From epidemics to pandemics: elucidating the dynamics of Ebola Virus and SARS-CoV-2

The advent of large-scale viral genomic sequencing has provided a rich source of data to explore the dynamics of infectious disease epidemics. In combination with the field of phylodynamics, which allows the inference of unobserved patterns from a relatively small sample of the true diversity of a virus, it has been used to great effect in the past decade. The most notable examples were during the West African Ebola Virus Disease (EVD) epidemic in 2013-2016 and the COVID-19 pandemic, still ongoing at the time of writing. The genomic datasets from these epidemics can be used to explore the evolution and transmission of viruses at different scales, from the effect of within-host evolution, to small-scale transmission networks, and national and international epidemic dynamics. I begin with the national-scale analysis of the dynamics of Ebola virus in Sierra Leone. I developed a phylogeographic analysis in a generalised linear model framework, at two geographical resolutions and in two epochs. I found that the focus of viral movement shifts from the source location in the east, to the capital city in the west. This chapter explores why different locations were important for viral transmission on a national level, and how well the gravity model of infection applies to the spread of Ebola virus in Sierra Leone through time and across different geographical scales. To address some of the issues in modelling a disease like EVD which has a high degree of superspreading, and to explore the impact of local contact networks, I created ABSynthE (Agent Based Synthetic Epidemic). ABSynthE is a flexible agent based model, which simulates an EVD epidemic across the population of Sierra Leone. ABSynthE outputs coalescent phylogenies, which are then used to obtain transmission parameters at each contact level by fitting to results from chapter 1. I found that without any intervention, just under half of the population of Sierra Leone may have been infected, regardless of which district the epidemic began in. There are now well over 8 million genomic sequences of SARS-CoV-2 available for analysis. Within the UK, the sampling is especially dense, allowing detailed epidemiological and phylodynamic analyses to be undertaken. In chapter 3, I explore the origins of the Alpha variant, the first variant of concern, which arose in South East England. I characterise the long ancestral branch, and find that it has a higher evolutionary rate compared to the background and Alpha clades, as well as a single intermediate sequence. I investigate the branches ancestral to the other variants of concern, and explore their mutational profiles, finding that Beta, Gamma and Omicron (but not Delta) have evidence for evolving in a similar manner to Alpha. I explore three different hypotheses for what this manner may be, and conclude that the most likely option is that they evolved within a persistently-infected, but not necessarily immunocompromised, host. Finally, I use the rich UK genomic SARS-CoV-2 dataset to elucidate the dynamics of the first wave of infection in early 2020, including the emergence of the D614G mutation; the Alpha wave, spreading from Kent and London to the rest of the country in late 2020 and early 2021; and the Delta wave, introduced into multiple regions, but mostly spreading from the North West of England in early 2021. I compare these waves, especially in terms of spreading from multiple introductions versus a single origin; and in the context of tightening or loosening non-pharmaceutical interventions

A longitudinal study of perfectionism and orthorexia in exercisers

Research suggests that trait perfectionism and perfectionistic self-presentation are related to orthorexia – a pathological obsession with correct nutrition. However, no studies have examined these relationships over time or compared the influence of the two aspects of perfectionism on orthorexia. In the present study we sought to address these two issues. Gym members who engaged in high degrees of exercise were recruited via social media platforms. They completed an online questionnaire that included the Multidimensional Perfectionism Scale-Short Form, Perfectionistic Self-Presentation Scale, and the Eating Habits Questionnaire on two occasions: 177 participants (Mean age = 31.6 years) initially completed the questionnaire and 82 completed the questionnaire six weeks later. A series of multiple regression analyses revealed that (i) trait perfectionism predicted an increase in orthorexia symptomatology over time with socially prescribed perfectionism and other-oriented perfectionism unique predictors of orthorexia, (ii) perfectionistic self-presentation predicted orthorexia over time with nondisplay of imperfection a unique predictor of orthorexia, and (iii) when considered alongside each other, only trait dimensions of perfectionism were unique predictors of orthorexia. The present study provides further evidence that perfectionism is related to orthorexia. In addition, the study also provides preliminary evidence that more engrained trait aspects of perfectionism are more predictive of intensifying orthorexia over time than the self-presentational aspects of perfectionism

Context-specific emergence and growth of the SARS-CoV-2 Delta variant

The SARS-CoV-2 Delta (Pango lineage B.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide1,2. The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virus genomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chains that later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing—and not the number of importations—were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventions to reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529)

Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool.

Funder: Oxford Martin School, University of OxfordThe response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the 'real-time' generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic's transmission lineages

Early insights from statistical and mathematical modeling of key epidemiologic parameters of COVID-19

We report key epidemiologic parameter estimates for coronavirus disease identified in peer-reviewed publications, preprint articles, and online reports. Range estimates for incubation period were 1.8–6.9 days, serial interval 4.0–7.5 days, and doubling time 2.3–7.4 days. The effective reproductive number varied widely, with reductions attributable to interventions. Case burden and infection fatality ratios increased with patient age. Implementation of combined interventions could reduce cases and delay epidemic peak up to 1 month. These parameters for transmission, disease severity, and intervention effectiveness are critical for guiding policy decisions. Estimates will likely change as new information becomes available

CLIMB-COVID: continuous integration supporting decentralised sequencing for SARS-CoV-2 genomic surveillance.

Funder: Wellcome TrustIn response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network

Accelerated SARS-CoV-2 Intrahost Evolution Leading to Distinct Genotypes During Chronic Infection

The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

SummaryGlobal 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.</jats:p

Generation and transmission of interlineage recombinants in the SARS-CoV-2 pandemic.

We present evidence for multiple independent origins of recombinant SARS-CoV-2 viruses sampled from late 2020 and early 2021 in the United Kingdom. Their genomes carry single-nucleotide polymorphisms and deletions that are characteristic of the B.1.1.7 variant of concern but lack the full complement of lineage-defining mutations. Instead, the remainder of their genomes share contiguous genetic variation with non-B.1.1.7 viruses circulating in the same geographic area at the same time as the recombinants. In four instances, there was evidence for onward transmission of a recombinant-origin virus, including one transmission cluster of 45 sequenced cases over the course of 2 months. The inferred genomic locations of recombination breakpoints suggest that every community-transmitted recombinant virus inherited its spike region from a B.1.1.7 parental virus, consistent with a transmission advantage for B.1.1.7's set of mutations.The COG-UK Consortium is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. O.G.P. was supported by the Oxford Martin School. J.T.M., R.M.C., N.J.L., and A.R. acknowledge the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z – ARTIC network). D.L.R. acknowledges the support of the MRC (MC_UU_12014/12) and the Wellcome Trust (220977/Z/20/Z). E.S. and A.R. are supported by the European Research Council (grant agreement no. 725422 – ReservoirDOCS). T.R.C. and N.J.L. acknowledge the support of the MRC, which provided the funding for the MRC CLIMB infrastructure used to analyze, store, and share the UK sequencing dataset (MR/L015080/1 and MR/T030062/1). The samples sequenced in Wales were sequenced partly using funding provided by the Welsh Government