COVID-19: Precautions, Vaccines and Treatments for Transplant Recipients

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COVID-19: Precautions, Vaccines, and Treatments for Transplant Recipients

Tuesday, November 9. 2021

Presenters: Alyssa R. Letourneau MD, MPH and Areej El-Jawahri MD

Presentation is 32 minutes with 27 minutes of Q & A.

Support provided for this webinar, in part, by Incyte.

Summary: There are several safe and effective vaccines for COVID-19. These vaccines are recommended for transplant patients in most circumstances. This presentation reviews guidelines, offers recommendations, and answers questions about the benefits of COVID-19 vaccines for transplant patients.

Highlights:

• Transplant recipients who contract COVID-19 have higher rates of severe illness, hospitalization, and mortality. Being within a year of transplant, remaining on anti-cancer therapy or systemic immunosuppression, and poor performance status elevate the risk of contracting COVID-19.
• COVID-19 vaccines are very safe, though transplant recipients may have common side effects that resolve in two or three days. More serious side effects like blood clots and myocarditis are quite rare and less risky than those associated with COVID-19 itself.
• For hospitalized patients, treatments include Remdesivir, dexamethasone, and agents to reduce systemic inflammation. Treatment decisions should be made in consultation with infectious disease doctors who can evaluate the risks for immunocompromised individuals.

Key Points:

(07:03) For transplant recipients more than two years out with no GVHD or immunosuppressive treatments, the risk of COVID-19 approximates that of the general population.

(09:51) Transplant recipients should wait three to six months after transplant to get vaccinated for COVIID-19 n order to get the most robust immune response.

(11:35) Vaccine response is lower in general for transplant recipients who are less than two years out after transplant.

(12:47) mRNA vaccines offer an especially robust immune response which makes them somewhat preferable for transplant recipients.

(17:16) Booster shots are recommended for transplant recipients, including those less than two years out after transplant and those with GVHD.

(18:14) Transplant recipients can mix and match vaccines; following the J & J vaccine with an mRNA booster may be especially helpful.

(21:23) Promising COVID-19 treatments include monoclonal antibodies which should be administered as early as possible in the illness course.

(25:35) Hydroxychloroquine and azithromycin are not effective treatments for COVID-19.

(26:11) We know little about long-term effects of the COVID-19 vaccines, but long-term effects of the disease itself are much worse .

(29:40) Additional boosters or vaccines may be advisable with more data or as new variants of COVID-19 appear.

(30:38) Those who have had COVID-19 should still get the vaccine since it provides potentially stronger immunity than the body’s reaction to the disease itself.

Transcript of Presentation:

(00:00) [Marla O'Keefe] Introduction. It is my pleasure to introduce Dr. Alyssa Letourneau and Dr. Areej El-Jawahri. Dr. Letourneau is the medical director of the Antimicrobial Stewardship Program at Massachusetts General Hospital. She's also an instructor of medicine at Harvard Medical School. Her clinical interest is seeing immunocompromised patients, including patients with leukemia, lymphoma, those who have undergone stem cell transplant, as well as patients who will undergo immune-modulating therapy.

(00:32) Dr. El-Jawahri is the Director of the Bone Marrow Transplant Program and the Associate Director of the Cancer Survivorship Program at Massachusetts General Hospital. She is also an Associate Professor of Medicine at Harvard Medical School. Her research interests include designing supportive care interventions to improve the care of patients with hematologic malignancies, with a special emphasis on patients undergoing hematopoietic stem cell transplantation.

(01:01) I look forward to hearing from both of them about COVID-19 and how we can all protect ourselves and our loved ones. Please join me in welcoming Dr. El-Jawahri and Dr. Letourneau.

(01:13) [Dr. Areej El Jawahri]          Overview of Talk. Hello, everyone, this is Dr. El-Jawahri. Actually, I will start us off today. Thank you for joining us today, and I will hand it to my colleague and friend, Dr. Letourneau, in a few slides. Our hope is to give you a little bit of an update on the state of the nation with COVID-19, talk specifically about COVID-19 in the context of transplant recipients, some of the most common questions that are coming up for our patients and their families.

We'll talk a little bit about vaccine recommendations for transplants specifically, and how do we treat COVID-19 in transplant patients, as well as kind of try to address some of the common myths about COVID-19 that we've heard in our clinical practice. And hopefully, this will be helpful and informative. We'll have plenty of time for questions, so please feel free to ask your questions. This is why we are doing this, is to really provide as much information as possible to our transplant community.

(02:12) COVID -19 continues to evolve and spread through community transmission in U. S. counties and worldwide. So, I don't think COVID-19 needs any introductions at this point. We are all living it and have been living it for quite a while. It has been really eye-opening. As you know, we had done this BMT InfoNet webinar about a year ago, so updating these numbers in terms of the pieces across the world is just really overwhelming for us, to be honest with you. If you think about it, there are now over 200 million cases worldwide.

(02:42) As you know, the deaths in the United States continue to climb. I remember the time when on the news we were watching to reach that 100,000 death number, and now, we're over 700,000 deaths across the United States with over 46 million cases in the United States as well. Approximately every day we're getting about 75,000 cases in the United States per day. You can see our trend. This is kind of the peak that we had before. We are entering into our fall peak here. As you can see in November, there's a little bit of a tick-up as well.

(03:21) So, needless to say, the story continues to evolve, and unfortunately, we continue to live through this pandemic across the United States and worldwide. This is a little bit of a sense of community spread. By the way, a lot of this information is available on the CDC website. And you can actually look at your own individual counties and cities as well.

(03:42) This is a map of the United States looking at community transmission across different counties. In the red are high areas of transmission. In blue, which is very little unfortunately on this slide, are areas with low transmission within the community. So, needless to say, across the United States, this continues to be a problem for us in terms of community spread across most of our counties across the United States.

