Research in detail
The section’s work has transformed our understanding of the natural history of TB infection, uncovered the mechanism of action of the BCG vaccine and defined the blueprint for a new universal pandemic influenza vaccine. The scientific discoveries enabled practical solutions for tackling infectious diseases including the FDA-approved, NICE-endorsed ELISpot IGRA (interferon-gamma release assay), which has transformed diagnosis and screening of TB. The ongoing research programme probes the immunologic and genetic factors that shape the natural history and clinical outcomes of TB and influenza infection while maintaining a strong translational theme by developing next-generation biomarkers for diagnosis, prognosis and risk stratification of TB and influenza infection.
Recently, the group’s epidemiological and public health research in collaboration with Public Health England (PHE) via the NIHR HPRU in Respiratory Infections delivered the evidence-base and blueprint for the new PHE and NHS National TB Strategy.
We aim to understand how the host immune response shapes the wide range of clinical outcomes following exposure to M. tuberculosis, and to translate our research findings from bench to bedside to deliver practical solutions to improve clinical management of tuberculosis patients and tuberculosis control at the global level.
The group’s core activities are in human cellular immunology, cell biology, mycobacteriology, human genetics and epidemiology. Although tuberculous disease is common, symptom-free tuberculosis infection and exposure to tuberculosis are even more common, but only a minority of people exposed to the bacterium actually develop disease. The host response plays a critical role at each stage in the natural history of tuberculosis.
Specifically, the tuberculosis theme of the Infection and Immunity Sections aims:
- To develop newer, more accurate tests of Mycobacterium tuberculosis (MTB) infection that can be used in clinics to distinguish active TB from LTBI by comparing and contrasting immune markers from people with LTBI to those from healthy volunteers.
- To immunologically distinguish active TB from LTBI in blood samples to ensure optimum treatment is given to patients.
- To immunologically distinguish recent from remote LTBI in blood samples as the risk of progression to active TB is higher in persons who are recently exposed compared to persons who were exposed many years ago.
- To identify immunological correlates of long-term containment of TB and early predictive markers of disease progression so that patients at highest risk of developing active TB can be given prophylactic drug treatment and followed up closely whilst those at low risk for developing active TB do not need to be treated or followed up.
- To identify biomarkers of sterilisation to enable treatment times to be targeted to individual patients and to help in the development of future targeted drug therapy.
- To characterise and compare immune responses between blood and sites of disease in active TB because in patients who are unwell it is clinically important to distinguish between patients with active pulmonary TB and those with LTBI and who are unwell due to another process.
- To characterise and compare immune responses in specific sites of disease between active and latent TB to enable us to develop tests that can distinguish between patients who have latent and active TB at the site of their disease. Such tests would be extremely important in rapidly distinguishing whether an unwell patient had active TB or whether they had latent TB and was unwell due to another process.
Influenza and other acute respiratory infections
As host to the NIHR HPRU in Respiratory Infections, the section is working on two different studies of the effectiveness of the recently licensed Live Attenuated Influenza Vaccine (LAIV) which has been shown to be more effective in children aged 2-16 years compared to inactivated flu vaccine. Firstly, the LAIV Immuno study which compares whether LAIV offers more protection for those with prior-vaccination exposure or not by sampling nasal swabs in the event of an influenza-like illness. The HPRU is co-ordinating a sub-study called LAIV Immuno CMI, which looks for cell-mediated immune responses in blood samples from the same children. Secondly, the HPRU is conducting LAIV Protect, following up 10-17 year olds receiving LAIV vaccine at two schools in Leicestershire to identify any adverse effects experienced by schoolchildren within seven days of receiving LAIV and to explore the incidence of flu in this vaccinated cohort and in those who did not receive LAIV. From this epidemiological study, a sub-study is being conducted called LAIV Protect Correlates, which takes extra blood samples from the children before and at intervals for two years after vaccination to study the quality, magnitude and longevity of cellular and humoral immune responses induced in secondary school children. These samples represent a significant and unique resource to assess the quality, magnitude and longevity of cellular and humoral immune responses induced by LAIV in this key age group targeted by the national LAIV programme.
