‘It’s Kind of a Catch-22’: Immunosuppression and COVID-19 Vaccines – MedPage Today

A recent study found fewer than 20% of solid organ transplant patients mounted detectable antibodies to SARS-CoV-2 following a first dose of COVID-19 vaccine, raising questions about vaccine protection in this population compared to immunocompetent people.

In the first part of this exclusive MedPage Today video, Editor-in-Chief Marty Makary, MD, MPH, of Johns Hopkins University in Baltimore, speaks to Dorry Segev, MD, PhD, associate vice chair of surgery at Johns Hopkins University School of Medicine and professor of epidemiology at Bloomberg School of Public Health, who authored the study. They discussed the study's findings, their applicability to those with chronic medical conditions on immunosuppressive therapies, and whether CDC's post-vaccination guidelines should be adjusted for these patients.

Following is a transcript of their remarks; note that errors are possible.

Makary: Hi, I'm Marty Makary with MedPage Today. I'm here with Dr. Dorry Segev, a professor and transplant surgeon at Johns Hopkins, a good friend and colleague. Dorry released a big study out this week that's making a lot of headlines and I thought we could talk to him about it. Dorry, welcome. Good to see ya.

Segev: Thanks Marty. Thanks for having me on.

Makary: Let's talk about the study that you have. It's an amazing study, it's on immunocompromised, immunosuppressed patients and you found that their antibody response is far weaker, almost a small fraction of what immunocompetent people have. Can you describe your study for the viewers here?

Segev: Yeah. So for context if you look at the big randomized trials, you know, tens of thousands of patients, basically 100% of immunocompetent people after dose one of the two-dose mRNA series already have detectable antibodies.

Makary: And how long, how long does that take, Dorry, to form, about a week and a half? Two weeks?

Segev: Two to three weeks is when they tested. It may form a little bit earlier, but certainly by two to three weeks after your first dose, nearly 100% of people have detectable antibodies. Obviously it goes up after your second dose, but it's detectable enough for us to consider it positive antibody by that early time period. Now in transplant patients, what we found is that only 17% have detectable antibody after dose one. Only 17%. And I'll just give you a little bit, a little overview of how we did the study.

So, we don't have access to vaccine like the big vaccine companies. So we did a post-marketing real world study. The day the first EUA became approved, we announced over social media that we were opening this study and that any transplant patient who was interested in participating can register on our website, transplantvaccine.org, and can send us their pre-vaccine samples, and then as soon as they get vaccinated, we can follow them post vaccine. We have more than 3,000 participants.

The first thousand came in like the first week, it was truly amazing. And a lot of the people who participated particularly early are healthcare workers. So, you know, to those watching who are healthcare workers, thank you for always contributing to research, even with your own participation in studies. And so we caught people as early as we possibly could, who had access to the vaccine. And so now we have data on hundreds of people who already got the vaccine, already got dose one, already got dose two, who are immunosuppressed, and we are able to follow what's happening to their antibodies. And so, we know that only 17% get detectable antibodies after dose one and worse, if you're on an antimetabolite like MMF or azathioprine, only 8% of people on an antimetabolite will have antibody after dose one. Which, as you might imagine, is quite scary as a transplant patient.

Makary: So your study was published this week in JAMA, and pretty remarkable, by the way, how you've been able to creatively recruit and find these people using social media. Is that recruitment process still open if somebody has transplant patients that they'd like to send your way in terms of the data?

Segev: Yeah, our recruitment is ongoing. And a lot of the reason for that is that there are new vaccines. So now the J&J is out, and we're certainly looking for transplant patients who are about to receive the J&J vaccine. But also we're looking at subgroups like people who are transplanted quite recently, people with more rare phenotypes. So basically we're encouraging any transplant patients to go to transplantvaccine.org and register if they want to participate. And we will tell them if we are recruiting people of that phenotype at that time.

Makary: What does this mean? You studied organ transplant recipients. What does this mean for say non-organ transplant recipients who are on immunosuppressive medications for other reasons?

Segev: So we are studying that. So we have a parallel study, vaccineresponse.org, which covers people with chronic conditions. A lot of which either the condition itself or the medications they take are immunosuppressing. And so we're studying people with autoimmune disease, IBD, cirrhosis, ESRD, HIV, et cetera. We're just starting to get data from that. I'll give you kind of the, the gestalt is that if you are on immunosuppression agents, such as mycophenolate, azathioprine, you will probably have a blunted immune response, no matter what reason [there] is for taking those immunosuppression agents.

Makary: And what's your pretest hypothesis in terms of how blunted relative to the significantly blunted response that organ transplant recipients have had?

