So I'm Helen McShane,
and I'm the director of the NIHR Oxford Biomedical Research Centre that is hosting this Oxford Reads Kafka TB event for us this evening.
The BRC represents a partnership between the University of Oxford and Oxford University Hospitals NHS Foundation Trust.
Sorry. Excuse me. We're funded by the government to conduct translational research for patient benefit.
That means developing new vaccines, new drugs, new diagnostic tests, new tools, all of which are designed to improve the health.
And wealth of the patient, of of patients and the NHS.
The BRC is organised into 15 themes,
one of which is called life saving vaccines and one of which is called Modernising Medical Microbiology and Big Infection Data.
The work of my research group sits within the vaccines theme, and the work of Phil's uh,
group sits within the modest Modernising Medical Microbiology group.
We both work on TB, so that's why we're here to talk to you today, because of course, the the whole,
um, of this week's events are really focussed around the fact that Kafka died 100 years ago of TB.
Um, uh, so that's that's why we're here today. I'm going to give a talk updating you on some of the progress in vaccine development.
Uh, we're then going to hear from Amy about the lived experience of having tuberculosis.
Uh, and then Phil is going to talk to us about, uh, some updates on diagnostic tests.
So when I was thinking about this talk, uh, I found this quote, um, or this comment where that Kafka saw his TB as a liberation.
I'm not quite sure I agree with that. Uh, and I'm quite sure that the 10.6 million, uh, people who developed TB in 2022,
not to mention the 1.3 million people who died in 2022 of TB, would describe it as a liberation.
TB remains a very significant global health problem around the world today.
It is probably, again the leading cause, infectious cause of death.
So I think it's overtaken Covid. Uh, and and got back into that number one position.
Drug resistance is an increasing problem. About half a million people have drug resistant TB every year.
And Phil will talk a little bit about that.
The geographical overlap with the HIV epidemic, which makes people more susceptible to TB and the burden of latent infection,
it's estimated that about a quarter of the world's population are latently infected with TB, and are at risk of reactivation.
Should that latent, uh, should they become immunocompromised for any reason.
TB is different to HIV and malaria. The other big what used to be called the big three pathogens in that we already have a vaccine,
BCG, which is one of the world's most widely used vaccines.
It's been given to over 3 billion people around the world.
And BCG has been around for over 100 years.
It was first given orally in 1921, and there have been many, many studies over the years looking at how well BCG works to protect people against TB.
We know that when it's given at birth, as it is throughout most of the developing world,
that it confers very good and reliable protection against disseminated TB.
So that's TB that's spread outside of the lungs, particularly that spread to the to the brain, something we call TB meningitis.
But what it really doesn't do very consistently is protect against lung disease, particularly in young adults.
Uh, and adolescents. It's very variable, the protection it confers against lung disease.
So the British MRC study conducted in this country in the 1950s shows the BCG was 80% protective, and that protected protection lasted for 20 years.
In comparison, protection seen in, for example, India or Africa is close to zero.
So one of the real challenges is what's underlying that variability.
And how can we develop better vaccines that protect more universally.
We know that giving BCG more than once doesn't make any difference.
It doesn't make it any better. And there is the sort of slightly curious literature which suggests that BCG, when given to neonates,
can protect against what we call all cause mortality, which means it reduces the deaths from things other than TB.
Now that's a variable effect. And it's seen in some studies some of the times, but is quite interesting when you think about how BCG might be working.
So this slide uh, which was taken from a meta analysis, looks at the reasons for the variability in protective efficacy of BCG.
And what we see is that latitude is very important.
So the closer you live to the equator, the less likely BCG is to work.
And we think that's because of exposure to things called non tuberculose mycobacteria.
So pathogens from the same family as TB that don't cause disease unless you're immunocompromised.
We also see that if you give vaccines for the vaccine as a neonates rather than to older age groups, it's much better at protecting.
And that's why W.H.O. policy is to give it ideally within the first seven days of life.
Importantly, what we also see is the BCG strain doesn't seem to make any difference. So BCG,
unlike most of the vaccines we use today, is not the same thing around the world.
It's not clonal. There are lots of different strains of BCG, but there's very little evidence that although those strains are genetically different,
they're probably not very different in how good they are at protecting against TB or not.
So how do we put all this together and how do we design a better vaccine against TB?
Well, because of that protection that BCG confers in the first few years of life against severe disease,
really BCG in some shape or form has to stay part of any new regime.
Um, and we know that you need to induce a very strong what we call cell mediated immune response.
So this means relying on the T cells in your blood.
So we know that, uh, all of the vaccines we give today, apart from BCG, work primarily via the induction of things called antibodies.
Whereas TB is a different ballgame, hides inside cells, which means that antibodies can't get to it.
So we actually need to induce the cell mediated arm of the immune response in order in order to develop a protective vaccine.
