COVID-19: What Transplant Survivors Need to Know in 2022

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COVID-19: What Transplant Survivors Need to Know in 2022

Monday, May 2, 2022

Presenter: John Wingard MD, Director of the Blood and Marrow Transplant, and Cellular Therapy Program at UF Health Cancer Center

Presentation is 52 minutes long with 10 minutes of Q & A.

Summary: COVID-19 can cause serious illness and death. This presentation discusses the the most effective strategies to prevent a COVID infection, and the pros and cons of medications available to treat transplant recipients who do become infected.

Many thanks to Takeda Pharmaceutical Company whose support, in part, made this workshop possible.

Highlights:

• COVID-19 is a highly virulent and highly contagious type of coronavirus. Transplant patients may not have a higher risk of contracting COVID, but it is more likely to cause severe disease if they do.
• Using a combination of strategies to avoid a COVID-19 infection such as physically distancing yourself from people who may be infected, wearing a mask, frequent hand washing, congregating only outdoors or in areas with good ventilation, testing, quarantining if you are exposed to someone with COVID1-19 is the most effective way to avoid a serious case of COVID-19.
• COVID-19 vaccine can help prevent a serious case of COVID in cancer patients, but their immune responses may be somewhat lower than the general population.

Key Points:

(02:17): COVID is particularly serious for people undergoing a blood or marrow transplant.

(05:23): Knowledge of how to treat COVID is rapidly changing making treatment decisions difficult.

(16:38): Influenza and COVID both affect the upper respiratory tract and spread into the lungs. Only COVID affects taste and smell.

(19:52): A person’s genetic makeup can provide more or less protection from infectious threats.

(20:45): Health conditions like obesity, pregnancy, heart disease or chronic obstructive pulmonary disease (COPD) can make people more susceptible to infections like COVID

(22:43): Rather than being seasonal, COVID has come at us in waves. Some of these waves have been more contagious than the original COVID, but cause less severe disease.

(27:53): People who are on maintenance therapy after transplant or on immunosuppressive drugs to control graft-versus-host disease (GVHD) have higher risk of developing a serious case of COVID-19 if they become infected.

(44:13): Monoclonal antibodies will neutralize vaccine protection so an interval between receiving monoclonal antibodies and a COVID vaccination is recommended.

(45:45) For transplant patients who are unlikely to respond to a vaccine, Evusheld can help prevent severe COVID-19 infection.

(49:38): People who are on medications after transplant should check with their doctor about potential drug interactions between the medications and any COVID therapy they are being offered.

Transcript of Presentation:

(00:01): [Michelle Kosick] Introduction. Hello, my name is Michelle Kosick. Welcome to the workshop, "COVID-19: What Transplant Survivors Need to Know in 2022." I'd like to thank Takeda Pharmaceutical company whose support helped make this workshop possible.

(00:18): Please join me in welcoming our speaker, John Wingard. Dr. Wingard is a Professor of Medicine at the University of Florida College of Medicine and Director of the Blood and Marrow Transplant, and Cellular Therapy Program. He is currently a member of the American Society for Hematology and American Society for Transplantation and Cellular Therapy COVID vaccine task force, and he chairs the Center for International Blood and Marrow Transplant Research/Research Outcomes Task Force on COVID. Please join me in welcoming this incredible expert, Dr. Wingard.

(01:02): [John Wingard] COVID is a problem that has been with us too long and is constantly changing. Thank you, Michelle. And it is a pleasure and honor to spend the next hour with you. Unfortunately, it's not a pleasure to address the topic I was asked to speak to you about, COVID-19. This, unfortunately, is a subject that's been with us far too long, now going on to two years. One would think that we would now know everything we need to know about this, but regrettably, we do not. And there isn't a week or two that goes by without some new revelation or change in our understanding about this virus and the threat that it poses to us.

And so there's a lot of information that we have learned, some information that we have learned that was incorrect and new information that we're learning. But also, fortunately, there's new hope with new preventive measures and new treatment measures that will allow us to lessen this threat.

(02:17): COVID is particularly devastating for people undergoing a blood or marrow transplant. I think that the words of this hematologist in Colorado, really capsulizes very well my feelings of what I have experienced over the last two years in taking care of patients with hematologic malignancies and those undergoing bone marrow transplant. And this hematologist mused that, "I've lost count of how many patients I've lost to COVID-19. I've probably lost way more patients to COVID-19 that I have to actual cancer in the last two years."

Indeed, although COVID has, worldwide, been devastating to many individuals, we know that the risk to patients with blood cancers and particularly the patients who are undergoing blood and marrow transplant are particularly devastating. And so the next few minutes that we will be together, I would like to review with you some of what we've learned.

