Pre-existing population immunity and SARS-CoV-2 variant establishment and dominance dynamics in the United States: An ecological study (preprint)

We conducted an ecological analysis of the dynamics of Delta and Omicron establishment and dominance in U.S. states. Omicron became the dominant circulating variant later in states with higher population-level immunity. By contrast, population immunity did not impact the rates of transition from prior variants to either Delta or Omicron.

Detection of the omicron variant virus with the Abbott BinaxNow SARS-CoV-2 Rapid Antigen Assay (preprint)

The US Centers for Disease Control and Prevention recommends rapid testing for SARS-CoV-2 infection as a key element of epidemic control. The Abbott BinaxNow is in widespread use in the United States for self-testing and as part of public health screening campaigns, but has not been evaluated for use with the omicron variant of SARS-CoV-2. We recruited individuals testing positive for COVID-19 PCR at an academic medical center. Anterior nasal swabs were stored in viral transport media and evaluated by viral load quantification and whole genome sequencing. We created serial dilutions from 2.5x103- 2.5x105 viral copies/specimen for two delta and omicron specimens, respectively, and tested each with the BinaxNow assay per manufacturer instructions. Results were interpreted by three readers, blinded to the specimen variant and concentration. All omicron and delta specimens with concentrations of 100,000 copies/swab or greater were positive by the BinaxNow Assay, a concentration similar to previously reported limits of detection for this assay. Assay sensitivity diminished below that. This study demonstrates that Omicron variant SARS-CoV-2 infections are detected by the BinaxNow rapid antigen assay. Additional laboratory and clinical validation assessments are needed to better determine their limits of detection and performance in real-world settings.

Longitudinal Characterization of Circulating Neutrophils Uncovers Distinct Phenotypes Associated with Disease Severity in Hospitalized COVID-19 Patients (preprint)

Multiple studies have identified an association between neutrophils and COVID-19 disease severity; however, the mechanistic basis of this association remains incompletely understood. Here we collected 781 longitudinal blood samples from 306 hospitalized COVID-19 + patients, 78 COVID-19 - acute respiratory distress syndrome patients, and 8 healthy controls, and performed bulk RNA-sequencing of enriched neutrophils, plasma proteomics, cfDNA measurements and high throughput antibody profiling assays to investigate the relationship between neutrophil states and disease severity or death. We identified dynamic switches between six distinct neutrophil subtypes using non-negative matrix factorization (NMF) clustering. At days 3 and 7 post-hospitalization, patients with severe disease had an enrichment of a granulocytic myeloid derived suppressor cell-like state gene expression signature, while non-severe patients with resolved disease were enriched for a progenitor-like immature neutrophil state signature. Severe disease was associated with gene sets related to neutrophil degranulation, neutrophil extracellular trap (NET) signatures, distinct metabolic signatures, and enhanced neutrophil activation and generation of reactive oxygen species (ROS). We found that the majority of patients had a transient interferon-stimulated gene signature upon presentation to the emergency department (ED) defined here as Day 0, regardless of disease severity, which persisted only in patients who subsequently died. Humoral responses were identified as potential drivers of neutrophil effector functions, as enhanced antibody-dependent neutrophil phagocytosis and reduced NETosis was associated with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirmed that while patient-derived IgG antibodies mostly drove neutrophil phagocytosis and ROS production in healthy donor neutrophils, patient-derived IgA antibodies induced a predominant NETosis response. Overall, our study demonstrates neutrophil dysregulation in severe COVID-19 and a potential role for IgA-dominant responses in driving neutrophil effector functions in severe disease and mortality.Funding:We acknowledge support from the Ragon Institute of MGH, MIT and Harvard, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476 – 01, CIVIC75N93019C00052, T32 GM007592), the American Lung Association, and the MGH Executive Committee on Research. A.-C.V. acknowledges funding support from the COVID-19 Clinical Trials Pilot grant from the Executive Committee on Research at MGH, a COVID-19 Chan Zuckerberg Initiative grant (2020-216954), and funds from the Manton Foundation and the Klarman Family Foundation.Declaration of Interests: M.S.F receives funding from Bristol-Myers Squibb. G.A. is a founder of Seromyx Systems Inc. N.H. holds equity in Biontech and holds equity in and advises Danger Bio. Ethics Approval Statement: The study was approved by the Mass General Brigham Institutional Review Board under protocol 2017P001681, with an approval for a waiver of informed consent in compliance with the 45CFR 46, 2018 Common rule.

Myocyte Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2 mediated myocarditis (preprint)

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 infection of host cells occurs predominantly via binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. Hypertension and pre-existing cardiovascular disease are risk factors for morbidity from COVID-19, and it remains uncertain whether the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) impacts infection and disease. Here, we aim to shed light on this question by assessing ACE2 expression in normal and diseased human myocardial samples profiled by bulk and single nucleus RNA-seq.