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The emergence of Omicron/BA.1 has brought new challenges to fight against SARS-CoV-2. A large number of mutations in the Spike protein suggest that its susceptibility to immune protection elicited by the existing COVID-19 infection and vaccines may be altered. In this study, we constructed the pseudotyped SARS-CoV-2 variant Omicron. The sensitivity of 28 serum samples from COVID-19 convalescent patients infected with SARS-CoV-2 original strain was tested against pseudotyped Omicron as well as the other variants of concern (VOCs, Alpha, Beta, Gamma, Delta) and variants of interest (VOIs, Lambda, Mu). Our results indicated that the mean neutralization ED50 of these sera against Omicron decreased to 66, which is about 8.4-folds compared to the D614G reference strain (ED50 = 556), whereas the neutralization activity of other VOC and VOI pseudotyped viruses decreased only about 1.2-4.5-folds. The finding from our in vitro assay suggest that Omicron variant may lead to more significant escape from immune protection elicited by previous SARS-CoV-2 infection and perhaps even by existing COVID-19 vaccines.

From December 2022 to January 2023, SARS-CoV-2 infections caused by BA.5 and BF.7 subvariants of B.1.1.529 (Omicron) spread in China. It is urgently needed to evaluate the protective immune responses in the infected individuals against the current circulating variants to predict the future potential infection waves, such as the BQ.1.1, XBB.1.5, and CH1.1 variants. In this study, we constructed a panel of pseudotyped viruses for SARS-CoV-2 for the past and current circulating variants, including D614G, Delta, BA.1, BA.5, BF.7, BQ.1.1, XBB.1.5 and CH.1.1. We investigated the neutralization sensitivity of these pseudotyped viruses to sera from individuals who had BA.5 or BF.7 breakthrough infections in the infection wave of last December in China. The mean neutralization ID50 against infected variants BA.5 and BF.7 are 533 and 444, respectively. The highest neutralizing antibody level was observed when tested against the D614G strain, with the ID50 of 742, which is about 1.52-folds higher than that against the BA.5/BF.7 variant. The ID50 for BA.1, Delta, and BQ.1.1 pseudotyped viruses were about 2-3 folds lower when compared to BA.5/BF.7. The neutralization activities of these serum samples against XBB.1.5 and CH.1.1 decreased 7.39-folds and 15.25-folds when compared to that against BA.5/BF.7. The immune escape capacity of these two variants might predict new infection waves in future when the neutralizing antibody levels decrease furtherly.

Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.

Background SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is now classified in the genus Coronavirus with closely related SARS-CoV. SARS-CoV-2 is highly pathogenic in humans and is classified as a biosafety level (BSL)-3 pathogen, which makes manipulating it relatively difficult due to its infectious nature. Methods To circumvent the need for BSL-3 laboratories, an alternative assay was developed that avoids live virus and instead uses a recombinant VSV expressing luciferase and possesses the full length or truncated spike proteins of SARS-CoV-2. Furthermore, to measure SARS-CoV-2 neutralizing antibodies under BSL2 conditions, a chemiluminescence reduction neutralization test (CRNT) for SARS-CoV-2 was developed. The neutralization values of the serum samples collected from hospitalized patients with COVID-19 or SARS-CoV-2 PCR-negative donors against the pseudotyped virus infection evaluated by the CRNT were compared with antibody titers determined from an enzyme-linked immunosorbent assay (ELISA) or an immunofluorescence assay (IFA). Results The CRNT, which used whole blood collected from hospitalized patients with COVID-19, was also examined. As a result, the inhibition of pseudotyped virus infection was specifically observed in both serum and whole blood and was also correlated with the results of the IFA. Conclusions In conclusion, the CRNT for COVID-19 is a convenient assay system that can be performed in a BSL-2 laboratory with high specificity and sensitivity for evaluating the occurrence of neutralizing antibodies against SARS-CoV-2.

