COVID-19: Road to Immunity and Vaccine Development

(Transcript has been lightly edited for clarity and length)

Aaram A. Kumar: Hi everyone, welcome to this episode of Science Speaks, a series from Sciencera that discusses a variety of topics about science and life in the world of science. Today we have with us Dr. Robert Carnahan, PhD. We’ll discuss with him the topic of COVID-19 immunity and vaccine development. Dr. Carnahan is the associate director of Vanderbilt Vaccine Center and an associate professor in pediatrics and radiology at Vanderbilt University Medical Center. He has a high level of experience with monoclonal antibodies and antibody engineering. He directed the Vanderbilt antibody and protein resource for over 10 years. The facility grew to comprise over 70 Vanderbilt investigators and several academic and industry partners from across the US, conducting around one hundred and fifty antibody projects per year.

Both academic and industry projects focused heavily on therapeutic targets like cancer, viral pathogens, autoimmunity and diabetes. Dr. Carnahan has brought this focus on innovation, applied generation and detailed characterization of antibodies to the Crowe lab and the Vanderbilt Vaccine Center during this time. He has also held numerous regional and national leadership roles within the Association of Biomolecular Research Facilities to develop advances in methodologies and technical standards, oversee collaborative studies and implement training opportunities for lab directors and personnel. He is also a national leader in the design and implementation of Lean management systems for biological laboratories.

So welcome, Dr. Carnahan. Thank you so much for taking the time to chat with us. We really appreciate it.

Robert Carnahan, PhD: Sure. Happy to be here. Thank you.

Aaram A. Kumar: So before we dive into the topics of COVID-19 immunity and vaccine development, could you give us a quick overview of the work done by Vanderbilt Vaccine Center? I mean, I recall that in the past, the Center has successfully developed multiple antibodies against a number of other viruses like Ebola, influenza, and Zika virus. Can you talk a little bit about it?

Robert Carnahan, PhD: Yeah, so the Vanderbilt Vaccine Center does tend to focus more on monoclonal antibody development than it does vaccines, but developing antibodies is actually a really useful activity for even vaccine development, because by developing and by understanding the human immune response and what kind of antibodies are generated to pathogens, that gives us a deeper understanding of what a good response looks like and the kind of response we want to elicit with the good vaccine.

So we see antibodies and vaccines having their own utility independent of one another, but they also have a strong synergy with one another in understanding each side of the coin helps one to design the other. Right. And so so that’s where we’re at. We’re at the interface of antibodies, understanding human antibody response and how that’s again, useful for its own purposes and then how that informs vaccine design. Yeah, we do focus almost exclusively on viral pathogens but we work on some other pathogens as well.

But definitely we operate in the infectious disease space. We have made antibodies to probably at this point 20 or more viral pathogens and Ebola and others. And then some of these have already made it into some stage of clinical development. Our Marburg antibody was shown to be efficacious and is actually being stockpiled by the US government as a as a medical countermeasure to Marburg. Our Zika antibodies are currently in preclinical development of the manufacturing process for future clinical trials. Chikun Gunya antibody was used in a clinical trial a couple of years ago and influenza is kind of one of our hallmarks. We continue to operate in influenza space looking for broader and broader anti-influenza antibodies.

Aaram A. Kumar: So thank you for that overview Dr. Carnahan. Really appreciate it. It’s very comprehensive and succinct the same time. So I was hoping we can kick off our discussion by talking about the pathophysiology and immunology aspects of COVID-19 for a bit. So, as we are still learning more about the mechanism of how this virus gets people sick, scientists are investigating what part of the pathophysiology or what part of the disease is caused by the viral infection itself versus what aspects are a result of a dysfunctional immune response. So on the one hand, it seems like you need to have a strong immune response to fight off the infection. And seems like groups with the robust immune responses, like young adults, for example, have better outcomes. On the other hand, we have had recent reports of drugs that overall suppress immune responses like corticosteroids reducing COVID-19 mortality in patients who are very sick. And so we also had, I think a recent study published last week, I think, that showed that the risk of death in patients with higher levels of biomarkers that can increase inflammation like interleukin six (IL-6) or tumour necrosis factor alpha (TNF-a). So those with these elevated levels of these cytokines, their risk of death was more than double that of patients who did not have these higher levels of cytokines. So how do we reconcile that or what does this tell us and what impact does it have on our treatment decisions?

