NIH opens study of COVID-19 vaccine booster in patients with autoimmune disease
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The NIH has launched a clinical trial to examine antibody responses to a COVID-19 vaccine booster dose in patients with autoimmune disease who failed to respond to the initial vaccine regimen.
According to a press release issued by the NIH, the phase 2 trial will also study whether pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra COVID-19 vaccine dose in this population.
“The NIH has launched an important study examining the effect of boosting and hold immunosuppressive drugs including mycophenolate mofetil or mycophenolic acid, methotrexate, or B cell depleting drugs to assess the impact on antibody response in a randomized designed trial,” Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic Lerner College of Medicine, at Case Western Reserve University, and RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, told Healio Rheumatology.
“Unfortunately, this is a real-time issue for patients with immune-mediated inflammatory diseases (IMIDs), including many rheumatic disorders, dermatologic disorders, multiple sclerosis and other neuro-immunologic diseases, as well as inflammatory bowel disease among others,” he added.
Big Month for the Booster Shot
August brought with it an avalanche of news regarding the potential use of a COVID-19 vaccine booster shot for certain patients.
On Aug. 12, the FDA announced an update to its emergency use authorization for the Pfizer-BioNTech and Moderna messenger RNA vaccines that allowed a third 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.”
Shortly after, a CDC advisory panel voted unanimously in favor of recommending a third dose of the COVID-19 vaccine in patients who are moderately or severely immunocompromised. The decision grants patients currently receiving high-dose corticosteroids, alkylating agents, antimetabolites, TNF inhibitors and other immunosuppressive biologic agents access to a booster dose of either the Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines.
According to the CDC, the third dose should be administered at least 28 days after a second dose of the same vaccine to eligible patients aged 18 years or older for the Moderna vaccine and 12 years or older for the Pfizer-BioNTech vaccine.
The American College of Rheumatology followed up Aug. 23, with an update to its COVID-19 vaccine clinical guidance, recommending a third dose of the mRNA vaccine in those receiving immunosuppressive or immunomodulatory therapy. These updated ACR recommendations follow the CDC guidance advising providers to administer the booster shot at least 28 days after the initial regimen.
Notably, the ACR also advises providers to hold certain immunomodulatory or immunosuppressive medications for 1 to 2 weeks following the booster dose, if disease activity allows. Exceptions to this guidance include glucocorticoids and anti-cytokine therapies, including most biologic agents. No consensus was achieved on whether anti-cytokine medications, such as TNF inhibitors and others including interleukin-17, IL-12/23, IL-23, IL-1R, IL-6R antagonists, meaningfully impair vaccine response to a degree that would warrant their temporary interruption.
Operating Without Data
Several studies have suggested that immunocompromised patients do not respond optimally to COVID-19 vaccination. In one example, published by Peter M. Izmirly, MD, of the New York University Grossman School of Medicine, in Arthritis & Rheumatology in early August, found that nearly 30% of patients with systemic lupus erythematosus demonstrate low response to the COVID-19 vaccine, with immunosuppression therapy associated with decreased protection.
Additionally, patients taking certain immunosuppressive agents — such as methotrexate and rituximab (Rituxan, Genentech) — can have a limited response to pneumonia and influenza vaccines, according to data.
However, data of any kind regarding a three-dose COVID-19 vaccine regimen, particularly regarding whether an extra dose would improve a previously lackluster antibody response, are — although promising — currently limited.
The results of the first randomized, placebo-controlled trial of a third vaccine dose in transplant recipients — also published in August, in The New England Journal of Medicine — demonstrated that an additional dose enhanced protection.
The data are similarly limited on the withholding of immunosuppressants when administering a COVID-19 vaccine booster.
“Most clinics are currently advising boosters consistent with current guidelines but whether to pause immunosuppression is a more controversial issue as yet there are no direct — in COVID-19 — data on the efficacy of such in IMIDs and many society guidelines proffer disparate guidance,” Calabrese said. “In our clinic, we have been recommending boosting and pausing most immunosuppressives consistent with the American College of Rheumatology updated clinical guidance.”
Enter the NIH Trial
The new NIH trial, called “COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders,” aims to enroll approximately 600 adults from across the United States with multiple sclerosis, pemphigus, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. Participants will be required to have demonstrated a negative or suboptimal antibody response to two doses of either the Moderna or Pfizer COVID-19 vaccines or one dose of the Johnson & Johnson vaccine, all received prior to enrollment.
Participants must also be receiving one of three immunosuppressive therapies: mycophenolate mofetil or mycophenolic acid, methotrexate or B-cell depleting drugs.
During the study, all participants will receive an extra dose of the same COVID-19 vaccine as their initial regimen. However, those taking mycophenolate mofetil, mycophenolic acid or methotrexate will be randomly assigned to either continue with their immunosuppressive drugs without any changes or to withhold them for a short time before and after receiving the booster.
The primary goal is to determine the proportion of participants who demonstrate a significantly better antibody response 4 weeks after receiving the vaccine booster than they did following their original vaccinations.
The study, sponsored and funded by the NIH National Institute of Allergy and Infectious Diseases (NIAID), will be followed for 13 months. Preliminary results are expected in November of this year, according to the NIH.
Another study, launched by the NIH on Aug. 10, will assess the antibody responses to a third mRNA vaccine dose in kidney transplant recipients who failed to respond to two doses of the Moderna or Pfizer series. Preliminary results of that pilot study are expected later this month.
Act Now, or Wait for Data?
In response to the new trial’s launch, Calabrese posed a question to his colleagues on Twitter: “Important study to assess the impact of booster and drug pausing in immunosuppressed — to ‘answer’ critical Qs on Ab response. Will you boost and/or pause your immunosuppressives or await the data?”
Speaking later with Healio Rheumatology, Calabrese said the current dearth of data, combined with the pressing urgency to protect immunosuppressed patients from COVID-19, has produced a clinical conundrum for rheumatologists. Should they act now or wait, potentially for months, for the data?
“In light of the launching of this study, will clinicians retain equipoise and continue their practice, or will they ‘pause’ and wait for data which will be many months in the offing?” he said. “I for one will continue to boost and pause immunosuppressives since in my mathematics, this represents a gambit to possibly increase the protection of vaccine efficacy versus a wait and hold position, where there is no chance for augmented immunity during this critical delta surge we are now in. What will you be doing?”
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NIH press release.
Kumar D, et al. N Engl J Med. 2021;doi:10.1056/NEJMc2111462.
Izmirly PM, et al. Arthritis Rheumatol. 2021;doi:10.1002/art.41937.
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