(04:12) Transplant recipients who contract COVID-19 have higher rates of severe illness, hospitalization, and mortality. So, with that back of mind, let's try to think about COVID-19 in the context of transplant recipients. Since we last actually provided information about this, there have been multiple studies since the beginning of the pandemic that have shown really very relatively consistent findings across transplant recipients, that the majority, the overwhelming majority of our transplant recipients who do contract COVID-19 are indeed hospitalized with this disease. About 20% of them have severe illness, and the mortality rates are anywhere between 22 to 35% across these studies.

(04:49) This is also true for blood cancer patients who do not receive a transplant. So, this is definitely a higher mortality group than our normal population with COVID-19. And it is important to note that we also have a lot of data in the context of blood cancers with or without a transplant, also suggesting similar numbers: higher risk of COVID-19 hospitalization and mortality in patients with blood cancers, as well as those who have both undergone autologous and allogeneic stem cell transplants.

(05:18) General risk factors for higher mortality include older age, male gender, and being a member of racial or ethnic minorities. Just to give you a sense, we also have a very good sense of risk factors for worse outcomes in the context of transplants. We hear often about the risk factors in the normal population, and some of them certainly apply here. Older age, particularly above 40 in the transplant world, is associated with worse outcome with this disease. So, if you are a transplant recipient who are above 40 years of age, you are a higher risk patient, again, not surprisingly similar to our normal population.

(05:51) We know that male recipients and marginalized populations, specifically racial and ethnic minorities, are at higher risk of mortality from this disease.

(06:00) For transplant recipients, being within a year of transplant, remaining on anti-cancer therapy or systemic immunosuppression, and poor performance status elevates the risk of contracting COVID-19. For transplants specifically, it's important to say that if you are within the first year post-transplant or if you are receiving anti-cancer therapy in the past year, those who received a transplant, specifically an allogeneic stem cell transplant, who continue to be on systemic immunosuppression ... and what I mean by that is systemic therapy like prednisone, tacrolimus, sirolimus, CellCept are some of the most common agents we use... if you are receiving rituximab, if you are receiving any systemic therapy for chronic graft-versus-host disease, these are all various risk factors for worse outcomes. These are the people we really worry about if they contract COVID-19.

(06:47) Anybody with a poor performance that is dysfunctionally limited is also at higher risk. So, again, some of those risk factors are common. You have heard a lot about them in the news, but the ones that are specific to transplant are worth mentioning.

(07:03) For transplant recipients more than two years out with no GVHD or immunosuppressive treatments, the risk of COVID-19 approximates that of the general population. I do want to clarify for people who have gone through transplants who are two years out from transplant, specifically off immunosuppression and no GVHD for those undergoing allogeneic stem transplant, and also for those who've gone through autologous stem cell transplant, if they don't have any recurrent disease, they are not receiving anti-cancer therapy, once you're beyond that two-year period, you are probably in that same category as the general population. Again, the general population risk factors are age, as we talked about, race, male gender. But really, your risk approximates the normal population if you are in that category.

(07:47) So, not every transplant recipient is the same. We do think of a transplant as a whole as a higher-risk group, but there are exceptions to that. And that's a very notable exception to highlight.

(08:00) For transplant recipients, potential complications include blood clots, kidney and liver problems, and post-acute COVID-19 syndrome. There are several complications that have been reported after COVID-19 infection in transplant recipients. Some of those are probably higher in our transplant recipients than the normal population, specifically blood clots, especially in patients with graft-versus-host disease. Graft-versus-host disease is an inflammatory condition. It causes inflammation in the body, and that's already a risk factor for blood clots.

(08:25) We've seen a lot of kidney and liver problems in patients who have gotten COVID-19. Inflammation of the heart muscle is more rare, but, certainly, we have seen a lot of that as well in our transplant recipients, especially those who have gone through an allogeneic stem cell transplant.

(08:43) And some of you may have heard of this post-acute COVID-19 syndrome. This is just that patients who have gone through this illness are certainly feeling some longer-term effects, both in terms of breathing, shortness of breath, fatigue, that we still don't honestly fully understand and, likely, will learn more and more about, that last beyond the time of the acute illness that they have. And that's something that we are seeing more in our transplant recipients.

(09:17) There are some data to suggest that for patients with graft-versus-host disease, an infection can certainly increase graft-versus-host disease symptoms. These are very limited data, but I will say clinically and anecdotally, we have seen this as well in the clinic. And again, that's not surprising. We used to see this with a lot of infections, including cold and flu infections, and when a patient has a viral infection, it triggers the immune system to fight this virus. And in the process of doing that, graft-versus-host disease symptoms can get exacerbated.

(09:51) Transplant recipients should wait three to six months after transplant to be vaccinated for COVID-19 to get the most robust immune response. So, just to be very clear about vaccine recommendations in transplant recipients, and then Dr. Letourneau will talk to us a little bit more about this, patients should receive COVID-19 vaccines at a minimum three months after autologous stem cell transplant. The reason to wait three months is mostly to ensure that people actually respond to the vaccine, that they actually have a robust immune response. There are no safety concerns about giving it sooner, but getting it earlier, you may not actually get a response and get the immunity we want it to get. So, the current recommendation is greater than three months after autologous stem cell transplant.

(10:31) For allogeneic stem cell transplant recipients, again, it's a minimum of three months, but definitely important to talk to your doctor because a lot of transplant clinicians are actually delaying the vaccine until at least four to six months after allogeneic stem cell transplant. I should say, these data are not based on COVID-19. These are actually based on expert consensus experience with a whole lot of immunizations that we do after your transplant.

(10:58) Many, many patients have gone through multiple immunizations, including the flu vaccine and our post-standard post-transplant vaccine. So, we have a very good sense of the immune response to various vaccines in transplant recipients. The data are still maturing for COVID-19, so we don't have great data on this, but we do know that these are the expert recommendation based on our experience with all types of vaccines. So, for allos, it might be a little bit later, but, again, this is an important area where you should talk to your doctor, depending on what's going on with your immune suppression, what's going on with your current care plan.

(11:35) Vaccine is lower, in general, for transplant recipients who are less than two years out. And we also know, and these data are very clear, that vaccine response is lower in transplant recipients compared to normal populations. And I should note that when I say vaccine response is lower in transplant recipients, I am not talking about people who are greater than two years out, again, off of immunosuppression. I'm talking about people who are still on immunosuppression, people who are relatively early in their transplant course.

