Setup of the first facility in the pilot phase

The foundation for the BioHub Facility was laid with the signing of a Memorandum of Understanding (MoU) between WHO and Switzerland on 24 May 2021. The MoU generally describes the concept and the roles and responsibilities of the parties involved. Later in October 2021, the Terms of Reference (ToR) between Spiez Laboratory and WHO were signed. The ToR further define the provisions set out in the MoU and clearly define the deliverables, which are essential to receive, store, grow, sequence and prepare BMEPPs for distribution to qualified entities. In addition, standard operating procedures (SOPs) for the defined tasks needed to be developed. Standard Material Transfer Agreements (SMTAs) 1 and 2 were drafted with input from Member States (figure 1). These SMTAs are the basis on which the BMEPPs are shared with the BioHub (SMTA 1) or obtained from the BioHub (SMTA 2) during the pilot phase. All relevant information on the BMEPPs is specified in the respective Annex 2 to the SMTAs. For the pilot phase, the WHO BioHub System is testing the sharing of SARS-CoV-2 variants only. As the SMTAs for sharing and obtaining BMEPPs contain generic provisions, once they are signed, there is no need to resign these agreements for future requests. Only signing of the Annex 2 of the corresponding SMTA is needed for each further operation. From the Swiss Confederation, consultations on these documents were supported by the Federal Office of Public Health and the Federal Institute of Intellectual Property. While this was a lengthy process, we expect that future facilities can benefit from the already existing documents, as these can be directly adopted or slightly adapted to different countries and their respective regulations.

After initial process testing and refinement of internal procedures, first samples were received on 9 December 2021, processed and the first transfer from the laboratory departed on 23 December 2021 (figure 1B).

Organisation of the WHO BioHub System

The WHO BioHub System is divided in two parts. The WHO BioHub Operations is located at WHO and is in charge of the coordination of the BioHub System. The BioHub Facility (located at Spiez Laboratory) on the other hand is responsible for the processing, storing and preparing the BMEPPs for distribution. Once a BMEPP is detected, national public health authorities can contact WHO BioHub Operations, where it will be assessed if the offered BMEPP is of sufficient importance to be included into the WHO BioHub System (figure 2A, step 1). Subsequently, coordination of the information exchange between the three parties BioHub Operations, BioHub Facility and providing institution is initiated (figure 2A, step 1). The director of the providing laboratory (or authorised government officials) must then sign the SMTA 1, which will be countersigned by BioHub Operations and the BioHub Facility (figure 2A, step 2), following execution of the SMTA 1 the transport is initiated by BioHub Operations using a courier company, however, all nationally relevant paperwork for customs and export of infectious material has to be obtained by the sending institution (figure 2A, step 3). International transport is facilitated through BioHub Operations. In the BioHub Facility, BMEPPs are characterised and prepared for further sharing. A qualified entity, that is, a laboratory meeting all relevant requirements defined by WHO, can then request a sample that is part of the collection of the BioHub Facility (figure 2A, step 11).9 The receiving laboratory must sign SMTA 2 (countersigned by BioHub Operations), fill in a biosafety and biosecurity checklist and obtain all applicable nationally relevant permits and then the sample(s) can be sent.

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Figure 2

(A) Workflow of WHO BioHub processes at Spiez Laboratory. (B) The BSL-3 laboratory at Spiez Laboratory. During the pilot phase, only SARS-CoV-2 is transferred between laboratories within the framework of the WHO BioHub System. (C) Spiez Laboratory’s BSL-4 laboratory. A future epidemic or pandemic pathogen might only be handled in laboratories of the highest biological safety level.

The Workflow at the WHO BioHub Facility

To maintain high standards for the distribution of BMEPPs to qualified entities, we developed a series of SOPs which regulate the individual steps. If a pathogen is deemed relevant for inclusion, the BioHub Facility, the provider and BioHub Operations agree on sample type, their number and a delivery date. SMTA 1 needs to be signed, transport organised and transport documentation prepared. Once all documents are approved, the samples are shipped, which takes between 1 and 5 days, depending on customs control as well as availability of transport (figure 2A, step 3). Furthermore, the temperature is recorded during transport and on arrival the samples are stored at −80°C (figure 2A, steps 3 and 4). Samples are transferred to the containment laboratory and BMEPPs are cultured on different cell culture systems to ensure optimal growth conditions. One part of the sample is directly processed for whole genome sequencing. Virus replication is determined by assessing the cytopathic effect and by quantitative PCR (figure 2A, steps 5 and 6). After successful propagation, cultures are harvested, aliquoted and stored at −80°C until shipment (figure 2A, step 7). The integrity of the stored samples is verified again by whole genome sequencing and viral titre is determined by TCID50. Additionally, the samples are examined for contamination (figure 2A, step 8). The genome sequence is checked for mutations with respect to the original material received (figure 2A, step 9). The genome sequence is uploaded to a public database (eg, GISAID, GenBank) and sent to WHO, where the data is recorded on an internal database and subsequently made available for interested entities (figure 2A, step 10).10 Institutes can find information on the available BMEPPs online and request a sample from the BioHub. BioHub Operations reviews if the requesting institute is qualified for the reception of the material and once the necessary SMTA 2 is signed, the transport has to be organised by the BioHub Facility in concordance with BioHub Operations, the courier company and the receiving institution before samples can be sent (figure 2A, steps 11, 12).

The many different steps in the process require different skills and close interaction between the involved individuals of the BioHub Facility and BioHub Operations, hence the maximum number of samples that can be processed in the laboratory needs to be determined and the following questions need to be answered critically. How many samples can be received and sent per week? How many samples can be processed in the laboratory? How much of which reagents need to be on stock (in emergency situations the supply chain can be strained)? Are there enough trained staff (for enhanced/maximum containment; sequencing; data analysis, etc)? And how many different BMEPPs can be stored at the facility? Is the storage system robust?

Furthermore, the involved stakeholders require frequent and efficient coordination, mainly between the BioHub Facility and WHO, but also with any provider or recipient of material.

Laboratory requirements for hosting a BioHub Facility

The laboratory must have permission to cultivate BMEPPs under biosafety level 3 and/or 4 (figure 2B,C). From a practical point of view, it is recommended to propagate the received BMEPPs with different cell culture systems, to increase the chance of an effective isolation of the BMEPP, in particular when only clinical specimens are available. To limit the acquisition of mutations, preferably only one passage on cell culture is performed if the titres are reasonably high. However, to obtain higher yields a second passage on cell culture might be required. To adequately characterise the virus and to ensure fast and high-quality sequencing data, laboratories should be equipped with the necessary sample preparation and sequencing equipment. In addition, computational and bioinformatics resources, with respect to both, equipment and personnel, are necessary to assemble and provide genomic information.

Experience in handling a variety of high-consequence pathogens is essential to rapidly adapt to changing needs. A BioHub Facility should be able to respond to developments in global health swiftly, that is, have the necessary national authorisation and rapidly establish the methodology for the characterisation of other BMEPP.

Legal and regulatory prerequisites

The pilot phase served to draft and establish the documents mentioned before, which are now ready to be used by future facilities but also by providers and recipients. Apart from these specific agreements, several further requirements need to be met to be fully prepared and functional as a BioHub Facility. From a national legal perspective, the laboratories need an operating licence to culture the micro-organism of concern. Furthermore, as laboratory personnel packs and sends the infectious substance, appropriate International Air Transport Association and/or Agreement concerning the International Carriage of Dangerous Goods by Road certification of the personnel is needed.