Stephen Russell, MD
Mayo Clinic Rochester and Vyriad
Interview Date: May 29, 2020

Antibody testing for the coronavirus is a work in progress. Dr. Stephen Russell, a world renown virologist at the Mayo Clinic and CEO of Vyriad has developed a new type of antibody testing to test not all antibodies, but only those that can neutralize the virus. The new test has now been through the clinical trial process and is available with a prescription from a doctor. In this fascinating show, Dr. Russell describes the need for the test, the way that the test works, how your immune system works to develop antibodies, if patients are likely to get re-infected from COVID-19 and how this virus is similar or different to other viruses like thee common cold or the flu. There is so much to learn about COVID-19 and your immune system in this fascinating show.

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Genentech, for their support of this Myeloma Crowd Radio program. 

The coronavirus is still part of our everyday lives, even as things are starting to open up over time and everyone's situation and state is different. Certain approaches like contract tracing or virus testing and protecting the most vulnerable are all important pieces of an overall strategy when dealing with this crisis. Everyone's experience has been different in different areas of the country, but we do need to protect those who are most susceptible to poor outcomes with this virus while the rest of us can and should try to live as normal a life as possible. 

Today's show is a very important one for the general population and for myeloma patients as we try to navigate this difficult situation with COVID as well as other diagnoses that affect our health in critical ways. On today's show, we have Dr. Stephen Russell of the Mayo Clinic. You may be familiar with his name as he created the measles vaccine for multiple myeloma. Dr. Russell, welcome back to the program.

Dr. Russell: Thanks very much, Jenny. It's a great pleasure to be on.

Jenny: Before we get started, I'll introduce you. At the end of the show, we'll open it up for caller questions. You'll be able to call 347-637-2631. Press 1 on your keypad if you have a question for Dr. Russell at the end of the show. 

Dr. Stephen Russell is the CEO of Vyriad. He is also the Richard O. Jacobson Professor of Molecular Medicine at the Mayo Clinic and President of the American Society of Gene and Cell therapy. He obtained his medical degree from the University of Edinburgh in 1982 and since that time has relentlessly pursued the goal of effective oncolytic virotherapy. He specialized clinically in Hematology and then undertook his PhD training at the Royal Marsden Hospital where he was the first to engineer both retroviral and parvoviral vectors to deliver interleukin genes for cancer immunotherapy. He then moved to Cambridge, England where he led a research team in the MRC Laboratory for Molecular Biology developing a novel method for antibody affinity maturation using phage display libraries, pioneered the display of antibody domains on retroviral vector particles and on the recombinant measles virus and founded Cambridge Genetics, a biotechnology, drug discovery company. In 1998, he moved to the Mayo Clinic where he founded the Department of Molecular Medicine and built a comprehensive oncolytic virotherapy program, developed innovative engineering approaches for targeting, arming and non-invasively monitoring OV infections. He orchestrated the GMP manufacturer and preclinical pharmacological, toxicological testing, IND filing and clinical translation of a number of Measles and Vesicular viruses for several different cancer indications. He has co-founded two oncolytic virotherapy companies, which merged in 2015 establishing Vyriad as the first multi-platform oncolytic Viralytics company. 

You have so much experience in this area, Dr. Russell. Maybe we just want to start with a few of the basics before we jump into the COVID. But what are antibodies and how do we develop them?

Dr. Russell: Antibodies -- by the way, thank you for that introduction. That was quite an introduction 

Jenny: Well, you have a lot to say.

Dr. Russell: Antibodies, they're obviously extremely important in myeloma. I imagine most people who've had to wrestle with myeloma do know something about antibodies. They're essentially Y-shaped molecules that are found in abundance in the bloodstream. The two tips of the Y are highly variable. In the bloodstream at any time, there may be ten to a hundred million different antibodies circulating, all of which have different tips on these Y-shaped molecules which allows them to interact with invading organisms. Antibodies are a critical part of our defense against infection. What they do is they lock on to the surface of bugs, whether that be bacteria or viruses or parasites. They then help the immune system to eliminate the infection from the body. 

That's what antibodies are. Where they come from is they come from antibody-producing cells, B-cells, which turn into plasma cells. Those plasma cells are really little factories that produce large amounts of the antibody. At any one time, your body is capable of producing about a hundred million different antibodies. 

You really only step up the production of those antibodies that are needed at a given time. Throughout life, we're continuously exposed to infectious agents in the environment. We often don't know about that, but our immune system does know about it. One of the things our immune system does to fight off those infections so that we never even become aware them is that it produces antibodies that happened to be a good fit with the bug that's invading. All through life, there's an increase in the production of certain antibodies that happened to be needed at a particular time to fight off a particular infection. After the infection has been cleared, the antibodies decline in the blood and the production of those antibodies is turned off. Then another wave of antibodies comes through another infection and so on and so forth. 