We will have more chance to chat about this because I know there are a lot of questions about this particular point. But with that, I want to turn it over to Dr. Letourneau to talk to us a little bit about available vaccines and treatments.

(12:15) [Dr. Alyssa Letourneau]          There are several COVID-19 vaccines available.  Thank you for that great summary thus far, and thank you for having us. Again, I'm excited to discuss this. So, as most of you probably already know, in terms of the available vaccines, we have the mRNA vaccines, which are available, which are made by Pfizer, BioNTech, and Moderna. And these are the vaccines that are relatively newer in terms of vaccines on the horizon, but are technology that have been used, actually, for many, many years and have been studied for many years.

(12:47) mRNA vaccines offer an especially robust immune response which makes them somewhat preferable for transplant recipients. The beauty of these mRNA vaccines is the robust immune response we have for these. So, to put this in perspective, March 2020, when this was all starting, I predicted we wouldn't have a vaccine probably for 18 months in anyone's arm, let alone a vaccine we would be happy with a vaccine that was effective in about 50% of people and would be available in that time frame. And sure enough, in less than 12 months, we had two vaccines that were more than 90% effective in the general population, which is very exciting.

(13:26) The other vaccine that's available is the J&J vaccine, which was produced by Johnson & Johnson and Janssen, and this is based on a non-replicating viral vector vaccine that uses an adenovirus-type technology, also technology that's been around and studied for many, many years. There are slight differences in these vaccines, as all of you have heard, I'm sure.

(13:48) The robustness of the response in the mRNA vaccines has made them somewhat preferred in our patients who are immunosuppressed. The J&J vaccine now, there's a recommendation that it really should be a two-dose vaccine at this time. And we can talk a little bit more about if you received the J&J whether getting a second J&J vaccine versus an mRNA vaccine is in your best interest. But all of these vaccines, thankfully, are quite effective and provide good immune response in patients who have normal immune systems, and we'll talk a little bit more about these.

(14:24) So, do they work? And as I mentioned, the mRNA vaccines are 94 to 95% effective, which is amazing. Again, we know that these work a little bit less in patients who are immunocompromised or on immunosuppression. And then, as I mentioned, there are some data that suggest there's a better response to the mRNA vaccines in some of our transplant recipients. But that does not mean that you are completely unprotected if you did not get the mRNA vaccine.

(14:52) These vaccines are very safe, though recipients may have common side effects that resolve in two or three days. Are these vaccines safe? I would say an overwhelming yes, which is one of the things that makes this also amazing in terms of the science that has been behind all of this. There are obviously some common side effects related to these. There's the local reaction that many people will have, which is pain at the injection site, which seems to be probably a little bit more than our flu vaccines, but slightly less than the shingles vaccines or Shingrix, which actually in head-to-head numbers causes more side effects than the mRNA vaccines.

(15:25) People can also get localized swelling in their arm, and most of this usually resolves within a few days. Others can have a systemic reaction. It's anywhere from 40 to 50% of patients may have fatigue, headache, muscle aches and pains, chills, sort of a flu-like illness, joint pains. But usually, this resolves within about three days, at most, after having that.

(15:48) More serious side effects like blood clots and myocarditis are quite rare and less risky than those associated with COVID-19 itself. And then there are some rarer side effects, obviously, with blood clots with the J&J vaccine. This was seen primarily in, I would say, women of reproductive age, having a risk for the blood clots. In the mRNA vaccines, the Moderna and Pfizer vaccines, there are rare cases of myocarditis, which has been mostly seen in young men. So, men in their teen years or in their 20s have been sort of the common patients that have seen that.

 (16:21) One thing to note is that blood clots are common in patients who get COVID-19 disease as is myocarditis in young patients who get COVID-19. So, when you look at the risks and benefits in terms of vaccines, the risk of getting myocarditis from the vaccine is less than the risk of myocarditis that one would get from contracting COVID-19.

(16:49) The blood clots are slightly different for those who have COVID-19 versus those who develop the blood clots that are believed to be related to J&J. But there are blood clots in patients who do get COVID-19. They're not the same type of severity as J&J, but the numbers in terms of the risk of getting that blood clot with J&J is still extremely low, which is why it is still approved by the FDA and the CDC for use in the United States.

(17:16) Booster shots are recommended for transplant recipients, including those less than two years out and those with GVHD. In terms of vaccine recommendations for transplant patients, we do know that getting an additional dose, especially for patients who had mRNA vaccine and, obviously, patients who received the J&J vaccine, getting a third dose has been shown to help increase some of the immunity. Some of the people that were recommending receiving a third dose, it's hard to say whether this is a booster or an additional dose. It may just be that these vaccines actually are a three-dose series, similar to our initial hepatitis B vaccine. But any who's 65 years of age or older really should be getting an additional dose.

(17:50)  Transplant recipients who are less than two years from their transplants should also get an additional dose. Transplant recipients with chronic GVHD or on other immunosuppression, we would advocate getting an additional dose. Again, the response, as Dr. El-Jawahri was talking about, we know is less, but there is some response, and therefore, we would like to try to boost that response as much as possible.

(18:14) Transplant recipients can mix and match vaccines; following the J & J vaccine with an mRNA booster may be especially helpful. Patients can mix and match between their vaccines for their booster. I would say the data, there is not robust data. Again, all of this data is emerging. I think part of the reason to say we can mix and match is so that people get their vaccines, and if, for some reason, one vaccine isn't available, we know it's safe and potentially beneficial to get one of the other vaccines. So, that's sort of the general thought process on that.

(18:42) How much of a boost you get if you mix and match, I would say, the data are still emerging in that area. And regardless, as I mentioned, if you received a J&J vaccine, we do know there are pretty good data to show that if you received one J&J vaccine, that boosting that with the mRNA vaccine in Moderna or Pfizer likely would boost your immunity slightly more, but not necessarily in the reverse - if you got the mRNA vaccines, getting your third as a J&J. It may, but it's not enough for us to say that that's what you should do. You are allowed to do that, but, in general, getting a third dose is going to help in general in terms of helping to boost your immunity.