Robert Carnahan, PhD: Sure, sure. Let me qualify anything I say by saying I’m a I’m a pretty focused, narrowly focused basic scientist. So I will speculate. But we would have to talk with clinicians and translational scientists to get a better feel for the pathophysiology and appropriate interventions. But I think I think what we’re learning is that in most ways, this virus, unlike sort of some of the sort of spikes in uncertainty and fear, it is not that unusual. In most respects, it works pretty much like we would expect. Like any other virus, you get infected. There is a certain course of viral disease, and then there’s an antibody and an overall immune response which generally clears it, and you’re fine. And like with most coronaviruses, the symptoms are quite mild. The body is in most cases, people are perfectly capable of responding and clearing the virus. The difference is, I think that we see that are pretty narrow. But important is one, the transmissibility of this virus is pretty high and so easy for it to transmit. We still don’t completely understand the transmission. Like what are the important factors? We understand some of them, but we don’t understand all of them. And the other thing is in a in a pretty defined subset of people, there is this secondary – it’s almost like there’s a secondary illness. There’s the viral course, and then there’s an inflammation course, as you said. And what we don’t totally understand is what the connecting point between those is like, what causes someone to transfer from a normal viral process into this sort of hyper-inflammatory process. And I think we’re still trying to understand that. We know that it seems clear that it has to do not just with the virus, but the person. We see certain populations like the elderly, people with diabetes and other underlying comorbidities seem to be more prone to this, but it’s still hard to understand the exact correlation. So but if we separate those out, I would say the antibodies and vaccines can help either way, because it does seem like it’s the viral process that leads to the inflammation process.

If we can intervene early enough during the viral part of the cycle, antivirals will have an effect. We see this with Remdesivir. The trials seem to say – it’s a limited benefit, it’s not massive – but it does have a benefit. But the benefit seems to be – I would say the data is still there’s still a lot of data to be generated, – but it seems to be early. Right. If you can get this. Of course, I’m sure if we if we knew ahead of time we could give someone Remdesivir, that would be a little tricky to be able to maintain that.

But if you can intervene early after infection, while the viral part of the cycle is still at play, then that can have a benefit. If it goes beyond that, then Remdesivir doesn’t have as much benefit, maybe potentially not any benefit at all if someone sort of made that transition from virus over to inflammation. So we know the viral process is the starting point and suppressing that with vaccines through natural immunity or antibodies through sort of engineered immunity, we’ll call it, or small molecules like Remdesivir, we can kind of stop, probably stop or limit that transition to inflammation. Where things like dexamethasone and suppressants, immunosuppressants come in is probably in that second phase where the inflammation, the inflammation and the immune system have kind of got themselves stuck in a little bit of a negative loop where there’s some bad stuff going on. Really, the virus at that point is either gone or at least very low. We don’t know. What we don’t know is if you had a really effective antiviral would still have an effect. I would say Remdesivir would not be a good example – this is kind of a general antiviral. A good monoclonal antibody might still have an effect because there might be low levels of virus at that point.

But in general, we’d say it’s not virus-driven at that point, it’s inflammation driven. So something that can just basically… It’s like a fire – if you want to have the firemen come in and douse the fire so that the body can start to recover. And that’s where I think if you gave steroids early, like when someone’s mounting an immune response, that probably wouldn’t be beneficial.

Aaram A. Kumar:  That could backfire even.

Robert Carnahan, PhD: Yeah, it might be bad. So I think that’s clear. It’s one thing for people to understand is… I won’t say there are two different illnesses, but there’s two distinct… To me it looks like there’s two distinct Phases which need their own medical countermeasure. And those medical countermeasures will be different, possibly.

Aaram A. Kumar: Thank you. That’s an excellent answer, a great explanation there. And I think one of the points you made about the the analogy about the firemen coming in and putting out fires – so that probably explains why the corticosteroid benefit that we have seen is also in very sick patients in much later stages and the reduced mortality is sort of as a last resort. Right, so, thank you. I appreciate that.

So I think, um, one thing I wanted to talk about was one of the concepts in immunology that have come up in recent discussions about the fight against COVID-19 is herd immunity. So I was thinking, can you talk a little bit about why herd immunity is important against an infection and how it can be achieved?

Robert Carnahan, PhD: Sure. I mean, yeah, herd immunity is an incredibly important public health concept. Herd immunity is where we basically get to a point where I would say defining herd immunity is specific to the pathogen. What level of immunity is needed to “achieve herd immunity” depends on how transmissible the pathogen is, how it transmits and other factors related to the specific pathogen and sort of its life cycle.

But the idea being that if you can reach a certain point of immunity across the population, you almost guarantee that you severely limit the ability of spread within the community, because the transmissibility meets up where if there’s one person infected, there’s enough immunity around them combined with the chance of transmission that you basically kind of eliminate it. If you have a really, really transmissible pathogen like measles, you have to have an incredibly high percentage of people immune for it not to transmit because it’s so transmissible, whereas other viruses that don’t transmit so well or transmit through alternate sort of more complicated mechanisms, maybe you don’t need as high a percentage.

So, yes, but I will say one thing people need to understand is the general way we achieve herd immunity is through vaccines, not through natural infection. We can do it, I mean, through the history of mankind, it’s been through natural infection. That’s the “traditional” way to do it, and that can be achieved here. But if we look at COVID-19, which I would say the studies look pretty conclusive now that the mortality rate is somewhere between a half a percent and one percent of all people infected will die. We would have to say, to achieve herd immunity, let’s say herd immunity is 70 percent. Well, you would say 70 percent of the United States, whatever that number is, something over two hundred million people.

