April 20—Chief Investment Officer Tony Roth speaks with Ofer Levy, MD, PhD, physician-scientist in pediatric infectious diseases, Director of the Precision Vaccines Program at Boston Children’s Hospital, and Professor at Harvard Medical School. Dr. Levy discusses the race to develop therapeutics, including plasma therapies, and when we can expect a viable vaccine.

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Ofer Levy, MD, PhD, Director, Precision Vaccines Program Division of Infectious Diseases, Boston Children’s Hospital, Professor, Harvard Medical School

Please listen to important disclosures at the end of the podcast.

Episode 7:
The Cure for What Ails Us
Part II: Injecting Prevention for One and All
Tony Roth, Chief Investment Officer Wilmington Trust Investment Advisors, Inc.
Dr. Ofer Levy, MD, PhD, Director of the Precision Vaccines Program at Boston Children’s Hospital, Professor, Harvard Medical School.

Tony Roth: Welcome to Wilmington Wealth Wise, the podcast dedicated to financial literacy, where we take complex ideas from the investment world and make them accessible to everyone. I’m your host, Tony Roth, Chief Investment Officer of Wilmington Trust.

This is the second episode of our two-part series focusing on the deep science underlying coronavirus. In our first episode we were joined by microbiologist Susan Weiss from the University of Pennsylvania. We covered the biology and epidemiology of the coronavirus and how the science community is unraveling the mysteries of the disease. In today’s episode we are joined by Dr. Ofer Levy. Dr. Levy is a physician scientist in pediatric infectious diseases and Director of the Precision Vaccines Program at Boston Children’s Hospital and Professor at Harvard Medical School. Dr. Levy will be discussing therapeutics and vaccination. Thank you, Dr. Levy for joining us today.

Ofer Levy: It’s my pleasure.

Tony Roth: I’d like to frame our conversation today by talking about the economic trajectory that the country is on right now. Of course, we’ve locked down the country in order to mitigate the spread of the virus to both flatten the curve from a health care system and at the same time buy us some time as physicians race across the world to develop new therapies and ultimately a vaccine.

We’re now at an interesting point in our journey, because the country is engaged in a national debate around how and when to restart the economy. And when we focus on that debate, we see two critical criteria that really stand out as variables that control how quickly we’re able to get back on our feet and how sustainable that recovery may be from an economic standpoint. The first one is that we truly believe that we need to have a greater bandwidth of testing that will enable us to have confidence that when we go out and engage with somebody else, whether it be in our own business or in a business that we are soliciting or frequenting as a client, that the individuals that we’re interacting with have some level of testing and hopefully are not ill and are hopefully not going to make us ill.

So testing is critical. But the other element, which is also vital and which we have a fair degree of optimism around, although not a tremendous amount of specificity, is the idea of a treatment or a cure. Of course, the holy grail will be a vaccine, and we’re going to talk a bit about where we stand in the process of creating vaccinations.

So, let’s get into it. Dr. Levy, there are a number of different kinds of therapeutic medicines that are being worked on. Some are existing medicines that are being used off-label. Other are entirely, if you will, new compounds or new approaches to developing an agent, if you will, to combat the coronavirus. And as we learned from the conversation with Dr. Weiss, there are different levels of intervention that we might seek to go after.

The first one would probably be preventing the virus from actually entering our cells in the first place so that even though we’re exposed the virus can’t find its way into the cells to then move onto the second stage, which would be replication. I think the place to start might be what are the most promising potential developments that you’re seeing around medicines and therapies that might be addressed to that first stage of the virus’ lifecycle?

Ofer Levy: Well, thank you for that, Tony. We face a very severe pandemic here and as you outlined there is huge effort internationally in the biomedical community to develop both therapeutic and preventative modalities to address this pandemic. And as I believe you correctly highlighted, it’s more likely that we will make progress sooner on the therapeutic end, whereas a vaccine is critical but may take a bit longer.

