COVID-19: What Transplant Patients Need to Know

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COVID-19: What Transplant Patients Need to Know

April 18, 2021

Presenters: Hannah Imlay MD, MS, University of Utah and Erica Stohs, MD, MPH, University of Nebraska Medical Center.

Presentation is 39 minutes followed by  20 minutes of Q & A

Disclosures: Hannah Imlay is a site investigator on trials for remdesivir (Gilead); Dr. Stohs is a site investigator for the Novavax COVID-19 vaccine trial.

Summary:   COVID-19 and its variants present ongoing risks to the general population and added risks for cancer patients, people with weak immune systems, and transplant survivors. This presentation reviews the basics about COVID-19, prevention strategies, recent variants, available therapies, and vaccine responses and provides specific advice for cancer patients and survivors.

Highlights:

• Active cancer increases the risk for severe illness if the patient develops COVID-19. 

• Patients with blood cancers may have a less robust response to COVID-19 vaccines than healthier individuals.

• Transplant recipients should consult with their doctor, but in general, they are encouraged to get whatever COVID-19 vaccine they can when it is available.

Key Points:

(04:58)   Patients with a blood cancer have a higher risk for a severe COVID illness than cancer patients with a solid tumor.

(05:15)   Patients should be tested for COVID-19 before beginning chemotherapy

(13:45)    Three variants of COVID-19 are of particular concern because they are more easily transmitted and can cause more severe disease

(20:37)    Pfizer and Moderna vaccines use messenger RNA  (mRNA) which does not alter a patient's DNA.

(24:55):   Johnson & Johnson and AstraZeneca vaccines use an adenovirus vector. These vaccines do not create an adenovirus infection in patientts.

(30:37):    Data on the effectiveness of currently available vaccines against variants of COVID-19 is mixed.

(34:14):    The Centers for Disease Control (CDC) is monitoring potential side effects of COVID 19 vaccines, such as severe allergic reactions (anaphylaxis) and blood clots

(36:19):    COVID-19 vaccines appear to provide less protection for people whose are immunocompromised than the general public.

(38:46):    Patients who are immunocompromised should continue masking, practicing social distancing and handwashing even after being vaccinated against COVIR-19.

(58:03)    If a person does not have side effects after getting a vaccine, that does not mean that the vaccine is less effective than it is in those who do get side effects.

Transcript of Presentation:

 (00:00): [Sue Stewart]     Introduction. Welcome to the workshop, COVID-19: What Transplants Survivors Need to Know.

My name is Sue Stewart and I'll be your moderator for today. I'd like to welcome our speakers Dr. Hannah Imlay and Dr. Erica Stohs.

Dr. Imlay is an assistant professor in the Department of Internal Medicine in the Division of Infectious Diseases at the University of Utah. She specializes in clinical care of immunocompromised patients including those undergoing a stem cell or solid organ transplant. Dr. Imlay has participated in clinical trials to develop therapeutics for COVID-19 and has been involved in developing institutional policy for testing, treating, and vaccinating COVID-19 patients.

Dr. Stohs is an assistant professor in the Department of Internal Medicine in the Division of Infectious Diseases at the University of Nebraska Medicine. She is also the associate medical director of the antimicrobial stewardship program and specializes in the treatment and prevention of infections in immunocompromised patients including recipients of bone marrow and solid organ transplants. Over the past year, she has been involved with clinical trials in the development of institutional protocols for COVID-19.

Please join me in welcoming Dr. Imlay and Dr. Stohs.

 (01:35): [Erica Stohs]        Overview of talk. Hello, this is Dr. Stohs. It's wonderful to be with you all today. I know it's been a trying year with COVID-19 impacting all of our lives so I just wanted to take a moment to acknowledge that and encourage as many questions as you have.

Just to get us going here are. Brief disclosures. Currently, I am a site investigator for the Novavax COVID-19 vaccine trial at our center and Dr. Imlay is a site investigator on trials with remdesivir.

Just to briefly outline what we're going to be covering today, we'll give a brief overview of COVID-19, discuss how COVID-19 spreads, talk about symptoms and treatment for COVID-19 as we know them as of today, and then finally, and probably most importantly, we'll be discussing prevention and that includes vaccines which I believe a lot of questions are coming these days.

 (02:40):        What is COVID-19?. First of all, just as a review, what is COVID-19. COVID-19 is the illness caused by the respiratory virus SARS-CoV-2. As you likely know by now, it is more contagious than the influenza virus and symptoms can be mild to severe. The onset is typically within two to 14 days after an exposure to someone who had COVID-19. Usually, the development of symptoms happens around the one-week mark but as you have heard why the quarantine period can be up to 14 days because it can take that long to show symptoms.

So far, it seems that COVID-19 does affect adults more than children, not to say children cannot get COVID-19 they certainly can and do present differently compared to adults. However, what we do know about all age ranges is that those with underlying medical conditions are at higher risk of developing serious complications.

 (03:49):    Active cancer increases the risk for severe COVID-19 illness. Therefore, what does it mean to have COVID-19 if you have cancer? We're still learning a lot about this topic and we'll develop more and more research and information as time goes on. But so far, what we see is having active cancer does increase your risk for severe illness due to COVID-19 and therefore that means higher risk for hospitalization, need for ICU care, and it often depends on a lot of other conditions and your age. Cancer is just one of the underlying medical conditions that can affect your development of COVID-19, what those symptoms are.

Briefly and in the data we know so far is cancer in remission, it's unclear how much this changes your risk for severe illness. It's really about what immunocompromising medications or underlying illness you have that may affect what severity of COVID-19 someone develops.

 (04:58):        People with blood cancers have higher risk for severe COVID illness than people with solid tumor cancers.