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

Background. Convalescent serum and blood were used to treat patients during outbreaks of Zaire ebolavirus (ZEBOV) infection in 1976 and 1995, with inconclusive results. During the recent 2013-2016 West African epidemic, serum/plasma from survivors of ZEBOV infection was used to treat patients in the affected countries and several repatriated patients. The effectiveness of this strategy remains unknown. Methods. Nine rhesus monkeys were experimentally infected with ZEBOV-Makona. Beginning on day 3 after exposure (at the onset of viremia), 4 animals were treated with homologous ZEBOV-Makona convalescent macaque sera, 3 animals were treated in parallel with heterologous Sudan ebolavirus (SEBOV) convalescent macaque sera, and 2 animals served as positive controls and were not treated. Surviving animals received additional treatments on days 6 and 9. Results. Both untreated control animals died on postinfection day 9. All 4 ZEBOV-Makona-infected macaques treated with homologous ZEBOV-Makona convalescent sera died on days 8-9. One macaque treated with heterologous SEBOV convalescent sera survived, while the other animals treated with the heterologous SEBOV sera died on days 7 and 9. Conclusions. The findings suggest that convalescent sera alone is not sufficient for providing 100% protection against lethal ZEBOV infection when administered at the onset of viremia.

To investigate the effects of nutritional intervention with resistance training on skeletal muscle mass in elderly patients with disabilities in a convalescent rehabilitation setting. A randomized controlled trial. (UMIN Clinical Trials Registry ID: UMIN000006238). A rehabilitation hospital. 39 elderly patients with decreased skeletal muscle mass in an inpatient convalescence rehabilitation unit. A combination of resistance training plus nutritional supplementation (R/N group) or resistance training alone (R group). The training and supplementation were conducted essentially from the patient's admission to discharge (2–6 months). The patients were evaluated at the time of admission and at the end of the intervention for skeletal muscle mass (calf circumference [CC] as a primary outcome, and arm circumference [AC]), hand grip strength (HG), Mini-Nutritional Assessment-Short Form (MNA®-SF) score, serum albumin level (Alb), body mass index (BMI), and activities of daily living (ADL) as represented by the Barthel Index (BI) score. Significant treatment effects were seen for CC, AC, BI, Alb in the R/N group compared to the R group. A mean treatment effect of 3.2 (95%CI: 2.0–4.4) was seen in CC, 1.4 (95%CI: 0.8–2.1) was seen in AC, 11.2 (95%CI: 0.5–21.8) was seen in BI, 0.3 (95%CI: 0.1–0.5) was seen in Alb. The results of this study suggest that nutritional intervention added to resistance training during convalescent rehabilitation may improve skeletal muscle mass and activities of daily living.

Purpose: Characterization of immune system heterogeneity in COVID‐19 patients by comparing the inflammatory markers heparin‐binding protein (HBP), serum amyloid A protein (SAA), IL‐6, and C‐reactive protein (CRP) in relation to viral burden, immune response, and tissue damage. Also, determine if prolonged elevations in these markers are associated with long‐term symptoms of COVID‐19. Methods: This study enrolled 106 hospitalized patients with PCR‐confirmed diagnoses of COVID‐19. Blood samples were collected within 24 h of admission ( t 24h ), at 48 h ( t 48h ), 7 days ( t 7d ), and long‐term, greater than 1 month, post discharge ( t LongTerm ). Serum levels of HBP, SAA, IL‐6, and CRP were measured using a commercial point‐of‐care device. Viral burden was assessed via serum viral spike S‐protein serum levels and specific immunoglobulins G, M, and D against S&N proteins, and SARS‐CoV‐2 proteins were quantified. Tissue injury was evaluated by measuring HMGB‐1 levels. Clinical data were reviewed retrospectively. Healthy individual samples served as controls. Results: COVID‐19 patients exhibited significantly elevated serum HBP and SAA compared to healthy controls. SAA levels normalized over 1 month, whereas HBP, CRP, and IL‐6 remained persistently elevated. Patients requiring intensive care unit (ICU) admission, endotracheal intubation, or extracorporeal membrane oxygen (ECMO) demonstrated higher CRP, IL‐6, and HBP at initial assessment. However, after 48 h, only IL‐6 was elevated in patients who subsequently expired. No significant correlations emerged between serum HBP levels and HMGB‐1, viral spike protein levels, or antibodies against SARS‐CoV‐2 proteins. Pre‐existing or acquired comorbidities did not significantly influence HBP or SAA concentrations. An analysis of biomarker profiles identified four distinct patient clusters, each characterized by unique inflammatory patterns that remained stable over time. Specifically, Cluster 1 exhibited low IL‐6 with high SAA and CRP. Cluster 2 had low HBP with the highest IL‐6. Cluster 3 demonstrated low SAA and CRP levels, and Cluster 4 exhibited robust inflammatory responses across all markers except IL‐6. Conclusions: The persistence of inflammatory markers suggests ongoing inflammatory responses post‐COVID‐19 infection. Significant heterogeneity observed in inflammatory responses upon admission indicates multiple distinct inflammatory phenotypes, which may have implications for clinical outcomes and management strategies.