In terms of the therapeutics, ways to treat people who are suspected or known COVID-positive and, for example, in hospital or even potentially in ICU, it is logical to look at agents that may be able to reduce the ability of this particular coronavirus, this SARS coronavirus-2 to enter human cells. And among those agents I would put high on the list are antibodies. Antibodies are a key arm of our adaptive immune system. As you know, antibodies are one way in which vaccines work, as well. Of course, you inject somebody with a vaccine and over weeks to months their immune system makes antibodies against the antigen that react with a pathogen and protect you. And similarly, convalescent plasma from individuals who have had COVID and recovered, that plasma, the plasma is the fluid phase of your blood, contains antibodies and may contain antibodies that can bind to the virus and stop it from entering your body’s cells.

So, some of your listeners may be aware that there are a number of academic and news reports around convalescent plasma. There’s precedent for this kind of approach. Convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS coronavirus-1 epidemic and the 2009/2010 H1N1 influenza virus pandemic and also the Middle East Respiratory Syndrome or MERS coronavirus epidemic in 2012. In all those cases, convalescent plasma was studied and showed some promise.

In the case of this current pandemic, this is – convalescent plasma has not, to be clear has not yet been approved for use by the U.S. Food and Drug Administration or FDA. It’s regulated as an investigational product. But, health care providers in acute care facilities can obtain COVID-19 convalescent plasma from an FDA registered blood establishment and there are more and more of these coming online.

Tony Roth: So, could I just ask you quickly about the notion of approval? Because, of course, approval, I think the way that the FDA uses the term, sort of connotes some degree of recognized efficacy. It doesn’t mean that if it’s not approved it can’t actually be used, because we know it’s being used and tried in the ways that you’re talking about, right?

Ofer Levy: Right. It can be used, but it has to be used to my understanding in the United States a physician, a health care facility, a hospital would have to obtain COVID-19 convalescent plasma from an FDA registered blood establishment. That would mean some sort of establishment that has the blood plasma. Typically, it’s cryopreserved, it’s frozen in a freezer somewhere, right, and it has registered with the FDA, which is a process.

Tony Roth: Right. Got it. Okay. And then, the other thing I want to just ask is before we get into some of the nuances of what’s going on with the success of convalescent plasma, let’s just assume that it was efficacious for a moment. Let’s say that it’s proven to be efficacious. It does strike me as a fairly personally invasive type of approach. You have to go out and get the plasma from someone that’s been ill. Obviously, there are a limited number of people out there that have been ill. And it seems expensive and sort of cumbersome to have to go out and get the plasma from everybody.

I’ve also read that if, in fact, this approach to in a way harvesting antibodies from someone that’s already had it through plasma and then putting it into somebody else that hasn’t had the disease to provide a prophylactic, if it actually were to work, is there a way that we could actually create the antibodies, sort of replicate them without having to use the plasma approach?

Ofer Levy: Yes. There is a way to do this. So, regarding just to finish, you know, on the convalescent plasma, a number of studies have come out in reputable journals. Journal of the American Medical Association on the 27th of March of this year described treatment of five critically ill patients with COVID-19 with convalescent plasma. These are small studies, not controlled in any way but look promising. And then Journal of Clinical Investigation, JCI, these are very solid journals, you know, peer reviewed, serious journals, had a review on deployment of convalescent plasma for prevention and treatment of COVID-19. So, there’s more and more in the medical literature about the rationale.

In terms of making it more druggable if you will, I agree with you. The approach of chasing down these different variable stocks of recovered plasma is cumbersome and not standardized. So, it’s a desperation measure. But, you know, some might say desperate times call for desperate measures. But, I think the horizon, you put your finger on it, would be to isolate the antibodies from that plasma that bind with high affinity to the coronavirus and are blocking antibodies and that can be assessed in in vitro assays, right. There are assays that test the ability of an agent, such as an antibody or a small drug or whatever people are studying, to block the ability of the virus to enter a human cell.

What’s happening now is a race to find which antibodies are most protective here, are best at binding and blocking the virus from getting into host cells, and then to produce those. We have a colleague in Vanderbilt, Dr. James Crowe, and he has Vanderbilt Vaccine Center there that is participating in DARPA’s Pandemic Protection Platform. Some of your listeners may be aware of the Defense Advanced Research Project Agency or DARPA. So the mission of DARPA, it’s an arm of the federal government. The mission of DARPA is to make sure that the United States is ahead of its strategic adversaries, both on defense and offense. We have participated in some DARPA projects. They’re usually very cutting edge and innovative.

