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1.
Preprint in English | bioRxiv | ID: ppbiorxiv-498834

ABSTRACT

Up to November 2021, over 200 different SARS-CoV-2 lineages circulated in Mexico. To investigate lineage replacement dynamics, we applied a phylodynamic approach to explore the evolutionary trajectories of five dominant lineages that circulated during the first year of the local epidemic. For most lineages, peaks in sampling frequencies coincided with different epidemiological waves of infection in the country. Lineages B.1.1.222 and B.1.1.519 showed comparable dynamics, represented by clades likely originating in Mexico and persisting for over a year. Lineages B.1.1.7, P.1 and B.1.617.2 also displayed similar dynamics, characterized by multiple introduction events leading to a few successful extended local transmission chains that persisted for several months. We further explored viral movements across the country, applied within the largest clades identified (belonging to lineage B.1.617.2). Many clades were located within the south region of the country, suggesting that this area played a key role in the spread of SARS-CoV-2 in Mexico.

2.
Preprint in English | bioRxiv | ID: ppbiorxiv-481609

ABSTRACT

The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organisation (WHO) as Alpha. Originating in early Autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is more typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK, and the imposition of new restrictions, in particular the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages which preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically-infected individual. We conclude that the last hypothesis provides the best explanation of the observed behaviour and dynamics of the variant, although we find that the individual need not be immunocompromised, as persistently-infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs to each other, and identify that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations, and its lack of rapid evolutionary rate on the ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms) it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.

3.
Preprint in English | medRxiv | ID: ppmedrxiv-21266601

ABSTRACT

Genetic recombination is an important driving force of coronavirus evolution. While some degree of virus recombination has been reported during the COVID-19 pandemic, previously detected recombinant lineages of SARS-CoV-2 have shown limited circulation and been observed only in restricted areas. Prompted by reports of unusual genetic similarities among several Pango lineages detected mainly in North and Central America, we present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them. Two of these lineages, B.1.628 and B.1.631, are split into two distinct clusters (here named major and minor). Our phylogenetic and recombination analyses of these lineages find well-supported phylogenetic differences between the Orf1ab region and the rest of the genome (S protein and remaining reading frames). The lineages also contain several deletions in the NSP6, Orf3a and S proteins that can augment reconstruction of reliable evolutionary histories. By reconciling the deletions and phylogenetic data, we conclude that the B.1.628 major cluster originated from a recombination event between a B.1.631 major virus and a lineage B.1.634 virus. This scenario inferred from genetic data is supported by the spatial and temporal distribution of the three lineages, which all co-circulated in the USA and Mexico during 2021, suggesting this region is where the recombination event took place. We therefore support the designation of the B.1.628 major cluster as recombinant lineage XB in the Pango nomenclature. The widespread circulation of lineage XB across multiple countries over a longer timespan than the previously designated recombinant XA lineage raises important questions regarding the role and potential effects of recombination on the evolution of SARS-CoV-2 during the ongoing COVID-19 pandemic.

4.
Preprint in English | medRxiv | ID: ppmedrxiv-21262680

ABSTRACT

Genomic surveillance of SARS-CoV-2 has played a decisive role in understanding the transmission and evolution of the virus during its emergence and continued circulation. However, limited genomic sampling in many high-incidence countries has impeded detailed studies of SARS-CoV-2 genomic epidemiology. Consequently, critical questions remain about the generation and global distribution of virus genetic diversity. To address this gap, we investigated SARS-CoV-2 transmission dynamics in Gujarat, India, during its first epidemic wave and shed light on virus spread in one of the pandemics hardest-hit regions. By integrating regional case data and 434 whole virus genome sequences sampled across 20 districts from March to July 2020, we reconstructed the epidemic dynamics and spatial spread of SARS-CoV-2 in Gujarat, India. Our findings revealed that global and regional connectivity, along with population density, were significant drivers of the Gujarat SARS-CoV-2 outbreak. The three most populous districts in Gujarat accounted [~]84% of total cases during the first wave. Moreover, we detected over 100 virus lineage introductions, which were primarily associated with international travel. Within Gujarat, virus dissemination occurred predominantly from densely populated regions to geographically proximate locations with low-population density. Our findings suggest SARS-CoV-2 transmission follows a gravity model in India, with urban centres contributing disproportionately to onward virus spread.