And then one percent of those would die as a sort of a progression towards herd immunity in the absence of a vaccine. So then, we’re talking about several million people. Now, that’s just ballpark. I don’t know if that’s the real number, but that’s the kind of reality we have to at least admit could be possible. So that’s where… Herd immunity in this case, we really want to achieve that through vaccines. We’ve seen places like Sweden and other countries sort of tinker with this idea of herd immunity. And what you see is that the rate of the virus is still so low that for them to for us to openly achieve herd immunity is going to take a really long time. And so that’s not something that’s going to happen in the next few years through natural processes, so we hope that we can do it through a vaccine process and then some medical countermeasures. Vaccines would have holes, right? Maybe they don’t work in every population equally well. Maybe in the immunosuppressed, vaccines don’t work well – maybe in infants, maybe in the very elderly. So that’s where we would have antibodies like the ones we and many other people have now developed, or small molecules like Remdesivir, dexamethasone – we need all these. It’s like one thing everyone needs to understand is most viruses and pathogens, Zika, for example, or Ebola – we’re to a point now where we just ran an Ebola clinical trial in the Congo last year after people working very, very hard for more than a decade or more on countermeasures, and we got to a point where we had a very sophisticated strategy that was able to be deployed and actually was quite successful. Here, we don’t have 10 years. We don’t even have 10 months. People are trying to learn everything about a new pathogen and to develop countermeasures and make them and deploy them and understand them all at the same time. And that’s definitely not how things work normally. It’s not how things work best. But obviously, we’re all trying to do the best we can in a really difficult situation.

Aaram A. Kumar: And I think that that breakneck pace, I heard one of our Vanderbilt alums, Dr. Ted Ross, mentioned about it, he called it “building a plane while you are trying to fly it”. Yeah. Thank you for that explanation on herd immunity. And I’m glad you talked about the human cost associated with this strategy where you sort of let the infection spread unchecked and a lot of people getting infected instead of trying to achieve herd immunity via vaccine and in the meantime, take measures to prevent spread as much as  possible.

So that’s that’s a great point. I want to go back for a second, if you don’t mind. To talk about, you know, as we just mentioned previously, there is a wide range of variability and disease severity with COVID-19, it looks like with some individuals being asymptomatic and then a lot of them getting sick but mounting an immune response and recovering versus the infection being more severe or even fatal for others. And then there are, of course, these recent reports talking about or confirming cases of re-infections or recurring infections. So, how do these factors come into play or how do they affect how we may design therapies or develop a vaccine against COVID-19?

Robert Carnahan, PhD: Sure. So, I will say, fortunately for us, this is not the worst-case scenario. I know that people find this hard to believe, but this is not at all the worst-case scenario. We actually know a lot about SARS-COV-2 because it is quite similar to SARS-COV-1 and it’s also similar to other coronaviruses. And so far, at every step, we we kind of go through this again. People are seeing science play out in real time, which is not normal for people. We have multiple studies, we learn over time, it refines… Science is a great process for refining and getting better. But like all processes, in the midst of it, it’s a little messy, right, where people put ideas on the table and then we have to all look at those ideas and see if we can confirm them or not. So but so far, I would say we have these moments where it’s like, oh, maybe SARS-COV-2 is different than all the coronaviruses. Then enough studies come out like, “oh no, actually it’s the same”. “It’s not the same, it’s the same”. And so I would say what we’ll probably find out is mostly it’s the same. We know that other coronaviruses, even seasonal, we can induce immunity. It can wane over time, that’s normal. It’s still lasts years, even when it’s naturally infected. So we could predict that a vaccine will induce immunity. It looks like in all the animal models and all the other coronaviruses, that’s going to be true. And with COV-2, I strongly believe that will be true.

We could also suspect that maybe it’ll wane over time. That wouldn’t be unusual. I’m not worried about the current publications about reinfection. One thing that people need to mention that kind of doesn’t get highlighted is that so far, all the people – yes, they were technically reinfected, we could detect virus after it was cleared and then the virus reappeared in the system and we were able to test it by very, very sensitive PCR methods. You’ve got to keep that in mind. And two – so far, not any of those people have manifested any particular symptoms of hard reinfection, which again, would be normal. They have an immune memory, probably both B cell and T cell memory, they get reinfected. Most of us clear it with the memory so quickly we couldn’t even detect that they have been reinfected. That’s probably quite common with all kinds of pathogens. Right? We get it, we’ve had it, Our body immediately responds and it’s gone before we can even detect it, let alone have symptoms.

Here we have a few individuals which we could sort of we were able to intervene probably because we’re so hyper-aware and testing is so broad. It’s actually like a consequence of our focus, not so much the immune system. So in places where they have really, really good surveillance systems like Hong Kong, they were able to detect that this person had virus present again, but they did not have symptoms. So, that just means that their immune system has detected it, it had a memory response. Maybe it took a minute for the memory to sort of ramp back up, but it did. And they were. And I think that will be the norm. It’s not like we won’t have some immunosuppressed people who can get reinfected and actually have symptoms on second exposure. I won’t say that’s impossible, but that won’t be the norm. The norm probably, almost certainly is going to be, yes, it’s technically possible, it probably happens and it won’t be a big deal. So that means that our vaccine, even if it only last three or four years, I think we’ll all take a four year vaccine at this point, right? Gladly. If the vaccine’s are going to work for four years and then you need to get immunized again, I think we would all be like, “OK, I’ll sign up for that”. People need not worry too much about it.

