A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.

Emerging variants of concern (VOCs) are driving the COVID-19 pandemic1,2. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs3. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S614G) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S614G in ferrets and two mouse models-the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S614G showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S614G in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S614G in naive animals.

Antigenic cartography using variant-specific hamster sera reveals substantial antigenic variation among Omicron subvariants.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has developed substantial antigenic variability. As the majority of the population now has pre-existing immunity due to infection or vaccination, the use of experimentally generated animal immune sera can be valuable for measuring antigenic differences between virus variants. Here, we immunized Syrian hamsters by two successive infections with one of nine SARS-CoV-2 variants. Their sera were titrated against 16 SARS-CoV-2 variants, and the resulting titers were visualized using antigenic cartography. The antigenic map shows a condensed cluster containing all pre-Omicron variants (D614G, Alpha, Delta, Beta, Mu, and an engineered B.1+E484K variant) and considerably more diversity among a selected panel of Omicron subvariants (BA.1, BA.2, BA.4/BA.5, the BA.5 descendants BF.7 and BQ.1.18, the BA.2.75 descendant BN.1.3.1, the BA.2-derived recombinants XBB.2 and EG.5.1, and the BA.2.86 descendant JN.1). Some Omicron subvariants were as antigenically distinct from each other as the wildtype is from the Omicron BA.1 variant. Compared to titers measured in human sera, titers in hamster sera are of higher magnitude, show less fold change, and result in a more compact antigenic map topology. The results highlight the potential of sera from hamsters for the continued antigenic characterization of SARS-CoV-2.

SARS-CoV-2 variant Alpha has a spike-dependent replication advantage over the ancestral B.1 strain in human cells with low ACE2 expression.

Epidemiological data demonstrate that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) Alpha and Delta are more transmissible, infectious, and pathogenic than previous variants. Phenotypic properties of VOC remain understudied. Here, we provide an extensive functional study of VOC Alpha replication and cell entry phenotypes assisted by reverse genetics, mutational mapping of spike in lentiviral pseudotypes, viral and cellular gene expression studies, and infectivity stability assays in an enhanced range of cell and epithelial culture models. In almost all models, VOC Alpha spread less or equally efficiently as ancestral (B.1) SARS-CoV-2. B.1. and VOC Alpha shared similar susceptibility to serum neutralization. Despite increased relative abundance of specific sgRNAs in the context of VOC Alpha infection, immune gene expression in infected cells did not differ between VOC Alpha and B.1. However, inferior spreading and entry efficiencies of VOC Alpha corresponded to lower abundance of proteolytically cleaved spike products presumably linked to the T716I mutation. In addition, we identified a bronchial cell line, NCI-H1299, which supported 24-fold increased growth of VOC Alpha and is to our knowledge the only cell line to recapitulate the fitness advantage of VOC Alpha compared to B.1. Interestingly, also VOC Delta showed a strong (595-fold) fitness advantage over B.1 in these cells. Comparative analysis of chimeric viruses expressing VOC Alpha spike in the backbone of B.1, and vice versa, showed that the specific replication phenotype of VOC Alpha in NCI-H1299 cells is largely determined by its spike protein. Despite undetectable ACE2 protein expression in NCI-H1299 cells, CRISPR/Cas9 knock-out and antibody-mediated blocking experiments revealed that multicycle spread of B.1 and VOC Alpha required ACE2 expression. Interestingly, entry of VOC Alpha, as opposed to B.1 virions, was largely unaffected by treatment with exogenous trypsin or saliva prior to infection, suggesting enhanced resistance of VOC Alpha spike to premature proteolytic cleavage in the extracellular environment of the human respiratory tract. This property may result in delayed degradation of VOC Alpha particle infectivity in conditions typical of mucosal fluids of the upper respiratory tract that may be recapitulated in NCI-H1299 cells closer than in highly ACE2-expressing cell lines and models. Our study highlights the importance of cell model evaluation and comparison for in-depth characterization of virus variant-specific phenotypes and uncovers a fine-tuned interrelationship between VOC Alpha- and host cell-specific determinants that may underlie the increased and prolonged virus shedding detected in patients infected with VOC Alpha.

