Supplementary written evidence by the Phage Research Centre, Leicester (PHA0046)

Drafted by Prof Martha Clokie with contributions from academics Dr Andrew Millard, Dr Ed Galyov and Dr Paul Robson, and two physicians Dr Mel Haines and Dr Marie Noelle Vieu.  Together we are the core staff of the newly established, first UK Centre for Phage Research, based at the University of Leicester https://le.ac.uk/research/centres/phage-research. 

The Inquiry has been very useful. It has allowed the various stakeholders to reflect on the potential of phage therapy and how it fits with the national AMR agenda and it has also opened up opportunities. There is now official engagement by relevant Government bodies about this technology and clearer commitment to work together on this agenda. We welcome the commitment of MHRA to developing regulations around emerging technologies.

The hearings allow us to identify some aspects that we think need clarification. 

Timeliness: Why is it particularly timely to study phages now in comparison to 100 years ago when they were first found?

While the use of bacteriophages is not a ‘new treatment’, genomics (a modern expanding technology), has allowed for safer, extended and tailored use, addressing a broader range of issues.

With the availability of genome sequencing, it is much easier to identify and classify phages based on their DNA or ‘genetic make-up’.  Previously bacteriophages were characterised based on what they killed so it wasn’t possible to determine how they worked, or which might be more effective.

Genome information allows researchers to design and engineer bacteriophages with specific properties or modifications, such as increased specificity or altered host range. This was not possible in the past because the genetic basis of phage infectivity was not understood.

Another important consideration is that genome information also allows researchers to understand the host range of bacteriophages, which is the range of bacterial strains that they can infect. This is important for developing phage therapies that are effective against specific bacterial pathogens. Therefore, we can potentially understand in advance which phages will work rather than having to do trial and error experiments.

Genome information can also now be used to evaluate the safety of phages for use in clinical settings. This includes identifying genes that could potentially cause harm to the human or other microbes. Previously the safety of phage therapies could only often be evaluated based on empirical observations.

Overall, the availability of genome information has greatly enhanced our ability to study and understand bacteriophages and has paved the way for the development of more effective and targeted phage therapies – hence the therapy is incredibly timely.

Bacteriophages also fit with the growing ‘personalised medicine’ approach in medical treatment. Personalised and targeted interventions (ref: https://www.england.nhs.uk/wp-content/uploads/2016/09/improving-outcomes-personalised-medicine.pdf

What are the advantages of phages compared to other technologies?

It was emphasised by many witnesses that bacteriophages are one of several modalities that can help to combat AMR.  This is true and it is important that we don’t view phages as the only ‘silver bullet’.  The World Health Organisation recently surveyed the pre-clinical pipeline of new approaches and categorised the other modalities as anti-virulence agents, biologics, decolonisation agents, immune modulators, microbiome modifying agents, and resistance modulating agents (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236604).  Although these ‘modalities’ are potential alternatives to antibiotics for treating AMR, it is important to acknowledge that of these modalities, phages are useful because of the advantages listed below.  In a highly cited review of this topic, of the 10 most likely antibiotic alternatives, 3 were phages (natural phages, engineered phages and phage lysins - the enzymes in phages that allow phages to kill bacterial cells). Czaplewski L (Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect Dis. 2016).

Readily available and inexpensive: Bacteriophages can be isolated and purified from natural sources, making them a potentially sustainable and adaptable solution to the problem of AMR.  Each bacterium has its own set of phages – so these novel approaches exist in nature.  They just have to be isolated and worked on to bring them and the products they encode to use. In contrast, the identifying target candidates from the other approaches is more complex and often requires large-scale investigation and screening, which can be resource-intensive and costly.

Specificity: bacteriophages are highly specific in their mode of action, meaning they only infect and kill the specific bacterial strain(s) they are designed to target. In contrast, many of the other approaches are less specific and can harm beneficial bacteria, leading to collateral damage to the microbiome and increasing the risk of developing secondary infections. 

Resistance: Bacteria can develop resistance to many antimicrobial products, including phages. However bacteriophages have evolved alongside bacteria and can adapt to overcome bacterial defenses, making it easier to overcome bacterial resistance, a natural phenomenon.  Phages may be used in combination or used in succession There is also growing evidence that phages can  make bacteria sensitive again to antibiotics.