Aaram A. Kumar: Right. Flu shots work seasonally, right. And we still… A lot of us still feel it’s not worth getting it (the flu) and risking it – especially in the elderly population or if it’s somebody that’s immunocompromised. So you still get it (flu shot) every year, even if the protection is only for a few months or to a year. So, yeah, I think that’s a great point. And I think it really helps people hear that the symptoms or the reinfection that we hear so much about happens with other pathogens as well.

And in this case, too, like in the cases, the symptoms are cleared or the virus was cleared pretty quickly. So that’s that’s definitely a good sign as opposed to I guess we do hear a lot of reports about, “Oh, no, is is this is the reinfection happening? Is this going to be really bad?” And like you said, science happening in real time and you’re thinking, “Oh, is this virus so unique? Is it so different?” So yeah, thank you for providing that context. So I know we touched a little bit up on the monoclonal antibodies and immune-based therapies. So speaking of those therapies, I know the team led by you and Dr. James Crowe have recently discovered some monoclonal antibodies that are promising candidates for prevention and treatment of COVID-19, I believe so I can get published the findings last month, right? And some of these antibodies were licensed by Astra Zeneca. So where do where do you see such antibodies fit in the big picture of managing the COVID-19 pandemic? Can you talk a little bit about that?

Robert Carnahan, PhD: Sure, yeah. I mean, again, with everything playing out in real time, it’s a little difficult to to say. I would say in the midst of uncertainty, we should try to pursue all options. So there’s no doubt we should be pursuing small molecules, vaccines, antibodies, complementary therapies like corticosteroids – all those should be on the table. If we have what we really all hope for, even us, which is a efficacious vaccine, that would be one case. So you would… One could ask: well, in the context of an efficacious vaccine, what role would antibodies play? Because vaccines would provide longer term immunity, probably at least years, if not lifetime; antibodies won’t do that. Antibodies are probably going to provide 6 to 12 months of protection. So what role would antibodies play in that context? Well, antibodies, would still have a role. We have to remember that the vaccine, even if it’s efficacious, may not be equally efficacious in all populations. Maybe it doesn’t work in pregnant females. Maybe it doesn’t work in people over the age of 80 because you do need a functional immune system for the vaccine. Yeah, basically the vaccine is saying this is what the virus looks like. And then your body says, OK, I’m going to mount a response to that thing. If you can’t do that, well, then that’s a problem. Antibodies. On the other hand, what we’ve done there is sort of gone fishing in someone’s immune system who successfully recovered. And we say, well, what antibody or antibodies allowed them to recover? And then we can just pluck that out of there, produce it in a factory and give it no need for, in general, much immune response on the part of the person. Now, of course, you need some complement immunity around the antibody, but it’s a much less of a burden on the receiver of the antibody. They don’t necessarily have to have a highly functional immune system for the antibody to work. So and there you would say, oh, there are going to be holes possibly in the vaccine where an antibody or other therapies would be delivered as an alternative or even in addition to a vaccine. It may not be either/or. This is still an emerging part of vaccinology, but there’s also some ideas out there that a vaccine and an antibody together actually mutually beneficial, that the antibody actually can stoke up the vaccine’s response. But that’s a whole separate thing. So there could be holes in the vaccine. Let’s say we have a vaccine that is not as efficacious.

Let’s talk about another about another thing. Post exposure. So you have prophylaxis. That’s where vaccines sort of shine the brightest. Now we have something called post-exposure prophylaxis. Now, let’s say you’ve been in a room with four other people and one of them had COVID-19 and you talked with them face to face for more than 15 minutes without a mask because you thought that they were not or it was a family member. Now, you don’t know if you have the virus, but you’ve been exposed.  You might already have it. At that point, a vaccine may or may not be helpful because the vaccine response takes 14 to 30 days to play itself out. If you even had a vaccine right, then it may not have… Antibodies shine really brightly there, because literally within a few hours, maybe even an hour of getting the antibody in your arm, you have circulating antibody protecting you from the virus. So even if there was an exposure, it would shut the viral process down pretty early. So that’s a better spot for antibodies. Now we move to therapy. Now, you’re two days into your infection process. Could antibodies work there? Our initial data in animal models says yes, the antibody still can be efficacious early in the viral infection process. Now, we are sure vaccines are probably not going to be very helpful; antibodies could be helpful. We would have to see in humans because one of the problems with our current models is none of them play out along the timelines of humans – they’re all accelerated. All the animal models are too fast. Humans play out slower. So we actually don’t know how many days into the infection process an antiviral antibody or antiviral drug would work. But we do know that the initial data with convalescent plasma and remdesivir suggest that antivirals do have a window once you’re already having that infection pathology that they can help. And then like I said earlier, so that might be a sweet spot for antibodies, which I think will be more efficacious than small molecules just because they’re more specific, they have super-high affinity. Also their half life, you have to remember, a single dose of an antibody you can get at once and it’s probably going to protect you for months, if not a year, whereas something like a small molecule would have to be dosed daily because their half-life is just so quick. But again, they both have their own roles. And then we go into the inflammation process. Probably antivirals may not have as big a role, but we don’t know whether antibodies in a late stage might work.