(19:26) Wearing a mask in public settings remains good advice. So thinking about what else can we do to protect ourselves, protect yourself and others, we still are suggesting that wearing a mask in public makes sense. A regular mask, either a surgical mask or a cloth mask should be fine, especially in indoor settings. Masking across the United States is varied in terms of the different communities where there's different rates of transmission. But, in general, we would say it would be good to continue masking to help protect yourself.

(19:58) Obviously, getting vaccinated as mentioned. These vaccines are safe and effective. If you're immunocompromised, getting your booster.

(20:06) Cocooning or vaccinating everyone around infants and family members is also helpful. I trained in adult medicine and pediatrics, so vaccines are close and dear to my heart. And I would say cocooning, which is what we do with infants, we always vaccinate everyone around an infant against pertussis or whooping cough, this is similar in terms of all the other diseases. I always educate the transplant patients that I see that it's time to get family, friends, and children all vaccinated against the flu and any of the other sort of transmissible viruses. They should all be up to date on their vaccines to help protect and cocoon the one who may not have as much of a response, so trying to encourage those who are around you to get vaccinated as well.

(20:47) In terms of COVID-19 treatments, this is all still emerging. Every day I feel like there's something new that's been, what's called, a preprint, which is data that are released that have not been peer-reviewed through a rigorous process and published in our official journals. Some of them do make it through, and some don't. So. It's a little hard to parse through the data sometimes. But, for now, in terms of mild to moderate disease, the things that we're doing in the outpatient setting really is supportive care, which we do for most of our viruses. And many people with mild symptoms can recover at home and do very well.

(21:23) Promising COVID-19 treatments include monoclonal antibodies which should be administered as early as possible in the illness course. There are monoclonal antibodies that are available. So, these are casirivimab and imdevimab, which is created by the Regeneron company, and then the Lilly antibodies, which are bamlanivimab and etesevimab, which are available in an outpatient setting. So, patients who are at high risk of severe illness, so obviously, most of the patients who are recent transplant recipients or who are on immunosuppression, they may benefit from receiving a monoclonal antibody.

(21:52): The key is getting it as early as possible in the illness course, preferably in the first few days, as soon as symptoms arise is when people have the greatest benefit. These are still under, what's called, emergency use authorization, and they're distributed to states based on numbers, and so can sometimes be hard to come by. But I would be sure to reach out to your oncologist to let them know how you're feeling to see if there's a program to be able to get an infusion near you. Both antibodies are available as an IV infusion that can be given. And then the Regeneron product is available as well as a subcutaneous injection with four shots that you get under the skin.

(22:38) One new treatments is Paxlovid which appears to decrease hospital admissions significantly. There's also hot-off-the-press this week, there's a promising new oral antiviral, which I have not learned how to pronounce yet, Paxlovid, from Pfizer that looks very promising. It looks like it decreases admissions to the hospital by about 80%. The monoclonals in these studies, which were mostly in patients who had functioning immune systems, some of the patient were immunosuppressed in those studies, they decreased hospitalization rates by about 70%. But, again, in those trials, they gave the antibodies very early on in the disease process.

(23:15) For hospitalized patients, there is Remdesivir, dexamethasone, and agents to reduce systemic inflammation. In terms of patients who end up in the hospital, we have some regimens that we can give them. There's an antiviral called Remdesivir. This is one that's been around since May of last year. And this really is for COVID-19 in hospitalized patients. There are some data suggesting we could potentially use it in the outpatient setting, but it is intravenous, and so it's a little bit more difficult to administer in that setting.

(23:40) Patients who are in the hospital and on oxygen, frequently, we give them dexamethasone as well, which is a steroid. This is given to patients who are not likely on baseline steroids to start with. They're not on certain other immunosuppressive regimens that may be doing the same amount of effort of work for the patient.

(23:59) There are other agents that we sometimes use to reduce systemic inflammation. There's something called tocilizumab or baricitinib that can be used. But, again, in patients who are severely immunocompromised, it's not clear if those benefit the patient or cause more harm in terms of immunosuppressing the patient further and increasing the risk of other infections down the line, such as fungal infections.

(24:23) For hospitalized patients, treatment decisions should be made in consultation with infectious disease doctors who can evaluate the risks for immunocompromised individuals. Typically, patients are seen jointly with the infectious disease service to be sure we're thinking about all the risks and benefits for these patients. For inpatients, there are some data to suggest that in immunocompromised patients that monoclonal antibodies may be beneficial. These are not approved for this indication at this time by the FDA, and so these are used on a case by case basis through a compassionate use program through Regeneron, which is the company that makes casirivimab and imdevimab, which is one of the monoclonals.

(24:57) This may change. There are emerging data that patients who are admitted to the hospital with COVID-19 but have not yet produced their own antibody, one of the antibodies that you make in response to the disease, that patients who get the monoclonal at that time do benefit. And so, in patients who are admitted who are severely immunosuppressed, that's the thought process that perhaps if they're not making their own antibodies that these monoclonals will be helpful.

(25:22) Again, if unfortunately, you're hospitalized, involvement of the infectious disease team is always helpful in making these determinations. And many of these things change on a week-by-week basis in terms of the data that are released.

 (25:35) Hydroxychloroquine and azithromycin are not effective treatments for COVID-19. A little bit about some myths that had come in, in terms of some of the questions that came in before the webinar as we were preparing this: are there other things that I can take that can make me feel better such as hydroxychloroquine, which was something we were giving early on or azithromycin. And there are pretty robust data now showing that these drugs really are not effective against viruses and, in particular, COVID-19. Azithromycin is a macrolide. It's a type of antibiotic, and hydroxychloroquine is actually an antimalarial. These have not been shown to be effective.

(26:11) We know little about long-term effects of the COVID-19 vaccines, but long-term effects of the disease itself are much worse. Worry about the long-term effects of getting the COVID-19 vaccine. Currently, we have no data supporting the long-term effects that we see from these vaccines. We know that vaccines are very safe. But we do know that we are still seeing some long-term effects of COVID-19 from actual disease and that some of these are likely much worse than any sort of long-term effect that we could anticipate from the vaccinations.