But Dr. Crowe is involved in the Pandemic Protection Platform or P3 for DARPA. It’s a five-year cooperative agreement to develop protective antibody treatments that can be rushed to healthcare providers within 60 days of a viral outbreak anywhere in the world.

So, you know, the Department of Defense has known that a pandemic like this was a threat and DARPA has been on it. But they have ultra-rapid antibody discovery technologies and they’ve already discovered SARS-CoV-2 antibodies and their partners have the manufacturing and product development expertise to turn these antibodies into effective biological drugs very quickly.

So, whether it’s his team or, you know, another team around the world, they’re obviously not the only team working on that approach, but it’s one prominent team. So, I think, you know, generating these kind of what we call monoclonal antibodies, very well-defined, that’s druggable and that’s scalable. It’s not cheap. It’s not cheap, but in general monoclonal antibodies, I’m just speaking in generalities here. Every drug obviously has to be independently assessed for safety and efficacy, but the general gestalt of the field is that monoclonal antibodies, they tend to be, you know, safe. There’s a lot of precedent, a lot of approved drugs that are monoclonal antibodies. But it’s going to take some time to isolate and scale and it’s going to be costly.

Tony Roth: Right. I mean, you know, one would think as a layperson, and I’m going to say that a lot in this conversation, inherently if the antibody was created by another human being there would be a sort of a natural aspect in which it’s safe as opposed to if it’s manufactured by some humanmade process.

Ofer Levy: Correct.

Tony Roth: That antibody could be more dangerous. And I don’t know if that’s true at all.

Ofer Levy: Well, I think, you know, again everything has to be independently assessed for safety and so, I don’t want to, you know, overstate.

Tony Roth: Yeah.

Ofer Levy: But in general, I think, you know, monoclonal antibodies have a long track record of safety and there are many approved drugs in the FDA armamentarium that are monoclonal antibodies. So, yeah. I think it’s a promising approach. It’s not going to be cheap.

Tony Roth: And apart from the cost, is it something that if they found, you know, let’s call it in this particular realm the silver bullet, they found a monoclonal antibody, whether it’s essentially replicating the antibody that exists in the convalescent plasma that humans are creating or whether it’s some permutation or variation of that, can they reproduce it in scale and can they do that quickly? Or is it the kind of thing like a flu vaccine that has to be – it takes six months in a chicken egg? How is that? How do you think about that?

Ofer Levy: Yeah. No. It’s not going to be a chicken egg approach. They’re going to have to scale. They’re going to have a production process. You know, it’s going to be a challenge. On the other hand, there are already many production processes for monoclonal antibodies that are FDA acceptable, right. So, it’s not like they’re moving in with the first ever example of an approach, right.

So, that’s going to be an advantage to them. But there are going to be particulars to scaling it and, but I think they’ll succeed in scaling it if it’s something promising. Given how huge the market is, how – the huge demand, I think they will succeed. What I don’t know is, you know, how expensive it’ll be and how rapid the scaling will be, etcetera.

The other thing is let me give you an example, Tony. There is a very effective monoclonal antibody that’s made against respiratory syncytial virus, RSV. Don’t know if you’ve ever heard of it. It’s the number one cause of infant hospitalization in these United States. And the way that drug – it’s a very safe drug, but expensive. The way that drug is used is seasonally. We give it in the winter months when that virus is circulating and we give it to the most susceptible, for example preterm babies who get the worst outcomes from RSV. And that’s a way to manage how to distribute a very costly drug.

I can imagine a scenario, Tony, where the first in line should be the frail, elderly in nursing homes and/or high-risk health care workers, right. You can define some populations who should be first in line.

Tony Roth: Yeah. It’s interesting because when we think about therapies, we think about it typically as a medicine that you give to somebody that’s already ill. But, I think the conversation that we’re having now is the idea that some of these so-called therapies, particularly at this stage, which is again the stage where you’re creating a blocker to enter the cell, may actually be something that you give to a higher risk individual, almost like a temporary vaccine in a way, something. Does that make sense?

Ofer Levy: Right. So, let me use the right term. That’s right, Tony. Yeah. It’s, well, we call that passive immunity, passive immunization. Active immunization is when we say good news, there’s a coronavirus vaccine. People get in line. They get an injection. That’s active immunization. You inject in the antigen and the human immune system will make an antibody against the antigen and, quote, remember it, right. That’s active immunization.