The convalescent plasma data is not great, but there is some suggestion that even in those later inflammatory stages, convalescent plasma has some impact. So that’s to say that there’s still some effect if you have good antibodies. Even when you’re in this inflammatory state, the antibodies seem to be able to help. They can’t make it go away, but they do seem like they improve things a little bit. But the data is still being generated there.

Aaram A. Kumar: Yeah, I think I think that’s that’s a great overview. So the molecules that have been licensed to Astra Zeneca, are they in clinical trials at this point? The monoclonal antibodies?

Robert Carnahan, PhD:  Sure. They are in what’s called phase one clinical trial, which is the initial safety study, and then looking at like what’s called PK (pharmacokinetics), what’s the distribution, and so on. Those are early stages, but like everything, I mean, there’s contingency plans to rush it forward if it looks promising and I don’t have any of that data. But yeah, it’s in Phase one right now.

Aaram A. Kumar: Gotcha. And just remembered, you said going fishing for antibodies and… sort of stretching that analogy a little bit, seems like directly giving monoclonal antibodies is like giving a man a fish to eat right away versus the vaccine is basically teaching him how to fish, but he may not have time; if that person is starving, you need to give him food right away. And I just thought about that.

Robert Carnahan, PhD: That’s a great analogy; I use that analogy, too.

Aaram A. Kumar: So I know we talked a little bit about vaccines. So I know a number of vaccine candidates are currently in clinical trials with some of them already in phase three, the last part of the trials, right. So I was thinking, could you give a little bit of perspective about the top vaccine candidates that are in phase three? Now, like I said, you don’t have to go into detail for all of them, but at least give a little bit of overview of what types of vaccine candidates are being tested, and are they right now planning to have these as a single dose where we only need to get the vaccine once, or do you have multiple shots or even have booster doses at a later point? How how are these planned? Could you talk a little bit about that?

Robert Carnahan, PhD: Sure. Yeah. I can’t give a comprehensive because there’s so much… I mean, I think there are over three hundred vaccine candidates. I’ll just talk about… This will be a sort-of-US-centric as well. So what we see here though, I think it’s kind of mirrored elsewhere because some of the lead molecules are what are called mRNA-based vaccines. So this is where if we think of the central dogma: DNA –> RNA –> protein; rather than giving them protein or some end product, which is what traditional vaccines that have been around do, either giving a piece of the virus or inactivated virus or protein; we’re moving upstream and giving them a coded message. The message is administered and it gets taken up into cells. And actually the cells in the body make the antigen the part that stimulates the immune system and they kick it out and it circulates. It’s a really cool technology. Moderna and I believe Pfizer and BioNTech, and a bunch of companies have been hammering away at this technology for years and… We worked with some of those just for full disclosure around antibodies and vaccines… And they are the most ahead out there, because the technology lends itself to rapid development, rapid manufacturing, and those look like they’ll be some of the first out.

The initial data for those looks promising. It does look like all the cases I’ve seen, at least it will be multiple doses. So you get a single one and then in maybe 15 to 30 days later, you get a booster to kind of stimulate immune system. That would make sense because the mRNA, again, is dependent on the host cell to make the antigen. So rather than giving sort of a giant dose of antigen, you’re kind of relying on the human immune system to sort of produce them. Maybe that doesn’t generate as much antigen early on. So it takes a little bit of time, maybe needs boosted, but ultimately you arrive at a point where there is immunity. I think that’s one group of vaccines. There’s a related ones where they’re using adenovirus to kind of do a similar thing. You’re basically incorporating the coding region of the antigen into an antiviral vector that gets into cells. And now you’re kind of doing the same thing. It’s being made by the host cell via a viral vector.

That doesn’t ultimately cause a long term viral infection or anything. In fact, it’s usually not species-matched, so it kind of self-limiting. It can only infect once. It can’t infect another cell. But what you do there is you’re kind of taking you’re juicing up the… using the system to make more antigen. Again, very limited data. It looks like that it does work a little faster. Maybe you only need one dose of that, though.

There’s some that look like they didn’t work well at all. There’s one out of China that didn’t look like it worked well at all. But Astra Zeneca has one of those. And it looked the initial data looked quite promising that maybe a single immunization would be sufficient.

I would say collectively, we all have to keep in mind that none of those have ever really been through a full FDA review. We think they’ll work. There’s lots of sort of R&D and preclinical work around those saying that they should work well, but we’ve never actually released those in a large scale. So those are like really cool technologies, but have not been really established in a way like we when you think of other protein-based vaccines or attenuated vaccines and so on.

Aaram A. Kumar: Right. Right.

Robert Carnahan, PhD: And those are shining because some of their key strengths is their flexibility. You can develop them quickly and rapidly and deploy them. Then we sort of move to the more traditional vaccine formats like protein. There’s a company in the United States being supported called Novavax, which is developing a Spike protein-based vaccine and and they’re moving quite rapidly. But when you’re making a protein, it just takes more time. And you see, I feel confident that will almost surely work, probably with one immunization. But we don’t have any data to know for sure that’s true. At least I haven’t seen any. But that’ll be kind of lagging behind there by a couple of months. And then not so much in the United States, but I know other countries – China being one and maybe some other ones – are looking at like inactivated versions of the virus, asking, is it possible. That’s another traditional vaccine platform, which will probably work. But again, now we have to think, “Oh, now we’re growing large and large amounts of virus and then we’re inactivating.

