Building a sustainable phage biobank – trials and tribulations

In an ideal world, a phage biobank would be a facility that serves as a primary research and therapeutic development resource for researchers studying critical infection, as well as to the wider community of infectious diseases, industry and biotech with an interest in critical infection.

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Associate Professor Ruby CY Lin & Professor Jon R Iredell.

The antibiotic crisis fast tracked bacteriophage (phage) therapy as the most obvious solution. Globally, there is combined 100-year track record of phage therapy and /or phage utilisation.

We envisaged that our clinical trial experience over the last 2 years1 using phage therapy paves the way for Phase II and III controlled, randomised clinical trials at various sites, nationally and internationally, and puts us in a unique position to develop a biobanking resource to serve research and the biotechnology industry.

During our clinical trial, we noted a glaring absence of a dedicated, centralised phage biobank in Australia that is committed to the collection of phages, their associated pathogens, and blood, tissue samples and clinical data from enrolled patients. We describe here the trials and tribulations of our journey so far.

Multi-party and multi-discipline approach

Functional biobanks have been implemented successfully in several countries especially for mammalian tissues, their associated diseases and associated biospecimen and clinical data. For phages, however, there are a handful of phage collections being curated with various degrees of fundamental information about each phage. For example, phage lytic activity against pathogens, annotated phage genome sequences, their targeted pathogen(s)’ sequence (whole genome sequencing (WGS)), and clinical data, if any.

In an ideal world, a phage biobank would be a facility that serves as a primary resource for researchers and for therapeutic development with multi-party collaborations and co-investments by other funders (public and/or private) to share the financing of and support the infrastructure over time.

Recently, Adaptive Phage Therapeutics was awarded an initial contract with the US Department of Defence for developing a PhageBankTM with the intent to use personalised phage therapeutics for treating bacterial infections. This is an initiative we are following closely.

Basic characteristics of a phage biobank

We consulted with a consortium of clinicians and researchers from New South Wales (NSW) Health Pathology, Westmead Hospital and our Institute to integrate existing phage collections to create a state-wide dedicated repository with a standardised governance as basis for diagnostics, epidemiology, research of human microbial pathogens, bio-surveillance and biosecurity (an under-researched area). This integrated phage biobank will be the fundamental resource for the extended demand of reference materials, genomics and surveillance of microbial pathogens from clinicians and researchers across our state and beyond i.e., globally.

So far, we can share the most valuable enabling features of a phage biobank (including but not limited to):

  • Basic characterisation, including: phage genome sequence and morphology (simple transmission electron microscopy), whether it is obligately lytic or whether it can integrate into the bacterial genome, “host range” (i.e., what bacteria it works against and what it doesn’t), its bacterial host WGS and interactions with antibiotics (clinical applications). Of note, machine learning can be applied to this vast amount of genomic data for specificity and sensitivity of a particular phage, its bacterial host and antibiotic interactions.
  • Purified preparations suitable for further testing – from low-purity preparations for in vitro studies right through to high-purity endotoxin-free preparations for in vivo use.
  • Manipulation of phages, i.e., synthetic/ host range modification.
  • Links to all published studies and relevant public-domain data on the virus.
  • Links to researchers with an interest or with ongoing projects, to foster collaborations. Phage Directory is a good example of facilitating phage researchers and phage resources.

We also noted the infrastructure required to enable this centralised phage biobank, i.e.,

  • Centralised Standard Operating Procedures for phage extraction, genome reporting, phage annotation (akin to MIAME and MINSEQE). For example, Sciensano, Belgium’s federal public health institute, issues a phage genetic passport to a specific phage, classified as an active pharmaceutical ingredient towards magistral preparations, and the U.S. Navy is working on an assessment pipeline towards a phage genetic readout to determine safety of phage as a therapeutic agent.
  • Centralised ethics, legal and governance for e.g., Material Transfer Agreement, patient information consent form for both research2 and biobanking, access to phages and associated human biospecimens and adherence to the Nagoya Protocol.
  • Centralised secure (scalable) server or cloud to house this database (within one’s state/country’s jurisdiction).
  • A dedicated, full time biobank officer in charge of culturing, sequence identification, phage quality control and meta-data entry.
  • A research nurse to assist with collections at the expanded network and ensure security and completeness of clinical specimen and metadata.
  • A dedicated full time data scientist to curate patient data and associated experimental data in a LIMS system (enable search and location functionalities), associated databases and, in our case, liaise with the Centre for Health Record Linkage - a secure, high performing data linkage system, first of its kind in Australia, that facilitates high-quality research and health policy decisions.
  • Different stream of income to maintain capacity i.e., business models to enable access to clinical isolates and phages for pharma and biotech R & D.

We are gradually realising the ability of this phage biobank to provide matched phages for patient samples (personalised phage therapy) in a NATA-accredited service eligible for Pharmaceutical Benefits Scheme rebates. Leveraging our expanding Pathogen Biobank3 collections, such a venture will be the first of its kind that is making a social and economic impact in services for medicine, industry and biotechnology.

1. Petrovic Fabijan, A., Lin, R.C.Y., et al. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nature Microbiology 17th Feb 2020, 10.1038/s41564-019-0634-z.

2. Lin, R.C.Y., Petrovic Fabijan, A., Atwood, L. & Iredell, J.R. State of the Regulatory Affair: Regulation of Phage Therapy in Australia. Capsid & Tail (2019).

3. Iredell, J.R. Lin, R.C.Y., et al. NSW Pathogen Biobank. Awarded by NSW Health through Biospecimen Collection Grant, NSW, Australia. (2019)

Ruby CY Lin

Project Manager / Adjunct Associate Professor / Genomic Chair (Westmead Research Hub), Westmead Institute for Medical Research

I help organisations build academic-industry hybrid teams. I have skill sets that are interchangeable between academia and industry. I have a proven track record of managing large scale multi-discipline projects within budget and time constraints. I am an effective communicator and collaborator, and have experience in mentoring, management and leadership. This is reflected in my capacity as a researcher where I was successful in securing over A$5.4 million research funding over the course of the last decade or so, and as the president of Australasian Genomic Technologies Association, a premier professional society in Australasia (2013-5). I am interested in implementing genomic (personalised) medicine into healthcare and better consumer health policy. My publications are available in ORCID (0000-0003-4163-511X), Google Scholar and Research Gate (>4000 citations), and I have >90 Internationally/nationally peer-reviewed conference presentations. My key skills are in the discipline of: Genomics, Transcriptomics, Cardiovascular Disease, Obesity, Cancer Biology, Animal models, Nucleic Acid technologies, microRNA, microRNA therapeutics, Systems Biology, Pharmacogenomics, Experimental Design, Budget project grants (strategic and translational perspective), Risk and feasibility assessment, Team Management, Mentoring, Establish networks amongst industry and academia (key stakeholders engagement) and of late ethics and governance for phage therapy clinical trials. I advocate for women in STEMM and do pro bono career coaching. I volunteer as a primary ethics coordinator and as a parent in the management committee for Out Of School Hours childcare at my kids' school, and I am a mentor for the Junior Science Academy holiday program at Macquarie University. During COVID lockdown I knitted beanies for friends and their babies and for colleagues. We also got a puppy since we are working from home. During the last 7 months I spent a lot of time on Zoom and eating chocolate (sometimes concurrently), as well as spending time writing grants and papers, and mentored/ing young scientists and clinicians who have reached out through LinkedIn.