What we’re talking about here with the monoclonal antibodies is passive immunization. In other words, the antibody is made outside the body and infused into your vein or injected into your muscle.
and that could be imagined both as a preventative, like almost like a passive vaccine, or an acute therapy, you know.

Tony Roth: Okay. Yeah, got it. So, before we leave this category of medicines that prevent viral entry into the cells, into the healthy human cells, one of the other medicines that I think if I understand it correctly exists within that stage is the hydroxychloroquine that the president’s talked a lot about. And, you know, we’re not, to be really clear this is not about being critical of the president or not being critical of the president or being supportive. All we’re trying to do is understand what the potential efficacy is of these different drugs we’re talking about.

So is this drug a drug that is at that same stage and what’s your sense of the drug at this stage? I know we’re waiting for final data and all that kind of stuff. But, do you have any guess or any sense?

Ofer Levy: Yeah. Yeah. So, you know, like each one of these agents has plus sides and has downsides, right, and has unknowns, right. And there are the known unknowns and the unknown unknowns as Secretary of Defense Donald Rumsfeld once said. So, hydroxychloroquine on the upside, it’s a drug that’s well known in the world. It’s licensed. It’s already used for malaria. It’s used for lupus and other autoimmune diseases. So, that’s a plus for that drug, right, because people know how to dose it, how to use it more or less, and are familiar with what side effects can pop up and so that’s an advantage. And there were some early reports out of China and elsewhere of potentially some benefit of this agent in a treatment scenario for somebody with COVID in a hospital. So, those are the plus sides and there are all sorts of anecdotal reports all the time. Somebody says, well, I took this, and I got better. Well, a lot of people didn’t take it and also got better. So, of course, we care about the biostatistics, right?

But the story is there that, you know, hydroxychloroquine’s mechanism of action is still under investigation. But, it kind of changes the way white blood cells take in fluid and particles from the outside and how they process those. this drug can also alter the immune response, inflammatory response to certain agents and mute it in some cases and where inflammation might be contributing to some of the lung damage in this disease that may be another way this drug might be helpful.

But here’s the issue. The issue is that the data that support the use of hydroxychloroquine or chloroquine for COVID-19 are really limited and inconclusive. You know, this drug had some in vitro activity against several viruses in a test tube culture outside the body, including coronavirus and flu. But, previous randomized trials for patients with influenza, for example, have been negative. And the COVID-19 studies for hydroxychloroquine that have been really people got excited about from France, it turns out those studies had serious methodologic flaws and a follow-up study still lacked a control group, and also, there was a small randomized study in China for patients with mild to moderate COVID but found no difference in recovery rates and the reports on adverse events have increased.

So, what we feel about hydroxychloroquine is that it might reduce the length of illness a little bit. It’s not a complete game-changer. It can have some side effects, including heart toxicity and changing the rhythm of your heart. And so, the best would be to refer patients to expedited, well-designed randomized trials to – that are appropriately powered with sufficient study participants so we get a clear read on this drug.

Tony Roth: And is it the case, was my premise correct that this is a drug that is primarily aimed at preventing entry of the virus into cells? Or does it actually act at a number of different places in the lifecycle?

Ofer Levy: Yeah, yeah, yeah, we don’t know. It may reduce the ability of the virus to get into the cell and/or it might just reduce the inflammatory response to the virus. It’s still under investigation how it would work.

Tony Roth: Okay, got it. Moving to the next category, which is once the virus enters the cells, it actually caused the body to recreate additional tokens of the virus in a sense. So, in this replication stage I know that Remdesivir is one of them. There may be others. What are the agents that you think are most promising? Tell us about them.

Ofer Levy: Right. So, we are optimistic about Remdesivir. It’s not a done deal. But, of the ones, you know, we’ve talked about it seems most ready for primetime and the evidence is promising. It is a nucleotide analog. In other words, it mimics part of the viral ribonucleic acid or RNA, the genetic material of the virus, and thereby inhibits the viral enzymes, the polymerases needed to replicate the virus.