The connection between that antibody production in myeloma is that in multiple myeloma, one of those antibody-producing cells will actually fail to die back at the appropriate time when the infection is over and it's no longer needed and it will carry on growing and producing large amounts of a single species of antibody, but it's of no value whatsoever because the infection that provoked its formation has long since gone. And that's the cell that becomes the problem in multiple myeloma. That's the connection between this antibody defense and the problem of multiple myeloma.

Jenny: In virus type diseases like COVID or whatnot, I know you've heard it compared to the flu and not compared to the flu and so when you think about antibody production, how it comes in waves like you're saying and comes and goes as needed (and our bodies are miraculous that way in my opinion) why don't we develop these longer term antibodies to things like the flu? They’re just different strains, I guess?

Dr. Russell: No. It's because of the flu virus is changing all the time. We develop antibodies to the flu viruses that we've seen and if that same flu virus came back and try to infect us a second time because this is the second aspect of the antibodies. It’s that once you have produced antibodies against the virus, although those antibody-producing cells die back, they do not die off completely and they remain a part of your immune memory so that if you see that same bug again, you can respond much more rapidly a second time than you did the first time because you have the slightly enlarged population of cells capable of producing those antibodies. 

So if we saw the same flu virus this year that we saw last year, we would get rid of it really quickly. The problem with it though is it's constantly changing. Every new flu virus to come in a new flu season is different from the flu virus that was around the preceding year. And flu viruses managed to mix and match themselves that there are lots of flu viruses that infect aquatic birds. And as they fly across the Atlantic and over ponds and lakes, they poop. They poop out flu viruses that infect other birds and other animals. A pig with a flu virus that it acquired from a bird flying over can then have recombination between its own flu virus and the flu virus that came in from somewhere else. 

Flu viruses are constantly breeding with each other and reassorting their genomes with each other. They have eight segments to their genome. When two flu viruses get into one cell, out can come a whole variety of different flu viruses. So flu evolves really fast. The flu that comes every year is different from the flu that came the year before, so that antibody memory is not useful in getting rid of the new flu virus. 

It's very different with other viruses that do not evolve in the same way that flu evolves. Measles virus, for example, just does not change over time. A vaccine that was obtained from the throat of one David Edmondston in 1954 when he was a young boy and had a measles infection, that's the vaccine that protects us all against measles today because the measles virus has not changed over the years. The memory of that single challenge with measles virus as a vaccine when we were given it as a child gives us lifetime protection against the measles virus. So viruses are very, very different in the degree to which they can change and evolve over time. In that regard, the immune memory may or may not be useful.

Jenny: So interesting. How does COVID-19 -- how is that different or the same from other common viruses?

Dr. Russell: Well, COVID-19, probably in terms of what we’ve just been talking about with flu and with measles, it’s probably somewhere in the middle. The coronaviruses are a family that pretty commonly are coming and infecting humans each year. Probably close to half of common colds are caused by coronaviruses, maybe a little less than half. About 30% of common colds are due to coronaviruses. 

There are four common types of coronavirus that come back and cause common colds and slowly change over time. Then these newer coronaviruses, the ones that caused SARS ten years ago or so and that subsequently caused the MERS, the Middle East Respiratory Syndrome, they are particularly nasty versions of the coronavirus that have evolved, we think, through the virus infecting other species and then moving via bats and other species back into the human population so that these are coronaviruses -- like the new one, the SARS-2 coronavirus -- for which there's really no prior human exposure and which have emerged from having evolved in some kind of animal species before they got transferred into the human population. 

Will this coronavirus that's currently causing problems stay the same over time? It looks like it's not changing rapidly as the pandemic spreads. And it looks like it may be that if we see this pandemic through to the end and create a vaccine to protect against this virus, we'll be able to get on top of it. But that doesn't mean that there won't be new coronaviruses coming and evolving in bats and camels and other species that could later come back and infect people even though they may be immune to this one. 

Jenny: You're saying it's probably not as wily as the flu in terms of mutating in that way?

Dr. Russell: It cannot mutate nearly as rapidly as the flu. It's much more slightly constrained. 

Jenny: Well, let's talk about antibody testing, I guess after someone tests positive for COVID and then whether they're asymptomatic or whether they have a full blown case with a lot of lung involvement or whatnot or the side effects. Let's talk about why testing for antibodies for COVID-19 is so important.

Dr. Russell: If you have antibodies detectable in your bloodstream against this particular coronavirus, the SARS-2 coronavirus, that means that you've definitely been exposed to the virus and you've had an infection even though that infection may have been asymptomatic, i.e., not caused any illness. It means that you've had an infection. It does not necessarily mean that you have recovered from the infection, nor does it necessarily mean that you are not shedding virus. But it does mean that you've definitely had exposure to the virus.

