What Researchers Can Learn from a Failed TB Vaccine Trial

A highly anticipated trial of a tuberculosis vaccine yields disappointing results.

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Schmidtsdrift, South Africa. A Bushman child suffering from tuberculosis bundled against the cold.

A highly anticipated trial of a tuberculosis vaccine yields disappointing results.

A vaccine designed to protect infants against tuberculosis (TB) isn’t as effective as researchers had hoped. The MVA85A shot, which contains a large snippet of the Mycobacterium tuberculosis bacterium, couldn’t mount a strong enough immune response in babies to protect them from infection.

In the study, which was conducted in South Africa, 2,797 infants aged four to six months were randomly assigned to receive either the MVA85A shot or a placebo and were followed for up to three years. All lived in areas where there is a high risk of TB infection, so as recommended by public health guidelines, all were also immunized with the existing TB vaccine, known as BCG. Developed 90 years ago, BCG is effective at controlling the type of TB that typically infects adults, primarily in the lungs, but is less effective at protecting young babies, who generally develop a different form of the disease that targets the brain, spine and other organs. In 2011, the World Health Organization reported 8.7 million new cases of TB, and 1.4 million deaths, which indicates how inadequate the current vaccine is in protecting against the disease.

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By the end of the study, 32 of the infants receiving the MVA85A vaccine developed TB, while 39 of the those in the control group did. That difference was not statistically significant, meaning that it was likely due to chance.

“We were surprised to see no enhancement of protection over BCG alone,” says Dr. Helen McShane, a professor of vaccinology at the University of Oxford and one of the senior authors of the study, published in the journal Lancet.

“It wasn’t exactly the answer we were hoping for,” says Dr. Ann Ginsberg, vice president of scientific affairs and acting chief medical officer of Aeres, the company that developed the vaccine. “But nonetheless, it is going to teach us a lot about how to move forward with TB vaccine development, and help guide our work.”

For one thing, the trial proved that it is possible to conduct a rigorous scientific study of a vaccine in a place hit hard by TB; some critics were skeptical about whether the results would be skewed by high rates of not just TB but related infections in the region.

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But the results also leave many important questions unanswered. It’s possible, for instance, that the BCG shot masked the effectiveness of the new vaccine; if babies’ immune systems are still developing, they may respond more strongly to the pathogen in an initial vaccine than in subsequent ones.

And even if the babies developed TB at similar rates, analysis of the blood of those who received the vaccine showed that they did mount immune responses to the TB bacterium. It simply wasn’t enough to ward off the infection. That alone, says McShane, is information that TB experts didn’t have before the study, and could help scientists to refine the shot to boost its effectiveness. “That’s a good example of the knowledge this trial provided that could help us and the whole TB vaccine community going forward,” she says.

For example, even if the immune response generated by the vaccine wasn’t enough to protect infants from TB, it’s possible that the response is sufficient to help those with advanced TB, including those who are also infected with HIV, to battle some symptoms and lessen the severity of their disease.

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So despite the disappointing results, the researchers aren’t ready to give up on MVA85A yet—nor is it their only option. There are a dozen vaccines currently being tested, some of which contain the same snippets of the M. tuberculosis bacterium in combination with other pathogens genes, and additional candidates that contain different ones. One of the formulations currently being tried is an improved version of BCG, which relies on using the entire bacterium to activate the immune system, and is currently is anywhere from zero percent to more than 80% effective in preventing TB in infants. The other approach, which was used in developing MVA85A, involves selecting only small section of the bacterium to present to the immune system, in the hopes that these are the most obvious red flags to alert the body’s defenses to the intruding pathogen..

After decades of stagnant interest in the field of TB vaccines, the growing burden of disease, as well as emerging drug-resistant strains of the TB bacterium, are pushing global health groups to invest and raise awareness about the need for more effective and robust vaccines. Technological advances in vaccine development are also helping reduce the cost of developing theses shots, which traditionally have not been attractive to pharmaceutical companies since most of the potential recipients are in developing countries where profits for such interventions are low. “The technology developments mean we can make new vaccines today that we couldn’t make before,” says McShane. Only by comparing the results of those trials against the current one involving MVA85A will scientists know which strategies produce the strongest immune response and how much of a response is needed to resist infection.

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“The only way to move forward is to do trials,” says McShane. “This trial is a landmark for the field and we can only move forward now with this data, so it’s important we continue this momentum.”

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