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BackgroundAdministration of plasma therapy may contribute to viral control and survival of COVID-19 patients receiving B-cell depleting agents that hinder the endogenous humoral response. However, little is known on the impact of anti-CD20 pre-exposition and the use of different sources of plasma (convalescent versus vaccinated) on the kinetics of SARS-CoV-2-specific antibodies and viral evolution after plasma therapy. MethodsEligible COVID-19 patients (n = 36), half of them after anti-CD20 targeted therapy, were treated with therapeutic plasma from convalescent (n = 17) or mRNA-vaccinated (n = 19) donors. Each plasma-transfused patient was thoroughly monitored over time by anti-S IgG quantification and whole-genome SARS-CoV-2 sequencing. ResultsThe majority of anti-CD20 pre-exposed patients (15/18) showed progressive declines of anti-S protein IgG titers following plasma therapy, indicating that they mostly relied on the passive transfer of anti-SARS-CoV-2 antibodies. Such antibody kinetics correlated with prolonged infection before virus clearance, contrasting with the endogenous humoral response predominantly present in patients who had not received B-cell depleting agents (15/18). No relevant differences were observed between patients treated with plasma from convalescent and/or vaccinated donors. Finally, 4/30 genotyped patients showed increased intra-host viral evolution and 3/30 included 1 to 4 spike mutations, potentially associated to immune escape. ConclusionsConvalescent and/or vaccinated plasma therapy may provide anti-SARS-CoV-2 antibodies and clinical benefit to B-cell depleted COVID-19 patients. Only a limited number of patients acquired viral mutations prior to clinical recovery, yet our study further emphasizes the need for long-term surveillance for intra-host variant evolution, to guide best therapeutic strategies.
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SARS-CoV-2 is currently causing an unprecedented pandemic. While vaccines are massively deployed, we still lack effective large-scale antiviral therapies. In the quest for antivirals targeting conserved structures, we focused on molecules able to bind viral RNA secondary structures. Aminoglycosides are a class of antibiotics known to interact with the ribosomal RNA of both prokaryotes and eukaryotes and have previously been shown to exert antiviral activities by interacting with viral RNA. Here we show that the aminoglycoside geneticin is endowed with antiviral activity against all tested variants of SARS-CoV-2, in different cell lines and in a respiratory tissue model at non-toxic concentrations. The mechanism of action is an early inhibition of RNA replication and protein expression related to a decrease in the efficiency of the -1 programmed ribosomal frameshift (PRF) signal of SARS-CoV-2. Using in silico modelling, we have identified a potential binding site of geneticin in the pseudoknot of frameshift RNA motif. Moreover, we have selected, through virtual screening, additional RNA binding compounds, interacting with the same site with increased potency.
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Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 SARS-CoV-2 genomes from Switzerland in 2020 - the 6th largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrast these estimates with simple null models representing the absence of certain public health measures. We show that Switzerlands border closures de-coupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86 - 98% reduction in introductions during Switzerlands strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Finally, we quantified local transmission dynamics once introductions into Switzerland occurred, using a novel phylodynamic model. We find that transmission slowed 35 - 63% upon outbreak detection in summer 2020, but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics. One Sentence SummaryPhylogenetic and phylodynamic methods quantify the drop in case introductions and local transmission with implementation of public health measures.
