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.