5.
Preprint in English | medRxiv | ID: ppmedrxiv-21262393

ABSTRACT

Genomic sequencing provides critical information to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments and vaccines, and guide public health responses. To investigate the spatiotemporal heterogeneity in the global SARS-CoV-2 genomic surveillance, we estimated the impact of sequencing intensity and turnaround times (TAT) on variant detection in 167 countries. Most countries submit genomes >21 days after sample collection, and 77% of low and middle income countries sequenced <0.5% of their cases. We found that sequencing at least 0.5% of the cases, with a TAT <21 days, could be a benchmark for SARS-CoV-2 genomic surveillance efforts. Socioeconomic inequalities substantially impact our ability to quickly detect SARS-CoV-2 variants, and undermine the global pandemic preparedness. One-Sentence SummarySocioeconomic inequalities impacted the SARS-CoV-2 genomic surveillance, and undermined the global pandemic preparedness.

6.
Preprint in English | bioRxiv | ID: ppbiorxiv-455799

ABSTRACT

More than 2 million SARS-CoV-2 genome sequences have been generated and shared since the start of the COVID-19 pandemic and constitute a vital information source that informs outbreak control, disease surveillance, and public health policy. The Pango dynamic nomenclature is a popular system for classifying and naming genetically-distinct lineages of SARS-CoV-2, including variants of concern, and is based on the analysis of complete or near-complete virus genomes. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2. It is therefore important to understand how much information about Pango lineage status is contained in spike-only nucleotide sequences. Here we explore how Pango lineages might be reliably designated and assigned to spike-only nucleotide sequences. We survey the genetic diversity of such sequences, and investigate the information they contain about Pango lineage status. Although many lineages, including the main variants of concern, can be identified clearly using spike-only sequences, some spike-only sequences are shared among tens or hundreds of Pango lineages. To facilitate the classification of SARS-CoV-2 lineages using subgenomic sequences we introduce the notion of designating such sequences to a "lineage set", which represents the range of Pango lineages that are consistent with the observed mutations in a given spike sequence. These data provide a foundation for the development of software tools that can assign newly-generated spike nucleotide sequences to Pango lineage sets.

7.
Preprint in English | medRxiv | ID: ppmedrxiv-21261148

ABSTRACT

High throughput sequencing enables rapid genome sequencing during infectious disease outbreaks and provides an opportunity to quantify the evolutionary dynamics of pathogens in near real-time. One difficulty of undertaking evolutionary analyses over short timescales is the dependency of the inferred evolutionary parameters on the timespan of observation. Here, we characterise the molecular evolutionary dynamics of SARS-CoV-2 and 2009 pandemic H1N1 (pH1N1) influenza during the first 12 months of their respective pandemics. We use Bayesian phylogenetic methods to estimate the dates of emergence, evolutionary rates, and growth rates of SARS-CoV-2 and pH1N1 over time and investigate how varying sampling window and dataset sizes affects the accuracy of parameter estimation. We further use a generalised McDonald-Kreitman test to estimate the number of segregating non-neutral sites over time. We find that the inferred evolutionary parameters for both pandemics are time-dependent, and that the inferred rates of SARS-CoV-2 and pH1N1 decline by [~]50% and [~]100%, respectively, over the course of one year. After at least 4 months since the start of sequence sampling, inferred growth rates and emergence dates remain relatively stable and can be inferred reliably using a logistic growth coalescent model. We show that the time-dependency of the mean substitution rate is due to elevated substitution rates at terminal branches which are 2-4 times higher than those of internal branches for both viruses. The elevated rate at terminal branches is strongly correlated with an increasing number of segregating non-neutral sites, demonstrating the role of purifying selection in generating the time-dependency of evolutionary parameters during pandemics.

8.
Preprint in English | medRxiv | ID: ppmedrxiv-21250944

ABSTRACT

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.

9.
Preprint in English | medRxiv | ID: ppmedrxiv-20218446

ABSTRACT

The UKs COVID-19 epidemic during early 2020 was one of worlds largest and unusually well represented by virus genomic sampling. Here we reveal the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 SARS-CoV-2 genomes, including 26,181 from the UK sampled throughout the countrys first wave of infection. Using large-scale phylogenetic analyses, combined with epidemiological and travel data, we quantify the size, spatio-temporal origins and persistence of genetically-distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown were larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, whilst lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.

10.
Preprint in English | medRxiv | ID: ppmedrxiv-20166082

ABSTRACT

Global dispersal and increasing frequency of the SARS-CoV-2 Spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of Spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.