If you look at how the antibody response develops after being exposed to the coronavirus, it gradually increases over a period of about two to three weeks. Typically, with most of the antibody tests, they're not going to be positive until about two weeks after the initial diagnosis of infection. Sometimes, they'll become positive sooner. Sometimes, they'll become positive later. It really depends on how strong the immune system is, how well it's reacting to the virus infection and how intense that virus infection is in a given individual. But the antibodies are really telling you that you have been exposed to the virus. 

Now, if you look then down in more detail at the antibodies that are generated against any virus, there are antibodies that can just bind to the virus but don't impact its ability to do its job and infect cells and take them over. And there are antibodies that do block the viral function. Those are the neutralizing antibodies. When you look across the testing landscape at the different tests that are available, the vast majority that are currently in use are simply testing other antibodies in the blood that can actually lock on to this virus and specifically recognize it. 

The test that we've developed at Vyriad is a neutralizing antibody test. It tests the functional aspect of these antibodies as to whether they can inhibit the infectivity of the SARS-2 coronavirus. That is a test that has been around for a long time. Labs, in order to test for neutralizing antibodies that can prevent the virus from infecting cells, what they typically do is they get a clinical isolate of the coronavirus. They work in a level three containment laboratory wearing bunny suits. They mix blood serum or plasma with the virus and they show that that blood is able to block the ability of the virus to infect. 

It's not really a scalable system to do that test on everybody who gets infected. What we did was to generate another virus, a new virus in which we've simply taken the coat from the coronavirus. We placed it on another virus so that now, this harmless virus that we've created looks to the antibodies in the blood as if it really is a SARS-2 coronavirus. So we're able to do that same neutralizing assay to determine whether the blood can neutralize the virus without having to dress up in bunny suits and going to a level three containment facility. That's the test we're talking about. It's obviously a more time consuming and involved test than the straightforward ELISA tests as they're called that are currently being used in many, many hospital laboratories that just simply test, “Is their antibody that can recognize a piece of the virus in the laboratory?” That's the difference between the test that we generated that's new and the tests that previously existed. 

We think there's a really important place for this type of test when we look at the landscape of what's going on in terms of testing for COVID at the moment. One particularly important area is that plasma donations are being given by patients convalescing from the virus because many of those patients have antibody in their bloodstream. That plasma is then being given to people who are infected with the virus who may be in the intensive care unit. To date, about 15,000 plasma donations have been administered to patients infected with COVID in the United States. It's really being used a lot. 

But at the moment, those plasma donors are simply being tested for whether or not they have antibody to the virus and not being tested to find out whether their antibody is capable of neutralizing the virus, nor are they being tested to find out how much antibody they have in the bloodstream. We think it's going to be very important to determine whether the best outcomes are for patients who've received a plasma donation that has a very high amount of neutralizing antibody as opposed to a very low amount of neutralizing antibodies. We think this is one important application of a neutralizing antibody test. 

Another very important application would be for comparing all these vaccines that are being developed at the moment. There are 130 or so vaccines currently in the running to treat the coronavirus. How are we going to determinate between them? Which ones are working best and which ones are working sufficiently? I think in order to compare the performance of those vaccines, we need a standardized test that can measure neutralizing antibody. At least it’s one of the critical readouts that we do for that. 

Then of course, for patients who have a compromised immune system, we really don't know much about the effectiveness of the antibody response to the virus. I think this is one area where it does apply to multiple myeloma. I think it's going to be really important to understand what kind of antibody response people with myeloma are having when they become infected with the SARS-2 coronavirus. What are the kinetics of the antibody response? How fast does it come up? Is it neutralizing antibody or not? Then, of course, how long does it stay in the blood for and when does it fade?

Jenny: Yes, absolutely. You brought up so many important points, so I might want to go backwards a little bit in terms of what you just said. When you have these antibody testing performed first, how is your test administered? You said it was a little more complicated than some of the other ones, but what does that mean? Then can you explain the difference between some of the results with IgM versus IgG and what that means? Then we'll go back and talk about the convalescent plasma. 

Dr. Russell: Okay. For the commonly used antibody tests, you can look at IgG, IgM and IgA. I think IgG and IgA are well known to myeloma patients. Maybe 20% of patients with myeloma have an IgA myeloma. And 50% or so, maybe a little more than that, have an IgG myeloma. IgM myeloma is actually extremely rare. 

What are these three antibodies? Well, IgM is different from the other antibodies. It's typically the first antibody to appear in the bloodstream after you've been infected with a virus or anything. An IgM antibody typically don't stay around for long. They're fast, but they're relatively inefficient in terms of getting rid of the bug. It's the IgG antibodies that come surging through later and which really do very efficiently and effectively lock onto bugs. Neutralizing antibodies that are IgG are going to be way more effective at controlling an infection. They're likely to stay around much longer. 