So, this is a small molecule that would mess up the virus’ ability to make more of itself and it’s called Remdesivir. And it’s shown to have activity against this SARS-CoV-2 outside the body in vitro as we say. And a recent study came out where remdesivir was provided on a compassionate use basis in the New England Journal just a few days ago. Patients were those with confirmed coronavirus infection who had an oxygen requirement and they received a ten-day course of this drug, Remdesivir 200 mg on day one followed by 100 mg daily for the next nine days. And they found that for this cohort of patients hospitalized with severe COVID who were treated with this Remdesivir clinical improvement was found in 36 of the 53 patients or 68%.

This was not a randomized, placebo-controlled study. But they report giving this drug to very ill people in hospital with coronavirus and dropping oxygen saturation, meaning respiratory distress, and nearly 70% got – showed improvement, clinical improvement after starting this antiviral. And – but they conclude that the measurement of efficacy will require ongoing randomized, placebo-controlled trials. That’s – the RCTs, randomized controlled trials, are the gold standard. So, more to come, but cautious optimism.

Tony Roth: So, efficacious, but even within the context of it being efficacious there’s obviously variability depending on the constitution of the individual patient. If in fact it pans out, it’s likely from what we’re seeing now that it’s going to be helpful for certain kinds of patients. Maybe we’ll figure that out; maybe we won’t. Maybe less helpful for other patients. Does that sound right?

Ofer Levy: Well, you know, to be strict about it, we really don’t even know the efficacy, right, because there was not a control arm. So, a mean reviewer might look at this and say, well, it’s all very exciting, but you didn’t have an arm of people who didn’t get the Remdesivir. So, where was the improvement there? Although, an improvement rate of nearly 70% sounds high relative to historic controls with that level of severity. So, cautious optimism that it may be efficacious. And then, usually with these kind of therapies, the earlier on you start them, the better off you are, yeah.

Tony Roth: Right. So, it could be, again, when we look at the data it could be that of the 70% there could be a distribution such that there’s a better correlation of success for the people that got it earlier. Who knows? But that could be.

Ofer Levy: Yeah. Wouldn’t surprise me. It’s true for many other agents. Yeah.

Tony Roth: Now, are there other agents within this second category of trying to prevent this, the virus from – I don’t know if this is what you call an antiviral or if an antiviral is a more generic term, but to prevent the replication within the cells of the virus. Are there others that you’re focused on that might seem hopeful to you or not particularly right now?

Ofer Levy: Yes. There is a drug that we should mention. It’s called Favipiravir, F-A-V-I-P-I-R-A-V-I-R. Favipiravir,

Tony Roth: Okay.

Ofer Levy: And it is a small molecule also known as Avigan, A-V-I-G-A-N. It’s an antiviral drug.

Tony Roth: I think I’m going to say it that way.

Ofer Levy: Yeah. It’s developed by Toyoma Chemical, which is a subsidiary of Fujifilm in Japan, and it has activity against many different kinds of RNA viruses and coronavirus is an RNA virus. And it’s shown in animals to have activity against influenza, West Nile virus, yellow fever virus, foot and mouth disease virus, and others. And the drug has – was approved on 15th of March 2020, in China with the name Favilavir for the treatment of influenza. The drug is also approved for use in clinical trials for coronavirus in China. So, in China there’s permission to use the drug on a research trial basis. And also, on the 22nd of March 2020, Italy has approved the drug for experimental use against COVID.
and the Guardian reported recently that medical authorities in China said the drug used in Japan to treat new strains of influenza appeared to be effective in coronavirus patients. And somebody named Zhang Xinmin, an official at China’s Science and Technology Ministry said that favipiravir, developed by a subsidiary of Fujifilm, had produced encouraging outcomes in clinical trials in Wuhan and Shenzhen involving 340 study participants. And the quote was, “it has a high degree of safety and it’s clearly effective in treatment.” Not seen them publish that data, so I can’t comment on the quality of the study design. But it said that the people who were given this drug turned negative for the virus after four days on median after becoming positive compared with a median of 11 days for those who were not treated with the drug. So, it seemed to rapidly hasten the clearance of the virus from the body and x-rays were said to confirm improvements in lung condition in 91% of those who got favipiravir.

So, you know, sounds good. Is it too good to be true? I don’t know. We need to see a publication to scrutinize it.

Tony Roth: And is there a particular reason – I know you didn’t mention that there had been any trials launched here in the U.S. Would there be a particular reason other than just bandwidth, etcetera, that we haven’t done one here on that drug? Or is there any significance to that?

