Tackling Vaccine Hesitancy: Knowledge vs Fear

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Scott Mackenzie: Hello, I'm Scott Mackenzie. The coronavirus pandemic has affected us all. And while at times, it may seem like a never-ending spiral of bad news, the truth is, there's real hope on the horizon. And at the center of that hope is the global vaccination effort.

The speed at which the scientific community has pulled together to develop and distribute not just one, but multiple vaccines is truly astounding. Global vaccination is our way out of this pandemic. But we cannot ignore the fact, however, that many people have both privately and publicly voiced their concerns and their fears surrounding vaccination. And if we're going to be successful in squashing this pandemic, these fears need to be addressed. The more we know, the less we fear.

So, with that in mind, we decided to reach out to some of the most knowledgeable in the field to help address some of those fears. Well, I am delighted to report that we have an exceptionally qualified expert with us today.

Dr. Derrick Rossi is a renowned stem cell scientist and a serial biotech entrepreneur. His development of the modified mRNA reprogramming technique was named by Time Magazine as one of the top 10 medical breakthroughs of 2010. And that same year, Dr. Rossi leveraged that very technology to co-found Moderna, a company focused on developing modified mRNA therapeutics, and whose COVID-19 vaccine is now a household name, and is being deployed as you know, all around the world. Time Magazine also named Dr. Rossi as one of the 100 most influential people in the world in 2011. And since that time, he has gone on to co-found a number of biotech companies, all focused on transformative medical techniques. In 2017, he helped launch Convelo Therapeutics, which is developing remyelination therapeutics for patients suffering from demyelination diseases such as multiple sclerosis, and he is currently serving as the CEO of Convelo. Derrick, thank you so much for joining us today.

Dr. Derrick Rossi: Good morning, everybody.

Mackenzie: You know, I sometimes think we don't fully appreciate just how amazing our immune systems are or how relentlessly they operate. But these systems are clearly the cornerstone of the inoculation process. So, I thought maybe we'd start at the very beginning and simply ask, what is a vaccine and how does it work?

Dr. Rossi: Sure. Well, it's a great question. So, I'd like to think of it in two parts. There's the upfront part with which is delivering the technology used to deliver the vaccine. And then, there's the second half of it, which is always the same, which is the body's immune system doing what it does. So, our body's immune systems carry on multiple functions, but the adaptive and immune system, basically surveil stuff that comes into us with the idea of recognizing self vs non-self. So, self, it doesn't respond to, which is good, unless you happen to have an autoimmune disease, and that happens to a lot of people, but that's an immune system gone wrong. But typically, your immune system wants to not react to self and react to non-self as a way of fighting off pathogens. So, vaccination itself takes advantage of what the body does on a day to day basis, which is recognize non-self and respond appropriately to it.

The front end of the vaccination is how do you deliver this non-self-entity to the healthy person, which is the process by which is called vaccination. And there's lots of different ways to do it. It  spans back hundreds of years, people were inoculating themselves in 15th century China against smallpox, believe it or not, was really the first thing we started to develop vaccination strategies against. And there what they did was, you know, somebody would get smallpox, it used to be a very prevalent disease, very deadly disease. And somebody would have had pox and survived it, the pustules of that would appear on the body, you know, once it was sort of burst there'd be sort of a white powder associated with it. They take a little bit of that, and scratch that into the skin of somebody who hadn't been infected yet. It was the little inoculum of viruses that came out of the out of the pustule and they had been dried by the sun or whatever, they weren't live anymore. The reason this technology isn't used at all is because sometimes there was live virus there and sometimes you would , by scratching the surface of the of the healthy person, you'd  infect them with smallpox. But the idea was – and they didn't know it of course, they didn't even know that there was viruses on there, that there would be sort of viral debris, viral particles, you'd scratch the surface of the skin, again, the immune system would kick in and say, hmm, there's stuff there that looks alien to me and mount an immune response to it. 

First, types of vaccinations were pretty primitive, as you can imagine, as I've just detailed. But then, it got a little bit more sophisticated. You would grow up large amounts of the pathogen in the lab, and then you would either inactivate it totally, so it was not infectious, or disable it in some way so that it was less pathogenic. And you would give that to a person. And again, they would see, their immune system would see this inactivated pathogen and mount an immune response to it so that when they saw the real pathogen, its healthy infectious self, they could mount an immune response to it.

Many technologies have come, and many are, interestingly, coming to the fore during this global pandemic, which are new ways of introducing the foreign, it's called an antigen, what the body responds to. So new ways of introducing the foreign antigen to the patient. So, mRNA is something that I've developed out of my lab at Harvard, but there's other adenoviruses, a way of delivering, again, parts of the virus to the person so that their immune system can kick in and do what it normally does on a day to day basis and ready the immune system so that when the person is out of the grocery store, or the gas station, or wherever they happen to be, and they come into contact with the live virus, their immune system is already primed to respond to it. It's not that you don't get infected once you've been vaccinated. You can still get a very low level of infection. But the point is that your immune system has already seen this thing before, and is totally primed to respond to it in a very quick and efficacious manner with the immune molecules such as neutralizing antibodies, or cell-based methods, cytotoxic T cells, various sort of levels of the immune system can respond to a pathogen. So, it's not just a one shot, if it doesn't – the antibodies don't work, you're done for, there's T cells are involved. It's a – our immune systems have been evolving since we've been evolving in the presence of viruses, and they've been trying to infect us, and we've been trying to come up with cool pathways to prevent that from happening.

