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Population-based prevalence surveys of Covid-19 contribute to establish the burden of infection, the role of asymptomatic and mild infections in transmission, and allow more precise decisions about reopen policies. We performed a systematic review to evaluate qualitative aspects of these studies, assessing their reliability and compiling practices that can influence the methodological quality. We searched MEDLINE, EMBASE, bioRxiv and medRxiv, and included cross-sectional studies using molecular and/or serological tests to estimate the prevalence of Covid-19 in the general population. Survey quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies. A correspondence analysis correlated methodological parameters of each study to identify patterns related to higher, intermediate and lower risks of bias. The available data described 37 surveys from 19 countries. The majority were from Europe and America, used antibody testing, and reached highly heterogeneous sample sizes and prevalence estimates. Minority communities were disproportionately affected by Covid-19. Important risk of bias was detected in four domains: sample size, data analysis with sufficient coverage, measurements in standard way and response rate. The correspondence analysis showed few consistent patterns for high risk of bias. Intermediate risk of bias was related to American and European studies, municipal and regional initiatives, blood samples and prevalence >1%. Low risk of bias was related to Asian studies, nationwide initiatives, reverse-transcriptase polymerase chain reaction tests and prevalence <1%. We identified methodological standards applied worldwide in Covid-19 prevalence surveys, which may assist researchers with the planning, execution and reporting of future population-based surveys.
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COVID-19/epidemiologia , Vigilância da População , COVID-19/diagnóstico , Teste para COVID-19/métodos , Humanos , Programas de Rastreamento/métodos , Vigilância da População/métodos , PrevalênciaRESUMO
BACKGROUND: Brazil is the third country most affected by Coronavirus disease-2019 (COVID-19), but viral evolution in municipality resolution is still poorly understood in Brazil and it is crucial to understand the epidemiology of viral spread. We aimed to track molecular evolution and spread of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Esteio (Southern Brazil) using phylogenetics and phylodynamics inferences from 21 new genomes in global and regional context. Importantly, the case fatality rate (CFR) in Esteio (3.26%) is slightly higher compared to the Rio Grande do Sul (RS) state (2.56%) and the entire Brazil (2.74%). RESULTS: We provided a comprehensive view of mutations from a representative sampling from May to October 2020, highlighting two frequent mutations in spike glycoprotein (D614G and V1176F), an emergent mutation (E484K) in spike Receptor Binding Domain (RBD) characteristic of the B.1.351 and P.1 lineages, and the adjacent replacement of 2 amino acids in Nucleocapsid phosphoprotein (R203K and G204R). E484K was found in two genomes from mid-October, which is the earliest description of this mutation in Southern Brazil. Lineages containing this substitution must be subject of intense surveillance due to its association with immune evasion. We also found two epidemiologically-related clusters, including one from patients of the same neighborhood. Phylogenetics and phylodynamics analysis demonstrates multiple introductions of the Brazilian most prevalent lineages (B.1.1.33 and B.1.1.248) and the establishment of Brazilian lineages ignited from the Southeast to other Brazilian regions. CONCLUSIONS: Our data show the value of correlating clinical, epidemiological and genomic information for the understanding of viral evolution and its spatial distribution over time. This is of paramount importance to better inform policy making strategies to fight COVID-19.
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COVID-19 , SARS-CoV-2 , Brasil/epidemiologia , Genoma Viral , Genômica , HumanosRESUMO
We report a rare case of a Brazilian adult woman with Ebstein's Anomaly who presented with pacemaker endocarditis caused by Propionibacterium acnes. Ebstein's Anomaly is a rare congenital malformation of the heart. Infective endocarditis is defined as an infection of heart valves, of the mural endocardium, of a septal defect, or of a cardiac electronic implantable device. Propionibacterium acnes is a skin commensal bacterium, that is usually considered as a contaminant, but can, on rare occasions, cause serious infections including endocarditis of prosthetic valves, native valves and cardiac electronic implantable devices. Diagnosis was made after nearly two years of investigation by identification of the organism by the MALDI-TOF technique and transoesophageal echocardiogram. The patient was successfully treated with daptomycin and device removal. She remains free of endocarditis after 32 months of follow-up.