Ofer Levy: It’s an excellent question and I don’t know the answer to it. I’m not sure this drug has made its way to the U.S., quite frankly. I know that the drug originates from Asia. There’s experience in Japan and China with it. Italy is looking at it. I know the government of Israel acquired a huge number of doses of this drug last week. That was reported in The Jerusalem Post through an agreement, a bilateral agreement with Japan.

I don’t know what’s happening with this drug in the U.S. It’s a great question. I need to look into that.

So, what do you think about the therapies that are less targeting the virus, but instead allowing the virus to sort of run its course and keeping the patient alive by controlling the symptoms like the cytokine storms, etcetera? Have we made any important insights on drugs that might be more efficacious or new drugs or whatnot in that area?

Ofer Levy: So, you might be familiar with a drug called tocilizumab. That is mab, you know, drugs that end in mab, M-A-B, usually are monoclonal antibodies. That’s how they get those names. So, tocilizumab is an antibody against IL6. You know, some of these antibodies are against cytokines which are signaling molecules that signal inflammation, were developed for various inflammatory conditions but are being repurposed or studied in COVID.

So, tocilizumab is a monoclonal antibody that binds a human signaling molecule called interleukin-6. Interleukins are messenger molecules that go between the white blood cells, So, this is a monoclonal antibody that binds an inflammatory signaling molecule called IL6 and thereby reduces some inflammatory conditions.

So, there have been case reports and small series with tocilizumab in COVID, you know, severe adult respiratory distress syndrome where you have like a whiteout of the chest x-ray and severe inflammation in the lung. And so, folks have been tempted to try to treat that with anti-inflammatories, steroids or tocilizumab. To my knowledge, there have not been any large randomized controlled studies that really nail it to show that – how to use this drug or whether it’s helpful. Theoretically, it could help – be helpful. Theoretically, it could be harmful. I mean, the body makes those inflammatory molecules for a reason. It’s trying to fight off a virus.

So, I think the jury’s out on that. I know that there are multiple randomized controlled trials going on right now to better assess that and other immunomodulatory agents and I suspect in the coming weeks and months we’re going to be seeing more and more higher quality reports that can help point the way.

Tony Roth: So, before we shift over to talk about vaccines and where we are in that journey, one of the thoughts that occurs to, again, a layperson is, if there’s efficacy on the part of some of these agents individually, does that imply that there is greater efficacy in combination? But is that someplace eventually that we may get where we still don’t have a vaccine in a few months, but they start using these in combination or maybe they’re already using them in combination?

Ofer Levy: Right. So, in some cases people in desperation understandably are just, you know, throwing in the kitchen sink, particularly when somebody’s very ill and you’re trying to save them from death’s door. On the other hand, in general, stepping back from the situation, whenever you have pharmaceutical agents that you’re thinking of combining, if you think about it in principle one of three things can happen. They can be indifferent to each other’s presence, and in which case you have additivity. They can actually mess up one another’s benefits, in which case you have antagonism and you certainly hope not to have that, but it can happen and there are examples in medicine where that happens. And then, the sweet spot is if you’re fortunate you have synergy that actually the beneficial effect of the combo is even better than the single agent. But you need studies to really sort that out. But a priori, you know, if you had an antiviral agent that reduced the replication of the virus in your body and you had an agent that proved to be helpful to reduce inflammation, those would logically go together. I mean it would be best to systematically study that, but a priori you would think that might be a good combination.

Tony Roth: Okay. So, let’s talk about vaccines. At the highest level there are so many, we’ve learned of so many from Moderna, which is probably the first one that got into clinical trials, to many others that we’ve heard about. J&J is starting in the fall and many in between. It would seem that we’ve got so many smart brains on this, the likelihood of not finding something, let’s say by a year from now, has got to be pretty small.

On the other hand, there are pathogens like HIV that we don’t after many decades have a vaccine. How does this fall on that continuum do you think?

Ofer Levy: We don’t have a licensed HIV vaccine. We had the RV144, which for the first time showed, you know, 40-plus percent effect against HIV, but it’s been a very long road and we’re not there yet. So, you’re right about HIV. It’s been pretty difficult. I do – I am cautiously optimistic we’re making progress with HIV as well, but that’s a separate story.