There are structural differences also between IgM and IgG antibodies that I don't think we need to go into. But then the IgA class is also worth considering because IgA antibodies get into the mucous lining the airways. They get into saliva. They get into nasal secretions. They get into mucosa. So everywhere in the body where there's a mucosal lining, there's going to be some mucus over that mucosa and these IgA antibodies get into that fluid. They’re therefore our first line of defense. If you inhale in a virus such as the SARS-2 coronavirus, the first thing it’s going to be hit by on its way in, it’s going to be that IgA antibody in the respiratory secretions or in the oral secretions. So IgA is a pretty important antibody in terms of the defense against respiratory droplet borne infections. 

IgG will stop the virus from spreading from that airway lining to other sites in the body. It’s going to take the virus out when it gets into the bloodstream. So these different antibodies do different jobs for you. The IgM comes up very fast. The IgG is slower but more efficient. The IgG gets into the respiratory secretions and helps defend against virus invasion from that direction. 

That's the meaning of going after those different classes of antibody with the testing that's out there. But as I said to you, none of the available tests look at this functional aspect of, “Can the antibody do more than just bind to the virus? Can it actually stop the virus from infecting?” That's where the new assay that we're talking about comes in. 

The way the assay works is that a blood sample arrives in the lab. It can either be serum or plasma, which is essentially what remains after you removed all the red and white blood cells from the blood. So a small amount of the serum or plasma is added to the virus that we've created. After those have been incubated together for half an hour, the mixture is then placed on growing living cells, which will then be infected by the virus unless the virus has been inactivated by the serum. 

If the virus is able to infect the cells, i.e., the patient is not immune, then a strong signal is generated when the virus infects the cells. The signal is actually -- it's a luciferase readout. So we're looking at the expression of firefly luciferase, which we can easily detect in that culture. But we don't do the detection until about 24 hours after we'd added the virus to the cell. So it takes that long for the signal to develop. 

So the readout for the assay is considerably slower than it would be for a standard IgG or MSA that is currently performed. Also, you have to keep these cells in an incubator at 37 degrees C so that they stay alive and are able to generate that signal. That's what I mean by being more involved. It's not so convenient to ramp up the throughput for an assay like this. 

For that reason, I think in general population screening kind of mindset, it would be better to use one of those more convenient assays and to use this assay as second tier of investigation.

Jenny: Now, this is open in a clinical trial. Correct?

Dr. Russell: Well, it was open in a clinical trial. The purpose of the trial was to validate the assay. When you're developing an assay – for lab tests, you have to know, “Does it work or not? Is it accurate? Is it effective? Can you trust the results?” 

We were developing this assay as fast as we could. But we needed to have samples from people who had definitely been exposed to the SARS-2 coronavirus and infected by it, as well as people who definitely have not been exposed. We needed to show that in those who are unexposed, the assay would be negative and those who had been exposed, it would be positive. We needed to look at the variability in those who had been exposed. So the clinical trial was to obtain those samples. 

Actually, we set up a station in Newark because we worked with a group called Biotrial that set up shop in Newark and obtained blood from people who had a proven SARS-2 coronavirus infection that had been PCR proven by testing their nasal swabs at least two weeks prior to when the samples were obtained. It was a shame because so many people showed up and said, “Hey I'm ready to give you blood. I'm ready to give you blood. I've had the infection,” but they didn't have that proven infection. They lived with somebody who's had an infection or they believe they've been infected, but they didn't have proof of it. So a lot of people came to help and then got sent away. 

It took quite a while for us to collect the samples from people who genuinely had proof that they had been infected. I'm pleased to say that all of those patients gave positive results in the assay and all those who were thought to be negative gave negative results. After that, we said, “Okay. Let's open it up. Let's look at people who believe they've been infected but don't know for sure.” Once we were confident in the results we were obtaining with the assay, we looked at people who fell into that category. We found that slightly under half of them had actually clearly been infected. A lot of people believe that they had had the infection who hadn't. It's very difficult to know. This testing for antibody does provide you with a mechanism where you can find out if were right or not in your prediction about having had the virus infection previously. 

We ran that trial through the Biotrial’s group. Also, here in Rochester, Olmsted Medical Center actually helped us and Mayo Clinic when we set up a tent outside the Vyriad headquarters and people came along. But at that time, there were virtually no people in the state of Minnesota who'd actually been exposed to the virus. That was how we obtained all our negative samples. Actually interestingly, still, the number of people who've been proven infected with the virus in the state is about 23,000 or so out of a population of 5.6 million. So it's still very early stages here in the state of Minnesota. 