And of course, we see that most obviously in patients with HIV, as their CD4 count comes down, the risk of getting TB goes up.
Um, broadly speaking, there are two strategies being pursued in the field.
The first is to say, well, let's leave BCG as it is a well-established part of the expanded program on immunisation led by W.H.O.
And let's develop a second vaccine, a booster vaccine to be given at a later point in time to improve the efficacy of BCG.
The alternative is to say, let's make a better BCG. And there are groups around the world genetically engineering either BCG or in fact,
Mycobacterium tuberculosis, uh, in order to make a better strain of BCG.
And of course, you could put the two together. So this slide illustrates the clinical development pipeline in the year 2000.
So here were all the vaccines that were in clinical trials in the year 2000.
No I haven't forgotten to paste the picture in. There were no new TB vaccines in clinical trials in the year 2000.
Which really for me represents decades of neglect in in funding for this field.
Uh, and I'm really just the idea that actually maybe we'd eradicated TB, whereas of course, we are very, very far from that, uh, that scenario.
So fast forward to 2024, and at least we actually have a pipeline.
Now, there are actually some vaccines in clinical trials.
But, there's always a but with TB, if you look at this more carefully, uh, there are some problems with it.
And there are two problems in particular. The first is, if I put up the pipeline from five years ago, you'd be hard pushed to see anything different.
So it's a very stagnant pipeline. Things are not moving very quickly.
The second problem with it is that it's a very thin pipeline, particularly on the left hand side.
So for clinical development pipelines, we want a very rich early pipeline because of the attrition.
Most things in early development fail. At best, probably 1 in 10 make it through to licensure and deployment.
What that means is we need a huge number of things on the left hand side to make
sure we actually have something we can pull through and make and use in real life.
This is a pretty thin left hand side of the pipeline.
So again, representing really lack of funding, uh, and sort of lack of, of global awareness of, of how pressing a problem this is.
So I'm going to now just illustrate, uh, briefly, uh, a couple of vaccines that have made it through to clinical trials.
So firstly, MVA, 85A, this was a vaccine my laboratory developed.
It was the first new TB vaccine to go into clinical trials anywhere in the world in 2002.
We conducted a very careful clinical development pipeline because it was the first vaccine, and we obviously wanted to be safe above everything else.
And despite eight years of lots of clinical trials and lots of trials showing like this slide does here, um,
that this vaccine was safe and was very potent at stimulating an immune response,
at least when we tested it in this country, when we got to test it in 3000 babies in South Africa,
We sadly saw that there was no difference between the vaccine arm and the placebo arm.
So although the vaccine was safe in this trial and the babies were perfectly.
Safe. There was no improvement in the rates of TB in the babies that got the vaccine compared with the placebo arm.
Enormously disappointing results for us and for the field.
But that's the price you pay for being the first. And we have to work out what we can learn from this study.
We took an immune sample from every single baby in that study.
So we went back to their samples taken at the beginning of the trial and said,
what can we learn from those samples that will help us develop better vaccines?
And what we learnt was two really important things. We learned that activated T cells.
So T cells, if you like, that, are really primed and ready for action.
All of them when were higher in the babies that went on to get TB compared with the controls.
That didn't go on to get TB. What's really interesting, what's causing that activation.
And we also found that the antigen specific response we were trying to induce with the vaccine was,
in fact lower in the babies that went on to get TB compared with the controls.
So perhaps if the vaccine had been a bit more potent and stimulated a stronger response, we might have seen a result that we had hoped to see.
This is slide really is to remind me that serendipity plays an important part in science.
So as part of the controls we do in our lab assays, we look at various, um,
peptides or proteins from other pathogens, really just to check that the cells are alive.
And as part of that, we had a, um, some peptides or some proteins from a virus called CMV, cytomegalovirus.
When we looked at the responses to this, we found that the babies who were CMV infected in about a quarter of them were
in the study were more likely to get TB than the CMV uninfected babies.
And then we knew that. Why is that? Well, we don't know, but we're working on it.
But actually, it reminds me that the infectious milia that people live in has an interaction with their risk of infectious diseases.
So why is TB vaccine development so difficult?
Well, the trials are very big and very expensive and take a long time, and I'll show you that in a minute.
We don't know what the animal models mean in terms of predicting human efficacy.
We don't have an immune correlate of protection, so we can't predict which vaccines will work.
We don't know whether the whole organism vaccines or just a few proteins.
There are 4000 to choose from. So how do we go about deciding, uh, is best?
And we have a very, very clever pathogen that's really good at hiding from the immune system.
So to end on a slightly more positive note, this is the most exciting result in the field in several decades.
So this is a vaccine developed originally by GSK, now being developed by the Gates Foundation.
3500 African adults who were already latently infected, vaccinated either with this vaccine called M72 or placebo.
And unlike the curves in the MVA study, you can see that these are a bit further apart, which is what you want.