Mackenzie: Yeah, and you mentioned that vaccines have been around for a very long time in various forms. But certainly, in the 20th century, we saw several significant ones in terms of impact. I mean, this is something that we should be familiar with, should we not?

Dr. Rossi: Well, yes, and no. We all get our first vaccines when we're infants. And so, I've been, as you can imagine, talking to media for the past year-and-a-half about this quite a bit. And it amazes me every time I do the level of undereducation around vaccines, what vaccines are, how they work. But I guess it shouldn't be that surprising. If you think that we get the first vaccines when we're infants, we don't ask questions. We then get vaccines later on when we're kids when we don't like needles. The only thing we're interested in is not getting the needles. And then, by the time you're an adult, you've gotten so many vaccines, you're like, Oh, well, they say it works, but you know, okay, I'll get my vaccine or I won't get my vaccine. And believe me, you can read any number of things on the internet to convince you one way or the other. The internet is a liar.

It's remarkable. It's a medicine, if you will, that we've been using for hundreds of years. We – pretty much almost all humans on the planet had been vaccinated against multiple things. Some people don't get their yearly flu shot, but many do. So, it's really a routine ritual, yet incredibly people don't really understand what it is or why they're doing it. They just do it because they always have, and it's never seemed to cause them any harm. And they've heard stories that – or maybe they stopped to think, hmm, when was the last time I saw somebody with smallpox walking around? Not that recently. Not that recently. There's been several diseases that had been eradicated through vaccination strategies. It's one of the most used in human history and effective medical paradigms that there are.

Mackenzie: And that leads us nicely into the big question that we're trying to address today, because certainly, the voices of fear that I hear are all around safety. So, I just wonder if we could just talk in terms of how safe are vaccines and maybe within the context of maybe other medicines that we take more routinely?

Dr. Rossi: Well, you can never say never in any aspect of biology, but I think the numbers here speak for themselves. Millions of people, now hundreds of millions of people have been vaccinated – well, okay, let me step back a second. First, there's something called clinical trials. And clinical trials are designed to address four things. Safety is number one – , safety's number two and number three, and number four is efficacy. So, it's all about safety. So, clinical trials are run – I'll just talk about the U.S. because I live in the U.S., although I'm Canadian. And the FDA is a very rigorous organization. It's really the global standard on, you know, putting drugs through clinical trials to prove their safety and efficacy before they go into patients. So, these trials have been run with many tens of thousands of people and now for many different vaccines pretty much all targeting – let's just talk about SARS-CoV-2, the spike protein, so the protein that is on the surface of the coronavirus that gives it  the corona like shape, the crown-like shape is these spike proteins sticking off the top. It's the thing that first engages with human cells to initiate the infectious cycle – too good thing to target if that's the thing that is responsible for initiating the infection cycle.

We have to know about the virology of coronaviruses, which we do. This is not the first coronavirus that we've seen before. So, a lot is known about coronaviruses and how they work and how they get into cells. But of course, everyone is different. SARS-CoV-2 has not been seen in humankind before. The good news is it's a class of virus that we know how to – we know the biology of that and how to target that.

I'm going quite far afield of the question that you asked, which was, how safe are these in comparison to other meds that we take? Well, a lot of other medicines that we take are actual – there's multiple different classes, obviously, but a lot of them are chemical compounds that are either synthetically derived or some variation of something that's derived from a plant or something like that. But they're usually small chemical molecules that get into the body to inhibit one part of a protein – or basically, usually what these things do is there's an enzymatic pocket for a protein and the small chemical medicine fits into that pocket so that the thing doesn't work anymore. It's usually inhibitory type medicines. Those are good and they've been proven – there are countless that all of us take on a regular basis. There are also many that have failed through clinical trial because they've proven to be unsafe. You're trying to target this one enzyme, but lo and behold, this small molecule hits something else in the cell that you don't want it to hit and it proves to be unsafe. And that's what's borne out in the clinical trials.

There are also biologic medicines, of which mRNA is and protein-based therapies or any gene therapy. These are newer, but again, they have proven in many cases effective. There are over 100 different FDA-approved protein therapies. So, I think it just starts – you know, really to get down to the core question, and I think it's partly true of this vaccine is how did this – because you're used to hear talking heads on the television last year, and I heard it many times, saying, there's no way in heck that a vaccine will be ready in 12 months, because they normally take several years to develop. And every time I heard that, I kept thinking to myself, well, they don't know the technology, because these new technologies are a lot faster. And that's one part of it. And the second part of it is that the clinical trials – there were still three phases of clinical trials run, but they were not done in the traditional manner, where you start phase one and you end phase one before you start phase two, and you end phase two before you start phase three. What they did in this case is they overlapped them with the idea of getting to the end quicker and quicker but in no way skipping any of the steps. All the steps have been done. They've just been done in parallel to speed up the process.

