Building a future for phage-based technologies—a thought leadership approach to accelerating progress in the UK

Abstract

Antimicrobial resistance is a global issue that threatens our ability to effectively manage and treat bacteria in the context of human health, animal health, and the environment. Bacteriophages provide a viable and necessary alternative to existing antimicrobials. Recognizing the extensive expertise and existing infrastructure that can support phage development in the UK, the Phage Innovation Network (PIN) was established with the aim of catalysing progress in this area. Through comprehensive consultation with the phage community and wider stakeholders, the PIN has carried out a variety of activities to address key issues that are considered to be preventative for the development and use of phage-based technologies in the UK. The successful outcomes of these activities demonstrate how this thought leadership approach has been effective in increasing engagement, delivering solutions, and supporting progress of the phage sector in the UK.

Sustainability Statement.

Antimicrobial resistance is a global issue that impacts all sectors under the One Health spectrum. Bacteriophage-based products and technologies provide solutions that can be applied across multiple sectors to address antimicrobial resistance and reduce antibiotic use. The activities described here are necessary for supporting and enabling development of such solutions and, in turn, make progress towards several of the United Nations sustainable development goals, including SDG2 (zero hunger), SDG3 (good health and well-being), SDG6 (clean water and sanitation), SDG14 (life below water), and SDG15 (life on land).

Introduction

Despite a history spanning more than a century and their recognized utility across multiple sectors, bacteriophages (phages) are still unknown to the vast majority of the global population. The year 1928 saw the commencement of the golden age of antibiotic discovery—a transformative time for medicine and our ability to manage bacterial burden (Hutchings et al. 2019). Progress in the identification and industrial scaling of natural product antibiotics and their translation into clinically significant drugs dwarfed attempts at using phages in the same way. However, overuse and misuse of antibiotics have positioned humanity on the edge of a post-antibiotic era. The emergence of multi-drug, and even pan-drug, resistant bacteria threatens our ability to treat common bacterial infections in humans and animals and manage the presence of bacteria in areas key to maintaining public health, including food production and water sanitation (World Health Organization 2024). Phages present a viable and sustainable solution that will contribute to civilization’s defence strategy against antimicrobial resistant bacteria—and we have never needed them more than we need them now.

The UK has an extensive knowledge base for phage research and development, spanning academia and industry, that has existed for several decades and has grown with increased support and interest in more recent years. Based on data available from Gateway to Research, a total of ∼£67.5 M of public funding has been awarded across 144 projects focussed on phage research and development since 2006, from investigations into basic phage biology through to development of phage-based products and scaling manufacturing processes (UK Research and Innovation 2024) Recent activities include the publication of a report by the Scottish Health Technologies Group recommending phage therapy for managing difficult-to-treat infections (Health Improvement Scotland 2024). Additionally, the UK government’s Science, Innovation and Technology Committee (SITC) conducted an inquiry into the antimicrobial potential of bacteriophages, prompted by a successful bid from Applied Microbiology International through the My Science Inquiry competition (House of Commons Science, Innovation and Technology Committee 2024).

Recognizing the flourishing knowledge base, increased interest, and through identification of the opportunity to unite the community and facilitate progress in this emerging area, Innovate UK Business Connect (IUK BC), formerly known as Knowledge Transfer Network, established the Phage Innovation Network (PIN). IUK BC has a decade of experience in running Innovation Networks that have focussed on a variety of topics across multiple sectors. Innovation Networks are designed to harness the power of collaboration, connecting people, ideas, and communities to address global challenges and enable positive change through innovation. The PIN was established with the intention of uniting key stakeholders across multiple sectors in the phage community to catalyse growth and accelerate development. An Advisory Board comprised of phage experts and other key stakeholders from industry, academia, government organizations, and the NHS was established to guide PIN activity and ensure delivery of intended impact. This summary highlights the key areas that have been the focus of PIN activity since its inception and the resulting impact of this work.

Direction

The primary activity that was carried out following the launch of the PIN programme was a workshop that brought together a diverse group of experts to collect valuable insights into the current state of phage research in the UK, existing strengths in the UK that can be utilized for progression, and steps needed to stimulate development of phage-based technologies for applications across different sectors. The information gathered through this workshop provided a comprehensive overview of the research, regulation, and innovation landscape at present, and the necessary actions that should be taken to ensure the development and implementation of phage-based technologies across multiple sectors in the UK.

