The Microbiology Society is a membership charity for scientists interested in microbes, their effects and their practical uses. It is one of the largest microbiology societies in Europe with a worldwide membership based in universities, industry, hospitals, research institutes and schools. Microbiology is the study of all living organisms that are too small to be visible with the naked eye. This includes bacteriophages and their bacterial targets.
Our principal goal is to develop, expand and strengthen the networks available to our members so that the science of microbiology provides maximum benefit to society.
We note that our submission reflects the views expressed by 17 members of the Microbiology Society who responded to our call for input. We present evidence provided by our respondents and provide recommendations where appropriate.
How well established is the evidence base for phages as an antimicrobial for humans? What are their strengths and weaknesses?
Some current research is outlined below. It is worth noting that while this question specifically addresses use of phages as antimicrobials in humans, use of phages in agriculture, for example to reduce antibiotic use in animals, could be beneficial.
Phages have been employed in Eastern Europe and Russia for decades. More recently there have been clinical trials in Western Europe, North America and Australia to test the efficacy of bacteriophages:
b) Phage therapy has been successfully employed by the NHS. A cystic fibrosis patient with a drug-resistant infection was treated successfully at Great Ormand Street Hospital. More recently, patients with diabetic foot ulcers were successfully treated and as a result NHS Scotland appointed the UK’s first clinical phage specialist.
a) Phages are very specific and can target a pathogen without destroying healthy microbiomes. Phages can be used in their naturally occurring form to create personalised medicines. In addition, phages can be optimised either through evolutionary adaptation and/or genetic modification to enhance antimicrobial properties.
b) There is evidence of synergy when phages are used in conjunction with conventional antibiotics,. Combination treatments could slow the development of resistance in bacteria and extend the utility of existing antibiotics.
e) Phages that target many multi-drug resistant bacteria have been identified and can be isolated from the natural environment at low cost.
f) Phages are self-regulating, so will increase at the site of infection and be cleared from the body once the infection is treated.
g) Due to the abundance of phages in nature, there is an extensive supply of potential alternative phages to be used if/when resistance to a phage develops.
h) Phages encode proteins (e.g., lysins and other enzymes) with antimicrobial properties that can be isolated from the self-replicating phage.
i) The application of multiple phages in ‘phage cocktails’ can prevent the development of resistance and/or direct the evolution of bacteria to reduce their pathogenicity.
a) Bacteria can evolve resistance to phages as they do when exposed to antibiotics. Determining the efficacy of applying phages to repeat infections requires further experimental data.
b) Phages have a number of genes with unknown function. Whether these genes can cause unforeseen interactions in vivo is unknown.
c) Unlike antibiotics, phage specificity requires the correct phages to be matched to an infecting pathogen. Identifying potential phages can take days to weeks and requires access to large phage biobanks. Compared to mass-produced antibiotics, phage therapy is labour intensive and not currently suitable for treating fast-progressing infections.
d) The high specificity of phages poses a challenge for standard design of clinical trials and most clinical studies have not been double-blind, placebo-controlled studies. More research is needed ahead of widespread use.
e) Phage therapy can only be deployed if the causative agent is known. For some infections, particularly those with multiple bacterial pathogens, this can pose a challenge with current diagnostics.
f) Some phages are difficult to store due to susceptibility to degradation by light, heat, pH and other external factors.
g) It is unclear how phages are distributed to different organs when inside the human body. Organ cells may respond in different ways making it difficult to determine clinical dosages. However, the self-replicating nature of phages at the site of infection reduces the need for precise dosing.
h) Understanding of the immunogenicity of phages is limited and some studies have identified low levels of interaction with the immune system7. While they do not appear to trigger a strong immune response, the initial application can trigger antibody production in the patient’s immune system. It is possible a second application of the same phage could elicit a stronger immune response. More research is needed.
i) Measures are needed to ensure patients are treated with virulent phages (that effectively destroy the target bacteria by bursting them open) and not temperate phages (that incorporate their DNA into the bacterial chromosome forming a ‘prophage’ that can help bacterial survival). When the bacterial host cell is under threat, prophages are triggered into a replicative cycle and act like virulent phages. Standardised procedures established in other countries can readily discriminate between virulent and temperate phages and could be adopted to reduce this risk.
j) There is a low risk that phages could transfer useful DNA from one bacteria to another. They can do this by mistakenly packaging bacterial DNA into their heads when they replicate, and sometimes incorporating bacterial DNA into their genome. If such DNA includes genes that encode antimicrobial resistance or virulence, there is a risk of transfer of these traits when infecting the next bacterial cell. It is worth noting that this risk is also posed by antibiotics, which can cause temperate phages within the patient’s own microbiome to switch to a lytic cycle.
