The complex situation for immunocompromised people and COVID-19 vaccines

Studies suggest the available shots don't provide enough protection, leaving more than nine million Americans with compromised immune systems stuck in a waiting game.

When Margaret Collins, a 43-year-old geologist from Fort Worth, Texas, got her first dose of the Moderna vaccine January 6, she came home and cried.

“I was finally getting the shot,” she says. “I saw it as a step back to the life that I loved.”

A self-described extrovert, Collins became a hermit during the pandemic. She and her husband rarely stepped outside, and never without a mask. Her caution is warranted because she suffers from a generalized autoimmune disorder that includes hepatitis, psoriatic arthritis, vitiligo, and type 1 diabetes. Collins is also particularly vulnerable to COVID-19 because she received a donated pancreas and kidney in 2014 and takes three medications to suppress her immune system so her body doesn’t reject those organs. Yet, vaccines work by harnessing the capability of a fully competent immune system.

Since the FDA authorized the first COVID-19 vaccine, people with compromised immune systems have lived in limbo, waiting to find out whether, or how much, vaccination might protect them. The vaccine clinical trials excluded nearly all immune-compromised people because including them might interfere with determining vaccine effectiveness for the general population. But that’s left this group with little data on what vaccination means for them. Now studies are trickling in.

“We’re starting to learn some of the things we don’t know, whereas before, it was a bunch of we don’t know what we don’t know,” says Peter Martin, a hematologist and oncologist at Weill Cornell Medicine in New York City.

It’s difficult to gauge the number of immune-compromised people in the U.S. One study estimates that 2.8 percent of people with private insurance take immune-suppressing drugs—about nine million Americans. But that doesn’t include Medicare or Medicaid patients, who are more likely to have some conditions requiring immunosuppression, says study author Beth Wallace, a rheumatologist at University of Michigan Medicine. It also doesn’t include people with immune-compromising conditions who aren’t taking immune-suppressing medications.

From the very beginning of the pandemic Collins worried how her body would respond to the vaccine. But when she later read a study of organ transplant recipients that found low antibody levels after the first mRNA vaccine dose, she panicked.

Even though she had been vaccinated and wore a mask, she thought “How safe was I? It really scared me.”

A follow-up study that found about half of transplant recipients responded to the vaccine offered her little comfort. “That’s essentially the flip of a coin,” Collins says. But a small study published Monday offers a flicker of hope.

After two doses of mRNA vaccine, 30 transplant recipients with no or low antibodies got a third shot, though not necessarily of the same vaccine they received first. The six people with low antibody levels subsequently developed higher levels, and a quarter of the others, who had never responded to the COVID-19 vaccine, developed antibody levels thought to be high enough to prevent COVID-19 after the third dose.

But this study has substantial limitations: It’s very small and involves a grab bag of different vaccine combinations. Further, the Food and Drug Administration has not authorized a third dose, and the Centers for Disease Control and Prevention currently advises against it. The authors concluded that their findings suggest the need for more studies to test third doses in people without fully functioning immune systems.

A diverse population

Immune-compromised people fall into two broad categories: Either they have an underlying condition that weakens their immune system, such as people with leukemia, uncontrolled HIV, or a rare genetic disease, or they have an underlying condition requiring immune-suppressing therapy, such as organ transplant recipients and people with rheumatic diseases (inflammatory, autoimmune conditions) or some cancers. A few conditions, such as chronic lymphocytic leukemia and lupus, fall into both categories.

Factors that might affect someone’s response to a vaccine include the medication they’re taking and what it does, how long they’ve been taking it, their specific disease, and their history of infection. For organ transplant recipients, the time since their transplant may also matter.

“That’s why it’s really important for people who have these immune-suppressed conditions to talk to an expert about their specific situation, because there is such a great amount of variability,” says Aaron Richterman, an infectious disease fellow at the University of Pennsylvania Perelman School of Medicine, regarding how immune-compromised people can assess their infection risk after vaccination.

Evidence so far is mixed

The wide range of conditions and drugs that weaken the immune system explain why the response to COVID-19 vaccines is so mixed. The evidence so far shows that transplant recipients, certain leukemia patients, and people taking a handful of specific medications have the poorest vaccine response. The drugs that appear linked with the poorest response include mycophenolate (prevents organ rejection), rituximab (treats some blood cancers and autoimmune diseases like rheumatoid arthritis), belatacept (prevents organ rejection), and methotrexate (treats a wide range of cancers and autoimmune diseases).

For example, the organ transplant study Collins read found only 54 percent of 658 organ transplantrecipients had any antibodies after two doses of the mRNA vaccine, particularly if they were taking a drug like mycophenolate. A similar study of 609 kidney transplant recipients found half had detectable antibodies after mRNA vaccination, but only 5 percent of those taking belatacept did. Transplant recipients produced even fewer antibodies in response to the one-dose Johnson & Johnson vaccine.

Studies in people with autoimmune disease have similarly shown that vaccine response typically depends on the specific drug they’re taking.

In a study of 404 people with rheumatic disease who had both doses of an mRNA vaccine, almost all had detectable antibodies, but those taking rituximab or mycophenolate had very low levels. Meanwhile, everyone taking anti-inflammation drugs called tumor necrosis factor (TNF) inhibitors to treat Crohn's disease or rheumatoid or psoriatic arthritis, had strong antibody responses.

Another study (preprint) of 133 people had similar findings: Antibody levels were 1/50 as high in people taking rituximab, a drug that intentionally depletes antibody-producing B cells, as in people with competent immune systems. Those taking certain chemotherapy drugs, rheumatoid arthritis drugs, or prednisone—a steroid that treats inflammation—also had lower antibody levels.