(03:29): The terms hematopoietic transplant (HCT), bone marrow transplant and peripheral blood stem cell transplant will be used interchangeably in this talk. First, a few words about the terminology. I am a hematopoietic cell transplanter, but of course, the reason that I use that term is that the older term, when I first started in this field, I was known as a bone marrow transplanter. But of course, the stem cells that we use to perform transplants today are more commonly obtained from the blood rather than the bone marrow, although the bone marrow is the origin of those stem cells. And so sometimes the term bone marrow or peripheral blood transplant, and often, stem cell transplant is used. And these are all interchangeable terms. But so that I don't confuse anyone, I'm using the term, HCT, since that's what, we, transplant professionals, refer to ourselves as what we do. But these terms can be used interchangeably.

(04:38): COVID-19 is an illness caused by the SARS-CoV-2 virus. Likewise, I will use the term COVID-19, but that is the same thing as COVID. And interestingly enough, we use the term COVID-19 or COVID to refer to the illness, but that illness is caused by a virus that's known as the SARS-CoV-2 virus. You've probably seen these terms in the news since it's been so widely discussed in the news media. But the SARS-CoV-2 virus is the virus that causes the COVID-19 illness. But for simplicity, I will just use the term COVID-19.

(05:23): Knowledge about how to treat COVID-19 is rapidly changing, which makes treatment decisions difficult. And then one other cautionary point is that this is a rapidly changing field of knowledge. Perhaps one of the most rapidly changes field of knowledge in the four decades that I have been practicing medicine. And oftentimes, this knowledge is communicated in the terms of news releases, not in peer reviewed publications in traditional medical journals.

(06:00): So I, as a physician, am often called upon to make decisions based on things that I have learned in a news release before that it gets released in a peer reviewed journal. It is so vitally important that we keep up to abreast with these new things, because many of the treatments and preventive measures are released even before they are FDA-approved through emergency release programs. And for us to provide optimal care, we often have to do this, and it is a little bit nerve wracking for me as a health professional, because I'm trying to convey information as carefully as I can. But at the same time, I do not have the traditional ways of looking at the data myself, making a judgment as to that, and also to see the data as reviewed by experts in the area to get their comments on the pros and cons of the new information being provided.

(07:20): And so some of these reports are very preliminary and the insights and recommendations change at a very rapid pace. Things that we learn today, oftentimes, are out of date, or they have changed in a week or two, maybe a month. And we have brought in patients for preventive measures and have taken those only to have to call upon them a month later and say,’ look, the dose that was recommended last month has changed and we need for you to come back to get a second dose of the medication or additional things’. Or ‘I know we told you, this is how many vaccines that you needed, but today, the information tells us that we need to do something very different’.

(08:13): So regrettably, some of the things that I mentioned today I do believe they may be out of date in a few weeks or a month or so. And that is, unfortunately, something that we have to live with. As honestly as we try to make recommendations and provide authoritative advice, we have to be cognizant that this is a changing field that we are dealing with.

(08:45): Five questions about COVID-19 will be addressed in this talk. When I was asked to give this talk, I asked Sue, what did I think were the most salient questions that the audience would like to hear? And she came up with five questions. The first is, how does COVID-19 compare or differ from other viruses like the annual flu? The second is, do transplant recipients have a higher risk of developing COVID infection? Do transplant recipients have a higher risk of developing a severe case of COVID and/or death? What precautions can a transplant recipient take to minimize the risk of a severe infection? And that would also ask who should be vaccinated and when? Is one vaccine better for transplant recipients than another, and what are the currently available treatments for COVID and what's in the pipeline? I will try to address these five questions in my presentation.

(09:56): COVID-10 is one of almost two dozen respiratory viruses, and they all have very similar symptoms. Question number one, how does COVID-19 compare or differ from other viruses like the annual flu? Well, the first point I would make is that when my patients say, Doc, I got the flu two weeks ago. I think to myself, well, that may or may not have been the flu, meaning influenza.  There are almost two dozen respiratory viruses and they all have very similar symptoms and it is very difficult to distinguish one infection versus another. And that may have been the flu, but it may have been one of those other, nearly two dozen viruses. And in fact, when a patient tells me, 'well, I don't get the flu vaccine because I've gotten it in the past and it never works. I always get the flu', I have a little twinge of regret because most of those infections that were thought to be influenza, unless there was a specific test to distinguish what that virus that was, probably weren't influenza. And that vaccine may or may not have been a failure because the infection that they became ill with may or may not have been influenza.

(11:40): Most coronaviruses are not as severe as influenza. Now, coronavirus is one of those nearly two dozen viral infections that we, in the human population, have been susceptible [to] for many, many generations. And in fact, most of the coronaviruses that cause human infection are what I call wimpy viruses. They are not nearly as severe, generally, as influenza, for example. And when I have a patient who has a respiratory syndrome and I do the testing to try to find out what viral infection that is, when I see a coronavirus, I say, well, that's good because that virus is generally associated with a much milder clinical course, fewer complications, less severe than a number of the other respiratory viruses that I worry about.