What early studies again have been showing is that the blood cancers, such as acute leukemia, non-Hodgkin's lymphoma, they have a higher risk for severe illness compared to those with solid cancers such as breast cancer or colon cancer.

 (05:15):        Patients should be tested for COVID-19 before beginning chemotherapy. Immunotherapies, hormonal therapies, and radiotherapy did not change the risk for severe illness from what we know so far. However, having chemotherapy within one month of developing COVID-19 has shown mixed results. Some people do just fine and while others get them a possibly more severe course of COVID-19. Therefore, currently, it's recommended that those who are about to go chemotherapy get a COVID-19 screen and that's common in many institutions now so that we're not giving chemotherapy to patients who actively have COVID-19.

(05:56)          Symptoms of COVID-19. You're probably all familiar with this by now and it varies greatly. But commonly what someone may develop as they develop COVID-19 are fevers and chills, cough, shortness of breath, difficulty breathing, loss of smell or taste, headaches, sore throat, nausea, vomiting, diarrhea, and muscle aches.

Warning signs that should really warrant you to get care immediately are if you're having difficulty breathing to the point of not being able to speak or catch your breath, not feeling like you can get a deep breath, those are important reasons to get help immediately. Similarly, if you're turning blue or gray or pale because you're not getting enough oxygen. Persistent chest pain or pressure as well as new confusion or trouble staying awake when you normally would be awake, those are also signs that your body may not be getting enough oxygen, and you need to seek care immediately.

[Hannah Imlay]       I'm going to take over for a couple slides, this is Hannah Imlay, and then I'll turn it back to Dr. Stohs.

(07:16)          The best treatment for COVID-19 depends on the stage of the disease.  I'm going to briefly touch on what we have in terms of COVID-19 specific therapies and in order to talk about that, what we often talk about is what we actually think is going on with the virus and with the immune system while people are developing symptoms.

I'm showing here unfortunately a bad case of COVID-19 where it clearly progressed from mild to moderate to severe to critical illness and need for ICU care. You can see that we think the first part of this illness often either before people develop symptoms or while they still have mild symptoms, that's really when the virus is replicating the most and that's actually one of the things that makes COVID-19 such a transmissible and such an infectious illness is that the viral load is highest when people actually feel the best.

Once people are hospitalized and they have severe COVID-19 or as they develop critical illness, we actually find that the numbers of the virus decrease and really, we think what's happening there is that the immune system is taking over and inciting a hyper inflammatory response and that's actually what gives people that strong need for oxygen, that's what causes so much lung inflammation and lung damage and need for life support.

 (08:18):   Monoclonal antibody treatments for COVID-19. Keeping that in mind, these are the major therapies that we're currently using for COVID-19 and these are quite widely used across the United States and in many cases across internationally. The first therapy that we often talk about is monoclonal antibodies. These are engineered antibodies and they're antibodies that are specifically designed to go bind the spike protein.

In that cute little cartoon, you can see those red spikes, those are the spike proteins and spike protein is critically important for SARS-CoV-2, that's what it uses to bind our cells and get into our cells and then kill our cells. If we can bind the spike protein, that can prevent a lot of illness or so we think and that's the reason we use some of these antibodies.

The two major antibodies that we use, I'm going to refer to them by their brand names, their company names. There's a Regeneron product which is two drugs, and Lilly product which is two drugs, and both of these have been widely used across the United States. We think these help when the virus is at the highest levels. You can see here we think early prior to hospitalization as a means to potentially prevent hospitalization and there's recently a trial that showed some efficacy in preventing actually developing disease after exposure to a household contact. Although I haven't seen the paper, I've seen the press release so I'm crossing my fingers for efficacy there.

 (09:47):     Remdesivir is an antiviral therapy to treat COVID-19. The second therapy that we commonly use is called remdesivir. This one is our only antiviral that we're currently using and it directly blocks the way that virus makes more genetic material and makes more RNA. We think that this helps early, again, when viral levels are the highest and based on clinical trial data, it's shown the most benefit among patients who are hospitalized but early in their hospitalization when they're requiring low amounts of oxygen.

 (10:15):   Dexamethasone is a steroid used to treat COVID-19. The last therapy that we're using on a widespread basis is called dexamethasone. This is very similar and is actually a type of steroid therapy. And so like we use for many theory therapies, the goal here is to block inflammation and to block inflammation that the body is doing in response to SARS-CoV-2 in the course of COVID-19. And so we use this in severe disease.

 (10:39):    Other treatments for COVID-19 that work for specific types of patients.

There are several additional drugs. When you read the news, you're inundated with all these potential options that may show activity against SARS-CoV-2 and COVID-19. Some additional drugs that we use in very select scenarios include convalescent plasma, baricitinib, and tocilizumab, and those really need a very specific patient in a very specific part of the disease and that's where we think those drugs are helpful.

(11:06)          Drugs that are not effective against COVID-19.  And then many, many, many, many things have not yet shown benefit or has not shown benefit despite multiple clinical trials. This is a short list of some things that came from early in the pandemic like hydroxychloroquine, some things that were tested later in the pandemic like ivermectin, but are not widely used for COVID-19 at the moment.

This is just a redemonstration of where we use each of these therapies. Monoclonal antibody, early remdesivir are in the middle of the disease, so relatively early in severe disease, and then dexamethasone once people get very sick.

But with these major three therapies with the adjunctive therapies that we have, we still think that even treatment that we have has not been enough to make this pandemic not a problem. We still need something more to keep people from getting sick and to prevent these severe outcomes.