And even more importantly, the vaccine arm is on the top.
So about 50% protection seen in this study.
So fantastic result for the field, but only 50%.
We have a Covid vaccine that's nearly 100% effective. We have an HPV vaccine human papillomavirus vaccine.
That's over 100%. We have to do better than this. That result needs repeating in a larger trial.
And just to give you a sense of the challenge, we've got a trial that's just out.
It's got 60 sites in Africa, Indonesia and Vietnam, 20,000 subjects.
This trial is going to cost over half a billion dollars.
We can't do many of these studies. Recruitment is underway and it's due to report in 2028.
So you can see the problem.
One of the things we're doing in my lab is to try and develop a human challenge, models to see if we can actually test vaccines,
to see whether they work in a human challenge model where we deliberately give people an infection before we move to these large efficacy trials.
We can do this in malaria. We can do it influenza. Why can't we do it in TB?
So we started by giving people BCG by the skin route.
And now we're doing this by aerosol directly into the lungs to mimic the natural route of infection.
We think this kind of model will help us test new vaccines.
This I'm going to skip over in the interest of time, but this just shows you the power of doing these kind of studies.
We can look in the lungs at the kind of cells that go into the lungs after we've infected people.
And that gives us new insights into immunity in people, in the target species, rather than in animal models that we don't know the relevance of.
But really, just to finish with a slightly salutary note,
and I'm very grateful to Barry Mannone from the Department of the Faculty of Modern Languages for drawing this to my attention.
There is some evidence that Kafka may have been an anti-vaxxer.
So, uh, he made friends with someone called Maurice Schnitzer.
Um, and you can see here no vaccinations. Uh, record I recorded on his military conscription card.
And there's his name from Doctor Franz Kafka. He's subscribing to this sort of, um, naturopath, uh, journal.
So, um, the irony of all of this is, even if 100 years ago, 110 years ago,
we had an effective vaccine against TB, I'm not sure Kafka would have had it.
So that may not have altered history.
So that, I hope, was just a little snapshot of of perhaps some optimism at the end of where we are with TB vaccine development.
I'm now going to hand over to Amy, who's going to talk you through, really the lived experience of living with TB.
Amy.
So Franz Kafka was just 40 years old when he sadly died from TB.
Which Which is actually the age that I am now.
So during my initial research into his life, I discovered that in addition to being a ferocious writer,
he was also a lawyer and legally educated as I am too.
However, unlike Kafka, I am extremely fortunate to be alive and able to share my story with you today.
I just want to start by saying thank you for being here this evening.
Um, there are a few things I hope you will take away from my personal experience.
Firstly, please never forget that at the heart of this terrible disease are ordinary people from all walks of life with hopes,
fears, worries, expectations, ambitions and dreams, all of whom deserve a chance at a future free from TB.
Secondly, TB has never been eradicated in the UK and if I hear this one more time, I will scream literally.
Um. In fact, confirmed cases of TB in the UK have risen sharply over the last few years since the Covid 19 pandemic.
So, like many other infectious diseases, TB acts as a kind of magnifying glass, exposing existing fault lines and inequalities,
especially in light of current challenges such as the cost of living crisis, housing shortages and poor living conditions,
the hostile environment, major pressures in the NHS and global conflicts.
It is more important than ever to be aware of TB and to understand the devastating consequences it can have.
So I was a student in my late teens when I first developed symptoms of TB.
And the most obvious symptom was a persistent cough or despite numerous courses of antibiotics, wouldn't go away.
And next came a slow, insidious fatigue, unexplained weight loss, lack of appetite, and finally, night after night of waking up, covered in sweat.
It was my friends, family, colleagues and even customers at the bar where I worked
to know just how ill I was before I did. I mean, I was otherwise young and healthy, so I thought, how could I be seriously unwell?
I thought these things happen to other people, not me. After nine months of visits to my GP,
I came home for Christmas from university where I was studying law and my GP finally referred me to hospital for an initial chest x ray,
suspecting I had asthma. I was given another course of antibiotics and a follow up chest x ray, and then I had nothing until two months later,
when I received a phone call from the chest clinic at my local hospital in London, asking why I hadn't turned up for an appointment
I didn't even know I had. So by now my condition had seriously deteriorated and I was in excruciating pain as my left lung had begun to collapse.
My appointment was rescheduled for six weeks later. By this time it was Easter holidays.
I had a bronchoscopy where a camera was inserted into my lungs, and the sample was taken to be tested, as well as three sputum samples.
So by this time I had an inkling that I might have TB.
After speaking to my GP, and when I asked the doctor who carried out the procedure if they thought I had TB, they said yes.
And they told me that if they couldn't diagnose me, I could die. A few weeks later, I got a call from the TB nurse who finally diagnosed me with TB.