It is important to note that the risks posed by many of these weaknesses become less significant when phage therapy is considered as a last resort treatment under compassionate use.
What regulatory approaches have been used by other countries for the use of phages and what lessons can the UK learn?
In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) classifies phages as ‘unlicensed specials’. UK manufacture of unlicensed specials must be done under Good Manufacturing Practice (GMP). GMP is the area of quality assurance which ensures that medicinal products are consistently produced and controlled according to quality standards. This requires a defined manufacturing procedure, a combination of physicochemical and biological tests and stringent production facilities. Whilst chemical products can be manufactured to this standard, phages are biological agents therefore it is more difficult to meet quality requirements such as stability and consistency. The MHRA does not require imported unlicensed specials to be manufactured under GMP, and previous use of phages in the UK (see point 1b) used phages which were manufactured abroad. There are not currently any GMP facilities for phage production in the UK. UK Phage Therapy is a novel non-profit organisation aiming to act as a specialist clinical phage centre able to manufacture phages under GMP protocol, however this initiative is in its preliminary stages and has not yet been fully established. With current technology, GMP manufacture of personalised phages for a single patient under compassionate use is cost- and time- prohibitive.
Phages are currently classed as medicinal products in Europe, a label designed for industrial pharmaceuticals which cannot be customised for individual patients.
The Declaration of Helsinki allows for the compassionate use of unlicensed medicines where proven treatments have been exhausted, provided the intervention is made the object of research designed to evaluate its safety and efficacy. This is how phage therapy is employed through much of Europe and the Western world on a case-by-case basis. The UK is a signatory to the Declaration of Helsinki.
A new Standardised Treatment and Monitoring Protocol (STAMP) for phage therapy has been approved in Australia that regulates the process of phage therapy rather than a specific phage product. It does not require phages to be made under GMP for their use in clinical trials. The lifting of the GMP requirement in Australia accelerates the clinical trial process and makes a personalised medicine approach feasible for compassionate use.
The Belgian regulatory framework for phage therapy is the most advanced in the EU and is effective in allowing for routine personalised treatment using magistral (a medical product prepared in a pharmacy in accordance with a medical prescription for an individual patient) phage preparations.
Since 2007, phages have been used sporadically to treat infections in the Queen Astrid Military Hospital in Brussels. In 2018, the production and characterisation of phages suitable for magistral preparations was approved by the Belgian health authority. This means that a physician in Belgium can prescribe phages, and a pharmacist can prepare a tailor-made phage cocktail which does not have to be manufactured under GMP.
In Poland, phage therapy is classed as an experimental treatment regime rather than a medicinal product so can be more easily prescribed when other treatments fail. This simplifies the compassionate use of phages.
This classification means that phage use is permitted under certain conditions, including approval by a bioethics commission, when other available treatment has failed. The Hirszfeld Institute of Immunology and Experimental Therapy produces tailored phage therapy products to physicians and has a continuously expanding phage collection.
In Georgia phage therapy is a standard medical treatment, and they are a leading nation in terms of bacteriophage research and production.
Phage products are classed as pharmaceuticals and require a marketing authorisation similar to other pharmaceutical products. The Eliava Institute of Bacteriophages, Microbiology and Virology produces over-the-counter phage preparations and products for clinicians. There is strong public trust in the treatment and it is routinely employed. We can learn from their efficient manufacturing and commercialisation process, and how phages came to be widely accepted by the Georgian public.
Phage therapy is regulated by the Food and Drug Administration (FDA) and can be employed as a last-resort treatment in the USA. Phages do not need to be manufactured under GMP for this purpose. In addition, products entering phase I clinical trials are not required to be manufactured under GMP, accelerating development and enabling the gathering of safety data across a large population.
In 2010, the US Navy Biological Defence Research Directorate launched an initiative to explore the use of phage therapy, and in 2016 it funded the development of Adaptive Phage Therapeutics (APT) which now acts as large phage bank.
Waiving the requirement for GMP manufacture of phages for compassionate use could align the UK with other successful international frameworks. For broad use and new off-the-shelf phage products to be feasible, significant investment is needed for a UK GMP manufacturing facility. Alternatively, GMP requirements could be lifted and a regulatory body established to monitor phages to an appropriate standard.
What opportunities does the UK have for regulatory divergence from the EU on phages, and what would the implications be?
What are the major barriers and opportunities relating to the development and deployment of phages in the UK?
How well developed is the UK’s phage research and clinical trial pipeline and how could it be improved?
The current pipeline from phage research through to clinical trial is undeveloped in the UK. According to clinicaltrials.gov, only two clinical trials on phage therapy have been initiated, one of which was withdrawn before completion.
