In the latest IAVI report from February 2024, Kristen Kresge Abboud spoke to Professor Lalita Ramakrishnan from the University of Cambridge who worked with colleagues to discover that almost everyone who falls seriously ill with tuberculosis (TB) does so within two years of infection. Furthermore, they discovered that many can clear TB on their own.
Professor Ramakrishnan, previously quoted as suggesting that “the whole idea that a quarter of the world is infected with TB is based on a fundamental misunderstanding”, outlined the implications of her research for vaccine development and explained the benefits of studying infection in zebrafish. The condensed interview is available on the IAVI site.
Can most people clear TB?
Recent research, published in American Journal of Respiratory and Critical Care Medicine in 2021, suggests that “the majority” of TB-immunoreactive individuals have cleared their infection while retaining immunological memory of it”. Therefore, it seems that the number of people “harbouring live M. tuberculosis is substantially lower than previously thought”. Indeed, in the interview, Professor Ramakrishnan refers to the “5-10%” of people who don’t clear it”. What, then, is the difference between these people and those who can clear it independently?
“The people who don’t clear TB don’t all have a single mutation that makes them unable to clear the infection. Rather, there are likely multiple paths to genetic susceptibility that the TB bacteria can exploit using myriad virulence deterrents.”
Seeing through infection
Professor Ramakrishnan describes studying TB infection in zebrafish as “a real boon”.
“Our zebrafish work has illuminated multiple steps of TB that would not be accessible in your traditional animal models because we can follow infection live and watch the interactions in a see-through host.”
This has allowed insights into “literally each step of infection”, including “how the bacteria survive the initial interaction with host macrophages”. Another aspect that is “intriguing” to Professor Ramakrishnan is the formation of the granuloma, which comprises infected macrophages that “undergo a specialised differentiation, recruiting many other types of immune cells to form this very complex structure”. Although granulomas can be “sites of enhanced host immunity and eradicate bacteria” in “many cases”, the bacteria exploit the granuloma for expansion in a “substantial minority of cases”.
“Paradoxically, they do this by accelerating the kinetics of granuloma formation, changing a host-protective structure into a harmful one. This is also something we have been able to discover by monitoring and manipulating granuloma kinetics in transparent larvae.”
What they found is that the TB bacteria kill infected macrophages and recruit new macrophages to “engulf the dying cells”, offering “new growth niches” for exponential growth.
“This process makes the disease more pathogenic, more transmissible, and more morbid.”
Communicating the risk and reality
Professor Ramakrishnan reflects that some people may be “concerned” that “by revealing that many fewer than 2 billion people are infected with TB, we were minimising the problem of TB”. She emphasises that “that is certainly not the case”.
“A disease that continues to kill over a million and a half people per year, despite the existence of antibiotics for more than 60 years, is nothing to be scoffed at.”
Indeed, she suggests that her research is “actually upgrading TB” in terms of virulence. Furthermore, she presents the case for “simplified technology” over the terms latent TB and active TB, which are “confusing”.
The terms that were proposed are:
- Uninfected – no infection, no disease, may or may not be TB immunoreactive
- Tuberculosis infection (TBI) – infected with live Mycobacterium tuberculosis
- Tuberculosis infection no disease (TBInd) – tuberculosis infection, asymptomatic and culture negative, may or may not be TB immunoreactive
- Tuberculosis (TB) – symptomatic and/or culture positive, may or may not be TB immunoreactive
Implications for vaccine research
“If I were running a vaccine trial, I’d be very happy to see the analyses we’ve provided because what they’re telling you is that instead of having to wait years and years to see if the vaccine worked or not, you should be able to discern efficacy within a year. That’s a huge benefit.”
Practically, testing a vaccine to prevent progression from latent infection to active TB requires the separation of people who have a positive skin test and are still infected from those who have a positive skin test but have “completely cleared the infection”. Otherwise, Professor Ramakrishnan states, you’re “really just ignoring the epidemiological data” and will “muddy the interpretation of the results”.
Do check out the full interview on the IAVI page here, and if you are interested in translating immunological evidence into vaccine development why not join us at the Congress in Washington this April or subscribe to our newsletters here?
