Study Identifies Why TB Vaccines Are Ineffective

While the tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has been around for nearly a century, it reduces the chance of infection by only 20 percent, whereas a truly effective vaccine such as the one for measles reduces infection by 95 percent or more. Recently, however, researchers at the Washington University School of Medicine in St. Louis have discovered that the reason the BCG vaccine and investigational vaccine candidates are not more effective is because the immune response is too slow; it’s not because the vaccines elicit an immune response that is too weak to control the infection. In people who are vaccinated against TB and later infected with the bacteria, activation of immune cells is delayed, allowing the bacteria to multiply. “It’s not a question of the magnitude of the immune response, it’s the timing,” said Shabaana Abdul Khader, PhD, an associate professor of molecular microbiology at the university. “Many people in the field of TB vaccine development have been working on increasing the strength of the immune response, and we could go on doing that, but if the timing is the same as for every other vaccine, it’s not going to change the outcome.”

Previous researchers found that vaccination with either BCG or investigational vaccine candidates doesn’t speed up the immune response against TB. Even in vaccinated mice, an immune response to the infection doesn’t start until two weeks after infection, giving the bacteria time to multiply to high levels. In an effort to determine whether speeding up the immune response would make a vaccine more effective, Dr. Khader and colleagues vaccinated mice with BCG, boosted a month later and a month after that, and challenged the mice with Mycobacterium tuberculosis, the bacteria that causes TB, while also giving the mice immune cells specially prepared to activate T cells. With the extra immune cells, the T cells started to fight infection seven to eight days after infection, rather than 12 to 14 days, causing the bacteria to drop by a factor of 10 or 100 and even to nearly undetectable levels.

Unfortunately, the technique can’t be replicated in real life since there is no way of knowing when people will be exposed to the bacteria. “In a way, this is really disappointing,” Dr. Khader said. “We start thinking that maybe none of the vaccines we have for TB will work. But then we come back to the table and say, ‘Let’s put our disappointment aside and figure out what we can really do from here.’ We might have to design an entirely different kind of vaccine if we want to elicit an immune response that eradicates infection. Or, maybe eradicating infection isn’t a realistic goal, but we can still make a vaccine that prevents disease or delays TB reactivation. We’re looking at TB from a different point of view now, and that’s exciting.”