Paper 2 : WHO Made It Again but With A Paper / Building the evidence for the use of bacteriophage therapy

Building the evidence for the use of bacteriophage therapy :

This paper was published by the World Health Organization on the 26th of May 2025. We do not have any of the legal rights from the article and just want to share this tremendous and quite unusual paper from the WHO which underlines very well how phage therapy is really about and how to use it in the future. We took some of the most interesting parts to have a quite short but complete summary. Good reading !

Source : 

www.tuftscimar.org

Overview

Bacteriophages (‎phages)‎ are a promising tool for addressing antimicrobial resistance, targeting harmful bacteria without disrupting beneficial microbiota. Safe for humans, they can enhance antibiotic treatments, particularly against resistant bacteria. The WHO Regional Office for Europe and the Global Antimicrobial Resistance Research and Development Hub are advancing evidence for phage applications through the “Vintage Innovation” initiative, adopting a One Health approach across human, animal and environmental sectors. This report summarizes outcomes from a number of activities, including webinars, expert consultations and a dedicated workshop that took place in Tbilisi, Georgia, on advancing the evidence for bacteriophages use.

WHO Team

Control of Antimicrobial Resistance CHP (AMR)

Editors

World Health Organization. Regional Office for Europe. (‎2025)

Number of pages

30

Reference numbers

WHO Reference Number: WHO/EURO: 2025-11441-51213-78039

Copyright       

Purpose and objective :

The overall aim of the workshop was to accelerate the development of the evidence base and assessing the potential of bacteriophages in preventing and controlling AMR. The key objectives were to discuss and understand the data needs of phage use from a scientifc, clinical and regulatory point of view. The target group for the workshop included a broad range of stakeholders, including international researchers, policy-makers, health-care professionals, regulators, phage manufacturers, phage users and representatives from the agriculture and environmental sectors, emphasizing the collaborative efort needed across various domains to address AMR by using bacteriophages

Main discussion topics :

The workshop focused on the latest developments, challenges and future directions in bacteriophage therapy. This report provides a detailed summary of their presentations and key points. Day ǻ of the workshop covered the clinical data needs for phages use, understanding the regulatory landscape, and the challenges associated with it. Day Ǽ, focused on the health economics of phage therapy, the regulatory framework for bacteriophages, including phage production and quality control, and real-world applications. The workshop programme can be found in Annex ǻ. Clinical data needs and innovative technologies in phage research – focus on use in humans. Understanding the potential and building the foundation 

Dr Miriam Dadiani and Dr Dea Nizharadze, Physician and Chief Physician, respectively, at the G. Eliava Clinical Phage Therapy Center, Georgia 

Title : Clinical use of phages in Georgia 

Summary :

               • presented on the broad and diverse clinical applications of phage therapy, emphasizing its efectiveness against various bacterial pathogens, including the conditions for compassionate and personalized phage therapy, both among over 5500 national patients and over 1500 international patients since 2018. 

Fig. 2 shows the proportion of 5256 phage-treated patients by type of medical specialty at the G. Eliava Phage Therapy Center from 2019 to 2023. Fig.3 illustrates the proportion of phage-treated patients by medical condition for the same group of 5256 patients. Fig. 4 displays the most common pathogens found among these patients and Fig. 5 depicts the most common phages developed against relevant pathogens. 

• detailed the real-world clinical applications and challenges encountered, providing a comprehensive overview of the current landscape of phage therapy in clinical settings. Fig. 2. Proportion of 5256 phage-treated patients by type of medical specialty at the G. Eliava Phage Therapy Center from 2019 to 2023 

Dr Jean Paul Pirnay, Queen Astrid Military Hospital, Belgium 

Title : Global perspectives on phage therapy – “It’s not a Medicine Jim” 

Summary :

• highlighted the lack of an adapted phage production and clinical trial framework and the unique challenges posed by phage therapy, including phage specifcity and resistance development and possible persistence and spread (including anti-phage defense systems); 

• emphasized the need for a tailored phage therapy approach to deal with specifcity and resistance issues; 

• presented the economic challenges from drug developers, noting the high cost and long duration to bring new phage products to market, and the fnancial difculties faced by companies; 

• discussed the magistral phage approach in Belgium, largely based on the G. Eliava Institute of Bacteriophages, Microbiology and Virology’s expertise, and which, despite not being GMP certifed, uses stringent quality measures; and 

• shared a retrospective analysis of 100 consecutive cases of personalized phage therapy and ongoing studies, demonstrating clinical improvement in 77% of patients and highlighting the need for combined antibiotic and phage therapy. The slide below (Fig. ȃ) shows an overview of clinical trials using phages in 2024 from the global platform on clinical trials named ClinicalTrials.gov (16) and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) (17).

