Rheumatologists use rituximab to treat patients with inflammatory rheumatic diseases. The monoclonal antibody targets CD20, eradicates peripheral B cells and suppresses B cell function, including immunoglobulin production. Thus, rituximab can inhibit the ability of novel antigens to induce an antibody response, which has raised concerns among healthcare providers and patients that its use may make patients more vulnerable to COVID-19.
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This fear was reinforced by a case series that reported two patients with lymphoma who were treated with rituximab and subsequently developed COVID-19 pneumonia with persistent viremia. The authors of the case report note the patients seemed unable to clear the viral infection, and they hypothesized viremia itself—as well as the duration of the viremic period—contributed to death.1
Does Vaccination Protect this Vulnerable Group?
The arrival of COVID-19 vaccines in late 2020 and early 2021 has led rheumatologists to question whether the vaccines will protect or even benefit patients treated with rituximab given their suppressed B cell function. (For more on this concern, read “COVID-19 Vaccine Efficacy & Safety Discussed at Town Hall”.)
A recent study indicates B cell depleting therapy with rituximab does, as anticipated, affect the humoral immune response to COVID-19 vaccination. However, the investigators found all B cell-depleted patients were able to mount a T cell-mediated immune response. Michael Bonelli, MD, a clinical rheumatologist at the Medical University of Vienna, Austria, and colleagues published the findings as a letter in May in the Annals of the Rheumatic Diseases and as a full article in July.2,3
The investigators selected five patients under regular and recent rituximab treatment and vaccinated them with the BNT162b2 (Pfizer/BioNTech) COVID-19 vaccine. As controls, researchers selected four sex-matched, healthy individuals who received two vaccinations with BNT162b2 and four unvaccinated healthy controls. In addition to measuring antibody response to the SARS-CoV-2 nucleocapsid and the receptor-binding domain of the spike protein, the researchers measured SARS-CoV-2 specific T cell reactivity via interferon-ɣ response to SARS-CoV-2 peptides.
“It’s a very specific question that we raised,” says Daniel Aletaha, MD, MS, MBA, head of division of rheumatology at the Medical University of Vienna, Austria.
His team attempted to quantify how many patients developed antibodies after vaccination (two out of five) and also had a cellular response (all five patients). Dr. Aletaha concludes from this finding that rheumatologists should be comforted that, although perhaps less than half of patients develop antibodies after COVID-19 vaccination, many will have cellular immunity.
“It’s reassuring that even if you have one of the more potent inhibitors of vaccine response, you have a decent response,” says Dr. Aletaha. “We, as rheumatologists, should really try to vaccinate all our patients.”
He emphasizes that rheumatologists treat a high-risk population. Because most, if not all, immunological patients are on immunosuppressive medication and, thus, vulnerable to viremia, they should be vaccinated.
“Yes, it is very important to get these patients vaccinated,” he says.
A Third Dose?
Like patients on rituximab, solid organ transplant recipients also have an attenuated antibody response to two doses of an mRNA vaccine against SARS-CoV-2, compared with healthy controls. This finding has led the transplant community to question whether a third dose of the vaccine may benefit transplant recipients.
In June, investigators from Johns Hopkins published the first report of patients with solid organ transplants receiving a third dose of vaccine directed against SARS-CoV-2.4 The researchers examined the antibody responses and vaccine reactions in transplant recipients who had a suboptimal response to standard vaccination and, subsequently, received a third dose of vaccine a median of 67 days after the second dose. The investigators described 30 patients with a mean age of 57 in the case series. Prior to being vaccinated, none of the patients reported an illness consistent with COVID-19. The investigators tested patients for antibodies against the spike protein nine days before they received their third dose of vaccine and 14 days after the third dose of vaccine.
This study revealed that antibody titers increased after the third dose in one-third of patients who had negative antibody titers after the second dose and in all patients who had low, positive antibody titers after the second dose. The most frequent systemic reaction (seen in 14 patients) after the third dose of vaccine was mild or moderate fatigue. The study did not measure T cell responses.
Dr. Aletaha’s group has just completed the first randomized controlled trial of a third dose of COVID-19 vaccine in patients with immune-mediated diseases who did not develop antibodies after the second dose. Their manuscript has just been submitted to a journal, and Dr. Aletaha hopes it will soon be published. The bottom line: It seems a sizable number of patients can improve their immune response after a third dose of vaccine.
Consistent with these findings, on Aug. 12, the U.S. Food & Drug Administration (FDA) amended the emergency use authorizations for both the Pfizer-BioNTech COVID-19 vaccine and the Moderna COVID-19 vaccine to allow for the use of an additional dose in certain immunocompromised individuals. The amendment permits a third dose to be administered at least 28 days following the two-dose regimen of the same vaccine for individuals 18 years or older who have undergone solid organ transplantation or who are diagnosed with conditions considered to have an equivalent level of immunocompromise, including patients with rheumatic disease and cancer survivors. (For information on the ACR’s support for a third shot, read “COVID-19 Vaccination in Patients with Rheumatic Disease”.)
Should the Previously Infected Be Vaccinated?
The findings have implications for patients who have been infected with COVID-19 and recovered. Dr. Aletaha says, in Austria, individuals who have COVID-19 are publicly recognized the same as vaccinated individuals. However, it’s not clear if formerly infected individuals have the same protection from disease as vaccinated individuals. Thus, notes Dr. Aletaha, vulnerable patients with rheumatic disease who have recovered from COVID-19 may still benefit from vaccination.
“The strategy is to give them an additional shot to achieve a boost,” says Dr. Aletaha, adding, “The first shot is the natural acquisition, and the second shot is the booster.”
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- Tepasse PR, Hafezi W, Lutz, M, et al. Persisting SARS-CoV-2 viremia after rituximab therapy: Two cases with fatal outcome and a review of the literature. Br J Haematol. 2020 Jul;190(2):185–188.
- Bonelli MM, Mrak D, Perkmann T, et al. SARS-CoV-2 vaccination in rituximab-treated patients: Evidence for impaired humoral, but inducible cellular immune response. Ann Rheum Dis. 2021 May 6. Online ahead of print.
- Mrak D, Tobudic S, Koblischke M, et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021 Jul 20. Online ahead of print.
- Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: A case series. Ann Intern Med. 2021 Jun 15;L21-0282. Online ahead of print.