Serum levels of interleukin-6 (IL-6) are increased in COVID-19 patients. IL-6 is an effective therapeutic target in inflammatory diseases and tocilizumab, a monoclonal antibody that blocks signaling via the IL-6 receptor (IL-6R), is used to treat patients with severe COVID-19. However, the IL-6R exists in membrane-bound and soluble forms (sIL-6R), and the sIL-6R in combination with soluble glycoprotein 130 (sgp130) forms an IL-6-neutralizing buffer system capable of neutralizing small amounts of IL-6. In this study, we analyzed serum levels of IL-6, sIL-6R and sgp130 in the serum of COVID-19 convalescent individuals with a history of mild COVID-19 disease and in acute severely ill COVID-19 patients compared to uninfected control subjects. Furthermore, we used single cell RNA sequencing data in order to determine which immune cell types are sources and targets of the individual cytokines and whether their expression is altered in severe COVID-19 patients. We find that sIL-6R levels are not only increased in acute severely ill patients, but also in convalescents after a mild COVID-19 infection. We show that this increase in sIL-6R results in an enhanced capacity of the sIL-6R/sgp130 buffer system, but that significantly enhanced free IL-6 is still present due to an overload of the buffer. Further, we identify IL-6 serum levels, age and the number of known pre-existing medical conditions as crucial determinants of disease outcome for the patients. We also show that IL-11 has no major systemic role in COVID-19 patients and that sCD25 is only increased in acute severely ill COVID-19 patients, but not in mild convalescent individuals. In conclusion, our study shows long-lasting alterations of the IL-6 system after COVID-19 disease, which might be relevant when applying anti-IL-6 or anti-IL-6R therapy.

The COVID-19 pandemic caused by SARS-CoV-2 is exerting huge pressure on global healthcare. Understanding of the molecular pathophysiological alterations in COVID-19 patients with different severities during disease is important for effective treatment. In this study, we performed proteomic profiling of 181 serum samples collected at multiple time points from 79 COVID-19 patients with different severity levels (asymptomatic, mild, moderate, and severe/critical) and 27 serum samples from non-COVID-19 control individuals. Dysregulation of immune response and metabolic reprogramming was found in severe/critical COVID-19 patients compared with non-severe/critical patients, whereas asymptomatic patients presented an effective immune response compared with symptomatic COVID-19 patients. Interestingly, the moderate COVID-19 patients were mainly grouped into two distinct clusters using hierarchical cluster analysis, which demonstrates the molecular pathophysiological heterogeneity in COVID-19 patients. Analysis of protein-level alterations during disease progression revealed that proteins involved in complement activation, the coagulation cascade and cholesterol metabolism were restored at the convalescence stage, but the levels of some proteins, such as anti-angiogenesis protein PLGLB1, would not recovered. The higher serum level of PLGLB1 in COVID-19 patients than in control groups was further confirmed by parallel reaction monitoring (PRM). These findings expand our understanding of the pathogenesis and progression of COVID-19 and provide insight into the discovery of potential therapeutic targets and serum biomarkers worth further validation.