INTERVIEW BY STEPHANIE DESMON
Dorry Segev, MD, PhD ’09, has been conducting research on the immune responses of people who are fully vaccinated against COVID but, because of their compromised immune systems, are not protected from the virus.
Segev is a Johns Hopkins transplant surgeon with a joint appointment in the Department of Epidemiology at the Bloomberg School.
Tell us about COVID-19 vaccines and people with compromised immune systems.
The COVID vaccines are a huge celebration of effectiveness. We've made this vaccine that's unbelievably good, and that works in nearly everybody with normal immune systems.
But there's a problem in that iIn order for a vaccine to work, it needs to activate your immune system to create B-cell responses, T-cell responses, antibody responses, et cetera. And there are people—millions of them in the United States and—who take immunosuppression medications. [These medications] specifically target certain parts of the immune system, for example, to prevent transplant rejection, or to prevent your immune system from attacking yourself in autoimmune diseases.
In these people, the immune system’s ability to respond to this vaccine is blunted. As a result, what is a celebration among everybody with normal immune systems is quite frustrating and frightening among people with suppressed immune systems.
You've recently published a paper about transplant patients. What did you find?
We've been studying transplant patients and people with autoimmune conditions since December 2020, when the FDA granted the vaccines emergency use authorization. In transplant patients in particular, the antibody response to vaccines is blunted.
To put some numbers on it: After one dose of the vaccine, 100% of people with normal immune systems will have some detectable antibody. Only 20% of transplant patients will show detectable antibodies after one dose. So that is a stark difference.
With the second dose of two-dose regimens with the mRNA vaccines, people with normal immune systems not only have an antibody response, but it's off the charts. And, still, half of transplant patients have no antibody response at all. In those who do have an antibody response, in general, the levels are much lower than those in people with normal immune systems.
This is quite frightening, but it's not a great surrogate for protection.
Why isn’t an antibody response a great surrogate for protection?
The immune system is complex. To simplify, we can imagine it as antibodies that are sitting around in your blood; B cells, which can make antibodies; and T cells, which do all sorts of other things like help B cells. All of these things need to work together.
What we can measure right now are antibodies. But the antibodies are the tip of the immunologic iceberg, and a lot is going on under the surface that we cannot measure.
It is possible that you could have a lot of antibodies but still have a blunted T cell response, for example. You need both of them to mount a protective response against the virus. In most people, antibodies would be a good surrogate because the antibodies, B cells, and T cells are all tied together.
But in people who take medication that blocks certain aspects of the immune system, this can be uncoupled. You can have intact B cell response, but your T cell response is totally blunted. With no T-cell response, there is no protection.
So that's why measuring antibodies in people on immunosuppression gives us some information, but it's hard to say “you have a lot of antibodies, so you must be protected” or “you don't have a lot of antibodies, so you must not be protected.”
So, should transplant patients get their antibodies tested?
The CDC doesn’t recommend antibody testing across the board, which makes sense because people with normal immune systems are going to have a good response—the efficacy [of some vaccines] is over 95%.
Transplant patients [may wish to] get an antibody test. Like a lot of things in medicine, a test is data but it's not all of the information.
If you're a transplant patient, and you had two doses, then you wait a month and get a reliable test and it's negative—that probably means you don't have good immunity.
The problem is with a positive antibody test. There's a wide range of “positive.”
Let's even say [your response is] off the charts. We still don't know if you have an intact T-cell response. And, in fact, a lot of transplant patients are on T-cell inhibitors, because the T-cell response is what facilitates acute rejection in the organs.
So, the results of an antibody test might not make any difference for patients trying to calculate their risk levels?
A positive antibody test—even a high positive antibody test—is not necessarily a promise of protection. If you're a transplant patient and you get tested, regardless of what your test shows, we're going to tell you to be careful out there until we have a better sense of the connection between what we see above the surface and what is happening below the surface.
What can be done for these folks? Would booster shots help?
That's the huge question for people with suppressed immune systems.
First of all, everyone should get vaccinated—unless you're one of the very, very, very rare people with a contraindication to vaccination—so we can reduce population prevalence and [protect] the immunosuppressed, vulnerable people we share this planet with. All transplant patients are recommended to get vaccination so that something starts to happen in your immune system.
The second thing is, if two doses didn't work, maybe a third dose will work. This [research] is happening: When we published our JAMA paper, one of my colleagues in France took it to the government and said, “We need to make doses available.” The French government initially said, “OK. Anyone who's immunosuppressed can have access to a third dose.”
When our second JAMA paper came out, the French government changed [their messaging] and said anyone who's immunosuppressed is recommended to get a third dose. I'm sure multiple studies are going to come out of France to tell us how this is working.
At the same time, there are people in the United States getting some sort of third booster dose. People are just doing it—people with immunosuppressed conditions and transplant patients [who] know how to navigate the health care system and know how to get what they want from the health care system.
In our observational study, we have studied people who have gotten their [third] doses. We're putting those data together, and they will hopefully be published soon. There's certainly going to be subsets of patients who didn't have a robust response to two doses who will have a much better response to three doses. And then there will be some who don't.
For those who don’t have a response to that third booster, what do we do? Does that mean reducing their immunosuppression?
That's risky. If you're a transplant patient, that means you could get rejection. If you're an autoimmune patient, that means you could have a major flare or something like that.
These decisions are tough, because they really require this risk-benefit balance: “What is the bad thing that will happen to you if we reduce this immunosuppression that you're on for a reason,” versus “Do we really need you to have a better immune response?”
On the flip side, a potentially less risky approach might be [the use of] monoclonal antibodies. There's been a lot of enthusiasm for post-exposure monoclonal antibodies. Giving these to transplant patients might be a way to buy us some time as we learn more. I have heard stories of people getting monoclonal antibodies through compassionate use arrangements with the FDA.
That’s starting to be explored, as community prevalence is not as low as we would like for it to be right now. There have been a lot of major changes in behaviors in vaccinated people, and with masks, and many abrupt changes in state mandates, and things like that. So right now, the environment is probably even a little bit more risky for a transplant patient than it was a month ago.
So everyone needs a vaccine, not just for themselves, but for the transplant patients and the compromised patients who can't make their own immunity?
For sure. Millions of people out there are vulnerable to this disease and [lack] the ability to mount an immune response to the vaccine. Those of us with normal immune systems need to be making antibodies to protect people with vulnerable immune systems.