(12:50): Some respiratory viruses, such as influenza, can be exchanged between animals and humans. Ironically, that is the family of viruses in which COVID is a member. And it's important to also remember that coronavirus, as well as the other respiratory viruses, infect animals as well as humans. And in fact, sometimes these viruses are exchanged between animals and humans. That's been best studied with influenza. Everyone's heard of swine flu or bird flu. And it's because those organisms, they are often in many animal populations, and they can spread to humans through human contact. And that is often how they in fact human populations.

(13:50): All viruses, not just COVID, can mutate into more or less virulent variations. A third important point about these respiratory viruses is that there are genetic variations in all of these viruses. and they have mutations and they evolve into either more or less virulent mutant variants. It's in all of the viruses, not just coronavirus, it's not a unique capability of COVID. It is true of all of these. And in fact, that's the reason, for influenza, that every year they have to change the makeup of the vaccine. It is because that the influenza strains that circulate in a given year are often not the strains that are circulating the following year. And so you constantly have to keep running after these in order to develop effective prevention strategies. And the coronaviruses have been with us for a very long time. And as I mentioned, they mostly cause very mild illness.

(15:04): Two previous coronaviruses, SARS and MERS, caused serious illness, but were not as contagious as COVID. Some of you may recall that COVID is not the first highly virulent coronavirus. And in fact, there are two that got notable notoriety and one was SARS virus and another was MERS. SARS occurred in East Asia, and then it spread to an outbreak in Canada a number of years ago. Most people that got infected died from that. It was a very serious infection. Fortunately, it was not as contagious.

(15:48): And MERS likewise infected the populations in the Mid East. And that tended to go away after a while because it lacked the same contagiousness that COVID has. And this is the same point I was just making: this is not the first variant to cause serious illness. Unfortunately, this is particularly nasty because of, not only for its risk for deadly harm, but because of being highly contagious. It combined both attributes of a very bad actor in something that has wreaked havoc among the human population.

(16:38): Influenza and COVID both affect the upper respiratory tract and spread into the lungs. Only COVID affects taste and smell. Okay. So what are some of the other comparisons that one could make between COVID and the other respiratory viruses? Well, these all tend to infect us in the upper respiratory tract, and it then spreads down into the lower respiratory tract and into the lungs. The one slight difference between influenza and COVID is the effect on the nasal passages. Local infection occurs with both viruses. Influenza is readily isolated from the nasal passages. In fact, that's one of the most readily accessible area to isolate the organism. But interestingly enough, it does not seem to cause the loss of taste and smell that is more characteristic of COVID, in comparison with influenza. But they both affect the respiratory passages and they both affect the lower lungs and lower airways in the lungs as well.

(17:55): Both influenza and COVID have global impact and significant death rates. Both influenza and COVID have global impact. I've listed on the left side. Every year from the World Health Organization, three to 5 million people develop severe influenza infections. And it's estimated somewhere between 290,000 and 650,000 deaths each year from influenza. With COVID now reaching two years, it's estimated that, this was in March when I made this slide, over 450 million cases. And it's widely believed this is a very low underestimate of the number of cases. And the death rate has been over 6 million, and again, way under count. In the daily, it was at that point 3,500 deaths per day.

(19:00): Now, in terms of the impact of COVID in the United States, influenza, there's roughly 33 million cases each year, 16 and a half million medical visits, nearly half a million hospitalizations and 35,000 deaths. That was an estimate in 2018- 2019 that winter season. And it varies anywhere from 10 to 50,000 deaths per year, each year when you look at this over a longer span of time. In contrast with COVID, there were 81 million cases over the two year period and approaching 1 million deaths during that two year span.

(19:52): Our personal genetic makeup may provide more or less protection from infectious threats. So there are a number of similarities. If you look at the risk factors for influenza severe disease, you can see here listed, smoking, and genetics. There are multiple variations in our genetic makeup. That is what makes us individually different. And some of those so-called gene polymorphisms, they confer differences. They either provide more protection, and in some cases, less protection against certain infectious threats. And that's certainly been found true for influenza. It's been found true for many bacterial fungal and viral infections. And that is true for influenza.

 . Some co-morbid conditions such as concomitant heart disease or chronic obstructive pulmonary disease, certainly make one more susceptible. Pregnancy, certainly more susceptible. Obesity and older age are certainly risk factors. And you can see I've put stars at the top of these columns. Those three stars all are very similar to the situation with COVID.

COVID has a propensity for causing more severe disease in males, certainly with older individuals and those with obesity. There are clearly genetic makeup differences among us that make some of us more susceptible than others. Certainly, there are a number of co-morbid conditions. You all have learned these, we all have learned these, diabetes, chronic kidney disease, heart disease, hypertension, respiratory illnesses. There are variety of risk factors that co-morbid conditions confer to us.