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Anomalia de Ebstein/complicações , Eletrodos Implantados/efeitos adversos , Endocardite Bacteriana/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Propionibacterium acnes/isolamento & purificação , Antibacterianos/uso terapêutico , Remoção de Dispositivo , Eletrodos Implantados/microbiologia , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/terapia , Feminino , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Marca-Passo Artificial , RecidivaRESUMO
Background: Large-scale sequencing of SARS-CoV-2 has enabled the study of viral evolution during the COVID-19 pandemic. Some viral mutations may be advantageous to viral replication within hosts but detrimental to transmission, thus carrying a transient fitness advantage. By affecting the number of descendants, persistence times and growth rates of associated clades, these mutations generate localised imbalance in phylogenies. Quantifying these features in closely-related clades with and without recurring mutations can elucidate the tradeoffs between within-host replication and between-host transmission. Methods: We implemented a novel phylogenetic clustering algorithm ( mlscluster, https://github.com/mrc-ide/mlscluster) to systematically explore time-scaled phylogenies for mutations under transient/multilevel selection. We applied this method to a SARS-CoV-2 time-calibrated phylogeny with >1.2 million sequences from England, and characterised these recurrent mutations that may influence transmission fitness across PANGO-lineages and genomic regions using Poisson regressions and summary statistics. Results: We found no major differences across two epidemic stages (before and after Omicron), PANGO-lineages, and genomic regions. However, spike, nucleocapsid, and ORF3a were proportionally more enriched for transmission fitness polymorphisms (TFP)-homoplasies than other proteins. We provide a catalog of SARS-CoV-2 sites under multilevel selection, which can guide experimental investigations within and beyond the spike protein. Conclusions: This study provides empirical evidence for the existence of important tradeoffs between within-host replication and between-host transmission shaping the fitness landscape of SARS-CoV-2. This method may be used as a fast and scalable means to shortlist large sequence databases for sites under putative multilevel selection which may warrant subsequent confirmatory analyses and experimental confirmation.
Viral mutations can potentially carry a transient advantage, being simultaneously favourable for replication within hosts (e.g. by evading host immune responses) and deleterious to transmission (e.g. by having reduced cell binding). To identify such mutations, called transmission fitness polymorphisms (TFPs), we developed a clustering algorithm entitled mlscluster that computes clade-level statistics based on the number of descendants, persistence times, and growth rates of clades carrying a specific mutation in comparison with their immediate sisters without the mutation, which usually are different than expected in the presence of such TFPs. We then applied it to a representative SARS-CoV-2 time-scaled tree with >1 million whole-genome sequences from England. Our statistical analysis suggested approximately constant levels of transient selection across waves driven by very distinct variants. It also showed that genomic regions of known functional significance such as spike, nucleocapsid, and ORF3a were enriched for TFPs. This is the one of the first studies to characterise SARS-CoV-2 recurrent mutations potentially under multilevel selection, providing empirical evidence for the existence of important tradeoffs in selection between intrahost replication and inter-host transmission. Therefore, it provides target mutations for realistic coalescent-based modelling and laboratory-based investigations of their impacts and mechanisms of interaction with human cells.