People with certain types of leukemia or lymphomas, particularly non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, also don’t produce many antibodies after vaccination, though people with most other cancers fare better. That’s particularly concerning since some people with CLL don’t know they have it, says study author Mounzer Agha, director of the Mario Lemieux Center for Blood Cancers at University of Pittsburgh Medical Center.

Those are just a sampling of the studies examining different immune-compromising conditions and medications, but all are small, providing only some insight into these specific conditions or therapies.

“What matters is how much immunosuppression you’re getting, what agents you’re getting, and possibly how long you’ve been getting them,” says Dorry Segev, a transplant surgeon and researcher at Johns Hopkins Medicine who wrote the organ transplant studies and several others above.

More than just antibodies

These studies also focus only on antibody response, which is just one component of the immune response.

“We think antibody levels may correlate to clinical protection to a degree,” Richterman says. But even in healthy people, he says, we don’t know the minimum antibody levels necessary to assure protection. Since the significance of antibody levels is ambiguous, the FDA and CDC recommend against antibody testing because it is unclear how to interpret the findings.

“Immunologic responses and effectiveness of a vaccine are two different things,” says Emily Blumberg, director of Transplant Infectious Diseases at Penn Medicine in Philadelphia. “We think vaccinating [transplant] patients may have a benefit above and beyond what you can measure with antibodies.”

That’s partly because vaccines induce immunity in multiple ways. One way is stimulating B cells to make antibodies, which explains why medications that reduce B cells—such as rituximab, methotrexate, mycophenolate, and steroids—result in such poor responses. But vaccines can also stimulate killer T cells, which attack infected cells, and helper T cells, which aid B cells and killer T cells.

“Our understanding of what’s happening on the T cell side is pretty close to zero,” Segev says. Studying T cell responses is difficult and costly, he adds, though his group and others are working on it.

Vaccines can also trigger the production of memory B cells, which remember how to make antibodies. “If you get the virus and the memory cells are there, then you can have a better and faster antibody response the next time around,” explains Ignacio Sanz, chief of rheumatology at Emory University School of Medicine. He believes that presence of memory B cells might partly explain why a third vaccine dose led to antibody production in transplant recipients without previous responses.

The only way to find out how effective the vaccines actually are in immune-compromised people is to wait fordata comparing infections between vaccinated and unvaccinated people in different immune-compromised groups, and that takes time.

What comes next

Where does all this leave the millions of people who don’t know if they are protected by the vaccine, especially with the CDC’s advice that vaccinated people can stop masking?

For now, “get vaccinated, act unvaccinated,” Segev says. But that’s a difficult message to communicate.

“One of the unintended consequences of [that message] is fueling vaccine hesitancy in patients who say, ‘Why should I bother if I’m not going to have a response?’” Blumberg says.

A February study of more than 1,200 people with autoimmune disease found that more than half wanted to get vaccinated, and a third were uncertain, despite studies showing the vaccines are safe for those with inflammatory diseases.

Alfred Kim, a rheumatologist at the Washington University School of Medicine who conducted one of the studies on people with rheumatic disease, agrees it can be confusing to advise patients to get vaccinated without being able assure it protects them, but “even partial protection is better than no protection,” he says.

That introduces another problem: How safely can immune-compromised people go out in public even if vaccinated?

“The CDC guidelines assume everybody is socially responsible, which unfortunately is not the case,” Agha says.

“Masks work, but masks work best if everybody is wearing them,” Segev says. “If you have a superspreader walking around Kroger spewing their Delta variant all over the store, and they’re standing next to an immunosuppressed transplant patient who tried their best to get vaccinated and is still wearing a mask, that [immunosuppressed] person is still at risk.”

While immune-compromised patients have always been more susceptible to infections, even before the pandemic, the stakes are higher now.

“With influenza, it was not such a great concern because patients do survive influenza even when they get quite ill,” Mounzer says. “With COVID, it’s a different story. There’s a real risk of dying from the disease.”

In a post-masking world, that makes even brief trips to the grocery store more complicated—and perilous—for immune-compromised people.

“As a society I think we have an obligation to come up with strategies to prevent those people from getting acutely sick so they can re-enter society like the rest of us are all ready to do,” Martin, the hematologist, says. “They’re just as ready as anybody else, and it’s terrifying to be in their position.”

Blumberg tells her patients to encourage friends, family members, and coworkers to get vaccinated. “The better job we do with vaccinating everybody, the less COVID there will be to make them sick,” she says.

That’s exactly what Collins, the vaccinated transplant recipient from Texas, is doing. But she has friends and family members who refuse to get vaccinated, and that frightens her, not only for herself but also for other immune-compromised family members and friends.

“If we reach herd immunity, then I have less to worry about,” Collins says. But she doesn’t think the country will reach that milestone, “which is scary for people like me.”

If social responsibility does not motivate people to get vaccinated, there’s also the specter of new variants. Evidence suggests that people whose immune systems don’t respond properly to infection could provide an ideal environment for mutations, says John Moore, a microbiologist and immunologist at Weill Cornell Medicine in New York City. “They have a lot of ongoing viral replication in their bodies for prolonged periods of time,” Moore says. “Virus replication in an antibody-low individual can drive the emergence of variants that are problematic on a societal basis, so this is not a trivial issue.”

In other words, protecting the most vulnerable members of society is ultimately the best way to protect all of society.

“These are the patients that are going to be a source of continued infection in the population,” Blumberg says. “If we don’t protect these immuno-suppressed hosts, we will have a harder time getting rid of the virus.”

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