(26:36) Colin Powell’s death even though vaccinated should not discourage others from getting vaccinated; he was quite elderly and had multiple myeloma which complicated his case.  I know that Colin Powell made the news in terms of the fact that he had been vaccinated but still died of COVID-19. And so why would somebody get the vaccine, seeing that clearly, it didn't work? Again, patients who are very immunocompromised may not respond to the vaccine. He was also, I believe, north of 80 in terms of his age, and we know that patients who are older also do not respond as robustly to the vaccine. But we do believe that even with those two factors, that vaccinating probably decreases the risk overall of COVID-19 disease and severity of COVID-19 disease.

(27:13) Colin Powell also had multiple myeloma, and we know that mounting vaccine responses is more difficult in that patient population. And so, for me as an infectious disease doctor, I would have recommended that he get vaccinated. But in terms of managing his COVID-19, I would have managed him in the sense that considered him not vaccinated in terms of his risk just because of his age as well as his multiple myeloma, meaning I would have advised him to continue to be very vigilant and be careful in terms of the activities that he was doing.

 (27:48) Even immunocompromised individuals can get some benefits from the vaccine. And the last myth that I have listed here is I'm so immunocompromised. Is there any point in getting the vaccine? And, again, we do believe that there is some response, although, obviously, it is not as robust as patients who are not immunocompromised, and you really should discuss your questions with your physicians as well.

(28:12) We don’t know what a sufficient level of antibodies to prevent COVID-19 looks like, but there are other immune benefits from the vaccine that are not easily measurable. And I think this is on the next slide, but I'll just mention it here. We do know that it's difficult to measure what the vaccine response is. We're still not sure what level of antibody makes a difference and how long that antibody lasts. But we do have some data to suggest that even if the antibodies that we can measure, even when we see that those go away, there are other immune responses that are not easily measurable that likely protect people from infection, so keep that in mind that there may be other things that are going on.

(28:45) So, additional questions that we had received are: where should my antibody level be? Should I have it tested? Again, it's not really clear at this point which level provides protection. If the level goes below a certain number, are we sure that that doesn't provide protection? And, again, those data are still coming out, and we're trying to look at that. We did have a clinical trial here, and I believe the data will be coming out soon, looking at antibody response to the vaccine.

(29:11) Antibody testing is not recommended since we don’t know what is truly effective at this time. But currently, I would say don't go out and get it tested because it's not clear what level is protective outside of clinical trials. And I would say if it is "high", that doesn't necessarily mean, I would say go do whatever you want, you're protected. Because I wouldn't feel comfortable saying that readily in terms of what we know thus far for those data.

(29:40) Additional boosters or vaccines may be advisable with more data or as new variants of COVID-19 appear. The ongoing question is, are we going to need additional boosters or additional vaccines? How is this going to go? And really, we're not sure. To me, it seems likely. Again, as I mentioned before, I think the vaccines really will be a three-dose regimen or potentially two-dose for J&J, and that that will just be the regimen that people need and that potentially we will need to get boosted, whether it be on a yearly basis or longer than that. I don't think it will be an every six-month basis. Although, again, time will tell in terms of seeing those data as they come out.

(30:13) The other thing that may happen is we're on the delta variant at this point, still the most common variant in the United States. The virus could still mutate, and the potential need of having to do an additional vaccine that has more protection against a different variant is definitely a possibility. And, again, we're just going to have to wait and see there.

(30:38) Those who have had COVID-19 should still get the vaccine since it provides potentially stronger immunity than the body’s reaction to the disease itself. And the last one is, I have had COVID-19, so should I get the vaccine? Yes, I would say studies suggest that, actually, protection from the vaccine is potentially stronger and longer lasting than the immune protection is from the virus. Potentially as well, you get a boost in your immunity from having had the disease and then getting your vaccine afterwards.

(31:05) The CDC website and Ask the Expert Site are good resources for more information. And then here's a list of resources. The Centers for Disease Control or the CDC, the website is there. There's lots of information there that changes and is updated as you go along. There are great slides in terms of how to protect yourself from COVID-19 on the CDC site as well.

(31:27) And then my favorite site is the Ask the Expert Site at the Immunization Action Coalition, which is also run by the CDC. And basically, for every single vaccine, not just COVID-19, there's a question and answer section that will answer all of your questions. It answers questions that have come in, and you can submit your own question if your question and answer isn't listed there. And I find that very helpful to have the updated answers on many of the common questions that we have.

(31:59) All right, I think that is our last slide. And now I think we can open it up for the question and answer section.

(32:09) [Marla O'Keefe] Q & A.  Thank you so much Dr. El-Jawahri and Dr. Letourneau. That was an excellent presentation. The information on COVID is constantly changing, so thank you for bringing us all up to date. So, we'll start with some questions.

The first one is, are there any reports of the vaccine triggering GVHD?

(32:30) [Dr. Areej El Jawahri]       That's a great question. The data are really limited. I would say there are case reports of the vaccine causing a slight flare in GVHD symptoms in people with severe chronic graft-versus-host disease. Case reports being one or two cases. That's what I mean by a case report. It's not a robust study that we can clearly say that it's linked to the vaccine.

(32:56) I will say that based on our experiments with vaccinations in patients with chronic graft-versus-host disease, this is definitely a theoretical risk that we keep in mind. So, for patients who have more severe chronic graft-versus-host disease, it's important to talk to your doctor about whether to get the COVID vaccine for multiple reasons. One is related to this issue, if there's any concern about an exacerbation. Generally speaking, most of us in the transplant community are more worried about people with chronic GVHD getting COVID than any theoretical risk of exacerbation of COVID symptoms.

(33:37) So, I would say talk to your doctor about that, but the risk is very, very low. We don't have a ton of data, but based on our experience with other vaccines, we can say that for most, the overwhelming majority of patients with chronic graft-versus-host disease, the COVID-19 vaccine is safe without a huge risk or even a small risk of increasing GVHD symptoms.

