The ICAReB Platform: A Human Biobank for the Institut Pasteur and Beyond

Philippe Esterre, Amina Ait-Saadi, Laurence Arowas, Sophie Chaouche, Nicole CorreCatelin, Christine Fanaud, Hélène Laude, Vesna Mellon, Valérie Monceaux, Gloria Morizot, Imène Najjar, Catherine Ottone, Blanca Liliana Perlaza, Blandine Rimbault, Linda Sangari and Marie-Noëlle Ungeheuer ICAReB platform (Investigation Clinique et Accès aux Ressources Biologiques/Clinical Investigation and Access to Research Bioresources) of the CTS (Center for Translational Science), and of CRBIP (Biological Resources Center of the Institut Pasteur), Institut Pasteur, 25-28 rue du Docteur Paris Cedex, FR


Project description
The ICAReB platform has been established in 2008 to provide for access of pasteurian research teams and beyond, to high-quality human bio-resources. Its main fields of interest are infectious diseases, immunology and more recently neurosciences. Two activities were developped, hence its name ICAReB, both certified following the ISO 9001 and NF S96-900 standards, respectively. More than 134,000 samples and their associated bio-clinical data (including vaccination status, ethnicity, medical history such as chronic inflammatory diseases and allergies) are currently collected, as well as environmental factors (lifestyle, international travels, microbial environment, dietary habits, exposition to stress and pollutants …) The Diagmicoll main cohort (Clinical trials reference: NTC03912246) affords bio-resources from healthy subjects primarily, for the National Reference Centers, so as to optimize and develop new diagnostic methods [1,3,4,5,8,10,13,20,21,28]. The CoSImmGEn cohort (Clinical trials reference: NTC03925272) has been set up to take in charge more complex needs such as longitudinal studies of the immune system and other integrative (e.g. metabolic/endocrine and neuro-cognitive) systems, encompassing their genetic and environmental determining factors [11,14,18,22,23,25,27,33,34,35,36,37].

Context Spatial coverage
The healthy volunteers cohorts (Diagmicoll & CoSImmGEn) mostly originate from the regional (Ile-de-France) population:

Steps Investigation methods
The main asset of our platform is represented by two large volunteers' cohorts. The healthy individuals are recruited during ambulatory clinical consultations organized at the ICAReB platform by our staff. Those volunteers actively participate in research protocols on human beings (including pathophysiology, immunology, genetics, epide-miology…), and their samples and associated data presently compose the biorepository available for research purposes. The Diagmicoll cohort includes approximatively 250 volunteers in the active file whereas the CoSImmGEn cohort is comprised of around 180 volunteers regularly followed up, from which genetic and environmental data are available.
Besides the recurrent work with pasteurian teams, ICAReB also builds partnerships with numerous external public and private institutions (research teams, hospitalbased staffs and clinical investigation centres, other bioresources centres, and companies) and is also developing a collaborative framework with European and international organizations. ICAReB is an active member of the French (membership number BB-0033-00062, see specific website: http://www.biobanques.eu/en/professional) and European (BBMRI under reference AO 203, website www. bbmri.eu) biobank networks.

Sample management
All the laboratory methods are based on standard operating procedures (SOP) and guidelines established within a quality management policy organized at the scale of the Centre de Ressources Biologiques de l'Institut Pasteur (CRBIP) structure, with a full access to the latest up-todate documents. The individual data records are pseudoanonymized according to the European (GDPR directive) and French (CNIL) laws in order to protect the participants' privacy. Sample quality controls are regularly performed following a biospecimen research schedule [8,18,23].

Data management
The ICAReB platform uses a BRC-dedicated LIMS for the bioresources management (MBioLIMS, ModulBio, Marseille France). In addition, in-house bioclinical databases have been constructed within a pre-formated, web-based framework (Voozano, Epiconcept company, Paris). More recently we have introduced an alternative web-based framework (RedCap, Vanderbuilt university, Nashville, USA) hosted by the informatic center, IP. Only authorized staff members can manage the bioresources, samples and data.

Stabilization/preservation
The following methods and containers are used for the collection and conservation of biological samples: -Tubes with Z serum clot activator for the collection of serum -DTA (ethylene diamine tetra acetic acid), hirudin, lithium-or sodium-heparin and sodium citrate tubes -DMSO (dimethyl sulfoxide) or PBS tubes for storage of plasma or peripheral blood mononuclear cells (PBMC), after Ficoll purification -Whole blood, in DMSO medium before freezing -Red blood cells packs, after Ficoll centrifugation -Paxgen blood DNA tubes and RNA tubes for storage of DNA and RNA -Empty tubes for the collection of urines -Swabs (with and without glycerolor physiologic serum-based conservatives possibly on nitrocellulose trips) for the collection of nasopharyngeal samples, tears (Whatman 41 strips, Schirmer Plus, GECIS, France) and saliva. -Glycerol-or physiologic serum based liquids, in addition to empty tubes, for the storage of stools. Ethanolfixed stool smears.
All the samples are stored in barcoded tubes. The storage systems are equipped with alarm systems and monitored 24/7 throughout the year.

