Pfizer vaccines are stored in a secure, locked cage in...

Pfizer vaccines are stored in a secure, locked cage in the basement of Ohio State's Schottenstein Center.  Credit: TNS/The Columbus Dispatch/Doral Chenoweth

COVID-19 shots may not work fully or at all for millions of immunocompromised Americans, about 3% to 4% of the U.S. population.

Emerging research shows that 15% to 80% 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.

Maria Hoffman's adopted hometown of Charleston, South Carolina, 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% acting like I am not immunized."

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. "If you aren't wearing a mask, we can't make you now," she said.

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 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 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, prednisone.

"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 Johns Hopkins 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.

The good news, Segev 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.

T cells may help

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, 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.

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.

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 is also concerning: A May 5 study published in JAMA found that 46% of 658 transplant patients did not mount an antibody response after two doses of the Pfizer-BioNTech or Moderna vaccines.

Researchers think this lack of reaction is probably a result of the immunosuppressive drugs they take.

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% 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.

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.

Seeking solutions

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.

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

Hoffman 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.

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

Latest videos