Analyzing potential TB vaccine

When results from a landmark tuberculosis vaccine trial in Cape Town, South Africa were published in The Lancet in February 2013, the headlines were grim, despite hopes that the trial would point toward a successful way to thwart one of the globe's biggest public health threats.

"TB vaccine candidate trial results disappoint," reported the University of Cape Town.

"TB vaccine trial is step forward though results 'not what hoped,'" said Oxford University's news team.

The vaccine — tested in nearly 2,800 infants — did not offer extra protection against developing tuberculosis, which last year killed 1.5 million people. South Africa has the second highest rate of TB cases and the highest rate of drug-resistant TB in Africa, according to the Centers for Disease Control and Prevention.

What went wrong? Ian Orme, Colorado State University Distinguished Professor in the Department of Microbiology, Immunology & Pathology, recently conducted a study that has provided some important new clues, and suggestions for other researchers.

Testing the TB vaccine

Orme and his research team in Fort Collins investigated whether the existing vaccine for TB, which goes by the acronym BCG (bacille Calmette-Guerin), worked equally well against different clinical strains of tuberculosis. BCG, developed in 1921, is the only available vaccine against TB.

The vaccine tested in Cape Town in 2013 was MVA 85A, a modification of the cowpox vaccine designed to express a major protein of the TB bacterium. It was meant to boost immune responses in infants already primed by the BCG vaccine.

In the CSU study, Orme and his team found that BCG strongly inhibited a number of virulent strains of TB obtained from the clinical trial site around Cape Town. "It performed so well in the preclinical model, we determined that to boost its effects further was essentially impossible," said Orme, also a co-founder of CSU's Mycobacteria Research Laboratories.

In other words, there's no way that MVA 85A could have provided the extra protection against TB that researchers were hoping for.

Analyzing a potential new vaccine

The CSU team also compared BCG with a newer version of the vaccine known as recombinant BCG-422. "What we hoped to see was that this recombinant vaccine would be better and stronger," said Orme. "In fact, we did not see that at all. We did not see any evidence of improvements in the immune response. When we did a longer-term test, the newly developed recombinant BCG wasn't actually as good as the 'regular' BCG."

Recombinant vaccines rely on one or more antigens — proteins associated with the target bacterium — that boost an immune response; in this case Mycobacterium tuberculosis, which causes TB.

Analyzing local TB strains is crucial

Orme said the research findings are important for several reasons. "If you're going to test a new vaccine in a specific place, you should look at the local strains first and see if your vaccines are effective against the local strains people are catching," he said.

Preclinical testing is important for financial reasons. This type of testing in animal models costs up to $300,000. Testing a new vaccine on humans in a clinical trial costs tens of millions of dollars. "It is important to 'look before you leap,' and, unfortunately, that's not what happened in Cape Town," Orme said.

Helen McShane, a Professor in the Nuffield Department of Medicine at the University of Oxfordled the 2013 clinical trial who led the 2013 clinical trial, described the CSU study as "really important."

"The results of our efficacy trial posed many questions," she said. "This paper illustrates the importance of taking into account different clinical strains of TB. Most of the vaccines out there use laboratory strains in testing. Ian has led the field to push for testing clinical strains."