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BACKGROUND: Epidemic waves of coronavirus disease 2019 (COVID-19) infections have often been associated with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Rapid detection of growing genomic variants can therefore serve as a predictor of future waves, enabling timely implementation of countermeasures such as non-pharmaceutical interventions (social distancing), additional vaccination (booster campaigns), or healthcare capacity adjustments. The large amount of SARS-CoV-2 genomic sequence data produced during the pandemic has provided a unique opportunity to explore the utility of these data for generating early warning signals (EWS). METHODS: We developed an analytical pipeline (Transmission Fitness Polymorphism Scanner - designated in an R package mrc-ide/tfpscanner) for systematically exploring all clades within a SARS-CoV-2 virus phylogeny to detect variants showing unusually high growth rates. We investigated the use of these cluster growth rates as the basis for a variety of statistical time series to use as leading indicators for the epidemic waves in the UK during the pandemic between August 2020 and March 2022. We also compared the performance of these phylogeny-derived leading indicators with a range of non-phylogeny-derived leading indicators. Our experiments simulated data generation and real-time analysis. FINDINGS: Using phylogenomic analysis, we identified leading indicators that would have generated EWS ahead of significant increases in COVID-19 hospitalisations in the UK between August 2020 and March 2022. Our results also show that EWS lead time is sensitive to the threshold set for the number of false positive (FP) EWS. It is often possible to generate longer EWS lead times if more FP EWS are tolerated. On the basis of maximising lead time and minimising the number of FP EWS, the best performing leading indicators that we identified, amongst a set of 1.4 million, were the maximum logistic growth rate (LGR) amongst clusters of the dominant Pango lineage and the mean simple LGR across a broader set of clusters. In the case of the former, the time between the EWS and wave inflection points (a conservative measure of wave start dates) for the seven waves ranged between a 20-day lead time and a 7-day lag, with a mean lead time of 5.4 days. The maximum number of FP EWS generated prior to a true positive (TP) EWS was two and this only occurred for two of the seven waves in the period. The mean simple LGR amongst a broader set of clusters also performed well in terms of lead time but with slightly more FP EWS. INTERPRETATION: As a result of the significant surveillance effort during the pandemic, early detection of SARS-CoV-2 variants of concern Alpha, Delta, and Omicron provided some of the first examples where timely detection and characterisation of pathogen variants has been used to tailor public health response. The success of our method in generating early warning signals based on phylogenomic analysis for SARS-CoV-2 in the UK may make it a worthwhile addition to existing surveillance strategies. In addition, the method may be translatable to other countries and/or regions, and to other pathogens with large-scale and rapid genomic surveillance. FUNDING: This research was funded in whole, or in part, by the Wellcome Trust (220885_Z_20_Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. KOD, OB, VBF and EMV acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. RMC acknowledges funding from the Wellcome Trust Collaborators Award (206298/Z/17/Z).
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Filogenia , Pandemias/prevenção & controleRESUMO
Inference of effective population size from genomic data can provide unique information about demographic history and, when applied to pathogen genetic data, can also provide insights into epidemiological dynamics. The combination of nonparametric models for population dynamics with molecular clock models which relate genetic data to time has enabled phylodynamic inference based on large sets of time-stamped genetic sequence data. The methodology for nonparametric inference of effective population size is well-developed in the Bayesian setting, but here we develop a frequentist approach based on nonparametric latent process models of population size dynamics. We appeal to statistical principles based on out-of-sample prediction accuracy in order to optimize parameters that control shape and smoothness of the population size over time. Our methodology is implemented in a new R package entitled mlesky. We demonstrate the flexibility and speed of this approach in a series of simulation experiments and apply the methodology to a dataset of HIV-1 in the USA. We also estimate the impact of non-pharmaceutical interventions for COVID-19 in England using thousands of SARS-CoV-2 sequences. By incorporating a measure of the strength of these interventions over time within the phylodynamic model, we estimate the impact of the first national lockdown in the UK on the epidemic reproduction number.
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The COVID-19 pandemic caused by SARS-CoV-2 has reached by February 2022 more than 380 million cases and 5.5 million deaths worldwide since its beginning in late 2019, leading to enhanced concern in the scientific community and the general population. One of the most important pieces of this host-pathogen interaction is the spike protein, which binds to the hACE2 cell receptor, mediates the membrane fusion and is the major target of neutralizing antibodies against SARS-CoV-2. The multiple amino acid substitutions observed in this region, specially in RBD have enhanced the hACE2 binding affinity and led to several modifications in the mechanisms of SARS-CoV-2 pathogenesis, improving the viral fitness and/or promoting immune evasion, with potential impact in the vaccine development. In this work, we identified 48 sites under selective pressures, 17 of them with the strongest evidence by the HyPhy tests, including VOC related mutation sites 138, 142, 222, 262, 484, 681, and 845, among others. The coevolutionary analysis identified 28 sites found not to be conditionally independent, such as E484K-N501Y. The molecular dynamics and free energy estimates showed the structural stabilizing effect and the higher impact of E484K for enhanced binding affinity between the spike RBD and hACE2 in P.1 and P.2 lineages (specially with L452V). Structural changes were also identified in the hACE molecule when interacting with B.1.1.7 RDB. Despite some destabilizing substitutions, a stabilizing effect was identified for the majority of the positively selected mutations.Communicated by Ramaswamy H. Sarma.