To what extent is the UK Government ensuring that phages research and development is adequately funded and supported?
There is a lack of phage specific funding calls in the UK. This means that phage therapy research applications are often unsuccessful. Phage specific funding calls and increased investment in infrastructure is necessary.
The 2014 Jim O’Neill review on AMR highlighted bacteriophages as a hope for the future, so we greatly welcome this inquiry reaching out to the phage community. The Microbiology Society is well placed to support its members and the wider scientific community to address and raise awareness of AMR and provide expert microbiological opinion and evidence for policymakers on topics such as this to combat this global issue. We wish to send a message of support to the UK Government and would welcome the opportunity to inform future projects.
 Stacey, H.J., De Soir, S. and Jones, J.D., 2022. The Safety and Efficacy of Phage Therapy: A Systematic Review of Clinical and Safety Trials. Antibiotics, 11(10), p.1340.
 Dedrick, R.M., Smith, B.E., Cristinziano, M., Freeman, K.G., Jacobs-Sera, D., Belessis, Y., Whitney Brown, A., Cohen, K.A., Davidson, R.M., van Duin, D. and Gainey, A., 2023. Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease. Clinical infectious diseases, 76(1), pp.103-112.
 Law, N., Logan, C., Yung, G., Furr, C.L.L., Lehman, S.M., Morales, S., Rosas, F., Gaidamaka, A., Bilinsky, I., Grint, P. and Schooley, R.T., 2019. Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient. Infection, 47(4), pp.665-668.
 Dedrick, R.M., Guerrero-Bustamante, C.A., Garlena, R.A., Russell, D.A., Ford, K., Harris, K., Gilmour, K.C., Soothill, J., Jacobs-Sera, D., Schooley, R.T. and Hatfull, G.F., 2019. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature medicine, 25(5), pp.730-733.
 Ennals, E. (2022, August 27). How an army of “friendly viruses” so small that there are more than 10 million of them in a thimbelful of sea water are leading the NHS’s war on superbugs. The Daily Mail.
 Nguyen, S., Baker, K., Padman, B.S., Patwa, R., Dunstan, R.A., Weston, T.A., Schlosser, K., Bailey, B., Lithgow, T., Lazarou, M. and Luque, A., 2017. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. MBio, 8(6), pp.e01874-17.
 Van Belleghem, J.D., Dąbrowska, K., Vaneechoutte, M., Barr, J.J. and Bollyky, P.L., 2018. Interactions between bacteriophage, bacteria, and the mammalian immune system. Viruses, 11(1), p.10.
 Luo, J., Xie, L., Liu, M., Li, Q., Wang, P. and Luo, C., 2022. Bactericidal Synergism between Phage YC# 06 and Antibiotics: A Combination Strategy to Target Multidrug-Resistant Acinetobacter baumannii In Vitro and In Vivo. Microbiology Spectrum, 10(4), pp.e00096-22.
 Oechslin, F., Piccardi, P., Mancini, S., Gabard, J., Moreillon, P., Entenza, J.M., Resch, G. and Que, Y.A., 2017. Synergistic interaction between phage therapy and antibiotics clears Pseudomonas aeruginosa infection in endocarditis and reduces virulence. The Journal of infectious diseases, 215(5), pp.703-712.
 Segall, A.M., Roach, D.R. and Strathdee, S.A., 2019. Stronger together? Perspectives on phage-antibiotic synergy in clinical applications of phage therapy. Current opinion in microbiology, 51, pp.46-50.
Chan, B.K., Sistrom, M., Wertz, J.E., Kortright, K.E., Narayan, D. and Turner, P.E., 2016. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Scientific reports, 6(1), pp.1-8.
 Dedrick, R.M., Smith, B.E., Cristinziano, M., Freeman, K.G., Jacobs-Sera, D., Belessis, Y., Whitney Brown, A., Cohen, K.A., Davidson, R.M., van Duin, D. and Gainey, A., 2022. Phage therapy of Mycobacterium infections: compassionate-use of phages in twenty patients with drug-resistant mycobacterial disease. Clinical Infectious Diseases.
 Liu, D., Van Belleghem, J.D., de Vries, C.R., Burgener, E., Chen, Q., Manasherob, R., Aronson, J.R., Amanatullah, D.F., Tamma, P.D. and Suh, G.A., 2021. The safety and toxicity of phage therapy: a review of animal and clinical studies. Viruses, 13(7), p.1268.
 Gurney, J., Brown, S.P., Kaltz, O. and Hochberg, M.E., 2020. Steering phages to combat bacterial pathogens. Trends in microbiology, 28(2), pp.85-94.