She said to me, and this is an exact quote I remember: you have World War three going on inside you.
It didn't actually come as a huge shock, and actually it was more of a relief, which might sound a bit strange, but I initially thought I had cancer.
Um, so now I had the correct diagnosis and I could start the start the start treatment at last.
So by now I weighed five and a half stone. Um, my hair was falling out and my left lung had completely collapsed.
So when TB was first mentioned to me by my GP, I was so shocked because like many people in this country, I thought TB was no longer a threat.
Besides, I'd had the BCG vaccine when I was 13, so I didn't think it was possible to catch it.
I was completely ignorant about it.
I didn't have any awareness of the havoc the disease was wreaking in other parts of the world and in certain affected communities here in the UK.
Um, but, you know, I'm embarrassed to admit that now, but sadly, I'm far from being the only one.
I suspect my GP didn't think of TB either, because I had no social or clinical risk factors.
So I didn't fit the so-called typical profile.
It's so important to remember that while some people are more at risk of TB, anyone who breathes can get TB.
Secondly, with the public so focussed on Covid.
Um, I am concerned that many will misstate their symptoms of TB for Covid and not seek medical help until a much later stage,
leading to delays in diagnosis that could have serious consequences and increase the risk of further transmission.
So by now I've been confined to my bed for about two months.
I felt like a zombie. I had didn't even have the physical energy to move around my house.
Eating was a huge challenge due to waves of nausea, and I couldn't stomach any food.
To avoid being admitted to hospital and fed by tube, I was prescribed a short course of high dose steroids to stimulate my appetite.
I then continue taking these long term to reduce the fluid in my left lung.
So my close contacts were also screened, and I was so afraid of what would happen if I'd infected any of my family, friends and flatmates.
I remember feeling at the time so much fear and guilt and worry.
I thought, how would they react? Or would they blame me?
Thankfully, nobody tested positive and my friends and family were very supportive and fairly level headed by this time.
Most of them knew that TB was curable, so I spent a month in home isolation.
Many of you may now have some idea of what this feels like thanks to thanks to Covid.
Eventually, after a month or so, I noticed an improvement in my energy levels.
Walking around the house felt easier, although I was still very short of breath and I found it difficult to wash my hair and cook meals.
So my mum had to do all of these things for me. I hadn't left the house at all, and my family suggested taking a trip out in the car with a friend.
I was not prepared for how I would feel being outside for the first time in about three months.
As I stepped out of the car, the sound of the other cars, the voices of people around me and even birdsong were magnified in my ears.
Everything felt too loud and too bright. I just wanted to get back to the safety of my bedroom.
I was suddenly overwhelmed with panic and I felt dizzy. I got back in the car immediately and my friend drove me back home.
I had no idea what was happening to me.
Nobody had prepared me for this, but I now know that it's not unusual to experiences after a long period of isolation indoors.
So the course of treatment for drug sensitive TB,
and I should say this also actually includes non TB drugs as well that I took involve taking approximately 13 tablets a day for six months,
although in my case it was extended to nine months. I hated those drugs.
I once heard John Moore-Gillon, who was a top TB specialist at the time, described them as the size of horse tablets and he wasn't wrong either.
The side effects were things like nausea and the most horrendous joint pains.
So back then, TB patients had to pay for their prescriptions out of their own pockets as it wasn't classed as long term treatment.
I wasn't well enough to work, and I came from a low income, working class family who were also struggling financially.
Over Christmas, my dad died very suddenly within 24 hours after a short illness, and things have been really tough ever since.
There was no additional financial support available for my university,
and by this time most of the government funded hardship funds had been allocated.
I wasn't eligible for any benefits because of my student status.
I had to pay for treatment out of my remaining student loan and extend my overdraft to cover this period.
Now, if someone in my situation, I had a roof over my head and family around me, was struggling to afford the cost of treatment.
Can you imagine what it was like for homeless people?
People would normally recourse to public funds.
Refugees and asylum seekers living on £5 a week. To complete treatment in those circumstances would have been a miracle today.
TB treatment is now free and everyone diagnosed with TB is exempt from charges.
The problem is patients don't present with TB, they present with a collection of symptoms.
So it is possible that people may be wrongly charged for treatment and with a hostile environment creeping into the NHS,
this put some communities at risk of racism, discrimination and prejudice.
Once I was no longer infectious, I was admitted to hospital for two weeks of intensive physiotherapy to try to inflate my left lung.
Unfortunately, this didn't work,
although my right lung did actually expand to help compensate as much as possible for the loss of function in the left lung.
It's actually quite amazing what the body can do sometimes.
So during this time I couldn't return to university to sit my interview exams, and later I made the decision to repeat my first year at university.
Once I was back at uni in the autumn, I continue treatment and travel back to London regularly for follow up appointments with my TB specialist team.
