Regional importation and asymmetric within-country spread of SARS-CoV-2 variants of concern in the Netherlands

  1. Alvin X Han
  2. Eva Kozanli
  3. Jelle Koopsen
  4. Harry Vennema
  5. RIVM COVID-19 molecular epidemiology group
  6. Karim Hajji
  7. Annelies Kroneman
  8. Ivo van Walle
  9. Don Klinkenberg
  10. Jacco Wallinga
  11. Colin A Russell
  12. Dirk Eggink
  13. Chantal Reusken

  • Curated by eLife

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    Evaluation Summary:

    The authors present an analysis of SARS-CoV-2 variant of concern movements into and within the Netherlands. The primary finding is that flight bans (in conjunction with other NPIs) were grossly insufficient at stopping the invasion of new variants into The Netherlands over a one-year period. Although consistent with similar analyses of other regions early in the pandemic, this manuscript provides additional evidence of the inadequacy of flight bans at stopping the spread of variants that are already widespread globally, especially (but not only) when importations continue via ground travel. The reviewers have questioned the rigor of the statistical models and the presentation of the main result, including analyses that were included but do not appear to contribute to the main argument.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Variants of concern (VOCs) of SARS-CoV-2 have caused resurging waves of infections worldwide. In the Netherlands, the Alpha, Beta, Gamma, and Delta VOCs circulated widely between September 2020 and August 2021. We sought to elucidate how various control measures, including targeted flight restrictions, had impacted the introduction and spread of these VOCs in the Netherlands.

Methods:

We performed phylogenetic analyses on 39,844 SARS-CoV-2 genomes collected under the Dutch national surveillance program.

Results:

We found that all four VOCs were introduced before targeted flight restrictions were imposed on countries where the VOCs first emerged. Importantly, foreign introductions, predominantly from other European countries, continued during these restrictions. After their respective introductions into the Netherlands, the Alpha and Delta VOCs largely circulated within more populous regions of the country with international connections before asymmetric bidirectional transmissions occurred with the rest of the country and the VOC became the dominant circulating lineage.

Conclusions:

Our findings show that flight restrictions had limited effectiveness in deterring VOC introductions due to the strength of regional land travel importation risks. As countries consider scaling down SARS-CoV-2 surveillance efforts in the post-crisis phase of the pandemic, our results highlight that robust surveillance in regions of early spread is important for providing timely information for variant detection and outbreak control.

Funding:

None.

Article activity feed

  1. Version published to 10.7554/elife.78770 on eLife
  2. eLife

    Author Response

    Reviewer #3 (Public Review):

    Han et al. present important insights into the effect of interventions on the regional importation and within-country spread of SARS-CoV-2 variants. The authors combine phylogenetic and epidemiological approaches to study the introductions and spread of SARS-CoV-2 variants in The Netherlands. The manuscript is clear, concise, and well-written.

    We thank the reviewer for considering our manuscript.

    1. The main focus of the study is on the effect of international travel restrictions, but these restrictions are not well defined. Moreover, the effect of travel restrictions cannot be distinguished from other restrictions and interventions that were enforced. It seems more appropriate to focus the paper on the effect of collective interventions on SARS-CoV-2 introductions and spread, rather than focusing on international travel restrictions.

    To be clear, we are investigating specifically how travel restrictions targeted at countries where VOCs first emerged did not deter the introduction of VOCs into the Netherlands. The restrictions are now more clearly defined in the text:

    Line 227: “To deter the introductions of novel VOCs into the Netherlands, travel restrictions were imposed on countries where the VOCs first emerged, including the United Kingdom between December 2020 and March 2021 due to the emergence of Alpha; South Africa and Brazil between January and June 2021 due to Beta and Gamma respectively; and India from April to June 2021 due to Delta. These travel restrictions include a ban on all incoming passenger flights except for those carrying cargo and medical personnel, on top of an entry ban for all non-European Union residents (Government of the Netherlands, 2021). On the other hand, travel within the Schengen Area of the European Union, which includes the Netherlands, remained possible during this period.”

    We had tried to infer effects of other public health interventions on VOC introduction and spread in the Netherlands based on phylogenetic analyses. However, we did not include these analyses in this work as it was difficult to derive precise conclusions because: (1) we lacked travel history data of sampled Dutch individuals, including if they were imported cases or not. As such, we were unable to directly infer the impacts of interventions and reliably estimate frequency of overseas introductions; (2) there have been changes to individual protective behaviours over time (Sharma et al., Nat Comms, 2021) which made it difficult to disentangle these effects from those due to non-pharmaceutical interventions; and (3) like many other countries, a variety of interventions and relaxation of rules were imposed in the Netherlands that overlapped during the study period, further complicating efforts to disentangle the effects of different events.

    1. Most introductions originated from other European countries and it would be valuable to perform a more in-depth analysis at the country level to understand patterns of introductions within Europe.

    It is difficult to perform a more in-depth analyses to elucidate country level contributions of VOC introductions into the Netherlands due to non-uniform levels of genomic surveillance efforts between different countries, sampling biases and a lack of travel history data or if a case was likely an imported one among the sampled Dutch individuals. Our inability to perform more in-depth reconstruction of importation events and estimate country-level importation risks into the Netherlands is now discussed as a limitation to our analyses – see response to comment 11 below.

    1. The authors conclude that robust surveillance in regions of early spread is important for variant detection and outbreak control. Given the retrospective nature of this study (the studied variants have mostly disappeared after the emergence of omicron), it would be good to further discuss how future outbreak control can be achieved in a timely manner.