Now, that's a risky thing from a business perspective to do, because it's expensive to run clinical trials. And usually, you don't run your phase two until you finish your phase one, because you don't know if you're phase one is going to be safe and effective. And you don't run your phase three until you get your data for phase two. But there was such a pressing need to get this, you know, a global pandemic of a pretty deadly virus, that this was the strategy that was taken by multiple companies and supported by governments. And it really accelerated the process. But it didn't skip any steps. The trials were very, very robust. They went through the same regulatory process, as they always do. And, interestingly, the review committees for the FDA that reviewed the final data package with the panels for these drugs, they were live – live streamed for these vaccines. That's usually not done. So, in a way of even increasing transparency, these meetings were live streamed. I watched them. I spent a day at my computer watching these meetings.

They normally happen in – you know, nobody's interested in those meetings. So, they're not live streamed. But they were live streamed for transparency. So, of all things, I hear this all the time from people they think, well, the speed is – how could it have been done so fast, and it was done in secret. It was done at record speed, because of this strategy that I told you about it, overlapping the clinical trials. The amount of money and tech and the technologies being very fast. But the fact of the matter is they went through all the regulatory processes. And you, everybody out there could have watched these meetings to see how rigorous they were when they were analyzing the data.

Mackenzie: I think that's a very good point. As you say that you've got all the processes in place. You have no risk of having to miss out on one of them. You've got governments supporting it. So, there's really no downside to taking that approach and plenty of upside, obviously.

Dr. Rossi: Well, like I said, the downside is a business downside. If a company – companies don't do this, because, well, moreover, you learn from your phase one. Phase one is usually a dosing trial, what's the best dose to give to a patient before you go into phase two. So, they did a couple of doses. They got early – the good news about vaccination, it's very – you can very quickly know whether, A, the dose is tolerable to somebody, and B, whether it's effective. You don't even have to measure whether they – they don't get COVID or not. You can just look in their peripheral blood for antibody production. Are the antibodies produced which happened within a week-and-a-half of getting your shot, is it eliciting the proper immune response? That's something you can easily measure non-invasively by taking a bit of peripheral blood off somebody. So, it just so happens that vaccination is a very good thing to do in this type of manner.

If, for example, you had to dose for a rare brain disease, let's say, that you would only know whether or not your drug worked a year in, let's say. You're never going to start your phase two or your phase three because you don't know whether or not the thing is working. You have no way of knowing. You don't have a biomarker that says, Yes, this Alzheimer's drug is slowing down the progression of the disease. You're going to have to learn that over the course of a long period of time. And that's the objective of the clinical trial. And you're not going to start your next phase until you know that because they're expensive trials to run.

Mackenzie: And maybe you could speak a little bit too about, sort of, sticking with this notion of the speed to market. It's not as if this mRNA, or this modified mRNA technology that you had developed 10 years before, wasn't already sort of in place to a certain extent. I wonder if maybe we could maybe get a little bit into the technology that you helped develop and frankly, was here just at the right time it seems?

Dr. Rossi: Yeah. Well, the point that I think you made is a good one. So, these technologies, not just the mRNA, but the adenovirus technologies used by other major pharma companies, which are also quick to market and approved, or emergency approved. These have been in development for a really long time, A. These things just don't pop out of nowhere and all of a sudden go into patients. For example, Moderna, I founded in 2010 and it's been in the clinic, it's already run phase one and phase two trials for many different programs, including many different vaccines. So, they already had this body of data that they could address for dosing, for safety. All those clinical trials were done within the auspices of the FDA. So, the FDA saw all that data and was very comfortable with that data. And in fact, Moderna worked very closely with the NIH and the National Institute of Infectious Disease to do these trials. And in fact, the technology emerged as potentially one of these game changers should a pandemic emerge, something that could be done really quickly, very, very quickly and very tailored to the disease itself.

Talk a little bit about the mRNA, which you alluded to. So, I always like to start here with the lay audience. And I'm sure some people in the audience know this already. But everybody knows what DNA is, or at least they've heard of DNA. DNA lives in the nucleus. It contains the instruction book for life. And people have also heard of proteins. And although people – proteins are a lot less refined – people think of proteins in terms of what they eat with their steak, or if they're getting enough proteins in their diet. , proteins are like the functional units of biology. They do all the busy work. They're the worker bees of the hive. DNA is, if anything, the queen bee, doesn't do anything, sits there at the center of the hive, gives out all the instructions, but doesn't do anything. It's very passive molecule.

But there's a neglected middle sibling that – you don't go from DNA, which contains the code to get the proteins. There's this intermediate molecule called mRNA, which is similar to DNA. It's a nucleic acid. It gets encoded genes. You've heard of genes. Genes are basically part of the instruction book, which encode a protein. We've got about 25,000 different proteins, but at least 25,000 different genes, they encode proteins, you know, 25,000 different worker bees performing different functions. But in order to make them from DNA, you need this intermediate molecule called messenger mRNA. That's what the M stands for, it's messenger. It carries this message from the DNA out of the nucleus into the cytoplasm to the protein production facility in the ribosome and proteins are made.