I started getting intermittent infections around this time, but otherwise all seemed to be going well.
And after nine months I finished my treatment. About 2 or 3 months later, I noticed changes in my energy levels.
I was sleeping a lot and genuinely not feeling very well. After coughing up quite a bit of blood,
I ended up in A&E. They discovered my heart rate was 167 and as soon as I saw the doctors eyes widened,
I knew what was coming next. They wanted to admit me to hospital for further tests.
To cut a long story short. I ended up heading back to London to see my TB specialist team, and I was treated for a chest infection.
I returned to university after the Easter holidays, but just a few weeks later,
I was admitted to hospital in London with a Pseudomonas infection and an empyema after being rushed into it into the resuscitation area.
This was when I was diagnosed with severe bronchiectasis, a lung condition that can cause infections in the lung due to excessive build-up of mucus.
So TB is one of the underlying causes. If that wasn't bad enough, I was having a relapse of TB and treatment was restarted.
It was also thought that the TB might be drug resistant. So it was an incredibly scary time. All the NHS
workers who entered my room will face masks and PPE,
which at that time was very bewildering and I was told by my TB nurse to prepare to be in hospital for a very long time.
I had to make a very difficult and last minute decision to suspend my degree studies and take a period of intermission for 12 months.
I had no idea how I was going to support myself financially.
I still had student status, so I couldn't apply for benefits,
but I couldn't access the government funded Access to Learning fund because it wasn't supposed to be relied upon as a sole means of income.
So I ended up living off credit cards and my over my student overdraft.
It wasn't long before I fell into debt. There is some good news
believe it or not. I didn't have drug resistant TB, but I would need intensive daily physiotherapy and lung surgery.
A pneumonectomy to me to remove my entire left lung.
This was originally scheduled for January, but unfortunately yes, you guessed it, there was another twist to this story.
I now had TB in my previously healthy right lung.
The damage in my left lung was acting as a reservoir of infection, and it would need to be removed as soon as possible.
So my plan to return to university from intermission was now in jeopardy, and I would need to consider my options and go through an appeal process,
as I didn't have an automatic right to extend my intermission to cover the summer term or repeat the year.
In May of that year, my lung surgery went ahead very successfully and my TB nurse said to me
You can have your life back now. But life had already been on hold for far too long.
I won my appeal and was able to return to university in September.
In November, the treatment for the TB in my right lung ended for good and to focus my recovery from surgery.
I signed up to run A5K race. Four months later, I didn't get medical clearance for that either, but I managed to raise £2,000 for TB alert,
who supported me partway through my treatment journey and gave me a reason not to give up.
So over the course of the academic year, my mental health began to seriously decline.
I was having panic attacks, stress induced meltdowns, and experiencing low moods.
I just stopped functioning altogether. Everything that happened to me over the last few years was starting to catch up with me.
My credit cards and overdraft debts had spiralled out of control,
and by the end of the summer term, I owed money to my university for accommodation rent.
My registration for the following academic year was now at serious risk.
There were so many people at my university, from the money advisor to the student at the students union,
to my student advisor and the head of finance and many others who really came through for me and went above and beyond their jobs.
They became my allies and I will never forget the support they gave to me.
I always got the impression that my university wanted me to succeed.
To cut another long story short, I did finish my degree, even though it took about six years.
Eventually, I was diagnosed with depression and anxiety and started having therapy through my university.
My GP said it was quite common for patients to experience both after having, and this is
his words, come close to death. But I had no idea what the impact that TB would have on my mental health.
Three years later, I was finally discharged from the clinic.
There are a few things I want to highlight here that the TB treatment journey does not end when the patient takes their last pill.
In my case, I still have ongoing breathlessness.
I walk much more slowly than most people, and I have to pace myself and take regular breaks when doing simple household activities.
It takes me weeks to recover from a chest infection and I have a rescue pack of antibiotics on standby.
My right lung is now scarred. I have a permanent chronic cough and a croaky voice and to clear the excess mucus in my right lung.
I do airway clearance exercises twice a day. This is my new normal.
I often wonder how different my story would have been if there had been an effective TB vaccine available.
A vaccine that could have prevented so much suffering and hardship for myself and for millions of people around the world.
We all saw during the Covid pandemic that when there is a will, there is a way.
I've had nine Covid 19 vaccines, but only one TB vaccine, the BCG,
which isn't effective in teenagers and adults against the most common forms of the disease.
I'm delighted by the speed of vaccine development and rollout for Covid 19,
but I can't deny the anger and resentment I feel about TB and affected communities being left behind for so long.
We deserve the same priority and investment. There is no doubt in my mind that if the burden of TB disease was spread more equally around the world,
rather than being concentrated in low income countries, it would be a very different story.
As far as funding is concerned. That speaks volumes.
Ten years ago I was diagnosed in.
