ABSTRACT
Background and Aims: Dialysis patients are extremely vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with high rates of hospitalization and mortality rates. In January 2021, the University of Virginia Dialysis Program initiated a program-wide vaccination campaign to administer the Pfizer BioNTech messenger RNA SARS-CoV-2 (BNT162b2) vaccine. The aim of this study was to characterize the long-term time-dependent decline in humoral immunity in hemodialysis patients. Methods: A prospective cohort study measuring serial monthly semiquantitative IgG antibody levels to the SARS-CoV-2 spike protein receptor binding domain in fully vaccinated in-center hemodialysis patients. Samples were collected monthly and tested for anti-SARS-CoV-2 antibodies against the anti-spike S1 domain for 2-6 months post full vaccination. Results were presented as internationally harmonized binding antibody units (BAU/ml). To analyze the change in antibody levels over time, a linear mixed model with random intercept and random slope was used for longitudinal antibody levels. A multivariable model was used to estimate the slope of antibody levels by adjusting for selected patient characteristics. Based on the estimated intercepts and slopes for each subject from the unadjusted model, 10-month antibody levels were projected. Results: The mean baseline antibody level was 647.59 BAU/ml and 87.88% (29/33) of patients were considered qualitatively positive. Two patients were negative at baseline and an additional two had borderline results. Patient antibody levels declined at an adjusted average rate of 31% per month. At 6 months postvaccination, 40% of patients remaining in the cohort possessed either negative or borderline IgG antibody levels. Projecting future antibody levels suggests that 65% of the cohort will progress to borderline or negative antibody levels at 10 months post full vaccination. Conclusion: The long-term vaccine response following vaccination with the BNT162b2 in hemodialysis patients was characterized. Our data add to the limited pool of data in this patient population and emphasize the critical need for vaccine boosters.
ABSTRACT
Background: Based on studies implicating the type 2 cytokine interleukin 13 (IL-13) as a potential contributor to critical coronavirus disease 2019 (COVID-19), this trial was designed as an early phase 2 study to assess dupilumab, a monoclonal antibody that blocks IL-13 and interleukin 4 signaling, for treatment of inpatients with COVID-19. Methods: We conducted a phase 2a randomized, double-blind, placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care vs placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results: Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator-free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were 2 deaths in the dupilumab group compared with 5 deaths in the placebo group (60-day survival: 89.5% vs 76.2%; adjusted hazard ratio [HR], 0.05 [95% confidence interval {CI}, .004-.72]; P = .03). Among subjects who were not in the intensive care unit (ICU) at randomization, 3 subjects in the dupilumab arm were admitted to the ICU compared to 6 in the placebo arm (17.7% vs 37.5%; adjusted HR, 0.44 [95% CI, .09-2.09]; P = .30). Last, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions: Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60. Clinical Trials Registration: NCT04920916.
ABSTRACT
People with diabetes mellitus are more vulnerable to viral infections including influenza and the ongoing COVID-19 pandemic. Fatal pneumonia and cytokine storm is a contributor to the mortality. We hypothesized that aberrant glycemic control induces an immune dysregulation, which compromises the anti-viral immunity and promotes inflammation by altering the balance of the protective T-regulatory cells (Tregs) and IL-17 responses. Indeed, comparison of the peripheral blood lymphocytes in a limited cohort of healthy controls (HC;n=4) and people with diabetes (n=9) showed profound immune dysregulation. As compared to HC (66±21 x10
ABSTRACT
Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.