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

1) Context of the research

Tuberculosis (TB) kills 1.5 million people each year. South Africa has one of the TB rates in the world: 1% of the population develops TB each year. 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 South Africa 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 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, has been shown to offer very limited protection against TB in Africa - if any - 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 weekly 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 5,400 primary schoolchildren in townships around Cape Town, where we have previously shown that 88% of people have low vitamin D levels. Participants will have a blood test for LTBI at baseline: those who test negative will be allocated to receive weekly doses of vitamin D or placebo (dummy medication with identical taste and appearance) at random. Study staff will visit children weekly 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.

The World Health Organisation aims to eliminate tuberculosis (TB) as a public health problem by 2050. Measures to prevent acquisition of latent TB infection (LTBI) will need to be implemented to achieve this goal. Vitamin D has long been known to enhance innate immunity to Mycobacterium tuberculosis (MTB), and Phase 2 clinical trials show that vitamin D supplementation enhances innate immune resistance to MTB infection.

We propose to conduct a Phase 3 double-blind randomised controlled clinical trial to determine whether vitamin D supplementation reduces risk of acquisition of LTBI in 5,400 initially uninfected Cape Town primary schoolchildren aged 6-9 years at enrolment. Study medication will be administered over 3 years as 156 directly-observed weekly oral doses of 14,000 IU (0.35 mg) vitamin D3 or placebo. We will employ a well-validated interferon-gamma release assay (QuantiFERON TB Gold) to determine whether participants have acquired LTBI at 3 years of follow-up (primary outcome). Logistic regression analysis will be performed on the intention-to-treat population to compare rates of LTBI in intervention vs. control arms at 3 years. The effect of vitamin D supplementation on incidence of active TB, absence from school due to acute respiratory infection and body mass index for age will also be determined (secondary outcomes) and an economic evaluation will be performed to estimate the cost-effectiveness of using vitamin D to prevent LTBI.

Results of this trial will inform TB control policy in South Africa and beyond. Vitamin D deficiency is highly prevalent globally: supplementation is safe and inexpensive, and intermittent bolus doses of vitamin D are effective in correcting deficiency and easy to administer. Vitamin D supplementation therefore represents a potentially highly cost-effective means of enhancing TB control in low resource settings which bear the highest burden of disease.

1. Who will benefit from this research?

The following groups stand to benefit from this research:

a) Vitamin D-deficient people in settings of high tuberculosis transmission, which include some of the world's most populous countries

b) Policy-makers in the TB control community at international, national and local levels

c) The TB and nutritional research communities, in particular epidemiologists and immunologists

d) The commercial private sector, in particular companies manufacturing vitamin D supplements

e) Partner academic institutions

f) Study participants

g) Study staff

2. How will they benefit from this research?

If the results of this trial are positive, the primary beneficiaries will be the wider public living in high TB transmission settings: they will benefit from the discovery that vitamin D supplementation will reduce their risk of acquiring LTBI. We will disseminate positive results of the trial widely, along with advice on how people can improve their vitamin D status. Vitamin D status can be improved at zero cost (e.g. by encouraging sun exposure) - thus results of the study could have a real impact on the health of the very poorest people who are at most at risk of TB.

Policy-makers in the TB control community will also stand to benefit - the trial could yield a new tool for TB control. Interested parties include those working internationally (e.g. WHO Stop TB Partnership and non-governmental organisations), nationally (e.g. governmental ministries of health and education) and locally (e.g. local governmental departments with responsibility for infection control / environmental health in schools). Results are potentially relevant internationally, as populations at risk of TB have been shown to have high rates of vitamin D deficiency in high- and low-resource settings alike. For example, the results of the study could inform TB control policy in the UK, where TB incidence is rising, and where we have previously shown vitamin D deficiency to be common (prevalence 94%) among people at highest risk of LTBI.

Researchers in TB epidemiology and immunology would also benefit from the study, which will generate new data not just about immunomodulatory effects of vitamin D, but also on the determinants of susceptibility to TB in schools. Improved knowledge about the transmission dynamics and natural history of LTBI could inform scientific efforts to develop interventions to control TB.

The commercial sector will also benefit from a positive result. Businesses making vitamin D supplements would stand to benefit in particular.

Several parties involved in the conduct of the study will also benefit. Individual participants will benefit from screening for active TB, which they would not otherwise receive. Research staff will benefit from training in GCP, clinical trials methods, phlebotomy and computer skills, all of which are applicable in the wider healthcare or academic sectors. Participating institutions will also benefit from the establishment of research infrastructure and links between researchers and schools that could be used to conduct further collaborative projects, with potential benefit to schoolchildren's health.

These benefits could all be realised rapidly. Unlike deficiencies in many other vitamins, vitamin D deficiency can be effectively corrected by administration of intermittent bolus doses. In our experience, people find this very acceptable, and administration is inexpensive, safe and easily observed. Positive results from this trial would be likely to result in widespread implementation of vitamin D supplementation for LTBI prevention within a relatively short period of time. This contrasts with implementation of a new vaccine, for example, which may be regarded with suspicion by some groups, and which may be costly, limiting uptake in low resource settings, where TB is most highly prevalent.