Tea Oshkhereli, Focal point for AMR in agriculture, Chief Specialist at the National Food Agency, Ministry of Environmental Protection and Agriculture, Georgia 

Title : AMR in the agricultural sector in Georgia 

Summary :

 • highlighted progress in controlling the use of antimicrobials in the food and veterinary sectors, and the ongoing challenges; 

• discussed the eforts of the European Network for Optimization of Veterinary Treatment (ENOVAT) and the importance of improving monitoring mechanisms for controlled substances; 

• emphasized the need for better education and awareness among veterinary professionals to reduce the misuse of medications and the importance of stringent control measures; and 

• presented the potential for phage research and application in the veterinary and agriculture sector, as outlined in the national AMR strategy and action plan of Georgia (2024-2030) (Fig. 11).

Dr Shawna McCallin, Balgrist University Hospital, University of Zurich, Zurich, Switzerland 

Title :  Phagistry 

Summary : 

• explained that Phagistry is an international patient registry dedicated to standardizing data collection and providing a tool for researchers and clinicians to document and share the clinical treatment and outcome of their phage-treated patients. It ofers treating physicians a centralized database to join for phage-related data, facilitating the standardization, sharing and analysis of phage therapy research. 

• described how phagistry supports the development of evidence-based phage therapy protocols and aims to overcome regulatory and technological barriers by promoting collaboration and knowledge exchange within the scientifc and medical community. The slide below (Fig. 12) shows an overview of the Phagistry set-up.

Focused sessions :  

Focused sessions on advancing phage therapy in human and agricultural sectors took place during the afternoon of 13-14 May. The summary below highlights the key messages from these two sessions ,focusing on data needs, regulatory hurdles and technological barriers , and outlining strategies to support the broader use of phage therapy. 

Clinical trial and regulatory challenges and solutions in phage therapy 

Facilitator: Shawna McCallin, Balgrist University Hospital, University of Zurich, Switzerland 

Co-facilitator: Jean-Paul Pirnay, Queen Astrid Military Hospital, Belgium 

Key discussion points :

Current data needs and regulatory environment. The session focused on the feedback provided by the EMA on the need to provide “acceptable efficacy” for phage therapy in clinical trials. The group discussed diferent endpoints, including microbiological, clinical and phage-specifc, and the potential pitfalls that may be encountered based on participants’ experience. The session highlighted the risk posed by current regulatory frameworks to the “real-world use” (defined as use, which is unapproved by regulatory agencies) of phage therapies. Medical researchers, such as Jean Paul Pirney, expressed frustration over the lack of recognition of the treatment effects observed from individual cases, especially from regulatory agencies for phage use, despite the increasing need and demand from patients. The focus was on aligning regulatory requirements to support clinical trial development and real-world use simultaneously. The cited regulatory challenges included stringent production requirements that would be unfeasible for longterm sustainable phage therapy (e.g. cocktail adaptation or personalized approaches). Participants debated about what constitutes acceptable efficacy for phage therapy, suggesting a combination of diagnostic criteria and patient outcomes. For example, in chronic infections, such as cystic fbrosis, improvements in the quality of life could serve as signifcant indicators. A standard RCT design is currently the requirement of EMA for marketing authorization. It was emphasized that, while this should be achieved in order to provide clear evidence for the value of phage therapy, it should not hinder the use of phages for the treatment of patients who need it now.

Several topics were addressed to overcome these challenges. 

- Defning adequate efcacy. 

-Establish acceptable efcacy criteria through diagnostics and patient outcomes. 