DNAs have been used as therapeutics. That's what gene therapy is, and some are FDA-approved and more on the way. Proteins certainly have been used as therapeutics. Over 120 different therapeutic proteins have been FDA-approved. And mRNA was this sort of neglected middle sibling. And we started to work on it in 2008, and others before us as well. We built on the work, very important work of others before us, and in parallel to envision bringing this as a therapeutic paradigm because, you know, DNA makes mRNA, makes protein, makes life. That's what I call the trifecta of life. Well, DNA mutation makes a defective mRNA, makes it defective protein, gives you disease pathology. So, there's over 6,000 genetic diseases that have this basis. There's a mutation in the DNA. It makes for a bad mRNA, because that code is directly translated to the mRNA, which makes a bad or defective protein, which gives you a disease pathology. So, when I first developed Moderna, this was the idea, was going after a genetic disease, not the DNA, but rather using this intermediate molecule to give to somebody that has a genetic disease, needs a proper protein made instead of the defective one that they make and using this mRNA as a strategy to do it.

The nice thing about mRNA, it's always the same. The sequence changes, but it's always a nucleic acid. It's always got these four building blocks, and you just shuffle around in different orders and a different protein comes out, but it's always the same. So, I imagine that the manufacturing was going to be pretty straightforward, because once you got it right for one, it's just a matter of changing the sequence and you can do it for another and another and another. That's unlike proteins. When you make protein therapeutics, every protein therapeutic, every protein is – you know, you've got tiny proteins, you've got big proteins, you've got collect constellated proteins, you've got phosphorylated proteins. Proteins are much more complex. The diversity of what proteins look like is huge compared to what mRNA looks like. It always looks like mRNA, just with a different sequence of these building blocks called nucleotides.

The COVID vaccine, we talked already about the spike protein being the thing on the surface of the coronavirus that first engages with human cells, it's the – you know, here's the spike protein, here's the human cell. And if you could see that, that's the thing that engages. It engages with a receptor on the human cells called the ACE2 receptor, sticks on there to initiate the infectious cycle. So, the vaccines that have all been developed are pretty much targeting just this – you know, it's, it's a mirror image for me. So, I think I'm holding up my left hand, but it's showing right on the screen. So, I keep going for the wrong hand.

Mackenzie: The spiky one.

Dr. Rossi: Yeah, the spiky one. So, now, the mRNA vaccines, for example, just encode for this spike protein. So, you're delivering that into the people. You're not getting any of the rest of the virus. The whole other part of the hand – you know, there's a lot of virus there that you're not getting. All you're getting is this – you know, the end of this spike protein expressed, and that's what's eliciting this immune response. And we know what the sequence of that thing is. We know what the genetic sequence is, so we can make it exactly for that spike protein, which is really effective. Because when you want to target a pathogen, you want your immune system to be very specific and very effective at targeting something bad, something you want it to target. And if you give it the exact sequence of what you want it to target, you've got a better chance at developing a good vaccine.

Then, for example, the influenza vaccine that we get every year. So, the influenza vaccine that we get every year is  made by old technologies that take a long time to develop, and they start making the next year's influenza vaccine before they  know what the predominant strain of influenza is going to be. So, that's why each year, sometimes you get a better vaccine, you know, they guessed right for the strain, as opposed to knowing exactly what the sequence is. So, to be honest, the mRNA technology is going to be used for influenza, multiple companies, including Moderna and BioNTech have started programs for influenza, because you can do it – again, you know the sequence, you can make it specifically tailored to exactly the sequence of the strain that you're trying to target. You can do it quickly. You can do it cost effectively and really, drive specificity in the immune system.

Mackenzie: Well, I understand that, and I may be wrong about this. But I understand that when you received the sequence, if I can put it that way, when it was published by the Chinese that it was a very short period of time from the time you had  created the messenger RNA.

Dr. Rossi: Yeah. Well, it wasn't me. So, I founded the company in 2010. And I served on the Scientific Advisory Board and the Board of Directors until 2014. Then I stepped away. So, I haven't been involved in Moderna, although obviously I know the science very well, and I follow it. And for a disclosure, obviously, I'm a stockholder as well. So, Moderna, you're exactly right. The Shanghai consortia published the sequence of the SARS-CoV-2 online. It was  guys at the NIH that were sort of thinking about another test case pandemic. That was being really led by people in collaboration with Moderna, but it was their idea. They saw something. The epidemiologists, they said, why don't we test it on this. And in collaboration with Moderna, they had a clinic ready, ready to go into patients, therapeutic grade, GMP, good manufacturing process, material to go into patients 42 days later. And it's because there was the sequence, you can very easily make a new mRNA. In my lab, when we were working on this in 2008-2009-2010, if we had an idea which we had many in the lab to express new proteins that we wanted to express, it would take us about two weeks to get one ready to get into cells and express the protein that we're interested in.

