Assessment of COVID-19 intervention strategies in the Nordic countries using genomic epidemiology

The Nordic countries, defined here as Norway, Sweden, Denmark, Finland and Iceland, are known for their comparable demographics and political systems. Since these countries implemented different COVID-19 intervention strategies, they provide a natural laboratory for examining how COVID-19 policies and mitigation strategies affected the propagation, evolution and spread of the SARS-CoV-2 virus. We explored how the duration, the size and number of transmission clusters, defined as country-specific monophyletic groups in a SARS-CoV-2 phylogenetic tree, differed between the Nordic countries. We found that Sweden had the largest number of COVID-19 transmission clusters followed by Denmark, Norway, Finland and Iceland. Moreover, Sweden and Denmark had the largest, and most enduring, transmission clusters followed by Norway, Finland and Iceland. In addition, there was a significant positive association between transmission cluster size and duration, suggesting that the size of transmission clusters could be reduced by rapid and effective contact tracing. Thus, these data indicate that to reduce the general burden of COVID-19 there should be a focus on limiting dense gatherings and their subsequent contacts to keep the number, size and duration of transmission clusters to a minimum. Our results further suggest that although geographical connectivity, population density and openness influence the spread and the size of SARS-CoV-2 transmission clusters, country-specific intervention strategies had the largest single impact.

The emergence of SARS-CoV-2 variants of concern is driven by acceleration of the evolutionary rate

The ongoing SARS-CoV-2 pandemic has seen an unprecedented amount of rapidly generated genome data. These data have revealed the emergence of lineages with mutations associated to transmissibility and antigenicity, known as variants of concern (VOCs). A striking aspect of VOCs is that many of them involve an unusually large number of defining mutations. Current phylogenetic estimates of the evolutionary rate of SARS-CoV-2 suggest that its genome accrues around 2 mutations per month. However, VOCs can have around 15 defining mutations and it is hypothesised that they emerged over the course of a few months, implying that they must have evolved faster for a period of time. We analysed genome sequence data from the GISAID database to assess whether the emergence of VOCs can be attributed to changes in the evolutionary rate of the virus and whether this pattern can be detected at a phylogenetic level using genome data. We fit a range of molecular clock models and assessed their statistical fit. Our analyses indicate that the emergence of VOCs is driven by an episodic increase in the evolutionary rate of around 4-fold the background phylogenetic rate estimate that may have lasted several weeks or months. These results underscore the importance of monitoring the molecular evolution of the virus as a means of understanding the circumstances under which VOCs may emerge.

The first wave of the Spanish COVID-19 epidemic was associated with early introductions and fast spread of a dominating genetic variant

The COVID-19 pandemic has shaken the world since the beginning of 2020. Spain is among the European countries with the highest incidence of the disease during the first pandemic wave. We established a multidisciplinar consortium to monitor and study the evolution of the epidemic, with the aim of contributing to decision making and stopping rapid spreading across the country. We present the results for 2170 sequences from the first wave of the SARS-Cov-2 epidemic in Spain and representing 12% of diagnosed cases until 14th March. This effort allows us to document at least 500 initial introductions, between early February-March from multiple international sources. Importantly, we document the early raise of two dominant genetic variants in Spain (Spanish Epidemic Clades), named SEC7 and SEC8, likely amplified by superspreading events. In sharp contrast to other non-Asian countries those two variants were closely related to the initial variants of SARS-CoV-2 described in Asia and represented 40% of the genome sequences analyzed. The two dominant SECs were widely spread across the country compared to other genetic variants with SEC8 reaching a 60% prevalence just before the lockdown. Employing Bayesian phylodynamic analysis, we inferred a reduction in the effective reproductive number of these two SECs from around 2.5 to below 0.5 after the implementation of strict public-health interventions in mid March. The effects of lockdown on the genetic variants of the virus are reflected in the general replacement of preexisting SECs by a new variant at the beginning of the summer season. Our results reveal a significant difference in the genetic makeup of the epidemic in Spain and support the effectiveness of lockdown measures in controlling virus spread even for the most successful genetic variants. Finally, earlier control of SEC7 and particularly SEC8 might have reduced the incidence and impact of COVID-19 in our country.

The impact of early public health interventions on SARS-CoV-2 transmission and evolution

BackgroundMany countries have attempted to mitigate and control COVID-19 through the implementation of non-pharmaceutical interventions, particularly with the aim of reducing population movement and contact. However, it remains unclear how the different control strategies impacted the local phylodynamics of the causative SARS-CoV-2 virus. AimTo assess the duration of chains of virus transmission within individual countries and the extent to which countries export viruses to their geographic neighbours. MethodsTo address core questions in genomic epidemiology and public health we analysed complete SARS-CoV-2 genomes to infer the relative frequencies of virus importation and exportation, as well as virus transmission dynamics, within countries of northern Europe. To this end, we examined virus evolution and phylodynamics in Denmark, Finland, Iceland, Norway and Sweden during the first year of the pandemic. ResultsThe Nordic countries differed markedly in the invasiveness of control strategies implemented. In particular, Sweden did not initially employ any strict population movement limitations and experienced markedly different transmission chain dynamics, which were more numerous and tended to have more cases, a set of features that increased with time during the first eight months of 2020. ConclusionTogether with Denmark, Sweden was also characterised as a net exporter of SARS-CoV-2. Hence, Sweden effectively constituted an epidemiological and evolutionary refugia that enabled the virus to maintain active transmission and spread to other geographic localities. In sum, our analysis reveals the utility of genomic surveillance where active transmission chain monitoring is a key metric.