Humoral immune escape by current SARS-CoV-2 variants BA.2.86 and JN.1, December 2023.

Variant BA.2.86 and its descendant, JN.1, of SARS-CoV-2 are rising in incidence across Europe and globally. We isolated recent JN.1, BA.2.86, EG.5, XBB.1.5 and earlier variants. We tested live virus neutralisation of sera taken in September 2023 from vaccinated and exposed healthy persons (n = 39). We found clear neutralisation escape against recent variants but no specific pronounced escape for BA.2.86 or JN.1. Neutralisation escape corresponds to recent variant predominance but may not be causative of the recent upsurge in JN.1 incidence.

Divergent Genotype of Hepatitis A Virus in Alpacas, Bolivia, 2019.

Hepatitis A virus (HAV) is a common human pathogen found exclusively in primates. In a molecular and serologic study of 64 alpacas in Bolivia, we detected RNA of distinct HAV in ≈9% of animals and HAV antibodies in ≈64%. Complete-genome analysis suggests a long association of HAV with alpacas.

Humoral immune responses remain quantitatively impaired but improve qualitatively in anti-CD20-treated patients with multiple sclerosis after three or four COVID-19 vaccinations.

OBJECTIVE: To analyze anti-SARS-CoV-2-S1-IgG levels, avidity, Omicron BA.2 variant neutralizing capacity, and SARS-CoV-2-specific T cells in anti-CD20-treated patients with multiple sclerosis (aCD20pwMS) after two, three, or four COVID-19 vaccinations. RESULTS: Frequencies of aCD20pwMS with detectable SARS-CoV-2-S1-IgG increased moderately between two (31/61 (51%)), three (31/57 (54%)), and four (17/26 (65%)) vaccinations. However, among patients with detectable SARS-CoV-2-S1-IgG, frequencies of high avidity (6/31 (19%) vs 11/17 (65%)) and Omicron neutralizing antibodies (0/10 (0%) vs 6/10 (60%)) increased strongly between two and four vaccinations. SARS-CoV-2-specific T cells were detectable in >92% after two or more vaccinations. CONCLUSION: Additional vaccinations qualitatively improve SARS-CoV-2 antibody responses.

The concepts of muscle activity generation driven by upper limb kinematics.

BACKGROUND: The underlying motivation of this work is to demonstrate that artificial muscle activity of known and unknown motion can be generated based on motion parameters, such as angular position, acceleration, and velocity of each joint (or the end-effector instead), which are similarly represented in our brains. This model is motivated by the known motion planning process in the central nervous system. That process incorporates the current body state from sensory systems and previous experiences, which might be represented as pre-learned inverse dynamics that generate associated muscle activity. METHODS: We develop a novel approach utilizing recurrent neural networks that are able to predict muscle activity of the upper limbs associated with complex 3D human arm motions. Therefore, motion parameters such as joint angle, velocity, acceleration, hand position, and orientation, serve as input for the models. In addition, these models are trained on multiple subjects (n=5 including , 3 male in the age of 26±2 years) and thus can generalize across individuals. In particular, we distinguish between a general model that has been trained on several subjects, a subject-specific model, and a specific fine-tuned model using a transfer learning approach to adapt the model to a new subject. Estimators such as mean square error MSE, correlation coefficient r, and coefficient of determination R2 are used to evaluate the goodness of fit. We additionally assess performance by developing a new score called the zero-line score. The present approach was compared with multiple other architectures. RESULTS: The presented approach predicts the muscle activity for previously through different subjects with remarkable high precision and generalizing nicely for new motions that have not been trained before. In an exhausting comparison, our recurrent network outperformed all other architectures. In addition, the high inter-subject variation of the recorded muscle activity was successfully handled using a transfer learning approach, resulting in a good fit for the muscle activity for a new subject. CONCLUSIONS: The ability of this approach to efficiently predict muscle activity contributes to the fundamental understanding of motion control. Furthermore, this approach has great potential for use in rehabilitation contexts, both as a therapeutic approach and as an assistive device. The predicted muscle activity can be utilized to guide functional electrical stimulation, allowing specific muscles to be targeted and potentially improving overall rehabilitation outcomes.

Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR.

BACKGROUND: The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. AIM: We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. METHODS: Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. RESULTS: The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive - Global (EVAg), a European Union infrastructure project. CONCLUSION: The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.

Assessment of the function and intergenus-compatibility of Ebola and Lloviu virus proteins.

Sequences for Lloviu virus (LLOV), a putative novel filovirus, were first identified in Miniopterus schreibersii bats in Spain following a massive bat die-off in 2002, and also recently found in bats in Hungary. However, until now it is unclear if these sequences correspond to a fully functional, infectious virus, and whether it will show a pathogenic phenotype like African filoviruses, such as ebola- and marburgviruses, or be apathogenic for humans, like the Asian filovirus Reston virus. Since no infectious virus has been recovered, the only opportunity to study infectious LLOV is to use a reverse genetics-based full-length clone system to de novo generate LLOV. As a first step in this process, and to investigate whether the identified sequences indeed correspond to functional viral proteins, we have developed life cycle modelling systems for LLOV, which allow us to study genome replication and transcription as well as entry of this virus. We show that all LLOV proteins fulfill their canonical role in the virus life cycle as expected based on the well-studied related filovirus Ebola virus. Further, we have analysed the intergenus-compatibility of proteins that have to act in concert to facilitate the virus life cycle. We show that some but not all proteins from LLOV and Ebola virus are compatible with each other, emphasizing the close relationship of these viruses, and informing future studies of filovirus biology with respect to the generation of genus-chimeric proteins in order to probe virus protein-protein interactions on a functional level.

Generation and Optimization of a Green Fluorescent Protein-Expressing Transcription and Replication-Competent Virus-Like Particle System for Ebola Virus.

Work with infectious Ebola virus is restricted to biosafety level (BSL) 4 laboratories. To overcome this limitation, life cycle modeling systems, which recapitulate part or all of the virus life cycle under BSL-1 or -2 conditions, have been developed. The tetracistronic transcription and replication-competent virus-like particle (trVLP) system is currently the most advanced of these systems and is particularly useful for drug screening. However, previous versions have used luciferase reporters, limiting the types of screening assays that can be performed. Here we describe the generation and optimization of a green fluorescent protein-expressing tetracistronic trVLP system, enabling high-content imaging and flow cytometry approaches.Summary: Transcription and replication-competent virus-like particle (trVLP) systems are powerful tools to model the life cycle of highly pathogenic Ebola viruses. Here we describe the generation of a novel, GFP-based trVLP system that allows high content imaging and flow cytometry approaches.

Analysis of a Putative Late Domain Using an Ebola Virus Transcription and Replication-Competent Virus-Like Particle System.

The Ebola virus (EBOV) matrix protein VP40 drives budding of virions and encodes 2 overlapping late domain motifs at amino acid positions 7-13 (PTAPPEY). However, these motifs are not absolutely essential for replication in cell culture, and recently a potential third late domain motif (YPx(6)I) was proposed at amino acid positions 18-26 of VP40. To analyze the importance of this motif in viral budding, we used a transcription and replication-competent virus-like particle system. Using this system, we show that this motif does not contribute to EBOV budding or particle propagation.

Post-conditioning with Cyclosporine A after a 24-hour cold ischemia in ex vivo reperfused pig lungs.