Through this scoping exercise it was highlighted that the UK has extensive and highly regarded academic bases in microbiology, phage, informatics, AMR research, and genomics as well as a comprehensive understanding of relevant bacterial targets for phage-based products through surveillance data collected by the UK Health Security Agency (UKHSA). In addition, existing infrastructure for genomics in the UK was considered to be key for sustainable development and use of phage-based therapies and technologies. In terms of steps for future development, establishment of manufacturing capability to produce phage products in accordance with Good Manufacturing Practice (GMP) standards was ranked of high importance by the contributors to this workshop. A national phage biobank was also highlighted as a key part of the infrastructure needed to deliver sustained access to and development of phage-based products, with lack of funding cited as the main reason as to why this resource does not already exist. Despite this, there has been progress in establishing a UK phage biobank. The Leicester Centre for Phage Research (LCPR) and University of Northumbria have setup a distributed phage bank between both Universities, with plans for further expansion subject to further funding. Finally, addressing the clarity of regulations relevant to the licensing processes for phage-based products was considered to be essential to enabling progression of the phage field.

The information summarized above was used to inform and direct the actions of the PIN and was compiled into a report containing further details of the outcomes of the discussions and the recommendations made by the experts who contributed (House of Commons Science, Innovation and Technology Committee 2024).

Regulation

In the UK, human medicinal products are regulated by the Medicines and Healthcare Products Regulatory Agency (MHRA), veterinary medicinal products are regulated by the Veterinary Medicines Directorate (VMD), and the Food Standards Agency (FSA) enforces regulations that encompass products applied to food. In the past, regulation has widely been considered a barrier to the use of phages for applications across multiple sectors (Food Standards Agency 2024, Medicines and Healthcare Products Regulatory Agency 2024, Veterinary Medicines Directorate 2024). However, pathways through which marketing authorization for phage-based products can be obtained do exist. In the UK, there is no regulatory barrier to the use of phages therapeutically in humans under specific circumstances and in accordance with the MHRA guidance on the use of unlicensed medicinal products known as ‘specials’ (Jones et al. 2023). Having said this, the diversity in the types of phage-based products (e.g. fixed products, personalized products, and engineered products) that are in development will likely necessitate refinement of existing regulatory frameworks and clarification from regulators on the appropriate pathway innovators should take when compiling evidence to support the licensing of a product.

Since launching at the beginning of 2023, the PIN has actively engaged with regulators responsible for different sectors. Acknowledging the community perception that regulations pose a barrier to the development and use of phages, the PIN has worked to facilitate conversations between regulatory groups and experts working in the phage field. The aim of this work was to unpick issues perceived by both regulators and innovators and work collaboratively to clarify the role of the regulator and the expectations of the innovator in the context of phage product development.

This work has led to a collaboration between the National Institute for Biological Standards and Control (NIBSC) Microbiome Group within the MHRA and LCPR. This partnership will carry out a feasibility study for the development of phage reference reagents that can be utilized during product development to validate and standardize methodologies and enable evaluation of reproducibility of results between studies (Sergaki 2024). The Microbiome Group at the MHRA has previously developed DNA and whole cell reference reagents for gut microbiome research, both of which are recognized as World Health Organization (WHO) International Reference Reagents (Amos et al. 2020, Sergaki et al. 2022). Development and utilization of such reference reagents for phages is of value particularly for the regulatory process, as demonstration that methodologies are validated using WHO standards instils greater confidence in results, though the use of reference reagents does not guarantee success regarding the marketing authorization process (Amos et al. 2020). It is important to note that although NIBSC is part of the MHRA, which regulates human healthcare and medicinal products, the reference reagents developed and produced by NIBSC can be utilized for product development across multiple sectors, including veterinary medicine and food production. With this in mind, as part of this project between the MHRA and LCPR, a consultation with UK phage experts and regulatory experts from the MHRA, VMD, and FSA was held to determine the technical and scientific requirements for biological phage reference reagents.

In addition to instigating exploration into the feasibility of phage reference reagents, the PIN has worked with the MHRA to develop non-binding guidance for the licensing requirements for phage products (Department of Health and Social Care 2024). As with the microbiome reference reagents, the MHRA has previously developed a similar handbook for innovators developing microbiome products (KTN Microbiome Innovation Network 2024, National Institute for Biological Standards and Control 2024). Based on this and the need for regulatory clarity highlighted by the phage community in the UK, the PIN Advisory Board worked with the MHRA to outline clear guidance for developers for navigating the regulatory process. Working in collaboration ensured that the guidance was appropriate in the context of phage product development while also maintaining the MHRA’s obligation to ensure that patients have access to therapies that deliver benefit with minimal risk. This guidance document has yet to be published but was referred to in the Government’s response to the SITC inquiry into the antimicrobial potential of bacteriophages that was carried out between 2023 and 2024 (Department of Health and Social Care 2024, House of Commons Science, Innovation and Technology Committee 2024). The guidance will undergo public consultation through the British Pharmacopoeia before its publication and will be subject to revision as the phage sector progresses and regulatory experience is gained (Department of Health and Social Care 2024).

