Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection (preprint)

Accumulating evidence points to persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals as a source of genetically divergent, novel lineages, generally characterised by increased transmissibility and immune escape. While intrahost evolutionary dynamics of the virus in chronically infected patients have been previously reported, existing knowledge is primarily based on samples obtained from the nasopharyngeal compartment. In this study, we investigate the intrahost evolution and genetic diversity that accumulated during a prolonged SARS-CoV-2 infection with the Omicron sublineage BF.7, estimated to have persisted for over one year in an immunosuppressed patient. Based on the sequencing of eight viral genomes collected from the patient at six time points, we identified 86 intrahost single-nucleotide variants (iSNVs), two indels, and a 362 bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate (ETA), and bronchoalveolar (BAL) samples. Notably, while significant divergence was observed between NP and BAL samples, most of the iSNVs found in ETA samples were also detected in NP or BAL samples. This suggests that NP samples may not offer a comprehensive representation of the overall intrahost viral diversity. Nonsynonymous mutations were most frequent in the spike and envelope genes, along with loss-of-function mutations in ORF8, generated by a frameshift mutation and a large deletion detected in the BAL and NP samples, respectively. Using long-range PCR on SARS-CoV-2 samples sequenced as part of routine surveillance, we validated that similar deletions causing ORF8 loss of function can be carried by SARS-CoV-2 during acute infection. Our findings not only demonstrate that the Omicron sublineage BF.7 can further diverge from its already exceptionally mutated state but also highlight that patients chronically infected with SARS-CoV-2 can develop genetically specific viral populations across distinct anatomical compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections.

Dispersal history of SARS-CoV-2 in Galicia, Spain (preprint)

The dynamics of SARS-CoV-2 transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the USA became increasingly significant. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2 (preprint)

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 has led to increased sampling of related sarbecoviruses circulating primarily in horseshoe bats. These viruses undergo frequent recombination and exhibit spatial structuring across Asia. Employing recombination-aware phylogenetic inference on bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed just ~1-3 years prior to their emergence in humans. Phylogeographic analyses examining the movement of related sarbecoviruses demonstrate that they traveled at similar rates to their horseshoe bat hosts and have been circulating for thousands of years in Asia. The closest-inferred bat virus ancestor of SARS-CoV likely circulated in western China, and that of SARS-CoV-2 likely circulated in a region comprising southwest China and northern Laos, both a substantial distance from where they emerged. This distance and recency indicate that the direct ancestors of SARS-CoV and SARS-CoV-2 could not have reached their respective sites of emergence via the bat reservoir alone. Our recombination-aware dating and phylogeographic analyses reveal a more accurate inference of evolutionary history than performing only whole-genome or single gene analyses. These results can guide future sampling efforts and demonstrate that viral genomic fragments extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses.

Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1 (preprint)

SARS-CoV-2 variants of concern (VOCs) arise against the backdrop of increasingly heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron genomes, we identified >6,000 independent introductions of the antigenically distinct virus into England and reconstructed the dispersal history of resulting local transmission. Travel restrictions on southern Africa did not reduce BA.1 importation intensity as secondary hubs became major exporters. We explored potential drivers of BA.1 spread across England and discovered an early period during which viral lineage movements mainly occurred between larger cities, followed by a multi-focal spatial expansion shaped by shorter distance mobility patterns. We also found evidence that disease incidence impacted human commuting behaviours around major travel hubs. Our results offer a detailed characterisation of processes that drive the invasion of an emerging VOC across multiple spatial scales and provide unique insights on the interplay between disease spread and human mobility.

Unravelling the effect of winter holiday celebrations on SARS-CoV-2 transmission (preprint)

Public holidays have been associated with SARS-CoV-2 incidence surges, although a firm causal link remains to be established. This association is sometimes attributed to events where transmissions occur at a disproportionately high rate, known as superspreading events. Here, we describe a sudden surge in new cases with the Omicron BA.1 strain amongst higher education students in Belgium. Contact tracers classed most of these cases as likely or possibly infected on New Year's Eve, indicating a direct trigger by New Year celebrations. Using a combination of contact tracing and phylogenetic data, we show the limited role of superspreading events in this surge. Finally, the numerous simultaneous transmissions allowed a unique opportunity to determine the distribution of incubation periods of the Omicron strain. Overall, our results indicate that, even under social restrictions, a surge in transmissibility of SARS-CoV-2 can occur when holiday celebrations result in small social gatherings attended simultaneously and communitywide.

