First New Tuberculosis Vaccine Trial in Nearly a Century Yields Disappointing Results

The first major study in nearly a century intended to test a new tuberculosis vaccine in infants was ineffective. The ‘MVA85A’ vaccine had been the most promising candidate among multiple TB vaccines in exploratory phases and was the first to be brought to human trial since 1921, when the Bacillus Calmette-Guérin (BCG) vaccine was developed. The BCG vaccine is still being used today, mostly developing countries, to protect against TB, though it is not always effective.  

The BCG vaccine is generally not recommended for use in the United States due to very low chances of TB infection and the fact that it is not always effective at warding off TB in adults. The vaccine can also interfere with a tuberculin skin test, which is used to determine if a person has been infected. However, TB is widely prevalent and a major cause of death in developing countries. The BCG vaccine is commonly administered to infants and neonates with coverage rates typically over 80 percent in affected populations. The vaccine is very limited however, as it can only protect against ‘disseminated’ TB in children. In other words, it has already spread from the lungs to other parts of the body. Primary infection and reactivation of latent TB are impervious to the vaccine. In order to curb the spread of TB in the developing world, a more effective means of vaccination in both children and adults is very much needed.

The study was double-blind, randomized, and placebo-controlled. In short, this is one of the most rigorous types of trials possible. The researchers randomly assign study participants to the placebo group or to the vaccine group. To prevent the researchers themselves from influencing the results (presumably the researchers want the vaccine to produce favorable results), the researchers do not know to which study participants have been assigned. The participants themselves are also unaware if they received the placebo or vaccine. This makes it "double-blind." The study is "randomized" because participants were randomly selected to be in one group or the other, and "placebo-controlled" pertains to a proportion of randomly assigned participants who did not receive the MVA85A vaccine, but went through the exact same study process as participants that did receive the vaccine. The results of those participants who received the vaccine were compared to the “control” group, in other words those who received the placebo.  The study took place in South Africa where  2797 infants aged four to six months, who had already received the BCG vaccine, were enrolled. Subjects were followed-up every three months for an average of two years. Although the primary objective of the study was to address safety and tolerance of the vaccine, efficacy was also tested in a subset of individuals in the study. MVA85A was shown to be only 17 percent effective at preventing infection from TB, which is statistically insignificant. In other words, it could not be ruled out that 17 percent was not due solely to chance or random error. The research, which was published in The Lancet online Feb. 4, notes that MVA85A was indeed well-tolerated and induced ‘modest cell-mediated immune responses,’ but as the results show, MVA85A did not produce the desired outcomes. The authors note that the (reason for) lack of effectiveness is unknown and requires further investigation.

"This is the first efficacy trial of a new TB vaccine since Bacille Calmette-Guérin, a significant step in itself, and there is much that we and others can learn from the study and the data it produced," Helen McShane from the University of Oxford stated. MVA85A was developed at Oxford with support from AERAS, which is a non-profit biotech company funded largely by the Bill and Melinda Gates Foundation. The Wellcome Trust, European Commission, and Emergent Biosolutions Inc. also supported research.

According to the 2012 WHO ‘Global Tuberculosis Report’, TB affects 8.7 million individuals worldwide and results in 1.4 million deaths each year. Developing countries are hardest hit by the infection, with an estimated 95 percent of all TB deaths occurring in lower to middle-income countries. Along with HIV, TB is a leading cause of death in South Africa.

Tuberculosis is spread from person to person through the air and is caused by a bacterium called Mycobacterium Tuberculosis. The bacteria typically attack the lungs but can affect any part of the body including vital organs such as the kidneys or brain. When left untreated, active TB can be fatal.  Some people are infected with TB, but do not get sick. This is “latent TB infection,” meaning that mycobacterium tuberculosis live in the body but without causing symptoms. During latent TB, the infection is not contagious. The WHO estimates that about one third of the entire world population is infected with latent TB and are therefore ‘not (yet) sick.’ Eventually, TB can multiply in these individuals and develop into TB disease. Once the immune system is overwhelmed and the now multiplying bacteria are ‘active,’ the person maybe become infectious and will require treatment.

In order to treat TB disease, a cocktail of drugs is taken for six to nine months, depending on recommendations by healthcare professionals. First-line treatment consists of the drugs isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). If latent TB is detected, it may also be treated, to prevent it from developing into active TB disease. Latent TB, being less severe, is easier to treat and therefore requires just INH, RIF, and RPT.

However, concerns over totally drug resistant TB or ‘MDR TB’ (multi-drug resistant TB) continue to drive research towards new treatment options. A new study just published by the CDC highlights the disturbing reality of MDR TB in South Africa. This particular strain of bacteria has developed mutations that render current drug cocktails useless. In the study, 93 percent of isolates tested from this MDR strain were immune to 10 anti-TB drugs. It is as important as ever to find an effective means to vaccinate against TB infection as the prevalence of untreatable cases spreads across vulnerable populations.

Luckily, advanced trials are taking place with other experimental TB vaccines.

"The results will take a few years," says Dr. Thomas Evans of AERAS. "So it's not around the corner, but they are in the queue and moving forward." While some call the results disappointing, Evans, commenting on the MVA85A trial, says "This trial leaves us optimistic, not pessimistic. Ten years ago, many doubted such a trial could be completed."

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