OBJECTIVE: To evaluate the effects of 1 and 5 µM of Cyclosporine A (CsA), administered 24 hours after a cold ischemic period, in an ex vivo reperfused pig lung model. METHODS: The experiments were performed in 15 pigs. Each pair of lungs was surgically separated. Extracorporeal perfusion and mechanical ventilation were started after a cold ischemia of 2 hours for one lung and 24 hours for the contralateral. We constituted three groups (n = 5 each): two groups for which the lung underwent a 24-hour ischemia received either 1 or 5 µM of CsA at the time of reperfusion, and a control group without CsA. For each group, lungs undergoing a 2-hour ischemia did not receive CsA. RESULTS: Reperfusion with either CsA increased the PO2 levels in a dose dependent manner, and reduced concentrations of the receptor for advanced glycation endproducts, compared to the control. The pulmonary arterial pressure, the capillary pressure, and the pulmonary vascular resistances were not increased, even with 5 µM of CsA. No significant change was shown on cytokines levels. DISCUSSION: Postconditioning with CsA improves lung function, after a 24-hour cold ischemic period. Either 1 or 5 µM seemed to be safe regarding the pulmonary vascular pressures and resistances.

Bacillus pervagus sp. nov. and Bacillus andreesenii sp. nov., isolated from a composting reactor.

Two strains, 8-4-E12(T) and 8-4-E13(T), were isolated from a biowaste composting reactor. Based on 16S rRNA gene sequences, both strains belong to the genus Bacillus. Strain 8-4-E12(T) was most closely related to the type strains of Bacillus shackletonii, B. acidicola, B. sporothermodurans and B. oleronius (96.4, 96.3, 96.0 and 95.6 % 16S rRNA gene similarity, respectively), whereas strain 8-4-E13(T) was most closely related to the type strain of Bacillus humi (96.5 % sequence similarity). Strains 8-4-E12(T) and 8-4-E13(T) shared 94 % 16S rRNA gene sequence similarity. The fatty acid profile of strain 8-4-E12(T) was dominated by saturated iso- and anteiso-branched fatty acids (iso-C15 : 0, anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0), and also contained considerable amounts of C16 : 0. The fatty acid profile of strain 8-4-E13(T) showed a predominance of iso-C15 : 0 (65 %), with smaller amounts of other saturated branched-chain fatty acids along with an unsaturated alcohol. Both strains contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine as major polar lipids. Additionally, strain 8-4-E12(T) contained an unknown lipid and strain 8-4-E13(T) two unknown (amino-)phospholipids. The diagnostic diamino acid found in the cell-wall peptidoglycan of 8-4-E12(T) and 8-4-E13(T) was meso-diaminopimelic acid. The predominant menaquinone was MK-7. The results of physiological and biochemical tests also allowed phenotypic differentiation of the two strains from each other and from related Bacillus species. On the basis of their phylogenetic, phenotypic and chemotaxonomic properties, strains 8-4-E12(T) and 8-4-E13(T) represent novel species of the genus Bacillus, for which the names Bacillus pervagus sp. nov. (type strain 8-4-E12(T) = DSM 23947(T) = LMG 27601(T)) and Bacillus andreesenii sp. nov. (type strain 8-4-E13(T) = DSM 23948(T) = LMG 27602(T)) are proposed.

SARS-CoV-2 rapid antigen test sensitivity and viral load in newly symptomatic hospital employees in Berlin, Germany, December, 2020 to February, 2022: an observational study.

