Professor Aaron Esser-Kahn: Second molecule, what we call a potential later that would sort of attenuate or reduce the amount of this sub unit. Professor Aaron Esser-Kahn: That was allowed to cross into the nucleus. What if we could limit the amount of inflammation, while still keeping all the good stuff that was coming along with the vaccination.
Could we basically make something that was Professor Aaron Esser-Kahn: Safer and possibly more efficacious. And so these were early experiments that we did in animals. We took a traditional flu vaccine. We added this potential later. It's the shorthand is Sn 50 because it blocks that P 50 sub unit.
Professor Aaron Esser-Kahn: And what you can see, and then we added in an adjutant. This is something that stimulates to our nine in this case. Professor Aaron Esser-Kahn: And what you can see here is that if you do activate it with an with an adjutant you do see much higher levels of TNF but when you activate it. Professor Aaron Esser-Kahn: When you add the potential later you reduce those levels back down.
So you can eliminate Professor Aaron Esser-Kahn: The things related to the side effects. Basically, reducing them back to zero or or near baseline that also bears out in the way that you measure side effects and animals which is weight loss. So when we feel when we get sort of side effects.
We have Professor Aaron Esser-Kahn: You know, we get kind of grumpy and we get a headache animals they do the same thing, but then they do eat. Professor Aaron Esser-Kahn: And so that that results in a weight loss. And so you measure weight loss in a mouse and the, the more grumpy, it is and less happy than more weight it loses. Professor Aaron Esser-Kahn: And so when you add an adjutant you'll see it typically loses about 5% but when we add our potential later you'll see that really only loses about 1% in these cases. Professor Aaron Esser-Kahn: And again, when we added this both with the when we potentially aided the attributes we got 100% protection and challenge which is again how you calculate Africa see typically that's for a human we call when we talk about a mouse, we just talked about present protection. Professor Aaron Esser-Kahn: And then what we were surprised that is when we took the conventional flu vaccine.
The flus on this from 2018 and we added in just the potential later on its own. We were able to produce Professor Aaron Esser-Kahn: To boost the amount of protection that the vaccine rendered very, very effectively. So now we're looking at Professor Aaron Esser-Kahn: A large grant that actually Jeff is part of as well as several other people within the CIC where we're going to look for thousands of these under a project that will last for five years with the NIH.
Professor Aaron Esser-Kahn: To explore just how far does this concept. Go, can we apply this universally to all vaccines. Professor Aaron Esser-Kahn: Or is it going to be something that's specific to just a few areas.
And so this is something where we've really tapped the knowledge of a huge number of investigators Professor Aaron Esser-Kahn: You know Jeff is is here. Andy Ferguson is another person that needed Sean Who's in BSD as well as folks at IIT RI who are just up the road. So it's actually a Professor Aaron Esser-Kahn: Crush Chicago, but I really wanted to highlight the person who started all of this Britney Moser. So I think for all of you who are unaware every really good idea in a lab starts with one graduate student.
Professor Aaron Esser-Kahn: Who and she really did all of the work to start this whole concept. And so I think it's really important to acknowledge how a single graduate student can have a huge impact. Professor Aaron Esser-Kahn: Not only on a program, but on the trajectory of labs on the trajectory of science in general and just how important it is to seed and support. Professor Aaron Esser-Kahn: Those individuals as they go along and that has now given birth to a project that's probably 20 people deep, as well as Brittany Cassidy and Matt Rosenberger who are now active on this project as well.
Professor Aaron Esser-Kahn: I'll wrap up here by by just showing you that this works as well to potentially eight coven vaccines. So we've done experiments with the spike protein. Professor Aaron Esser-Kahn: In the last few months to demonstrate that we can boost the effectiveness of sort of traditionally an invented spike protein vaccines. So again, here's the spike protein and we're just abbreviating that is S here. Professor Aaron Esser-Kahn: So this is sort of what you get.
