COVID-19 and Rheumatology

COVID-19 and Rheumatology

Disclosures: Calabrese, Connolly, Paik and Winthrop report no relevant financial disclosures.
August 09, 2021
7 min read

A Shot in the Dark: 'Limited data' exist for COVID-19 booster in immunocompromised patients

Disclosures: Calabrese, Connolly, Paik and Winthrop report no relevant financial disclosures.
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Immunocompromised individuals have a number of justifiable concerns surrounding COVID-19. One of those concerns is that a two-dose vaccine schedule may not produce a sufficient antibody response to protect them from the virus.

But hope may be on the horizon. On July 12, Israel’s Ministry of Health began offering a third dose of the Pfizer vaccine to severely immunocompromised adults. This may herald a similar booster approach in older and vulnerable populations in other parts of the world, including the United States.

When discussing a third COVID-19 dose with patients who are immunocompromised, Julie J. Paik MD, MHS, keeps the discussion grounded in reality. “We discuss that there is limited data on a third dose in patients on immunosuppression,” she told Healio Rheumatology. “All data currently relates to patients with solid organ transplants on immunosuppression.” Source: Adobe Stock

In fact, there is movement in that direction domestically. On the same day as Israel’s decision to proceed with a COVID-19 booster shot, Pfizer began making the case to U.S. federal health officials that a third dose of the vaccine is necessary in the same vulnerable populations that are eligible in Israel. They suggested that the third booster should be administered 6 to 12 months after receiving the two-shot regimen.

Data of any kind surrounding a three-dose COVID-19 vaccine regimen are limited. As experts begin to investigate the feasibility and utility of a third dose, there are a handful of points to consider.

One is that there has been some evidence showing that being immunocompromised hinders the efficacy of SARS-CoV-2 messenger RNA (mRNA) vaccines, even after the second dose. Another is the question of whether a third dose would, in fact, elevate a previously insufficient antibody response.

Digging deeper, the type of immunosuppressive drugs a patient is receiving may play a role in antibody response. The risks and benefits of a third dose should be considered as well.

Finally, there is the question of resource allocation: millions of Americans and individuals worldwide have not yet received their first dose, so justifying a third in certain populations raises ethical questions.

As clinicians who deal with immunocompromised patients wrestle with these questions, an early clinical trial may point the way toward a three-dose COVID-19 vaccine schedule.

First of Many Studies

In their observational study published in JAMA, Boyarsky and colleagues assessed antibody responses to mRNA COVID-19 vaccines in a cohort of 658 transplant recipients. Eligible participants had completed the series between December 16, 2020, and March 13, and were followed through April 13.

Results showed that just 15% of participants had a measurable antibody response after the first and second doses. Moreover, 46% demonstrated no antibody response after the first or second doses, whereas 39% had no antibody response after the first dose but showed some antibody response after the second.

Kevin L. Winthrop

“We have seen lots of small articles like this at this point,” Kevin L. Winthrop, MD, MPH, director of the Center for Infectious Disease Studies at Oregon Health & Science University, told Healio Rheumatology. “There is no question that certain subgroups of immunocompromised patients have decreased responses. However, it is not yet clear if this is clinically meaningful. For those that mount no measurable humoral response, I think it is likely they are less protected.”

Cassandra Calabrese

Cassandra Calabrese, DO, director of the Rheumatology–Infectious Disease Clinic and training program at the Cleveland Clinic, also believes that a third dose is likely in the cards for immunocompromised populations. However, more questions than answers remain. “This paper has demonstrated that the second dose is still not 100% effective,” she said, and added that it is difficult to glean what a response to a third dose may look like from available studies.

A critical step in understanding how a third dose may or may not benefit patients is simply understanding why there is a poor response in the first place.

Behind Insufficient Responses

“Patients take immunosuppressive medication to dampen down their immune system to treat underlying autoimmune disease or to prevent organ rejection after transplantation,” Julie J. Paik, MD, MHS, assistant professor of medicine in the division of rheumatology at the Johns Hopkins School of Medicine, said in an interview. “Immunosuppressive medication can reduce the immune system’s ability to respond to vaccines or stop the immune system from ramping up after vaccination.”

Julie J. Paik

It is known that patients taking certain immunosuppressive agents — such as methotrexate and rituximab (Rituxan, Genentech) — can have a limited response to pneumonia and influenza vaccines, according to Paik. “We are now learning that certain immunosuppressive therapies are also hampering the immune response to SARS-CoV-2 vaccination,” she said.

Researchers like Paik and Caoilfhionn M. Connolly, MD, MSc, a clinical fellow in the division of rheumatology at Johns Hopkins Hospital, are beginning to see patterns in COVID-19 vaccine responses. “We have also learned that different types of immunosuppressive therapies limit the immune response to SARS-CoV-2 vaccination more than others,” Connolly said.