(12:02):        How to protect yourself against COVID-19. The prevention comes in two flavors. One of those are traditional public health maneuvers like masking, distancing, hand washing. I think South Korea referred to it as cluster busting so not getting too close or gathering with other people and that's maybe my favorite term. And then vaccination and multiple vaccines are available and we'll discuss those briefly.

Before we discuss those, we're going to briefly talk about the spread of variants of SARS-CoV-2 and how does that change these strategies.

(12:36): [Erica Stohs]        How COVID-19 spreads. I'll take back over here and also just remind us how COVID-19 spreads because that's important in understanding preventive measures.

First of all, being in close contact with someone who's infected is going to be the most common way that someone develops COVID-19. You breathe in respiratory droplets or aerosols that an infected person is coughing or sneezing out, so you either breathe in those droplets or you touch them in some form and then you touch your nose, your eyes, or your mouth and that infects yourself. That's, in general, how this virus spreads.

Now, it's more common if you're going to be an environment that has poor ventilation. That was why a lot of times we're avoiding large crowds and then avoiding areas just with poor ventilation. For example, airplanes have higher ventilation and so it's a little bit less likely that you're going to have these droplets spreading, but of course, we'll get into in a second is masking is going to be key.

(13:45):        Novel COVID-19 variants.  Let's first talk about novel variants because this has obviously created a lot of concern over the past few months and so understanding what's happening here is helpful.

This is the SARS-CoV genome. This is the picture depicting different parts of the virus and the genetic code for them. With all viruses, there are mutations that are happening gradually. The key though is when it hits a certain area that it can change how the virus spreads the transmissibility, how severe the illness becomes, and that's where we start to worry about variants of concern.

There are different ways that the CDC refers to these. There may be variants of interest and variants of concern. When they're looking at the genetic sequences and what happens with that virus, they note that there are certain variants that have a higher risk of transmissibility, that they can develop more severe disease, or they may evade our current therapies that are available including vaccination.

(14:59):      The three COVID-19 variants that are currently causing concern. At the moment, there are three variants of concerns that we are monitoring for. And the CDC is the warehouse for all this information. The different states and jurisdictions across the country are now reporting different viral strains. They're getting sequenced to determine if they are in fact a novel variant.

Now, variants can be referred to in a lot of different ways. The way the CDC refers to them here is B.1.1.7 or B.1.351 or P.1. Another way that these are referred to is by the country of origin or where they first identified it. The United Kingdom, Brazil, and South Africa.

We're getting more and more information about what COVID-19 circulating is one of these variants and the issue, of course, is that we're seeing higher transmissibility than we did a year ago in the pandemic. That's why prevention is key and masking is key.

But just to show you one more slide here is that there is a map on the CDC website as well to show you the density of the cases of these novel variants or variants of concern. You can see the states here and identify where you are to get a sense of how many novel variants you're seeing there.

The other thing to think about here is this is population dependent here. Your high density or high populated areas are probably going to have higher numbers. And then also, it's highly dependent on which states are actually reporting or submitting their COVID-19 SARS-CoV viruses for sequencing.

(16:43):        Preventing transmission of COVID-19. How to prevent transmission? This is a lot of the public health measures we were just discussing and why in the age of higher transmissible variants, it's important to still wear a mask when you're out in public, to maintain that six feet distance between. And crowds, avoid crowds when you're able to. Of course, wash your hand and now get vaccinated when you're eligible.

(17:11):        When is wearing a mask important to prevent COVID-19 transmission? There was a lot of questions a few months ago about masking and when can we start lifting the masking mandates. But at present, it's still encouraged to wear masks, if you're in public, certainly, while you're traveling, if you're around any visitors, or if, of course, somebody else who may be sick with COVID-19 or has actually developed it.

(17.34)          Which mask provides the best protection against COVID-19?  What mask is best? About the end of February and in March, there was discussion about these double masking that was being recommended. Ultimately, what mask is best is all about the fit and the filtration of the mask. In general, a mask should cover the nose and mouth. As you may see people in public, they have their mask below their nose, defeating the point. You want to have it fully covered your entire nose and mouth.

And then when it comes to double masking or not, it's really about it fitting snugly against the size and underneath your chin to make sure you're not having a lot of gaps. It's trying to keep those virus particles from escaping out the side. 

Using a nose wire, some of these masks have a moldable wire that you can shape to your nose can help. And then the double masking comes in just to help improve that gap along the sides of your face or any other gaps that may be existing. It's not necessary to wear a double mask all the time, it may just be something to help with your mask fitting. And if you have a good mask already, that may be all you need.

And then just a reminder, these masks that have valves are not recommended because those allow viral particles to escape.

 (19:00): [Hannah Imlay]  How vaccines work.  I'm going to take back over at this point and start talking about vaccinations, which is the latest and greatest part of this pandemic and hopefully continues to be the latest and greatest part of this pandemic.

I'm going to talk about vaccines in general and then get into the vaccines that are specific for COVID-19 and talk about how they work as well. The goals of a vaccine is always to train your immune system to recognize parts of a virus and ideally, it's parts of a virus that are crucial for the virus doing the damage that it likes to do.

In this case, again, you see a little cartoon here of SARS-CoV-2 and those the red spikes on the outside are called spike protein and those are critical for the virus causing damage because they are what binds to human cells and allows it to enter human cells. And so all the vaccines that we have currently all target spike protein. This is important and we think that it's also a good thing because our immune response can sometimes be more nonspecific than what we can make vaccines to be.

Our immune system will do whatever it can to bind to whatever part of the virus that it can recognize and make an immune reaction to it. But those parts of the virus may not be something that are critical for causing disease. In that way, we actually think that the vaccines that we can create may in fact provide more specific activity against viruses than what we can do from our own immune system.

