George Franklin III is one of the longest-surviving kidney transplant recipients in the U.S. Now 67, he received his lifesaving surgery 46 years ago, which has enabled him to lead a healthy and active life—swimming, bowling, visiting friends and even competing in a sporting tournament known as the International Transplant Games. But since the beginning of the COVID pandemic, he hasn’t been able to do any of these things. Like most transplant recipients, Franklin, who lives in western Maryland, has to take medication to suppress his immune system and prevent his body from rejecting the donor organ. In March 2021 he received the Johnson & Johnson COVID vaccine but did not develop detectable levels of antibodies. “Those of us that have no antibodies,” he says, “it’s as if we’ve never taken a shot.” (In November 2021 he got the Moderna vaccine and finally developed antibodies.)
Franklin is one of many people who belong to this vulnerable club. Former secretary of state Colin Powell, who died in October 2021 from COVID complications, was among them. He had been vaccinated but suffered from multiple myeloma, a blood cancer that attacks infection-fighting white blood cells and is often treated with drugs that suppress the immune system even further.
The pandemic has forced everyone to adjust to restrictions on normal life. But for those who belong to a broad category known as immunocompromised, even ordinary activities come with extraordinary risks. This umbrella term includes people whose immune systems have been weakened by diseases such as cancer, HIV infection or autoimmune disorders or by immunosuppressant treatments such as steroids, chemotherapy or drugs that prevent rejection of transplanted organs.
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Studies have shown that immunocompromised people are more vulnerable to being hospitalized or dying from COVID and less likely to develop strong protection from vaccination. There have been hopeful signs. Additional doses of some COVID vaccines, strategic timing of immunosuppressant treatments and prophylactic COVID treatments may boost protection among a subset of these people and restore at least some of the freedoms they have lost during the pandemic.
But tempering that hope is the emergence of new variants—such as Omicron—that might erode some of the vaccines’ immunity. In the months after it was first reported, the Omicron variant appeared likely to evade at least some of that protection, and researchers were urgently working to determine just how much.
With Omicron, “I worry a lot for our immunocompromised folks,” says Dawn Bodish, an immunologist at McMaster University and a Canada Research Chair in Aging and Immunity. “A few months ago I said confidently, ‘Ah, fourth doses, nobody’s thinking about that.’ Now we all are—and mixing and matching the vaccine types and really optimizing the dosing regime, so these people can be protected as best as we’re able.”
Incomplete Protection
There is still much we don’t know about how well the COVID vaccines work in people with immunosuppressing diseases or treatments, because the clinical trials that preceded their approval excluded this group for safety reasons. But scientists have begun to study this question. A recent report from the U.S. Centers for Disease Control and Prevention that examined immunocompromised people who received mRNA vaccines found that vaccination was 77 percent effective against hospitalization with COVID, compared with 90 percent for immunocompetent people. But the effectiveness ranged widely depending on the immune condition, from 59 percent for organ or stem cell transplant recipients to 81 percent for people with a rheumatological or inflammatory disorder.
Dorry Segev, a professor of surgery at Johns Hopkins University, and his colleagues have been studying how well transplant recipients and others with suppressed immune systems respond to the COVID vaccines. In June 2021 he and his team published a study in JAMA showing that out of more than 650 transplant recipients who received an mRNA COVID vaccine (either Pfizer’s or Moderna’s), 46 percent had no detectable response after one or two doses; 39 percent did not have a response to one dose but did after a second. In a separate study, they found that transplant recipients who received the Johnson & Johnson vaccine were much less likely to have a detectable response than those who had an mRNA vaccine. This lack of protection could be dangerous: Segev and his colleagues found that vaccinated recipients were 82 times more likely to have a breakthrough infection than the general population and 485 times more likely to be hospitalized and die from it.
To prevent his body from rejecting the donor organ, Franklin takes immunosuppressive medication, but it also makes him vulnerable to COVID and other infections. Credit: Alyssa Schukar
Around the same time, Segev and his colleagues published a study online in the Annals of Internal Medicine of 30 transplant recipients who received a third dose of a COVID vaccine. Six of them had low but detectable antibody levels after their initial two shots, and 24 had no detectable antibodies. Of those who had low antibody levels, all six had high levels after the third dose. But only six of those who had no antibodies had high antibody levels after a third dose.
These findings helped to form the basis of the cdc’s decision in August 2021 to make a third dose available to immunocompromised people, before booster shots were authorized for all adults. In some people—mostly those with autoimmune diseases—“a third dose helps a lot and gets them over that hump to a more protected level of antibody,” Segev says. Most transplant recipients, however, have not been as fortunate. “Only a fraction of transplant patients who got a third dose reach that kind of a milestone.” For people who get vaccinated while waiting for a transplant, however, there is good news. “They will likely have a very, very good vaccine response—way better than they’ll get once they’re on immunosuppression,” Segev says.
Another highly vulnerable group is patients with blood cancers, such as Powell. Nearly 35,000 people in the U.S. are diagnosed with multiple myeloma every year. The disease attacks bone marrow plasma cells, which make antibodies in response to the virus that causes COVID—and to the vaccines. Drugs prescribed to treat it kill off normal plasma cells, as well as cancerous ones, further compounding the problem.
Diana M. Chavez of Los Angeles was diagnosed with multiple myeloma in 2020. “Nothing is more difficult than getting a cancer diagnosis during a pandemic,” she says. “It’s unknown territory.” Chavez, age 66, had to attend doctor’s appointments alone and was not able to have visitors in the hospital because of COVID restrictions. “There was no relative or friend who could be my advocate to remind me of all the questions I had and needed to ask, with all the decisions I had to quickly make,” she says.