Genomic epidemiology of SARS-CoV-2 within households in coastal Kenya: a case ascertained cohort study (preprint)

Background Analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic sequence data from household infections should aid its detailed epidemiological understanding. Using viral genomic sequence data, we investigated household SARS-CoV-2 transmission and evolution in coastal Kenya households. Methods We conducted a case-ascertained cohort study between December 2020 and February 2022 whereby 573 members of 158 households were prospectively monitored for SARS-CoV-2 infection. Households were invited to participate if a member tested SARS-CoV-2 positive or was a contact of a confirmed case. Follow-up visits collected a nasopharyngeal/oropharyngeal (NP/OP) swab on days 1, 4 and 7 for RT-PCR diagnosis. If any of these were positive, further swabs were collected on days 10, 14, 21 and 28. Positive samples with an RT-PCR cycle threshold of <33.0 were subjected to whole genome sequencing followed by phylogenetic analysis. Ancestral state reconstruction was used to determine if multiple viruses had entered households. Results Of 2,091 NP/OP swabs that were collected, 375 (17.9%) tested SARS-CoV-2 positive. Viral genome sequences (>80% coverage) were obtained from 208 (55%) positive samples obtained from 61 study households. These genomes fell within 11 Pango lineages and four variants of concern (Alpha, Beta, Delta and Omicron). We estimated 163 putative transmission events involving members of the sequenced households, 40 (25%) of which were intra-household transmission events while 123 (75%) were infections that likely occurred outside the households. Multiple virus introductions (up-to-5) were observed in 28 (47%) households with the 1-month follow-up period. Conclusions We show that a considerable proportion of SARS-CoV-2 infections in coastal Kenya occurred outside the household setting. Multiple virus introductions frequently occurred into households within the same infection wave in contrast to observations from high income settings, where single introduction appears to be the norm. Our findings suggests that control of SARS-CoV-2 transmission by household member isolation may be impractical in this setting.

Impact and mitigation of sampling bias to determine viral spread: evaluating discrete phylogeography through CTMC modeling and structured coalescent model approximations (preprint)

Bayesian phylogeographic inference is a powerful tool in molecular epidemiological studies that enables reconstructing the origin and subsequent geographic spread of pathogens. Such inference is, however, potentially affected by geographic sampling bias. Here, we investigated the impact of sampling bias on the spatiotemporal reconstruction of viral epidemics using Bayesian discrete phylogeographic models and explored different operational strategies to mitigate this impact. We considered the continuous-time Markov chain (CTMC) model and two structured coalescent approximations (BASTA and MASCOT). For each approach, we compared the estimated and simulated spatiotemporal histories in biased and unbiased conditions based on simulated epidemics of rabies virus (RABV) in dogs in Morocco. While the reconstructed spatiotemporal histories were impacted by sampling bias for the three approaches, BASTA and MASCOT reconstructions were also biased when employing unbiased samples. Increasing the number of analyzed genomes led to more robust estimates at low sampling bias for CTMC. Alternative sampling strategies that maximize the spatiotemporal coverage greatly improved the inference at intermediate sampling bias for CTMC, and to a lesser extent, for BASTA and MASCOT. In contrast, allowing for time-varying population sizes in MASCOT resulted in robust inference. We further applied these approaches to two empirical datasets: a RABV dataset from the Philippines and a SARS-CoV-2 dataset describing its early spread across the world. In conclusion, sampling biases are ubiquitous in phylogeographic analyses but may be accommodated by increasing sample size, balancing spatial and temporal composition in the samples, and informing structured coalescent models with reliable case count data.

Comparing the evolutionary dynamics of predominant SARS-CoV-2 virus lineages co-circulating in Mexico (preprint)

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.

Comparing the evolutionary dynamics of predominant SARS-CoV-2 virus lineages co-circulating in Mexico (preprint)

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.

SARS-CoV-2 genomic surveillance in Rwanda: Introductions and local transmission of the B.1.617.2 (Delta) variant of concern (preprint)