(22:04): Most respiratory infections are seasonal. That's certainly true for the nearly two dozen respiratory viruses. There's one respiratory virus that doesn't follow that pattern. Although influenza does, parainfluenza, it's first cousin, we see this year round. But most of these occur in cold weather months. So in the autumn, we begin to start seeing influenza and the other respiratory viruses and they go through the spring.

(22:43): Rather than being seasonal, like most viruses, COVID has come at us in waves. In contrast, unlike endemic coronavirus, the coronavirus strains that we have lived with for generations, pandemic COVID-19 variant of coronavirus comes at us in waves. And this is in the state of Florida. So these were three surges that we experienced in 2020 and 2021, which you can see each of the surges has higher peaks, broader area under the curve of these. What I didn't show you is in January 2022; we had our worst peak that dwarf 2020 and 2021. It was far worse. And that has only abated in the last six to eight weeks where there's been a tremendous down swing in our state as in many other states as well.

(23:54): Some variants of COVID-19 are more contagious than the original COVID, but result in a less severe infection. That's a big difference. COVID just keeps coming at us. It comes at us in waves as there are variants that newly come on the scene. We had Alpha, Delta and Omicron, a whole host of variants that keep arising. And some seem to be much more contagious, although others seem to be associated with less severe infection. Some variants have been both, highly contagious and highly variable.

(24:32): And of course, none of us know what the future holds, but we're beginning to be hopeful as more and more people have either become infected or suitably vaccinated, to reduce the spread of this pathogen through our population. And so hopefully, we are getting to a different phase of this. But you can see that this comes at us in waves, and that's very different than most of the endemic respiratory viruses that we have had for quite a long time.

(25:13): For transplant patients, the risk of getting infected by COVID-19 is probably not higher than the general public.  The second question that Susan thought you would be interested in is whether or not transplant recipients have a higher risk of developing COVID infection. Now, we've seen a lot more transplant patients die from COVID infection, but probably the risk of getting the infection is not any higher. But what happens after the patient is infected is clearly very different. It's more likely to cause severe disease. And the reason why it may seem that a higher percentage of BMT patients get COVID is that we typically don't get tested until we get sick. And so if you have an infection that's not symptomatic, you're less likely to get infection. So there's, what's we call an ascertain bias. Since more people are getting sick, we do more tests, we discover more cases, and it looks like a higher percent. But it's really because they're getting sicker and being tested more. And so I think that probably the infection rate is not higher and there's not been any study that's just looked at prevalence of infections in both asymptomatic and symptomatic. That would be the way to really find out for sure.

(26:47): Transplant patients and those with a blood cancer have a much higher risk of getting a severe case of COVID-19 than the general population. But clearly, the third question is, do transplant recipients have a higher risk of developing a severe case and/or death? And the answer that we have very good data on, the answer unfortunately is yes. If you look at death rate from COVID in patients with blood cancer, it's all patients with blood cancers, whether they got a transplant or not, it is clearly much higher than in the general population. This is one series, but other series shows similar rates of 17%. And that would be compared with the general population of 1.2%. And if you look at death rates from COVID in transplant recipients, during the first year, it's even higher, 22%. But interestingly enough, after the first year, it's a bit lower, but still higher than that in the general population.

(27:53): People who had an autologous transplant (transplant using their own cells) may have an ongoing increased risk of a contracting a serious case of COVID-19 if they are on maintenance therapy after transplant. Similarly, with auto transplants, the rate is lower than during the first year after an allogeneic transplant, but it is higher than in the general population. It becomes more complicated as to the role of the transplant itself because in many auto transplant patients, particularly those transplanted for myeloma, those transplanted for Hodgkin's disease, there is ongoing therapy after the transplant, and that plays a role in the effect of COVID on that individual's risk of having a serious infection as well. And we know that there are several risk factors associated with transplant. The more recent the transplant took place to where you are today, that plays a role. In other words, the longer you are awhile from transplant, the lower the risk is, and the more likely your risk will approach that of the general population.

(29:06): Being on immunosuppressive therapy, such as steroids to treat GVHD, may increase the risk of acquiring a serious COVID-19 infection.  But it's a complicated question because some of the patients who receive transplant continue to be on maintenance therapy after an auto transplant. And for allogeneic transplants, many of the patients are still receiving immunosuppressive therapy to suppress or treat graft-versus-host disease. And at least in the early studies, it looked like being on active immunosuppressive therapy was a greater hazard than the occurrence of graft-versus-host disease. But those were early reports. And I suspect over time, we'll learn more about this. And we will find, as we have found with all the other respiratory viral infections. And many of the other infectious pathogens after transplant, that it is associated with chronic or ongoing graft-versus-host disease.

