The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the ...effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody
. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab
, S2X259
and S2H97
. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.
The infectious coronavirus disease 2019 (COVID-19) pandemic is an ongoing global healthcare challenge. Up to one-third of hospitalised patients develop severe pulmonary complications and acute ...respiratory distress syndrome. Pulmonary outcomes following COVID-19 are unknown.
The Swiss COVID-19 lung study is a multicentre prospective cohort investigating pulmonary sequelae of COVID-19. We report on initial follow-up 4 months after mild/moderate or severe/critical COVID-19 according to the World Health Organization severity classification.
113 COVID-19 survivors were included (mild/moderate n=47, severe/critical n=66). We confirmed several comorbidities as risk factors for severe/critical disease. Severe/critical disease was associated with impaired pulmonary function,
diffusing capacity of the lung for carbon monoxide (
) % predicted, reduced 6-min walk distance (6MWD) and exercise-induced oxygen desaturation. After adjustment for potential confounding by age, sex and body mass index (BMI), patients after severe/critical COVID-19 had a
20.9% pred (95% CI 12.4-29.4% pred, p=0.01) lower at follow-up.
% pred was the strongest independent factor associated with previous severe/critical disease when age, sex, BMI, 6MWD and minimal peripheral oxygen saturation at exercise were included in the multivariable model (adjusted odds ratio per 10% predicted 0.59, 95% CI 0. 37-0.87; p=0.01). Mosaic hypoattenuation on chest computed tomography at follow-up was significantly associated with previous severe/critical COVID-19 including adjustment for age and sex (adjusted OR 11.7, 95% CI 1.7-239; p=0.03).
4 months after severe acute respiratory syndrome coronavirus 2 infection, severe/critical COVID-19 was associated with significant functional and radiological abnormalities, potentially due to small-airway and lung parenchymal disease. A systematic follow-up for survivors needs to be evaluated to optimise care for patients recovering from COVID-19.
Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. ...In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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•SARS-CoV-2 RBD is immunodominant and accounts for 90% of serum neutralizing activity•RBD antibodies decline with a half-life of ∼50 days, but their avidity increases•Structural definition of a SARS-CoV-2 RBD antigenic map using monoclonal antibodies•ACE2-binding site dominates SARS-CoV-2 polyclonal neutralizing antibody responses
Serological analyses of ∼650 SARS-CoV-2-exposed individuals show that 90% of the serum or plasma neutralizing activity targets the virus receptor-binding domain, with structural insights revealing how distinct types of neutralizing antibodies targeting the ACE2-binding site dominate the immune response against SARS-CoV-2 spike.
The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We ...describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.
Immunocompromised patients may be at increased risk for complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, comprehensive data of SARS‐CoV‐2 infection in ...solid organ transplant (SOT) recipients are still lacking. We performed a multicenter nationwide observational study within the Swiss Transplant Cohort Study (STCS) to describe the epidemiology, clinical presentation, treatment and outcomes of the first microbiologically documented SARS‐CoV‐2 infection among SOT recipients. Overall, 21 patients were included with a median age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations). The most common presenting symptoms were fever (76%), dry cough (57%), nausea (33%), and diarrhea (33%). Ninety‐five percent and 24% of patients required hospital and ICU admission, respectively, and 19% were intubated. After a median of 33 days of follow‐up, 16 patients were discharged, 3 were still hospitalized and 2 patients died. These data suggest that clinical manifestations of SARS‐CoV‐2 infection in middle‐aged SOT recipients appear to be similar to the general population without an apparent higher rate of complications. These results need to be confirmed in larger cohorts.
This study describes the epidemiology, clinical presentation, treatment, and outcome of the first 21 solid organ transplant recipients infected with SARS‐CoV‐2 in the Swiss Transplant Cohort Study.