Genomic epidemiology reveals transmission patterns and dynamics of SARS-CoV-2 in Aotearoa New Zealand

New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nation-wide lockdown of all non-essential services to curb the spread of COVID-19. New Zealand has now effectively eliminated the virus, with low numbers of new cases limited to new arrivals in managed quarantine facilities at the border. Here, we generated 649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected between 26 February and 22 May 2020, representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. The proportion of D614G variants in the virus spike protein increased over time due to an increase in their importation frequency, rather than selection within New Zealand. These data also helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, Re, of New Zealands largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in a transmission lineage of more than one additional case. Most of the cases that resulted in a transmission lineage originated from North America, rather than from Asia where the virus first emerged or from the nearest geographical neighbour, Australia. Genomic data also helped link more infections to a major transmission cluster than through epidemiological data alone, providing probable sources of infections for cases in which the source was unclear. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.

Tracking the COVID-19 pandemic in Australia using genomics

BACKGROUNDWhole-genome sequencing of pathogens can improve resolution of outbreak clusters and define possible transmission networks. We applied high-throughput genome sequencing of SARS-CoV-2 to 75% of cases in the State of Victoria (population 6.24 million) in Australia. METHODSCases of SARS-CoV-2 infection were detected through active case finding and contact tracing. A dedicated SARS-CoV-2 multidisciplinary genomic response team was formed to enable rapid integration of epidemiological and genomic data. Phylodynamic analysis was performed to assess the putative impact of social restrictions. RESULTSBetween 25 January and 14 April 2020, 1,333 COVID-19 cases were reported in Victoria, with a peak in late March. After applying internal quality control parameters, 903 samples were included in genomic analyses. Sequenced samples from Australia were representative of the global diversity of SARS-CoV-2, consistent with epidemiological findings of multiple importations and limited onward transmission. In total, 76 distinct genomic clusters were identified; these included large clusters associated with social venues, healthcare facilities and cruise ships. Sequencing of sequential samples from 98 patients revealed minimal intra-patient SARS-CoV-2 genomic diversity. Phylodynamic modelling indicated a significant reduction in the effective viral reproductive number (Re) from 1.63 to 0.48 after the implementation of travel restrictions and population-level physical distancing. CONCLUSIONSOur data provide a comprehensive framework for the use of SARS-CoV-2 genomics in public health responses. The application of genomics to rapidly identify SARS-CoV-2 transmission chains will become critically important as social restrictions ease globally. Public health responses to emergent cases must be swift, highly focused and effective.

Temporal signal and the phylodynamic threshold of SARS-CoV-2

The ongoing SARS-CoV-2 outbreak marks the first time that large amounts of genome sequence data have been generated and made publicly available in near real-time. Early analyses of these data revealed low sequence variation, a finding that is consistent with a recently emerging outbreak, but which raises the question of whether such data are sufficiently informative for phylogenetic inferences of evolutionary rates and time scales. The phylodynamic threshold is a key concept that refers to the point in time at which sufficient molecular evolutionary change has accumulated in available genome samples to obtain robust phylodynamic estimates. For example, before the phylodynamic threshold is reached, genomic variation is so low that even large amounts of genome sequences may be insufficient to estimate the viruss evolutionary rate and the time scale of an outbreak. We collected genome sequences of SARS-CoV-2 from public databases at 8 different points in time and conducted a range of tests of temporal signal to determine if and when the phylodynamic threshold was reached, and the range of inferences that could be reliably drawn from these data. Our results indicate that by February 2nd 2020, estimates of evolutionary rates and time scales had become possible. Analyses of subsequent data sets, that included between 47 to 122 genomes, converged at an evolutionary rate of about 1.1x10-3 subs/site/year and a time of origin of around late November 2019. Our study provides guidelines to assess the phylodynamic threshold and demonstrates that establishing this threshold constitutes a fundamental step for understanding the power and limitations of early data in outbreak genome surveillance.

Direct RNA sequencing and early evolution of SARS-CoV-2

Fundamental aspects of SARS-CoV-2 biology remain to be described, having the potential to provide insight to the response effort for this high-priority pathogen. Here we describe the first native RNA sequence of SARS-CoV-2, detailing the coronaviral transcriptome and epitranscriptome, and share these data publicly. A data-driven inference of viral genetic features and evolutionary rate is also made. The rapid sharing of sequence information throughout the SARS-CoV-2 pandemic represents an inflection point for public health and genomic epidemiology, providing early insights into the biology and evolution of this emerging pathogen.