Maria Hoffman feels as though she has been left behind. Her adopted hometown of Charleston, S.C., is hopping — with restaurants and bars fully open, park concerts in full swing and maskless friends reuniting with hugs on streets.

Hoffman, 39, is fully vaccinated and eager to rejoin the world. But as a kidney transplant patient, she is hesitant to participate for fear of becoming infected. “Risk is very different for people in my situation,” she said. “I am 100 percent acting like I am not immunized.”

The state worker is among millions of immunocompromised Americans, about 3 to 4 percent of the U.S. population, for whom the shots may not work fully, or at all, and who are unsure of their place in a country that is increasingly opening up. Emerging research shows that 15 to 80 percent of those with certain conditions, such as specific blood cancers or who have had organ transplants, are generating few antibodies.

Federal health officials’ decision last week to rescind almost all masking and distancing recommendations for those who are fully vaccinated only added to the sense of fear, isolation and confusion for those with immune issues. On Twitter and other social media platforms, many such patients expressed frustration that the change might leave them with less — not more — freedom as their risk of infection grows as more of their neighbors and co-workers ditch their masks.

On May 16, Rochelle Walensky, director of the U.S. Centers for Disease Control and Prevention, spoke about the agency’s change on mask-wearing. (The Washington Post)

Hoffman, who has been advised by her doctors to act as though she never got the shots, recounted how she visited a grocery store Thursday but became anxious and left after a maskless man struck up a conversation.

“I wear my mask out of respect for others, and for those who are sick,” she said. “If you aren’t wearing a mask, we can’t make you now.”

Vaccine makers excluded immunocompromised people from their clinical trials in an understandable rush to develop a way to protect as many people as quickly as possible. As a result, there’s limited information about how this group is reacting to the shots, as well as to the loosening of Centers for Disease Control and Prevention restrictions.

The ability of such patients to fend off the novel coronavirus is not just a footnote in the pandemic involving one unlucky group — but potentially a critical part of the narrative about how new, more contagious variants are continuing to emerge worldwide.

The interaction between immunocompromised people and the virus is perhaps one of the pandemic’s most fraught questions. Case studies have detailed how some patients can have active infections for many months — resulting in questions about whether they can act as incubators for mutations that lead to new variants and underscoring the need for an effective vaccine strategy not just for their sake, but for the greater good.

CDC Director Rochelle Walensky and White House adviser Anthony S. Fauci highlighted the challenges of such patients and the vaccines in a recent news briefing in which they acknowledged that the first documented case of the so-called New York variant, B. 1.526, was found in a patient with advanced AIDS.

“Early studies actually show that these variants could emerge in a single host — in a single immunocompromised host,” Walensky said.

But neither the federal government nor vaccine makers Pfizer-BioNTech and Moderna has stepped up to do a comprehensive study about whether the vaccines protect people with immune issues. As such, most of the research has been conducted piecemeal in academic centers — and many are reaching differing, sometimes conflicting, conclusions.

Early data suggests that the vaccines offer some protection, although perhaps to a lesser degree, for most patients with HIV and autoimmune conditions such as rheumatoid arthritis. But there’s worry about people with blood cancers and transplant recipients. Some of the weakened response appears to be related to certain immunosuppressive drugs, and potentially a commonly prescribed steroid.

“The overwhelming majority of transplant patients, even after a second dose of the vaccine, appear to have suboptimal protection — if any protection — from the vaccine, which is frightening, disappointing and a bit surprising,” said Dorry Segev, a researcher at the Johns Hopkins University School of Medicine.

For most of the pandemic, Segev said, it was rare to see transplant recipients get sick with covid-19, the disease caused by the coronavirus, because they had been so careful about staying at home. But that changed over the past two months, with newly infected patients now coming in at a pace of nearly one each day, he said.

Many tell the same story: After being fully vaccinated, they had finally ventured out for a meal, reunited with family members or otherwise relaxed their social distancing precautions.

“We expected a slightly blunted effect,” Segev said, “not something this stark.”

The good news, he and other researchers say, is that scientists are prepared with some potential solutions, such as boosters or high-dose shots. They just need to scramble to study them so they can offer them as soon as possible.

Immune mystery

The body’s immune system can be a capricious thing.

It can serve as a defensive shield one minute, and then shift into overdrive the next and attack itself. Many scientists believe that figuring out the puzzle of how the different components work together and how to control them is one of the holy grails of medicine that could lead to cures for many of the ills that plague humanity.

But compared with, say, the heart, researchers’ understanding of the immune system is still limited. They’ve long known, for example, that vaccines work better in some people than others but they are still trying to figure out why.

From studying other vaccines, for instance, they know that age and underlying conditions can be factors. People older than 65 have been shown to produce 50 to 75 percent fewer antibodies in response to flu shots than their younger counterparts, which is why manufacturers produce a high-dose version for them. HIV patients often receive three hepatitis B shots, instead of two.

Given this knowledge, some differences in the coronavirus vaccine response of immunocompromised people were expected.

Most of the work has looked at only one facet of the immune response — the creation of antibodies, which are simple to measure with a blood test. Studies have mostly focused on the mRNA vaccines made by Pfizer-BioNTech and Moderna because they are most widely used.

At the University of California at San Francisco, Monica Gandhi and her colleagues found that HIV patients seem to produce fewer antibodies on average, but she is optimistic that the amount is sufficient to protect most people.

She said one recent study showed that another arm of the immune system — T cells, or the white blood cells that fight infection — appear to respond to the vaccines similarly in both HIV patients and those without the disease.

“With the antibody response being blunted, but the T-cell response not, it may mean more susceptibility to mild infection, but not likely severe disease,” she said.