(34:04) [Marla O'Keefe] Thank you. The next question is, there's a chart you had, the risk factor chart. And someone asked if you could explain what poor performance meant?

(34:16): [Dr. Areej El Jawahri]     Yeah, my apologies for that. So, poor performance status reflects how functional somebody is. I should have been a little bit more clear. Basically, if people are sedentary, not moving a lot around, spending 50% of their time or more in bed or in a sitting or lying position, we think of them as having lower functional or lower performance status. So, if you are someone who spends greater than 50% of your time in bed, that would be a poor performance status. And that is a risk for higher complications from COVID-19 in our transplant population.

(34:55) [Marla O'Keefe] Thank you. If a transplant patient had two Moderna shots prior to transplant, would the third booster shot be considered the first, or do they have to get both shots again, or a booster? And how many days following day zero should the shot be administered?

(35:20) [Dr. Alyssa Letourneau] Yeah. I mean, that's a great question. I don't think we have figured this out. But I think I would treat it similar to our other vaccines in our transplant recipients where we restart their series afterward. We redo all our pneumococcal vaccines. We redo our Tdaps. And so I think I would plan on just redoing that, restarting the series afterwards. Dr. El-Jawahri, what would you say?

(35:51) [Dr. Areej El Jawahri]       Yeah, I agree. We don't have this exactly right. We don't have the data, but I think essentially transplant experts and people have been doing a lot of vaccine research in the context of stem cell transplant. We know that transplant reduces your immunity from prior vaccination. So, our recommendation has been across the board to restart your vaccine sequence. And the timing, again, is slightly different for autologous, allogeneic. And I actually see a couple of questions about CAR T, so I'll try to answer that as well.

(36:29) For autologous stem cell transplant, , we're waiting a minimum of three months. For CAR T, somewhere between that two to three months. There's even less data in the CAR T population, but we know that at some point between that two, three months from having an autologous stem cell transplant, we should think about restarting the vaccines or doing the COVID-19 vaccine.

(36:51) And for allogeneic stem cell transplant recipients, a minimum of three months, but many of us on the transplant community side are pushing it out about four to six months in the allo population, not for safety concerns - these vaccines are incredibly safe - but it's more for us optimizing the response. We want to make sure people are responding to the vaccine and getting some immunity to it. And it does seem that patients who've gone through an allo transplant, at least based on our historical data on how they respond to vaccines in general, have less robust response during that three-month period. So, four to six months is more reasonable.

(37:34) [Marla O'Keefe]      Thank you for catching all of that. The next question is, do you need to reach a specific CD4 count cutoff in the allo transplant patient prior to giving the COVID vaccine?

(37:50) [Dr. Areej El Jawahri]       We have a very informed group here. I love it. I love these questions. So, the answer is no because we don't have data on them, unfortunately. But I do think this brings up a really important point that, in general, when we talk about vaccinations and the way we measure response to vaccination, it's worth probably spending a couple of minutes just talking about that the fact that the immune system has many different players that really protect us from infections.

(38:21) And one component of that is antibodies. And, certainly, antibodies is an important part of that. But the reality is vaccines do more than generate antibodies. They generate what we call cellular immunity, which is a different type of immunity that your immune system can have to protect you from infections like COVID-19. And I would say the third piece, that really is probably the most convincing piece of evidence we always get for whether a vaccine works or not, is does it reduce the risk of transmission, does it reduce the risk of severe infection.

(38:56) So, just keep in mind that patients who have gone through transplant, depending on their chemotherapy regimen, the type of treatment they receive, they could have different components of their immune system compromised. So, certainly, some patients, for example, I saw a question about rituximab. Rituximab impairs your B cells. And those B cells are responsible for antibody production. So, while patients who get rituximab may have less antibody protection from COVID-19 vaccine, they may actually have very good cellular protection, which is something we don't measure clinically, we can't measure clinically.

(39:35) So, this is a long-winded to say that this is more complex than just antibodies or just CD4 count or just T cell immunity. There are multiple components or compartments of the immune system that we really activate with a vaccine to help protect us, and for transplant recipients, one component might be weaker than others. But the reality is our hope that by activating all of them ... and we know that the vaccines activate all of them ... that we would get some protection from at least one of them depending on how the body responds to the vaccination.

(40:11) [Dr. Alyssa Letourneau] That was an excellent answer. I would just add that in patients with HIV who have CD4 counts, who have untreated HIV, or who have severe HIV/AIDS with low CD4 counts less than 200, that we would still vaccinate them at that time for those exact reasons as well. Again, these vaccines don't have live virus in them, so they're safe to be given regardless of immune suppression, whereas certain vaccines that have live virus, so the chickenpox vaccine that we give to children, the yellow fever vaccine, the measles, mumps, rubella, which has live attenuated measles virus, those we would not give to patients with low CD4 counts or in patients who are on immunosuppression. But, the COVID-19 vaccines do not have any live virus so they're safe from that perspective as well.

(41:05) [Marla O'Keefe] Thank you. Next question is, do IVIg infusions affect efficacy of vaccines, either helping or hurting?

(41:17) [Dr. Areej El Jawahri]       They do not. They should not.

(41:21) [Dr. Alyssa Letourneau] I was going to say the same thing.

(41:24) [Marla O'Keefe] Okay. Next question, I am 16-months post-allo transplant and have chronic GVHD. It is currently under control, and I am no longer taking tacrolimus or prednisone. What is the risk of GVHD being exacerbated by the COVID vaccine?

(41:43) [Dr. Areej El Jawahri]       That's a great question. So, I think in a case like yours, your GVHD is under control. You're off systemic immunosuppression. Again, I'm not your doctor, so I would say still talk to your doctor. But the likelihood is exceptionally low that you would have any issues with the COVID-19 vaccine in terms of having exacerbation of GVHD symptoms. And we should say also it's important to note even in other vaccines where we have more data on this idea that maybe a vaccine could increase slightly GVHD symptoms, that the increase in GVHD symptoms is typically very transient in these other cases, meaning it happens for a few days or a week or two and then it goes back to where it was.