(30:06): Multiple, overlapping precautions are the best way to minimize risk of acquiring COVID. So given that these are substantive problems in the transplant recipient, the fourth question that I was asked to address is, what precautions can a transplant recipient take to minimize the risk of a severe COVID infection? Well, as with most things in life, an ounce of prevention is more than a pound of cure. And I think that prevention is clearly an important facet to reducing the risk of serious, bad things happening to one after a transplant. And I think the way to view prevention was capsulized in this cartoon in the New York Times in 2020, better than anything else that I have seen. And what they have represented in this cartoon is that there are some things that you, as an individual, can do on your own, you don't need help from anyone else.

And then there's a set of things that we as a community can do. These are shared responsibilities, and each slice of this Swiss cheese represents either a personal or shared action that one can take. And if you start on the left side and those little green, not the usual red color to coronavirus, but those little green spiky things, those are the viruses. And each slice is the depiction of a slice of Swiss cheese with their characteristic holes. And as you can see, and I think that red arrow depicts that if you take one action, there's a sizable number of those particles that are going to get through that first slice. But behind that slice is another slice of the cheese and those holes, some of the holes are still lined up, but others are in different locations.

(32:30): Physical distancing, masking, hand hygiene, and limiting the time you are exposed to people with COVID are highly effective steps individuals can take to minimize their risk of a COVID infection. And so a particle that gets through the slice, some of those are going to get blocked by that second one. And yet still some will get through and you have a third set of holes in the third slice. And again, that will block some of the virus and not others. And you can go on and on. So one of the interesting things, if you just look at each one of these actions, you can look at, first is that physical distance. That's a good idea. And what was shown in the influenza epidemic in 1917, 1918 is that, if you just had cities stop congregating and having meetings and so forth, that actually was beneficial in reducing infection rates. And then if you have people wearing masks, particularly high efficiency masks, that's going to block something. But neither of these is foolproof. If you then add hand hygiene, because oftentimes, these environmental surfaces will harbor viable viruses, and where do we put our hands? We're always putting our hands on our face, our lips, our noses. And so we often contaminate ourselves, but if we use proper hand... Then we can look at limit your time. If you have to be in a space where there are lots of other people, limit your time there so you reduce your exposure to others that may have the virus.

(34:28): Improving ventilation in buildings, offering COVID testing, quarantining people who are infected with COVID, and vaccination can reduce the risk of developing a COVID infection. Then we start moving into some shared responsibilities. If we have good ventilation systems in our buildings, if we look at fast testing and quarantining, those are important measurements. If we get good messaging from our government and financial support to mitigate harm to individuals so that an individual is not faced with, well, if I don't go to work, I'm not going to get paid. But if I go to work and I'm infected, I could expose somebody else and cause harm. And if we can reduce those disincentives from doing the right thing, that could be useful. And then if you're unlucky to get infected, but you then go into quarantine and isolation, you can reduce spread to others. And then finally, the final piece of the Swiss cheese is the vaccine. And certainly, not one of these issues will be the most effective, but it is a combination of things that need to be looked at.

(35:51): There are now three FDA-approved vaccines for COVID. All have good safety records, but the J&J vaccine, in rare cases, can cause a serious clotting disorder. And so there are three vaccines that have been approved. Two are messenger RNAs. One is an adenovirus, the J&J vaccine. It's important to remember that none of these are live vaccines, all have some side effects. They tend to be generally mild. And there have been huge, enormous safety records in large and rigorous trials. Except with J&J, there is a rare but serious clotting disorder that has been discovered.

(36:23): An important point about the messenger RNAs, although this is stated to be a new technology, there's been decades of developmental work on this and what this vaccine does, it gives the message, a small snippet of RNA. RNA is something that is part of our cellular machinery. We have DNA in the nucleus. It makes a message to make a protein in the cell. This is normal human physiology. And that goes to ribosomes, that then construct the translation of the genetic message into a protein. And that's exactly what this messenger RNA.

(37:09): Messenger RNA vaccines, such as the Pfizer and Moderna vaccines, do not affect a person’s DNA and are safe and effective. It's important to note that our cells, each cell makes thousands of messages every day. And the life expectancy of that messenger RNA is from a few hours until a day at most. And it gets destroyed within the cell. But before it's destroyed, it makes that protein, known as the spike protein. And that protein goes to the surface and it gives a powerful message to the rest of the body. 'Hey, this cell is infected'. It's not really infected, but it sends a message because of the expression of that protein, that this is infected. Important to note that the messenger RNA is broken down, it never integrates into the DNA as no other messenger RNA does either. And so this is a very safe and effective technology. Those spiked proteins then allow the rest of your immune system, that's circulating in your blood to start making antibodies and to make cellular immunity.