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COVID-19 , SARS-CoV-2 , Humanos , Glicoproteína da Espícula de Coronavírus , Brasil , Pandemias , Evolução Molecular , Mutação , GlicoproteínasRESUMO
The COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people since its beginning in 2019. The propagation of new lineages and the discovery of key mechanisms adopted by the virus to overlap the immune system are central topics for the entire public health policies, research and disease management. Since the second semester of 2020, the mutation E484K has been progressively found in the Brazilian territory, composing different lineages over time. It brought multiple concerns related to the risk of reinfection and the effectiveness of new preventive and treatment strategies due to the possibility of escaping from neutralizing antibodies. To better characterize the current scenario we performed genomic and phylogenetic analyses of the E484K mutated genomes sequenced from Brazilian samples in 2020. From October 2020, more than 40% of the sequenced genomes present the E484K mutation, which was identified in three different lineages (P.1, P.2 and B.1.1.33 - posteriorly renamed as N.9) in four Brazilian regions. We also evaluated the presence of E484K associated mutations and identified selective pressures acting on the spike protein, leading us to some insights about adaptive and purifying selection driving the virus evolution.
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Mutação , Filogenia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Brasil , COVID-19/virologia , Evolução Molecular , Genômica , Humanos , SARS-CoV-2/isolamento & purificação , Seleção GenéticaRESUMO
The COVID-19 pandemic has already reached more than 110 million people and is associated with 2.5 million deaths worldwide. Brazil is the third worst-hit country, with approximately 10.2 million cases and 250 thousand deaths. International efforts have been established to share information about Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemiology and evolution to support the development of effective strategies for public health and disease management. We aimed to analyze the high-quality genome sequences from Brazil from February 2020-2021 to identify mutation hotspots, geographical and temporal distribution of SARS-CoV-2 lineages by using phylogenetics and phylodynamics analyses. We describe heterogeneous sequencing efforts, the progression of the different lineages along time, evaluating mutational spectra and frequency oscillations derived from the prevalence of specific lineages across different Brazilian regions. We found at least seven major (1-7) and two minor clades related to the six most prevalent lineages in the country and described its spatial distribution and dynamics. The emergence and recent frequency shift of lineages (P.1 and P.2) carrying mutations of concern in the spike protein (e. g., E484K, N501Y) draws attention due to their association with immune evasion and enhanced receptor binding affinity. Improvements in genomic surveillance are of paramount importance and should be extended in Brazil to better inform policy makers about better decisions to fight the COVID-19 pandemic.
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COVID-19 , Pandemias , Filogenia , SARS-CoV-2 , Brasil/epidemiologia , COVID-19/epidemiologia , COVID-19/virologia , Genoma Viral , Humanos , Mutação , SARS-CoV-2/classificação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Almost a year after the COVID-19 pandemic had begun, new lineages (B.1.1.7, B.1.351, P.1, and B.1.617.2) associated with enhanced transmissibility, immunity evasion, and mortality were identified in the United Kingdom, South Africa, and Brazil. The previous most prevalent lineages in the state of Rio Grande do Sul (RS, Southern Brazil), B.1.1.28 and B.1.1.33, were rapidly replaced by P.1 and P.2, two B.1.1.28-derived lineages harboring the E484K mutation. To perform a genomic characterization from the metropolitan region of Porto Alegre, we sequenced viral samples to: (i) identify the prevalence of SARS-CoV-2 lineages in the region, the state, and bordering countries/regions; (ii) characterize the mutation spectra; (iii) hypothesize viral dispersal routes by using phylogenetic and phylogeographic approaches. We found that 96.4% of the samples belonged to the P.1 lineage and approximately 20% of them were assigned as the novel P.1.2, a P.1-derived sublineage harboring signature substitutions recently described in other Brazilian states and foreign countries. Moreover, sequences from this study were allocated in distinct branches of the P.1 phylogeny, suggesting multiple introductions in RS and placing this state as a potential diffusion core of P.1-derived clades and the emergence of P.1.2. It is uncertain whether the emergence of P.1.2 and other P.1 clades is related to clinical or epidemiological consequences. However, the clear signs of molecular diversity from the recently introduced P.1 warrant further genomic surveillance.