(42:25) We haven't seen GVHD exacerbations that are out of control from prior vaccinations. Again, we have limited data on COVID-19, but given the information you have given me, I would say, yes, absolutely. There's very low risk of having GVHD exacerbation, and the COVID vaccine is a great thing to get.

(42:46) [Marla O'Keefe] Kind of feeding into that same question, how is it possible to distinguish acute COVID inflammatory response and exacerbation of GVHD from COVID?

(43:01) [Dr. Areej El Jawahri]       So, I think there's a couple of things. So, acute inflammation from ... It's not really clear to me if the question is acute inflammation from a COVID-19 vaccine or a COVID-19 infection. For a COVID-19 infection, we have certain inflammatory markers that we see increase in the context of infection that are actually not increased dramatically in patients with graft-versus-host disease. GVHD is more of a clinical picture and clinical diagnosis, so we often, specifically in the context of chronic GVHD, we're watching for the clinical syndrome, people who are having mouth involvement that's getting worse, people who are having eye involvement that's getting worse, skin involvement that's getting worse.

(43:45) So, yes, GVHD is an inflammatory disease, and there are some markers in inflammation that are slightly increased in GVHD, but it's nothing like what we see in the acute infection of COVID-19. Actually, that acute inflammatory state from COVID-19 is actually similar to acute treatment with CAR T cell therapy. So, for those of you who are commenting on CAR T, this is kind of a robust inflammatory response that can happen, and there are a lot of markers of that response that we measure routinely for CAR T during acute therapy. We measure routinely in patients who are hospitalized with COVID-19. We do not measure those in patients with graft-versus-host disease.

(44:32) [Marla O'Keefe] Thank you. Thanksgiving for us would be five vaccinated adults and two children under four. Can we do this safely for one of us being one year out from bone marrow transplant?

(44:50) [Dr. Alyssa Letourneau] Thank you. It's a different question. I would say that it's very much ... There are a couple ways to think about this. So, it's what risk tolerance is for the people involved as well as what the other people are doing that are gathering. So, excellent that everybody is vaccinated. I would say that's the number one thing. And obviously, the young children are unable to be vaccinated at this point.

(45:24) There's always risks, so regardless of what is done, there's always a risk that somebody could get COVID and transmit it to the person who is one-year post-transplant. It depends on what the immune suppression is for the patient that's one year post-transplant, if they're still on some immune suppression versus not, so the risk for that person.

(45:44) There's the risk of what the people are doing. So, are the young children in school or in daycare or in settings where they may get COVID asymptomatically? And then what are the other people who are doing that are vaccinated, that is, are they going to the grocery store unmasked or doing other things that may put them at risk for COVID-19? Since they're vaccinated, they may not develop symptoms, but they could potentially transmit.

(46:09) I would say that the safest way to do it, if you do want to gather, is actually if you're able is to be able to test for COVID-19. I would say you test two weeks before you get together, ideally with a PCR, but you could potentially do it with one of the rapid home tests. And then test on the day that you get together. The reason I say the two weeks before, some of these tests, stay positive for some time. So the PCR tests, if you have lingering virus in your nose, some people can have it in there for up to three months after having been infected, I say do it two weeks before because if they have some there, by two weeks after, they should not be shedding.

(46:52) If they actually do have COVID and it's not a false positive, they would be out of quarantine and okay to see people the two weeks after. And then you test that day to be sure everybody is negative when they get together. I would say that would be the safest way to do it. Although the risk is not zero, that is a relatively safe way. And I would say in those interim two weeks between the testing, that that would be a time where people try to be slightly more careful in terms of the interactions they're having with others.

(47:26) [Dr. Areej El Jawahri]       Yeah, and I just want to acknowledge here, Dr. Letourneau, that was a great answer. But I do think these are really difficult questions. And I just want to acknowledge how hard this is. This is stressful. And it's really tough to have to make these decisions. It's all about balancing risk and obviously, potential for these important milestones. After all, many of you have gone through transplant so you can have your life back and be able to do the things that you want to do, and certainly, spending quality time with family during the holidays is an important aspect of that.

(48:01) So, we're not going to give you a perfect answer here because we don't have a perfect answer. It's all about minimizing risk. We're never going to get risk down to zero.

(48:11) So, I also want to acknowledge that there's a ton of misinformation out there, which has been really, really hard. It has made our job, it has made patients' capacity to really integrate this information so much harder. So bear with us. We're in a lot better place than we were probably a year ago, and we'll probably continue to get into a better place as we have more effective therapies and at least have more and more people vaccinated.

(48:37) But I just wanted to acknowledge this is hard, so I'm sorry. Every one of us is going through this. I'm especially sorry for our transplant recipients and CAR T cell recipients and our patients with cancer who are receiving treatment because I think this is an impossible place to be for a long time. And we just want to recognize that and just say, "We're there with you. You have a team of doctors who deeply care about this." Your doctors are thinking about this each and every day. So, certainly, feel free to reach out to them with one of these questions as well.

(49:08) [Dr. Alyssa Letourneau] Yeah, I mean, one additional thought is also outdoors, depending on where you live in the country, outdoors is always much safer than indoors. So, being able to eat outdoors or in a well-ventilated area is also safer. Here in New England, November can either be 60 degrees like it is today or 25 degrees and snowing. So, it all depends on that as well.

(49:33) And I forgot. I've been doing this, obviously, as an infectious disease doctor, and I'm also very risk-averse in terms of this because I also have young children at home who are not vaccinated, and so have been living through this. And I am actually quite hopeful that in the spring, that the spring/summer next year that this will all start being in a much better place, especially if we can get children vaccinated.

(50:01) There are some other monoclonals coming on the horizon made especially for transplant patients and patients at risk of disease, where it would be a monoclonal infusion that would help prevent infection. And it sounds like it would be an infusion once a year that could potentially get us through the next year so that we could get more folks vaccinated and hopefully get this to be a disease that we think about not on a daily basis but more as an episodic disease that we see here and there but that most people are protected.

(50:40) [Marla O'Keefe] Well, thank you so much for those encouraging and compassionate words. I think we're all feeling it. The next question is, did either of the pharmaceutical companies do clinical trials with stem cell transplant recipients?