Ten years ago, I was diagnosed with an inflammatory condition that affects both my joints and skin.
My history of TB and long surgery meant that they first had to rule out TB in my bones as a differential diagnosis,
and my reduced lung capacity meant that it was too risky to have the first line treatment choice.
I am now severely immunosuppressed, which carries a serious risk of infection, including TB, and I'm back into the care of the chest clinic.
Although with a different hospital trust. I'm monitored very carefully,
by the head of the TB speciality and I am extremely grateful to be so well looked after.
This means that the risk of catching TB again is never off the table.
I experienced so much uncertainty and fear throughout this entire journey.
To say that TB turned my life upside down is a huge understatement, but in some ways it was also a turning point for me.
I've always said that TB politicised me and helped to spark an interest in TB advocacy and social justice, which has led my entire career so far.
I am a member and chair of the TB action Group, the UK's only advocacy network for people affected by TB.
I went from being adamant that I wanted to put this whole awful experience behind me forever and never think about TB again.
But obviously that didn't happen because I wouldn't be here talking to you now.
I just want to end by paying tribute to every TB survivor I've had the privilege to meet,
either in person or online, from all over the UK, and even as far away as the US, India and South Africa.
They know who they are.
Their courage, friendship, solidarity and extraordinary activism inspire and motivate me to do better and to keep believing that progress is possible.
Every single one of us has truly earned the label of TB survivor.
Thank you for listening. Amy, that was absolutely extraordinary.
Thank you for sharing such a very personal and incredibly moving experience with us all.
That's really difficult to follow. Thank you very much.
We now have our third speaker.
There will be an opportunity to ask questions at the end, and all three of us will be outside milling around with the exhibition and drinks.
But I'm going to hand over now to Philip, who's going to give us our third talk on TB diagnostics.
Thank you, Helen.
And thank you, Amy. Um. That's.
So I'm afraid I'm a pacer. So I've got a microphone. So slight change of gear now.
I'm going to talk about fairly recent advancements in diagnostics that hopefully could have helped Amy at least just a bit of that journey.
Um, so as Helen said at the start, I work in the MMM unit,
which is actually set in the top floor of the John Radcliffe Hospital, there's a few people here in the audience.
And one of the things we do, there's quite a few things we do, is translating genetics into, um, clinical microbiology.
And I'm going to talk about, uh, TB.
So because we haven't had enough about TB, just I've come up with some minis I'm buying, I've found these in the literature.
This and nice little snapshot. So just in case you didn't know, TB has killed more people than any other infectious disease ever.
In fact, um, from genetics, we now know that TB is being with humans for tens of thousands of years.
Um, and left Africa when the first humans migrated out of Africa about 70,000 years ago and moved with them around the world.
And actually post industrialisation in Europe, it's estimated that about 20% of all deaths were caused by tuberculosis,
and it's also been estimated in the last 200 years, about a billion people have died of TB.
But we've sort of forgotten about it. Reminds me a bit of Covid.
Um, you know, it's it's it's strange.
It's it's been such a influence on human history.
So we're here because Franz Kafka died in 1924 of laryngeal TB.
Um, if you go to the exhibition, there's a bit more information. But he basically coughed up blood in 1917.
So 77 years before he died, he was in and out of various sanatoriums.
Um, the last one was near Vienna. Now, interestingly, the first, um, suggestion of, uh, sanatarium was by this guy,
George Boddington in Sutton Coldfield in Birmingham, which is again curious because that's where I grew up.
Anyway, that's another story, but TB is full of all these little peculiarities.
And another one I like is the first randomised clinical trial was for TB.
It was streptomycin in 1948. And what they found was that it was very successful.
But quite quickly the, the the bacterium evolved the resistance.
And to this day, as you've heard from Amy, we treat people, well
I don't, but clinicians treat people with multiple antibiotics.
So the current treatment, if you have regular susceptible TB is for drugs that you've probably never heard of,
because they're not the sorts of things you get given when you normally go to the GP because they're pretty specific to TB
usually, um, for six months, which is quite a long time, but it's necessary because of the disease.
Now, resistance is obviously complicated because you're being treated with multiple drugs and there are various definitions, and it's fairly low
globally, it's about 3% of new infections according to the W.H.O., are multi-drug resistant.
But if you've been previously diagnosed or treated for TB, that rises to almost 20%.
And obviously, you know, these proportions are going to rise as we keep using antibiotics.
Um, and then this wasn't a problem that obviously Kafka had to face.
The treating resistant TB is inevitably a lot more complicated.
Um, there have been some new drugs come on in the last couple of years, which has been very helpful.
And also then there have been some new regimens developed and approved and endorsed by the W.H.O.,
um, which is talked about on the right. That's from two years ago.
So there's a new regimen for people who have multidrug resistant TB that's only six months long,
which is a big improvement over the previous, possibly 18 months of treatment.
