Untangling introductions and persistence in COVID-19 resurgence in Europe

Abstract

After the first wave of SARS-CoV-2 infections in spring 2020, Europe experienced a resurgence of the virus starting in late summer 2020 that was deadlier and more difficult to contain¹. Relaxed intervention measures and summer travel have been implicated as drivers of the second wave². Here we build a phylogeographical model to evaluate how newly introduced lineages, as opposed to the rekindling of persistent lineages, contributed to the resurgence of COVID-19 in Europe. We inform this model using genomic, mobility and epidemiological data from 10 European countries and estimate that in many countries more than half of the lineages circulating in late summer resulted from new introductions since 15 June 2020. The success in onward transmission of newly introduced lineages was negatively associated with the local incidence of COVID-19 during this period. The pervasive spread of variants in summer 2020 highlights the threat of viral dissemination when restrictions are lifted, and this needs to be carefully considered in strategies to control the current spread of variants that are more transmissible and/or evade immunity. Our findings indicate that more effective and coordinated measures are required to contain the spread through cross-border travel even as vaccination is reducing disease burden.

Extended Data Figure 1.

Monthly international mobility data matrices: international air traffic data (a), international Facebook mobility data (b), and international Google mobility data (c). For Facebook data, we also report the single social connectedness index matrix (SCI, b).

Extended Data Figure 2.

Estimated introductions through time in the 10 European countries and circular migration flow plots summarizing the estimated transitions between the countries for different time intervals throughout the SARS-CoV-2 evolutionary history. (a) The introductions through time serve as an illustration and are based on the Markov jump history in the MCC tree. We note that the posterior distribution of trees is accompanied with considerable uncertainty about the location of origin, destination and timing of the transitions, which is difficult to appropriately visualize. The grey box represents the time period from June 15^th to August 15^th. (b) The circular migration flow plots are based on the posterior expectations of the Markov jumps. The sizes of the plots reflect the total number of transitions for each period. In these plots, migration flow out of a particular location starts close to the outer ring and ends with an arrowhead more distant from the destination location.

Extended Data Figure 3.

Pairwise mobility data among the 10 countries included in the phylogeographic analysis and other European countries. Heatmap cells are coloured according to international Google mobility data for the time period between January and October 2020.

Extended Data Figure 4.

Conceptual representation of persistent lineages and introductions during the time interval delineated by the evaluation time (T_e) and the ancestral time (T_a). At T_e, we evaluate how many lineages are circulating in the location of interest, in this case 12 (lineages in other locations are represented by thick grey branches). We subsequently identify whether these lineages maintained this location up to T_a in their ancestry or whether they result from an introduction event in the time interval of interest. By determining whether other lineages circulating in the location of interest at T_e are descendants of the same persistent lineage or whether they share an introduction event, we identify the unique persistent lineages or introductions, in this case 2 and 4 respectively. In addition to the proportion of unique introductions (p₁ = 4/6), we also summarize the proportion of their descendants at T_e (p₂ = 9/(9+3) in this case) and the proportion of their descendants in terms of sampled tips after T_e (p₃). Those tips are not shown here but conceptually represented for both introductions and persistent lineages by ovals.

Extended Data Figure 5.

Scatter plots of the difference in the logit proportion of unique introductions (p₁) and the logit proportion of their descendants on August 15^th (p₂) against incidence and the difference in the logit proportion of unique introductions and the logit proportion of descendant tips after August 15^th (p₃) against incidence. Both plots are shown for the period between April 15^th and June 15^th, for the period between June 15^th and August 15^th, and for the period between August 15^th and October 15^th, respectively. The p-values in the lower right corner of the plots are the p-values for the hypothesis tests based on the t-statistic evaluating whether the regression coefficient in a linear regression model is different from 0.

Extended Data Figure 6.

Estimated geographic origin of viral influx over the summer (June 15^th - August 15^th, 2020) in each country. Each bar plot summarizes the posterior Markov jump estimates into a specific country. For the bar representing a low number of introductions into Portugal, a magnified view is provided.

Extended Data Figure 7.

Phylogeographic transitions for lineages B1.1777/20A.EU1 and B1.160/20A.EU2. Cumulative phylogeographic transitions are summarized as posterior mean estimates with 95% HPD intervals over time for four types of Markov jumps. For B1.1777/20A.EU1: i) from Spain to the UK, ii) from Spain to other countries, iii) from the UK, and iv) from other countries; For B1.160/20A.EU2: i) from France to the UK, ii) from France to other countries, iii) from the UK, and iv) from other countries.

Figure 1.. Mobility, genome sampling, case counts and phylogeographic summaries through time for 10 European countries.

The first panel summarizes the country-specific Google mobility influx in the 10 countries during two-week intervals, while the second panel depicts the weekly genome sampling by country used in the phylogeographic analysis. In the remaining panels, we plot for each country the ratio of introductions over the total viral flow from and to that country (for two-week intervals) and a monthly normalized entropy measure summarizing the phylogenetic structure of country-specific transmission chains. The posterior mean ratios of introductions are depicted with circles that have a size proportional to the total number of transitions from and to that country and the grey surface represents the 95% highest posterior density (HPD) intervals. The posterior mean normalized entropies and 95% HPD intervals are depicted by dotted lines. These normalized entropy measures indicate how phylogenetically structured the epidemic is in each country, and ranges from 0 (perfectly structured, e.g., a single country-specific cluster) to 1 (unstructured interspersion of country-specific sequences across the entire SARS-CoV-2 phylogeny). The introduction ratios and normalized entropy measures are superimposed over COVID-19 incidence (daily cases/10⁶ people) reported for each country through time (coloured density plot). The two vertical dashed lines represent the summer time interval (June 15^th and August 15^th, 2020) for which we subsequently evaluate introductions versus persistence (cfr. Figure 2).

Figure 2.. Posterior estimates for the relative importance of lineage introduction events in 10 European countries and their association with incidence.

We report three summaries (posterior mean and 95% HPD intervals) for each country: the ratio of unique introductions over the total number of unique persisting lineages and unique introductions between June 15^th and August 15^th, 2020 (p₁), the ratio of descendant lineages from these unique introduction events over the total number of descendants circulating on August 15^th, 2020 (p₂), and the ratio of descendant taxa from these unique introductions over the total number of descendant taxa sampled after August 15^th, 2020 (p₃) (cfr. Extended Data Figure 4). The dot sizes are proportional to: (1) the total number of unique lineage introductions identified between June 15^th and August 15^th, 2020, (2) the total number of lineages inferred on August 15^th, 2020, and (3) the total number of descendant tips after August 15^th, 2020.

Figure 3.

Phylogeographic estimates of SARS-CoV-2 spread in 10 European countries. The tree on the left represents the maximum clade credibility tree summary of the Bayesian inference. Colours correspond to the countries in the legend. The two clades corresponding to B1.160/20A.EU2 and B1.177/20A.EU1 are highlighted in grey. The circular migration flow plots for these variants are based on the posterior expectations of the Markov jumps. In these plots, migration flow out of a particular location starts close to the outer ring and ends with an arrowhead more distant from the destination location. For B1.177/20A.EU1, we also summarize phylogeographic transitions as posterior mean estimates with 95% HPD intervals over time for four types of Markov jumps: i) from Spain to the UK, ii) from Spain to other countries, iii) from the UK, and iv) from other countries.