ABSTRACT
Background During the SARS-CoV-2 pandemic, many countries directed substantial resources towards genomic surveillance to detect and track viral variants. There is a debate over how much sequencing effort is necessary in national surveillance programs for SARS-CoV-2 and future pandemic threats. Aim We aimed to investigate the effect of reduced sequencing on surveillance outcomes in a large genomic dataset from Switzerland, comprising more than 143k sequences. Methods We employed a uniform downsampling strategy using 100 iterations each to investigate the effects of fewer available sequences on the surveillance outcomes: (i) first detection of variants of concern (VOCs), (ii) speed of introduction of VOCs, (iii) diversity of lineages, (iv) first cluster detection of VOCs, (v) density of active clusters, and (vi) geographic spread of clusters. Results The impact of downsampling on VOC detection is disparate for the three VOC lineages , but many outcomes including introduction and cluster detection could be recapitulated even with only 35% of the original sequencing effort. The effect on the observed speed of introduction and first detection of clusters was more sensitive to reduced sequencing effort for some VOCs, in particular Omicron and Delta, respectively. Conclusion A genomic surveillance program needs a balance between societal benefits and costs. While the overall national dynamics of the pandemic could be recapitulated by a reduced sequencing effort, the effect is strongly lineage dependent - something that is unknown at the time of sequencing - and comes at the cost of accuracy, in particular for tracking the emergence of potential VOCs.
ABSTRACT
Vaccine hesitancy is one of the major obstacles for successfully combating the ongoing COVID-19 pandemic. To achieve a sufficiently high vaccination rate, calls for compulsory vaccinations have been discussed controversially. This study analyses what drives citizens? attitudes towards compulsory vaccination during the COVID-19 pandemic. Specifically, we are interested in the impact of party- and expert cues on public attitudes. We further expect populist attitudes to be an important indicator of the rejection of compulsory vaccination due to their scepticism towards science. To test these expectations, we rely on a cueing experiment conducted on a sample of 2265 German citizens. We test for the effects of in-party and out-party cues as well as public health expert cues. We find evidence for in-party cues, meaning that respondents adjust their position on this issue in the direction of their most preferred party. Similar results can be found for public health expert cues. However, there is no evidence for out-party cues. Further analyses reveal that support for compulsory vaccinations is not affected by left-right placement directly. Instead, only the combination of right-wing attitudes and populism negatively affects support for compulsory vaccination.
ABSTRACT
Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The ability of antibody-based therapies, including convalescent plasma, to affect established disease remains to be elucidated. Only few monoclonal therapies and only when used at a very early stage of infection have shown efficacy. Here, we conducted a proof-of-principle study of convalescent plasma therapy in a phase I trial in 30 COVID-19 patients including immunocompromised individuals hospitalized early after onset of symptoms. A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients in conjunction with detailed post-hoc seroprofiling of transfused convalescent plasma, allowed deciphering of parameters on which plasma therapy efficacy depends. Plasma therapy was safe and had a significant effect on viral clearance depending on neutralizing and spike SARS-CoV-2 antibody levels in the supplied convalescent plasma. Endogenous immunity had strong effects on virus control. Lack of endogenous neutralizing activity at baseline was associated with a higher risk of systemic viremia. The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their endogenous neutralization status recipients benefitted from therapy with high neutralizing antibody containing plasma. In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia in the early stages of infection and provide directions for improved efficacy evaluation of current and future SARS-CoV-2 therapies beyond antibody-based interventions. Incorporating an assessment of the endogenous immune response and its dynamic interplay with viral production is critical for determining therapeutic effects. One Sentence SummaryThis study demonstrates the impact of exogenous antibody therapy by convalescent plasma containing high neutralizing titers on the rapid clearance of viremia in the early stages of SARS-CoV-2 infection.
Subject(s)
COVID-19 , ViremiaABSTRACT
Genome sequences allow quantification of changes in case introductions from abroad and local transmission dynamics. We sequenced 11,357 SARS-CoV-2 genomes from Switzerland in 2020 - the 6th largest effort globally. Using these data, we estimated introductions and their persistence throughout 2020. By contrasting estimates with null models, we estimate at least 83% of introductions were adverted during Switzerland's border closures. Further, transmission chain persistence roughly doubled after the partial lockdown was lifted. Then, using a novel phylodynamic method, we suggest transmission in newly introduced outbreaks slowed 36 - 64% upon outbreak detection in summer 2020, but not in fall. This could indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.