So, as Amy said, often, uh, if you are suspected of having TB, you will give a sputum sample and that will be sent off for testing.
And the two things are really looking for, uh, are there any mycobacterium tuberculosis in that sample?
And if there are, what antibiotics could you be treated with?
So the traditional way of doing this would be to culture the sample, say to grow it in some nutrients that it likes and the other bacteria don't.
Um, and then I've got ahead of myself by one slide.
Okay. So yeah. So throughout this I want to use a simile of, of imaging.
So when we're looking at a sample in a clinical microbiology lab,
what we're trying to see is which basically trying to capture the picture of what's in there,
you know, uh, is there some TB,
are there some other bacteria or other things that might have been in your upper respiratory tract when you gave the sample?
You know, there's going to be a lot of human cells in there from you, you know, what's in there.
And just like there are different ways of, you know, drawing a picture or capturing an image, there's different ways of looking inside these samples.
So the the traditional way is to grow it.
As I started to say, the problem with that, or the several problems with it, is it just takes a very long time.
So it can take up to some 6 to 8 weeks to get a result back from the lab, because TB just grows so slowly and there's been some nice advances.
Um, these magic tubes, um, because they glow when there's, when there's mycobacterium in there,
So it's made it much easier.
But fundamentally, you know, being told I'll give you a call in two months when the results come back, it's it's not good for anyone.
So in an imaging simile this is a bit like, well, I have to paint the picture because I need you.
It's very skilled. Um, I need some equipment, I need some reagents, I need some experience.
It's a difficult job to to carry out these types of, uh, tests, and it fundamentally, it's going to take you quite a long time.
So then genetics can play a role, and I'm skipping over lots of other ways of diagnosing here that I just don't have time to go into.
Um, and focusing on, um, whole genome sequencing here, you still have to grow it for a bit, but then you can heat kill it.
Take it outside the Cat 3 lab. I should say. You've got to do all this in a BSL 3 lab because TB, it's a very dangerous pathogen.
Then you can put it on a genetic sequencer. That will just give you a whole bunch of fragments of genetic material and say, well,
you work it out I've sort of done the hard bits, which hasn't really, but it gives you this problem.
And then then you need to solve that problem. So that's when you now need a second speciality.
Who hasn't been on the scene until now, which is a bioinformatician
so someone who can handle genetic information and process it and they need to write, uh, what we usually call a pipeline.
So a series of pieces of software that process those reads and hopefully give you the answers you're looking for.
And that's often done on some local compute that you've squirrelled away somewhere in your hospital or public health body.
So this is it's difficult, but it's a big improvement because you can do it in about a week.
So that's a big acceleration from say, 6 to 8 weeks to a week.
So that's that in itself is a is a huge advantage.
Um, but as I'll come back to it's it's quite tough to do.
So in my simile this is a little bit like, I think the invention of photography.
So wow. You know we've now got large plate cameras. They're expensive.
But you can take an image pretty quickly. But then you also need a thing called a dark room.
And you need to get you need to go and buy a developer. You need to keep buying all these reagents.
And you need to learn the skill of how to develop, um, photographs.
So it's possible, but it's the kind of the preserve of the few.
So it's done in high income countries, in, um, public health institutes, large tertiary research hospitals, that sort of thing.
The good news is, England was the first country to implement this at the national public health level back in about 2018,
and that was research that was done in the unit where I am now that got translated out into PHE,
as it was then and the other home nations have followed suit.
So that's really good news. Anyone who had a has a suspected mycobacterial infection.
That sample have been sequenced since about that date.
That won't have sped up the GP necessarily, but it will have sped up the process after the sample was sent off.
I just want to spend a very quickly talk about why the genetics is challenging, because these sequences do seem like magic.
But all they, as I said, all they do is they just give you bits of genetic material and say, right, you sort that out.
Um, and it's a bit like doing a jigsaw puzzle with a few rather important differences.
One is you might have up to 10 million pieces, which is going to make it a bit harder.
The pieces will also overlap with each other. And you don't know how because the fragments are quite random.
The some of them are going to have errors because the machines aren't perfect and you don't know which ones.
Which is so hard. And because you've got, you know, you've almost certainly got multiple bacterial, um, pieces of DNA in there.
It's a bit like having, you know, doing a jigsaw,
or rather taking several jigsaws and mixing them up and then trying to just do one of them and not put in the wrong piece and that sort of thing.
So it's it's very difficult. And bioinformatics is a, is a difficult, um, subject, so why bother.
We've already said one of the key things is speed is we can do this much more quickly, which for TB is really important.
Two other things. Um, accuracy.
This is it's arguably more accurate, but that's difficult to prove because you're comparing it to something that is hard,
which is culture and difficult because it's TB. And then the second one is epidemiology.