Now, here, it's a little bit longer, because you have to do larger scale up and it has to be done under – you know, we were doing at the lab bench with pipettes and tubes and not in clean spaces or anything like that. But part of the reason that it was so rapid too for Moderna is because they had invested in the infrastructure for manufacturing this technology. There's a GMP grade manufacturing facility in Norwood, Massachusetts, about 20 minutes – I keep sort of – it's that way – about 20 minutes from me here in Newton, Massachusetts. They had invested in that a number of years ago, which was good move. Typically, preclinical stage companies don't make factories, they don't invest in factories. But they were smart, they invested in factories. So, they were ready to go there. So, it's the confluence of many things. But at core is this really cool technology.

Some of the other vaccines that are out there are also nucleic acid based. So, for example, the adenoviral vectors by AstraZeneca and Johnson & Johnson, those are adenoviral based. They're DNA based. But again, it's nucleic acid. If you know the sequence, you can quickly make the sequence, put it into an adenovirus, which we and many organisms get infected by adenovirus all the time, they cause the common cold . But you can sort of gut out the genetic material and replace it with something that you  want it to express. And that's what these technologies are. But again, they're…

Mackenzie: So, using that as a transport – using that to transport it?

Dr. Rossi: Yeah, basically. Yeah, it's a good delivery vehicle. Good delivery vehicle. Again, back to our initial discussion is, how do you get the sort of antigen into the patient, you know, you got to deliver it in some way that you have to expose the person's immune cells – a system to it for the person to respond to it for their immune system. You have to get it in.

Mackenzie: But in the messenger RNA, that's a fairly transient thing, is it not?

Dr. Rossi: Yeah. It's a relatively labile molecule. DNA is a much more stable molecule. It's a double helix instead of a single. I can't do a double helix with my finger. If I could twist my finger around, it'd be a double helix. mRNA is single stranded. It's more unstable. It's degraded by enzymes called RNases. These are proteins, the worker bees, that degrade RNA. But it is long lived enough to get into the cell, deliver its message, go to an organelle in the cell called the ribosome, which is the protein making factory, it goes in, gets fed into the ribosome and a protein is made that's encoded by the mRNA. And then, it's degraded and recycled – the nucleotides are recycled, but the protein is made. You don't need the protein sustained for a long period of time. You need it expressed. You need it recognized by the immune system. You don't need it expressed anymore after that.

Vaccination is a really good application for the technology because all you need to do is a transient exposure to the immune system of the antigen, the spike protein in this case, and then the immune system does what the immune system does, it responds.

Mackenzie: Yeah, and some of the numbers that we hear all the time in the media about how effective the vaccines are, I wonder if you could just maybe help for those of us who are not familiar with what these numbers  mean. When someone says something is 94% effective, what are they saying? What does that mean?

Dr. Rossi: Basically, there's two groups of people in these clinical trials. There are those that get the placebo, which is basically sugar, water, usually nothing, salted water, versus those that get the experimental arm. There's equal numbers of those people. They're given a dose on day one. And depending upon how the clinical trial is designed, usually they start monitoring whether or not the person gets COVID in this case either after the first injection, or after the second injection, if there happens to be two injections. And then, you just basically follow the cohort. So, in the phase three trial for Moderna there were 15,000, people that got the placebo and 15,000 that got the mRNA vaccine. Those people don't know what they get. It's blinded. And in fact, the injectors don't even know what they get. It's coded. That's important, because you don't want people rigging the results. So, it's called a double blinded study. And then, you just follow the data on whether or not those in the controlled arm, placebo arm, versus those in the experimental arm, what the rate of getting COVID is. And then, secondarily, is it severe COVID, does it lead to hospitalization, does it lead to death. And when you've got this statistical power of 30,000 people in the trial, you can make pretty highly significant assessments of the data to come up with a number like 94% efficacious.

So, I'm going to basically – you know, this is a X-axis and a Y-axis. And now, I'm going to have to use my hand on the X-axis. But basically – and this is the incidence of getting COVID. So, the people on the placebo arm, it goes up like this, they're getting more and more COVID. The people on the vaccine arm are staying down here for the same amount of period, they're not getting COVID. Nobody got severe disease. One person died that was on the placebo arm. And they set X number of infections before they could do their analysis. They wouldn't have to wait for 15,000 infections. They set a number that they feel like there's enough statistical power to be able to make a conclusion. In fact, the pandemic was raging so much that they  got way over the number that they had originally set. So, it was  196 infections, almost all of which were in the placebo arm. There was, I think, 8 in the vaccination arm. And really, that efficacy is really extraordinary. That's a very, very effective efficacious vaccine. Don't forget that the FDA was setting maybe 60%, 70%, they would have been happy with that, to get those numbers because even that given to the population could really help in a pandemic.