11.
Preprint in English | medRxiv | ID: ppmedrxiv-20131748

ABSTRACT

BackgroundCOVID-19 pandemic is underway. Some COVID-19 cases re-tested positive for SARS-CoV-2 RNA after discharge raising the public concern on their infectivity. Characterization of re-positive cases are urgently needed for designing intervention strategies. MethodsClinical data were obtained through Guangdong COVID-19 surveillance network. Neutralization antibody titre was determined using a microneutralization assay. Potential infectivity of clinical samples was evaluated after the cell inoculation. SARS-CoV-2 RNA was detected using three different RT-PCR kits and multiplex PCR with nanopore sequencing. ResultsAmong 619 discharged COVID-19 cases, 87 were re-tested as SARS-CoV-2 positive in circumstance of social isolation. All re-positive cases had mild or moderate symptoms in initial diagnosis and a younger age distribution (mean, 30.4). Re-positive cases (n=59) exhibited similar neutralization antibodies (NAbs) titre distributions to other COVID-19 cases (n=150) parallel-tested in this study. No infective viral strain could be obtained by culture and none full-length viral genomes could be sequenced for all re-positive cases. ConclusionsRe-positive SARS-CoV-2 was not caused by the secondary infection and was identified in around 14% of discharged cases. A robust Nabs response and a potential virus genome degradation were detected from nearly all re-positive cases suggesting a lower transmission risk, especially through a respiratory route.

12.
Preprint in English | medRxiv | ID: ppmedrxiv-20077396

ABSTRACT

BackgroundThe first case of COVID-19 was detected in Brazil on February 25, 2020. We report the epidemiological, demographic, and clinical findings for confirmed COVID-19 cases during the first month of the epidemic in Brazil. MethodsIndividual-level and aggregated COVID-19 data were analysed to investigate demographic profiles, socioeconomic drivers and age-sex structure of COVID-19 tested cases. Basic reproduction numbers (R0) were investigated for Sao Paulo and Rio de Janeiro. Multivariate logistic regression analyses were used to identify symptoms associated with confirmed cases and risk factors associated with hospitalization. Laboratory diagnosis for eight respiratory viruses were obtained for 2,429 cases. FindingsBy March 25, 1,468 confirmed cases were notified in Brazil, of whom 10% (147 of 1,468) were hospitalised. Of the cases acquired locally (77{middle dot}8%), two thirds (66{middle dot}9% of 5,746) were confirmed in private laboratories. Overall, positive association between higher per capita income and COVID-19 diagnosis was identified. The median age of detected cases was 39 years (IQR 30-53). The median R0 was 2{middle dot}9 for Sao Paulo and Rio de Janeiro. Cardiovascular disease/hypertension were associated with hospitalization. Co-circulation of six respiratory viruses, including influenza A and B and human rhinovirus was detected in low levels. InterpretationSocioeconomic disparity determines access to SARS-CoV-2 testing in Brazil. The lower median age of infection and hospitalization compared to other countries is expected due to a younger population structure. Enhanced surveillance of respiratory pathogens across socioeconomic statuses is essential to better understand and halt SARS-CoV-2 transmission. FundingSao Paulo Research Foundation, Medical Research Council, Wellcome Trust and Royal Society.

13.
Preprint in English | medRxiv | ID: ppmedrxiv-20064980

ABSTRACT

The COVID-19 pandemic is straining public health systems worldwide and major non-pharmaceutical interventions have been implemented to slow its spread1-4. During the initial phase of the outbreak the spread was primarily determined by human mobility5,6. Yet empirical evidence on the effect of key geographic factors on local epidemic spread is lacking7. We analyse highly-resolved spatial variables for cities in China together with case count data in order to investigate the role of climate, urbanization, and variation in interventions across China. Here we show that the epidemic intensity of COVID-19 is strongly shaped by crowding, such that epidemics in dense cities are more spread out through time, and denser cities have larger total incidence. Observed differences in epidemic intensity are well captured by a metapopulation model of COVID-19 that explicitly accounts for spatial hierarchies. Densely-populated cities worldwide may experience more prolonged epidemics. Whilst stringent interventions can shorten the time length of these local epidemics, although these may be difficult to implement in many affected settings.

14.
Preprint in English | bioRxiv | ID: ppbiorxiv-046086

ABSTRACT

The ongoing pandemic spread of a novel human coronavirus, SARS-COV-2, associated with severe pneumonia disease (COVID-19), has resulted in the generation of thousands of virus genome sequences. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding phylogenetic diversity of SARS-CoV-2. We present a rational and dynamic virus nomenclature that uses a phylogenetic framework to identify those lineages that contribute most to active spread. Our system is made tractable by constraining the number and depth of hierarchical lineage labels and by flagging and declassifying virus lineages that become unobserved and hence are likely inactive. By focusing on active virus lineages and those spreading to new locations this nomenclature will assist in tracking and understanding the patterns and determinants of the global spread of SARS-CoV-2.