 (20:37):    Vaccines for COVID 19 .  This is a list of the currently authorized vaccines in the United States. Those are the top three. When I'm talking about vaccines here, I'll refer to them again by their company name because I think that's generally what people know them as.

You can see here the Pfizer and the Moderna are both mRNA type vaccines and are both authorized. The Johnson & Johnson and the AstraZeneca are both adenovirus vectors. The Johnson & Johnson is currently authorized in the United States and we'll talk about that more in a little bit.

And then the Novavax which is a protein subunit vaccine and is not yet authorized in the United States. But my guess is that if we're going to authorize additional vaccines, it will probably be the AstraZeneca and the Novavax.

(21:23)  The Pfizer and Moderna vaccines are mRNA vaccines. I'm going to talk about mRNA vaccines first. These again are the Pfizer and the Moderna and mRNA here stands for messenger RNA. Most of the cells in our body create proteins and when they do, they take DNA, they convert it into messenger RNA and then they convert that messenger RNA using cell machinery into protein. This is really what our DNA makes as the first step in creating protein. MRNA itself is not very stable. It's an email telling yourself how to make spike protein and then that email is deleted after a short period of time. It doesn't last.

The vaccine itself is made up of mRNA. That's that red part in the middle. There's some sugars, salts, and some carrier fluid inside of the vaccine and then it's surrounded by an oily coat. And the oily coat is for binding the cells. But essentially, this is a pretty simple vaccine. There's not a lot in there.

When the vaccine works, it's injected into a muscle in a patient. The vaccine fuses with a cell and the mRNA is released into the cytoplasm of the cell. The cell machinery uses that mRNA to create spike sub proteins, the little bits of spike protein which then combine to form mature spike and then spike protein is displayed on the outside of the cell.

 (22:45):   Can an mRNA vaccine integrate into a person’s DNA. One question that I've heard a lot is, "Can the vaccine integrate into my DNA?" And I think RNA is genetic material, DNA is genetic material, this is a reasonable question. Are these genetic material... Is the mRNA going to join my DNA? And it's really not for two separate reasons.

The first reason is that the mRNA only goes into the cytoplasm. It doesn't go into the nucleus which is where all of our DNA is stored and because there's not a whole lot in that vaccine, there's no receptors on that mRNA to be even let into the nucleus. That's the first reason.

The second reason is because it's a one-way street between DNA to RNA to protein and human cells don't have anything to reverse the direction of that one-way street. And so we actually can't turn RNA into DNA. This can't actually integrate into our DNA.

(23:41):   mRNA vaccines create attach a protein to cells that trains the immune system to fight COVID-18.  After mature spike protein is created and put on the outside of the cell, it's used to train immune responses for different types of immunity. We refer to those as B cell and T cell immunity.

Our helper T cells really help both B cells and T cells learn an immune response. B cells are responsible for creating antibodies and then later stimulating cells to produce antibodies. Again, antibodies that go out bind the spike protein and prevent the virus from doing what it wants to do which is to bind H2 receptor on our human cells and cause disease. And then the T cell response can kill cells that are infected with SARS-CoV-2. Even if there's no virus outside the cell, even if the virus is inside the cell and antibodies can't really get to it, activated killer T cells can recognize cells infected with this virus and then go out and sacrifice them to save the surrounding cells.

These different subtypes of the immune response will become very important later when we're talking about the data that we have for immune responses.

(24:55):     The Johnson & Johnson and AstraZeneca vaccines use a modified adenovirus, instead of mRNA, to fight  COVID 19. The second major type of vaccines is the adenovirus vector vaccine. These are the Johnson & Johnson and the AstraZeneca and in this case, there's DNA that's encoding for the SARS-CoV-2 spike protein, again, with a spike protein, packaged inside an adenovirus. It's really important to recognize that this adenovirus is not infectious, it can really only inject spike protein DNA, it can't infect the cell, it can't make more adenovirus. This is not a replicating and not alive vaccine.

I counsel many, many, many of my immunocompromised patients don't get live vaccines, etc., etc. This does not count. This is safe for immunocompromised patients to get because this will not replicate.

This is a similar diagram of how adenovirus vector vaccines get inside the cell. In this case, the cell engulfs the adenovirus which has some receptors on it that allow it entry. The adenovirus here traveled to the nucleus and injects DNA into the nucleus where the cell converts DNA to mRNA and then the rest of the process is pretty similar to the mRNA vaccine. The mRNA is transported out of the nucleus. Cell machinery creates spike protein sub proteins which combine to form mature spike protein and then spike is displayed on the outside of the cell where it can train again B cells, activated killer T cells, and helper T cells to make a memory immune response.

(26:23):          Novavax is another vaccine for COVID 19.  The last type of vaccine we're going to talk about is the Novavax vaccine or protein subunit vaccine and this is essentially just like protein. Depending on how you think about it, this might be the most simple design of all. These are spike proteins that are connected by a nanoparticle to keep them stabilized. They're injected into your muscle and then cells recognize them, eat them up, chew them up, and again, present them on the outside of the cell to help train the immune system.

(26:55):    How effective are each of the COVID-19 vaccines? How well does the vaccine do against COVID-19? These numbers are continually evolving because many of the patients that were enrolled in the original clinical trials are still being followed and so their successes or failures against COVID-19 are still being recorded. You may see new numbers in the next coming weeks or months.

But here briefly, the vaccines that are authorized in the United States, you can see on the left the age of authorization. The Pfizer is the one that is authorized for 16- and 17-year-olds, the other two are authorized only for 18 and up. But the Pfizer and the Moderna have both been doing trials in younger patients including children and I believe are amassing their data to submit to the FDA that discusses safety and efficacy of these vaccines in younger patients down to 12 years old. That authorization may change in the coming again weeks to month.

