Investing in the future of phage therapy

Issue 207 | January 20, 2023
13 min read
Capsid and Tail

This week, we’re republishing an article Dr. Jon Iredell and Jessica Sacher wrote for GARDP Revive, the Global Antibiotic Research & Development Partnership.

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Bacteriophage Summit banner

From A-Z of phage development, the 5th Bacteriophage Therapy Summit is the definitive commercial-orientated conference to accelerate phage-based applications for organizations pioneering with phage pipelines.

Explore advancements in clinical trial design to push medicinal phage therapies to the clinic, CRISPR-based gene editing to improve functionality, the rise of lytic technologies, and alternative potential for phage technologies beyond human health. This is the conference of the year for biopharma, clinicians and consumer product developers to harness the safety and efficacy of phages.

Download the full Event Guide here
This event takes place February 21 - 23, 2023

What’s New

National Geographic visited and wrote about Dr. Lillian Musila (Kenya Medical Research Institute) and her colleagues about their identification of over 150 phages and work toward using them to address AMR. The article features several Phages for Global Health researchers!

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Phages for Global HealthPhage bank

Lucía Blasco and colleagues published a new paper describing 32 new phage tail-like bacteriocins (pyocins) from a clinical collection of Pseudomonas aeruginosa and their potential use as typing markers and antimicrobial agents.

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Research paperBacteriocins

Hawkins et al. published a new paper which provides the first complete structural analysis of the S. epidermidis–infecting phage Andhra. Key findings include elucidating critical features for virion assembly, host recognition, and penetration, as well as identifying two proteins that comprise the tail tip heterooctamer.

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Research paperStructural biology

The International Committee on Taxonomy of Viruses recently adopted a binomial naming format for virus species. A new paper describes how to create Latinized binomials for virus species, how to automatically generate large batches of novel genus and species names, and why the new format for species names does not actually affect virus names.

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Research paperTaxonomy

Steffanie Strathdee, Graham Hatfull, Vivek Mutalik and Robert Schooley wrote a new review of the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions.

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Phage TherapyReview

Latest Jobs

Post DocMolecular Biology
Joachim Jakob Bugert at Bundeswehr Institute of Microbiology in München is looking for a postdoctoral researcher. The successful candidate must have a PhD in molecular biology, experience with annotation and functional evaluation of virus/bacteriophage genomes, experience with virus/phage molecular biology, and experience with Gibson assembly, with experience with reporterviruses being a plus.
AquaculturePhD project
The Department of Biology, Marine Biological Section at the University of Copenhagen is inviting applicants for a PhD fellowship in bacteriophage-pathogen interactions and the potential of using phages to control fish pathogenic bacteria in the production of fish in aquaculture.
PhD projectPhage ecology
A PhD student position in freshwater phage ecology is open at the Department of Aquatic Microbial Ecology, Institute of Hydrobiology, Biology Centre of the Czech Academy of Sciences.
Molecular biologyCDD Engineer
The University of Toulouse is hiring a CDD Engineer in Molecular Biology to work on a project called PHAG 2S, which seeks to understand the mechanisms governing the interactions between pathogenic bacteria and bacteriophages.
FacultyBiologySEA-PHAGES
The Department of Biology at Drexel University in Philadelphia, PA is hiring an assistant professor to teach undergraduate courses in biological sciences for the 2021-22 academic year. The faculty position is expected to have primary responsibility in delivering our SEA-PHAGES and SEA-GENES lab courses.

Community Board

Anyone can post a message to the phage community — and it could be anything from collaboration requests, post-doc searches, sequencing help — just ask!

Raphael Hans wrote a new blog post on phage mediated biocontrol of phytopathogens for thephage.xyz.

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Blog postPhytopathogens

The Ibadan Bacteriophage Research Team, an undergraduate SEA-PHAGES team at the University of Ibadan, Nigeria, announces the launch of the 2nd edition of the team’s journal issue, PHAMILIA. This is the very first undergraduate research journal focused on bacteriophage biology. It showcases publications on diverse subjects of bacteriophage biology, from the team and other guest writers. To download:  https://ibadanphageresearchteam.org/

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Phage biologyJournalUndergraduate phage research

Investing in the future of phage therapy

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Jon Iredell MBBS PhD FRACP FRCPA FFScRCPA FASM
Senior Infectious Diseases Specialist
ProfessorPrincipal Investigator
The Westmead Institute for Medical Research, Sydney, Australia
The University of Sydney, Sydney, Australia

Prof Iredell originally trained as an intensivist and is one of the few Infectious Diseases physicians and the only formally qualified clinical Microbiologist with full professional membership of the ANZ Intensive Care Society. He is Director of the Centre for Infectious Diseases & Microbiology (CIDM) Laboratory Services, Westmead Hospital, Professor of Medicine and Microbiology (conjoint) at Sydney Medical School, senior staff microbiologist in NSW Pathology and NHMRC Practitioner Fellow since 2011. He has secured millions of research funding with infectious diseases focus.