 Yadav, M.K., Song, J.J., Singh, B.P. and Vidal, J.E., 2020. Microbial biofilms and human disease: a concise review. New and future developments in microbial biotechnology and bioengineering: Microbial biofilms, pp.1-13.
 Parasion, S., Kwiatek, M., Gryko, R., Mizak, L. and Malm, A., 2014. Bacteriophages as an alternative strategy for fighting biofilm development. Polish Journal of Microbiology, 63(2), p.137.
 Hatfull, G.F. and Hendrix, R.W., 2011. Bacteriophages and their genomes. Current opinion in virology, 1(4), pp.298-303.
 Podlacha, M., Grabowski, Ł., Kosznik-Kawśnicka, K., Zdrojewska, K., Stasiłojć, M., Węgrzyn, G. and Węgrzyn, A., 2021. Interactions of bacteriophages with animal and human organisms—safety issues in the light of phage therapy. International Journal of Molecular Sciences, 22(16), p.8937.
 Hyman, P., 2019. Phages for phage therapy: isolation, characterization, and host range breadth. Pharmaceuticals, 12(1), p.35.
 Enault, F., Briet, A., Bouteille, L., Roux, S., Sullivan, M.B. and Petit, M.A., 2017. Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. The ISME journal, 11(1), pp.237-247.
 McGannon, C.M., Fuller, C.A. and Weiss, A.A., 2010. Different classes of antibiotics differentially influence Shiga toxin production. Antimicrobial agents and chemotherapy, 54(9), pp.3790-3798.
 UK phage therapy, UK Phage Therapy. Available at: https://ukphagetherapy.org/ (Accessed: December 20, 2022).
 World Medical Association. (2001). World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bulletin of the World Health Organization, 79 (4), 373 - 374. World Health Organization.
Bacteriophage News (2022) Stamp protocol approved for phage therapy in Australia, Bacteriophage News. Available at: https://www.bacteriophage.news/stamp-protocol-phage-therapy-in-australia/ (Accessed: December 16, 2022).
Djebara, S., Maussen, C., De Vos, D., Merabishvili, M., Damanet, B., Pang, K.W., De Leenheer, P., Strachinaru, I., Soentjens, P. and Pirnay, J.P., (2019). Processing phage therapy requests in a Brussels military hospital: Lessons identified. Viruses, 11(3), p.265.
 Pirnay, J.P., Verbeken, G., Ceyssens, P.J., Huys, I., De Vos, D., Ameloot, C. and Fauconnier, A., 2018. The magistral phage. Viruses, 10(2), p.64.
 Żaczek, M., Weber-Dąbrowska, B., Międzybrodzki, R., Łusiak-Szelachowska, M. and Górski, A., 2020. Phage therapy in Poland–a centennial journey to the first ethically approved treatment facility in Europe. Frontiers in Microbiology, 11, p.1056.
Innovate UK KTN launches Phage Innovation Network (2022) Innovate UK KTN. Available at: https://ktn-uk.org/news/innovate-uk-ktn-launches-phage-innovation-network/ (Accessed: December 15, 2022).
Early Access to Medicines Scheme (EAMS): Task Group and principles (2016) GOV.UK. Available at: https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-how-the-scheme-works/early-access-to-medicines-scheme-eams-task-group-and-principles (Accessed: January 11, 2023).
 Jones, E.H., Letarov, A.V. and Clokie, M., 2020. Neat science in a messy world: the global impact of human behavior on phage therapy, past and present. PHAGE, 1(1), pp.16-22.
 Macdonald, K.E., Stacey, H.J., Harkin, G., Hall, L.M., Young, M.J. and Jones, J.D., 2020. Patient perceptions of phage therapy for diabetic foot infection. PloS one, 15(12), p.e0243947.
 Beck, A., Wurch, T., Bailly, C. and Corvaia, N., 2010. Strategies and challenges for the next generation of therapeutic antibodies. Nature reviews immunology, 10(5), pp.345-352.
Home - ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/ (Accessed: December 21, 2022).
Priority Programme "New Concepts in Prokaryotic Virus-Host Interactions – From Single Cells to Microbial Communities" (2020) Deutsche Forschungsgemeinschaft. Available at: https://www.dfg.de/foerderung/info_wissenschaft/2020/info_wissenschaft_20_48/index.html (Accessed: December 20, 2022).
UK phage therapy, UK Phage Therapy. Available at: https://ukphagetherapy.org/ (Accessed: December 20, 2022).
 O'Neill, J., 2016. Review on antimicrobial resistance: tackling drug-resistant infections globally: final report and recommendations