Hitting an Invisible Target in TB Vaccine Design

I have a troubled relationship with Twitter. It’s an unredeemable hate sort of thing. I’m generally an inane mix of angry opinion and low self-esteem so, in theory, we’re perfect for each other. I just don’t feel it, though. I had a quick look for online videos in the same vein of the YouTube self-hypnosis that resolutely failed to rid me of my flying (crashing) phobia. Instead, I somehow ended up discovering that my Worldwide Twitter Rank is 56,082,003, which is actually better than I’d expected given that there are over 300 million users. It also turns out that the most prolific Twitter user in the world is @VENETHIS, who tweets mostly about their video game exploits from the look of things. I was selfishly hoping for something more…impactful?

Anyway, this brings me nicely round to the BCG vaccine (I’m up in the top million when it comes to tenuous segueing). BCG is the world’s most prolific vaccine. Unfortunately, it doesn’t always have all that much impact on TB. Some vaccinated people appear to be protected from infection, others…aren’t. So we need a new vaccine. Only, I’ve often heard it said that there is no natural immunity to TB. As in, the immune system appears to lack an anti-TB protocol - the same anti-TB protocol that a vaccine such as BCG is supposed to prime.

Vaccines, on the whole, work by preparing the immune system to meet a future infection with lots and lots of antibodies. This is where TB poses a challenge. The role of antibodies in protecting against TB is controversial and, in the past, has pretty much been ignored. It’s all about the cell-mediated branch of the immune system, cry the immunologists. Our new vaccine needs to stimulate T-cells not antibody production! In reality, of course, it’s far more complicated than one or the other in isolation, so it’s exciting to see recent renewed interest in understanding how antibodies play a role in fighting off TB.

A new PNAS paper from Babak Javid’s lab in China looked at healthcare workers repeatedly exposed to TB who remained healthy. For the uninitiated, not everyone who comes into contact with the pathogen will develop active TB. Around 10% will completely fight off an infection before it takes hold. Of the rest, 90% will succeed in keeping an infection in check. The people who do develop TB are actually a minority, albeit a minority that tallies up to around 10 million cases a year. So understanding what is different about those who control TB compared to those who don’t is a big deal. It can provide important clues to understanding what, exactly, constitutes a protective immune response against TB. Answer this, and vaccine developers would have a real target to aim for.

Javid and colleagues wanted to look more closely at those sidelined antibodies. They picked a busy TB hospital in Beijing where protective measures to stop healthcare workers from being exposed to TB are sorely lacking (that’s an entirely different post), and isolated antibodies from 48 healthy workers and 12 active TB patients. Everyone had anti-TB antibodies, as expected, and there were more in those actively fighting the infection. The big question was if any of these antibodies do anything useful?

So the scientists ‘vaccinated’ mice with the purified antibodies and exposed the mice to TB. Interestingly, antibodies from 7 of 48 healthcare workers provided the mice with moderate protection against infection. It's worth noting that this protection needed the mice to have a functioning cell-mediated immune response which, in the authors’ words, suggests that the protective antibodies “are part of a complex interplay between the pathogen and host immune system.” In short, there’s no one answer to what protects some people against TB and no single cell type holds the solution to designing a better vaccine. Antibodies are likely one piece of the puzzle, but a piece that shouldn't be ignored.

Going back to that old saying about there being no natural immunity to TB - this is based on the observation that patients who've previously had a TB infection are susceptible to catching it all over again. Only it ignores everyone who doesn't develop the disease in the first place. It's like claiming that all toddlers hate broccoli based on a questionnaire posted on a 'my child won't eat vegetables' advice forum. Maybe that anti-TB immune protocol does exist, after all, just not in the people who are generally studied when it comes to TB - i.e. TB patients.