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Phage microbiologist and co-founder of Phage Directory
Co-founderPostdoctoral Researcher
Skills

Phage characterization, Phage-host interactions, Phage Therapy, Molecular Biology

I’m a co-founder of Phage Directory and have a Ph.D in Microbiology and Biotechnology from the University of Alberta (I studied Campylobacter phage biology). For Phage Directory, I oversee community building, phage sourcing, communications, science, and our awesome team of volunteers.

As of Feb 2022, I’ve recently joined Jon Iredell’s group in Sydney, Australia as a postdoctoral research scientist for the Phage Australia project. I’m diving back into the lab to help get Phage Australia’s country-wide phage therapy system up and running here, working to streamline workflows for phage sourcing, biobanking and collection of phage/bacteria/patient matching and monitoring data, and integrating it all with Phage Directory’s phage exchange, phage alerts and phage atlas systems. I’m also delving into phage manufacturing and quality control.

This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).

The O’Neill report on antimicrobial resistance (AMR) to the UK government points to bacteriophage (phage) therapy as the premier alternative to antibiotics.[1] They are the ultimate precision antibacterial – the most abundant and diverse microorganism on the planet.[2]

Phage resistance vs antibiotic resistance

The bacterial-phage, predator-prey relationship matured before the evolution of hominids[3] and is an important part of ecosystem homeostasis.[4] By contrast, antibiotic resistance is still evolving through gene acquisition[5] and fundamental adaptations in bacterial populations.[6]

Natural and evolved resistance to phage attack can be overcome by phage-phage, and phage-antibiotic, combinations. The use of phages to which phage-resistance is more ‘costly’ to the bacterium to develop, the ‘training’ of phages against target pathogens to ensure this, and therapeutic phage diversity are all expected to be important to prevent emergence of phage-insensitive bacterial pathogens.[7]

Precision antimicrobials: a double-edged sword

A previous writer in this series[8] pointed to increasing interest in pathogen-specific approaches to multi-drug resistant (MDR) infections.[6-11] A precise tool such as a phage is an ideal, pathogen-specific option; neither affected by nor contributing to AMR.

Collateral damage to the human microbiota is minimised by the extreme precision of phage therapy. However, this means that each phage may be used much less than a broad-spectrum antimicrobial and economies of scale may be harder to achieve.

Endpoint QC processes provide flexibility, allowing for phages to be administered safely, even given phage-phage differences. There is a precedent now in Belgium for adapting this type of pathway for the routine use of phages.

Achieving economies of scale

In principle, phage therapy should be cheap. Phages are plentiful and ubiquitous; easily modified by forced evolution or bioengineering; and easy to culture and purify. However, production according to traditional Good Manufacturing Practice (GMP) standards[9]  is infrastructure-intensive and expensive. It is viable only if economies of scale – where average costs per unit produced decrease with an increased magnitude of production – can be achieved.

A separate production plant dedicated to each phage is not likely to be economical. Even moving to small-scale GMP-certified facilities for savings in consumables leaves more significant, important, overhead costs in production and quality control (QC) that pertain to each individual batch. Yet we must be responsive to immediate, local needs for highly diverse, safely produced phages. How can we do this?

One way is to increase the number of patients each phage batch treats. A simple calculation illustrates the need to keep wastage under 90% if possible: i.e., >10% of a batch should be used before the expiry date (Fig. 1), since 5% usage costs 20-fold more than 99.9% usage, 10% costs 10-fold more, 20% 5-fold more, and so on – since batch costs are fixed. Phages can achieve this if they are effective against a sufficiently broad range of commonly encountered bacterial strains, like Staphylococcus aureus and Pseudomonas aeruginosa), are supported by good distribution logistics, and have a good shelf-life.

For example, if the shelf-life of a phage product is 12 months, a 1,000-dose batch (assuming 30 doses per course) means each batch must treat approximately eight patients a year to place phage acquisition costs in the range of a moderately expensive modern antibiotic.

https://revive.gardp.org/wp-content/uploads/2023/01/Fig1-1024x734.png

Figure 1. The relationship between the percentage of batch cost (vertical axis) and batch usage (horizontal axis) indicates an inflection point at ~10% usage.

The simple logic of these economics drives production towards common bacterial targets, often achieved by including multiple phages (the so-called phage ‘cocktail’) in one standardised GMP production line.

Ensuring safety

The expensive and time-consuming process of traditional clinical trials for antibiotics is even less suited to highly personalized antimicrobials like phages. Given their inherent safety, phages fit well into an endpoint, quality-control framework, in which the end product’s safety is regulated, similar to the way in which blood products are regulated. This provides an effective safety mechanism in the absence of end-to-end GMP process control.

For phages, an endpoint quality control (QC) process that prevents injection of live bacteria, inflammatory debris (e.g., lipopolysaccharide/ ‘endotoxin’), and bacterial or chemical toxins and ensures that the infusion product is non-irritant (e.g., buffered solution in physiological pH range) is essential. These data can be presented in a standardised document with evidence that the phage itself has no undesirable biological characteristics. In the absence of comprehensive assays to detect all undesirable characteristics, it is additionally essential to ensure that the phage production strain encodes nothing that may present a risk in the final therapeutic product.