Diversity and targetability:  Phages are both the most numerous and diverse biological entities on the planet and each bacterial species studied has it’s own set of phages that target and kill it.  Furthermore, bacteriophages can be identified or engineered to target specific bacterial strains, making them more effective against antibiotic-resistant infections. In contrast, many other approaches are often less targetable and may not be as effective against specific bacterial strains that are associated with AMR. 

One health: Bacteriophages fit well with a one health agenda whereby they could potentially be used in livestock to reduce the ultimate transmission of AMR bacteria to humans.  This is not as applicable to the other modalities listed above.

While phages offer these advantages over other approaches for treating antimicrobial resistant bacterial infections, each approach has its own strengths and weaknesses and may be better suited to specific infections/patient populations.  In some cases phages could be used in combination with other approaches. Further research is needed to fully evaluate the safety and efficacy of phage and other modalities combined and to determine the most effective strategies for treating AMR. Specific funding for phage therapy development is required to allow rapid progress to respond to the urgency of AMR. 

The phage therapy vision is NOT to substitute antibiotics, but to ‘to protect the medicine that protects us’. The Centre for Phage research is adopting this vision and has already taken the following steps to progress: development of phage bank and compassionate use to build systematically the evidence of efficacy and safety; fundamental research to strengthen and guide the therapeutic use of phages;  based on this knowledge progressing with clinical trials targeted to specific conditions identified as priority for phage therapy, especially infections caused by antibiotic resistant bacteria and/or requiring use of last line antibiotics; 

Antibiotics are essential to modern medicine. Phages can protect them by modifying (reducing) bacterial resistance to antibiotics by removing the selective pressure on bacteria that antibiotic use imposes.  They can also protect by providing an alternative to treat AMR bacterial infections.  Potentially they could also be used instead of antibiotics from the ‘watch’ and ‘reserve’ categories.

We should be aware of non-scientific factors that might impact on decision to invest in phage research 

It is important to note that the study of bacteriophages, or phage therapy, has been and in some cases remains subject to prejudice and scepticism due to historical events and misconceptions.  

During the Cold War, the former Soviet Union conducted extensive research on phages for medical purposes, while the West focused primarily on antibiotics. This led to a perception that phage therapy is a Soviet technology, and it is still associated with communist ideology, which contributed to a lack of interest and funding for phage research in the West.

Clearly with the advent of antibiotics in the mid-20th century, the use of phage therapy declined in Western medicine. This was due in part to the success of antibiotics in treating bacterial infections, but also to some early failures and difficulties in implementing phage therapy in clinical settings. This led to a perception that phage therapy was a ‘failed’ technology superseded by antibiotics.

For some time the mechanisms of action and potential as a therapeutic tool were not well understood.  However technological progress has led to greater understanding on how phages work and their challenges.

Interest in phage therapy has recently been renewed due to the increasing prevalence of antibiotic-resistant infections and the recognition of the potential benefits of phage therapy, such as their specificity, adaptability, and potential to overcome bacterial resistance. As more research is conducted on phage therapy, it becomes clearer of where and how phage therapy could be beneficial. More data is needed to be collected to confirm effectiveness and safety and this requires funding. 

Producing phages as licenced or unlicenced medicine

Although phages can currently be used as an unlicensed medicine there are several advantages to having bacteriophages be a licensed medicine and this requires a dialogue with regulators to move to a point where phages can be licensed. Although it is important for bacteriophages to be used as an unlicensed medicine in the short term as people are dying from multi-resistant antibiotic infections and need treatment, the advantages of developing a licensed product are as follows:

Quality control. Licensed medicines are subject to stringent quality control standards, which ensure that they meet specific requirements for safety, purity, and potency. This provides reassurance to patients and healthcare providers that the product they are using is safe and effective.

Regulatory approval. To become a licensed medicine, bacteriophages must undergo regulatory approval by government agencies so MHRA or the VMD for humans and animals respectively. This involves a rigorous evaluation of the safety and efficacy of the product, as well as its manufacturing process and quality control standards. Regulatory approval provides a level of confidence in the safety and effectiveness of the product.

Reimbursement and Market Access. Licensed medicines are more likely to be widely used within the NHS making phage more widely accessible to patients.

10 May 2023