The second thing to notice is that the Johnson & Johnson is only one dose and it's the only one of these vaccines to be only one dose. And then the third thing to notice right off the bat is to go all the way to the right side of the table and know that all of them have 100% efficacy against mortality which is something that's super powerful that is actually too good for us to hope for and that's really fantastic about the current vaccine that we have available.

Then I want you to focus on this middle column. Does it prevent any COVID? Because I think this is important. And this means does it prevent symptomatic COVID or any reason that someone would have been tested for COVID because that was one of the endpoints in all of these studies. And the thing that jumps out here is that the Johnson & Johnson is the lowball number here. I think that's unignorable.

(28:43):    Take the first available vaccine against COVID-19. There're several things about this number and I think these are important points. Most major societies, including the CDC, the NCCN, etc., all say, if you have a vaccine available, take that vaccine. Don't worry about the number here. I think that's right and I think there's additional things to think about.

What's important to remember is that none of these vaccines have been tested head-to-head. The Johnson & Johnson was tested a little bit later than these other two and were tested at more global sites and in sites where variants were circulating. That may be a reason for that number being lower that is important and it's important that it was tested in those areas.

But I think the other thing is that the number one protection for any person against getting COVID-19 is nobody giving them COVID-19. The way that we can make it so that nobody's actually transmitting COVID-19 is to as rapidly and completely vaccinate everyone as quickly as we possibly can in all of our more local and more global communities. We think a number of over 50% is good enough to do that as long as we can do it quickly and completely.

What I tell my patients is that if you have a choice, I agree that the mRNA vaccine may have higher immunogenicity and more likelihood of protection. But if that choosing an mRNA vaccine results in you getting your vaccine even a week later than you would have done if you chose the Johnson & Johnson, you should go ahead and choose an adenovirus vector vaccine because this is good enough and we need to get everybody vaccinated as rapidly and as completely as possible.

I meant to click that earlier so that question came up but that was the answer.

(30:37):    Are the current COVID-19 vaccines effective against the COVID-19 variants that are developing?  What about variants? Not all vaccines have been tested in people against all of the variants. There're two different types of experiments we can do to figure out how well the vaccines protect against variants.

One of the types of experiments is for people who have been vaccinated using all of these different types of vaccines, take the antibodies from their blood, and then test them against different variants and see how well or how poorly they do with different variants compared to the wild type or the "normal" circulating strains.

These data that I'm showing here are actually from when vaccines were tested in people in areas where variants were circulating. You can see for the B.1.1.7., the tested vaccines, it looked like protection was pretty similar for the Novavax and the AstraZeneca among areas where B.1.1.7 was circulating and that's borne out by these test tube studies as well.

The B.1.351 is where we get more concerned. You can see here that among people where the variants were circulating, there was generally a drop in efficacy of each of these different types of vaccines and the AstraZeneca had quite low efficacy against this variant.

The Pfizer vaccine has had a very small trial but showing very good efficacy. We'll have to make sure that that efficacy lasts as they continue to follow these patients. But overall, that Pfizer data is pretty hopeful that we may maintain efficacy even among the B.1.351.

And then the P.1 has a limited number of data to support whether there will be immune escape or not in people. We have a little bit of data from the J&J that was tested in an area with P.1 circulating virus although they didn't figure out which patients had P.1 versus other variants.

And then Moderna, we wait to see information. Again, all we have from the Moderna data is the test tube data.

(32:45):     How well do the COVID-19 vaccines work in stem cell transplant patients?   How well does vaccination work among stem cell recipients? Unfortunately, there were very few patients on immunosuppression enrolled in any vaccine trials. There were some patients who had cancer but they weren't on active therapy.

 (32:59): The potential concerns that we think about and that we must think about specific to stem cell recipients include safety of these vaccines in this population and then efficacy or how well these vaccines work in this population.

 (33:14): With respect to safety, anytime we think about introducing a new vaccine in patients who have immune problems which are many patients with stem cell transplants, that's when we start to think of theoretical risks of immune reactions. If the vaccine is very immunogenic, it elicits a strong immune response. Something we have to keep in the back of our mind and track when we start to see data are, are the rates of GVHD going up, for example. Are the rates of autoimmune disease going up in this patient population, for example?

 (33:47): And so far, these are theoretical risks. We haven't seen those reactions happen in a stem cell transplant population. Instead, other side effects are probably pretty similar to the general population. Actually, the most common side effect they don't have up here which is pain at the site of injection but headache, muscle pain, and fevers and chills are all very notable among patients getting the vaccine.

(34:14):     Side effects of COVID-19 vaccines: allergic reaction (anaphylaxis) and blood clots. There are long-term side effects being tracked by the CDC and the FDA. And so far two major side effects have been identified. The first are these cases of acute allergic reactions also called anaphylaxis identified in association with specifically the mRNA vaccine. They are quite rare, so two to five cases per million, but that's why after getting vaccinated, we sit around for 15 minutes. If you have a history of an acute allergic response, we sit around for 30 minutes to make sure that those will not occur after vaccination.

The other long-term side effect that has so far been identified by the CDC is the association of dangerous blood clots with the Johnson & Johnson vaccine. This has occurred in what we think currently are about six cases in seven million doses that are distributed. And the ACIP, the CDC, and the FDA are investigating these responses over the next couple of weeks to determine is that number correct, is it happening more frequently, less frequently, and figuring out what is happening with these reactions and so we can treat them, we can prepare for them, etc.