When these numbers first started coming out, it's interesting because BioNTech and Moderna basically use a very similar mRNA technology and the efficacy rate for both of the trials is 94% to 95%. It's remarkable. It gives confidence too because they are two independent studies, two independent companies, two independent review panels, trials done in different parts of the planet. So, very, very effective vaccines. And of course, it's a pretty high bar. And some of the other vaccines that have come in second or third or fourth or fifth in the race and they're getting 78% efficacy, or 76%, it was  really, really good numbers. Those are really good numbers. But people are were like, oh, that's not 94, I don't want to get that one. And then, you've got people that want to vaccine shop. So, I  advocate that if it is approved, if it is an approved vaccine, that means that it's reached – it's proven itself both efficacious and safe. And when you show up at the pharmacy, or your doctors, you should get the vaccine that's offered to you, because it's been through the regulatory process to be safe and effective. And don't vaccine shop, get what's offered to you because you're much better off being vaccinated than being unvaccinated.

Mackenzie: Right. And is there is there any numbers yet on the how efficacious these vaccines are for some of the variants that are now coming out?

Dr. Rossi: Yes, there is. So, there's both real-world data for trials that are ongoing still for which variants have emerged as the predominant strains. But there's experimental ways that you can determine this. So, somebody that's been vaccinated, let's say, with Gen 1 vaccine for the original, non-variant SARS-CoV-2 virus, you can take their antibodies, which you can get by drawing peripheral blood out of them. And these people, you know, it's easy to draw peripheral blood. And then, you can measure whether or not how effective their antibodies are at neutralizing the ability of the variant strain to infect cells in a tissue culture dish, basically.

These experiments have been done for pretty much all variants that are constantly emerging, because there's still such a huge pandemic raging and viruses mutate, that's what they do. So, it's not surprising there's variants. And so, by and large, the Gen 1 vaccines have been very good at neutralizing most of the variant strains. The one exception to that is the – and that by the way includes the U.K., the strain that first emerged in the U.K. that is  more infectious, it's more infectious. The mutations in the spike protein make it latch on to human cells more tightly, which of course, gives it a selective advantage. It can really latch on there without falling off. So, that's the mutation that occurred in the U.K. So far, the vaccines that have been developed are all just as effective at neutralizing that variant. But the exception is the variant that first emerged in South Africa.

The vaccines that – that Gen 1 vaccines can still neutralize that variant, but not as effectively. So, that one has changed the spike protein enough that the antibodies don't bind to it quite as well, the neutralizing antibodies. And so, some of the companies, including Moderna, have made a variant-specific vaccine for the South African variant. South African variant emerged in October of 2020. And by February, Moderna was shipping the variant-specific vaccine to the NIH, the National Institutes of Health, for testing in patients. So, again, very fast turnover for like a variant-specific vaccine.

Viruses are great evolutionary units. They're about as good of an evolutionary unit as it possibly can be, especially when they're replicating hundreds of trillions of times in people. You can imagine the opportunity for mutations to arrive, which would provide a selective advantage, you know, something that gives it a bit of an edge. This is how evolution works. So, this is how these variants are emerging. And so far, the vaccines and the immunization has proven to be effective against these, maybe less so against South African variant. So, I think you're likely to see variant-specific boosters in the future. So, a booster shot is you get a – you know, your immune system has – it's been primed by vaccination, but at some point, it wanes, that immune response wanes. So, you give a booster to jack it up again, to make sure that it's really ready should somebody get infected. So, I think we'll see variant-specific boosters in the future.

Mackenzie: Well, this is a silly question to ask, do you have to go through this rather robust and rigorous regulatory process every time you come up with a…?

Dr. Rossi: It's a great – it's not a silly question. It's  probably, I think, one of the most important questions. Well, you'll notice that we don't have clinical trials for our influenza vaccine every year. We don't, because we've done it enough. We've done it for decades. We feel comfortable with the core technology. We know it's safe. We know it's efficacious. That's not going to happen just yet with some of these newer technologies, simply because they haven't been around long enough. Although, I would argue that when you have 3, 4, 5 billion people vaccinated with, let's say, an mRNA – well, okay. Moderna has promised a billion doses, Pfizer BioNTech 1.5 billion this year. That's 2.5 billion doses. They're always looking for opportunities to increase their production. That's the bottleneck, . So, there will be billions of people vaccinated.

At some point, the regulatory agencies are going to say, okay, we've had a billion people vaccinated, and it really works. And it really doesn't have any measurable side effects, or you know, maybe there's one in a million person that has an adverse reaction, allergic reaction and their EpiPen takes care of it, something like that. True of any medicine; never say never in biology. So, at some point, I do believe that these – that you won't have to go through the regulatory process just as the influenza vaccine does not have to go through the regulatory process every year, yet it's given to hundreds of millions of people every year. But these new technologies, and rightfully so, they have to go through enough people and enough regulatory, FDA regulatory to give comfort that the technology is safe, basically safe.

Mackenzie: Yeah, of course. And I mean, there's been a number of variants that have come up, but it's hard to know, but with such a widespread infection, and as you say, it's constantly mutating, should we be expecting lots of variants on the horizon? Is this something that changes from virus to virus? Or how should we look at that?