As an antibody tighter, which is again the thing that the best correlates with protection. We now know Professor Aaron Esser-Kahn: After the last couple of weeks. This is sort of the protection, the levels of antibody that you get if you use CPT G which is again a traditional adjutant Professor Aaron Esser-Kahn: Coincidentally, this is very similar to the levels of antibody that the Mr. And a vaccines produce if you add in our potential Gators.
This is the protein one. This is a small molecule one Professor Aaron Esser-Kahn: You can increase that by almost an order of magnitude. Again, this is just by adding a simple small molecule that just shifts the way the cell understands the information Professor Aaron Esser-Kahn: And the last experiment. I'll show you is not only do we get more antibody, but those antibodies are much more effective at neutralizing the coronavirus Professor Aaron Esser-Kahn: So this is a neutralization as a witch.
Just as you put the antibody in and you see if you can block it from entering a human cell. And so you just keep diluting the antibody down and you see, when does it stop being able to Professor Aaron Esser-Kahn: Block it from entering the human cell. And when we added our potential gators we basically ran out of dilutions you can see just started blocking on being unable to do that here as we were running out.
So it was it was not only Professor Aaron Esser-Kahn: Much higher levels of antibody, but the antibodies were much more effective at blocking the virus from entering. So I think these were both very interesting Professor Aaron Esser-Kahn: Observations that we made as we were looking at how to use these so Professor Aaron Esser-Kahn: You know this, we were developing all this before we got the data about just how effective the RNA vaccines are and and just how good Professor Aaron Esser-Kahn: Regular antibody titers are so I think the key things are, you know, you can influence safety and efficacy and interesting new ways. Professor Aaron Esser-Kahn: The great news for Cobra vaccines that they're already quite high. The safety margins look Professor Aaron Esser-Kahn: Great. And it looks like we're going to have some approved vaccines, fingers crossed in the near future, of course, everybody has to review the data in great detail that's going to be the most important part Professor Aaron Esser-Kahn: But to show you what we've been doing, just to summarize, we showed I showed you that we could look at how many viruses.
Professor Aaron Esser-Kahn: Are needed to, you know, and molecules are needed to activate a cell I showed you some of these images about how we could take active movies. Professor Aaron Esser-Kahn: Making movies of exactly how a cell looks when it's being activated and then I showed you an example of how understanding these sort of molecular level details could be used to change the conversation. Professor Aaron Esser-Kahn: Manipulate a cell and then change the safety and efficacy of even traditional vaccines by potentially eating them. Professor Aaron Esser-Kahn: And I really just wanted to finish up here by acknowledging the people in my lab. Professor Aaron Esser-Kahn: Because they're the most important elements, they're the ones that do all of the work I sometimes come up with the ideas. Professor Aaron Esser-Kahn: Mostly I act as a cheerleader and and so Zander is the one who does all of the imaging Ethan is the one who did all of the counting Brittany Is is the Professor Aaron Esser-Kahn: Student I already mentioned, who's really pursuing the potential theatre work but this whole group is really working together as a collective to come up with these ideas that them.
Professor Aaron Esser-Kahn: And generate them. It's a living body that works together collectively to Professor Aaron Esser-Kahn: You know, push all of these ideas forward and they're really the most critical part of the lab. So with that, Professor Aaron Esser-Kahn: I'd like to thank all of you for your time, attention and interest in the litany of questions. I see coming down the pike. And I'd be happy to. Professor Aaron Esser-Kahn: Take the time to answer a few of them.
And I shouldn't forget the folks at the alumni group who were kind enough to invite me to give this lecture. So thank you so much. And I'd be happy to answer any questions.
Professor Jeffrey A. Hubbell: Or thank you very much for that presentation going through some of the details of your data, but also Professor Jeffrey A. Hubbell: very understandable level how vaccines work and from a molecular and cellular perspective.
We've got about 10 minutes left for questions and I'll try to walk us through Professor Jeffrey A. Hubbell: Some of the questions that have been posed either before or during the talk. So you mentioned the concept of durability and questions coming in from Peter love Professor Jeffrey A. Hubbell: Kent Cynthia about durability durability mean how long the patient or the subject stays effectively vaccinated. Does it mean the shelf life of the material.
