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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329413

ABSTRACT

The emergence and rapid spread of SARS-CoV-2 variants may impact vaccine efficacy significantly 1 . The Omicron variant termed BA.2, which differs genetically substantially from BA.1, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed 2,3 . Here, we used antigenic cartography to quantify and visualize antigenic differences between SARS-CoV-2 variants using hamster sera obtained after primary infection. Whereas early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape (vaccine-induced) antibody responses as a result of different antigenic characteristics. Close monitoring of the antigenic changes of SARS-CoV-2 using antigenic cartography can be helpful in the selection of future vaccine strains.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314838

ABSTRACT

A new phase of the COVID-19 pandemic has started as SARS-CoV-2 variants are emerging globally, raising concerns for increased transmissibility. Early 2021 the B.1.1.7 (or Alpha) variant, became the dominant variant globally and epidemiological data suggests this variant spreads faster than its ancestors. However, this does not prove that a variant is intrinsically phenotypically different, let alone more transmissible or fit. Therefore, rapid phenotyping of SARS-CoV-2 variants of concern is urgently needed. We found that airway, intestinal and alveolar organoids infected with the B.1.1.7 variant produced higher levels of infectious virus late in infection compared to its 614G-containing ancestor. The B.1.1.7 variant also had a clear fitness advantage in human airway organoids. In alveolar organoids, the B.1.1.7 variant induced lower levels of innate immunity. These findings suggest that the B.1.1.7 variant is phenotypically different from its ancestor and may explain why this clade has spread rapidly across the globe.Funding Information: This work was supported by Netherlands Organization for Health Research and Development (10150062010008;B.L.H.), PPP allowance (LSHM19136;B.L.H.). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874735. Declaration of Interests: H.C. is inventor on patents held by the Royal Netherlands Academy of Arts and Sciences that cover organoid technology. H.C.’s full disclosure is given at https://www.uu.nl/staff/JCClevers. All other authors have nothing to declare. Ethics Approval Statement: The Medical Ethical Committee of the Erasmus MC Rotterdam granted permission for this study (METC 2012-512). The study was approved by the UMC Utrecht (Utrecht, The Netherlands) ethical committee and was in accordance with the Declaration of Helsinki and according to Dutch law. This study is compliant with all relevant ethical regulations regarding research involving human participants.

3.
Elife ; 102021 04 09.
Article in English | MEDLINE | ID: covidwho-1389777

ABSTRACT

Virus propagation methods generally use transformed cell lines to grow viruses from clinical specimens, which may force viruses to rapidly adapt to cell culture conditions, a process facilitated by high viral mutation rates. Upon propagation in VeroE6 cells, SARS-CoV-2 may mutate or delete the multibasic cleavage site (MBCS) in the spike protein. Previously, we showed that the MBCS facilitates serine protease-mediated entry into human airway cells (Mykytyn et al., 2021). Here, we report that propagating SARS-CoV-2 on the human airway cell line Calu-3 - that expresses serine proteases - prevents cell culture adaptations in the MBCS and directly adjacent to the MBCS (S686G). Similar results were obtained using a human airway organoid-based culture system for SARS-CoV-2 propagation. Thus, in-depth knowledge on the biology of a virus can be used to establish methods to prevent cell culture adaptation.


Subject(s)
Epithelial Cells , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Virus Cultivation/methods , Virus Internalization , Animals , Cell Line , Chlorocebus aethiops , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Proteolysis , Respiratory System/cytology , Respiratory System/virology , Serine Proteases/metabolism
5.
J Infect Dis ; 223(12): 2020-2028, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1246725

ABSTRACT

Effective clinical intervention strategies for coronavirus disease 2019 (COVID-19) are urgently needed. Although several clinical trials have evaluated use of convalescent plasma containing virus-neutralizing antibodies, levels of neutralizing antibodies are usually not assessed and the effectiveness has not been proven. We show that hamsters treated prophylactically with a 1:2560 titer of human convalescent plasma or a 1:5260 titer of monoclonal antibody were protected against weight loss, had a significant reduction of virus replication in the lungs, and showed reduced pneumonia. Interestingly, this protective effect was lost with a titer of 1:320 of convalescent plasma. These data highlight the importance of screening plasma donors for high levels of neutralizing antibodies. Our data show that prophylactic administration of high levels of neutralizing antibody, either monoclonal or from convalescent plasma, prevent severe SARS-CoV-2 pneumonia in a hamster model, and could be used as an alternative or complementary to other antiviral treatments for COVID-19.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/therapy , Lung/pathology , SARS-CoV-2/immunology , Virus Replication/drug effects , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , COVID-19/immunology , Cricetinae , Disease Models, Animal , Humans , Immunization, Passive , Lung/drug effects , Virus Shedding/drug effects , Weight Loss/drug effects
6.
Viruses ; 13(4)2021 04 01.
Article in English | MEDLINE | ID: covidwho-1162341