(38:27): The current COVID vaccines provide 90% protection against serious COVID illness. Even if you had a previous COVID infection, the vaccines provide additional protection. So how good are the vaccines in the general population? They provide greater than 90% protection against serious illness. Now, it's important to remember that there are some breakthrough infections, but they tend to be asymptomatic or mild. Those breakthrough infections tend to occur at the surface of the respiratory lining, that is in the nasal passages, in the throat, in the upper airways. And the reason is that immunity that the vaccine causes affects the blood cells that make the antibody and the cellular immune protection. But those stay in your blood and protect your internal organs. They don't get to the surface of your nose very well. And that's why there are some breakthrough infections. It's not a failure, it's just, that's the way these vaccines work. So these vaccines are more effective than many of the vaccines that we employ elsewhere. And in particular, the vaccines in the United States are more effective than other countries' vaccines, particularly in China. And even though you've had a prior infection, these vaccines offer added protection.

(39:55): For cancer patients, although the vaccines work, the response rate is somewhat lower, particularly for patients who have lymphoma or chronic lymphocytic leukemia (CLL), and those on ibrutinib or rituximab. Unfortunately, the J&J vaccine has a lower rate of protection than other messenger RNA variants and it also provides protection against different variants. But this is not a big issue because the messenger RNA vaccines provide pretty good protection against Omicron and other variants, at least so far. But over time that immunity wanes. And so that's why there's been a push to get boosters when you have been more than four months out after the vaccine. Unfortunately, for cancer patients, although the vaccines work, their responses are somewhat lower. And one study showed that about 25% of patients failed to mount an antibody response after the second dose of vaccine. And those are particularly true for individuals who have lymphoma or chronic lymphocytic leukemia. And there are certain cancer drugs such as ibrutinib, rituximab that can block antibody responses. There are many others too. I didn't list all these because, unfortunately, these have not been well studied and this information is changing over time.

(41:21): Vaccination too soon after transplant may not produce a strong immune response. And small studies showed that 43% who did not respond to two vaccine doses, did respond to a third vaccine. And several studies in patients who underwent transplant showed reasonably good responses if they were first vaccinated more than a year. But early after transplant, the responses are not quite as good. And so after many discussions with the CDC in February 2022, the CDC agreed to revise their vaccination for transplant patients to include four vaccine doses for the Pfizer and Moderna and three for the Johnson vaccine. And you can see that this is sort of the schedule, the first three doses at a month interval, and the fourth dose about three months after the second.

(42:27): A shorter interval between the original vaccine and boosters may benefit transplant recipients. And what has been advised is that there should be a shorter interval before you get the booster, after the initial vaccine series. And that for certain subgroups. And the HCT group is that, even though you've been vaccinated before you had the transplant, you should undergo the full vaccine schedule after transplant. And some discretion was given into the clinical decision making because the situation will vary according to the situation, particularly if you're getting additional immunosuppressant therapy or chemotherapy. The rationale behind this is because, again, high community transmission, loss of protection over time, and also the fact that two doses just did not provide adequate immunity in transplant recipients.

(43:37): And I'm going to pass over this for time. And it's important to recognize that the peak response to a vaccine occurs about 10 to 14 days after the vaccine. [The reason that] this is important Is that because oncologists and transplanters often will recommend suspension of certain treatments for about two weeks after the vaccine in order to give your immunity its best opportunity to respond to the medication.

(44:13): Monoclonal antibodies reduce your ability to respond to vaccines. The other important point is if that you're given a monoclonal antibody, that will neutralize the vaccine and will thwart your ability to respond. And so an interval is generally recommended before you get the vaccine if you are given a monoclonal antibody. And further, it often calls upon your transplanter or oncologist to weigh the decision about, should one avoid certain drugs that could suppress immune responses so that you optimize the chance the person will respond?

(44:57): Rely on your doctor and good authoritative sources of information about the risk of COVID and vaccines for transplant recipients. Now, there are good authoritative sources of information to get advice about this. And these are being updated. There's a lot of information on the web that is not authoritative, and quite frankly, misleading but there are several sources. One that is specific for transplant recipients is by the American Society of Hematology and the American Society of Transplant and Cellular Therapy. And these are generally updated. I've provided you here with the website link. This is periodically updated, and I would recommend that you keep an eye on this.

(45:45) For transplant patients who are unlikely to respond to a vaccine, Evusheld can help prevent severe COVID infection. Well, what about if you find that your immunity is so suppressed that you're not likely to respond to the vaccine? And that's the situation very early after transplant [where] you may find yourself. And there is a monoclonal antibody. It is a combination of two antibodies. I'm not going to try to pronounce the names of these, but it is simpler to know the brand name is called Evusheld. And this is a monoclonal antibody approved for pre-exposure prevention. It has very good activity against the Omicron variant. It's been tested in patients with moderate to severe immunodeficiency. And it was found to reduce symptomatic COVID by 77% with protection lasting as long as six months. And so this is particularly useful early after the transplant where one might not be expected to respond to the COVID vaccine. And this is widely used and is also useful for a patient getting active immunosuppressive therapy either for the treatment of acute leukemia or the treatment of chronic graft-versus-host disease.

