A project of the AAMC and CDC
aamc.org does not support this web browser.

Calling the shots: Who needs a third dose?

By Beth Howard
Sept. 21, 2021
A female patient talking to a female doctor in a hospital room. Both are wearing masks.

Leah Parker, a family nurse practitioner in Indian Trail, NC, was relieved to be among the first to get a vaccine against COVID-19. She has rheumatoid arthritis and gives herself injections of a powerful anti-inflammatory drug every other week to suppress her immune system, which prevents her body from attacking itself. “As an immunocompromised health care provider taking care of patients it was very important for me to get the vaccine as soon as it became available back in January,” she says.

But when her rheumatologist tested her weeks after her second dose of the Pfizer BioNTech COVID-19 vaccine, Parker, 42, was dismayed to learn her levels of antibodies against the virus were low. “I was frustrated and discouraged because I did not want to get sick,” she says, “nor did I want to expose any of my patients.”

For her, the CDC’s recent recommendation that people with compromised immune systems receive a third dose of their vaccine came as welcome news. “I was in line at CVS early that next morning,” Parker says.  

Others have followed her lead. Casey Quinlan, 69, a health care multimedia specialist in Richmond, VA, who has metastatic breast cancer, also rushed to roll up her sleeve for an additional dose of her mRNA vaccine. “I got my third jab on Tuesday, August 17, in the first full week that a third shot was available, after reading the CDC recommendations and seeing my condition listed,” she says.

“We knew that immunocompromised patients were not as well protected by the vaccines,” says Camille N. Kotton, MD, clinical director of the Transplant Infectious Disease and Compromised Host Program at the Massachusetts General Hospital in Boston and a member of the CDC’s Advisory Committee on Immunization Practices (ACIP), which came up with the new recommendations. “That’s why we wanted to push this forward and give them additional doses of the vaccine in order to optimally protect them. They were really being left behind and unprotected.”

Who’s eligible for a third dose?

While the idea of giving booster shots to all vaccinated Americans is being debated and investigated, the current recommendation for a third dose only pertains to specific populations who may have insufficient protection from their initial doses. They include people with blood and solid tumor cancers, recipients of solid organ or stem cell transplants, people with severe immunodeficiencies or HIV, and those being treated with chemotherapy, TNF blockers, biologic agents such as rituximab, or high doses of corticosteroids for autoimmune and other disorders. The recommendation also applies only to those who received the two-dose mRNA vaccines (Pfizer and Moderna).

Charles E. Crutchfield III, MD, clinical professor of dermatology at the University of Minnesota Medical School, treats many patients with chronic inflammatory and autoimmune skin conditions like psoriasis and scleroderma who need to be on anti-inflammatory and immunosuppressant drugs all the time. “I want to make sure that they’re aware that they need a third dose,” he says, adding, “I’m pleased that 99% say ‘I’m ready. Let’s do three.’”

The reasons for the shift in policy are not surprising. Data show that people in these groups have a higher risk of getting severely ill from COVID-19 and having prolonged illness. “How severe a case it is depends on patients’ immune status and their viral load — how much virus they’ve been exposed to,” says Jennifer M. Dan, MD, PhD, assistant professor at UC San Diego in La Jolla, CA, and an infectious disease specialist at UC San Diego Health, “and then their body’s ability to defend against it.”

Studies show the effectiveness of the mRNA vaccines in immunocompromised and immunosuppressed patients ranged from just 59% to 80% after the second vaccine dose, compared to 91% to 94% for people who have normal immune function, according to the CDC.

Another issue: “When immunocompromised people get infected, they tend to have virus for a lot longer and the virus stays with them and replicates and replicates, which can allow mutations to form,” Kotton says. “We worry that not protecting the immunocompromised is bad for them, but possibly also for society at large.”

Significantly, “New research shows about 40% of breakthrough infections were in people who were immunocompromised,” Kotton says. Yet this group makes up just 2.7% percent of the population.

At the same time, there’s growing evidence that a third dose does make a difference for those who need it. Among those who had no detectable antibody response to the initial mRNA vaccine series, 33% to 50% developed an antibody response to an additional dose, according to data from the CDC. Reactions to the third dose were similar to those that patients experienced after their first doses.