ABSTRACT

Coronavirus (CoV) spillover events from wildlife reservoirs can result in mild to severe human respiratory illness. These spillover events underlie the importance of detecting known and novel CoVs circulating in reservoir host species and determining CoV prevalence and distribution, allowing improved prediction of spillover events or where a human-reservoir interface should be closely monitored. To increase the likelihood of detecting all circulating genera and strains, we have modified primers published by Watanabe et al. in 2010 to generate a semi-nested pan-CoV PCR assay. Representatives from the four coronavirus genera (α-CoVs, ß-CoVs, γ-CoVs and δ-CoVs) were tested and all of the in-house CoVs were detected using this assay. After comparing both assays, we found that the updated assay reliably detected viruses in all genera of CoVs with high sensitivity, whereas the sensitivity of the original assay was lower. Our updated PCR assay is an important tool to detect, monitor and track CoVs to enhance viral surveillance in reservoir hosts.


Subject(s)
Coronavirus/classification , Coronavirus/genetics , Coronavirus/isolation & purification , Polymerase Chain Reaction/methods , Animals , Animals, Wild , Clinical Laboratory Techniques/methods , Coronavirus Infections/virology , Disease Reservoirs/virology , Genome, Viral , Host Specificity , Humans , Limit of Detection , Pandemics , Phylogeny , RNA, Viral
7.
Nat Commun ; 12(1): 1653, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1132073

ABSTRACT

SARS-CoV-2 emerged in late 2019 and caused a pandemic, whereas the closely related SARS-CoV was contained rapidly in 2003. Here, an experimental set-up is used to study transmission of SARS-CoV and SARS-CoV-2 through the air between ferrets over more than a meter distance. Both viruses cause a robust productive respiratory tract infection resulting in transmission of SARS-CoV-2 to two of four indirect recipient ferrets and SARS-CoV to all four. A control pandemic A/H1N1 influenza virus also transmits efficiently. Serological assays confirm all virus transmission events. Although the experiments do not discriminate between transmission via small aerosols, large droplets and fomites, these results demonstrate that SARS-CoV and SARS-CoV-2 can remain infectious while traveling through the air. Efficient virus transmission between ferrets is in agreement with frequent SARS-CoV-2 outbreaks in mink farms. Although the evidence for virus transmission via the air between humans under natural conditions is absent or weak for SARS-CoV and SARS-CoV-2, ferrets may represent a sensitive model to study interventions aimed at preventing virus transmission.


Subject(s)
Air Microbiology , COVID-19/transmission , Ferrets/virology , SARS Virus , SARS-CoV-2 , Severe Acute Respiratory Syndrome/transmission , Aerosols , Amino Acid Substitution , Animal Fur/virology , Animals , COVID-19/virology , Disease Models, Animal , Female , Fomites/virology , Influenza A Virus, H1N1 Subtype , Models, Biological , Orthomyxoviridae Infections/transmission , Polymorphism, Single Nucleotide , SARS-CoV-2/genetics , Severe Acute Respiratory Syndrome/virology , Time Factors , Viral Load , Viral Zoonoses/transmission , Viral Zoonoses/virology , Virus Shedding
8.
Nat Med ; 26(9): 1405-1410, 2020 09.
Article in English | MEDLINE | ID: covidwho-653871

ABSTRACT

In late December 2019, a cluster of cases of pneumonia of unknown etiology were reported linked to a market in Wuhan, China1. The causative agent was identified as the species Severe acute respiratory syndrome-related coronavirus and was named SARS-CoV-2 (ref. 2). By 16 April the virus had spread to 185 different countries, infected over 2,000,000 people and resulted in over 130,000 deaths3. In the Netherlands, the first case of SARS-CoV-2 was notified on 27 February. The outbreak started with several different introductory events from Italy, Austria, Germany and France followed by local amplification in, and later also outside, the south of the Netherlands. The combination of near to real-time whole-genome sequence analysis and epidemiology resulted in reliable assessments of the extent of SARS-CoV-2 transmission in the community, facilitating early decision-making to control local transmission of SARS-CoV-2 in the Netherlands. We demonstrate how these data were generated and analyzed, and how SARS-CoV-2 whole-genome sequencing, in combination with epidemiological data, was used to inform public health decision-making in the Netherlands.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/genetics , Genome, Viral/genetics , Pandemics , Pneumonia, Viral/genetics , Betacoronavirus/pathogenicity , COVID-19 , Clinical Decision-Making , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Netherlands/epidemiology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Public Health , SARS-CoV-2 , Whole Genome Sequencing
9.
Nat Commun ; 11(1): 3496, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640239