-Evaluating diferent criteria for various conditions, such as chronic infections, was deemed crucial. -

-Appropriate study designs for phage therapy. 

-Combining phage therapy with antibiotics in clinical trials and comparing outcomes to antibiotics alone was suggested, but the superiority margin required would necessitate large populations. 

-The importance of publishing observational results to inform trial designs was emphasized. 

-Clinical trial outputs and endpoints. 

-Participants discussed the need for clear primary and secondary endpoints, including microbiological counts, patient-reported outcomes, and changes in virulence of the bacteria, which may be a challenge to clearly demonstrate. 

-There is a need to establish robust criteria for evaluating bacterial changes and patient quality of life improvements. -

-The endpoints would provide a comprehensive measure of phage therapy’s efcacy and safety. 

-Legal and production needs. 

-Educating legal authorities about phage therapy and adapting production processes to comply with regulatory standards were seen as essential steps. 

-The development of frameworks that support fexible phage composition and dosage adjustments is also needed.

- Educational Initiatives. Implement programmes to educate legal authorities and clinical practitioners about phage therapy.

Innovative technologies in phage research 

Facilitator: Professor Thomas Sicheritz-Ponten, University of Copenhagen, Denmark 

Co-facilitator: Professor Martha Clokie, University of Leicester, United Kingdom of Great Britain and Northern Ireland 

Key discussion points 

Lack of advanced phage bioinformatic tools and limited expertise. The need for robust data storage and sharing mechanisms, particularly in the absence of centralized repositories, was emphasized. The session highlighted significant gaps in phage-specific analytical tools as a technological barrier. Proposals included developing hybrid workshops and establishing “phage ambassadors” – regional experts trained in phage research and application. 

Several topics were addressed to overcome these challenges. 

- Infrastructure development is needed and funding for an international phage bioinformatic infrastructure should be undertaken. 

-Capacity-building and training, such as in-person or hybrid workshops, was discussed, to train regional experts and create standardized online resources for phage bioinformatics, as well as sharing phage-specific DNA extraction and sequencing protocols. 

-Develop easy-to-use online phage-specific analytic tools, such as phagecompass (18) and phabox (19). 

- Develop and curate phage-specific databases and algorithms, which can deal with the extreme diversity and “unknowns” of phage genomes. 

Phages in practice: clinical applications 

Key discussion points

Structuring data collection to support phage therapy . Phagistry aims at capturing data from the clinical experience . Phagistry may also contribute to the design of future clinical trials . To inform regulatory approaches , parallels were drawn from other fields, such as microbiome research, which may inform regulatory approaches for phage therapy and allow for a more flexible, sustainable approach to phage products . Concerns were raised on how this would comply with production requirements from regulatory bodies, such as EMA, and the practical applicability for phages.

Regulatory guidance and emergency use. Creating a sustainable regulatory framework for phage therapy was a key focus of the discussion. Participants stressed the need for adaptable phage mixtures and realistic requirements, avoiding unfair comparisons with antibiotics. A parallel system to facilitate real-world use and to address how phage therapy could be used in low- and middle-income countries (LMICs), was also discussed. As regulatory agencies in LMICs often adopt regulations from high-income countries, setting overly stringent requirements or restricting access to real-world applications could end the use of phages in LMICs. This is particularly concerning since LMICs are predicted to the highest death rates due to AMR. 

Several topics were addressed to overcome these challenges. 

- Engage with regulatory bodies to align phage therapy protocols towards what is considered robust evidence by these authorities. Develop flexible regulatory frameworks to support realworld personalized and sustainable use and clinical trials. Create robust evidence through RCTs and observational studies to supportregulatory approval. 

- Develop educational initiatives for legal authorities and clinical practitioners about phage therapy. 

- Enforce collaborative efort for international data sharing and collaboration to standardize phage therapy practices. Establishing comprehensive, standardized data collection and sharing mechanisms is a high priority. 

Phage therapy in practice: real-world applications and outcomes in agriculture 

Key discussion points 

Phage therapy is becoming an increasingly viable alternative to antibiotics in agriculture, ofering solutions to various bacterial infections in animals and plants. Despite its potential, there are numerous challenges to overcome, particularly in demonstrating its efcacy and practical application in diverse environmental settings. 