Now, Biotrial have now decided to go ahead and offer the test commercially at their site in New Jersey. I think they're intending to start obtaining serum samples from people that will be sent over here. Monday next week I think is when they start doing that.

Jenny: So you're really through that process of validation and now you're ready?

Dr. Russell: Yes. Exactly.

Jenny: Let's go back to the convalescent plasma idea -- so people are now using this strategy of people obtaining the plasma from people who have already tested positive and then giving it back. But what you're saying was really important and I want to call it out. So they're not testing in these donors basically like how strong is the antibody -- and does it have the antibody that will actually kill the virus because what's the point of giving the donation of the sample to somebody with active infection if it's not going to actually do anything?

Dr. Russell: Yes. I think the reality is that there is such incredibly high demand for plasma therapy because people are in the intensive care unit. There's a high risk of death. And so that, “What can you do?” One of the things we can do is convalescent plasma. So people use whatever tests they have available locally. If it's a quantitative test, then they'll say, “Okay. We want people to have above a certain level of antibody.” But if they don't have a quantitative, then that goes by the wayside. 

If they have access to one of these level three facilities that can do the neutralizing antibody test, then sometimes, that does get done. But it's a hodgepodge of different testing methods that have been used around the country. There are now many, many patients who've been treated and we don't really know at this point what the significance of the level, the absolute level of antibody and more specifically of neutralizing antibody in the donor. We don't know what impact that has had on the outcomes of the plasma therapy studies. That does fairly urgently need to be looked at. I think this is one area where this test can help.

Jenny: In terms of treatment strategies for severe COVID symptoms, do you believe convalescent plasma is a good strategy in general or are you seeing more effective therapies like tocilizumab or things like that being more effective? Or does it just matter based on the level of neutralizing antibodies, right?

Dr. Russell: I think it's going to depend on the level of neutralizing antibodies. We actually put a number on the level of neutralizing antibodies. That number ranges, so if you test positive, then the absolute number ranges from 30 units to 3,000. You can see it's a big difference across the spectrum of people who've recovered from the coronavirus infection. 

On the cautionary front, there is some evidence from work that's been done in rhesus monkeys suggesting that it if you have a low level of immunity to the virus, then it may cause worse lung damage than if you had no immunity. So this is a concept that is worrying that small amounts of antibody may actually result in worse lung damage. I think for that reason, plasma donation should really come from those donors who have pretty high levels of antibody so that they really are going to be helpful for the recipient.

Jenny: Is there any way of asking your doctor about that if you do end up in the hospital with COVID and asking them what level of antibody is in this donation you're getting?

Dr. Russell: I think it's actually a question that should be asked. I mean I would recommend that that discussion should take place.

Jenny: I think most people have no idea and that's such a fascinating idea about this lung damage. Are you seeing the same thing with the blood clots? Because I know we're hearing a lot about blood clots regardless of level of symptom, other symptoms.

Dr. Russell: The evidence that I just was outlining comes from a study in rhesus monkeys in which the readout was lung damage and lung damage only. So that was the only thing that was looked at in that study. As far as what goes on in the clinic, it's not yet known. There's one published study that I'm aware of from Mount Sinai Hospital which is very encouraging for plasma therapy. It was just published a few days ago in this new journal, bioRxiv, which is a great journal where so many non-peer reviewed data being published really quickly so that information can be disseminated. 

What they were able to show was that the outcomes for the patients who they had given plasma to were better than the outcomes for historical control patients. It seems that it was better to start the therapy before the patient was on the ventilator in order to get that good outcome. So It's not the strongest sort of supportive data for the approach that you'd want, but it's at least the start. And there are certainly evidence from other diseases that plasma therapy really can be beneficial in helping to eliminate an infection. But again, I do think it's important to look at the absolute level of antibody in the donor.

Jenny: Then if your new development and your new test is you said the second tier, how does someone access the test? Or how are you working to disseminate or distribute your test because it sounds like something that more people?

Dr. Russell: Yes. The real heavy lifting on that is being done at Mayo Clinic. The test was developed at Vyriad, which is based here in Rochester, Minnesota, which is where the main campus of Mayo Clinic is. We've been, for several weeks now, working with Mayo to transfer the technology into the Mayo Clinic laboratories so that Mayo can scale it up and make it more widely available. Mayo Clinic, you may not know this but the laboratory arm of Mayo Clinic is -- it's very wide, far-reaching. There are maybe 2,400 health centers around the country that send samples to Mayo Clinic laboratories for testing. It's a really good hub from which to make this test available. 

Now, of course, when transferring a complex assay like this from one lab to another, it's not something you can do overnight. You have to be absolutely certain that the people performing the test are able to do so reliably and to conduct the assay in a way that gives the same result no matter who's the operator. The reagents have to be proven to work in the new site where the assay is being set up. Mayo is currently working through its validation process. It's a pretty comprehensive validation process that will be completed before the assay is made generally available through Mayo Clinic. That will take another week, maybe two weeks before the assay is available through that. 