So that’s the manufacturing there is more complicated, more dangerous, requires a lot more control.” So we’re going to have multiple candidates, it’s going to be a weird time… Usually you have sort of one vaccine or two vaccines to choose from, you know a lot about them. Here we’re going to have a lot of vaccines that work from very different technological perspectives, have different delivery strategies, different regimens for how often you get it. So it’s going to be a bureaucratic… We have to really have our government agencies really, really engaged in thinking about this. It’s a really complicated problem that we have the ability to solve. But it’s just we have to be out ahead of it because it’s going to be a little complicated.

Aaram A. Kumar: So, as you said, there are there are a lot of these candidates right now and some of them may even be ready to administer around the same time. So is that… Is that a good thing for a pandemic that’s of this scale. And especially given the variability, I would imagine in that case, having more options would be helpful. Is that accurate?

Robert Carnahan, PhD: Yeah, yeah. I mean, you know, I guess it’s kind of like community is not a gambling analogy. You know, we put our bets down on as many things as we can and some of them may not work well, but at least we would have some that work, maybe some working out well, some work medium, some work awesome. So at least in that first burst of activity of immunization, we’ve gotten some people well-protected and some people intermediately protected. That’s way better strategy than say I’m going to put it all on Red five – Red, number five, and then it doesn’t turn out to be that one and nobody is winning. Yeah, I do think we’re doing the right thing in sort of betting on different technologies, betting on different delivery strategies. We will have to acknowledge the fact that unlike in the normal world where we would know which ones work best here, we’ll figure it out when it’s used. And that’s not an ideal situation. I do think that the safety profile of all of them look pretty good, maybe even excellent in most cases.

So I don’t think we’re necessarily risking safety, though, though I do think I will say I’m a strong advocate that the Phase three Clinical trial needs to run its full process. That’s how we know, in a lot of people, rare events didn’t happen. The Phase one trial can be in as few as fifty people. Right. That’s not a very strong demonstration. That’s an initial safety demonstration, very initial. But if you have an event that’s happening at one in a thousand or one in ten thousand, you have to run the Phase three trial to see that kind of event.

And that’s the more typical kind of adverse events we see with drugs and vaccines and every kind of thing. Is there not one in a hundred is there one in a thousand or one in ten thousand. And so you got to let those trials run so that we can not only see it, but we can understand it. We need to see it more than once to say, was it an individual, something about that individual that – so it’s not something for us to generally be worried about.

It was really kind of a unique situation for an individual – or more worrisome when you see it multiple times, was it a population?

We have to do thirty or forty thousand people to get enough people over the age of 70 to say, oh, you know what? In people over 70, there’s this adverse event that happens 10 percent of the time. You’ve got to have enough numbers to power that. You got to let the Clinical trial process play itself out. We’re already expediting crazily.

Aaram A. Kumar: Right? Yeah, the pace is just breathtaking to me. Like usually we say vaccines could take three to four years, maybe even more. Right, and so a lot of these candidates, when we say, would be ready in a year or even less. But yeah, that just seems so wild, especially given some of those, like when we as you said, some of those molecules, if you see adverse effects, you need to have that strength of several thousands of patients to detect that one in a thousand event or one in two thousand event and sometimes that happens much later after like in post marketing studies, right? So I think yeah, that’s that’s a great point. Dr. Carnahan. So you mentioned, you know, it is known that there are some populations that are more risk than others, as you said. So we may need to go for a separate vaccine for them or a higher dose like we have with flu. So are there any specific studies or analysis being conducted or planned in high-risk groups like older populations or those with comorbidities, for example, that… That you are aware of?

Robert Carnahan, PhD: Well, again, we’re kind of in this nontraditional space. And I will say I’m for sure not a clinical trial expert. I just I don’t know much more than the general person, just from reading a little bit. What you see is a lot of the people who are the companies moving forward with vaccines, they’re really trying to be diligent. Yeah, everyone has to understand, no one wants an adverse event less than them. They really don’t want one, not just for financial reasons, but like, the entire company is based on these. They’re all working hard. These are really serious scientists who really want to contribute. They don’t want an adverse event. So what you see them doing, I specifically heard this one with Moderna, but I know other companies are doing as well –  they’re trying to push into some of these populations where there might be issues or at least where we’ve seen worse outcomes like in African-Americans, the elderly… They’re trying to specifically enroll people in those populations to detect these events. Is there something there? Is there are certain kinds of comorbidities where the vaccine doesn’t work very well? So that’s just an efficacy question. But there could be an adverse event question, too. Is there certain populations where they’re adverse events? As you kind of said earlier, a lot of this stuff – Phase three, but then we have post-marketing where we continue to monitor these adverse events, which a lot of times are going to happen later.