ABSTRACT

SARS-CoV-2, a coronavirus that emerged in late 2019, has spread rapidly worldwide, and information about the modes of transmission of SARS-CoV-2 among humans is critical to apply appropriate infection control measures and to slow its spread. Here we show that SARS-CoV-2 is transmitted efficiently via direct contact and via the air (via respiratory droplets and/or aerosols) between ferrets, 1 to 3 days and 3 to 7 days after exposure respectively. The pattern of virus shedding in the direct contact and indirect recipient ferrets is similar to that of the inoculated ferrets and infectious virus is isolated from all positive animals, showing that ferrets are productively infected via either route. This study provides experimental evidence of robust transmission of SARS-CoV-2 via the air, supporting the implementation of community-level social distancing measures currently applied in many countries in the world and informing decisions on infection control measures in healthcare settings.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Animals , Antibodies, Viral/blood , Betacoronavirus/genetics , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Disease Models, Animal , Ferrets , Genome, Viral/genetics , Humans , Pandemics , Rectum/virology , Respiratory System/virology , SARS-CoV-2 , Sequence Analysis, RNA , Virus Shedding
10.
Lancet Infect Dis ; 20(11): 1273-1280, 2020 11.
Article in English | MEDLINE | ID: covidwho-623256

ABSTRACT

BACKGROUND: 10 days after the first reported case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the Netherlands (on Feb 27, 2020), 55 (4%) of 1497 health-care workers in nine hospitals located in the south of the Netherlands had tested positive for SARS-CoV-2 RNA. We aimed to gain insight in possible sources of infection in health-care workers. METHODS: We did a cross-sectional study at three of the nine hospitals located in the south of the Netherlands. We screened health-care workers at the participating hospitals for SARS-CoV-2 infection, based on clinical symptoms (fever or mild respiratory symptoms) in the 10 days before screening. We obtained epidemiological data through structured interviews with health-care workers and combined this information with data from whole-genome sequencing of SARS-CoV-2 in clinical samples taken from health-care workers and patients. We did an in-depth analysis of sources and modes of transmission of SARS-CoV-2 in health-care workers and patients. FINDINGS: Between March 2 and March 12, 2020, 1796 (15%) of 12 022 health-care workers were screened, of whom 96 (5%) tested positive for SARS-CoV-2. We obtained complete and near-complete genome sequences from 50 health-care workers and ten patients. Most sequences were grouped in three clusters, with two clusters showing local circulation within the region. The noted patterns were consistent with multiple introductions into the hospitals through community-acquired infections and local amplification in the community. INTERPRETATION: Although direct transmission in the hospitals cannot be ruled out, our data do not support widespread nosocomial transmission as the source of infection in patients or health-care workers. FUNDING: EU Horizon 2020 (RECoVer, VEO, and the European Joint Programme One Health METASTAVA), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health.


Subject(s)
Betacoronavirus/genetics , Community-Acquired Infections/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Cross Infection/epidemiology , Health Personnel , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Adult , Aged , COVID-19 , Community-Acquired Infections/virology , Coronavirus Infections/virology , Cross Infection/virology , Cross-Sectional Studies , Female , Genetic Variation , Hospitals, Teaching , Humans , Male , Mass Screening/methods , Middle Aged , Netherlands/epidemiology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Whole Genome Sequencing , Young Adult
11.
Science ; 368(6494): 1012-1015, 2020 05 29.
Article in English | MEDLINE | ID: covidwho-71867

ABSTRACT

The current pandemic coronavirus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), was recently identified in patients with an acute respiratory syndrome, coronavirus disease 2019 (COVID-19). To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or Middle East respiratory syndrome (MERS)-CoV and compared the pathology and virology with historical reports of SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in the absence of clinical signs and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, whereas they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 causes COVID-19-like disease in macaques and provides a new model to test preventive and therapeutic strategies.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Models, Animal , Lung/pathology , Macaca fascicularis , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Aging , Animals , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Female , Lung/virology , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Pulmonary Alveoli/pathology , Pulmonary Alveoli/virology , Respiratory System/pathology , Respiratory System/virology , SARS Virus/isolation & purification , SARS Virus/physiology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Virus Replication , Virus Shedding
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