ABSTRACT
Definition of SARS-CoV-2 antibody responses is essential to verify protective immunity following infection and vaccination. Here, we devised a versatile serological test, named ABCORA, that is based on a multifactorial analysis of SARS-CoV-2 and circulating human coronavirus (HCoV) antibody responses. Utilizing empirical tailored cut-offs and computational approaches based on training and validation cohorts comprising pre-pandemic (N=825) and SARS-CoV-2 infected plasma donors (N=389), we defined several analysis strategies that allow a highly accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity. Intriguingly, HCoV reactivity was significantly higher in SARS-CoV-2 negative donors. Amongst SARS-CoV-2 infected individuals, elevated SARS-CoV-2 responses were linked to higher HCoV activity suggesting that pre-existing HCoV immunity may confer protection against SARS-CoV-2 acquisition and promote development of SARS-CoV-2 specific antibody responses. Deciphering interdependencies between SARS-CoV-2 and HCoV immunity should be enforced as understanding their impact on infection may allow soliciting cross-protective activities for broader coronavirus prevention.
Subject(s)
Severe Acute Respiratory SyndromeABSTRACT
Background and aims: The facilitating role of the school setting in SARS-CoV-2 infection spread is still debated and the potential of school closures to mitigate transmission unclear. In autumn 2020, Switzerland experienced one of the highest second waves of the SARS-CoV-2 pandemic in Europe while keeping schools open, thus offering a high-exposure environment to study SARS-CoV-2 infections in schools. The aim of this study was to examine longitudinal change in SARS-CoV-2 seroprevalence in children and the evolution of clustering within classes and schools from June to November, 2020, in a prospective cohort study of school children in the canton of Zurich, Switzerland. Methods: Children from randomly selected schools and classes, stratified by district, were invited to participate in serological testing of SARS-CoV-2 in June-July and October-November 2020. Parents of children filled questionnaires on sociodemographic and health-related questions. 55 schools and 275 classes within them were enrolled, with 2603 children participating in the first, and 2552 in the second testing (age range 6-16 years). We evaluated longitudinal changes of seroprevalence in districts and investigated clustering of seropositive cases within classes and schools. Results: Overall SARS-CoV-2 seroprevalence was 2.4% (95% CrI 1.4%-3.6%) in summer and 4.5% (95% CrI 3.2%-6.0%) in not previously seropositive children in late autumn, leading to estimated 7.8% (95% CrI 6.2%-9.5%) of ever seropositive children, without significant differences among lower, middle and upper school levels. Among the 2223 children with serology tested twice, 28 (40%) of previously positive were negative, and 109 (5%) previously negative became seropositive. Seroprevalence was not different between school levels or sexes, but varied across districts (1.7% to 15.0%). Between June-July and October-November 2020, the ratio of diagnosed to newly seropositive children was 1 to 8. At least one newly seropositive child was detected in 47 of 55 schools and 125 of 275 classes. Among the classes with at least 50% and [≥]5 children tested, 0, 1-2 or >=3 seropositive children were present in in 90 (58%), 57 (37%) and 7 (5%) out of 154 classes, respectively. Class level explained slightly more variation of individual serological results (standard deviation (SD) 0.97) than school level (SD 0.61) in the multilevel logistic regression models. Symptoms were reported for 22% of seronegative and 29% of newly seropositive children since summer. Conclusions: Under a regimen of open schools with some preventive measures in place since August, clustering of seropositive cases occurred in very few classes and not across entire schools despite a clear increase in seropositive children during a period of high transmission of SARS-CoV-2.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Background A high volume of testing followed by rapid isolation and quarantine measures is critical to the containment of SARS-CoV-2. RT-PCR of nasopharyngeal swabs (NPS) has been established as sensitive gold standard for the detection of SARS-CoV-2 infection. Yet, additional test strategies are in demand to increase and broaden testing opportunities. As one attractive option, saliva has been discussed as an alternative to NPS as its collection is simple, non-invasive, suited for children and amenable for mass- and home-testing. Methods Here, we report on the outcome of a head-to-head comparison of SARS-CoV-2 detection by RT-PCR in saliva and nasopharyngeal swab (NPS) of 1187 adults and children reporting to outpatient test centers and an emergency unit for an initial SARS-CoV-2 screen. Results In total, 252 individuals were tested SARS-CoV-2 positive in either NPS or saliva. SARS-CoV-2 RT-PCR results in the two specimens showed a high agreement (Overall Percent Agreement = 98.0%). Despite lower viral loads in saliva, we observed sensitive detection of SARS-CoV-2 in saliva up to a threshold of Ct 33 in the corresponding NPS (Positive Percent Agreement = 97.7%). In patients with Ct above 33 in NPS, agreement rate dropped but still reaches notable 55.9%. Conclusion The comprehensive parallel analysis of NPS and saliva reported here establishes saliva as a reliable specimen for the detection of SARS-CoV-2 that can be readily added to the diagnostic portfolio to increase and facilitate testing.