Access to doses

ACIP purposely formulated its guidelines to make it easy for eligible patients to get the third dose. A doctor’s prescription isn’t necessary.

“We wanted to make it as barrier free as possible,” says Kotton. “Basically, people can just go to their local pharmacy or wherever they’re giving COVID vaccines and say, ‘Hey, I’m immune compromised. Give me my shot.’”

Some practices are messaging eligible patients about the recommendation through their electronic health record or health portal. “And it seems that a tremendous number of patients have heard it on the news,” Kotton says. Crutchfield is administering the vaccine right in his clinic.

Depending on the patient’s condition, there may be specific considerations. For instance, cancer patients should speak with their doctors about timing the third dose to get optimal protection. According to the American Cancer Society, patients may be advised to wait until their immune system has recovered from treatment before getting vaccinated. Or they may be able to wait a few weeks after getting the shot to start the immunosuppressive treatment.

“The recommendations for bone marrow transplantation are to wait until about three months [to get a COVID-19 vaccine] when we think that a person’s engrafted and are able to make a response,” Dan says. “That’s based on data from influenza vaccine studies.”

Kotton advises organ transplant patients to get vaccinated before immunosuppression. “That said, we have hundreds of thousands of organ transplant patients out there. We can’t turn back the clock for them,” she says. “But for people who are waiting for transplants, we very strongly recommend getting the vaccine prior to transplants in order to get the best immune response possible.”

The American College of Rheumatology (ACR) has issued guidelines for people with arthritis and other rheumatologic disorders who are on immunosuppressant or immunomodulating medications. The organization recommends a brief break from many of these agents if possible, one to two weeks after receiving the third dose, to improve the immune system response. This includes medications such as methotrexate and JAK inhibitors but doesn’t necessarily apply to biologic drugs. See the guidelines for specific drug information.

The ACR also recommends timing the COVID-19 vaccination around the patient’s medication dose. For example, with rituximab, patients should try to get the third vaccine dose close to their next infusion, when the immune system is likely to mount a strong response.

A work in progress

While the additional doses are rolled out, researchers and physicians continue to research and tinker with vaccine schedules. Information about an additional dose of the J&J vaccine for immunocompromised patients is expected from the manufacturer soon, which would pave the way for an additional dose for those who are relying on its protection.

There’s some evidence that patients would benefit from taking a different type of vaccine the third time around. “Some studies suggest that if you mix and match vaccines, you get a much better response,” says Crutchfield. More research is needed before the CDC guidelines change, though. Currently, the recommendation is to try to take the same mRNA vaccine you were given initially. However, if it’s not available, it’s fine to get the other one as a third dose.

Research is also looking at other protective measures. For example, monoclonal antibodies, which are now used to treat people with COVID-19 illness, could be deployed to guard people with conditions that undermine their immunity. “There are studies opening up,” Kotton says.

The CDC doesn’t recommend using antibody tests to guide vaccination decisions or to determine a patient’s vulnerability to COVID-19. Antibody tests give only one picture of immune response.

“There are two types of immunity — antibody and cellular,” says Kotton. Although antibody tests are simple, cellular immunity components like T-cells are much harder to measure. “What we are seeing is that there can be a real disconnect between the antibody response and the cellular immune response,” she says. “Some immunocompromised people seem to have a really robust antibody response, but not as strong a cellular response and vice versa.” And no one knows yet how that translates into immunity against COVID-19 infection.

Health officials do stress continuing to take protective measures like wearing a mask indoors, keeping distance between yourself and others, and avoiding crowded places.

“This is an ongoing process,” says Kotton. “We have to think long-term about how to protect folks, not just this month or next month, but this fall and this coming year. The vast majority of us have really good protection from two doses of mRNA vaccine. And the vast majority of people with breakthrough infection still do quite well.”

The CDC and the American Society of Transplantation (AST) have issued the following guidance for clinicians regarding administration of a third dose of COVID-19 vaccine for immunocompromised patients.

CDC guidance

AST guidance