(35:25):     Were COVID-19 vaccines developed too quickly to be safe?  A question I get a lot is that the vaccines were produced very quickly, should I be worried that they haven't been tested enough? And honestly, this was a question that I worried about too, initially, because we were pushing, pushing, pushing to get these out. I've been very pleasantly surprised and very pleased, I guess it shouldn't have been surprised, that the transparency here has been fantastic. All of the data that the FDA see when they see whether they want to authorize this vaccine is data that I can Google very easily on my computer and see all of the 72 pages of FDA briefing documents about each of these vaccines that was presented in vaccine court.

In general, the red tape that was cut in order to produce these vaccines were all red tape associated with breaking barriers, making it easier to produce vaccines, and not safety regulations that were shortcutted or anything like that.

(36:19):    How effective are the COVID-19 vaccines for transplant patients and people on immunosuppressant drugs?  The next big topic is efficacy. We all know going into this that there's a lower likelihood that patients with a history of stem cell transplant or with a history of immunocompromised will respond to vaccines. That has been demonstrated with other vaccines. The way to get around that is that patients with recent stem cell transplants with recent immunosuppression may need to delay until a better time. This is really a conversation, and I advised that all my immunocompromised patients should talk about this directly with their physician, to figure out when is the optimal time to be vaccinated.

We have very early data after the second dose about immune responses among patients with hematologic malignancies showing about half of the antibody response in what we see in patients who are immune competent. We don't have good second dose data for any other immunocompromised population to date but that's something that we are waiting for.

Another strategy is that caregivers and family members should be immunized when they can be because, again, that's the number one thing that prevents our immunocompromised patients from getting sick is making sure that nobody transmits it to them.

(37:32):    Can antibody testing tell you how well you responded to the COVID-19 vaccine?. And then the last thing is, I get this question a lot, can you tell whether I've responded to the vaccine? Can you check my antibody? And the major societies including the NCCN, etc., say no, we actually don't know enough about those antibody responses for a number of reasons to say whether that's actually the right test to do and what you would do after you receive that result.

Some of the issues include, if I get a three, I know that's probably better than a zero and less good than a 20, but is that enough to provide protection? Is it not good enough to provide protection? If it's not good enough to provide protection, we do not have the vaccine supply or any data about boosters although that data will be coming to say whether I should get vaccinated again. It's really difficult to know what to do with that data and so currently, routinely, we are not doing it, although some transplant centers are or as a part of clinical trials.

And then, if patients have already had COVID-19, I still recommend that they get vaccinated. Again, if they're immunocompromised, we can't rely on that immune response to actually protect them against future episodes of COVID-19 and we have seen reinfection especially in the immunocompromised population.

(38:46):   Patients who are immunocompromised should continue masking, practicing social distancing and handwashing even after being vaccinated against COVIR-19. There's different information out there about what can I do once I'm vaccinated and I think the CDC released a lot of information that everybody was very excited about saying once you're fully vaccinated, you can gather indoors with other fully vaccinated people outside of your household without a mask, you can travel domestically, you don't need to quarantine if you've gotten exposed. You do need to mask in public and you do need to avoid multi household gathering so there's still some limits.

But what applies to immunocompromised patients? The NCCN unfortunately, says again the data on the effectiveness of these vaccines in cancer patients remains unknown. The CDC type of recommendations do not apply to our cancer patients, to our stem cell recipients, unfortunately, until we have more information. That means including still wearing masks around different households, maintaining social distancing, avoiding crowds or cluster busting, and that the family circle should be vaccinated as early as possible. Again, this concept of cocooning and we will get more information and we'll get more information on the use of boosters or revaccination. We just don't have it yet.

(39:56):   Summary: COVID-19 prevention, vaccination, precautions. To summarize what we just talked about, COVID-19 remains a major threat especially among immunocompromised patients. This is not over until it's over. It can result in life-threatening respiratory infection. We have to rely on prevention. It is the key to control and masking and distancing are the cornerstone and the tried and true methods especially against new variants that may not be as responsive to vaccines.

Vaccination is important but the efficacy is unclear among immunocompromised patients and contact should absolutely get vaccinated for that reason to protect everyone around them.

I want to thank everybody for listening and thank you for having us and we'll take questions when they're available.

(40:38): [Sue Stewart]     Q & A session.

Thank you, Dr. Stohs and Dr. Imlay. That was a great presentation. And yes, indeed, there are a lot of questions out there.

(40:46):         Transplant patients should wait until they are 3-months post-transplant before getting the COVID-19 vaccination.  I think the first question I'd like to ask is one that I hear frequently. Is there a difference in terms of efficacy of the vaccine and risk of getting the vaccine? If you're, say, five or 10 years out of transplant and off all immunosuppressants versus somebody that's just recently out of transplant.

(41:09): [Erica Stohs]  Yeah. Referring to the question is regarding difference in how long you are out from transplant and your response or efficacy, at the COVID moment, the NCCN or National Cancer Care Network is recommending that transplant recipients who are just three months or fewer out from their transplant wait on getting their vaccine. The earliest is three months after transplant before you should be getting vaccination.

How long after that is entirely dependent on likely your immunosuppression and underlying condition. If you're on a lot of immunosuppressive agents that are suppressing that B cell, T cell responses that Dr. Imlay was showing in those graphs, if your body doesn't have the ability to make antibodies, then you're likely not going to be making as effective of a response to the vaccine when you receive it.

As far as how many and then how long after transplant does it make you more and more likely to respond, we don't know the answers to that yet. We're just now starting to vaccinate the general public and transplant patients in general. So we'll know more as we go on. But very much, it's probably going to be a direct response of what your body's able to generate as far as your immune system. Are you making B cells and T cells? And are they working appropriately?

