Pulmonary function and survival one year after dupilumab treatment of acute moderate to severe COVID-19: A follow up study from a Phase IIa trial (preprint)

Background: We previously conducted a Phase IIa randomized placebo-controlled trial of 40 subjects to assess the efficacy and safety of dupilumab use in those hospitalized with COVID-19 (NCT04920916). Based on our pre-clinical data suggesting downstream pulmonary dysfunction with COVID-19 induced type 2 inflammation, we contacted patients from our Phase IIa study at 1 year for assessment of Post Covid-19 Conditions (PCC). Methods: Subjects at 1 year after treatment underwent pulmonary function testing (PFTs), high resolution computed tomography (HRCT) imaging, symptom questionnaires, neurocognitive assessments, and serum immune biomarker analysis, with subject survival also monitored. The primary outcome was the proportion of abnormal PFTs, defined as an abnormal diffusion capacity for carbon monoxide (DLCO) or 6-minute walk testing (6MWT) at the 1-year visit. Results: Sixteen of the 29 one-year survivors consented to the follow up visit. We found that subjects who had originally received dupilumab were less likely to have abnormal PFTs compared to those who received placebo (Fishers exact p=0.011, adjusted p=0.058). We additionally found that 3 out of 19 subjects (16%) in the dupilumab group died by 1 year compared to 8 out of 21 subjects (38%) in the placebo group (log rank p=0.12). We did not find significant differences in neurocognitive testing, symptoms or CT chest imaging between treatment groups but observed evidence of reduced type 2 inflammation in those who received dupilumab. Conclusions: We observed evidence of reduced long-term morbidity and mortality from COVID-19 with dupilumab treatment during acute hospitalization when added to standard of care regimens.

Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients (preprint)

We sought to discover links between antibody responses to SARS-CoV-2 and patient clinical variables, cytokine profiles and antibodies to endemic coronaviruses. Serum from patients of varying ages and clinical severity were collected and used to probe a novel multi-coronavirus protein microarray containing SARS-CoV-2 proteins and overlapping protein fragments of varying length as well as SARS-CoV, MERS-CoV, HCoV-OC43 and HCoV-NL63 proteins. IgG, IgA and IgM antibody responses to specific epitopes within the spike (S), nucleocapsid (N) and membrane proteins (M) were higher in older adult patients. Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses when compared to the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these serosilent individuals with cytokine analysis revealed significant differences in IL-10, IL-15, IP-10, EGF and sCD40L levels when compared to seroreactive patients in the cohort.

IgG Antibodies against SARS-CoV-2 Correlate with Days from Symptom Onset, Viral Load and IL-10 (preprint)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a pandemic of the respiratory disease coronavirus disease 2019 (COVID-19). Antibody testing is essential to identify persons exposed to the virus and potentially in predicting disease immunity. 183 COVID-19 patients (68 of whom required mechanical ventilation) and 41 controls were tested for plasma IgG, IgA and IgM against the SARS-CoV-2 S1, S2, receptor binding domain (RBD) and N proteins using the MILLIPLEX(R) SARS-CoV-2 Antigen Panel. Plasma cytokines were concurrently measured using the MILLIPLEX(R) MAP Human Cytokine/Chemokine/Growth Factor Panel A. As expected the 183 COVID-19 positive patients had high levels of IgG, IgA and IgM anti-SARS-CoV-2 antibodies against each of the viral proteins. Sensitivity of anti-S1 IgG increased from 60% to 93% one week after symptom onset. S1-IgG and S1-IgA had specificities of 98% compared to the 41 COVID-19 negative patients. The 68 ventilated COVID-19 positive patients had higher antibody levels than the 115 COVID-19 positive patients who were not ventilated. IgG antibody levels against S1 protein had the strongest positive correlation to days from symptom onset. There were no statistically significant differences in IgG, IgA and IgM antibodies against S1 based on age. We found that patients with the highest levels of anti-SARS-CoV-2 antibodies had the lowest viral load in the nasopharynx. Finally there was a correlation of high plasma IL-10 with low anti-SARS-CoV-2 antibodies. Anti-SARS-CoV-2 antibody levels, as measured by a novel antigen panel, increased within days after symptom onset, achieving > 90% sensitivity and specificity within one week, and were highest in patients who required mechanical ventilation. Antibody levels were inversely associated with viral load but did not differ as a function of age. The correlation of high IL-10 with low antibody response suggests a potentially suppressive role of this cytokine in the humoral immune response in COVID-19.