Phages: a virus on our side?

Chantal Babb de Villiers, Senior Policy Analyst at the PHG Foundation, talks us through bacteriophages, otherwise known as phages, their growing interest, their current usage and what might be needed for phage therapy to take the next steps towards public healthcare.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.
 
In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.
 
If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

Regarding phages, Chantal has written a briefing on Phage therapy to treat AMR infections as well as two blogs: Examining whether viruses can combat antimicrobial resistance and Viruses for good – the case for phages.

If you have any questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: 0:12

Welcome to'Making science work for health', the PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. The progress being made by teams of scientists and researchers around the world is gaining more interest and attention. Many of the latest advances feature genomics and omics related technologies. The field in which the PHG Foundation has more than 25 years of experience, helping policymakers get to grips with practical, on the ground delivery.'Making science work for health' aims to look behind the hype and explain what new science means for patients, health professionals, and members of society. My name is Ofori Canacoo, part of the communications team at the PHG Foundation, and host of'Making science work for health'. For this episode, we're talking about phages. There is a growing problem of bacterial infections becoming more resistant to antibiotic treatment. Several institutions are looking into how this issue might be resolved. One promising field is bacteriophages, otherwise known as phages, which has the potential to be a powerful tool in healthcare's arsenal. Dr Chantal Babb de Villiers, Senior Policy Analyst in Biomedical Science at the PHG Foundation, joins us to discuss the growing interest in phages, their current usage, and what might be needed for phage therapy to take the next steps towards public healthcare. Hello Chantal.

Chantal: 1:38

Hello Ofori, how are you?

Ofori: 1:40

I'm good, how are you?

Chantal: 1:41

Very good, thank you. Thank you for having me here.

Ofori: 1:43

Well, thank you for joining us again. Let's get right into it. We're talking about phages, so to start off with, could you tell us what phages are?

Chantal: 1:53

So what are bacteriophages? So phages are viruses that can infect bacteria. So it's useful to kind of think of it as a lock and key where you've got the lock, which is the bacteria, and then you've got a key, which is the phage. The phage finds the bacteria and can actually unlock it, or in this case, burst and kill the bacteria. So this is where the interest is. Because phages are highly specific to the bacteria, they don't actually affect any of the human cells around them, and will only target and kill the bacteria. So, phages are one of the most abundant organisms on the world. There's millions and billions of them all around us all the time. And there's been a lot of progress made on the science of phages, where the technology has improved, that we can understand their genomes a lot better, and as well as the imaging. So we know how to look at phages a lot better, and they're classed according to what their genetic content is, as well as the morphology of the phages. So how they actually look. Having this information and knowledge has allowed us to understand a lot more about phages recently.

Ofori: 2:59

So why is there a growing interest in phages?

Chantal: 3:03

Because phages can target specific bacteria, there's growing interest in using phages to treat bacterial infections, primarily around the fact that antimicrobial resistance(AMR) is increasing as significantly as it is. So AMR is a major problem. It's a critical global health threat, and each year over a million people are dying of antimicrobial resistance or AMR infections, and we're trying to find alternatives to antibiotics. For too long, antibiotics have been the go to for the treatment of infections, which has resulted in ever increasing number of antimicrobial resistance, or in this case, bacteria and antibiotic resistance, and we're looking for alternatives. We need to find other solutions that can combat antimicrobial resistance, and that can provide care and treatment for people who have got these infections.

Ofori: 4:02

So phages could be a potential solution to the challenge of antimicrobial resistance.

Chantal: 4:07

Yeah, the hope is definitely there that they'll be part of the solution, that there'll be another alternative in the toolbox to combat AMR infections. Because Phages are so specific to the bacteria that they're infecting. They are very targeted, unlike antibiotics, which are very broad spectrum and can harm human cells as well. There's a lot of hope that phages are going to be a good alternative and a good use against antimicrobial infections. So, especially for people who've got no other alternative and there is no other life saving opportunities for them. This is definitely something that provides hope for people.

Ofori: 4:47

Are phages being used in clinical practice?