Dr. Rossi: Yeah. Well, there's  a selective pressure to both mutate but to not change the shape of the spike protein so much that it no longer engages with its human receptor. So, it's a physical interaction. I'm just going to say that these are my fingers. My hand is, again, it's the wrong side. I wish I could flip this so that I wasn't coming off the wrong side of the screen. So, let's imagine this is the spike protein. And now, this is the ACE2 receptor and that has to fit in there for this infectious cycle to begin. So, you can't turn this thing into something that looks like this, because it just won't be able to fit into that. So, there's a selective pressure to keep the spike protein relatively looking like the spike protein. But again, some of the variants have made it and I wish I could alter my finger enough. Let's just say I did this with my finger to  make it  engage even stronger. This is some of the variants that have emerged right now. It's  – it's a selective advantage. It's a stronger interaction. So, there's both a selective pressure to come up with new variants that increase the likelihood that variants will be able to better propagate, but there's a selective pressure also to keep the spike protein not so differentiated that can no longer interact with the receptor that it interacts with on human cells.

Mackenzie: And can you foresee us having taking COVID vaccine on an annual basis like we do with flu or is this something that would be…?

Dr. Rossi: The question is, is the virus going to become endemic? Or is it just going to be something that ebbs and flows like influenza? I don't know. Nobody knows yet. Although I think it's likely because of the incredible spread of the virus on the planet and the number of people infected, and the opportunity for selected variants to emerge, which is, like I said, the more people you infect, the more mutation occurs during replication of the viral genome. That's the only time mutation will occur. And most of the time mutation is bad. It doesn't give a selective advantage at all. But at some frequency, some mutant arises, that's like, oh, that  makes me even more fit than – I can run a little bit faster than everybody else in the pack here. I've got that selective advantage.

Given the numbers of people infected, the opportunity for a positive selective advantage is massive. And you see it already in these variants, and there's sub-variants, and there's variants of variants. Now there's even variants – it's not just the spike protein. Let's not forget the viral genome has many genes in it that's responsible for the viral like life cycle. So, I think that given the amount of viral replication that's occurred on planet earth, it's likely that variants will emerge that become endemic.

Secondly, people that refuse to get vaccinated. So, they have – everybody has the right to say, no, I just don't want to get vaccinated, I don't think it should be required. On the other hand, those people are a breeding ground for new variants. Because if they get infected, they're going to see 100 trillion replications in their body and one of those trillion replications might lead to a new variant that evades all of the vaccines, the vaccine strategies. So, vaccine hesitancy is not good for the population as a whole. Although I do understand that people should have the choice to say, well, I just, you know, I get it, although usually they don't get it, because they don't understand the science and they're not scientists or clinical people. And so, this is why I'm doing this today is to try to sort of let people know a little bit about the science of these vaccination and virology. And I'm not a virologist, by the way. I'm a molecular biologist. So, I know enough about virology and I know about evolution. I was in molecular genetics at U of T , the town in which you sit right now, many years ago. But I think any biologist knows this.

And so, I think the more we get out there and talk about the real science, the better we're going to be of. I've talked to a lot of people, and I've done a lot of media things and this and that. And after the discussion, the feedback is, oh, boy, if I really even knew that this is something that the immune system normally does on a day to day, I didn't even realize that that's what vaccine does…

Mackenzie: Exactly, yeah.

Dr. Rossi: … I think it's incredible.

Mackenzie: Well, that's why we're so appreciative that you're doing this today because that's exactly what we hope people will get out of this. I want to just maybe just go slightly off the COVID track for just a second because I'm so fascinated by the mRNA technology. Because as I understand it, when you established Moderna or co-founded Moderna, you weren't really thinking about vaccines at the time, were you?

Dr. Rossi: Yeah. Well, I was trained as a molecular geneticist. And so, I was thinking genetics and genetic disease, I go back to mutation in DNA makes a bad mRNA, makes a bad protein, gives disease pathology, for which there are over 6,000 genetic diseases, and that doesn't include cancer, because all of cancer is basically mutation driven. So, I was thinking primarily in this field, and not in the field of vaccines, although it is a really great application for the technology, because you have to give a person, it's non-invasive, you get one or two shots, you can measure their peripheral blood, did you respond to it in a good way or not? It's a really easy clinical trial to run just to see whether or not it's safe, and it does what you think it does.

I think it's a great application. But I don't think it's the only application I think there's going to be – and indeed, Moderna has a deep pipeline of mRNA therapeutics and BioNTech. And by the way, there's mRNA therapeutics companies sprouting up like mushrooms all over Boston, Cambridge here and all over the planet. I even was involved in U of T Entrepreneurship Week event a couple of weeks ago and heard of another Canadian mRNA-based company. So, there's going to be – that's great  for the whole field. So, there's going to be literally many dozens of mRNA companies working on different things and discovering different things to move the technology beyond viruses and into genetic diseases and chronic diseases.

One of the challenges that we had when I founded Moderna was what do we work on, what should we program one, two and three, because there are a thousand things you can work on and you kind of don't want to get it wrong. You don't want to go down the wrong, or something that's going to prove to have some point down the road a technical challenge that you didn't think of. So, you want to set the technical bar as low as possible. , vaccine is perfect for that. It's a very, very low technical bar. But I think you'll see – I think mRNA therapeutics are here. And a large industry has been spawned. And I would say Moderna led the way certainly with that, and the industry has been spawned. And I think it's going to – of course, I've drank the Kool Aid, and I remind everybody that I'm still a stockholder in this company. So, I do have a biased opinion of the technology. But I have that biased opinion because I'm a scientist.