(42:46): [Sue Stewart] All right, thank you.

(42:48): We have a question here. Which type of vaccine is less likely to exacerbate graft versus host disease? The adenovirus or the mRNA virus?

(43:00):  [Hannah Imlay] Yeah, so good question.

I think the question is about this risk. Is eliciting an immune response going to stir up my GVHD or create GVHD if it wasn't there to begin with? We haven't seen any signals so far to know whether that's even going to happen much less which vaccine that that would happen with. We simply don't know.

But at the moment, all of those risks of stirring up GVHD or other hyperinflammatory responses to vaccination are really theoretical. They're what we are keeping in the back of our mind and watching the side effects to make sure in three months we can tell people, yes, this may happen, this may not happen, etc. We don't know that that will happen with immune responses to vaccine and we don't know if it will happen, which vaccine it may happen with.

(44:00): [Sue Stewart] Okay, the next question is about trust, I guess. The questioner wants to know, if there's a conflict of interest in the fact that Moderna and the NIH, which is a government agency, code patent for the COVID vaccine, can you trust that they are being honest in reporting their results?

(44:26): [Erica Stohs] Yes, I'll try to address that one.

I think it's key to understand that there are multiple bodies and doctors and scientists who are looking at the data from all of these vaccine trials. They have to be submitted to various groups along the process of becoming a vaccine. There's a data safety monitoring board who's going to be reviewing the data as it comes in from these different trials. It'll go to the members of the FDA who are reviewing data. If they see anything that is concerning or suspicious, they will not allow these trials or they will not approve these vaccines for use.

I would say that even if anyone there's a lot of skepticism out there and concern about that trust perhaps with different groups and what these companies may have relationships with, but I would say overall, this data is being looked at by so many different agencies and groups that if there's any concern that that would be discussed and it's been transparent so far so hopefully that would continue to be the case publicly.

(45:43): [Hannah Imlay] Just to hop on to that answer. Dr. Stohs and I both know one of the physicians on one of the committees responsible for reviewing these vaccines and there are many physicians that have nothing to do with the NIH that gained no financial benefit that are part of these groups that Dr. Stohs was referring to that are reviewing these data.

(46:04): [Sue Stewart] That's good to know. Thank you so much. All right. The next question is for patients taking Rituxan or rituximab, is there any data on how well the Moderna or Pfizer shots work at building a response?

(46:18): [Hannah Imlay] Yeah, so I can address this one. We do actually have a little bit of data here for rituximab. But even before we had data, this was a group of people we were especially concerned about. Rituximab directly interferes with the ability of B cells to simply exist much less to develop a memory immune response.

The data we currently have looks at antibodies. It actually is data among patients with autoimmune conditions that are taking it for autoimmune conditions but shows a substantially less ability of these patients to generate antibodies against SARS-CoV-2 after vaccination and that is after two doses of mRNA vaccination. Among fully vaccinated patients, we think that those patients probably have about 50 fold less antibody production than everybody else.

I want to say that there's a caveat here and that what we measured was the antibody response. As in the slides that we showed, we know that there are B cells and then there are also T cells and those T cell responses have not been well measured by currently existing studies simply because it's hard to do a T cell assay and it takes a lot of resources and is very finicky in terms of what you can do with the sample. We have to wait until looking at that data more closely.

The NCCN and other major societies do recommend for patients who are on biologic therapy that that needs to be taken into consideration so that includes rituximab, that needs to be taken into consideration for when is the best time to be vaccinated. And again, I would say cocooning is really our best bet here until we get more data.

(48:09): [Erica Stohs]  Cocooning is referring to vaccinating your family members and caregivers.

(48:14): [Sue Stewart] Thank you for that clarification. All right. The next question comes from someone who is having a little bit of difficulty with family masking. She is fully vaccinated but there are members of her family, not her immediate household, but members of her family who refuse masking and she wonders, given the fact that she's fully vaccinated, how risky is it for her to be around people who are not masking?

(48:46): [Erica Stohs] Yeah, so this is a very common occurrence across the country. I would say that there's a lot of factors in there that may be influencing her risk. It's hard for me to address all of that. But I would say first and it would be important that those family members that she's around who are not masking to know if they are vaccinated themselves, if they are fully vaccinated, she is fully vaccinated, that risk of needing a mask is going to go down. However, I don't know what her level of immunosuppression is to say how at risk she is and how well she responds to the vaccine.

I think there's just a lot of risk factors there that are involved. It's hard to answer that directly. But of course, it would be nice for family members she's around to be wearing masks and one preventive measure she can take even though she's fully vaccinated is to still wear a mask especially if she doesn't know where family members are vaccinated yet and how responsive everyone is to the vaccine.

(49:55): [Sue Stewart] All right. The next person wants to know whether flying or driving is a safer mode of transportation for a vaccinated immunocompromised patient if travel is necessary.

(50:09): [Hannah Imlay] Yeah, hard question. The question here is risk of travel among vaccinated immunocompromised patients. I will say that I think here it very much depends as Dr. Stohs talked about whether or people on airlines are still fully masking and if they're fully masking, the risk is much lower. However, as more and more people are being vaccinated, some of these things are being less well adhered to.

I would always say that if I have a patient who I'm not trusting their immune response to vaccine, I would still advise them to drive unfortunately rather than fly.

(50:55): [Sue Stewart] All right then. Next question is a person who has a monoclonal antibody treatment shortly after diagnosis with COVID-19, should they be tested again for COVID afterwards? And if so, how long afterwards?

(51:14): [Erica Stohs]

If someone's received monoclonal antibody treatment, my take would be that they tested positive for COVID-19 in order to have qualified to receive monoclonal antibodies. Therefore, there is no clear recommendation on needing to test again for COVID-19.

