Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens (preprint)

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, the usage of S2 as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design highly stable S2-only antigens retaining a closed prefusion conformation. Weighted ensemble simulations provide mechanistic characterization of the S2 trimer opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Alchemical free energy perturbation calculations and a corroborating set of experiments confirm that V991W and T998W in the central helices of S2 stabilize the trimer in the closed prefusion conformation, producing an antigen with increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

Synthetic repertoires derived from convalescent COVID-19 patients enable discovery of SARS-CoV-2 neutralizing antibodies and a novel quaternary binding modality (preprint)

The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has sparked concern over the continued effectiveness of existing therapeutic antibodies and vaccines. Hence, together with increased genomic surveillance, methods to rapidly develop and assess effective interventions are critically needed. Here we report the discovery of SARS-CoV-2 neutralizing antibodies isolated from COVID-19 patients using a high-throughput platform. Antibodies were identified from unpaired donor B-cell and serum repertoires using yeast surface display, proteomics, and public light chain screening. Cryo-EM and functional characterization of the antibodies identified N3-1, an antibody that binds avidly (Kd,app = 68 pM) to the receptor binding domain (RBD) of the spike protein and robustly neutralizes the virus in vitro. This antibody likely binds all three RBDs of the trimeric spike protein with a single IgG. Importantly, N3-1 equivalently binds spike proteins from emerging SARS-CoV-2 variants of concern, neutralizes UK variant B.1.1.7, and binds SARS-CoV spike with nanomolar affinity. Taken together, the strategies described herein will prove broadly applicable in interrogating adaptive immunity and developing rapid response biological countermeasures to emerging pathogens.

The efficacy and safety of COVID-19 vaccine: A protocol of systematic review and meta-analysis (preprint)

Background: The coronavirus disease 2019 (COVID-19) is one of the most wide-spread and threatening infectious diseases in human history. Experts in the field of medicine and biology are working to develop methods to treat and prevent COVID-19. Currently, COVID-19 is predominantly treated with symptomatic therapy and there is still a lack of effective antiviral therapy. Therefore, the prevention and control of novel coronavirus is primarily focused on vaccine development. Several vaccines have been developed, but their relative efficacy and safety have not been proven. Therefore, the aim of this study is to investigate the efficacy and safety of COVID-19 vaccines. Methods: and analysis: The electronic databases we will use to retrieve information include PubMed, The Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database and Weipu Electronics. The retrieval period is from the establishment of the database to March 2021. All randomized controlled trials in humans vaccinated with COVID-19 were collected, and data were independently selected and extracted according to predesigned inclusion/exclusion criteria. Full-text screening, data extraction and quality assessment were conducted independently by two reviewers. Two additional investigators will conduct report quality, risk of bias, sensitivity analysis and subgroup analysis to ensure the reliability of our study results. The software RevMan 5.3 was used for statistical analysis. Systematic review and meta-analyses will be conducted to evaluate the pooled evidence of efficacy and safety of the COVID-19 vaccines. Result: This study will evaluate the efficacy and safety of the COVID-19 vaccines. Conclusion: The conclusions of this study will provide an evidence-based analysis of the safety and efficacy of COVID-19 vaccines. Systematic review registration: PROSPERO CRD42021242581

The Influences of COVID-19 on Patients with Chronic Kidney Disease: A Multicenter Cross-Sectional Study (preprint)

Background: The outbreak of coronavirus disease 2019 (COVID-19) has attracted global attention. This study aimed at exploring the change of illness, daily life and psychological responses during the pandemic of COVID-19 among chronic kidney disease patients.Methods: The study was conducted by collecting the questionnaires in 5 nephrology centers. The questionnaire consisted of two main parts: the influences of COVID-19 and assessment of anxiety by using Self-Rating Anxiety Scale. The first part included (1) basic demographic data; (2) the influences of COVID-19 on the illness and daily life; (3) patients’ psychological responses during the epidemic.Findings: 612 patients were included and divided into two groups according to eGFR. 96 patients (34%) in CKD stages1-2 group and 141 patients (42.7%) in CKD stages 3-5 group had reduced their follow-up frequency (p=0.031). More patients with CKD stages 1-2 consulted online (25.9%), p=0.005. Besides, patients with CKD stages 3-5 group tended to be more anxious about follow-up(p=0.002), fearful of being infected with COVID-19 (P=0.009), more likely to feel symptoms getting worse (p=0.006) and gained more help from medical staff during the pandemic period (p=0.038). The standard scores of SAS were 48.58±7.082 and 51.19±5.944 in CKD stages 1-2 group and CKD stages 3-5 group, respectively (p<0.001). And there were significant differences in the severity of anxiety (p=0.004).Interpretation: COVID-19 had a greater impact on patients with CKD stages 3-5 than stages 1-2 in illness, daily life and psychological disorder. Patients with CKD stages 3-5 were more anxious during the pandemic of COVID-19. Funding: None.Declaration of Interests: The authors declare that they have no conflict of interest.Ethics Approval Statement: The study was in compliance with the Declaration of Helsinki and was approved by the ethical committee of West China Hospital of Sichuan University.