Gandhi said that although more research is needed, the strong T-cell response may reflect how many people with HIV in the United States are quite healthy because they are treated with retroviral drugs. She said the situation may be different in Africa and other parts of the world for those not on treatment. She said she gave one of her vaccinated patients who had zero antibody response an extra dose of the Johnson & Johnson coronavirus vaccine.

For most of her patients, however, she said she has “no concerns yet.”

“We are a very tightknit HIV community. We all talk, and would know if we were seeing a lot of breakthrough infections,” she said. “But fortunately we are not.”

‘Disheartening’

The results have been more disappointing for some other types of immunocompromised patients.

Mounzer Agha, a hematologist at the University of Pittsburgh Medical Center and lead author of a study on blood cancers and the vaccines posted online before peer review, described how crushed he felt when he saw the low antibody results for nearly half of the 67 patients his group tracked.

Patients on treatments that impact B-cell function appeared to have the weakest results. That made sense to him because B cells produce antibodies.

But the data also contained what he called an “unwelcome surprise”: Patients with a condition known as chronic lymphocytic leukemia had a very weak response even if they were not undergoing treatment. The condition, which affects the blood and bone marrow, can sometimes be asymptomatic.

“When I found patients who had never received therapy still did not respond to the vaccine, that was very disheartening,” he said. “Now what are you going to do for these individuals?”

Agha said his clinic has been scrambling to reassess care plans in the context of the pandemic. Some patients who are more stable are taking cancer treatment “holidays” while they get the vaccine; others have opted to forgo the shots.

“The information has come out so recently that there are no clinical guidelines, and decisions have to be made on a case-by-case basis on the fly,” he said.

Agha said he fears that for some patients, the vaccines may never work even at higher doses, and that they will have to rely on the inoculation of those around them for their safety.

“Everyone should get the vaccine for the sake of their loved ones,” he urged. “Everyone knows someone who has cancer. And if you care about that person, you should get the vaccine and tell your friends to get it.”

As for transplant patients, the early data are also concerning: A May 5 study published in JAMA found that 46 percent of 658 transplant patients did not mount an antibody response after two doses of the Pfizer-BioNTech or Moderna vaccines.

“Although this study demonstrates an improvement in … antibody responses in transplant recipients after dose two … these data suggest that a substantial proportion of transplant recipients likely remain at risk for covid-19 after 2 doses of mRNA vaccine,” the researchers wrote. They think this lack of reaction is probably a result of the immunosuppressive drugs they take.

Segev, a co-author, said that although antibody reaction is only part of the picture, “knowing what we know about immunosuppression, I would be surprised if transplant patients who had no antibody response had a robust T-cell response.”

“The irony of it all is transplant patients were being very, very careful,” he said, adding: “It’s a very scary problem.”

In St. Louis, Washington University’s Alfred Kim said that although the majority of patients with autoimmune conditions who were studied are mounting a healthy antibody response, about 15 percent had very blunted or undetectable antibody responses. The participants in the study had a wide range of illnesses, including inflammatory bowel disease, systemic lupus and rheumatoid arthritis.

The original study, which has not yet been peer reviewed, was based on 133 people, but it has now grown to more than 300, with similar results.

As with the blood cancer study, many of those most severely affected were on B-cell-depleting medications, such as rituximab, used to treat certain autoimmune diseases and cancer, or ocrelizumab, a newer drug for multiple sclerosis.

Patients taking drugs for rheumatoid arthritis were likely to have a moderately reduced response.

Kim, an assistant professor in the division of rheumatology, said one perplexing finding is that steroid use also appeared to diminish the vaccine response. Although he cautioned that only a small number of patients were involved, he said prednisone, which is used to treat such conditions as arthritis in adults and breathing difficulties in children, appeared to result in a tenfold reduction in antibody production, regardless of the dose given if administered around the time of the vaccine.

“Right now, we’re telling them to pretend they weren’t vaccinated,” Kim said. “That is the easiest solution but it’s only a short-term one. The step beyond is: What do we do to mitigate this?”

Boosting immunity

Numerous potential solutions for the immunocompromised are being debated. One simple idea is to provide one or more booster shots for those with weak responses. So an immunocompromised person might get three doses of the Pfizer-BioNTech or Moderna vaccine, instead of two.

Another possibility is to try preventive doses of lab-produced antibody proteins known as monoclonal antibodies that until now have been mostly used as treatments for those who are infected with the coronavirus.

One thing doctors don’t recommend is for vaccinated people to get antibody tests. First of all, no one knows what levels of antibodies are effective against the virus. Moreover, Kim emphasized that antibodies are only one part of the immune system and that it’s possible that the vaccines have activated other, more difficult-to-measure components.

“It’s not something that we can act on,” he said of such information. “All it can do is mount worries for the patient.”

Many physicians urge immunocompromised patients to continue to practice social distancing and take other precautions.

Seville Christian, 60, an HIV-positive substance abuse counselor in San Francisco, has been working in person through the pandemic and said she plans to continue to do so.

But she said optional social outings will remain off the table. Even though she planned to get her second shot May 12, she will go to restaurants only for takeout, meet friends virtually and minimize her time in stores until the science is clearer.

She’s still weighing whether return to her to church, fully masked, when it reopens.

“I wish I could go back to normal, but there are still a lot of questions I have,” Christian said.

Hoffman, too, is struggling to navigate the new normal in Charleston. After having a kidney transplant at age 9 and spending most of her childhood in hospitals, she is acutely aware of her mortality. So she said she tries to find the right balance between living her life and staying safe.

When a friend gets married in Ohio in a few weeks, she hopes to go and participate in the outdoor events. She is also talking to friends about reserving a socially distant spot for an outdoor band performance. But otherwise, she’s continuing to keep her distance from others.

“I just love talking to people and meeting people,” she said. “It has been crazy and lonely.”

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