Endpoint QC processes provide flexibility, allowing for phages to be administered safely, even given phage-phage differences. There is a precedent now in Belgium for adapting this type of pathway for the routine use of phages.[10]

fig 2

Figure 2. The minimum documents every prescriber needs for phage therapy.

In the absence of full GMP certification with end-to-end process control, the responsibility for patient safety and the evaluation of risk and potential benefit is often devolved locally to the prescriber and/or the institution with the most direct and explicit duty of care (such as a health care organisation). This is typically handled at the level of a jurisdictional ethics committee, often by delegation to a specialised therapeutics subcommittee (‘drug committee’). The phage, bacterial production strain and manufacturing safety data sheets will be required by the institutional review board/drug safety committee for every bacteriophage considered for use (Fig 2). In our own institution, we provide this in the form of four documents regarding the therapeutic material and provide the therapy within a standardised treatment and monitoring framework. The type of evidence required may vary with jurisdiction to some extent, but some guidelines are published.[11][12]

If we can get the economics right and design systems that reflect the critical attributes of phages, phage therapy has the potential to provide a safe, AMR-proof safety net upon which governments and hospitals can rely. This challenge is one that prescribers, regulators and the industry must meet.

Redesigning how we pay

Just as we need fit-for-purpose regulatory mechanisms, it is essential that payment mechanisms are designed to fit. Volume-based pricing has strangled antibiotic profitability but value-based (outcome-based) models, with payments based on patient outcomes, are an attractive potential solution[12] that could work for phages. For example, given the costs of a prosthetic hip joint infection,[13] and the estimated efficacy of phages in such settings,[14] maintaining an anti-staphylococcal phage service should be a cost-effective use of health resources. Public-private partnerships[15] or a subscription model such as recently launched in the UK[16] are sensible, potential routes forward.

A GMP framework that allows sufficient diversity and caters to sufficient demand means that most needs will be met and that phage production can be cost-effective. On the other hand, a well-regulated and highly standardised end-point QC will allow safe high-quality ‘special case’ production for individuals and means that we can provide a phage solution for every bacterial problem. For the best of both worlds, we may therefore need to consider two complementary processes, at least initially.

If we can get the economics right and design systems that reflect the critical attributes of phages, phage therapy has the potential to provide a safe, AMR-proof safety net upon which governments and hospitals can rely. This challenge is one that prescribers, regulators and the industry must meet.

References

  1. O’Neill, J (2016) Review on antimicrobial resistance: tackling drug-resistant infections globally: final report and recommendations.
  2. Suttle, CA (2005) Viruses in the sea. Nature, 437(7057), 356-361.
  3. Brussow H, Hendrix RW (2002). Phage genomics: small is beautiful. Cell 108:13–16
  4. Naureen Z, Dautaj A, Anpilogov K, Camilleri G, Dhuli K, Tanzi B et al. (2020) Bacteriophages presence in nature and their role in the natural selection of bacterial populations. Acta Biomed. Nov 9;91(13-S):e2020024.
  5. Liebert, CA, Hall, RM, Summers, AO (1999) Transposon Tn 21, flagship of the floating genome. Mol. Biol. Rev., 63(3), 507-522.
  6. Fajardo-Lubián A, Ben Zakour NL, Agyekum A, Qi Q, Iredell JR (2019) Host adaptation and convergent evolution increases antibiotic resistance without loss of virulence in a major human pathogen. PLoS Pathog. Mar 15;15(3):e1007218
  7. Borges A. (2021) How to train your bacteriophage. Proc Natl Acad Sci USA 118 (28): e2109434118
  8. Rossolini GM (2021) Rapid diagnostic tests to support clinical trials of antibiotics. GARDP REVIVE.
  9. Therapeutic Goods Administration (2017) Good manufacturing practice – an overview.
  10. Pirnay, JP., Blasdel, B.G., Bretaudeau, L. et al.Quality and Safety Requirements for Sustainable Phage Therapy ProductsPharm Res 32, 2173–2179 (2015)
  11. Khatami A, Foley DA, Warner MS, Barnes EH, Peleg AY et al. (2022) Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial. BMJ Open 12 (12); e65401.
  12. Suh et al. (2022). Considerations for the Use of Phage Therapy in Clinical Practice. Antimicrobial Agents and Chemotherapy. 66 (3).
  13. PwC Health Research Institute (2019) Six drug pricing models have emerged to improve product access and affordability.
  14. Klouche S, Sariali E, Mamoudy P (2010) Total hip arthroplasty revision due to infection: a cost analysis approach. Orthop. and Trauma: Surgery and Research. 96(2): 124-139
  15. Genevière J, McCallin S, Huttner A, Pham TT, Suva D. A (2021) Systematic review of phage therapy applied to bone and joint infections: an analysis of success rates, treatment modalities and safety. EFORT Open Rev. Dec 10;6(12):1148-1156
  16. BSAC (2021) Vanguard Report: The future of drug development
  17. Mahase E. 2020. UK launches subscription style model for antibiotics to encourage new development. BMJ. 369
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