irishtimes– It took less than a year to develop and trial vaccines for Covid-19. But developing new vaccines is not always so successful. Three diseases have proven especially challenging – tuberculosis (TB); HIV/Aids and malaria.
Though TB might seem like a disease of yesteryear in Ireland, this is consistently the biggest infectious disease killer on the planet, overtaken only by Covid-19 during the pandemic. There is just one vaccine for TB – the BCG vaccine – which is remarkable given how old it is.
This summer marked the 100th anniversary of the first use of BCG, with no newer licensed vaccines for TB since, despite many attempts. BCG still protects young children in parts of the world where the disease remains rampant.
“Infants are very susceptible to getting TB,” says Prof Hazel Dockrell, an Irish-born immunologist at the London School of Hygiene & Tropical Medicine. “BCG is still widely given to babies to provide protection from disseminated forms of TB, but it gives variable protection to adolescents and adults [against lung disease].” She describes TB as “a much trickier infection to protect against than SARS-CoV-2”.
Antibiotics
An estimated billion people have succumbed to TB in the past two centuries, including 1.4 million deaths in 2019. The bacterium lies latent today in almost two billion people, and 10 per cent to 15 per cent will go on to develop lung disease. There are an estimated 10 million active cases of TB. The disease can be treated with antibiotics, but it takes many months, and there’s no guarantee it won’t come back. We need a new TB vaccine.
Prof Dockrell grew up near Terenure and studied natural science in Trinity College Dublin, where initially she wanted to be a chemist, but fell in love with microbiology. After completing a PhD in London on autoimmunity, she began researching how the immune system responds to malaria.
She moved to the London School of Hygiene & Tropical Medicine and studied leprosy, working with scientists in Karachi, Pakistan. This sparked her interest in a bacterium that is related to leprosy – Mycobacterium tuberculosis – which causes TB. She subsequently researched TB vaccines in Malawi and Uganda. “TB, malaria and HIV have all been very tough to develop vaccines for,” she adds.
For Covid-19, the strength of antibody response has offered a good yardstick for how well the vaccine will work. Scientists are not quite sure what response TB vaccines should be causing, but believe T cells, perhaps localised to the lungs, might be crucial for protection. T cells help other immune cells kill bacteria within cells, and they can directly kill infected cells.
“HIV and TB are similar in some ways. The arm of the immune system that must engage is the T cell immune response. But almost every vaccine that we have works by generating neutralising antibodies,” says Prof Stephen Gordon, infectious disease researcher at University College Dublin. “For TB, we don’t think neutralising antibodies are going to be enough.” This likely has contributed to TB vaccine failures.
When first inhaled into the human lung, TB bacteria enter our cells and may become walled off by scar-like tissue. “It can just sit there for decades, and your immune system basically holds it in check,” Gordon points out. “But the bacterium is still viable. It is just waiting for its moment.” If that person gets an HIV infection, becomes malnourished or their immune system becomes suppressed, the infection awakens and the person can suffer full-blown TB.
As an ancient human foe, TB is well adapted to infecting and hiding inside our cells. “Once TB gets inside a cell, it manipulates the environment to reduce the ability of that cell to induce a good immune response,” Dockrell says.
“It is one of the most successful pathogens in the world,” notes Gordon, “infecting a quarter of the world’s population.”
A new vaccine could prevent adolescents or young adults from infection, or help to keep latent infections (and spread of TB) in check. There are more than a dozen vaccine hopefuls in clinical trials, but one challenge again is that we still do not know what exactly immune protection against TB looks like.
Complexity
Another difficulty is the complexity of the TB bacterium. Coronaviruses have one main protein (the spike) that they use to invade our cells. Covid-19 vaccines use the spike protein to tutor our immune system on the virus. “TB has thousands of proteins, and it is so much harder to choose which one to use to make a vaccine,” Dockrell notes. One option is to choose an entire, living bacteria, but one which does not cause disease.
Indeed, BCG vaccine is a living bacteria, with a fascinating backstory involving the humble spud. It was developed by two French bacteriologists who grew a bovine relative of TB, Mycobacterium bovis, on potato slices soaked in glycerin and ox bile.
“They noticed that the bacteria lost some of its virulence and this flicked on a lightbulb that this was a route to weakening this bacterium,” Gordon adds. After 13 years, the French scientists generated what became known as the Bacille Calmette-Guerin (BCG) vaccine and showed it could protect cattle from TB.
BCG was first given to an infant in a Parisian hospital on July 18th, 1921, whose mother and family members had died of TB. More and more children then began to receive the vaccine. Today, the vaccine is no longer administered widely in European countries, but still given to babies in countries with high rates of TB and to high-risk groups elsewhere.
By tweaking BCG genetically, German scientists have developed what they hope is a better version of BCG, including for adults. There is also a trial in Africa that involves young adults receiving BCG follow-up jabs.
Another vaccine candidate (MTBVAC) developed in Spain is a TB strain weakened by mutations. One promising vaccine candidate consists of two TB proteins and an immune-boosting agent. This could be safer in those infected with HIV, since live bacterial vaccines are less suitable for those with a suppressed immune system.
Still, no new vaccine has proven its worth in a large phase-three trial. These are expensive to run, since it can take a few years to figure out if the vaccine has worked or not even in one individual. “The holy grail would be stopping infection, but that is going to be really difficult,” says Gordon, who believes that preventing disease will likely be more achievable – as has been the case with Covid-19.
There is also the problem that TB impacts some of the poorest parts of the world, such as sub-Saharan Africa and India, and their most impoverished people. This has held up some vaccine trials, according to Prof Thomas Scriba, TB vaccine scientist at the University of Cape Town in South Africa, who blames a lack of resources; an extreme aversion to investment risk and a general lack of urgency in TB vaccine development.
“TB is never going to be a lucrative disease to tackle and for that reason the biomedical and pharmaceutical players tread very carefully,” he says. “This is in such stark contrast to the warp speed that has been applied to Covid-19, where the entire world can clearly sense the threat on their doorstep.”