So we’re not going to have that when we start to probably roll out the vaccine. What will we do? So the fastest vaccine licensure in the history of the world, I believe, is four years. That’s because the phase three clinical trials and they waited a while, they let things happen. The average is decades. Vaccines generally take decades for full licensure release because companies want to be sensitive to this. Like about what happens to all these subpopulations initially and then over time. If we want to resolve the situation, we all have to agree that we’re going to take on a little risk as a society. We don’t know exactly. I think it’s quite low risks, but some risk that we don’t get to do that. But we do have to balance. How much risk are we willing to take. Now to gain a month, it’s probably not worth it to take much risk. To gain years – these post marketing studies will take years – we’ll probably have to take some risk on. But that’s sort of like trying to balance it all out.

Aaram A. Kumar: There is there is a little bit of a push from some of these vaccine makers, the pharmaceutical companies themselves, to make sure that the clinical trials are truly running their course and do their due diligence. And they are not by regulatory agencies or they are not submitting these to regulatory agencies until they believe their candidate is truly ready.

Robert Carnahan, PhD: Yeah, yeah. Their reputation… It’s not just that they want to help. They’re trying to contribute. There’s also the reputation of their company. It goes beyond just the vaccine. If the vaccine doesn’t work and has numerous adverse events, that’s a tremendous problem for them as an entire company across all the things they work on.

Aaram A. Kumar:  Right, absolutely. So you said, you know, so far it looks like from what data we have seen of these candidates, the safety profile looks overall good, which is a good sign, right. But the vaccines might be differently efficacious in people, especially given the variability of how the disease affects everyone. So there is a concern that the deploying of weakly effective vaccine could actually make the COVID-19 pandemic worse, especially if authorities or vaccinated individuals wrongly assume that it makes them completely immune, right, leading to sort of a complacency or a reduction in other COVID-19 prevention or control measures. How valid is this concern?

Robert Carnahan, PhD: Well, we will see. That’s where we have to have… To me. And again, the non expert, we got to have the full phase three data in front of us. What kind of immunity did it generate? How reliable was that? Was it 90 percent of the time? There was a robust immune response, in which case we can all feel pretty good. Was it 52 percent of the time? In which case we actually now we probably go it’s a 50-50 shot of someone’s then we would have to say, do we still deploy the vaccine? Yes. But now becomes really important that we have an assay to determine the efficacy of the vaccine on an individual basis. So there you would say it just becomes a strategic question. I don’t think it’s a game changer. It’s not a stopper. It just is. Then you have to say, OK, Rob, you’re going to come in. I’m going to give you your initial, you’re going to come back in a month later. I’m going to give you your boost.

Then you’re going to come back in a month later. I’m going to take your blood and I’m going to run an assay and say, yes, you look like you’re good or yes or no, you don’t. And and then in the context of that, again, another strategic thing would be we would start to pull back on the prevention measures in accordance with what we’re seeing at that assay. Once we say, you know, seventy five percent of the United States has gotten their dual immunizations and they’ve gotten there at the screen and it looks like they’re mostly protected now. Then we would have, Again, we ramped up stage one, two, three, four. That’s how we did it in Nashville. I don’t know how you did where you are. So then we should also be clear that it should go down four-three-two-one or … It should go backwards. It shouldn’t just be like, hey, we have a vaccine, magic is here. Let’s go!

Aaram A. Kumar: Yeah, I think that’s that’s a great point that personally, given that the vaccine is on track to become the fastest developed vaccine in history, right? And I definitely agree that it’s really important that we have clinical trials run their course and we make sure we really evaluate how much the different candidates work instead of yeah, like you say, this is a magic bullet, we are good. It almost feels like, oh, you know, this is still taking a lot of time. And for a lot of people, like you said earlier, it’s science happening or unraveling in front of their eyes in real time. Then, suddenly they’re like, oh, you know, eighteen months is too long or even a year is too long. So do you have an idea of how close are we to a safe and effective COVID-19 vaccine or what is a realistic timeline, you think, for making a safe and effective vaccine available to the public?

Robert Carnahan, PhD: Well, I would say, we what we how we should ask that the clinical trial process needs to play out and that dictates the timeline. Again, you’ve heard people say over and over, I think, who know or are more knowledgeable about this than me, that the clinical trials that people look like they’re launching and the rate at which they’re accruing patients looks like they will have accrued a significant a sufficient number of people for their phase three in later this year, something like November or December.

Then there’ll be a time period in which they analyze the data and we all sort of pick it apart. It needs to be reviewed by someone outside that organization. That’s how science works. It’s a self-correcting process. So it’s not like just because the data is there, we all say it’s OK. The FDA needs to see it, but other people, independent parties need to review it just to make sure that everyone agrees. And that’s all predicated on the fact that we don’t see, again, a totally normal thing to happen in a clinical trial is give you an example is that something bad happens to an individual patient has a severe response.

A person maybe dies. That is a normal event. Because you have to remember, we’re doing thirty thousand people in the context of a clinical trial, it’s very likely someone’s going to die amongst thirty thousand people. Now, the question is, did their death or adverse response tell us something about the vaccine? One completely normal answer would be no, it actually had nothing to do with the vaccine. That actually that was something that would have happened or or it’s not very related to the vaccine.