Predictors of clinical deterioration in non-severe patients with COVID-19: a retrospective cohort study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains pandemic with considerable morbidity and mortality around the world. The aim of this study was to identify the predictors for clinical deterioration in patients with COVID-19 who did not show clinical deterioration upon hospital admission. METHODS: Two hundred fifty-seven patients with confirmed COVID-19 pneumonia admitted to Guangzhou Eighth People's Hospital between 23 January and 21 March 2020 were retrospectively enrolled. Demographic data, symptoms, laboratory values, comorbidities and treatments were all collected. The study endpoint was clinical deterioration within 20 days from hospital admission. Univariate and multivariable logistic regression methods were used to explore the risk factors associated with clinical deterioration. RESULTS: A total of 49 (19%) patients showed clinical deterioration after admission. Compared with patients that did not experience clinical deterioration, clinically deteriorated patients had more dyspnea, cough and myalgia (65.3% versus 29.3%) symptoms and more had comorbidities (89.8% versus 36.1%). Clinical and laboratory characteristics at admission that were associated with clinical deterioration included senior age, diabetes, hypertension, myalgia, higher temperature, systolic blood pressure, C-reactive protein (CRP), procalcitonin, activated partial thromboplastin time, aspartate aminotransferase, alanine transaminase, direct bilirubin, plasma creatinine, lymphocytopenia, thrombocytopenia, decreased albumin and bicarbonate concentration. Medical history of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers and metformin were also risk factors. CONCLUSION: The four best predictors for clinical deterioration were CRP, procalcitonin, age and albumin. A "best" multivariable prediction model, resulting from using a variable selection procedure, included senior age, presentation with myalgia, and higher level of CRP and serum creatinine (bias-corrected c-statistic = 0.909). Sensitivity and specificity corresponding to a cut point of CRP ≥18.45 mg/L for predicting clinical deterioration were 85% and 74%, respectively.

Practical considerations for Ultraviolet-C radiation mediated decontamination of N95 respirator against SARS-CoV-2 virus (preprint)

Decontaminating N95 respirators for reuse could mitigate shortages during the COVID-19 pandemic. We tested a portable UV-C light-emitting diode disinfection chamber and found that decontamination efficacy depends on mask model, material and location on the mask. This emphasizes the need for caution when interpreting efficacy data of UV-C decontamination methods.

Post-Traumatic Stress Disorder in Patients with Rheumatic Diseases During the COVID-19 Outbreak​ (preprint)

Background: The COVID-19 pandemic is not only a traumatic event, but a collective stressor unfolding over time, causing alarming implications for the mental health. This study aims to shed light on the mental health status of patients with rheumatic disease (RD) during the massive outbreak of COVID-19 in China, especially the prevalence and severity of post-traumatic stress disorder (PTSD) compared with the levels in healthy people. Methods: A questionnaire survey was conducted in a cross-sectional study of 486 RD patients and 486 healthy control subjects. We collected participants’ demographic and clinical characteristics and surveyed the prevalence and severity of PTSD and sleep quality in the samples using the PTSD Checklist for DSM-5 (PCL-5) and 4 items from the Pittsburgh Sleep Quality Index (PSQI). Findings: Compared with healthy control subjects (n=486), RD patients (n=486) had a higher prevalence of PTSD (12·1% vs. 4·1%; p<0·001). They also had higher total scores on the PCL-5 and on all four items from the PSQI (p≤ 0·001). Female gender, old age, poor sleep quality, long duration of RD, poor subjective evaluation of the disease and pessimistic subjective perception of the epidemic were identified as risk factors for PTSD in RD patients during the COVID-19 epidemic. Interpretation: During the COVID-19 outbreak, RD patients presented a higher prevalence and severity of PTSD and more sleep disturbances. Our findings confirm the importance of psychological assessment and mental health care in addition to regular clinical care for RD patients during the pandemic. Funding: National Natural Science Foundation of China, China Ministry of Science and Technology, Shanghai Municipal Key Clinical Specialty Fund.Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: This study was approved by the Human Research Ethics Committee of Changzheng Hospital, and informed consent was obtained from all participants.

Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension (preprint)

With the capability of inducing elevated expression of ACE2, the cellular receptor for SARS-CoV-2, angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ARBs/ACEIs) treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the correlation of ARBs/ACEIs usage with the pathogenesis of COVID-19 in a retrospective, single-center study. 126 COVID-19 patients with preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine (HPHTCM) in Wuhan from January 5 to February 22, 2020 were retrospectively allocated to ARBs/ACEIs group (n=43) and non-ARBs/ACEIs group (n=83) according to their antihypertensive medication. 125 age- and sex-matched COVID-19 patients without hypertension were randomly selected as non-hypertension controls. In addition, the medication history of 1942 hypertension patients that were admitted to HPHTCM from November 1 to December 31, 2019 before COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical and laboratory data were collected, analyzed and compared between these groups. The frequency of ARBs/ACEIs usage in hypertension patients with or without COVID-19 were comparable. Among COVID-19 patients with hypertension, those received either ARBs/ACEIs or non-ARBs/ACEIs had comparable blood pressure. However, ARBs/ACEIs group had significantly lower concentrations of CRP (p=0.049) and procalcitonin (PCT, p=0.008). Furthermore, much lower proportion of critical patients (9.3% vs 22.9%; p=0.061), and a lower death rate (4.7% vs 13.3%; p=0.216) were observed in ARBs/ACEIs group than non-ARBs/ACEIs group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACEIs in COVID-19 patients with preexisting hypertension.