Non-bivalent COVID-19 boosters fail to protect against omicron in patients with ARDs
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After a third COVID-19 vaccine dose, patients with autoimmune rheumatic diseases often fail to mount an effective response useful in preventing omicron breakthrough infection, according to data published in Annals of the Rheumatic Diseases.
The data come from patients who had received non-bivalent COVID-19 vaccine doses earlier in 2022. The CDC recommend the bivalent COVID-19 booster vaccines that target the omicron variant on Sept. 2.
“Some patients with [autoimmune rheumatic diseases (ARDs)] reportedly have higher breakthrough infection rates,” Woo-Joong Kim, MD, of the Graduate School of Medical Science and Engineering, at the Korea Advanced Institute of Science and Technology, and co-authors wrote. “Unfortunately, patients with ARDs undergoing immunomodulatory therapies are excluded from COVID-19 vaccination trials, and there is limited data on immunogenicity of vaccines for the circulating SARS-CoV-2 variants of concern (VOCs).”
To investigate whether COVID-19 vaccines can help patients with autoimmune rheumatic diseases mount responses against omicron variants of SARS-CovV-2, Kim and colleagues conducted an observational cohort study. Patients in South Korea with autoimmune rheumatic diseases who had received a second or third dose of an mRNA COVID-19 vaccination were asked to enroll during standard outpatient visits. These visits were conducted during the pandemic surge caused by the omicron variant in South Korea, which peaked on March 16.
Autoimmune rheumatic diseases included in the study were systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, Behçet’s disease, adult-onset Still’s disease, antineutrophil cytoplasmic antibody-associated vasculitis, systemic sclerosis and IgG4-related disease. Patients were excluded upon diagnosis of COVID-19 or exposure to any anti-CD20 therapy.
Researchers collected blood samples upon enrollment between Jan. 12 and March 11, and follow-up lasted through breakthrough infection or April 6. Additionally, healthy control patients who did not receive any immunosuppressant therapies were included.
The authors tested the presence of neutralizing antibodies with a modified GenScript cPass surrogate virus neutralization test. Researchers used “semi-structured, in-depth” phone interviews on April 6 and 7 to confirm the occurrence of a breakthrough infection during the follow-up period.
In total, the study included 149 patients with autoimmune rheumatic diseases and 94 health care workers without autoimmune rheumatic diseases acting as controls. All participants had been vaccinated with mRNA — either BNT162b2 or mRNA1273 — or viral vector — AZD1222 or Ad26.COV2.S — vaccines based on approved schedules. Among the included patients, 68.5% received their third dose of a non-bivalent mRNA vaccine prior to enrollment.
The mean cross-neutralizing responses targeting the omicron variant manifesting after two doses was 11.5% in patients with autoimmune rheumatic diseases and 18.1% in the control group (P = .007). Significantly fewer patients in the autoimmune rheumatic disease group than the control group mounted appropriate responses following a third dose — 26.8% vs. 50.3% (P < .0001).
Additionally, within 6 weeks, significantly lower omicron-neutralizing responses were found in patients with autoimmune rheumatic diseases who developed a breakthrough infection (P = .018), according to the researchers.
he third dose of an mRNA vaccine could improve the cross-neutralization of the SARS-CoV-2 omicron variant in patients with ARDs, although more than half of the patients failed to generate omicron-neutralizing antibodies,” Kim and colleagues wrote. “Our study sheds light on the relative deficiency of the omicron-specific neutralizing responses in patients with ARDs and their anticipated vulnerability to breakthrough infection.
“As new SARS-CoV-2 variants are expected to circulate, further research on effective vaccination strategies for patients with immune dysfunction is urgently required,” they added.
References:
- Landewé RBM, et al. Ann Rheum Dis. 2022;doi: 10.1136/annrheumdis-2021-222006.
- Sun J, et al. JAMA Intern Med. 2022;doi:10.1001/jamainternmed.2021.7024.
Perspective
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Andrew J. Laster, MD, FACR, MACR
This study is of potential interest because it looks at the immune response of patients with autoimmune rheumatic disease (ARD) to the omicron variant after vaccination with either two or three doses of the original, “non-bivalent” COVID-19 vaccine, and uses a new surrogate measure for detection of neutralizing antibodies.
Neutralizing antibodies (NAb) represent a subset of antibodies to the spike protein, which prevent SARS-CoV-2 viral entry into human cells by binding to the ACE-2 receptor binding domain (RBD). As such, NAb are felt to be more predictive of protection from COVID-19 as compared with the broader category of anti-spike antibodies that are typically measured in a commercial lab.
Previous assays for NAb used live cells and live virus, or pseudo-virus, measuring the ability to reduce lysis of cells or plaque formation (PRNT or plaque reduction neutralization test). The assay took several days to run, required biocontainment facilities and, as such, was not commercially available. The surrogate ELISA assay used here detects functional immunoglobulins in patients’ serum that block the interaction between a tagged RBD of the SARS-CoV-2 spike protein and the human ACE2 receptor.
The test correlates well with standard PRNT assays, takes 1 to 2 hours to run, has received emergency use authorization by the FDA, and can be used in a commercial lab with the potential of high throughput.
This study was performed in South Korea in January to March of 2022, coincident with the COVID 19 pandemic omicron surge. Patients with ARD were excluded if they had received anti-CD20 therapy, chemotherapy or had been previously diagnosed with COVID-19. Those on methotrexate, mycophenolate mofetil or a JAK inhibitor were told to hold their medication for 1 week after the third vaccine dose. Subjects received either the mRNA (BNT162b2 or mRNA1273) or viral vector (AZD1222 or Ad26.COV2.S) vaccines.
When patients with ARD were compared to healthy controls recruited among health care workers, they had similar levels of NAb to the ancestral/wild type COVID-19 after two doses of the non-bivalent vaccine, but statistically significantly lower levels of NAb to the omicron variant after the second as well as third doses of the non-bivalent vaccine.
The authors conclude that this was likely related to their underlying ARD and/or immunomodulatory therapies. However, the significant age difference of almost 20 years between the controls, with a median age of 38.5 years, and ARD patients, with a median age of 55.3 years, may be playing a role given the known senescence of the immune response to vaccines with aging. Moreover, the rate of breakthrough omicron infections was not significantly different in the ARD group (19.2%) vs. the control group (33%) (P = .71), although mean time from third dose to infection was shorter in the ARD group (93 days) vs. the controls (122 days).
Additionally, no differences were seen between the two cohorts when T-cell reactivity was measured using IFN- levels following stimulation with SARS-CoV-2 S1 peptide.
Regardless of whether the differences in NAb are related to aging, the underlying ARD and/or immunosuppressive drugs, patients in the United States with ARD are probably best served by obtaining the new bivalent COVID-19 vaccine unless they have recently been infected with the omicron BA.5 variant, had an original COVID-19 vaccine booster within the last 2 to 3 months, demonstrated an allergic reaction to the vaccine or have previously demonstrated a failure to generate an antibody response to the original COVID-19 vaccine and are on every-6-month pre-exposure prophylaxis with Evusheld (tixagevimab plus cilgavimab, AstraZeneca).
The ability to rapidly measure NAb to COVID-19 and emerging variants of concern may aid future studies of vaccines and the immunogenicity of patients with ARD on specific immunomodulatory drugs.
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