Biobanking

Phage banks, defined as pre-characterized collections of phages, can be valuable resources for the management of future outbreaks of AMR bacteria (Nagel et al. 2022). As mentioned previously, this was highlighted by experts as key infrastructure for development in the UK, but the impact and access to phages that biobanking infrastructure can provide is also relevant to managing outbreaks in lower- and middle-income countries (Nagel et al. 2022). At present, there is no guidance on how to characterize, store, and transport phages across international borders. Harmonization of phage biobanking practices will be key to ensuring quality of collections and associated data as well as enabling expedited transfer of phages when requested.

In a move to address this, Phages for Global Health (PfGH), funded by the Burroughs Wellcome Fund, initiated a project to draft phage biobanking guidelines through consultation with the global phage community (Nagel 2024). The PIN was invited to collaborate on this project with PfGH, Phage Canada, Phage Australia, and Phage Directory. At the time of writing, the PIN has worked with PfGH to convene over 100 phage scientists from 28 countries to develop recommendations for building and managing a phage biobank. Following an initial online survey and two meetings with both in-person and virtual attendees, four focus areas for the guidance were identified: phenotypic phage characterization, genotypic phage characterization, physical storage, and data management. Accessibility has been a key consideration during the discussions hosted through this project with the intention of ensuring that the quality and control practices that are recommended can be implemented by researchers and organizations with any level of resource.

The final output of this work will be a publication outlining the recommendations that have been decided upon following this community consultation process. The intention of the publication is not to be directive, but to present the opinions of the global phage community and establish the foundation for building harmonized quality control processes that can be implemented universally. The recommendations are actively being drafted (at the time of publication of the current article) with the expectation that they will be finalized and submitted for publication by the middle of 2025. The recommendations will likely need to be reviewed and updated at regular intervals in the future as collective knowledge of phages and development of practices progress.

Awareness

Raising awareness of the progress in phage R&D and the variety of applications phages can be used for has been at the forefront of the work of the PIN, as has increasing the engagement in this area (Innovate UK Business Connect 2024c). This has been approached in a variety of ways. Groups and organizations on the periphery of the phage sector who have an interest in the field but are not yet actively involved have been invited to participate in workshops and discussions. In addition to this, information about phage use and development has been shared utilizing opportunities to present to a variety of audiences, including the Food Standard Agency’s Advisory Committee for the Microbiological Safety of Food, the Pathogen Surveillance in Agriculture, Food and the Environment (PATH-SAFE) and Food Safety Research Network (FSRN) Showcase, the Food and Drink Federation Food Microbiology Committee, and at the Emerging Antimicrobials and Diagnostics in AMR conference (Advisory Committee on the Microbiological Safety of Food 2024, AMR Insights 2024, Pathogen Surveillance in Agriculture, Food and the Environment 2024). The PIN has also hosted webinar sessions to provide a platform for researchers and developers to showcase their work to international audiences and produced a report, through AgriFood Africa Connect, highlighting the utility of phage in the African Agrifood sector, showcasing some of the work that has been carried out in this area by African researchers (Innovate UK Business Connect 2024a, Innovate UK 2024, Innovate UK Business Connect 2 024b).

As well as this, the PIN delivered the UK Phage Innovation Showcase in partnership with the LCPR, Innovate UK and the FSRN (Innovate UK Business Connect 2024d). This event united multiple sectors on the topic of phage and showcased translational research into developing phage-based technologies for use in crop health, food safety, veterinary medicine, and human medicine. The presentations and panel discussions held throughout the event explored common challenges in the development and implementation of phage-based technologies experienced across each sector and discussed how the phage community can work together to further research and growth of this area in the UK.

Concluding remarks

The growth in knowledge and progress made in the phage sector over the last decade is undeniable, as is the opinion that phages are necessary to ensuring sustained access to antimicrobials for generations to come. Over the last year, the activities of the PIN have supported development of phage-based technologies in the UK and catalysed progress through addressing key issues raised by stakeholders and actively working to overcome them. The actions taken by PIN regarding the development of the UK phage sector have helped to underpin decision-making for delivering impacts on sustainability, contributing to progress towards the United Nations sustainable development goals. The outcomes of this work to date demonstrate how community-centric thought leadership is an effective way of making progress and instigating change. The PIN will continue to play a key convening role, bringing together experts and utilizing their ideas, insights, and opinions to influence and inspire the community to further phage development in the UK.

Conflict of interest

F.E.H. is an employee of Innovate UK Business Connect. D.L.S. is a member of the Innovate UK Phage Innovation Network Advisory Board and holds the position of Guest Editor for the ‘Diversity of bacteriophages and their contribution to improve animal, environmental, and human health’ themed collection. D.L.S. has not peer-reviewed or made any editorial decisions for this manuscript. No other conflicts of interest apply.

Funding

No funding to declare.

Author contributions

Francesca E. Hodges (Conceptualization [equal], Project administration [lead], Writing - original draft [lead], Writing - review & editing [lead]), and Darren L. Smith (Conceptualization [equal])

Data availability

No new data were generated or analysed in support of this policy-in-practice paper.