So, yeah, I think this is a matter of opinion. But, as you highlight, there are so many groups of such high quality and who are now well-funded all over the world racing, using completely different approaches towards vaccines that it just seems a priority very, very likely that in the coming months to a year to a year-plus there’ll be more and more progress and some good news on that front.

That said, it won’t be as fast as the therapeutics. The therapeutics, you know, patients are already in randomized studies for these therapeutics and anti-inflammatory agents. So, I suspect week by week we’ll learn more about those as the studies come out. But, the vaccines, you know, as you know, some Phase 1 studies have begun. But even if a Phase 1 study is promising showing, you know, you had 40, for example, 40 participants. These are typically small studies. Nothing terrible happened. You know, it looked, appeared safe and the vaccine for coronavirus, whatever approach it was, it induced some antibodies against the spike protein. You know how the coronavirus looks like these spiked structures. And antibodies against a spike are believed to inhibit the ability of the virus to infect your cells.

So, that would all, you know, be a promising step forward. But, with just 40 study participants you then need to take it to Phase 2 or Phase 3, you know, do it in hundreds and then in thousands of individuals. And there may be some way to accelerating some of that, but not all of it. And then, even if you say lo and behold we’ve now tried this vaccine in a few hundred or even a thousand or two thousand individuals and not only does it look safe and induce antibodies, it appears to actually reduce the rate of being infected with COVID, that would be the strongest evidence, right? That would be a great moment.

We’re probably months to maybe a year away from that. And then, even if you get to that moment, how do you scale the thing? You need to get hundreds of millions of doses, if not billions of doses of this vaccine. So, it’s doable. It’s tractable, far from trivial, very expensive, and it will require a lot of unprecedented collaboration across government, academia, industry, different countries. So, you know, I think we can get there, but it’s not trivial.

Tony Roth: So, let’s go back to smallpox and juxtapose that to the flu. And I’m making some assumptions here because the smallpox vaccine was sufficiently effective that we don’t have smallpox anymore. Having said that, would a vaccine do you think for coronavirus be like a smallpox vaccine, which is to say that anybody that gets the vaccine, you’re set? Or we all get flu vaccines, right, and there are different strains of the flu every year and I always get a vaccine and some years I say, well, the vaccine didn’t do anything because I got the flu this year.

Do you think that this is the kind of virus that we’ve got a good chance of getting a vaccine that’s going to work for everybody and work really with a very high degree of effectiveness? And would it be the kind of vaccine that you’d just get once or do you think it would be something like the flu where you need it every year?

Ofer Levy: Right. So, it’s it really will be distinct from those scenarios. On the good news front, coronavirus doesn’t shift as radically as flu does. Flu has a segmented genetic material. It does – its nucleic acids are multiple, so you can get these reassortments where you’ll get suddenly what we call antigenic shifts. You can get a sudden shift in a flu strain and create a pandemic strain that, you know, nobody has immunity to.

Coronavirus doesn’t have that kind of multiple segments to its nucleic acid. So, there’s a little bit lower – not a little, a substantially lower risk of a sudden shift of this current coronavirus. That said, it’s changing and there are something like seven or eight strains that are being tracked around the world of this particular pandemic, and there are risks that it keeps evolving, although it’s already pretty good at infecting everybody, so it’s not under a lot of pressure to do so.

We don’t know how long immunity will last. How long will natural immunity last for those who have recovered from coronavirus and have made antibodies? And we don’t know it’s just antibodies. Antibodies are a convenient measure. But it could be that your T-cell responses are also important, different arms of immunity to protect against coronavirus.

But the punch line is somebody who’s recovered from the infection is probably protected against it for some time. But, is that months? Is that years? Is it decades? We don’t know. And, like, similarly for a vaccine we develop, we can show it’s safe, we can show it induces antibodies and T-cells and other helpful arms of immunity. How long does that protection last? You know, we don’t know. It’s a natural experiment, right.

So, there are some vaccines that protect for a few months or a year or two years and then wane, you know. And if this virus, as Dr. Fauci has pointed out, can go into circulation and come back every winter, etcetera, that’s going to become an issue as well. So, can we, you know, make a good vaccine that has – induces long-lasting immunity?

