Breakthrough in TB research

There has been a resurgence of tuberculosis around the world, according to the World Health Organization. The latest research shows that nearly nine million people develop the infection and about two million people die from the disease, each year. TB is also now reported to be the biggest killer of women.

The World Health Organisation, which has declared TB “a global health emergency”, predicts that by 2020 nearly one billion people will be newly infected with TB. Of these, some 70 million will die. TB blackspots include eastern Europe with 250,000 cases a year, south east Asia, with three million cases a year and sub-Saharan Africa with two million cases a year.

Another aspect in the resurgence of the disease is the development of drug resistant strains, which now affect up to 50 million people. The drug-resistant TB strain recently hit the headlines when doctors in Glasgow revealed they were treating Scotland’s first diagnosed case of the drug-resistant XDR tuberculosis. The patient is reported to have come to the UK from Somalia and was isolated at the Gartnavel General Hospital. Although this was the first case of its kind reported in the UK since the revised definition of XDR-TB was published by the World Health Organization in 2006, an earlier case in 2003 was retrospectively identified as XDR-TB. About half of XDR-TB cases are fatal.1

Understanding more about the transmission of TB between people is key to combating this threat and it is hoped that research recently published in the UK could offer a significant contribution to this understanding.

Lead investigator Professor Mike Barer, professor of clinical microbiology in the department of infection, immunity and inflammation at the University of Leicester, said: “Strenuous efforts are being made to reduce the global burden of tuberculosis, a disease which kills four people every minute. Our success so far has been limited for many reasons; one of these is our failure to control the spread of TB from one person to another. “Very little is known about this vital part of the bacterium’s life cycle. If scientists could understand more about the transmission of TB between people, they might identify new therapeutic and preventative targets.

“We examined TB in sputum samples from infected patients to get a snapshot of the disease at the point of its transmission to a new person and ask how the characteristics of these bacilli compare with those of TB growing in the laboratory.”

Professor Philip Butcher and his team at St Georges, University of London exploited the genome sequence information of the TB bacteria generated by the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute. They studied all the genes that are expressed by the bacteria in sputum having being coughed up from the lungs of TB patients using microarrays or gene-chips, made available through the Wellcome Trust funded Bacterial Microarray Group at St George’s.

Importantly, the St George’s team developed a novel way to study the small numbers of bacteria present in sputum and this discovery will open the way to investigate why bacteria in TB lungs are so hard to kill with antibiotics. The research identified for the first time that the TB bacterium lays down body fat that may help it survive passing from one person to another and, in the process, the bacteria increase their resistance to the action of anti-TB drugs. “This work forms the foundation to develop a new drug that works effectively against these fat and lazy bacteria,” said Prof. Butcher. “We hope that our new ability to monitor these sleepy and resistant bacteria in sputum will enable us to treat the disease more quickly,” Prof. Barer added.

The research findings are reported to challenge the established view that the TB bacteria coughed up in sputum by infected individuals are rapidly multiplying. In addition, the study sheds light on the story of “persister bacteria” in TB – a mysterious population believed by many to be the reason why TB patients have to be treated for at least six months. Dr John Moore-Gillon, vice president of the British Lung Foundation, which co-funded the research, added: “This research helps us understand just why the TB bug is an extremely tough cookie built to survive. It adds to our knowledge of why TB bacteria are so difficult to eradicate from the body and why drug resistant strains such as XDR-TB develop. This research may pave the way for new types of drugs that could stop TB in its tracks.” The full findings are published in the Journal, Public Library of Science Medicine (www.plosmedicine.org).

Hope for booster vaccine

Hopes are also being raised for a booster vaccination according to Helen McShane, from the Jenner Institute, University of Oxford. She revealed, at a presentation at the Royal College of Physicians earlier this year, that a booster vaccination is showing promise in trials, known as MVA85A, which is derived from the smallpox virus. She explained the importance of research in this area: “Globally the incidence rate of TB is increasing annually by 1%, which has been made even more challenging by an overlap with HIV – the biological synergism between TB and HIV has had a devastating impact in some areas,” she commented.

“If that is not enough, it is estimated that a third of the world’s population is latently infected with TB and are therefore at risk of reactivation of the infection if they become immuno-suppressed. We are not going to control this epidemic with the tools that we currently have. We need new drugs, diagnostic tests and vaccines if we are to stop this pathogen.”