Mackenzie: Right. Well, listen, there's also one last question I wanted to touch on. And obviously, this is not going to be our last pandemic. It's hard to know what lessons  have been learned. But we certainly hope that lessons have been learned. But I wonder if you would have any recommendations for our governments, for the people that are leading us as a society in preparation for the next pandemic?

Dr. Rossi: Yeah. Well, you're right. It's not if, it's when. So, it's definitely coming, another pandemic. Just the way we live, you know. And the speed with which these things can spread around the planet is incredible. I mean, Wuhan in late 2019 and the whole planet in early 2020, it's pretty impressive. Again, kudos to the viruses. They're really impressive. Some people don't even think they're organisms, because they don't fulfill all the criteria for organisms. That's an interesting scientific debate.

I've been talking to both the Ontario government and the federal government about – and the good news is governments, not just Canadian, but around the planet are – you know, I've been talking to the Egyptian Government – the bottleneck has been production of the vaccines, basically. Now that they're approved, emergency approved, everybody says, well, why can't we all get ours tomorrow, and they can't all get theirs tomorrow, because it's a production bottleneck. So, first and foremost, I think it's a manufacturing challenge. So, I would argue that countries and provinces should have in-country manufacturing capability.

Now, you have to be careful, because you don't want to just have a manufacturing facility for one thing, and if that thing goes away, you've got a factory sitting there doing nothing. You can't do that. So, I would bet on a technology. I would argue that mRNA is a good one to bet on, because there are going to be many different mRNA medicines, and you could be banking therapeutics for this or that disease most of the time, and if a pandemic rolls out, you can switch to doing – you know, because again, it's the same core technology, just a different sequence. All of a sudden, you can be making your COVID vaccine in-house. So, I would argue that manufacturing should be invested in. And I know a lot of countries around the planet are thinking about this. Certainly, the companies are thinking about this.

But it comes down to even fundamental biology like virology. It's not a very glamorous field, you know, I study viruses. Really? I mean, it seems – people aren't very enamored by that. But if we didn't have hardcore virologists studying viruses, we wouldn't know about these darn things and how to respond to them. So, I would say, continued funding in basic research, I'm not just talking about virology. I mean, a great example – the example I like to give for this is, many in your audience have probably heard of CRISPR, CRISPR Therapeutics. It's a technology that  we were involved in earlier as well. And I founded a CRISPR company as well. But that CRISPR is basically bacterial immune system against viruses that infect bacteria. Now, if you presented that to somebody on an elevator and say, what are you working on? Look, I work on how viruses infect bacteria. They'd look at you and think, what the hell are you doing that for? Well, you lo and behold, CRISPR emerges from this study and now there's – it's a huge industry. There are three therapeutic CRISPR companies in Boston, Cambridge alone that have all gone public. They're in the clinic for many different applications. So, that's basically funding a basic research where very, very basic research – you know, viruses infecting bacteria, it doesn't get any more basic than that. But this really important medical technology came out of it. So, I advocate strongly for governments not to neglect funding basic science.

Mackenzie: Yeah. Sounds good. Any last words you'd like to offer our audience and particularly those who might be, as they say, vaccine hesitant?

Dr. Rossi: Well, I would just say that don't believe what you read on the internet. I really want to have a T-shirt made The Internet Is A Liar. You can literally find anything and everything on the internet. Anybody can post anything. But I would encourage people to listen to people that are  experts in fields and how they think about things. And if you really – you know, you always hear about people that are vaccine hesitant, they've done their research. Well, that means they've gone into the internet, and they found sites, obscure sites that have said this or that or the other, that are  not science sites. So, if you really want to do your research, find a scientist and ask them what they think about science. Because people aren't trained in science. They're not able to assess whether or not something is real or not real or a good idea or a bad idea. I mean, it's just like any other profession. We're just talking about science right now. But it's any other profession. If I'm going to redo the electricals in my house, I'm not going to ask the guy that I work with in the lab to come and rewire my house. That would be a really stupid idea. They're great scientists. They know nothing about wiring of a house. So, follow the real true science here. And I would argue get yourself vaccinated, get protected. But of course, it's within everybody's right to say, not for me.

Mackenzie: Right. Well, we really do appreciate having a real scientist, such as yourself, making those comments. Listen, Dr. Rossi, we very much appreciate you taking the time to speak with our audience and help them learn a little bit more about the vaccines and the technology. And I just like to say I guess on behalf of the countless people who are also benefiting from your work and the work of your colleagues and the whole scientific community, just thank you so much for what you've done. Thank you.

Dr. Rossi: My pleasure, Scott.

Mackenzie: And thank you for watching, especially those of you with concerns surrounding the COVID-19 vaccination. We sincerely hope that some of what you've heard today will help you with your decision to get vaccinated. If you have any comments or suggestions, please write us at vaccine@morningstar.com. For Morningstar, I'm Scott Mackenzie.

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