Subject(s)
COVID-19 , NasopharyngitisABSTRACT
Pathogen genomes provide insights into their evolution and epidemic spread. We sequenced 1,439 SARS-CoV-2 genomes from Switzerland, representing 3-7% of all confirmed cases per week. Using these data, we demonstrate that no one lineage became dominant, pointing against evolution towards general lower virulence. On an epidemiological level, we report no evidence of cryptic transmission before the first confirmed case. We find many early viral introductions from Germany, France, and Italy and many recent introductions from Germany and France. Over the summer, we quantify the number of non-traceable infections stemming from introductions, quantify the effective reproductive number, and estimate the degree of undersampling. Our framework can be applied to quantify evolution and epidemiology in other locations or for other pathogens based on genomic data.
ABSTRACT
Cytokine storm resulting from a heightened inflammatory response is a prominent feature of severe COVID-19 disease. This inflammatory response results from assembly/activation of a cell-intrinsic defense platform known as the inflammasome. We report that the SARS-CoV-2 viroporin encoded by ORF3a activates the NLRP3 inflammasome, the most promiscuous of known inflammasomes. ORF3a triggers IL-1 beta expression via NFkB, thus priming the inflammasome while also activating it via ASC-dependent and -independent modes. ORF3a-mediated inflammasome activation requires efflux of potassium ions and oligomerization between NEK7 and NLRP3. With the selective NLRP3 inhibitor MCC950 able to block ORF3a-mediated inflammasome activation and key ORF3a residues needed for virus release and inflammasome activation conserved in SARS-CoV-2 isolates across continents, ORF3a and NLRP3 present prime targets for intervention.
Subject(s)
COVID-19ABSTRACT
The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.
Subject(s)
Hepatitis, Viral, Human , Emergencies , Adenomatous Polyposis Coli , Drug-Related Side Effects and Adverse Reactions , COVID-19ABSTRACT
Since entering the human population, SARS-CoV-2 (the causative agent of COVID-19) has spread worldwide, causing >100 million infections and >2 million deaths. While large-scale sequencing efforts have identified numerous genetic variants in SARS-CoV-2 during its circulation, it remains largely unclear whether many of these changes impact adaptation, replication or transmission of the virus. Here, we characterized 14 different low-passage replication-competent human SARS-CoV-2 isolates representing all major European clades observed during the first pandemic wave in early 2020. By integrating viral sequencing data from patient material, virus stocks, and passaging experiments, together with kinetic virus replication data from non-human Vero-CCL81 cells and primary differentiated human bronchial epithelial cells (BEpCs), we observed several SARS-CoV-2 features that associate with distinct phenotypes. Notably, naturally-occurring variants in Orf3a (Q57H) and nsp2 (T85I) were associated with poor replication in Vero-CCL81 cells but not in BEpCs, while SARS-CoV-2 isolates expressing the Spike D614G variant generally exhibited enhanced replication abilities in BEpCs. Strikingly, low-passage Vero-derived stock preparation of 3 SARS-CoV-2 isolates selected for substitutions at positions 5/6 of E, and were highly attenuated in BEpCs, revealing a key cell-specific function to this region. Rare isolate-specific deletions were also observed in the Spike furin-cleavage site during Vero-CCL81 passage, but these were rapidly selected against in BEpCs, underscoring the importance of this site for SARS-CoV-2 replication in primary human cells. Overall, our study uncovers sequence features in SARS-CoV-2 variants that determine cell-specific virus replication, and highlights the need to monitor SARS-CoV-2 stocks carefully when phenotyping newly emerging variants or potential variants-of-concern.