Chavez did not develop a protective antibody response after two doses of the Moderna vaccine, but she finally did after a third. She takes a steroid medication as part of her myeloma treatment, but she decided to briefly pause taking it around the time she got her third shot. (She informed her doctor of her intention. Patients should always consult their physicians before stopping or changing any treatment regimen.) “For the first time yesterday, I went out with a friend and had breakfast,” Chavez says. But she is still being cautious. “Sometimes, even under the best of circumstances, when you’re trying to be mindful, things still happen,” she says, adding that the big question about cancer patients who are able to have a response to the vaccine is “How long will it hold? Are we going to have to keep getting vaccinated?”
In July 2021 James Berenson, medical and scientific director of the Institute for Myeloma & Bone Cancer Research in West Hollywood, Calif., and his colleagues published a study online in the journal Leukemia of the immune response to mRNA vaccination among multiple myeloma patients. They found that only 45 percent of those with active myeloma developed an adequate level of antibodies after two doses of the Pfizer or Moderna vaccine, and 22 percent had a partial response. Study participants who received the Moderna vaccine had higher antibody levels than those who received the Pfizer shot, Berenson found. “We discovered older folks like Colin Powell—those who are over about 70 and those people with lower lymphocyte [immune cell] counts, with lower antibody levels reflective of this impaired immune system, who are doing poorly with their myeloma, those people who’ve [had] other treatments or were failing their treatment—were much less likely to respond” to COVID vaccination, Berenson says. He is now studying the effect of additional vaccine doses in multiple myeloma patients, and the results, he says, are “shockingly promising.”
Antibody levels are only one part of immune protection, however. T cells and memory B cells also form a critical part of the body’s immune arsenal after vaccination or infection, but Segev’s and Berenson’s studies did not evaluate them, because they are harder to measure. T cells may provide some protection even in people who lack detectable antibodies.
Before the pandemic, Franklin was physically active and competed in the International Transplant Games. But COVID has limited the activities he can safely do. Credit: Alyssa Schukar
Immune Boost
Reassuringly, people with some types of autoimmune diseases have had fairly good responses to vaccination. Segev and his colleagues studied vaccinated people with rheumatic and musculoskeletal diseases—such as inflammatory arthritis or lupus—and found that the vast majority of them produced COVID antibodies after two doses of the mRNA vaccines.
Clinical neuroscientist Tjalf Ziemssen of University Hospital Carl Gustav Carus in Dresden, Germany, and his colleagues have been analyzing the response to COVID vaccination in patients with multiple sclerosis, a disease in which the immune system attacks the fatty sheath that protects nerves in the brain and spinal cord. It is often treated with immune-modulating drugs called S1P receptor modulators and anti-CD20 monoclonal antibodies. In patients taking the latter, Ziemssen and his team found that the response among B cells (which produce antibodies to COVID) was fairly low but that there was a good response involving T cells (which attack and kill viruses such as the COVID-causing SARS-CoV-2). Patients taking S1P receptor modulators had a weaker response, but about two thirds still developed a B or T cell response, or both.
Ziemssen does not recommend changing the dosing of multiple sclerosis treatment to improve the vaccine response. Rather he suggests that patients getting infusion treatments for the disease should wait a month after an infusion to get vaccinated. In patients who had a good B and T cell response, he recommends a booster shot at six months. For those who did not have a good response, he recommends a third dose given sooner.
Still, many people with other, rarer immune diseases are left wondering whether they are protected against COVID. Dinah S., who asked that her last name not be given to maintain her privacy, has a rare condition called mucous membrane pemphigoid, which causes blistering of the gums and other areas. She takes mycophenolate mofetil, an immunosuppressant drug often prescribed for organ transplant recipients, and has taken the steroid prednisone in the past.
Dinah was part of Segev and his colleagues’ studies. She initially received two doses of the Pfizer vaccine, but an antibody test revealed she had no response. She then got the one-dose Johnson & Johnson shot and was still negative for antibodies. So Dinah next got three Moderna doses, after which she finally achieved a response similar to that in healthy people who have had two doses. The entire process lasted six months. “My ordeal has contributed to approval of boosters for everyone but especially for immunocompromised people,” she says. “Boosters work and are needed!”
Since the pandemic began, Dinah has remained effectively locked down in a “bubble” of three people, taking strict precautions to limit her infection risk. Now that she has a measurable response to her vaccinations, she says she is finally able to relax a bit. “The big excitement that the vaccine brings me is that I might get to go into a grocery store for the first time since before lockdown,” she says. “Fully masked, at a quiet time of day and in a big airy store, but still. The bulk spice and tea aisle calls to me.”
Johns Hopkins’s Segev recommends a three-pronged approach to improving the vaccine response among people with weakened immune systems. First, he suggests trying a third dose. If that does not work, some patients may be able to temporarily reduce the amount of immunosuppressive medication they are taking (although only if their doctor deems this safe) and get another dose. Finally, if vaccination fails, Segev recommends giving patients monoclonal antibodies as a form of passive immunity against COVID. A monoclonal treatment is currently authorized for use after confirmed infection with or exposure to COVID, but Segev hopes the Food and Drug Administration will consider allowing this option for prophylactic use.
Vaccination is not the only protective measure immunocompromised people can take. They can avoid crowds or being indoors with unvaccinated individuals or those with frequent exposure to other people. They can wear a high-quality mask such as an N95 around people they do not live with and increase ventilation by opening windows and using air purifiers. They can have others test themselves before interacting with them. These precautions, though more onerous than a shot in the arm, are effective when layered together. “The best thing we can do for immunocompromised people,” Segev says, “is for everybody else to get vaccinated, so that we protect our vulnerable friends and neighbors.”