Post-vaccine seronegativity predicts breakthrough COVID-19 in patients with AIRD
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Lack of antibody response following COVID-19 vaccination is the strongest predictor of breakthrough infection in patients with autoimmune rheumatic disease, according to data published in Annals of the Rheumatic Diseases.
“Patients with autoimmune rheumatic diseases (AIRD) have reduced responses to COVID-19 vaccination,” Padmanabha Shenoy, MD, DM, of the Center for Arthritis and Rheumatism Excellence (CARE), in Cochin, India, told Healio. “There is no biomarker to predict successful vaccination, and current recommendations do not support the use of antibody titers to measure protection from COVID-19.”
To analyze the incidence and risk factors for breakthrough COVID-19 infection in patients with autoimmune rheumatic disease, Shenoy and colleagues prospectively followed 630 fully vaccinated patients from the Center for Arthritis and Rheumatism Excellence, in southern India. All participants had been diagnosed with an autoimmune rheumatic disease and completed two doses of a SARS-CoV2 vaccine. Individuals with prior COVID-19 infection were excluded. Enrollment began in March 2021, with follow-up ending in October 2021.
The researchers assessed antibodies to receptor binding domain of spike protein (anti-RBD) in all participants 4 to 6 weeks after the second vaccine dose. Participants were then stratified based on antibody response, with “good responders” demonstrating greater than 212 IU, “inadequate responders” having a range of 0.8 to 212 IU, and those with less than 0.8 IU identified as “non-responders.” After a minimum of 8 weeks post-vaccination, patients were followed up with every 2 months to identify breakthrough COVID-19 infection. In addition, all sero-converted participants who had contact with COVID-19 were examined for neutralizing antibodies.
Among the 630 participants, 78.6% received the AstraZeneca AZD1222 vaccine, while the remaining received the BBV152 vaccine, developed by Bharat Biotech International in India. The mean age of the participants was 55.2 years.
According to the researchers, the mean post-vaccination antibody titer was 854.1, with 60.3% identified as “good responders,” 22.7% as “inadequate responders” and 16.9% deemed “non-responders.”
In all, breakthrough COVID-19 infection occurred in 7.4% of participants, at a mean follow-up of 147.3 days. Breakthrough cases were proportionately highest among non-responders, at 17.75%, followed by inadequate responders, at 9.09%. Only 3.95% of good responders experienced breakthrough COVID-19. In a log-rank analysis, the researchers found that antibody response (P < .00001), vaccine type (P = .003) and mycophenolate mofetil use (P = .007) were significant predictors of breakthrough infection. However, in the multivariate Cox regression, only vaccine non-response was significantly associated with breakthrough COVID-19 infection (HR = 3.6; 95% CI, 1.58-8).
Among patients who were sero-converted and had contact with COVID-19, neutralization levels varied between those who did and did not develop infection.
“We showed that patients with AIRD having low anti-spike antibody titers are having higher risk of breakthrough infections,” Shenoy said. “The study provides a cheap and commonly available biomarker for estimating vaccination success. We do not need complicated T-cell assays — only antibody levels are sufficient as a predictor. Patients with inadequate anti-spike antibody titers should be shielded from infection and prioritized for booster doses.”
Perspective
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Since the onslaught of COVID-19 beginning in December 2019, and its arrival in the United States in March 2020, the rheumatology community has wondered how our patients with autoimmune rheumatic diseases would fare relative to the general population. Evidence is mixed regarding whether the presence of a rheumatic disease is associated with a higher risk for contracting COVID-19 or more adverse outcomes. Beginning in January 2021, vaccines emerged allowing us to try to prevent infection — or at least serious infection and serious outcomes.
It seems that our medications impact vaccine responses to varying degrees. Breakthrough infections in patients with autoimmune rheumatic diseases are associated with a higher risk for death and post-COVID sequelae. One problem has been the reliability of assays to measure antibody titers. Current guidelines advise against estimating antibody levels post-vaccination. Also, there are data suggesting that, even in the absence of such antibodies, cell-mediated immunity induced by vaccines might be protective against COVID-19.
In this study 60% of the patients had a good response to vaccination, 22% had an inadequate response to vaccination and 18% had no response. Breakthrough infection occurred in 7.4% of the patients and was associated with non-response to vaccination. Additionally, 18% of the non-responder group developed an infection, as did 9% of the inadequate responder group and 4 % of the good responders.
Survival also related to vaccine response, but there was overlap between the groups. We may therefore need to reconsider the need to obtain antibody titers, specifically in our rheumatic disease patients on immunosuppressive therapies. The reliability of the assays will also need to be addressed. Those medications demonstrated to be especially problematic with regard to generating an immune response to COVID-19 vaccination have been B-cell depleting therapies, prednisone — especially at higher doses — Janus kinase inhibitors, and mycophenolate mofetil.
Two caveats to consider in this study are, first, that it was performed in India, where the vaccines used were not the same as those in the United States and, second, the study was performed when it was the delta variant that was surging.
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