ABSTRACT
BackgroundDialysis patients are extremely vulnerable to SARS-CoV-2 infection. We recently reported the results of a prospective cohort study measuring serial monthly semi quantitative IgG antibody levels to the SARS-CoV-2 spike protein receptor binding domain in fully vaccinated in-center hemodialysis patients after receiving the BNT162b2 (Pfizer-BioNTech) mRNA vaccination. MethodsProspective cohort study measuring the serologic response of hemodialysis patients to a booster dose of BNT162b2 vaccine at an average of 2, 6 and 11 weeks post vaccination. ResultsOf 35 hemodialysis patients in the original cohort, 27 (77.1%) received a third dose of BNT162b2. Antibody level significantly increased from pre-booster to 2 weeks post-booster (median (25th, 75th percentile) from 59.94 (29.69, 177.8) to 6216 (3806, 11730)), an average increase of 112 fold. Antibody levels dropped to a median of 2654 BAU/mL (1650, 8340) 6 weeks post-booster and to a median of 1444 BAU/mL (1102, 2020) between weeks 6 and 11 post-booster. Antibody levels at 11 weeks remained an average of 40 fold higher than pre-booster levels. Overall, antibody levels declined 47% month to month post-booster. Nine (33%) patients had negative or borderline detectable antibody levels pre-booster and 8 of 9 developed positive (>35.2 BAU/mL) antibody levels post-booster. Those with prior infection had a lower proportional increase in antibody level (51 fold) compared with the median change in COVID naive patients (144 fold) from pre-booster to 2 weeks post-booster. ConclusionsOur data demonstrates that hemodialysis patients obtain a robust humoral response from a third dose of the BNT162b2 vaccine although antibody levels wane over time.
ABSTRACT
BackgroundA profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. MethodsWe conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days. FindingsForty eligible subjects were enrolled from June to November of 2021. There was no difference in adverse events nor in ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate compared to the placebo group (89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.0-0.72, p=0.03). There were fewer subjects admitted to the ICU in the dupilumab group compared to placebo (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. InterpretationDupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. Trial RegistrationThis trial is registered with ClinicalTrials.gov, NCT04920916. FundingVirginia Biosciences Health Research Corporation, PBM C19, Henske Family Foundation, National Institutes of Health, National Cancer Institute
ABSTRACT
Dialysis patients are extremely vulnerable to SARS-CoV-2 infection with high rates of hospitalization and mortality rates estimated at 20-30%. In January of 2021, the University of Virginia Dialysis Program initiated a program wide vaccination campaign administering Pfizer BioNTech mRNA SARS-CoV-2 (BNT162b2) vaccine. To characterize the time-dependent decline in humoral immunity, we performed a prospective cohort study measuring serial monthly semi quantitative IgG antibody levels to the SARS-CoV-2 spike protein receptor binding domain in fully vaccinated in-center hemodialysis patients. Measurements were taken beginning at 2 months post full vaccination through 6 months after full vaccination. Early results showed similar seroconversion rates as prior studies with 88% obtaining positive antibody levels. Those with prior infection obtained the highest antibody levels. Over the ensuing months, patient antibody levels declined at an adjusted average rate of 31% per month. At the conclusion of the study, 40% of patients remaining in the cohort possessed either negative or borderline IgG antibody levels. Projecting future antibody levels based on the slopes of antibody level decay suggests 65% of the cohort will progress to borderline or negative antibody levels at 10 months post full vaccination. In summary, we studied long term vaccine response following vaccination with the BNT162b2 mRNA vaccine in hemodialysis patients. Our data adds to the limited pool of data in this patient population and will help to inform the discussion about vaccine booster needs and frequency.
ABSTRACT
Patients with End Stage Kidney Disease requiring dialysis are exceedingly vulnerable to SARS-CoV-2 infection with high hospitalization rates and mortality. Despite this risk, little is known about real world dialysis patient SARS-CoV-2 vaccination acceptance. Surveys of the general population suggest significant vaccine hesitancy and high potential for refusal. From January 27th to March 12th 2021, the University of Virginia (UVA) Health System, in partnership with the Virginia Department of Health / Blue Ridge Health District (BRHD) provided on-site mobile vaccination clinics at 12 UVA dialysis sites. We conducted a cross-sectional study to evaluate vaccine acceptance and evaluate factors associated with refusal. Of 859 dialysis patients with complete vaccination data, 80% received at least one dose of vaccine and 87% of these vaccinations were provided by the UVA/BRHD partnership. The overall patient refusal rate was low at 14%. Patients refusing SARS-CoV-2 vaccine were more likely to be female, younger and missing a documented flu vaccination during the 2020-2021 season. Attributes such as race or prior infection with SARS-CoV-2 were not significantly associated with vaccine refusal. In conclusion, dialysis patients in our program were surprisingly likely to accept vaccination for SARS-CoV-2. Identifying attributes associated with refusal may help target populations at high risk of vaccine refusal.
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 interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab 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, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases. SummaryL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronans receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.