In the meantime, as I said, it's going to be made available from Monday through the Biotrial group in the New York. They can take samples from people in the tri-state area. But it is a physician ordered test. It has to be ordered by a physician. In general, if anyone wants to go to Biotrial and get the job, they need to have a prescription from their physician ordering the test, which is called IMMUNO-COV. 

It's not quite at the point where it's generally available to everybody. We have the capacity to test a thousand samples a day, but we certainly are not a center for collection of blood. The order needs to come from a physician. Then the blood needs to be sent to the lab and have the test done. 

Jenny: Well, with your experience with vaccine development, can I ask some vaccine-related questions? There was a couple and a myeloma doctor. The husband acquired a very serious case of COVID-19 and the wife was asymptomatic but tested positive. On a rapid test, it showed very strong IgG antibodies for the husband but not the wife. Her concern was even if we develop a vaccine for COVID, barring finding these neutralizing antibodies to be placed in that vaccine, then how effective would a vaccine actually be? Just with your background of vaccine development, I just like to hear your perspective of where you see the vaccines headed.

Dr. Russell: Well, I think that it's a very important point that you're making through that story about exposures of the virus doesn't necessarily result in the generation of high-titer neutralizing antibody that's going to protect you from re-exposure. That's obviously the concern with the vaccines that are being developed. It’s will they or will they not give you sufficient levels of neutralizing antibodies that you're going to be protected against infection. 

Now, I think it's very interesting looking at the whole epidemiology of this thing. It does appear that there are likely to be many people who are just intrinsically resistant to the virus and who may be exposed to it but don't actually get infected and therefore, don't generate an antibody response. Those same individuals, if they were vaccinated, probably would develop an immune response because remember, natural exposure, maybe a droplet landing on your oral mucosa or on your hand and you touch your face, which just has a few infectious virus particles in it, which may not be enough to establish an infection and which may be rapidly eliminated by your body before you ever develop an antibody response. 

With a vaccine, it's much more intentional. Nobody gets away with a single droplet on a mucous membrane. It's like the needle goes in and, boom, you've got lots of vaccine in there. Or if it's given by another route, it's always going to be certain that the vaccine was delivered in a sufficient amount that your immune system has to sit up and pay attention. I think it's going to be very intentional with vaccines, but they are going to perform differently from each other. Some will be successes and some will be failures. And I suspect there’ll be a small number of winners that end up being the favored vaccines as we move forward.

Jenny: Yes. I'm just wondering. Who is likely to recontract COVID-19? I guess we just don't know because of some of this recombination, that idea that you were discussing earlier.

Dr. Russell: Yes. I think this question of, “Can you get reinfected? Will you get reinfected?” I am less worried about that. I think it may be getting a bit too much emphasis, I think. I think there's little evidence for people getting the infection twice. I'm not aware of people who've had SARS-2 who've got sick, recovered and then it's come back and reinfected them. There is evidence that that can happen with coronaviruses generally. There was a paper recently published out in New York City showing that with some of those common cold coronaviruses, you can get the same virus twice in the same year. That is thought to be because the antibody responses that happened after the first infection are rapidly lost and there isn't much memory and so the same virus can come back in the second time. 

I think that's one of the things that is going to be very important to evaluate with the vaccines that are being used. It’s not only, “Do they give you a decent level of protective immunity,” but number two, “Is it durable?” It’s important on those trials to retest people after three months, six months, a year and make sure that the immunity is maintained. If it's not, then maybe revaccination will be required, just a booster vaccine at a later time point.

Jenny: That's very commonly done, I think, even for myeloma patients who have a lower immunosuppressed immune system. Even for the regular vaccines, they’ve suggested that they get boosters and more frequent dosing of some of those -- 

Dr. Russell: Absolutely. I mean this is very familiar territory in myeloma because we know that the disease and the treatment for the disease are both immunosuppressive. We know that myeloma patients, particularly after going through stem cell transplant, will lose their immunity to a significant degree against tetanus, pertussis, measles, mumps, rubella, et cetera. That's the whole purpose of the revaccination programs that are implemented after stem cell transplant.

Jenny: You mentioned a multi-step strategy in terms of vaccination testing. If you had to employ a national testing strategy, how would you approach it? Would you test everyone? Would you just test high risk? When would you use the secondary test as a deeper, more knowledgeable or more informative test? What do you suggest? There's so much confusion right now around testing. It's a little frustrating, I think, for everybody.

Dr. Russell: Yes, it is. I think it depends on what your question is. I mean if your question is simply, “Well, how many people in this population that I'm looking at have actually been exposed to the virus,” then I think you really want a fast, cheap, reliable test to indicate to you whether you have a 5% or 10% or 20% frequency in the population. 

