A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based mRNA vaccine or convalescent individuals exhibited neutralizing titers, which were reduced 2-3.5 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The L452R mutation reduced neutralizing activity of 14 out of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 out of 10 NTD-specific mAbs since the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and formation of a new disulphide bond, as revealed by mass spectrometry and structural studies.
SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.
Critical COVID-19 is a life-threatening disease characterized by severe hypoxemia with complex pathophysiological mechanisms that are not yet completely understood. A pathological shift in the oxyhemoglobin curve (ODC) was previously described through the analysis of p50, intended as the oxygen tension at which hemoglobin is saturated by oxygen at 50%. The aim of this study was to analyze Hb-O2 affinity features over time in a cohort of critically ill COVID-19 patients, through the analysis of ODC p50 behavior. A retrospective analysis was performed; through multiple arterial blood gas (ABG) analyses, each p50 was calculated and normalized according to PaCO2, pH and temperature; patients’ p50 evolution over time was reported, comparing the first 3 days (early p50s) with the last 3 days (late p50s) of ICU stay. A total of 3514 ABG analyses of 32 consecutive patients were analyzed. The majority of patients presented a left shift over time (p = 0.03). A difference between early p50s and late p50s was found (20.63 ± 2.1 vs. 18.68 ± 3.3 mmHg, p = 0.03); median p50 of deceased patients showed more right shifts than those of alive patients (24.1 vs. 18.45 mmHg, p = 0.01). One-way ANOVA revealed a p50 variance greater in the early p50s (σ2 = 8.6) than in the late p50s (σ2 = 3.84), associated with a reduction over time (p < 0.001). Comparing the Hb-O2 affinity in critically ill COVID-19 patients between ICU admission and ICU discharge, a temporal shift in the ODC was observed.
Background In the pandemic scenario, critically ill COVID-19 patients’ management presented an increased workload for Intensive Care Unit (ICU) nursing staff, particularly during pronation maneuvers, with high risk of complications. In this contest, some authors described an increase in complications incidence after pronation. An ICU Pronation Team (IPT) was implemented to support this maneuver. Material and methods Retrospective analysis was conducted on consecutive critically ill COVID-19 patients in COVID-19 Center in southern Switzerland, between March and April 2020. Aim of the study was to determine rates and characteristics of pronation-related complications managed by IPT according to standard protocols. Results Forty-two patients undergoing mechanical ventilation (MV) were enrolled; 296 prone/supine positioning were performed, with 3.52 cycles/patient. All patients were equipped with arterial line, central venous catheter, urinary catheter, 28 (66%) endotracheal tube, 8 (19%), tracheostomy, 6 (14%) dialysis catheter, 3 (7%) abdominal drainage and 8 (19%) femoral thermodilution catheter; mean BMI was 28.3 kg/m 2 . One (0.3%) major complication was observed, while fourteen (33.3%) patients developed minor complications (pressure injuries). ICU length-of-stay and MV days correlated with both incidence (p = 0.029 and p = 0.015 respectively) and number (p = 0.001 and p = 0.001 respectively) of pressure sores (n = 27). Propensity matching score analysis did not show any protective factor of pronation regarding pressure injuries (p = 0.448). No other significant correlation was found. Conclusion Multidisciplinary healthcare professional management can reduce most severe complication related to pronation in critical care setting. Rather than from pronation, the persistent high rate of minor complications appeared to be related to disease severity.
Background COVID-19 is a multisystem disease complicated by respiratory failure requiring sustanined mechanical ventilation (MV). Prolongued oro-tracheal intubation is associated to an increased risk of dysphagia and bronchial aspiration. Purpose of this study was to investigate swallowing disorders in critically ill COVID-19 patients. Material and methods This was a retrospective study analysing a consecutive cohort of COVID-19 patients admitted to the Intensive Care Unit (ICU) of our hospital. Data concerning dysphagia were collected according to the Gugging Swallowing Screen (GUSS) and related to demographic characteristics, clinical data, ICU Length-Of-Stay (LOS) and MV parameters. Results From March 2 to April 30, 2020, 31 consecutive critically ill COVID-19 patients admitted to ICU were evaluated by speech and language therapists (SLT). Twenty-five of them were on MV (61% through endotracheal tube and 19% through tracheostomy); median MV length was 11 days. Seventeen (54.8%) patients presented dysphagia; a correlation was found between first GUSS severity stratification and MV days (p < 0.001), ICU LOS (p < 0.001), age (p = 0.03) and tracheostomy (p = 0.042). No other correlations were found. At 16 days, 90% of patients had fully recovered; a significant improvement was registered especially during the first week (p < 0.001). Conclusion Compared to non-COVID-19 patiens, a higher rate of dysphagia was reported in COVID-19 patients, with a more rapid and complete recovery. A systematic early SLT evaluation of COVID-19 patients on MV may thus be useful to prevent dysphagia-related complications.
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