(47:09): Now, when we first had pandemic, we didn't have any treatments available. If one developed [COVID], we just had to hope for the best. But now, there are three classes of treatments that are highly effective. One is drugs that work against the viruses. A second group is an anti-inflammatory drug, like steroids, given in low doses or even some other immunosuppressive drugs. And then there are monoclonal antibodies. There are some therapies that work for some variants, but not so good against Omicron. And some have been studied only in moderate to severe infections.

(47:58): If you become ill with COVID, monitor your oxygen level using a pulse oximeter, that can purchased at a drug store, and go to the hospital if your oxygen level falls below 90. And it's important to know, if you become ill with COVID to monitor yourself and the oxygen level through a pulse oximeter that you put on your finger, which you can buy at a drugstore. It Is a very handy thing to have. If your oxygen level falls below 90, you need to get to a hospital.

(48:21): And it is crucial that you start therapy very early. And some of these treatments are [given] intravenously. Some of the newer drugs are oral, but they are still in short supply and they may have potentially serious drug interactions. There's one in particular that is particularly effective, and it is very promising and is now becoming more widely available. And again, this is a combination of two antiviral drugs, but it's known as Paxlovid. It's made by Pfizer.

(48:58): There's another combination by Merck that is a little bit less effective, but these are for patients, and it was studied with moderate to severe disease in individuals not vaccinated. And they had to be treated within five days after onset. And this reduced the risk of hospitalization or death from 6% in these moderate to severe individuals to 0.7. That has dropped very low. It's a relative risk reduction of 88%.

 (49:38): Be cautious about drug interactions if you are offered treatment for COVID.  Ask your doctor whether the treatment is safe and effective for you. But there are important drug interactions. You will have seen at these "test to treat” sites. There are 20,000 that have been set up where you get your test, and they will give you the drug at the same point. But if you are on medications, it's important to find out if there are important drug interactions so that you don't make the situation worse. And so it's crucial to check with your local physician unless they provide you with counseling at the testing site.

(50:17): And so it's important, if you get infected, that you contact your physician as early as possible, because early is crucial. And the treatment keeps changing. Every two weeks, I get a new set of instructions from my hospital of what the current preferred treatment is. And in part, it changes depending on the variants that we are facing. In part, it varies according to supply of the drugs we have available. And so it's a good idea to contact your physician or transplant team if you develop infection, and don't just shake this off. Do it as early as possible because sometimes these drugs or treatments are in short supply, and it takes some time to identify a source for these.

(51:11): There are additional sources of authoritative COVID information people can consult. Now, there are also other sources of authoritative COVID information. I have listed these here for your use. And please, avail yourself of these because, again, these do change over time, and I think that it is important that you be mindful of these potential changes. With that, I will open up the questions for the remaining time. Thank you.

Question and Answer Session

(51:46): [Michelle Kosick] Dr. Wingard, what an incredible and informative presentation. There is a plethora of questions around this, and we're going to do our best to get to as many as we can. There's a lot of questions that you actually answered, but we're going to go ahead and get started.

(52:11): Would you advise a patient who had childhood chickenpox and now has a low lymphocyte count to receive prophylactic acyclovir prior to receiving their first COVID-19 vaccine? There have been reports that COVID-19 vaccination can temporarily decrease the lymphocyte count and that can trigger shingles. Is there a certain CD4 count you would want or that you would be concerned with?

(52:39): [Dr. John Wingard] Well, so we like to see the CD4 count to be 200 or above. That was a lesson that I learned in HIV many years ago. And that is a general guide, that, if it's below that, you are perhaps more susceptible. I'm not aware of any data that would suggest that, in fact, treating with acyclovir would increase the CD4 count and make your response to vaccination better or worse. I frankly don't know. I'm not aware of any data to that. That's an interesting comment though.

(53:26): [Michelle Kosick] Thank you. The next question is, what is your opinion about a transplant survivor, who has been vaccinated, being around a person who has chosen not to be vaccinated? Is there more of a chance for me catching it versus being around someone who has been vaccinated?

(53:45): [Dr. John Wingard] Okay. Again, there are nice studies that if you have two individuals that are wearing masks, it reduces your risk when compared with one person wearing a mask and another person not wearing a mask. This question frequently comes up with my patients who say, I want to go to this family reunion or my mother's 90th birthday. I know there are going to be family members who are not vaccinated. What's my advice? Unfortunately, one cannot say with an assurance that there is no risk.

(54:25): Unfortunately, we don't live in a risk-free world, but I would recommend that they have to weigh for themselves the value of that encounter with folks that are not vaccinated. And if you choose to be in gatherings with other folks who might not be masked, being outdoors, and certainly have - I think, one of the questions is, I've had my three vaccines, well, now it should be four vaccines - be fully vaccinated, wear a mask, try to be outdoors. If you think about that Swiss cheese example, try to have as many of those preventive measures in place as possible to reduce your risk. None of us can reduce our risk to zero, unfortunately.