I don't think, for that kind of testing, you would be particularly interested in the test that we're talking about here. I think if you're looking at the efficacy of vaccines, that's really clinical trial stuff, but it's going to be thousands upon thousands of people because those clinical trials are going to have to go through phase 1, 2, 3. And for each vaccine we’re talking about, it's going to be thousands of people that need to be evaluated. I think in those trials, it's really going to be important to have that standardized testing with neutralizing antibody. But also, with IgA, I think it's very important that we look at whether or not people are developing mucosal immunity. I think those other screening assays for the IgG and/or AGM are valuable to include. So I'd advocate a lot of testing to go on when we're looking at comparing the performance of vaccines and people who've enrolled into those clinical trials. I wouldn't rely on a single assay. It’s, I guess, what I'm saying for that.

Population screening, I don't know. As soon as you screen the population, it’s going to change and you'll have to come back and screen again. I also don't know what the right answer is in terms of this passport thing that people have been talking about with the back-to-work passport. I mean it’s clear that if you want to pronounce yourself safe, then you need to be negative for the coronavirus antigen or negative for the coronavirus genome. You need that diagnostic test for, “Do you have coronavirus,” to be negative. And you need a positive antibody test. That tells you, “Yeah, you've had the virus and it's gone. Now, you're immune.” There's quite a lot of testing to tick that box. I imagine there's a huge number of people who would go away from the testing disappointed and wondering about whether or not they really can go back into the workforce. I'm just not sure that's going to be a realistic way forward.

Jenny: Yeah. Well, yeah, that's complex and laborious and I don't know. It's all very confusing. I would like to open it up for caller questions. Dr. Russell, you are such an amazing expert in this field. It's just stunning that you've taken the time to share this with us. So my thanks to you, before we open this up to caller questions. We'll start with our first caller - go ahead with your question.

Caller: Hi. Thank you. I have two questions. One is there’s a lot of misinformation about high risk so who is a high risk for dying or being hospitalized for COVID? Does that include cancer and myeloma patients? My second question is you mentioned that -- when Jenny was talking about the doctor's wife who went asymptomatic that she might not have had an immune response even if she tested positive for the virus. How often does that happen in people that are asymptomatic? How does that lack of antibody affect our knowledge of how many people have gotten the disease and our view of future studies of antibody testing, if that makes sense? Thank you.

Dr. Russell: Okay, thanks. On the first question of who's high risk, clearly, there's a significant increase in mortality as you march through the age groups. It's very low in children. It's pretty low before age 50 even. From 40 to 50, it's about 0.4%. Then beyond age 50, it starts going up and it goes up pretty high over the age of 80. 

Co-morbidities have been evaluated and there are many conditions which are associated with a worse outcome; one of which is cancer. There was a study just recently published in The Lancet looking at the various risk factors associated with death from SARS-2 coronavirus infection. The overall mortality in patients with cancer, including hematologic malignancies, was 13%, which is a high number. The median age, I think, of that population was 66. Based on that paper, I would argue that, yeah, I mean the patients with cancer, on chemotherapy, are going to be at increased risk. 

There’s another study. It was recently published in bioRxiv showing that patients with hematologic malignancies are at higher risk than those with solid tumors which, again, you'd expect because of the immunosuppressive nature of the treatment for blood cancers and because of the immunosuppressing effect of the blood cancers. So there is an increased risk. I mean it's an infection you don't want to get and it's an infection you do not want to get even more if you have a blood cancer. The risk increases. It doesn't increase dramatically on account of those conditions, but it's definitely increased.

On the doctor and the doctor's wife, I don't actually know enough about it to really comment on that. I think I'd want to know what contact there was between the doctor and his wife, how much the doctor was shedding. Could it have been that his wife was just testing positive because she'd been in close contact with her husband but was not actually infected, just carrying PCR positive material? What tests was used? Was that test reliable? I know the FDA have been actually withdrawing their emergency use authorizations for some of the tests that are out there on account of unreliable test results. There can be false positive results for tests. So it's an unusual scenario and it does raise all kinds of questions, but I don't know exactly how to interpret it without knowing more.

Jenny: Yes, thank you for your question. Okay. We'll take two more short, very short questions because we're at the top of the hour. Please go ahead with your question.

Caller: Hi, Dr. Russell. I just have a quick question for you. When do you see a COVID vaccine being ready for the general population? How fast is the FDA working on this?

Dr. Russell: I'm an optimist on this. But my optimism may not mean the same as your optimism. I think that it's not unrealistic to think about having a vaccine by the end of the year that's ready for general use. I've never seen anything like it in my life, the speed with which people are moving and the fact that they're running everything in parallel. 

