Since 2022, the response to COVID-19 pandemic gradually abandoned the domain of crisis management and is becoming part of the routine surveillance activities. With this optic, the surveillance systems implemented during the crisis (comprised the SARS-CoV-2 variant surveillance systems) must be integrated within the existent structures and be prepared for future emergencies, adapting them to other pathogens.
Funding
In April 2022, the European Commission, via their executive agency HaDEA, invited the countries that had previously been financed via the HERA incubator (France among them) to submit a project to their call for proposals EU4Health. This new call had as main objective to consolidate the whole-genome sequencing and RT-PCR activities in countries having benefited from financing in 2021, in order to ensure the sustainability of their capacities and the integration of the developed infrastructures into the epidemic surveillance and investigation systems, in synergy with the ongoing efforts taking place at an international scale. The activities financed by this project must allow to reinforce capacity-building in the involved countries outside of a crisis context and be extended to other pathogens other than SARS-CoV-2.
Objectives of the project: SEQ4EPI, pathogen sequencing for epidemiology
The SEQ4EPI project, carried by Santé Publique France and the National Reference Centre for Respiratory Infections, aims to support the sustainability of the genomic surveillance systems built during the pandemic and prepare them for future crisis, reinforcing the genomic surveillance activities in different dimensions (extension to other pathogens, development of genomic analysis tools, reinforcement of the epidemiological analysis capacities) during a period of 3 years (01/01/2022 – 30/09/2025). The objectives of SEQ4EPI are structured in two different time horizons:
- Between 2022 and 2024, the sustainability of the SARS-CoV-2 genomic surveillance and its integration in the routine activities.
- Between 2023 and 2025, the extension of the existing systems that were implemented for SARS-CoV-2 to other pathogens with strong emergence potential. 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.
Conducted activities as of 31 march 2024
The SEQ4EPI project is included in a larger framework of the EMERGEN consortium activities. If EMERGEN goes beyond 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 main data source for SARS-CoV-2 genomic surveillance and the project staff needs to ensure its maintenance.
The first objective of the SEQ4EPI project was to strengthen existing genomic surveillance (concerning SARS-CoV-2) by reinforcing Santé publique France’s activities. The goal is to progressively expand them to other emergence-prone pathogens. A large survey was developed and sent out to all NRL in order to better understand of their sequencing activities, their methods/tools supporting them and their needs depending on the pathogens they work with.
We have produced several documents with the aim of adapting SARS-CoV-2 sequencing strategy to the evolution of the surveillance such as a detailed note exploring sampling strategies for an efficient SARS-CoV-2 variant monitoring. Since then, its recommendations have been implemented. More work is ongoing between the NRL for Respiratory Viruses and Santé publique France to continue this transition from emergency COVID-19 response to routine surveillance. The output of SARS-CoV-2 genomic surveillance was included in the evolution from a COVID-19 specific surveillance to an integrated acute respiratory illness (ARI) surveillance, with the publication of 35 COVID-19 specific bulletins and then 26 ARI bulletins since the beginning of the project in October 2022.
Regarding the EMERGEN-DB bioinformatics platform, a unit dedicated to its management and extension is being created at INSERM to ensure the sustainability of the EMERGEN-DB database. This database is essential to SEQ4EPI activities. Santé publique France is monitoring closely the transfer of the database to this newly created unit to ensure 1) that there will be no disruptions impacting Santé publique France capacity to access these data and 2) that the unit will remain adapted to the needs of public health actors such as Santé publique France, NRLs and ANSES.
The SEQ4EPI project is part of a larger work on the post-pandemic sustainability of the EMERGEN consortium. A new consortium agreement for EMERGEN 2.0 is being developed. Discussions with ANSES have been initiated to strengthen the One Health aspects of EMERGEN. Within the SUM’EAU project of SARS-CoV-2 monitoring in wastewater, a working group on waste water sequencing was created.
The second objective of the SEQ4EPI project is to define and implement analysis tools to better monitor viral epidemics, for SARS-CoV-2 and other viruses, based on bio-informatics, phylogenetics and phylodynamics techniques.
The NRL for Respiratory Viruses has developed a framework for early detection of SARS-CoV-2 variants that may cause detection issues. It is routinely used and will be continuously improved. More particularly, this framework aims to ensure the constant reliability of detection tools (RT-qPCR) and consists in 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 global impact of current mutations on each primer/probe, by viral lineage. The follow-up work is ongoing to broaden the scope of the framework to 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 indications) and metadata (geography, sampling dates, etc.) to reconstruct putative local transmission chains. Genomic and phylogenetic data are also used in an under-development framework aiming at inferring epidemiological parameters (reproductive number). It is based on common phylodynamic models and tools (e.g. Beast).
The third SEQ4EPI objective is to keep the necessary human resources (Santé publique France epidemiologists) at the national and regional level for signal investigation, laboratory network animation and risk analysis. Over the first 18 months of the project, activities evolved from a majority of day-to-day surveillance work, with a high workload at both regional and national offices, to more time dedicated to prospective activities.
Epidemiologists at national and regional levels conducted routine activities on SARS-CoV-2 variants, including :
- organizing surveillance strategy with weekly Flash investigations,
- feedback of laboratories with 137 regional EMERGEN Newsletter sent out,
- monitoring surveillance data and identifying signals
- communicating results with weekly epidemiological bulletin and 18 monthly risk analyses. A working group designed a new format for variant risk analyses and this template has been used since March 2024.
Targeted investigations of variant BA.2.86 were started in august 2023 in order to assess its characteristics and public health impact. Over 200 cases were reported to regional epidemiologists and 147 of them were investigated with a standardized questionnaire. Results were published in the risk analysis of 11/12/2023 and included in a publication that is being finalized.