Rebranding Tuberculosis

If infectious diseases were monsters, what would they look like? I imagine malaria would be a terrible mosquito-like creature made of bones, with a wickedly sharp proboscis and a throbbing gut of fiery red blood. Diarrhoeal disease would rise from a swamp of sewage, grinning with its skull’s jaw as it handed out cups of contaminated water to the unsuspecting. And tuberculosis? The biggest infectious disease killer in the world, with 1.8 million deaths from the infection in 2015 and 10.4 million new cases? I struggle to anthropomorphise TB and part of the reason for this is all thanks to the Victorians.

TB was the subject of a 19th century romanticisation that existed in direct opposition to the reality of the disease. Literature, operas, poetry and plays of the day were filled with references to TB, or consumption as it was commonly known, as something to aspire to. In Metzengerstein, Edgar Allan Poe writes: “I would wish all I love to perish of that gentle disease. How glorious! to depart in the hey-day of the young blood - the heart all passion - the imagination all fire - amid the remembrances of happier days - in the fall of the year - and so be buried up forever in the gorgeous autumnal leaves!” Sounds like a blast, doesn’t it?

When I started writing Catching Breath - The Making and Unmaking of Tuberculosis I wanted to cover this romanticisation of TB as an example of how the disease had left its mark on human culture. The poetic swooning! The tragic heroines cut down in the bloom of their lives! The feverous intensity of these martyrs to creativity and passion. Only, I don’t think it is possible to focus on this historical portrayal of TB without adding to the ‘TB is a disease of the past’ story, which I didn’t want to do. Catching Breath was about what has made TB the disease it is today and how we’re going to unmake it. So I left the 19th century romanticisation to other writers and tried to focus on the here and now.

I couldn’t get away from this disease of past thing, though. Whenever I mentioned TB to one of my non-scientist friends, I invariably heard something along the lines of ‘didn’t we already cure it?’. It felt like I was living in two worlds: one in which TB is an underfunded humanitarian disaster the full extent of which we still don’t fully grasp (the TB world); and one in which TB is a throwback to a bygone era that just doesn’t evoke all that much fear or concern compared to something like malaria or HIV, which most know are massive problems in world medicine (the everyone else world).

There’s a lot of great TB advocacy going on that gets across the true toll, but it’s taking its time to worm its way into the public perception of this disease among those living in low TB incidence countries. I think this harms TB control efforts. While TB is not a big problem in high income countries such as the UK, eradicating the disease is not going to happen without partnerships between those countries worst affected and richer countries like my own. And the ‘disease of the past’ stereotype does little to keep the reality of TB at the front of people’s minds.

I don’t think it’s any coincidence that HIV has gone from a death sentence to a manageable condition in just twenty years alongside a brilliant example of how infectious disease advocacy should be done. The HIV world succeeded in branding the infection as a modern monster that could be defeated, just so long as the funding and the political will was there to make it happen. Could we see the same for TB? I don’t know. It’s a difficult task as TB has spent a very long time twisting itself up with human lives. And in the past, the TB world hasn’t done the greatest job of convincing people that a) TB is a worthy opponent and b) it’s a fight we can win. Things are changing, though.

Catching Breath ended up as a scientific biography of TB that touches upon some of the ways in which the disease has shaped the various populations its encountered during its long history, minus the romance. My career as a scientist was all about finding ways to understand the TB bacillus in the hope that we might, one day, be able to truly turn it into a piece of history. For now, though, TB is very much here to stay.

Refocusing the Microscope

I grew up staring out at the stars through my parents’ antique telescopes; marvelling at the tiny pinpricks of twinkling light and how, on a clear night, the Milky Way streaked across the sky. There are more than 100 billion stars in our galaxy, and more than 1,000 billion galaxies in the universe. How many of them, I used to ask myself, contained planets that were home to life like our own sphere of rock and ocean? It was always the potential for life that fascinated me, be it aliens with copper in their blood and sulphurous breath, or plants with red leaves and a taste for nickel. It felt like us humans were just a small part of something infinite in its vastness and, when I thought about it too hard, I became a lone comet tumbling through 46 billion light years of unknowable space.