(55:21): [Michelle Kosick] So true. And unfortunately true, right? Another question is, if my donor was fully vaccinated or already had COVID, would I get some protection from his or her stem cells?

(55:33): [Dr. John Wingard] Great question. There are some data that suggest that you can, that the donor immunity is conferred, at least for a time, to the recipient. This, to my knowledge, has not been studied with COVID, this has been studied with some other viral infections where we could detect some immunity transmitted and also allowed the recipient's responses to vaccines to be a bit better. These are very small studies, and we don't really know for sure. It has been recommended that we do not recommend that the donors get vaccinated in order to confer the immunity to the recipient because we don't know.

(56:30): [Michelle Kosick] Thank you. Can you get a booster after getting Evusheld? It would be my fourth vaccine.

(56:37): [Dr. John Wingard] Yes, we do recommend. The first priority is to get your vaccination. But we don't recommend starting the COVID vaccination until at least three months after the transplant. And even that may be a bit early. There's an ongoing study with the BMT CTN that is looking at whether three months is as good as six months. None of us really know for sure. The early data suggested the earlier you give a vaccine compared to the transplant, that the response rate may be lower. I have seen some preliminary data, but it hasn't been fully vetted yet, that suggests that the vaccine responses at three months may be as good as at six months. But I think we need more information about that.

(57:30): But what we are doing is recommending the Evusheld early after transplant. And then, because we know prior to three months, this will give you protection during that first three months before you can get the vaccination. You can then go ahead and get the COVID vaccination when you're at least a month out after the Evusheld, although the CDC has now, I think, remove that wait. But I think that we haven't seen any data to support that recommendation. So I'm a little skeptical that that should be done, personally.

(58:15): [Michelle Kosick] The next question is, is vaccination protection stronger the further time I'm away from my transplant date?

(58:27): [Dr. John Wingard] If what that question is intended to mean, if I get the vaccination say two years after the transplant, rather than one year, yes. Higher likelihood of getting a good, strong response.

(58:42): [Michelle Kosick] I'm a four- year AML transplant survivor. Despite two boosters. I was just asked and got an injection of monoclonal antibodies. What will this do? Is it standard practice now? I read only for two year survivors.

(59:00): [Dr. John Wingard] I'm not sure I understand that question. If the patient has chronic GVHD, we are recommending that they get Evusheld. To interrupt the vaccine schedule, get Evusheld to get protection. Then we wait in our center four weeks and then resume the vaccine schedule. And that's how we are doing it. The effects of Evusheld wear off after a few months, but this will buy crucial time, particularly, when there's a lot of virus circulating in the general population. But the monoclonal is not a replacement for the vaccine. It just buys you a safe period of time where you're not likely to respond to the vaccine.

(59:59): [Michelle Kosick] Would wearing two masks, a K95 and a KN95, prevents you from catching COVID at an event where there are some non-vaccinated people?

(01:00:11): [Dr. John Wingard] No, it'll be hard to breathe if you wear two N95s. What is generally done in the hospital is you put your N95 mask on, and then you put a surgical mask on top of that. The surgical mask protects you from droplets. And that preserves the longevity of that N95. That's what's done in the hospital environment.

(01:00:44): [Michelle Kosick] Perfect. Can COVID vaccine exacerbate GVHD?

(01:00:51): [Dr. John Wingard] Well, we don't know. There's no data that we know of that would say that. There has been a concern about that because we know certain viral infections can precipitate or exacerbate graft-versus-host disease. So there's always been a concern about vaccines. For example, the Shingrix vaccine that was tested in auto transplants, not tested yet in allogeneic transplant. And it's been slow uptake in the allogeneic recipient population because some individuals have had a concern about that. I shared that concern. Although now, we have several years under our belt, and nothing has emerged. And so I'm more freely giving that vaccine. But it's not a trivial concern. But to date, there is nothing that has been reported in terms of exacerbating that. It's more of a theoretical concern. The threat from dying from COVID is much greater than the small, but real, theoretical risk in my view.

(01:02:03): [Michelle Kosick] And our final question of this session is, what are the side effects of Evusheld and how long does its protection last?

(01:02:13): [Dr. John Wingard] Evusheld, it's two injections in the butt, and it can be sore. So you could have some potential bleeding or soreness in the gluteal areas. If your platelets were low, sometimes we transfuse patients to minimize the risk of bleeding. The major risk is allergic reactions. That requires us to keep individuals who get it for about an hour for observation. Those are the major side effects. There has been some report of potentially cardiac arrhythmias. Although whether that was in individuals who had cardiac arrhythmias and whether or not that was related to the antibody or not, is not clear.

(01:03:14): [Michelle Kosick] Closing. What an honor to moderate your session Dr. Wingard. You have shared such important information with our audience. Thank you to our participants for your excellent questions. On behalf of BMT implement and our partners, I want to thank all of you. Please contact BMT InfoNet, if we can help you in any way.