Daily Respiratory Research Analysis

The current COVID-19 vaccines are suboptimal against the evolving SARS-CoV-2 variants, particularly in high-risk populations. A next-generation vaccine strategy capable of effective induction of respiratory mucosal immunity remains to be clinically developed. Here, we report an open-label, multi-arm phase 1 study (NCT05094609) to evaluate a multi-antigenic COVID-19 vaccine delivered once via inhaled aerosol to the lung of intramuscular mRNA-vaccinated humans without or with prior SARS-CoV-2 infection (uninfected vs infected). Escalating doses of a human adenoviral (HuAd)-vectored or chimpanzee Ad (ChAd)-vectored vaccine are evaluated in the uninfected cohort. A selected Ad vaccine is further evaluated in the infected cohort. The safety is assessed as a primary outcome. Ag-specific immune responses (secondary outcome) are assessed in peripheral blood and in respiratory tract via bronchoscopy at baseline and at timepoint(s) post-vaccination. Eighteen-65-year-old, healthy participants who have received at least 3 doses of mRNA COVID-19 vaccine are enrolled with those vaccinated with any Ad-vectored COVID-19 vaccine excluded. At baseline, there is minimally detectable mucosal immunity in the lung of uninfected or infected humans. While all tested doses (1×10

MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower airway. We identified 560 major allele homozygous patients, and 426 and 50 with 1 or 2 copies of the variant allele, respectively. MICBG406A conferred reduced odds of severe COVID-19. MICBG406A homozygous participants demonstrated 34% reduced cumulative odds for mechanical ventilation or death and 43% reduced risk for mortality. Patients with MICBG406A variant alleles had reduced soluble inflammatory mediators and differential regulation of multiple immune pathways. These findings demonstrate a potentially novel association between increasing MICBG406A variant allele copies and reduced COVID-19 severity, independent of SARS-CoV-2 viral burden and humoral immunity, suggesting the NKG2D-ligand pathway as an intervention target.

BACKGROUND: Small airways disease is a feature of many respiratory conditions. Currently available methods of diagnosing small airways lack sensitivity and/or cannot evaluate spatial heterogeneity. New diagnostic strategies for diagnosing small airways disease are needed. METHODS: We determined the regional displacement of lung tissue calculated from fluoroscopic lung images acquired at multiple angles over sequential time points as a surrogate of ventilation. We applied this technique, which we call X-ray velocimetry (XV), to patients with chronic obstructive pulmonary disease (COPD) and impaired spirometry and veterans with deployment-related constrictive bronchiolitis (DR-CB) but preserved spirometry to determine XV-derived biomarkers specific for each condition. RESULTS: We identified disease- and stage-specific XV biomarkers for COPD patients that correlated with airflow obstruction on spirometry. Further, we identified a set of XV-derived biomarkers that could distinguish veterans with DR-CB from controls despite normal spirometry in most patients from both groups. CONCLUSIONS: XV may provide a safe and widely-available strategy for diagnosing small airways disease while preserving spatial information. Future studies are required to validate the biomarkers described here in larger patient cohorts. TRIAL REGISTRATION: Not required for this study. However, participants enrolled at VUMC were enrolled under ClinicalTrials.gov study NCT04489758 (submitted 07/23/2020).