We are, as a program, a precision vaccines program, developing small molecules called adjuvants from the Latin adiuvāre to help or aid. These are like rocket fuel that enhance the immune response to a vaccine and boost the antibody level and the duration of antibody because we believe we’re going to need long-term protection against this pathogen. And adjuvants are also a solution for vulnerable populations like the elderly who tend not to give a very robust vaccine response.

Elderly, among the elderly there are many non-responders. Whenever you give a vaccine, there’s a certain percentage of a population that are non-responders, don’t make enough antibody. That’s particularly true among the elderly.

So, an adjuvant, a small molecule that enhances innate immune responses, that boosts the overall response to the vaccine, is a key way to get vulnerable populations like the elderly to respond better. So, what we’re doing in our program is actually screening small molecules against human elderly white blood cells to advance those that look best against the most vulnerable human population and then take those into the animal models. It’s a very different way to develop a vaccine.

Tony Roth: Fascinating stuff. Well, Dr. Levy, I want to thank you so much for being here, but more importantly for everything that you’re doing.

Ofer Levy: Tony, can I add one more quick point before we say goodbye, really important.

Tony Roth: Yes. Oh, please.

Ofer Levy: There’s a new vaccine concept out there. Look it up. It’s repurposing an old tuberculosis vaccine called Bacille Calmette-Guérin, BCG. It’s given around the world where there’s tuberculosis. But the thing is it’s a live vaccine. It’s a weakened germ, a mycobacterium bovis. It’s the cow tuberculosis. It’s a cousin of the human tuberculosis.

Turns out these live vaccines rev up your innate immune system and make you more broadly protected against a range of pathogens. So now, there are studies up and running in Australia, the Netherlands, and other countries to repurpose this tuberculosis vaccine called BCG to enhance nonspecific immunity against coronavirus. We don’t know yet if it’s going to work. There’s scientific rationale that it might. Those studies are underway and we’re looking to start one in the U.S. as well and we’ll see if that can help. And that would be for high risk healthcare workers or elderly individuals, for example.

Tony Roth: So that would be essentially what you call passive immunity, another form of passive immunity?

Ofer Levy: No, not passive. No, passive – no, no, passive is when you have the – you make the antibody outside the body and you infuse it. No. This would be active immunity, but it would be active innate immunity. It would not be a coronavirus vaccine per se. It’s a vaccine that revs up your innate immune system so that your white blood cells are good at fighting all sorts of different viruses and bacteria and that for a few months would rev up your immunity in general and shield you, hopefully, until a more specific coronavirus vaccine were developed.

But the beauty of the BCG is it’s already used safely around the world to prevent tuberculosis. So, there’s a whole evidence base of safety behind it.

Tony Roth: Got it. So, it’s basically temporary active immunity.

Ofer Levy: Yes.

Tony Roth: If it works. If it works against this particular pathogen.

Ofer Levy: Got it.

Tony Roth: Thanks, Dr. Levy. Let me take a moment to summarize the key points from today’s conversation. The first is that there are a number of promising agents that we know about and there are so many that are actually being explored. There may be others that turn out to be promising. But certainly, just with Remdesivir and Avigan alone, there’s really good hope that we may learn in coming months as we get the clinical studies and the numbers that these compounds are actually effective against coronavirus and in an important way. So, that’s very promising.

The second thing I would say is that there is a good likelihood, not a high likelihood, that we get a vaccine sometime in the next 12 months. But, the third thing I would say as a takeaway is that we have to set our expectations around the length of time that it will take us to get to the other side of this journey that we’re on, because even when we get a vaccine, which is the ultimate cure, the ultimate answer, it’s going to take a meaningful period of time to ramp that vaccine up and really get it around the world unless there are multiple vaccines that prove efficacious. And so, we’re going to have to be patient with the process here and we’re probably going to be living with some of the mitigation and social distancing and masks for quite some time before we get to the other side of this journey.

So, thank you again, Dr. Levy.

Ofer Levy: Thank you so much. It was my pleasure.

Tony Roth: Thank you all for joining us today. Please send your feedback or suggestions for future podcast topics to wealthwise@wilmingtontrust.com. And finally, I encourage you to go to wilmingtontrust.com for a roundup of our blog posts and media contributions related to coronavirus for market, economic, and global health perspectives. Thank you all very much.

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