Chantal: 4:49

So in the UK at the moment, they're mainly used for compassionate use cases. So you'll sometimes see them in the press, where they've been used for very specific untreatable infections. So in these situations, there has been nothing really left to do, but there's no guarantee that they'll always work. And there's a number of criteria that have to be met before a phage can be considered to be used for an infection. However, there are places in the world where they have been used, particularly in Eastern European countries, and this is historical because around the time that antibiotics were discovered, so were phages. And these countries decided to continue doing research and work on phages, while a lot of other places, including Europe, a lot of effort was put into looking at antibiotics and understanding and utilising antibiotics rather than looking at alternatives.

Ofori: 5:42

So why then were antibiotics more appealing than phages, do you think?

Chantal: 5:48

Probably because it's a lot simpler. You come up with the formulation, you put it together, you've got a dose, you give the dose to people. Whereas phages, you've got to find a match to the bacterium. You've got to look for that key and lock situation. So you've got the lock and you need to find the key and finding that key can be very complicated and difficult. And this is where some of the challenges around using phages is happening and we're encountering. Trying to figure out how we're going to implement and use phages.

Ofori: 6:22

So what practical challenges or limitations do we face when trying to implement phage therapy?

Chantal: 6:27

So at the moment there's still a number of issues that we need to resolve and figure out and a lot of this information needs to come from clinical trials. So at the moment, there is a lack of standardised protocols that outline the dosing or the duration and the clinical monitoring that needs to take place for the use of phages and in clinical care. We need to validate the diagnostic surrogates that are being used to monitor how effective phages are working in individuals who are being treated and then one of the more complicated ones is sourcing the phages, so actually finding a phage that matches the bacteria that's causing an infection. The supply can be variable and depends on the bacteria and being able to identify the phage that will match that bacteria can be quite difficult. And this is where the establishment of libraries is becoming valuable in speeding up this process.

Ofori: 7:22

Are these dedicated libraries?

Chantal: 7:23

Yes, yeah. So there are phage libraries that have been set up by research groups in different institutes where they're collecting phages. They have a variety of different phages in their libraries. You can think of it as a lock and key. They've got all the keys. They're now trying to find locks that these keys can go to. The establishment of these diverse phage libraries has become really important in being able to use phages more widespread and more widely. So these libraries have also enabled us to understand a lot more around how we're going to generate these phages, the protocols that are needed for their use, the cutting edge technologies to catalog them, so the sequencing and the different imaging technologies that are being used and how to isolate, detect, purify, and characterise all these phages from all the diverse different environments where you can find them. They can be found everywhere around the globe and in every environment and people will literally go around picking up samples and then taking them back to generate them and put them within these libraries and catalogue them in the hopes that when someone comes along with a bacterium that needs a treatment or needs a phage to use for treatment, they can go into the library and pull them out and see of these ones that we've got, which one of them will actually match the bacteria.

Ofori: 8:45

So would regulations for phages be in any way similar to current medicines?

Chantal: 8:50

So phages are not considered are not your usual medicine. They are organisms and therefore can change. And often they do require a host to survive, and as such they do not follow the usual pathway to medicinal regulations and medicinal licensing pathways. So bacteria can vary enormously and so do phages and making sure you pick the right phage for the bacteria is very important. And we can rarely do that confidently without actually doing experimentation and testing and matching the phage to the bacterium. They then need to be purified and formulated for that infection. So, in addition, there is also the arms race that is happening, so as the bacteria adapts or evolves and changes, so do the phages to be able to continue to infect them.

Ofori: 9:41

But the phages would only evolve or change in response to the bacteria?

Chantal: 9:47

Yes. Yeah. They are adapting with each other. So that's why there's an arms race taking place. Yeah. So if we look at the regulations in the UK, there are actually none that are specific for phages. However, we've learned that MHRA is developing a non-binding advisory guidance for phage therapy in humans. And this is highly anticipated and will provide more clarity for the field to move forward. Other countries have already acknowledged that the classification of phages needs careful consideration. So if we look, for example, at Belgium, alongside their conventional medicinal product development and licensing pathways, they've also got a magisterial phage preparation framework. And this framework means that phages can be delivered to individual patients under the direct responsibility of medical doctors and pharmacists, whilst the production and quality control requirements are being met. So this, it ensures that the quality and safety of individual phages is being controlled by independent and approved laboratory. So they're fulfilling the requirements of ensuring the safety for patients.

Ofori: 10:56

Okay, so with all this work looking into phages, we still wouldn't be expecting it to completely replace antibiotics, would we?