It’s not generalizable to the population. But what happens is you have to pause the phase three and investigate that. That’s the safe and normal thing to do, come back with a conclusion and say it was or wasn’t related to the intervention and then move forward or not. So all of this talk of November, December is predicated on the fact that we don’t have any of that. But that’s a totally normal event in a Phase 3 trial. This is totally normal.

It’s expected you have a lot a lot of people involved with all kinds of different health issues that have nothing to do with the vaccine. So anyway, even if we get through that unscathed, there are no adverse events that we have to slow down, then we have to talk about – even the governments across the world have been preparing for manufacturing. So this stuff is already being made, even though we don’t know if it works, which is a good strategy, I’m not against that. But even if we had a warehouse full of an efficacious vaccine on December 1st, how long does it take to get that down to a level where non frontline people, people who don’t need it first get it in a Walgreens to walk into a Walgreens and or CVS or whatever or their local health care clinic and get it. You know, that’s a distribution issue. And it has to be done correctly, especially just think about what you said:

If it’s two doses and you have to keep track of the timing between the doses and get to just know that that itself is going to take months to play out. And I think we’re thinking I mean, a realistic expectation to me would be in March or April of next year, a somewhat large percentage of the population will be receiving the vaccine around that time. That would be if everything goes perfectly. People receiving the vaccine on a large scale in 2020 – I don’t see that lining up with the timelines, except maybe in some one percent perfect world, which, you know, we have to be careful of that world because it can happen, but…, it could backfire too, right.

Aaram A. Kumar: Yeah. We want to do our due diligence, like you said. And so, you know, sort of going off of that. What are some of the potential issues that can rise if we rush the vaccine to market like a less effective one or even worse, you know, something that has potential harmful effects. Would this lead to a decrease in overall confidence in vaccination or not just for COVID, but for other universal vaccination as well?

Robert Carnahan, PhD: Yeah, you hit it exactly on the head. You have the sort of what we call the the proximal issues. I’ll say the short-term ones… The short term ones are we have people who have serious side effects and we have to deal with that. And that’s not good for any of us right in the pandemic. Now, we also have layered on a layer of another layer of complexity of people having adverse events and then does that tie to particular comorbidities or populations or whatever.

So they have this short term problem, which would be, again, a big burden in the context of what we’re dealing with. Equal or bigger is just that overall. We know the adverse events affect all of us, how we think about things. Right. We still are or even non-adverse events, just bad publicity or bad studies. The MMR vaccine, I pointed out to people we still have a ongoing issue with vaccine resistance that ties to studies which were retracted and were not done in a correct way or not interpreted in a correct way. But that’s had a tremendous impact on vaccination, not just with MMR. That’s the weird thing you have to remember, is that we shouldn’t think of it that way. But people think of vaccines as a thing. They shouldn’t. Like, vaccines aren’t really a one thing that’s like saying cancer drugs is a thing. Well, cancer drugs, like there’s all kinds of different cancers.

But people tend to think of vaccines is like this monolithic thing. Like they all work the same way they don’t they work by completely different mechanisms. They work at different levels of efficacy in all kinds of things and stuff. But the problem is, since they have that name on them, a failure of a vaccine in one space can affect people’s willingness to entertain a vaccine in another space, so there the real harm is that we rush out a vaccine, it turns out to be low efficacy: we see this. We’re always fighting this battle. But like people, when they have a flu vaccine and the vaccines don’t work, I got the flu vaccine, I still got the flu. It’s like, well, let’s be cautious to say that, like, flu vaccines are kind of guesswork because flu is constantly changing. When you have the right one, it works well. It’s just we we have no way to necessarily know with the certainty that you got the right one.

But that doesn’t mean that you weren’t protected. All the times you didn’t get it when you did it… Because you don’t remember it because you didn’t get the flu. So but you remember the one year you did get the flu.

Aaram A. Kumar: Yeah, that’s true. We do have that sort of selective memory and that unfortunately, a lot of public health interventions to work very similarly, right? Like we look back and like salt, like iodine, iodine in salt or like fluoride in water – any of those stuff, we don’t think about it, but it’s working well. And the one time any of this doesn’t work, we immediately go to be like, “wait a minute, that did not work for me”. And so it is it is unfortunate that, like you said, it can have that long-lasting repercussions. And so, yeah, I’m really hoping that the vaccine trials run their course and we get a good candidate or maybe multiple good candidates that they can be mass-produced and given to people in a safe and effective manner.

And in the meantime, we we don’t push for… like you said, know, herd immunity is a very important concept, it needs to be achieved for the population. But typically it’s done via vaccination. So we cannot have, like you said, a few hundred million people being infected and even half a percent  mortality of that is one million, right. So it’s that’s such a heavy cost. And so we probably need to be more aware of that and really take preventive measures that’s necessary and let science take its course.

So we have covered quite a few topics today. And I know we’re coming up on the hour. So, this has been a really great discussion. Really appreciate you taking the time today to spare your insights with us and providing us all of this information. So on behalf of Sciencera, myself, and our viewers, thank you very much, Dr. Carnahan. We really appreciate it!

Robert Carnahan, PhD: Sure. It was great, thank you.

Aaram A. Kumar: Thank you.