National Reference Centres, sentinels guarding against pathogens

With Muhamed-Kheir Taha, Head of the Invasive Bacterial infections Unit and the National Reference Center (CNR) for Meningococci and Haemophilus Influenzae, a designated WHO Collaborating Center for bacterial meningitis

While National Reference Center (CNR) status can only be acquired once scientific expertise has been proven in a specific field, it is nevertheless clear that this expertise develops through "real world" contact with the pathogens targeted by CNRs.

Through its research on the biology of living organisms, the Institut Pasteur works with known microorganisms, which provide genuine test tube models. Alongside the research units, the CNRs monitor and analyze circulating pathogens on a daily basis. This work tests our hard-won knowledge, significantly increasing its reliability and validity by confronting it with an enormously diverse range of pathogen-patient pairings.

The CNRs derive crucial knowledge from this mutual enrichment between basic research and public health. As such, the Institut Pasteur's involvement in 19 of around 40 CNRs operating in France is an undeniable strength, enabling it to advance research and protect public health. CNRs play a key role in health crises. This role as sentinels reflects a specific view of our value.

From its inception, the Institut Pasteur played a major role in public health as a dispensary for rabies treatment as well as a research center for infectious diseases. This role now finds its direct expression in the CNRs' activities. They reflect recognition of our scientific expertise and ability to collaborate within the epidemiological surveillance ecosystem. In recent years, the CNRs have become bona fide decision-making tools for the public authorities, extending their role as sentinels to become key stakeholders in a coordinated response to pathogenic threats.

As recognized by the scientific community and public, the CNRs continue to prove their worth by responding early to emerging health crises and helping to prevent many others. We can only be proud of contributing to their success and thus continuing to pursue the Institut Pasteur's original mission.

The CNRs' missions

• concerning the microbiology and pathology of infectious agents, the development, optimization, validation and distribution of medical biology examinations; the identification and confirmation of pathogens;
• Scientific or technical advice in response to any request from the French Health Minister, Santé publique France (SpF) and health professionals;
• The contribution to epidemiological surveillance:

-by leading a network of laboratories responsible for handling examinations and subsequently transmitting results,

- by carrying out the analyses necessary for the monitoring of pathogens

• Immediately alerting Santé publique France, the French Ministry of Health, and, where applicable, the Regional Health Agency to any finding likely to present a risk or threat to public health.

Salmonella

2017 salmonella alert: how Institut Pasteur has raised the alarm

 

Operation and remit

CNRs are appointed for a five-year period by the French Ministry of Health on the basis of proposals from Santé publique France following an assessment of applications by a committee of experts. Specifications are drawn up setting out specific missions for each CNR. To conduct certain missions, a CNR can rely on one or more laboratories (no more than three) known as "associated laboratories." To ensure their missions are performed optimally, CNRs are involved in numerous national and international collaborations, particularly with public and private medical test laboratories, physicians from the "Sentinelles" network, Santé publique France for epidemiological surveys, health authority departments, research laboratories and organizations (Inserm, CNRS, Anses, Ifremer, etc.) and industrial laboratories. Most CNRs are also members of European networks (including the European Centre for Disease Prevention and Control – ECDC) or international networks (the World Health Organization (WHO) – see below).

The Institut Pasteur hosts 19 laboratories (13 coordinating and 6 associated laboratories). These monitor the following 17 pathogens:

Viruses

• Respiratory infection viruses including influenza and SARS-CoV-2
• Rabies virus
• Viruses causing hemorrhagic fevers such as Lassa and Ebola
• Hantaviruses spread by rodents
• Arboviruses (see article at the end of this special feature)
• Enteroviruses and parechoviruses, particularly those causing poliomyelitis

Bacteria

• The genus Clostridium including the bacterium causing botulism
• The genus Yersinia including the plague bacillus
• The genus Corynebacterium including the bacterium causing diphtheria
• The genera Shigella, Salmonella and Escherichia coli responsible for foodborne infections
• The genus Leptospira that can cause kidney failure
• The genus Listeria including "refrigerator bacteria" that cause listeriosis
• Meningococci and Haemophilus influenzae, which cause meningitis
• Vibrios including the cholera agent
• The genus Bordetella including the whooping cough bacillus

Fungi

• Candida, aspergillus, cryptococcus and other invasive mycoses

Parasites

• The genus Plasmodium that causes malaria

With François-Xavier Weill, Director of the CNR for Escherichia coli, Shigella and Salmonella

Prologue

CNRs play a pivotal role in a well-established system governing the surveillance of pathogens. What is the process for switching from sentinel to alert status? Here is a close look at one potential scenario…

Step 1: the threat

Cases of infection with a pathogen that is under surveillance are reported in various parts of the country. These have been identified by both hospital-based and non-hospital-based medical test laboratories that have diagnosed one or more patients. Two scenarios:

• either the disease in question is designated as notifiable (there were 36 such diseases in 2022), in which case any samples taken from patients are sent to the dedicated CNR for analysis of the responsible strains;
• or it is not designated as a notifiable disease but strains are submitted for microbiological surveillance and may be sent to the CNR for characterization and typing to identify the source of an infection or detect a chain of infection.

Step 2: expert assessment

Any samples received are identified using advanced technologies (genome sequencing since 2017) to precisely type the exact strain of the responsible pathogen. This microbiological work involves comparing the sampled pathogen with a genome database to determine other genetically related strains and thus trace the outbreak's origins. The results of these analyses are then passed on to Santé publique France, so it can assess the epidemiological situation. This is done in real time for notifiable diseases and at regular intervals for other diseases. For foodborne infections, any samples taken from potentially contaminated food or subject to systematic surveillance are passed on to the CNR for comparison of strains taken from clinical samples with strains taken from food samples in an attempt to identify the source of contamination.

Step 3: the alert

In most cases, the identified pathogen is known. Sometimes, a new strain or variant is identified, adding to knowledge of the associated disease. An alert is issued once the situation exceeds known parameters for normal circulation. This occurs in cases where a new, more aggressive and/or more communicable and/or more antibiotic-resistant strain is identified. Sometimes, case numbers rise quickly or their geographic concentration suggests a common source of infection. All situations are closely monitored to prevent a potential outbreak. The CNR teams immediately alert Santé publique France, which may decide to expedite an epidemiological survey to ascertain the source of contamination. Other institutional stakeholders may also become involved depending on the pathogen type. These include the general directorates of ministries (of agriculture/food, health, the economy, etc.) if the investigation relates to a foodborne infection.

Step 4: monitoring and advice

Once the alert has been issued, the CNRs continue their work in two parallel areas. The first involves monitoring the development of the emergence with enhanced case tracking to map the circulation of the responsible strain. The second involves supporting the public health authorities with insights on how to respond to the alert, for example by recommending the most appropriate diagnostic testing methods for the identified strain.

Epilogue

The outbreak has been contained, its source identified, and measures taken to prevent its resurgence. However, the CNR's role as a sentinel does not stop there. It continues to monitor circulating pathogens and keeps records of this latest alert, which constitute a vital tool for quickly identifying any future re-emergences of infection. Some CNRs store all the strains they receive over periods spanning decades (for example, the CNR for Escherichia coli, Shigella and Salmonella has retained hundreds of thousands of strains since 1947). This valuable knowledge supports the work of research units, shedding light on pathogens' genetic diversity and evolution over time. Some CNRs also conduct cohort tracking surveys, which involve monitoring a defined population over time to study the incidence of health events in order to improve our understanding of diseases.