SEQ4EPI project
EU4Health Call for Proposals (European Commission): Direct grants to Member State authorities: Strengthening national infrastructures and capacities for whole genome sequencing (WGS) and/or reverse transcription polymerase chain reaction (RT-PCR) to respond to the COVID-19 pandemic and future health threats.
Since 2022, the response to the COVID-19 pandemic has gradually moved beyond the realm of crisis management and is becoming part of routine surveillance activities. With this in mind, the surveillance systems implemented during the crisis (including those for monitoring SARS-CoV-2 variants) must be integrated into existing structures and prepared for future emergencies, adapting them to other pathogens.
Funding
In April 2022, the European Commission, through its executive agency HaDEA, invited countries that had previously received funding through the HERA incubator (including France) to submit a project in response to its EU4Health call for proposals. The main objective of this new call was to consolidate whole-genome sequencing and RT-PCR activities in countries that received funding in 2021, in order to ensure the sustainability of their capacities and the integration of the developed infrastructures into epidemic surveillance and investigation systems, in synergy with ongoing international efforts. The activities funded by this project must enable capacity-building in the participating countries outside of a crisis context and be extended to pathogens other than SARS-CoV-2.
Project Objectives: SEQ4EPI, Pathogen Sequencing for Epidemiology
The SEQ4EPI project, led by Santé Publique France and the National Reference Center for Respiratory Infections, aims to support the sustainability of the genomic surveillance systems established during the pandemic and prepare them for future crises, strengthening genomic surveillance activities in various areas (expansion to other pathogens, development of genomic analysis tools, and enhancement of epidemiological analysis capabilities) over a three-year period (January 1, 2022 – 09/30/2025). The objectives of SEQ4EPI are structured across two distinct time frames:
Between 2022 and 2024, ensuring the sustainability of SARS-CoV-2 genomic surveillance and its integration into routine activities.
Between 2023 and 2025, the extension of the existing systems implemented for SARS-CoV-2 to other pathogens with high potential for emergence. This extension will begin with other respiratory viruses (influenza, RSV) but will not be limited to them.
The activities planned in the SEQ4EPI project aim to:
Strengthen the coordination activities of Santé publique France to consolidate the existing genomic surveillance activities established for SARS-CoV-2 and gradually expand them to other emerging pathogens, including other respiratory viruses.
Define and implement analytical tools to better monitor viral epidemics, for SARS-CoV-2 and other viruses, based on bioinformatics, phylogenetic, and phylodynamic techniques.
Maintain a team of epidemiologists at the national and regional levels for signal investigation, laboratory network coordination, and risk analysis.
Activities conducted as of March 31, 2024
The SEQ4EPI project is part of the broader framework of the EMERGEN consortium’s activities. While EMERGEN encompasses more than SEQ4EPI—which focuses on public health and surveillance activities—the coordination of this consortium is essential to the success of SEQ4EPI. For example, the EMERGEN database is the primary data source for SARS-CoV-2 genomic surveillance, and the project staff must ensure its maintenance.
The primary objective of the SEQ4EPI project was to strengthen existing genomic surveillance (for SARS-CoV-2) by bolstering Santé publique France’s activities. The goal is to gradually expand these activities to other pathogens prone to emerging. A comprehensive survey was developed and distributed to all National Reference Laboratories (NRLs) to better understand their sequencing activities, the methods and tools they use, and their needs based on the pathogens they work with.
We have produced several documents aimed at adapting the SARS-CoV-2 sequencing strategy to the evolution of surveillance, such as a detailed note exploring sampling strategies for efficient monitoring of SARS-CoV-2 variants. Since then, its recommendations have been implemented. Further work is ongoing between the NRL for Respiratory Viruses and Santé publique France to continue this transition from the emergency COVID-19 response to routine surveillance. The output of SARS-CoV-2 genomic surveillance was incorporated into the shift from COVID-19-specific surveillance to integrated acute respiratory illness (ARI) surveillance, with the publication of 35 COVID-19-specific bulletins and subsequently 26 ARI bulletins since the project’s inception in October 2022.
Regarding the EMERGEN-DB bioinformatics platform, a unit dedicated to its management and expansion is being established at INSERM to ensure the sustainability of the EMERGEN-DB database. This database is essential to SEQ4EPI activities. Santé publique France is closely monitoring the transfer of the database to this newly created unit to ensure 1) that there will be no disruptions affecting Santé publique France’s ability to access these data and 2) that the unit will remain aligned with the needs of public health stakeholders such as Santé publique France, NRLs, and ANSES.
The SEQ4EPI project is part of a broader effort to ensure the post-pandemic sustainability of the EMERGEN consortium. A new consortium agreement for EMERGEN 2.0 is currently being developed. Discussions with ANSES have begun to strengthen the One Health aspects of EMERGEN. Within the SUM’EAU project on SARS-CoV-2 monitoring in wastewater, a working group on wastewater sequencing has been established.
The second objective of the SEQ4EPI project is to define and implement analytical tools to better monitor viral epidemics—including those caused by SARS-CoV-2 and other viruses—using bioinformatics, phylogenetics, and phylodynamics techniques.
The NRL for Respiratory Viruses has developed a framework for the early detection of SARS-CoV-2 variants that may cause detection issues. It is routinely used and will be continuously improved. More specifically, this framework aims to ensure the consistent reliability of detection tools (RT-qPCR) and consists of bioinformatics methods that monitor the emergence of mutations in viral genomes that may affect the stability of the binding of these primers and probes, which is crucial for virus detection. To do so, it compares the sequences of the RT-qPCR primers and probes with the currently circulating virus genomes and defines a scoring scheme based on the positions of mutations on the primers/probes. This scoring scheme is then used to assess the overall impact of current mutations on each primer/probe, by viral lineage. Follow-up work is ongoing to expand the scope of the framework to address sequencing issues (sequencing primers rather than RT-qPCR primers/probes). Both tools are freely available at https://gitlab.pasteur.fr/cnrvir/projects/seq4epi.
In parallel, the NRL for Respiratory Viruses is developing a pipeline to detect and investigate potential clusters of SARS-CoV-2. This framework is based on the analysis of a combination of phylogenetic data (leveraging genomic information) and metadata (geography, sampling dates, etc.) to reconstruct putative local transmission chains. Genomic and phylogenetic data are also used in a framework currently under development aimed at inferring epidemiological parameters (reproduction number). It is based on common phylodynamic models and tools (e.g., Beast).
The third SEQ4EPI objective is to maintain the necessary human resources (epidemiologists from Santé publique France) at the national and regional levels for signal investigation, coordination of the laboratory network, and risk analysis. Over the first 18 months of the project, activities shifted from primarily day-to-day surveillance work—which entailed a heavy workload at both regional and national offices—to a greater focus on prospective activities.
Epidemiologists at the national and regional levels conducted routine activities related to SARS-CoV-2 variants, including:
organizing surveillance strategies with weekly Flash investigations,
providing feedback to laboratories through 137 regional EMERGEN newsletters sent out,
monitoring surveillance data and identifying signals
communicating results through weekly epidemiological bulletins and 18 monthly risk analyses. A working group designed a new format for variant risk analyses, and this template has been in use since March 2024.
Targeted investigations of the BA.2.86 variant began in August 2023 to assess its characteristics and public health impact. Over 200 cases were reported to regional epidemiologists, and 147 of them were investigated using a standardized questionnaire. The results were published in the risk analysis dated December 11, 2023, and included in a publication currently being finalized.
