Tuberculosis (TB), is a complex and preventable disease caused by Mycobacterium tuberculosis (M. tuberculosis). Most individuals infected with M. tuberculosis remain well by containing the pathogen immunologically. Five to ten percent of infected persons develop disease, leading to onward transmission of M. tuberculosis. It is well known that HIV infection increases the risk of progression to TB, but the effect of other viral infections on the natural history of TB remains ill-defined. Identifying modifiable factors that increase the risk of progression to TB in those already infected could lead to innovative interventions to curtail the epidemic. An under-researched area to date is the role of non-HIV viral triggers.

The public health benefit of identifying common viral infections, such as influenza, which increase the risk of TB, and which can be targeted with vaccine interventions, may be substantial. In the UK, TB incidence could be reduced in key risk groups (e.g. household contacts of people with TB) through targeted vaccination. In higher burden countries such as South Africa, reductions in community-wide M. tuberculosis transmission could be achieved through larger scale vaccination of people in high-risk populations (e.g. people living with HIV).

Our hypothesis is that influenza trigger progression to TB, and that vaccination-induced prevention of influenza reduces the risk of TB.
Research questions

1. Does influenza increase the risk of TB in the UK?
2. Does prevention of influenza through vaccination reduce the risk of TB in the UK?
3. What would be the impact on TB incidence in South Africa of increased influenza vaccine coverage?

Research questions 1 and 2 will be addressed using the UK Clinical Practice Research Datalink (CPRD), which includes routinely-collected anonymised longitudinal primary care data on 11.3 million patients who are representative of the UK population for age and sex. Widely validated data on demographics, diagnoses, prescriptions, immunisations, investigations, and referrals are available. Data linkages to episodes of admitted patient care in all NHS hospitals in England and Wales (Hospital Episode Statistics) and death certificate data from Office for National Statistics are available.

1. Does influenza increase the risk of TB in the UK?
   Study population: Patients aged ≥ 15 years included in the CPRD
   Exposure: Influenza-like illness (ILI)
   Outcome: TB
   Study design: (i) Longitudinal cohort study (ii) Self-controlled case series (SCCS)2,3

2. Does prevention of influenza through vaccination reduce the risk of TB in the UK?
   Study population: Patients aged ≥ 15 years included in the CPRD and eligible for the influenza vaccination as per guidance at the time
   Exposure: Influenza vaccination
   Outcome and study design as above.

For research question 3, the student will develop and calibrate a mathematical model of tuberculosis and influenza transmission in South Africa, incorporating the impact of influenza on the risk of developing TB. They will model different levels of influenza vaccine coverage in different risk groups, and estimate the impact on TB incidence and mortality.