And that's something you basically get for free with genetics because you've got the entire genome.
So what do I mean by that. Well in Covid we got quite used to this idea of we can infer, uh,
if two samples taken from two people are part of the same outbreak or cluster because the genomes of their pathogen are very similar.
And you can do exactly the same thing with TB. And this was an example back from 2018, um, where they were able to show how, uh,
patients with multi-drug resistant TB moved through Europe and caused these, um, separate outbreaks in different countries.
And then, of course, you can do something about it and you can find these people and treat them and stop those outbreaks.
Just to point out, the threshold they were using was only five, uh, snips are basically five letter changes in the whole genome.
In the genome of TB is about 4.4 million letters long.
So you've actually in doing that jigsaw puzzle, you've got to get it pretty accurate.
Otherwise you can't do this sort of thing as well. So why is it so difficult?
There's lots of reasons and I'm not going to talk about all of them. Um, I'm going to just talk about two of them.
This is one, which is that actually, even if,
even if you can do all that perfectly and you can work out what the genome of the pathogen that's infecting someone is,
it's still quite hard to work out what antibiotics you should give them.
So some work, um, led from our unit by Derek Crook.
This ran for about six years. This was a major Wellcome project.
Uh, they collected about 20,000 clinical samples of TB worldwide from, uh, memory, 11 different countries with 14 different laboratories.
They were all sequenced. They all had a panel of antibiotics tested.
And as a result, we did some really nice science.
Um, it was picked up in the press a little as well.
But actually the thing that I'm most proud of is that data set, along with some other historical samples and some extra samples we collected actually,
immediately before the pandemic, that whole data set, we kind of did all the data cleaning, and it was handed over to the W.H.O.
And that that indirectly led to them publishing their first catalogue of genetic mutations associated with resistance in TB.
So that was back in June 2021. Uh, and in November last year, um, they've updated it with a slightly improved version.
So that's really good. And that helps move us along this pathway.
So the second thing I'm going to talk about, um, about why it's difficult is there's no standard way of determining the TB genome.
It's basically informatics is hard and it's very difficult for labs to set up.
So the story here starts in May 2021, when we started working with Oracle on a cloud based platform for Covid processing.
And that has led to this thing we call GPAS, which I'm going to call second generation,
where now the biomedical scientists can do the sequencing, but now they just basically drag and drop the file up into the cloud.
It will process the genetics for them. And the, uh, report can come back in less than an hour.
It's not speeding things up a much, just a day or two perhaps, but it makes it much, much simpler and straightforward to do this kind of work.
So I'm just going to quickly go through some screenshots because I wasn't feeling brave enough to do this live.
Um, this was actually some batches I was uploading last night.
Um, I wasn't up at this time. The computer is doing me.
Um, so if we just zoom in, they're all batches of 50 TBs and we go and look at this one because it kind of looks interesting.
Um, this is all in the browser. So a lot of work is gone into this.
Um, what we see is a lineage three TB. It looks pretty good from a kind of quality point of view I don't want to bore you,
but it's definitely MDR, so it's resistant to three of the four first line drugs.
So you do not want to be giving those drugs to that patient.
Um, but healthily, it's resistant to uh, basically the second line drugs, the flow clean lines and so on.
So the hope is that this information would help the clinician choose the appropriate treatment for that patient.
And then you can see down the bottom, um, we get uh, some of the it's part of a cluster as well.
So this kind of I think in my simile brings us up to about 1900, um, which is when Kodak released the Brownie.
And the thing about the Brownie was the film was put inside a cartridge.
And what that meant was you could take photos until your cartridge was all used up,
but then you could send the film off to a lab to be processed, and then you got the photos back.
And so you didn't need a darkroom anymore, and the cameras could be quite made, quite small and cheap.
And I read, I didn't realise that the Brownie started off as a children's toy.
I don't think genetics has. But anyway, um, and so it led to this kind of democratisation of photography.
Um. So if we think back 100 years, um, and go and look in exhibition, there's some quite gruesome artefacts, um, showing, sort of illustrating, uh,
Kafka's journey with TB, you know, 100 years later,
I think we're hopefully on the verge of really beginning to use genetics to help us treat this disease better.
Um, it's interesting thinking forward a 100 years. Um, um, sorry.
Coming up, TB's probably still going to be here I'd expect, even with vaccines and everything.
You know, latently it's in a quarter, a third of the world's lungs.
So it's gonna you know, I don't think eradication is really on the cards.
Will how we we've made it through the whole pandemic.
Will we still be giving antibiotics? But we have to individually diagnose everyone.
I really don't know. So it's just we're thinking on that. Um, a lot of people involved, um, in the past and a lot of this work.
So that's just to show you just how many, I suppose it's all quite small writing.
Um, and lots of, uh, funders and other peoples as well.
So thank you very much.