Several topics were addressed during the discussion. 

- Efficacy challenges. The efectiveness of phage therapy must be clearly demonstrated to gain widespread acceptance. This involves proving that phages can signifcantly reduce bacterial infections in agricultural settings. However, the complexity of using phages in the environment, where many variables are at play, presents a signifcant challenge. 

- Applications doses. Several case studies highlight the success of phage therapy. For example, experiments have shown good results against Aeromonas. Trials targeting salmonella, E. coli, and Enterococcus in chickens and pigs conducted before the COVID-19pandemic successfully eliminated E. coli and Enterococcus at a concentration of 1. Other experiments with titres ranging from 10^5 to 10 ^6 ave also been conducted, showing varying degrees of success. 

Mode of administration in chicken farms. In chicken farms, phages are primarily used as a preventive measure rather than a treatment. It is more efective to administer phages through water rather than feed, as it ensures better control and consistent intake by the chickens. Prophylactic use in young chicks is preferred, as it does not need to be prolonged. 

- Economic and practical considerations at the farm level. Farmers generally prefer immediate solutions, such as antibiotics, which are readily available and afordable. Therefore, phage therapy must be costefective and easily accessible. This necessitates close collaboration between veterinarians and farmers to ensure the practical application of phage therapy. 

- Broader applications. Phage therapy is also being explored in aquaculture, such as in Georgian salmon farms and dairy farming, where phages are used to treat mastitis. Also, phages are used in mastitis treatment of cows with a patented phage product called Mastiphage. Initially a small project, it has now expanded. Farmers send milk samples for bacterial identifcation and use phages to wash cows instead of injecting them. However, the washing of cows requires larger volumes of phages, potentially increasing costs. 

- Phages in small animals. Phages are used to address common infections in small animals, including wounds and respiratory tract infections. 

- Phages in plants. Research is ongoing to use phages against bacterial diseases in plants, such as tomatoes and potatoes, with promising in vitro results. 

- Addressing resistance. The emergence of phage-resistant bacteria is a risk, which can be mitigated by the use of phage mixtures with overlapping host ranges, which are less likely to lead to resistance. Mixtures are also more efective and provide quicker results, especially when used in controlled environments, such as water supplies for poultry. However, more information regarding the emergence, extent, persistence and spread of resistance in phage cocktails is required. 

- Innovations and future directions. In Georgia, phage therapy has been used innovatively to treat various conditions, from bee diseases to male pig infertility caused by testicle infections. Phages have also been explored for use against anthrax and Brucella, mainly for diagnostic purposes due to regulatory constraints. 

- Need for resources and collaboration. There is a pressing need for a veterinary network to facilitate access to phages, improved statistical information on AMR, and more resources for research. Curiousity-driven research and enhanced collaboration among stakeholders are crucial to overcoming the challenges and realizing the full potential of phage therapy in agriculture. 

In conclusion, while the practical application of phage therapy in agriculture faces several hurdles, its successes and ongoing innovations underscore its potential.

Conclusion :

The workshop underscored signifcant advancements in the use of phages across the One Health spectrum while also highlighting ongoing challenges, particularly for regulatory frameworks, clinical trials and economic sustainability. Key takeaways included the need for well-designed clinical studies, collaboration with governing agencies for improved regulatory guidelines, and strategic funding to support the development and application of phage therapy. The discussions highlighted the potential of phages in various applications, from clinical treatments to agricultural use, emphasizing the importance of collaboration and continued research to fully realize their benefts in combating bacterial infections and AMR. The WHO Regional Ofce for Europe together with the Global AMR R&D Hub aim to assess the potential for expanding the application of bacteriophages across the human health, agriculture and environmental sectors through fostering dialogue, building networks and providing a platform for scientifc exchange and best practice sharing. Ultimately, this could support reducing the reliance on antibiotics and efectively address resistant infections. 

References : view online from page 23 to 24

FULL PAPER HERE : https://www.who.int/europe/publications/i/item/WHO-EURO-2025-11441-51213-78039