Patient information leaflets can reduce antibiotic prescription rates by improving knowledge and encouraging shared decision making (SDM) in patients with respiratory tract infections (RTI). The ...effect of these interventions in antibiotic low-prescriber settings is unknown. We conducted a pragmatic pre-/post interventional study between October 2022 and March 2023 in Swiss outpatient care. The intervention was the provision of patient leaflets informing about RTIs and antibiotics use. Main outcomes were the extent of SDM, antibiotic prescription rates, and patients' awareness/knowledge about antibiotic use in RTIs. 408 patients participated in the pre-intervention period, and 315 patients in the post- intervention period. There was no difference in the extent of SDM (mean score (range 0-100): 65.86 vs. 64.65, p = 0.565), nor in antibiotic prescription rates (no prescription: 89.8% vs. 87.2%, p = 0.465) between the periods. Overall awareness/knowledge among patients with RTI was high and leaflets showed only a small effect on overall awareness/knowledge. In conclusion, in an antibiotic low-prescriber setting, patient information leaflets may improve knowledge, but may not affect treatment decisions nor antibiotic prescription rates for RTIs.
In this study, we compared IFA and real-time PCR in bronchoalveolar lavage specimens of HIV infected patients. A total of 66 BALs from 62 HIV patients were included in the study. 30 IFA positive and ...36 IFA negative specimens were tested with real-time PCR, targeting the major surface glycoprotein. We performed a retrospective analysis of the patient's medical records, compared the results of the IFA and PCR tests and analyzed costs, expenditure of time and personal expenses.
All of the 30 IFA positive samples were PCR positive. 35 of 36 IFA negative probes were also negative in the PCR assay. Considering the PCR results as a binary outcome (positive/negative) sensitivity was 100%, specificity 97.2%. The patient with negative IFA and positive PCR had a clear clinical picture of PCP and responded to PCP treatment. PCR was more than twice as expensive and time-consuming as IFA. Diagnostic accuracy for PCP of PCR and IFA was comparable in HIV-infected patients, but IFA was significantly less expensive and less time-consuming. Therefore, IFA testing can continue to be used as gold standard in the diagnosis of PCP in HIV patients. However, in special cases, IFA may lack sensitivity and PCR should be added to the diagnostic armamentarium.
The COVID-19 pandemic required careful management of intensive care unit (ICU) admissions, to reduce ICU overload while facing limitations in resources. We implemented a standardized, ...physiology-based, ICU admission criteria and analyzed the mortality rate of patients refused from the ICU. In this retrospective observational study, COVID-19 patients proposed for ICU admission were consecutively analyzed; Do-Not-Resuscitate patients were excluded. Patients presenting an oxygen peripheral saturation (SpO.sub.2) lower than 85% and/or dyspnea and/or mental confusion resulted eligible for ICU admission; patients not presenting these criteria remained in the ward with an intensive monitoring protocol. Primary outcome was both groups' survival rate. Secondary outcome was a sub analysis correlating SpO.sub.2 cutoff with ICU admission. From March 2020 to January 2021, 1623 patients were admitted to our Center; 208 DNR patients were excluded; 97 patients were evaluated. The ICU-admitted group (n = 63) mortality rate resulted 15.9% at 28 days and 27% at 40 days; the ICU-refused group (n = 34) mortality rate resulted 0% at both intervals (p < 0.001). With a SpO.sub.2 cut-off of 85%, a significant correlation was found (p = 0.009), but with a 92% a cut-off there was no correlation with ICU admission (p = 0.26). A similar correlation was also found with dyspnea (p = 0.0002). In COVID-19 patients, standardized ICU admission criteria appeared to safely reduce ICU overload. In the absence of dyspnea and/or confusion, a SpO.sub.2 cutoff up to 85% for ICU admission was not burdened by negative outcomes. In a pandemic context, the SpO.sub.2 cutoff of 92%, as a threshold for ICU admission, needs critical re-evaluation.
Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral ...spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus. In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus, short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.
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