Caoilfhionn M. Connolly

Connolly and Paik were also involved in the research from Boyarsky’s group. “In our study, we found that patients taking mycophenolate or rituximab were least likely to have an antibody response after vaccination,” Connolly said. “We do not yet have as much data on the other side of the immune system, also known as the cellular immune response.”

Patients taking these medications should be aware of the potential for suboptimal vaccine response, according to Connolly. They require “ongoing vigilance in observing non-pharmacological preventative measures.”

A third dose has been reported to boost some of these patients into “a measurable range” of antibody response, according to Winthrop. “But many still do not reach this range, depending on what immunosuppressives they are on,” he said.

Winthrop believes that patients on B-cell depletion therapy or mycophenolate mofetil should be tested after vaccination. “For those with no measurable response, I think it is reasonable to boost them once more,” he said. “But it might do nothing unless you can alter their rituximab or MMF dosing around the booster.”

What is to be Gained?

As with any novel health care intervention, it is important to take a hard look at the risks and benefits before implementing on a broader scale. “Potential benefits of a third dose include augmentation of the antibody response, thereby increasing the efficacy of the vaccine,” Connolly said. “This can extend the immune response and help overcome viral immune-evasion/variants.”

Adverse events, ranging from local side effects such as pain, swelling or redness to systemic side effects such as fatigue, myalgia and fever are the most serious potential drawbacks, according to Connolly. However, she stressed that the safety profile of available vaccine products and series “have been very encouraging.”

To that point, in another study published in Annals of Internal Medicine that also involved Boyarsky at Johns Hopkins, Werbel and colleagues administered a third dose in 30 solid organ transplant recipients who had mounted a suboptimal response to a standard COVID-19 vaccination schedule. The third doses were given between March 20 and May 10.

Antibody testing conducted at a median of 14 days (IQR, 14 to 17 days) after the third dose showed that among six patients with low-positive antibody titers before the third dose, all had high-positive antibody titers after the third, according to the findings. Conversely, among 24 patients with negative antibody titers before the third dose, just 25% had high-positive antibody titers in the wake of the third dose.

“It is encouraging that antibody titers increased after the third dose in one third of patients who had negative antibody titers and in all patients who had low-positive antibody titers,” the researchers wrote. “Antibody responses, however, appear to vary, and potential risks, such as organ rejection, should be evaluated on an individual basis.”

A greater body of data will solidify the risk/benefit profile, according to Paik. “Currently, there is early observational data in solid organ transplant patients on immunosuppression who have received an additional booster dose,” she said. “The findings of these studies from the U.S. and France would suggest that an additional booster dose is both safe and effective in increasing the humoral/antibody response to vaccination in the majority of these patients. There is no data yet in other immunocompromised populations.”

As rheumatologists await further data that shows response rates in patients with specific autoimmune and rheumatic conditions, it is likely that they will be discussing the possibility of a third dose with increasing frequency.

Talking to Your Patients

While a third dose seems like a self-evident choice for patients in immunocompromised groups, Paik keeps the discussion grounded in reality. “We discuss that there is limited data on a third dose in patients on immunosuppression,” she said. “All data currently relates to patients with solid organ transplants on immunosuppression.”

That said, Paik stressed that the data from the transplant population have thus far been very encouraging. “In France, all patients on antimetabolite therapies, such as azathioprine or mycophenolate, and anti-CD20 therapies like rituximab have been receiving third dose booster vaccines since April, but there is not a formal recommendation for third dose vaccination in the U.S.”

Connolly described booster dosing, at the moment, as a “theoretical option” for immunocompromised individuals demonstrating suboptimal antibody responses to standard vaccine series. Like many experts, she is anxiously awaiting further word from the CDC.

But data are required. “To determine the safety and immunogenicity of booster dosing in immunocompromised patients, a formal clinical trial should be undertaken,” she said. “Some studies are, in fact, planned in transplant patients.”

While waiting for those data to emerge, it is imperative to keep an eye on the big picture, according to Calabrese. “The important message here is that immunocompromised persons need to maintain caution, especially now with the spread of the Delta variant,” she said. “We are seeing breakthrough infections even in immunocompetent vaccinated persons.”

It is for this reason that the ethical debate about a third dose in the immunocompromised vs. any dose in the immunocompetent is so critical. There are no easy answers. That said, Connolly stressed that striking the right balance is essential to achieving the overall goal of eliminating COVID-19 altogether. “The U.S. is in the enviable position of having surplus vaccines,” she said. “Thus, there should be continued focus on both increasing vaccine uptake to significantly reduce community transmissibility as well as protecting the most vulnerable.”

For more information:

Caoilfhionn M. Connolly, MD, MSc, can be reached at 5501 Hopkins Bayview Circle, JHAAC 1B1, Baltimore MD 21224; email:

Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195.

Julie J. Paik, MD, can be reached at 5200 Eastern Avenue, MFL- Center Tower Suite 4500, Baltimore, MD 21212; email:

Kevin L. Winthrop, MD, can be reached at 270 Southwest Pavilion Loop OHSU Physicians Pavilion, Suite 320; Portland, OR 97239.