There's they're willing to predict how durable these vaccines are going to be Professor Aaron Esser-Kahn: Oh, that's a, that's a great question. So when I referring to durability. I mean, the length of time that the immune response will last rather than the shelf life of the Professor Aaron Esser-Kahn: Vaccine itself that's traditionally how we defined her ability in the Professor Aaron Esser-Kahn: In the field. And that's an.
It's a very interesting question because again it's something that is very difficult to predict. So it really has to be measured empirically. And so we'll have to see how how the durability of these things last over time.
Professor Aaron Esser-Kahn: It's going to be interesting to to observe. One of the most interesting things in the piece that I cut out of my talk for time. Professor Aaron Esser-Kahn: Is that some vaccines have incredible durability, most notably the yellow fever virus vaccine which can last for an entire lifetime. And so the question is what makes some Professor Aaron Esser-Kahn: Viruses and vaccines sell effective at inducing responses in some that only lasts for a few years and this is one of the questions that I'm particularly interested in trying to to answer.
Professor Jeffrey A. Hubbell: Another question coming in from from Wendy and and for others that they Sherman William Professor Jeffrey A. Hubbell: One of the features of the flu vaccine that makes it less effective than others, is the fact that the flu is mutating so quickly. That's one of the features. Professor Jeffrey A. Hubbell: How quickly is that is SARS co V2 mutating and will that
make us have to retool the vaccine after a period of time to deal with it was no news. Professor Aaron Esser-Kahn: Yeah, that's a, that's a great question. I think one that's actively on everybody's mind. I'm not sure there's any way to answer that.
Professor Aaron Esser-Kahn: Definitively. Um, but, you know, the sort of good news, bad news. Part of the situation is that there's a lot of active infection of this disease going on, and a lot of sequencing happening every day. Professor Aaron Esser-Kahn: As we test people.
So, and, you know, as I mentioned, if you want to look at this more detailed Trevor Bedford is really the person to Professor Aaron Esser-Kahn: To look into. He tracks. Basically, both of these diseases on a daily basis.
Professor Aaron Esser-Kahn: And you can go to his website next strain to look at mutation rates, but what he's observed is that the mutation rate for covert is is remarkably low among the lowest Professor Aaron Esser-Kahn: Known mutation rates for for viruses of respiratory viruses. And so it really seems like compared to most of the viruses that are out there, it's it's mutating at a rate that's much slower. Professor Aaron Esser-Kahn: Than what we've seen for things like flu.
So, at least based on what we know, in the past, if that's a good predictor for what we see in the future, which is not always true. It seems unlikely that it will be Professor Aaron Esser-Kahn: That the mutations will change. The other thing that we now know is that many of the mutations are not in the region.
Professor Aaron Esser-Kahn: Associated with the binding and and that's the region that these antibodies are targeting and so it again. Seems like unlike the flu, which mutates a lot of its mutations are in the area that the antibodies target. Professor Aaron Esser-Kahn: This seems like the mutations that we are seeing are not in the area, the antibodies are are focused on. And so that's another very reassuring fact about about how this will work.
Professor Jeffrey A. Hubbell: There are several questions on safety, you know, so for example with the Mr. And a vaccine from Tallinn. And this is a vaccine technology that's not been used in people before Professor Jeffrey A. Hubbell: So how does one judge safety in a clinical study, and
then what does one expect based on the biology of Mr. In a delivery in terms of safety profiles. Professor Aaron Esser-Kahn: Yeah, I think this is a great question. I think there are two important things to Professor Aaron Esser-Kahn: Note here which is well, people will while there are no approved Mr RNA vaccines. I think it's a little bit of a misnomer to say it's never been used in people before because there have been am RNA vaccines have gone through phase one. Professor Aaron Esser-Kahn: Trial. So there are data on the safety of how Mr na work