Trial of vitamin D supplementation to prevent acquisition of latent tuberculosis infection in schoolchildren (ViDiKids)

1) Context of the research Tuberculosis (TB) kills 1.5 million people each year. India has the highest number of TB cases in the world - some 2.2 million in 2011 alone. The World Health Organisation aims to eliminate TB by 2050. TB usually arises when a dormant infection with TB bacteria, termed 'latent TB infection' (LTBI) becomes active. LTBI is usually acquired in childhood following inhalation of TB bacteria coughed up by a person with infectious active TB. By the time they reach adulthood, approximately 80% of people in India will have acquired LTBI. In 10-20% of these people, LTBI will reactivate to cause active TB disease in their lifetime. Preventing people - especially children - from acquiring LTBI in the first place could therefore dramatically reduce the number of people who go on to develop active TB. Currently, however, conventional approaches to TB control focus instead on finding and treating people with infectious active TB in order to break the cycle of transmission. This strategy will not eliminate TB in countries where it is very common because new cases of active TB will continue to arise from the many people who have LTBI. The existing TB vaccine, BCG, does not prevent LTBI, and a recent trial of a new vaccine had disappointing results. New strategies to protect children from acquiring LTBI will therefore be needed if the 2050 elimination target is to be met. We propose that supplementation with vitamin D - the sunshine vitamin - could boost immunity to TB bacteria, and thereby prevent LTBI in children exposed to infectious TB. Vitamin D has long been recognised to boost immunity to TB bacteria. Before the discovery of antibiotics, cod liver oil (rich in vitamin D) and sunbathing (which boosts vitamin D levels) were both used to treat TB. Laboratory experiments show that vitamin D helps white blood cells to kill TB bacteria. Studies in patients show that those with lower vitamin D levels are more susceptible to acquiring LTBI after exposure to an infectious TB case. Moreover, a recent clinical trial in 120 schoolchildren in Mongolia showed that vitamin D supplementation reduced risk of acquiring LTBI by 59%. Although promising, this study was small, and a much larger trial is needed before vitamin D can be recommended for TB prevention. 2) Aims and objectives The primary aim of this research is to determine whether a monthly vitamin D supplement, taken by mouth for 3 years, can reduce the risk of acquiring LTBI among schoolchildren in an area where TB is very common. We will achieve this by conducting a clinical trial in 6,750 primary schoolchildren in New Delhi. Despite plentiful sunshine, vitamin D deficiency is present in 85% of schoolchildren in New Delhi, possibly as a result of air pollution which blocks out sunshine. Participants will have a blood test for LTBI at baseline: those who test negative will be allocated to receive 36 monthly doses of vitamin D or placebo (dummy medication with identical taste and appearance) at random. Study staff will visit children monthly for 3 years to give doses of study medication and check for TB symptoms. At the end of the study, rates of LTBI will be compared between children who received vitamin D vs placebo. 3) Potential applications and benefits If results are positive, vitamin D could be used to prevent LTBI in children. Vitamin D deficiency affects 1 billion people worldwide, and 2 billion are estimated to have LTBI: results of our study could therefore have global importance. Several groups could benefit from the study. Vitamin D deficient people at risk of TB would benefit from the discovery of a cheap, safe method of reducing their TB risk. The TB control community would benefit from the discovery of a new tool for TB control. TB researchers would benefit from new scientific insights into the effects of vitamin D. Study participants will benefit, as they will receive screening for TB which they would not otherwise have had.