I mean typically, when you're developing a new vaccine or a new approach, you generate the reagent. You then do the mouse studies. You then do the non-human primate studies. You then go to FDA with the data. Between that and going to the FDA, you make sure you've got your manufacturing facility and all your methodology sorted out. You then design your clinical trial, take it to the FDA. You then wait for them to give you permission and go into the clinic. 

Well, here, what people are doing is they're running it all in parallel. So they're saying, “Okay. We've got a vaccine. We don't know whether it works in mice or in non-human primates. We don't know whether we can manufacture it. Let's just design the clinical trial, fix up all those animal studies to go forward, do the manufacturer. Let's run it all in parallel and throw the money at everything so that we can get into the clinic at the earliest possible time point.” People are doing that. They're throwing huge amounts of money to accelerate everything by running it all in parallel and sequentially. I don't think they're compromising safety, but they're just moving mountains to make it happen rapidly. 

The early data coming out from the Moderna clinical study are pretty encouraging. It's only eight patients. But an initial dose of that vaccine that they've developed followed a month later by a booster has generated good antibody responses in the patients that they administered the vaccine to. There's another study from a Chinese group using an adenovirus that doesn't actually look so promising because the vaccine hasn't generated as high an antibody response as you'd like to see. But it's moving very fast. There's so many more that are moving at breakneck pace to try and catch up and overtake these ones. It's the best race to watch. I'm sure it's going to be successful rapidly. I'm optimistic about the end of this year. I think this, what's it called? Operation – oh, I'm forgetting what President Trump's name to the operation is. But anyway, it's all moving fast and I think it's a good thing.

Jenny: Oh, it's a fantastic thing. Caller, go ahead with your question.

Caller: Hi, Dr. Russell. Hi, Jenny. It's Dana Holmes. Thanks so much for taking the call. Dr. Russell, I have a question because you mentioned typically, myeloma patients are immune compromised. So we basically need functioning B-cells to produce healthy functioning plasma cells, which in turn produce healthy, normal antibodies. We know that this is a myeloma patient’s challenge. So what are memory T-cells in infection? Do myeloma patients create these when they are exposed to a viral antigen such as SARS-2?

Dr. Russell: Myeloma patients can generate immunological memory. So those memory B-cells are actually -- it's a very big question that you've asked. What are those memory cells? We're not completely on top of that in terms of the science behind it, but patients with multiple myeloma can generate B-cell memory. They also can generate B-cell antibody responses in the same way that normal people can up to a point. 

But in general, as you I'm sure understand, myeloma patients do have an immune paresis. They do have a weak -- a smaller antibody response to challenge with viruses or bacteria than people without multiple myeloma. It's both a disease and the drugs that are used for the disease that contribute to that. But there is nevertheless the ability to generate memory. That's evidenced by what happens following those post-transplant revaccinations. You see good long term, sustained immunoresponses to the viruses that people are revaccinated against. I think it's all a question of degree. 

The occasional patients with multiple myeloma have such lousy B-cell responses that they do need intravenous immunoglobulin. There are people born with agammaglobulinemia who make no antibodies. Those people tend to get recurrent infections. They'll get chickenpox once and they're not immune to it thereafter, so they get chickenpox again. Their immune system is able to get rid of the chickenpox, but it just doesn't have the memory and so the chickenpox comes back in. They don't have the antibody there to fight it, so they're relying on other arms of the immune system to fight off the infection. It's a complex thing. 

Myeloma patients do generally have lower antibody titers than normal people. Sometimes, they're so low you've got to give intravenous immunoglobulin. But usually, they’re good enough to actually fight off infections and give you some memory. I think myeloma patients will be protected by vaccination, but they may need higher doses. They may need more frequent dosing with the vaccine in order to get that protection.

Jenny: Thank you. That was an excellent question and thank you so much for your answer. Well, Dr. Russell, thank you so much for joining us today. You've shared so much about this and given us a lot of great answers. We just appreciate your time. We appreciate all this amazing work that you're doing to develop accurate testing and potentially, vaccines to help with this disease as well as myeloma. It's truly stunning what you're working on.

Dr. Russell: Well, thanks very much, Jenny. It's my pleasure to be on the show. I want to wish everybody well with the fight against multiple myeloma in this COVID-19 era. I think the thing you have to bear in mind is that not treating myeloma is the most important risk that you confront. So you have to keep moving with your therapy and find a way to do it. Stay safe and wear masks. Take hand sanitizer with you wherever you go and make sure and be sensible and avoid being exposed.

Jenny: Oh, thank you so much. It's very wise counsel. I know a lot of doctors are saying the same thing. You can't ignore what you have to deal with in front of you at the moment, so very good counsel. Thank you. 

We appreciate all our listeners. Thank you so much for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.