Who qualifies for a coronavirus booster shot? Why it’s still unclear.

While people with immune-compromising conditions rejoice over the FDA decision, may questions remain unanswered.

“Finally!” exclaimed Margaret Collins, a 43-year-old geologist from Fort Worth, Texas, in response to the news that the U.S. Food and Drug Administration has authorized the use of booster vaccine doses for some people with weakened immune systems.

The Pfizer-BioNTech and Moderna COVID-19 vaccines normally require two doses to elicit full immunity. But this week the FDA updated its authorization for both shots based on mounting evidence that a third dose could significantly increase protection for certain immunocompromised people, who have been showing a decreased response to these vaccines.

Collins had received both doses of the Moderna vaccine but recently learned that she has virtually no antibodies against the SARS-CoV-2 virus. She tried to get a third dose at a local pharmacy, but the pharmacist told her they couldn’t administer it under the original FDA authorization. After hearing about the revised authorization late Thursday night, she immediately made an appointment for Friday.

“FDA authorization of a booster for immunocompromised people is wonderful news for the millions of immunocompromised people in the United States who have spent the last several months knowing that they had a suboptimal response to the vaccine and desperately waiting for some opportunity to improve their immune response,” says Dorry Segev, a transplant surgeon and researcher at Johns Hopkins Medicine. Segev published the earliest studies on vaccine-induced immune response in transplant recipients.

After initially calling for a moratorium on all COVID-19 booster shots until more people across the world had gotten vaccinated, the World Health Organization clarified its guidance a week later regarding when boosters might be justified, including inadequate protection in certain risk groups. For those who lack fully functioning immune systems, such as transplant recipients, a booster shot might mean the difference between remaining bunkered down at home and being able to venture a bit more into the world again.

“You’re dealing with a transplant community that has faced death and survived,” says Valen Keefer, a 38-year-old patient advocate in Auburn, California, who received a donated kidney 19 years ago and a liver three years ago. “For me personally, I don't want to do anything to compromise or risk my health. But then you have the other side, that you want to live life to the fullest.”

That tension has been exacerbated by people who refuse to wear masks or haven’t had the vaccine yet, says Keefer, spurring some people to seek a booster even before the FDA changed its authorization.

“Our community has been so desperate that they’ve been lying about it and going to get a third booster shot because some people that have no antibody response may have jobs out in the public and can't be as careful. So now, you have people that haven’t even gotten one dose, and you have us begging for a third dose just to protect ourselves.”

A third dose is safe

Several recent studies have shown that a third mRNA vaccine dose is safe to administer to solid organ transplant donors and can increase antibodies in some patients who responded poorly to the first two doses of the mRNA vaccines.

Segev published a case series in June that found a third of fully vaccinated transplant recipients with no antibodies had responded to a third dose, and all those with low levels developed strong antibody responses afterward. A subsequent pair of larger French studies confirmed the safety of a third dose and its ability to substantially boost antibody levels in those with weak or no response to two doses.

The most recent study, published in the New England Journal of Medicine one day before the FDA’s decision, is the only randomized controlled trial of a third dose in organ transplant recipients. It found a significantly greater immune response in the study group that received a third dose and concluded that the dose is “safe when risk versus benefit was considered.”

“These studies showed that the third booster is effective in inducing a good antibody response in this population—but still not to the same level expected in otherwise normal individuals—and hopefully this will be the case for other immune-compromised patients,” says Mounzer Agha, director of the Mario Lemieux Center for Blood Cancers at University of Pittsburgh Medical Center.

The next step will be conducting studies to determine the best timing for a third dose and “how to help those who fail to respond to the third vaccine dose,” he says.

All immunocompromised people are not the same

The FDA’s authorization now allows for an extra dose in “certain immunocompromised individuals, specifically, solid organ transplant recipients or those who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.” That might include people with certain blood cancers or those taking medications such as rituximab, which deplete B cells—the body’s antibody factories.

But the “devil is in the details,” says Peter Martin, a hematologist and oncologist at Weill Cornell Medicine in New York City. “The definition of immunocompromised is vague,” and people in this population vary based on their condition and how much their immune system is suppressed.

“There are probably some people who will not benefit from any number of additional doses, there are some people who might need extra doses to augment their immune response, and there are some people, such as cancer patients, who were transiently immune suppressed when they received their vaccine and are likely now nearly normal and would clearly benefit from an additional dose,” he said. “There is probably another group of people who are mildly immune compromised but responded to the vaccine and probably don’t really need a vaccine. This group with the transient immune compromise clearly has the most to gain.”

Now that the FDA has made its announcement, Emily Blumberg, director of Transplant Infectious Diseases at Penn Medicine in Philadelphia, hopes for more specific guidance from the U.S. Centers for Disease Control and Prevention. The CDC’s Advisory Committee on Immunization Practices meets on August 13 to make its recommendation for whom among the wider group of immunocompromised people should receive a third dose.

“I think that interpretation is going to be very difficult, especially because the levels of evidence vary so widely depending on the population,” Blumberg says.

Alfred Kim, a rheumatologist at the Washington University School of Medicine, also hopes the CDC will clarify the guidance regarding which vaccine brands to use for extra doses. The new authorization only applies to Pfizer-BioNTech and Moderna, leaving no guidance for immune-compromised people who may have received the Johnson & Johnson vaccine.

Paul Offit, director of the Vaccine Education Center and an infectious disease pediatrician at Children’s Hospital of Philadelphia, echoed concerns about grouping all immunocompromised people under one umbrella and pointed out another key question about administering third doses in practice.

“You would like to have some advice on how to manipulate their therapy,” Offit says. For instance, “if you’re getting methotrexate for your rheumatoid arthritis, would it be reasonable when you give a booster dose of vaccine to withhold the methotrexate? If so, for how long?” That kind of guidance could be essential to improving patients’ immune response to the vaccine. “What I fear is going to happen is we’re just going to get a blanket recommendation.”

Offit has previously served on ACIP and currently serves on the Vaccines and Related Biological Products Advisory Committee (VRBPAC), a group of independent experts outside the FDA that reviews evidence and makes recommendations to the agency regarding authorizations and approvals. But the FDA did not consult VRBPAC on this decision, Offit says.

Segev has just begun an study that will eventually address the question of whether it’s safe and effective to temporarily reduce patients’ immunosuppressive therapy before they get a third dose. He also hopes to gather more safety data regarding which patients might benefit most from a third dose.

“There are some situations where this will be a very easy decision, and there are some situations where this will be a little bit trickier of a decision,” Segev says. For his transplant patients, Segev says there could be a risk that the transplanted organ is rejected because of the immune activation after a booster dose.

“That’s why we’re studying transplant patients very carefully.” But with many other immune-compromised populations, the third dose will be as safe as the second dose, he adds. “Then, really the question is, does the person need it? And I hope that people work with their doctors to figure that out.”

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