    We have now briefly discussed this in the last Discussion paragraph:

    Line 400: “As such, a robust level of surveillance efforts should still be maintained in these dominant source locations to provide timely actionable information on novel variant detection as well as infection control. These surveillance efforts should encompass a minimal level of clinical diagnostic testing capacity be maintained to ensure clinical genomic surveillance remains sensitive enough for early detection of novel variants (Han et al., 2022). Wastewater surveillance could also be included to facilitate early variant detection and identify cryptic transmissions amid falling testing rates (Karthikeyan et al., 2022).”

  3. eLife

    Evaluation Summary:

    The authors present an analysis of SARS-CoV-2 variant of concern movements into and within the Netherlands. The primary finding is that flight bans (in conjunction with other NPIs) were grossly insufficient at stopping the invasion of new variants into The Netherlands over a one-year period. Although consistent with similar analyses of other regions early in the pandemic, this manuscript provides additional evidence of the inadequacy of flight bans at stopping the spread of variants that are already widespread globally, especially (but not only) when importations continue via ground travel. The reviewers have questioned the rigor of the statistical models and the presentation of the main result, including analyses that were included but do not appear to contribute to the main argument.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  4. eLife

    Reviewer #1 (Public Review):

    As mentioned, this paper sought to estimate the impact of flight bans on the importation of major SARS-CoV-2 variants, especially Alpha and Delta, which caused large outbreaks in The Netherlands. The analysis also investigates intranational spread, finding (as expected) that early importations into denser source regions facilitated spread to rural regions. Finally, the authors analyze variant growth rates in different age groups, concluding that although Delta spread especially well in younger adults, displacement of Alpha by Delta was comparably fast in all age groups.

    The work is especially strong because of the systematic collection of sequences in The Netherlands over this time period, coupled with rich genomic surveillance in neighboring regions. It demonstrates conclusively that travel bans were too late to slow the rate of spread of multiple variants, including those that did not ultimately take off (Beta and Gamma), and that ground importation from other European countries continued through periods of varying restrictions. This is important evidence that flight bans, even in populations with good surveillance, are basically useless.

    The major limitation of this work is that the sequences from The Netherlands and other countries are of course not "random." Biases in sequencing (relative to the underlying distribution of infections) could distort perceived flows between regions. This has not been fully quantified, but at the same time, this paper is not trying to make strong quantitative claims about the precise rates of migration. The sequencing program in The Netherlands during this period was one of the best in the world.

    Overall, although the results here are not surprising, this paper constitutes a solid contribution to our knowledge of the spread of new variants to different populations.

  5. eLife

    Reviewer #2 (Public Review):

    Han, Kozanli et al. set out to analyse the introductions of SARS-CoV-2 variants of concern (VOC) in the face of targeted flight restrictions. The authors find, in line with prior observations and common wisdom, that targeted flight restrictions are not effective at preventing the introductions of new lineages. Han, Kozanli et al. then draw their attention to the diffusion of SARS-CoV-2 VOCs Alpha and Delta within the Netherlands, finding that more populous regions are more likely to serve as points of introduction and thus fuel the growth and dissemination of viral lineages in-country. The authors draw attention to the lifting of restrictions within the Netherlands, particularly noting the rise in cases in younger age groups following it and linking this surge to the opening of nightclubs. By estimating the growth rates of Alpha and Delta variants within the Netherlands (including growth rate estimates split by age) the authors confirm known differences in VOC transmissibility and the added effect of (presumably behavioural) different behaviours of each age group.

  6. eLife

    Reviewer #3 (Public Review):

    Han et al. present important insights into the effect of interventions on the regional importation and within-country spread of SARS-CoV-2 variants. The authors combine phylogenetic and epidemiological approaches to study the introductions and spread of SARS-CoV-2 variants in The Netherlands. The manuscript is clear, concise, and well-written.

    1. The main focus of the study is on the effect of international travel restrictions, but these restrictions are not well defined. Moreover, the effect of travel restrictions cannot be distinguished from other restrictions and interventions that were enforced. It seems more appropriate to focus the paper on the effect of collective interventions on SARS-CoV-2 introductions and spread, rather than focusing on international travel restrictions.

    2. Most introductions originated from other European countries and it would be valuable to perform a more in-depth analysis at the country level to understand patterns of introductions within Europe.

    3. The authors conclude that robust surveillance in regions of early spread is important for variant detection and outbreak control. Given the retrospective nature of this study (the studied variants have mostly disappeared after the emergence of omicron), it would be good to further discuss how future outbreak control can be achieved in a timely manner.

  7. ScreenIT

    SciScore for 10.1101/2022.03.21.22272611: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All sequences were aligned to hCoV-19/Wuhan/WIV04/2019 (WIV-04; EPI_ISL_402124) using MAFFT v7.42733.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    Assessment of convergence (effective sample size > 200) was performed using Tracer v1.7139.
    Tracer
    suggested: (Tracer, RRID:SCR_019121)
    To understand within-country source-sink dynamics during early introductions and proliferation patterns during later periods, we used BEAST v.
    BEAST
    suggested: (BEAST, RRID:SCR_010228)
    Using these sequences, we then reconstructed approximate ML phylogenies using FastTree v2.1.1142.
    FastTree
    suggested: (FastTree, RRID:SCR_015501)
    Similarly, we reconstructed an ML phylogenetic tree under the HKY+G nucleotide substitution model using IQ-TREE after removing any molecular clock outlying sequences identified by treetime.
    IQ-TREE
    suggested: (IQ-TREE, RRID:SCR_017254)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  8. Version published to 10.1101/2022.03.21.22272611v1 on medRxiv