Segev: Pretty blunted. I think that's our pretest hypothesis. I mean, these agents, they work, they blunt the immune response. And part of that is blunting the immune response to a vaccine, which is, it's kind of a catch-22, because I want my transplant patient immunosuppressed so that they don't get a rejection, they don't get development of de novo donor specific antibodies, et cetera. But I also want them to respond to the vaccine.

I'll tell you some other interesting things. In transplant patients who had COVID-19, in convalescent transplant patients, we do see an immune response that is actually relatively durable. So we published another paper a couple months ago, looking at people who are three to six months out from getting COVID who were transplant patients. And they actually had detectable antibody. I will say though, that the first thing we do when a transplant patient develops COVID, now they're sick with COVID, we turn off their MMF. And so it could very well be that by dropping their MMF so that they could recover from the disease, we also allowed their immune system to develop a durable, natural immunity to that disease.

We're also seeing in people who are convalescent, who then get the vaccine, they also have a very good response to the vaccine. So I think it's some combination of the natural priming from the initial COVID infection, then the vaccine can do some of its work. It could very well be that if we gave transplant patients a third dose, that they may be as responsive to the vaccine as immunocompetent people. But right now we're just not able to do that because that's not how the vaccine rollout is working.

Makary: Sounds like a great study to consider for somebody. There's a body of literature on those who may be immune without antibodies. Their T-cells may be activated and elevated, and it may be more common in these European studies, among people who are asymptomatic, they had the infection, but felt great. Any thought about whether or not there may be some immunity, either partial or minimal among people that have been vaccinated, but have no antibodies?

Segev: Yeah. I mean, certainly T-cell immunity is really important as we know. There's a reason we have T-cells and they help. And we just don't know in transplant patients. Part of what we're doing in our study is looking at T-cell responses. Now, I call this real science, right? There's measuring antibodies -- I can send somebody and get an antibody test and think I'm doing science, but really to do real science, you have to actually study the repertoire of T-cells, the activation of T-cells and things like that. Real science obviously takes more time. So we're still trying to understand what is happening in the T-cell repertoire of these transplant patients. But it's quite possible that they're getting an immune response that's T-cell mediated that's not antibody mediated.

I will tell you though, anecdotally, half of medicine is done through science and half of medicine is done through, "Well, this is what happened to my last patient, so I'm going to change my practice entirely based on this anecdote."

You know, anecdotally I have like last week, there were new guidelines released that said that vaccinated individuals can relax their public health measures. And just yesterday, I talked to one of my colleagues in New York who told me about two patients, transplant patients, who completed their vaccine series, read the guidelines last week and said, "Oh, wow, we're great." Went out, got COVID and are now hospitalized with COVID infection.

So, you know, there are breakthroughs, there are known breakthroughs through the current vaccination practices. And I would certainly let this be a strong caveat that transplant patients should not assume they have immunity just because they finished vaccination. And I'm worried that people will relax their public health behaviors as that's what the talk is. But if you're immunosuppressed, if you are a transplant patient, that is not a wise thing to do today, without at least checking your antibodies and understanding what kind of immune response you got.

Makary: Dorry, roughly how many people in the United States have had an organ transplant and how many more have some degree of immunosuppression, is it about 10 million people that have had some immunosuppression?

Segev: Yeah. So the estimates are about half a million people are walking around with an organ transplant who are on some amount of immunosuppression. And there are about 11 million people taking immunosuppression for other conditions like autoimmune conditions.

Makary: So your study just published has a lot of implications for the CDC. And one of the reasons I wanted to give you a platform here to say something is that, I would hope that the CDC could modify those guidelines they just put out on what vaccinated people can do based on your study. If you were to modify those guidelines, what do you think the stipulation should be?

Segev: Yeah, I mean, you know, in fairness, there is a small fine print caveat in the CDC guidelines that say immunocompromised patients, we don't know what's going to happen with the vaccine. I would love for it to be stronger, for it to cite the JAMA paper that we just published. So we published it two days ago and we've gotten 55,000 views on this paper. And I think all 55,000 have emailed me with questions about it, which is fine. Anyone's welcome to email me. But it may take me some time to get back to them.

I would love for the CDC to say much more firmly, if you are taking immunosuppression do not assume you have immunity because you have been vaccinated. I would also love for this country to prioritize the caregivers' immunization, to prioritize vaccines for caregivers of people who are not going to have a good immune response to the vaccine. So transplant patients live with family members who take care of them. They should be vaccinated to protect the transplant patient because the transplant patient can't necessarily mount their own protection.

And the third thing I would love to see is some way for transplant patients who, after two doses, have had no immune response, to either get a third dose or to get a different agent. So maybe if the mRNA approach didn't work, get the Johnson and Johnson or something like that, to either cross over to a different system of vaccination or to just get a third dose of the vaccine they've already gotten. And I would love for that to be available to people.

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'It's Kind of a Catch-22': Immunosuppression and COVID-19 Vaccines - MedPage Today