In addition, the Section has recently commenced a study on Severe Community-Acquired Pneumonia (S-CAP) which will enrol 60 patients in ECMO centres around the UK and combines cutting-edge bioinformatics with 16S RNA sequencing and metagenomic approaches to improve detection of potentially aetiologic bacteria, viruses and hard-to-culture organisms in the 50% of S-CAP patients that have no microbiologic diagnosis following conventional testing. Ultimately this could substantially upgrade PHE’s diagnostic service capability for CAP patients as well as improving the national capacity to rapidly detect novel or emergent respiratory pathogens.
The Infection and Immunity Section has many scientific objectives, some of which are dependent on the availability of the research tissue bank. Some of the key research objectives for flu and other acute respiratory infections are as follows:
- To develop diagnostic tests for other granulomatous diseases.
- To characterise the immune responses for other granulomatous diseases, such as sarcoidosis
- To identify and test new strategies for prevention of Influenza infection
- To characterise the immune responses in individuals with Influenza and respiratory infections.
- To identify biomarkers that can distinguish people at risk of severe respiratory viral infections
- To develop tests to identify new emerging respiratory virus infections and hard-to-culture organisms.
- To develop non-invasive sampling methods for respiratory infections
- To investigate novel serological assays respiratory viral infections.
Prompt, accurate diagnosis and treatment of TB are essential to improve individual patient outcomes, as well as to prevent onward transmission in the community with its attendant health-care associated and social costs. However, currently available tests, which are mostly about a century-old, have poor diagnostic sensitivity or require a long wait for results (2-6 weeks). The lack of adequate diagnostic tools is thus a major roadblock to rapid, accurate diagnosis of TB and timely treatment.
In recent years, numerous studies have described host response-related biomarkers which differ between those who have active TB disease and those who have either other diseases or latent TB infection. The NIHR-funded VANTDET (Validation of New Technologies for the Diagnostic Evaluation of Tuberculosis) project aims to validate recently discovered transcriptomic, proteomic, and cellular immune signatures for their use in the diagnostic work-up of active TB. This project utilises a large cohort of individuals who were suspected of having active TB as part of routine clinical practice in various NHS sites in the South of England. By using state-of-the-art transcriptomic, proteomic, flow cytometry and molecular techniques, we will validate the role of new diagnostic tests for TB in routine NHS practice, delivering blood tests that can rapidly rule-in and rule-out a diagnosis of TB.
Traditional diagnosis of TB is based partly on the tuberculin skin test. Blood tests such as QuantiFERON GOLD In-Tube (QFT-GIT) and T-SPOT.TB are now available. However, these two tests are not used as part of current NHS practice due to lack of evidence about how well the tests perform when diagnosing active TB in routine clinical practice.
The purpose of the IDEA study was to compare the ability of QFT-GIT and T-SPOT.TB to detect people with active TB from those without active TB in a population suspected of the disease. Researchers assessed new blood tests that are currently being developed for diagnosis of active TB and recruited 1,074 patients with suspected TB from 14 NHS hospitals in London, Slough, Oxford, Leicester and Birmingham into our study. The IDEA study results will include recommendations based upon the evidence generated in this study, on the accuracy and clinical utility of diagnostic strategies that include IGRAs, and how they compare to conventional diagnostic testing for the work-up of patients suspected of active TB. An evidence-based optimal testing algorithm that defines the role of IGRAs in the diagnostic work-up of suspected active TB in the NHS will be presented and the cost-effectiveness (from an NHS perspective) of each testing strategy will be quantified and compared. Recommendations will also be provided for TB patients co-infected with HIV. The report will summarize findings particularly relevant to UK TB control policy, including health and health economic effects on TB transmission in the UK.