The emergence of the SARS-CoV-2 Delta variant of concern (lineage B.1.617.2) in late 2020 resulted in a new wave of infections in many countries across the world, where it often became the dominant lineage in a relatively short amount of time. We here report on a novel genomic surveillance effort in Rwanda in the time period from June to September 2021, leading to 201 SARS-CoV-2 genomes being generated, the majority of which were identified as the Delta variant of concern. We show that in Rwanda, the Delta variant almost completely replaced the previously dominant A.23.1 and B.1.351 (Beta) lineages in a matter of weeks, and led to a tripling of the total number of COVID-19 infections and COVID-19-related fatalities over the course of only three months. We estimate that Delta in Rwanda had an average growth rate advantage of 0.034 (95% CI 0.025-0.045) per day over A.23.1, and of 0.022 (95% CI 0.012-0.032) over B.1.351. Phylogenetic analysis reveals the presence of at least seven local Delta transmission clusters, with two of these clusters occurring close to the border with the Democratic Republic of the Congo, and another cluster close to the border with Tanzania. A smaller Delta cluster of infections also appeared close to the border with Uganda, illustrating the importance of monitoring cross-border traffic to limit the spread between Rwanda and its neighboring countries. We discuss our findings against a background of increased vaccination efforts in Rwanda, and also discuss a number of breakthrough infections identified during our study. Concluding, our study has added an important collection of data to the available genomes for the Eastern Africa region, with the number of Delta infections close to the border with neighboring countries highlighting the need to further strengthen genomic surveillance in the region to obtain a better understanding of the impact of border crossings on lowering the epidemic curve in Rwanda.

Comprehensive immunovirological and environmental screening reveals risk factors for fatal COVID-19 during post-vaccination nursing home outbreaks (preprint)

COVID-19 vaccination has resulted in excellent protection against fatal disease, including in the elderly. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases) by combining SARS-CoV-2 aerosol monitoring, whole-genome phylogenetic analysis, and immunovirological profiling by digital nCounter transcriptomics. Phylogenetic investigations indicated each outbreak stemmed from a single introduction event, though with different variants (Delta, Gamma, and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 days after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 signatures and reanalysis of single-cell RNAseq data highlights the unique immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy including environmental sampling, immunomonitoring, and early antiviral therapy should be considered to prevent post-vaccination COVID-19 mortality in nursing homes.

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

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes 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. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter- regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta's invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

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

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes 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. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter-regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta’s invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization (preprint)

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa 1,2 . It has in the meantime spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of about 32 mutations in the Spike, located mostly in the N-terminal domain (NTD) and the receptor binding domain (RBD), which may enhance viral fitness and allow antibody evasion. Here, we isolated an infectious Omicron virus in Belgium, from a traveller returning from Egypt. We examined its sensitivity to 9 monoclonal antibodies (mAbs) clinically approved or in development 3 , and to antibodies present in 90 sera from COVID-19 vaccine recipients or convalescent individuals. Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 5 to 31 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies.

Leveraging of SARS-CoV-2 PCR cycle thresholds values (Ct) to forecast COVID-19 trends (preprint)

IntroductionWe assessed the usefulness of SARS-CoV-2 RT-PCR cycle thresholds (Ct) values trends produced by the LHUB-ULB (a consolidated microbiology laboratory located in Brussels, Belgium) for monitoring the epidemics dynamics at local and national levels and for improving forecasting models. MethodsSARS-CoV-2 RT-PCR Ct values produced from April 1, 2020, to May 15, 2021, were compared with national COVID-19 confirmed cases notifications according to their geographical and time distribution. These Ct values were evaluated against both a phase diagram predicting the number of COVID-19 patients requiring intensive care and an age-structured model estimating COVID-19 prevalence in Belgium. ResultsOver 155,811 RT-PCR performed, 12,799 were positive and 7,910 Ct values were available for analysis. The 14-day median Ct values were negatively correlated with the 14-day mean daily positive tests with a lag of 17 days. In addition, the 14-day mean daily positive tests in LHUB-ULB were strongly correlated with the 14-day mean confirmed cases in the Brussels-Capital and in Belgium with coinciding start, peak and end of the different waves of the epidemic. Ct values decreased concurrently with the forecasted phase-shifts of the diagram. Similarly, the evolution of 14-day median Ct values was negatively correlated with daily estimated prevalence for all age-classes. ConclusionWe provide preliminary evidence that trends of Ct values can help to both follow and predict the epidemics trajectory at local and national levels, underlining that consolidated microbiology laboratories can act as epidemic sensors as they gather data that are representative of the geographical area they serve.