(50:56) [Dr. Areej El Jawahri]       No, so the data on transplant recipients is coming, obviously. And we're doing some, not from the initial trials of the vaccine approval, but, certainly, we've collected data through several organizations. The Center for International Blood and Marrow Transplants has done a phenomenal job of really collecting information across the country and the world about vaccines, vaccine advocacy in the context of transplant. And then there have been numerous reports from multiple institutions collaborating together to give us a sense of what happens when patients who have gone through transplant do get COVID-19.

(51:35) There are also international organizations in Europe that have looked at outcomes of patients who have gotten COVID-19, so the trials, the specific trials I think you're referring to, did not include this population. So, we are gathering data after having a lot of people around the world get these vaccines.

(51:59)[ Marla O'Keefe] I am five and a half years post-transplant but take a low dose of NEXAVAR. Is that considered an immunosuppressant?

(52:11) [Dr. Areej El Jawahri]       No, it shouldn't be considered an immunosuppressant. Yeah, we do think about it as a little bit of an immunomodulatory drug, but it should not reduce your immunity to COVID or response to the COVID vaccine.

(52:34) [Marla O'Keefe] Thank you. How soon and up until when can we tell if we are totally safe upon exposure to someone who is COVID positive?

(52:47) [Dr. Alyssa Letourneau] So, 14 days is sort of the token amount of time. That's the longest incubation period from time of exposure to disease. I did not mention this before, which is the, again, emergency use authorization. So, the way that things are currently approved for the monoclonals in the United States is through this emergency use. And there's supply that's distributed across the U.S. based on cases.

(53:20) For casirivimab and imdevimab, so for the Regeneron product, the emergency use authorization does allow for post-exposure prophylaxis. So, this would be for patients who have an exposure to COVID as per CDC guidelines, which is unmasked within six feet for more than 15 minutes within a 24-hour period. You can see I do this a lot. And so that would be considered an exposure.

(53:50) And then the post-exposure prophylaxis with the monoclonal is allowed for patients who either have not been vaccinated and are at high risk of progression to severe disease - so patients who are older or who have other underlying medical conditions - and for patients who are vaccinated who are not expected to mount an immune response to the vaccine, which are sort of the same population that we've been talking about and many of you here, so patients on immunosuppression, early post-transplant, et cetera. So patients would qualify for that.

(54:24) And then the thought is that trying to give that earlier rather than later, because essentially what we're doing is giving antibodies to you to help prevent the disease from taking hold. So, those are also available. The difficultly with it is that it's an IV infusion or a subcutaneous injection and being able to set up a system to be able to do that. I know that some systems have had some difficultly doing that.

(54:53) And then, obviously, if there's a constraint on being able to do those infusions or the subcutaneous injections, at least in our system, we prioritize the patients who have known COVID-19 and are at highest risk, which include the populations that I talked about, to be treated. And then we march down the line. And then if we have patients that have had exposures that are at high risk, we would infuse them.

(55:22) Well, the hope is that the antiviral will help decrease all of this and we'll be able to get that out and about because that's an oral pill as opposed to an infusion or an injection. But for patients who are potentially exposed and who are at high risk, this will be something that we can do in the clinic if we can give it just under the skin to help their patients. So, that is one of the things that we are hoping for coming up.

(55:51) [Marla O'Keefe] Okay, thank you. This person is asking, in Great Britain, they are giving immunocompromised patients third doses of mRNA and then boosters after several months. Is that the recommendation here, or are we leaning towards that?

(56:08) [Dr. Alyssa Letourneau] That is not the recommendation yet, but I expect that it will probably be coming down the pipeline soon. But currently, it's just that we're only at a third dose right now in terms of what we are recommending. But, again, I think in the coming months, we'll probably get additional doses, especially for patients who are immunocompromised.

(56:29) [Marla O'Keefe] Okay, someone had asked about the statistics from your presentation. Were those for people who had been vaccinated like the sides effects and what not?

(56:39) [Dr. Areej El Jawahri]       It's unclear which statistics they're talking about. So I think for the data on risk of the disease in terms of both outcomes as well as complications, generally a lot of these data, we're kind of playing catch up. A lot of these data are in patients who weren't vaccinated because they were collected pre-vaccinations, and now we have enough follow-up to look at that.

(57:09)  So, I would say it depends a little bit on which statistics people are talking about. We do know that vaccinated individuals, there are certainly breakthrough cases as we are seeing in the comments. But vaccinated individuals post-transplant, vaccines definitely are protective, but they are certainly less effective than we see them in the normal population. Some reports suggest about 70 to 75% efficacy as opposed to close to 93, 95% efficacy of the vaccine, of the mRNA vaccines in a normal population.

(57:45) And I should say that we at least also think that vaccines not only can be protective from getting the infection, but they could also lead to less severe disease when people do get infected. So, yeah, I don't know exactly which statistics this question was about, but just to kind of give you a general sense of the stuff that we have. We will have more and more data on the vaccinated individuals, obviously, because that has definitely ... This is becoming more and more the norm, so we will have more data on that. We just need time to see these data.

(58:28) [Marla O'Keefe] Thank you. All right, this will be our last question. Do you know if it is okay to get the vaccine if you have antiphospholipid antibodies?

(58:47) [Dr. Areej El Jawahri]       Yes, from my understanding it is safe. I would say probably getting the mRNA vaccine would be considered safer, more that the J&J vaccine has been related to having other clotting issues. Again, that risk is extremely, extremely low, but those risks have not been seen with the mRNA vaccines. So, I would say since the antiphospholipid antibody syndrome can sometimes be related to clotting, staying away to an additional risk from the vaccine would make sense.

(59:20) [Marla O'Keefe] Closing. Okay, thanks for helping me out there on that word. All right, I think we're going to need to close this session now. Thank you, Dr. El-Jawahri and Dr. Letourneau for an informative presentation. On behalf of BMT InfoNet, I would like to thank you and Incyte, who sponsored this webinar, as well as all those who participated in the webinar.