When I grew tired of feeling small, I played with my parents’ brass microscopes, with their chipped lenses and seized knobs. At first it was leaves and hair and globules of pond water dripped directly onto the mirrors. I never saw very much but the hidden microscopic world fascinated me as much as looking out at the stars. I must have been about ten when the concept of bacteria first took hold of me. I think it was via a book mentioning Anton Van Leeuwenhoek who, back in the 17th century, had fashioned himself a homemade microscope to look at what he described as ‘wee animalcules’ and ‘cavorting beasties’ in fresh water. Of his animalcules, Leeuwenhoek said ‘ten thousand of these living creatures could scarce equal the bulk of a coarse sand grain.’ My view of the universe we live in stretched a little further, much like it had the moment when I’d realised the stars could all be someone else’s sun.

I grew up to become a microbiologist and not an astronomer. From a distance, both fields looked similar to me. Both saw the universe through lenses and mirrors, only one was looking up and the other down. I wanted to see the smallest living creatures in the world because, if we don’t even understand the extremes of life on our own planet, how can we hope to comprehend the breadth of life to be found throughout the rest of existence. The microbial universe was as beautiful as the night sky, with the way Bacillus subtilis formed fractal-like patterns across an agar plate or the rainbow hues of cyanobacteria radiating from the edges of the Yellowstone hot springs. Even the pathogenic species could be wondrous in the way that, wherever you look, life has found a way and a home.

I didn’t intend to work on a pathogenic species at first, but the days of Leeuwenhoek observing his animalcules are long gone. Microbiology, on the whole, is all about using our knowledge of microbes to better humankind—by finding a cure for tuberculosis, in the case of my own research. I envy astrobiologists their timeline, in a way. How they are still explorers who, one day, may be the first to see alien cavorting beasties in a droplet of water from Neptune or the traces of past life in a sample of silica from Mars. But I suppose any field can lose its shine when you zoom in to focus on the minutiae. That’s what happened for me, at least.

From the world’s biggest infectious disease killer, to a yellowy suspension of cells shaking in an incubator, to a fingerprint of proteins making dark bands on a Western blot. Somewhere in my ten-plus years in the lab, the beauty of the microbial world got lost among diagrams of signalling pathways and overly simplified models to distill the behaviour of bacteria down into something predictable. Does it remove some of the wonder of the solar system to understand the physics that hold our planets in orbit around the sun? Only if you spend so much time hunched over your mathematical formulae that you forget to look up at the sky from time to time.

So I left. There were other factors involved in my decision, of course. The birth of my daughter, for one, which re-centred my view of the universe around this one, impossibly bright point of light. But mostly it was that I’d spent too long looking down that microscope and had lost sight of everything else. The day after I handed in my resignation, a publisher at Bloomsbury messaged me to ask if I’d ever thought of writing a popular science book. Two years later, Catching Breath - The Making and Unmaking of Tuberculosis is on its way to publication. I started out intending to shine a light on how Mycobacterium tuberculosis, the bacterium behind the disease, is the cleverest of them all. Only, the gravitational pull of my own cavorting beastie kept changing my focus. It’s no longer M. tuberculosis that fascinates me, but the place it occupies in the world.

I used to think of the microbial universe as something separate from us, to be observed from a distance. Only, microbes—the ones on our skin, in our guts, floating around in our drinking water, or causing infections such as TB—make up the fabric of our lives. We exist in a vast, interconnected world in which no one species lives its life in isolation. There’s no good guys and bad guys here, not really; just a huge tapestry of life that isn’t always sewn in humankind’s favour. Catching Breath isn’t a zoomed in review of the scientific research into M. tuberculosis. I’ve taken a step away from my own work and tried to tell a story of how TB fits into the rest of the world and, in doing so, I’ve remembered why I got into research in the first place.