Genomic Sequencing of SARS-COV-2 in Rwanda: evolution and regional dynamics (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), is a single-stranded positive-sense ribonucleic acid (RNA) virus that typically undergoes one to two single nucleotide mutations per month. COVID-19 continues to spread globally, with case fatality and test positivity rates often linked to locally circulating strains of SARS-CoV-2. Furthermore, mutations in this virus, in particular those occurring in the spike protein (involved in the virus binding to the host epithelial cells) have potential implications in current vaccination efforts. In Rwanda, more than twenty thousand cases have been confirmed as of March 14th 2021, with a case fatality rate of 1.4% and test positivity rate of 2.3% while the recovery rate is at 91.9%. Rwanda started its genomic surveillance efforts, taking advantage of pre-existing research projects and partnerships, to ensure early detection of SARS-CoV-2 variants and to potentially contain the spread of variants of concern (VOC). As a result of this initiative, we here present 203 SARS-CoV-2 whole genome sequences analyzed from strains circulating in the country from May 2020 to February 2021. In particular, we report a shift in variant distribution towards the newly emerging sub-lineage A.23.1 that is currently dominating. Furthermore, we report the detection of the first Rwandan cases of the VOCs, B.1.1.7 and B.1.351, among incoming travelers tested at Kigali International Airport. We also discuss the potential impact of COVID-19 control measures established in the country to control the spread of the virus. To assess the importance of viral introductions from neighboring countries and local transmission, we exploit available individual travel history metadata to inform spatio-temporal phylogeographic inference, enabling us to take into account infections from unsampled locations during the time frame of interest. We uncover an important role of neighboring countries in seeding introductions into Rwanda, including those from which no genomic sequences are currently available or that no longer report positive cases. Our results point to the importance of systematically screening all incoming travelers, regardless of the origin of their travels as well as regional considerations for durable response to COVID-19.

Early introductions and community transmission of SARS-CoV-2 variant B.1.1.7 in the United States (preprint)

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2500 COVID-19 cases associated with this variant have been detected in the US since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight the primary ports of entry for B.1.1.7 in the US and locations of possible underreporting of B.1.1.7 cases. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.

SARS-CoV-2 European resurgence foretold: interplay of introductions and persistence by leveraging genomic and mobility data (preprint)

Following the first wave of SARS-CoV-2 infections in spring 2020, Europe experienced a resurgence of the virus starting late summer that was deadlier and more difficult to contain. Relaxed intervention measures and summer travel have been implicated as drivers of the second wave. Here, we build a phylogeographic model to evaluate how newly introduced lineages, as opposed to the rekindling of persistent lineages, contributed to the COVID-19 resurgence in Europe. We inform this model using genomic, mobility and epidemiological data from 10 West European countries and estimate that in many countries more than 50% of the lineages circulating in late summer resulted from new introductions since June 15th. The success in onwards transmission of these lineages is predicted by SARS-CoV-2 incidence during this period. Relatively early introductions from Spain into the United Kingdom contributed to the successful spread of the 20A.EU1/B.1.177 variant. The pervasive spread of variants that have not been associated with an advantage in transmissibility highlights the threat of novel variants of concern that emerged more recently and have been disseminated by holiday travel. Our findings indicate that more effective and coordinated measures are required to contain spread through cross-border travel.

Phylogenetic analyses of SARS-CoV-2 B.1.1.7 lineage suggest a single origin followed by multiple exportation events versus convergent evolution (preprint)

The emergence of new variants of SARS-CoV-2 herald a new phase of the pandemic. This study used state-of-the-art phylodynamic methods to ascertain that the rapid rise of B.1.1.7 "Variant of Concern" most likely occurred by global dispersal rather than convergent evolution from multiple sources.

SARS-CoV-2 genomic characterization and clinical manifestation of the COVID-19 outbreak in Uruguay (preprint)

COVID-19 is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared by the World Health Organization as a global public health emergency. Among the severe outbreaks across South America, Uruguay has become known for curtailing SARS-CoV-2 exceptionally well. To understand the SARS-CoV-2 introductions, local transmissions, and associations with genomic and clinical parameters in Uruguay, we sequenced the viral genomes of 44 outpatients and inpatients in a private healthcare system in its capital, Montevideo, from March to May 2020. We performed a phylogeographic analysis using sequences from our cohort and other studies that indicate a minimum of 23 independent introductions into Uruguay, resulting in five major transmission clusters. Our data suggest that most introductions resulting in chains of transmission originate from other South American countries, with the earliest seeding of the virus in late February 2020, weeks before the borders were closed to all non-citizens and a partial lockdown implemented. Genetic analyses suggest a dominance of S and G clades (G, GH, GR) that make up >90% of the viral strains in our study. In our cohort, lethal outcome of SARS-CoV-2 infection significantly correlated with arterial hypertension, kidney failure, and ICU admission (FDR < 0.01), but not with any mutation in a structural or non-structural protein, such as the spike D614G mutation. Our study contributes genetic, phylodynamic, and clinical correlation data about the exceptionally well-curbed SARS-CoV-2 outbreak in Uruguay, which furthers the understanding of disease patterns and regional aspects of the pandemic in Latin America.