15.
Preprint in English | medRxiv | ID: ppmedrxiv-20047076

ABSTRACT

COVID-19 is caused by the SARS-CoV-2 coronavirus and was first reported in central China in December 2019. Extensive molecular surveillance in Guangdong, Chinas most populous province, during early 2020 resulted in 1,388 reported RNA positive cases from 1.6 million tests. In order to understand the molecular epidemiology and genetic diversity of SARS-CoV-2 in China we generated 53 genomes from infected individuals in Guangdong using a combination of metagenomic sequencing and tiling amplicon approaches. Combined epidemiological and phylogenetic analyses indicate multiple independent introductions to Guangdong, although phylogenetic clustering is uncertain due to low virus genetic variation early in the pandemic. Our results illustrate how the timing, size and duration of putative local transmission chains were constrained by national travel restrictions and by the provinces large-scale intensive surveillance and intervention measures. Despite these successes, COVID-19 surveillance in Guangdong is still required as the number of cases imported from other countries is increasing. HighlightsO_LI1.6 million molecular diagnostic tests identified 1,388 SARS-CoV-2 infections in Guangdong Province, China, by 19th March 2020 C_LIO_LIVirus genomes can be recovered using a variety of sequencing approaches from a range of patient samples. C_LIO_LIGenomic analyses reveal multiple virus importations into Guangdong Province, resulting in genetically distinct clusters that require careful interpretation. C_LIO_LILarge-scale epidemiological surveillance and intervention measures were effective in interrupting community transmission in Guangdong C_LI

16.
Preprint in English | medRxiv | ID: ppmedrxiv-20044925

ABSTRACT

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has spread globally, resulting in >300,000 reported cases worldwide as of March 21st, 2020. Here we investigate the genetic diversity and genomic epidemiology of SARS-CoV-2 in Northern California using samples from returning travelers, cruise ship passengers, and cases of community transmission with unclear infection sources. Virus genomes were sampled from 29 patients diagnosed with COVID-19 infection from Feb 3rd through Mar 15th. Phylogenetic analyses revealed at least 8 different SARS-CoV-2 lineages, suggesting multiple independent introductions of the virus into the state. Virus genomes from passengers on two consecutive excursions of the Grand Princess cruise ship clustered with those from an established epidemic in Washington State, including the WA1 genome representing the first reported case in the United States on January 19th. We also detected evidence for presumptive transmission of SARS-CoV-2 lineages from one community to another. These findings suggest that cryptic transmission of SARS-CoV-2 in Northern California to date is characterized by multiple transmission chains that originate via distinct introductions from international and interstate travel, rather than widespread community transmission of a single predominant lineage. Rapid testing and contact tracing, social distancing, and travel restrictions are measures that will help to slow SARS-CoV-2 spread in California and other regions of the USA.

17.
Preprint in English | medRxiv | ID: ppmedrxiv-20026708

ABSTRACT

The ongoing COVID-19 outbreak has expanded rapidly throughout China. Major behavioral, clinical, and state interventions are underway currently to mitigate the epidemic and prevent the persistence of the virus in human populations in China and worldwide. It remains unclear how these unprecedented interventions, including travel restrictions, have affected COVID-19 spread in China. We use real-time mobility data from Wuhan and detailed case data including travel history to elucidate the role of case importation on transmission in cities across China and ascertain the impact of control measures. Early on, the spatial distribution of COVID-19 cases in China was well explained by human mobility data. Following the implementation of control measures, this correlation dropped and growth rates became negative in most locations, although shifts in the demographics of reported cases are still indicative of local chains of transmission outside Wuhan. This study shows that the drastic control measures implemented in China have substantially mitigated the spread of COVID-19.

18.
Preprint in English | medRxiv | ID: ppmedrxiv-20019844

ABSTRACT

Respiratory illness caused by a novel coronavirus (COVID-19) appeared in China during December 2019. Attempting to contain infection, China banned travel to and from Wuhan city on 23 January and implemented a national emergency response. Here we evaluate the spread and control of the epidemic based on a unique synthesis of data including case reports, human movement and public health interventions. The Wuhan shutdown slowed the dispersal of infection to other cities by an estimated 2.91 days (95%CI: 2.54-3.29), delaying epidemic growth elsewhere in China. Other cities that implemented control measures pre-emptively reported 33.3% (11.1-44.4%) fewer cases in the first week of their outbreaks (13.0; 7.1-18.8) compared with cities that started control later (20.6; 14.5-26.8). Among interventions investigated here, the most effective were suspending intra-city public transport, closing entertainment venues and banning public gatherings. The national emergency response delayed the growth and limited the size of the COVID-19 epidemic and, by 19 February (day 50), had averted hundreds of thousands of cases across China. One sentence summaryTravel restrictions and the national emergency response delayed the growth and limited the size of the COVID-19 epidemic in China.

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