Subject(s)
COVID-19ABSTRACT
Importance: Understanding transmission and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in school children is critical to implement appropriate mitigation measures. Objective: To determine the variation in SARS-CoV-2 seroprevalence in school children across districts, schools, grades, and classes, and the relationship of SARS-CoV-2 seroprevalence with self-reported symptoms. Design: Cross-sectional analysis of baseline measurements of a longitudinal cohort study (Ciao Corona) from June-July 2020. Setting: 55 randomly selected schools and classes stratified by district in the canton of Zurich, Switzerland (1.5 million inhabitants). Participants: Children, aged 6-16 years old, attending grades 1-2, 4-5 and 7-8. Exposure: Exposure to circulating SARS-CoV-2 between February and June 2020 including public lock-down and school closure (March 16-May 10, 2020). Main Outcomes and Measures: Variation in seroprevalence of SARS-CoV-2 in children across 12 cantonal districts, schools, and grades using a Luminex-based antibody test with four targets for each of IgG, IgA and IgM. Clustering of cases within classes. Analysis of associations of seropositivity and symptoms. Comparison of seroprevalence with a randomly selected adult population, based on Luminex-based IgG and IgA antibody test of Corona Immunitas. Results: In total, 55 schools and 2585 children were recruited (1337 girls, median age 11, age range 6-16 years). Overall seroprevalence was 2.8 % (95% CI 1.6-4.1%), ranging from 1.0% to 4.5% across districts. Seroprevalence was 3.8% (1.9-6.1%) in grades 1-2, 2.5% (1.1-4.2%) in grades 4-5, and 1.5% (0.5-3.0%) in grades 7-8. At least one case was present in 36/55 tested schools and in 43/128 classes with [≥]50% participation rate and [≥]5 children tested. 73% of children reported COVID-19 compatible symptoms since January 2020, but none were reported more frequently in seropositive compared to seronegative children. Seroprevalence of children was very similar to seroprevalence of randomly selected adults in the same region in June-July 2020, measured with the same Corona Immunitas test, combining IgG and IgA (3.1%, 95% CI 1.4-5.4%, versus 3.3%, 95% CI 1.4-5.5%). Conclusions and Relevance: Seroprevalence was inversely related to age and revealed a dark figure of around 90 when compared to 0.03% confirmed PCR+ cases in children in the same area by end of June. We did not find clustering of SARS-CoV-2 seropositive cases in schools so far, but the follow-up of this school-based study will shed more light on transmission within and outside schools. Trial registration: ClinicalTrials.gov Identifier: NCT04448717, registered June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04448717
Subject(s)
COVID-19ABSTRACT
Background: Super-spreaders are individuals infecting disproportionately large numbers of contacts. They probably play a crucial role in the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We describe a super-spreading event within a team working in an open-space office and investigate factors potentially having facilitated SARS-CoV-2 transmission.Methods: In this retrospective cohort study, semi-structured telephone interviews with all team members were carried out to identify symptoms, contacts, and adherence to basic hygiene measures. During site visits, we gathered information about workplace and seating arrangements. The secondary attack rate in office and households was calculated. Potential respiratory viral co-infections were assessed by multiplex PCR. SARS-CoV-2 whole-genome sequencing was performed using a tiled-amplicon sequencing approach.Results: Of 13 team members, 11 fell ill with Coronavirus disease 2019 (COVID-19). Due to the sequence of events and full genome sequence data, one person was considered the index case for this outbreak, directly infecting 67% to 83% of the teammates. All team members reported repetitive close contacts among themselves during joint computer work, team meetings and a “Happy Birthday” serenade. Two individuals shared nuts and dates. The arrangement of the office and meeting rooms precluded sufficient adherence to physical distancing. The index case and a further individual were diagnosed with an adenovirus serotype 4 co-infection. Conclusion: We identified several environmental and behavioral factors that probably have facilitated the transmission of SARS-CoV-2. The relevance of the adenovirus co-infection remains unclear and merits further investigation.
Subject(s)
Coronavirus Infections , Coinfection , COVID-19 , Adenoviridae InfectionsABSTRACT
Background: In intensive care units (ICUs) treating patients with Coronavirus disease 2019 (COVID-19) invasive ventilation poses a high risk for aerosol and droplet formation. Surface contamination of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) or bacteria can result in nosocomial transmission.Methods: Two tertiary care COVID-19 intensive care units treating 53 patients for 870 patient days were sampled after terminal cleaning and preparation for regular use to treat non-COVID-19 patients.Results: A total of 176 swabs were sampled of defined locations covering both ICUs. No SARS-CoV-2 ribonucleic acid (RNA) was detected. Gram-negative bacterial contamination was mainly linked to sinks and siphons. Skin flora was isolated from most swabbed areas and Enterococcus faecium was detected on two keyboards.Conclusions: After basic cleaning with standard disinfection measures no remaining SARS-CoV-2 RNA was detected. Bacterial contamination was low and mainly localised in sinks and siphons.