Type of long-term preservation
Freezing of aliquots is made in manual freezers (-80°C) or liquid nitrogen cryo tanks.
A new room-temperature storage method (Imagene, Genopole campus, Evry, France) using laser-seal capsules (DNA shells® and RNA shells®, for DNA and RNA, respectively) is currently used for long-term preservation, after being tested in the context of a pilot study.

Storage temperature
The storage temperature (-196°C liquid nitrogen, -80°C, and room temperature) depends on material type and research project criteria.

Shipping temperature from patient/source to preservation
For the Diagmicoll and the CoSImmGEn cohorts, the sampling is directly managed at the ICAReB platform. For others cohorts, the storage temperature depends on material type and research criteria.

Shipping temperature from storage to research use
The shipping temperature (-80°C (on dry ice), -20°C (on ice), +4°C or room temperature) depends on material type and research criteria.

Quality assurance measures
Being a doubly affiliated entity (to CTS for clinical investigation activity and to CRBIP for biobanking), the platform is doubly certified: following the ISO 9001:2015 and the NF S96-900 (French norm) standard, respectively.

Source of associated data
For healthy volunteers on on hand, the associated data are obtained at the first inclusion visit and include: complete medical history, vaccination certificates and possible medical or laboratory records. In addition, some questionnaires may be used to meet the specific research projects criteria (for example: lifestyle, depression scale, cognitive status …).
Associated data may also originate form care entities, when patients are recruited outside the Institut Pasteur.

Ethics statement
All research projects have previously received both institutional and external -so-called Comité de Protection des Personnes -ethical committee approval, some of them going in addition through an institional review board (IRB) agreement.
ICAReB works in conformity with the ethical guide- Following the present European guidelines for Responsible Research and Innovation, the ICAReB platform is organizing an on-going, two-way communication process at all steps, i.e. during and after the research studies themselves [9,16]. Recent colloquia in 2016, 2018 and 2020, in the IP historical amphitheater, allowed the meeting of healthy volunteers, patients, physicians and researchers (see at the bottom of our homepage). This initiative is interpreted as an observational investigation on volunteers/patients-centered health interaction project [32], which is unique in this academic context.

Bioresource name
Clinical investigation and Access to Research Bioresources platform, Institut Pasteur.

Bioresource location
The bioresources are located in dedicated rooms on the site the Institut Pasteur, Paris, France (see https://www. pasteur.fr/en). This research institute is a non-profit private institution, managing an interface with 32 institutes (the so-called International Network of Pasteur Institutes).

Bioresource type
ICAReB is an Infectiology, Immunology and Genetic biobank, located within an international research campus (Institut Pasteur, Paris, France).

Type of sampling
As a central research infrastructure, ICAReB is implicated in many research projects requiring high quality samples for their experiments. Most of the samples (134,211 on 2018, December report) are collected within the platform during a succession of follow-up visits as long as accepted by the healthy volunteers. 28,742 aliquots are available (end of 2018) from the Diagmicoll or CoSImmGEn cohorts, the later comprising in addition genetic and environmental criteria.
In parallel, disease-based cohorts are recruited and bioresources collected in accordance with various research projects (for example, one on Hidradenitis suppurativa [6], one on Listeria infection -associated pathologies [30] and the WHO Human African Trypanosomiasis specimen biobank [7].

Disease status of patients/source
Hidradenitis suppurativa (the patients from the Verneuil's disease cohort, followed at the neighboring medical center of the IP, come France but also from all over the world).
Listeria -associated pathologies (foeto-maternal infection, neurologic form, septicemia): the patients from this multicenter observational national study on listeriosis and Listeria (MONALISA and ListeriaGEN cohorts) come from a national hospital recruitment.
For Trypanosoma gambiense or T. rhodesiense African trypanosomiasis (WHO HAT specimen bank), the patients have been recruited from 13 centers and 6 affected African countries (Chad, Democratic republic of Congo, Guinea, Malawi, Tanzania and Uganda).
Borrelia burgdorferi and other as yet undefined tickborne pathogens (OHTICKS): the patients are recruited in 3 main regions in France: Auvergne, Franche-Comté and Ile-de-France.
Patients with infectious diseases of unknown etiology come from all over France and occasionnaly from abroad (Pathodisc/PATHO-HTS).

Clinical characteristics of patients
Inclusion criteria, stage of the disease, evolution and treatment informations are collected depending on the project specifications

Size of the bioresource
ICAReB is a Institut Pasteur-associated infrastructure with no expiry date. The number of full time employees presently working is 11.

Access criteria
ICAReB can provide bioresources from healthy volunteers (DIAGMICOLL and CoSImmGEn cohorts) to researchers worldwide, both from academic or private organisms. Inquiry forms can be obtained from its website or directly (demandeRBH@pasteur.fr), leading to an interactive process the approval after evaluation by the scientific committee of the biobank (CoSciB) if no previous scientific evaluation has been performed. In this case, a reply can take about 3 weeks.

(4) Reuse potential
As multiple aliquots are obtained from a single sample, the re-use is possible providing that the respective donors have given their informed consent to the re-use. Moreover, if necessary, consent for new specific research projects may be sought for from still active or connected healthy volunteers.