She explained that BCG, if given at birth, provides good protection against disseminated disease and TB meningitis during the first 10 years of life. However, it does not provide protection against adult lung disease. The Modified Vaccinia Ankara currently subjected to trials is an attenuated strain of the smallpox virus. She pointed out that it has an excellent safety record and is good at boosting previously primed T cells, making it ideal for boosting the protection of BCG.

The booster has been subjected to trials on humans in the UK and Gambia and further investigations are currently ongoing.

The safety data to date has been excellent, Helen McShane reported: “Although most individuals experience a local reaction, and some report mild systemic affects such as feverishness, a total of two hundred subjects have been vaccinated without any serious adverse affects.

“We have found that for individuals, who have already been immunised with BCG, an injection of MVA85A induces significantly higher levels of T cells one week after vaccination. These levels remain higher at six months, when compared to groups where BCG or MVA85A were given on their own,” she explained.

The vaccine has also been tested on latently infected individuals, in the UK, as the team were concerned that it may prove less effective for this population. However, positive results have been reported for this group.

“We are now currently recruiting people who are HIV infected to participate in trials, as this group would be an important target group for the booster vaccination. People with HIV are particularly susceptible to TB, so the aim would be to vaccinate this population early on, before they became profoundly immuno-suppressed to reverse this susceptibility. It could have a huge impact,” she commented. “So far there have been eight volunteers and the safety record has been very good – importantly, there have been no increases of viral load or CD4 count,” she reported.

However, she acknowledged that further research is required, involving larger numbers, to establish why there are differences between individuals in the levels of response. Further RCTs are planned later this year, in South Africa, which will include the boosting of infants at 16 weeks of age and comparisons with a placebo. The trial will last for three to four years, she explained.

“To summarise our findings with this vaccine to date, it has been safe and immunogenic in every population it has been tested on. There are three indications for which we believe it could be used for if efficacy trials are successful: as a booster vaccine in infancy (four to six months), as a booster in adolescents when we know the effects of BCG are starting to wane, and also as a booster which is given on HIV diagnosis.”

Helen McShane also revealed that her team at Oxford will be looking at mucosal routes to vaccination and shall be exploring evidence in animal models that the best method of achieving TB protection is to deliver a vaccine via the lungs. She intends to test this hypothesis in larger animal models and ultimately in humans, using an aerosol device currently being developed by the World Health Organization for the administration of measles vaccines.

References

1 www.bbc.co.uk, 21 March 2008.

Vitamin D deficiency link with TB

Researchers at the Central Middlesex Hospital in London have studied an ethnically diverse population in London, with TB, and uncovered interesting findings. The results are expected to lead to new trials to investigate a new line of treatment.

Patients with active tuberculosis are more likely to be vitamin D deficient than the rest of the population, according to new research presented at the annual Society for Endocrinology BES meeting in Harrogate. The discovery has lead to suggestions that it may be possible that vitamin D supplementation could reinforce current treatments or be used as a preventative measure against tuberculosis.

Researchers at the Central Middlesex Hospital in London, led by Dr Vassiliki Bravis, examined the prevalence of vitamin D deficiency in an ethnically diverse population in London who had active tuberculosis. Out of 158 patients in the study, only 11 (7%) had adequate vitamin D levels. Additionally, patients’ vitamin D levels did not vary seasonally as expected, but remained constant throughout the year.

In the UK, vitamin D levels should fluctuate seasonally with the amount of sunlight individuals are exposed to, being higher in the summer and lower in the winter. Approximately 14.5% of the UK population is vitamin D deficient. However, vitamin D deficiency is more common among the Asian and African population, in whom TB infection is also more prevalent.

Researcher Dr Vassiliki Bravis said: “Previous research has shown that high levels of vitamin D can help inhibit tuberculosis infection.

Our work shows that, within a London population, the majority of TB patients we treat are vitamin D deficient. “Currently, we don’t know whether this vitamin D deficiency is a contributing factor towards them developing the disease or whether tuberculosis infection makes the body process vitamin D in an abnormal way, meaning that sufferers subsequently become vitamin D deficient. Looking towards the future, we now need to carry out trials to establish whether vitamin D supplementation could be used effectively to either prevent or help treat tuberculosis infection.”