Chantal: 11:05

No, that's very unlikely to occur mainly because that is the gold standard for care and ethically, you would not want to remove that level of care for patients. But also interestingly, we might not want to because some trials have demonstrated that the bacteria actually becomes sensitive to the antibiotic again once they start using phages. So that means that in the presence of phages, the antibiotics are becoming effective again. So we'll start to learn more as trials are done and start to understand if we would actually only want to do phage on their own, or if you would want to keep it as a dual treatment of phage and antibiotics.

Ofori: 11:45

So what's needed to help phage therapy reach its full potential.

Chantal: 11:49

So for human treatment applications, phages are generally considered to be safe and safe to use on humans, but we need clinical trials to evidence this and to provide evidence of their quality and the efficacy of these trials, that there is a clinical use for phages. And we've had some clinical trials take place and they've provided us with many lessons that we've learned from, but we need more to better understand the effectiveness of phages in clinical care. And there is a general agreement that the current clinical trial protocols are not suited. And we need new strategies to enable clinical trials to demonstrate the feasibility of this potential therapeutic.

Ofori: 12:36

Okay. So what are the lessons learned that you spoke about?

Chantal: 12:39

So yes, so from these clinical trials, they learned a lot around how they're actually going to use phages within clinical care. And the lessons that were learned ranged from regulatory hurdles, the production of phages, how to keep them stable for delivery; to hospitals to reach the patients, how the logistical issues around getting a sample from the patient to these institutes or libraries where they can find matches for phages, as well as delivery mechanisms of how to get the phage to the site of an infection. So for example, there was a study looking at using inhalers to deliver phages to the lungs of people that had lung infections. And the phages were being effective, but it was actually the inhaler mechanism that reduced the potency of the phages. So it wasn't that the phages weren't working, but we weren't able to deliver the phages to the sites of infection in an efficient way. So these are the types of lessons we're learning from these trials. It's not necessarily around the usefulness of phages, it's around the logistics and the administration of phages that we've been learning a lot. And also, the regulations around it. So understanding what is required to have a safe product used on clinical patients. Looking ahead, there is a need for increased phage production to support large scale use and to support trials that we need to have taking place. And to do this, It would be useful and needed to establish some sort of phage manufacturing process that would meet standards such as good manufacturing practice. And to achieve these good manufacturing practice standards, there is a relatively high financial burden to establish this, which has been a hindrance to advance the field to go forward. There are places that exist that can produce phages at GMP or good manufacturing practice level. And those are actually the ones that are being used in the UK in clinical practice for compassionate use. So they're usually imported from overseas where they have got facilities doing it to these standards.

Ofori: 14:54

So are we in any way close to phage therapy being fully implemented in the UK?

Chantal: 15:00

So, definitely whilst phage use is available in the UK, it's very much on an ad hoc basis and it's very much, there's a process that needs to be followed to get compassionate use of phages at the moment. But there are signs that we are heading towards wider implementation, which is very exciting because there is so much potential for phages to be useful in clinical practice, but there's still numerous issues that need to be resolved, but it is promising that there is a lot of increased interest and focus on their potential use. And some of this interest comes from, for example, the House of Commons Science, Innovation and Technology Committee report on the antimicrobial potential of bacteriophages, which highlighted the exciting possibilities of using phages. The report also goes into and discusses the safety, efficacy, and regulatory challenges of using phages in clinical settings within the UK. And there was a government response to this report earlier this year that acknowledged the important role that phages could have, as well as acknowledging the challenges and barriers to their use within the UK. The biomedical research community is certainly ready and trying to get phages implemented into healthcare. There are new funding streams becoming available, the technology has improved that we understand phages a lot better, and globally clinical trials for that phage therapy are underway. But as mentioned, we need more and a careful design of these trials to ensure that they are informative and provide information that is needed to move phage therapy towards clinical applications.

Ofori: 16:42

Great. Chantal, thank you very much for joining us and no doubt we'll have you on again.

Chantal: 16:48

Oh, thank you. It's been a pleasure as always. Thank you so much, Ofori.

Ofori: 16:58

And that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org. And if you have any further questions about the topic, then you can email us at intelligence@phgfoundation.org. Thank you for listening and we look forward to bringing you a new topic in the next episode.