Now, there may be reasons that your individual providers want to check it and those could be many. But in general, that's not a requirement necessary to relook at your COVID-19 status after you've received monoclonal antibodies.

Now, in order to receive vaccination, if you have received monoclonal antibodies for COVID-19 in the past, right now, the CDC is recommending to wait 90 days after receipt of monoclonal antibodies to be vaccinated.

Hopefully, that answers all those questions.

(52:02): [Sue Stewart] Thank you. Next question. If you have a low CD4 count, how does that affect the vaccine?

(52:11): [Hannah Imlay] Yeah, that's a great question. The question is about the association between CD4 counts and vaccination and I think we don't have good data to address that question at the moment. We do think that CD4 cells are some of the cells that are most helpful in generating an immune response. Prior to knowing any data, I think we would all be concerned that lack of CD4 cells may inhibit a vaccine response. But we're still waiting for data to test whether can you actually look at cell subsets and predict someone's vaccine response to the COVID-19 vaccines.

(52:55): [Sue Stewart] All right. The next person said, "Admittedly, I'm a little spooked. I'm a senior and 11 months after transplant for myeloma. I made it through that and would hate to have a reaction to a vaccine. Is this rational?"

(53:10): [Erica Stohs] Yeah, I can address that. Everyone's hesitancy and concerns are born out of an important place and I think that that's not an unreasonable concern. But I would say that these are important conversations to have with your individual oncologists or providers. Should the fact that someone had myeloma and had their transplant at any time frame, like a year out or so, it shouldn't impact the vaccination.

If your provider is encouraging vaccination, my guess is that they're probably also going to be recommending additional vaccines that are part of routine health maintenance. Having that conversation with your oncologist I think would be helpful because if you're tolerating other vaccines or have seen that if you are a particularly allergic person who does have an allergic reaction, then I could see why that that would be a concern.

I would say take all of those concerns, write down why you're particularly nervous about it, and just have that conversation even if it's now's not the right time and you're just worried but will reconsider, that's an important thing, too. There may be a lot involved with if you're on any maintenance medications after your transplant that would impact your vaccine response and timing. I think again I would address with your oncologist.

(54:49): [Sue Stewart] The next person wants to know. She had the J&J vaccine. She wants to know if she needs to get a booster and if so, should they boost her via J&J booster or should she switch to Moderna or Pfizer?

(55:05): [Hannah Imlay] Yeah. Thank you for that question. The question is about J&J vaccines and it's about boosters. As I briefly mentioned during the presentation, the J&J vaccine is currently on hold so even if you wanted to get a J&J multiple rounds of vaccination, it's currently unavailable while some of these reports of blood clots are being more thoroughly investigated.

The second part of the question is about boosters and we simply don't know yet. We actually have no data about whether boostering is safe, boostering is effective, et cetera. That's certainly something people are going to be thinking about especially with the J&J which is that single dose vaccine. These are dated and these are questions that are going to hopefully start to become answered in the next weeks to months with research trials, but at the moment, the recommendation is not to get a booster vaccine after any type of vaccination.

(56:01): [Sue Stewart] Next question. Can oral chemotherapy make a person more susceptible to COVID? This person has been on Sprycel since her BMT 15 years ago. So far, she's been very careful during the last year not to go out and eat but she wonders if her susceptibility to COVID is higher than anybody else.

(56:25): [Erica Stohs] Yeah, I can take this one. All depends, I would say, on a lot of different things. First of all, what type of chemotherapy is this patient receiving and the timing of which she's receiving it because somebody who's just received the cytotoxic chemotherapy who has no white cells is going to be more susceptible to developing a severe COVID-19 illness potentially than someone who has not.

It would depend on what the timing of the chemotherapy, what the chemotherapy is. And then, as far as risk, everyone, there's the exposure risk of you being in contact with somebody with COVID-19 and so what's the risk of transmissibility to you. That has to do with taking those public health measures. And then the other is how risk of the severe course of COVID-19.

I think that particular question is probably important to discuss with oncologists or your local provider to understand the nuances of that. Yeah, I think that's probably where I leave that one.

(57:37): [Sue Stewart]

Okay. And then, unfortunately, we're at the end of time so I have time for one more question and several people have asked this particular question so I'll pose it to you. If you have only mild or no side effects after the Pfizer vaccine or the Moderna vaccine, does that mean that your immune protection is less than other people who get side effects and reactions?

(58:03): [Hannah Imlay] Yeah, thank you for this question. This is actually one of my favorite questions because I think much has been made of the immune response after the vaccine saying, "That's your immune system working. That's great." And then it leaves a lot of people feeling, "Well, actually, I didn't have that many side effects. Does that mean I'm not protected?" And the answer here is that there's no correlation. In the vaccine trials, when we watched people extremely carefully, many people had no symptoms and many people had no reaction. It was a notably high proportion that did have reactions but there were still very many people who didn't have reactions and yet, almost all of those people developed very good immune responses.

The answer here is that you can't really read into the immune response that... Or sorry, the side effects you had from a vaccine and make implications and make conclusions about your own immune response. Unfortunately, you can't go by that and also fortunately. Don't worry if you did not have much of a response.

(59:09): [Sue Stewart] I think you probably put the minds of many people at ease with that response.

And with that, unfortunately, we're going to need to close this session. I want to thank Dr. Imlay and Dr. Stohs for an excellent presentation and the audience for some excellent questions. We have so many more that we'd like to get to but can't. But hopefully, you now have a better understanding of COVID-19 and what you need to do in order to stay safe. So thank you, everyone, and have a great afternoon.