George Franklin received a kidney transplant 46 years ago. Now age 67, he is among the longest lived kidney transplant recipients. But during the pandemic, he has not been able to engage in many of the activities he normally enjoys—bowling, swimming or just visiting friends and neighbors. 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 he received the Johnson & Johnson COVID vaccine—the first one he could get—but he has not developed detectable levels of antibodies.

Many people who are vaccinated have simply gone on with their lives, “but those of us that have no antibodies, it’s as if we’ve never taken a shot,” Franklin says. “At 67 years old, and having had a transplant for 46 years, you don’t want to blow it.”

Franklin is one of many Americans who are part of this vulnerable club. Former secretary of state Colin Powell died in October from COVID complications. 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. Powell, who was 84 years old, had also been diagnosed with Parkinson’s disease.

Throughout the pandemic, most people have had to adjust to the restrictions of life under COVID. 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 immunity-suppressing treatments such as steroids, chemotherapy or drugs that prevent the rejection of transplanted organs.

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. But there are also some hopeful signs: additional doses of some COVID vaccines, strategic timing of immunosuppressive treatments and prophylactic COVID treatments may boost protection among some immunocompromised individuals—and restore at least some of the freedoms they have lost.

The COVID vaccines’ clinical trials did not include immunocompromised people, so less is known about how well they work in that population. 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 individuals. 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 rheumatologic or inflammatory disorder.

Back in March Dorry Segev and his colleagues at Johns Hopkins University published a study in JAMA that included more than 400 organ transplant recipients who received an mRNA COVID vaccine (either Pfizer’s or Moderna’s). The researchers found that only 17 percent had detectable levels of antibodies to the virus after one dose, and those who had Moderna seemed to do better than those who had Pfizer. In a subsequent study that included more than 650 transplant recipients, they found that 46 percent had no detectable response after one or two doses of the Moderna or Pfizer vaccine; 39 percent did not have a response to one dose but did after a second. A separate study found that transplant recipients who had the Johnson & Johnson vaccine were much less likely to have a detectable response than those who had an mRNA vaccine. In September Segev and his colleagues also published a study in the Annals of Internal Medicine of 30 transplant recipients who received a third dose of a COVID vaccine. Six of the patients had low but detectable antibody levels after their initial two shots, and 24 had no detectable antibodies. Of those that 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.

The findings helped form the basis of the CDC’s decision to make a third dose available to immunocompromised people, Segev says. “In some folks, a third dose helps a lot and gets them over that hump to a more protected level of antibody,” he says. In some others, however, “it does not get them fully over that hump.” Segev notes that many people who have autoimmune diseases and got a third COVID vaccine dose now have very high levels of antibodies, whereas “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, 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 group that is highly vulnerable to COVID is patients with blood cancers such as Powell. Nearly 35,000 Americans 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, who asked that her married name be used to maintain her privacy, was diagnosed with multiple myeloma last year. “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 so after a third. She takes a steroid medication as part of her myeloma treatment, but she decided to pause taking it briefly around the time she got her third shot. (She informed her doctor of her intention. Patients should always consult their doctors 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?”

James Berenson, medical and scientific director of the Institute for Myeloma & Bone Cancer Research in West Hollywood, Calif., and his colleagues published a study of the immune response to mRNA vaccination among multiple myeloma patients in July in Leukemia. 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.

Antibody levels are only one part of immune protection, however. Cells known as B cells and T cells also form an important part of the body’s adaptive immune system. But they were not measured in the study.

Berenson says he and his colleagues have a paper coming out in a few weeks on the effect of additional vaccine doses in multiple myeloma patients. Although he cannot yet comment on the results specifically, he says they were “shockingly promising.”

People with some types of autoimmune diseases have had fairly good responses to vaccination. For example, 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 (MS), 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 immunity-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 MS 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.

Johns Hopkins’s Segev recommends a three-pronged approach to improving the vaccine response among immunocompromised people. First, he recommends trying a third dose. If that does not work, some patients may be able to temporarily reduce the amount of immunosuppressive medication they are on (though 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. Monoclonals are currently authorized for use after confirmed infection or exposure to COVID, but Segev hopes the Food and Drug Administration will consider allowing this option for prophylactic use.

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 healthy people who have had two doses. The whole 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.”