BACKGROUND: Evolving SARS-CoV-2 variants and changing levels of pre-existing immunity require re-evaluation of antigen-detecting rapid diagnostic test (Ag-RDT) performance. We investigated possible associations between Ag-RDT sensitivity and various potential influencing factors, such as immunisation status and viral variant, in symptomatic hospital employees. METHODS: In this observational study, RT-PCR, Ag-RDT, and symptom-specific data were collected at three SARS-CoV-2 test centres for employees of the Charité-Universitätsmedizin Berlin hospital (Berlin, Germany). Employees reporting SARS-CoV-2-like symptoms, those at an increased risk of infection (eg, due to contact with an infected person), those testing positive in a previous self-administered Ag-RDT, or those seeking release-testing to return to work at least 7 days after a positive RT-PCR test were eligible for combined testing by RT-PCR and Ag-RDT. Only data from individuals with an ongoing SARS-CoV-2 infection as assessed by RT-PCR were used for further analysis. Bayesian regression analyses were done to evaluate possible differences in viral load and Ag-RDT sensitivity according to viral variant and immunisation status (previous vaccination or recovery from infection), using data from first RT-PCR positive samples in an infection. A comprehensive logistic regression analysis was used to investigate potential concomitant associations between Ag-RDT sensitivity and level of pre-existing immunity, time post symptom onset, viral load, gender, age, and Ag-RDT device. Ag-RDT performance was also compared between supernatants from cell cultures infected with the omicron variant of concern (VOC) or the wild-type strain (pre-VOC). FINDINGS: Between Nov 30, 2020 and Feb 11, 2022, a total of 14 773 samples from 7675 employees were tested for SARS-CoV-2 by both RT-PCR and Ag-RDT. We found a negative association between immunisation status and Ag-RDT sensitivity in symptomatic employees, with an observed sensitivity of 82% (94% highest posterior density interval [HPDI] 78-86) in immunologically naive participants compared with 73% (68-78) in multiply immunised individuals (ie, those with at least two vaccinations or recoveries from infection) and median log10 viral loads of 7·02 (IQR 5·83-8·07) and 8·08 (6·80-8·89), respectively. The dominant viral variant changed several times during the study period, from the pre-VOC period (sensitivity 80% [94% HPDI 75-85] in symptomatic participants) through the alpha variant (82% [70-94]), delta variant (75% [69-82]), and omicron variant (72% [65-79]) waves, concomitantly with a steep increase in vaccination coverage in our dataset. In a comparison of Ag-RDT performance on cell culture supernatants, we found no difference between the wild-type and omicron viral variants. INTERPRETATION: On the basis of our findings and data from other studies, we hypothesise that the observed reduction in clinical Ag-RDT sensitivity, despite higher SARS-CoV-2 RNA loads, is due to shorter incubation times later in our study period resulting from increased population immunity or changes in immune response dynamics caused by later SARS-CoV-2 VOCs. FUNDING: Berlin University Alliance, German Ministry of Education and Research, the EU (Projects EU4Health and ReCoVer), and the Berlin Institute of Health.

The human cytoplasmic RNA terminal U-transferase ZCCHC11 targets histone mRNAs for degradation.

Inhibition of eukaryotic DNA replication leads to the rapid suppression of histone synthesis, via 3' uridylation of cytoplasmic histone mRNAs followed by their Lsm1-7-mediated decapping and degradation. Here we show that the human cytoplasmic RNA terminal U-transferase ZCCHC11, recently implicated in microRNA metabolism, associates with replication-dependent histone mRNAs. Knockdown of ZCCHC11 selectively blocked histone mRNA degradation following inhibition of DNA replication, whereas knockdown of PAPD1 or PAPD5, previously proposed as candidate histone mRNA U-transferases, had no such effect. Furthermore, a reduction in the proportion of histone transcripts that were uridylated was observed following ZCCHC11 knockdown. Our data indicate that ZCCHC11 is the terminal U-transferase responsible for targeting human histone mRNAs for degradation following inhibition or completion of DNA replication.

A Rare Case of Diffuse Alveolar Hemorrhage Caused by Fentanyl Inhalation.

Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening pulmonary disorder characterized by blood accumulation in alveolar spaces, often associated with autoimmune diseases and infections. Drug-induced causes of DAH, including inhalation of substances like fentanyl, are emerging concerns. A 40-year-old male with bipolar disorder and polysubstance abuse presented with altered mental status and hemoptysis after inhaling an unknown substance. Physical examination revealed respiratory distress, pinpoint pupils, and severe hypoxemia. Naloxone administration improved his condition. The workup showed negative infection markers, positive fentanyl-specific urine test, and diffuse bilateral opacities on imaging. Bronchoalveolar lavage confirmed DAH with >20% hemosiderin-laden macrophages. Steroid treatment resulted in marked improvement. Drug-induced DAH, such as fentanyl inhalation, should be considered in patients with altered mental status and pulmonary symptoms following substance use. Comprehensive evaluation and targeted treatment are crucial for optimal outcomes.

A Rare Case of Valproic Acid Toxicity Requiring Hemodialysis.

Valproic acid poisoning can have mild to fatal consequences depending on its body concentration. There are rare case reports and barely any known controlled studies on the use of hemodialysis as a last treatment resort. We report a rare valproic acid poisoning case at One Brooklyn Health/Interfaith campus, New York City, warranting intubation and hemodialysis. The patient is a 47-year-old male with a past medical history of seizure disorder, polysubstance use disorder, schizophrenia, and gastroesophageal reflux disease (GERD) who was brought to the medical emergency department (ED) for intentional valproic acid overdose with 60 tablets of his prescribed home Depakote DR 500 mg (~30 g). The patient's other outpatient medications included valproic acid, trazodone, acetaminophen, famotidine, fluoxetine, folic acid, hydrocortisone-aloe, multivitamin, nicotine polacrilex, and thiamine. The patient's initial blood tests showed high valproic acid, ammonia, ethanol, and lactate. About six hours after ED admission, the patient became somnolent, desaturated to 74% on a non-rebreather oxygen mask, warranting intubation and hemodialysis after noticing persistently high serum concentrations of valproic acid. The relatively low molecular weight (144 Daltons) and low volume of distribution of valproic acid suggest a potential benefit from hemodialysis, especially at a serum concentration of >850 mg/L or in the event of a shock. In this patient, mentation and stability status were improved after hemodialysis. Hemodialysis appears to be the last treatment resort for severe valproic acid poisoning.

Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron.

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.

90K/LGALS3BP expression is upregulated in COVID-19 but may not restrict SARS-CoV-2 infection.

Glycoprotein 90K, encoded by the interferon-stimulated gene LGALS3BP, displays broad antiviral activity. It reduces HIV-1 infectivity by interfering with Env maturation and virion incorporation, and increases survival of Influenza A virus-infected mice via antiviral innate immune signaling. Its antiviral potential in SARS-CoV-2 infection remains largely unknown. Here, we analyzed the expression of 90K/LGALS3BP in 44 hospitalized COVID-19 patients at multiple levels. We quantified 90K protein concentrations in serum and PBMCs as well as LGALS3BP mRNA levels. Complementary, we analyzed two single cell RNA-sequencing datasets for expression of LGALS3BP in respiratory specimens and PBMCs from COVID-19 patients. Finally, we analyzed the potential of 90K to interfere with SARS-CoV-2 infection of HEK293T/ACE2, Calu-3 and Caco-2 cells using authentic virus. 90K protein serum concentrations were significantly elevated in COVID-19 patients compared to uninfected sex- and age-matched controls. Furthermore, PBMC-associated concentrations of 90K protein were overall reduced by SARS-CoV-2 infection in vivo, suggesting enhanced secretion into the extracellular space. Mining of published PBMC scRNA-seq datasets uncovered monocyte-specific induction of LGALS3BP mRNA expression in COVID-19 patients. In functional assays, neither 90K overexpression in susceptible cell lines nor exogenous addition of purified 90K consistently inhibited SARS-CoV-2 infection. Our data suggests that 90K/LGALS3BP contributes to the global type I IFN response during SARS-CoV-2 infection in vivo without displaying detectable antiviral properties in vitro.