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Accelerating the development of effective vaccines for protection against Mycobacterium tuberculosis

In the absence of a robust correlate(s) of protection against human tuberculosis (TB) and a validated animal model of the disease, tools to facilitate vaccine development and testing must be identified. The mycobacterial growth inhibition assay (MGIA) has been used as an ‘ex vivo challenge model’ to analyse vaccine efficacy, offering insight into the summative capacity of a mixed population of ex vivo-derived host cells to control mycobacterial growth after vaccination. To date, preclinical MGIA protocols have been established for use with splenocytes and bone-marrow-derived macrophages in mice.

Since TB is predominantly a pulmonary infection, and MTB challenge studies commonly enumerate bacterial burden in both the lung and spleen of infected animals, we aim to develop a lung MGIA as a complementary tool for the preclinical evaluation of existing and experimental TB vaccine strategies. Growing evidence of variation in BCG protection against different lineages of MTBC highlights the importance of a method in which the protective efficacy of candidate vaccines can be tested against clinical MTBC strains, as well as laboratory strains.

This project aims to adapt the current splenocyte MGIA protocol for lung cells in category-3 containment facilities. Where differences in growth inhibition between vaccines or lineage are noted, RNA seq will be performed to determine alterations in gene expression and pathway activation which account for these variations, as well as identify a potential correlate(s) of protective efficacy. In combination with current methods of preclinical TB vaccine assessment, the ex vivo lung MGIA could be used in the future as a tool for analysis of vaccine efficacy and the underlying immune mechanisms associated with vaccination.

Project dates: October 2016 - December 2020

Project lead and staff: Hannah Painter (L), Helen Fletcher and Andrea Zelmer

Collaborating institution: St George's University of London (Dr Rajko Reljic)

Funder: MRC and Rosetrees Trust

ACT|IMP: a TB Modelling and Analysis Consortium collaboration with partners at the school and outside to link intervention activites to epidemiological impact

The aim of the project is to support decision-makers and modellers, through the development of a database which collects the inputs and activities employed in TB interventions and links it to health outputs and outcomes. The database is designed to imporve acesses to evidence, which can be used to inform resource allocation.

Project dates: August 2018 - December 2019

Project lead and staff: Richard White, Madeleine Clarkson and Finn McQuaid

Collaborating institution: Malawi Epidemiology and Intervention Research Unit 

Funders: Bill & Melinda Gates Foundation and ISSF via Wellcome Trust

Adherence Support Coallition to End TB (ASCENT)

The ASCENT project brings together four consortium partners to address current access barriers in order to catalyse global adoption and uptake of TB digitial treatmen adherence technology interventions. LSHTM will be conducting the research arm of this project; running a pragmatic trial in Ethiopia to assess the effectiveness of the intervention, conducting costing studies to assess the patient and health system costs, and using modelling to project the epidemiological and economic impact of scale-up.

Project dates: July 2019 - December 2022

Project lead and staff: Finn McQuaid, Katherine Fielding, Rein Houben, Richard White and Debora Pedrazzoli

Funders: KNCV, Aurum, Path

A randomized open-label trial to evaluate the efficacy of periodic high dose rifapentine and INH for three months compared to continuous INH preventive therapy in HIV-infected and TB-infected individuals in South Africa

An RCT comparing a single course of IPT to periodic rifapentine and isoniazid for TB prevention among HIV-positive people. 

Project dates: April 2016 - February 2020

Project lead and staff: Katherine Fielding, Alison Grant

Collaborating institution: Aurum Institute

Funder: USAID

A randomised controlled trial (RCT) to evaluate a scalable active case finding primary care-based intervention for tuberculosis using a point-of-care test

Project dates: 2019 - 2023

Project lead and dates: Keertan Dheda, Richard White, Tom Sumner, Taane Clark, Anna Vassall and Helen Ayles

Collaborating institution: University of Cape Town

Funder: Medical Research Council (MRC)

Building investigator links for studies on the roles of complement C1q and endoplasmic reticulum (ER) stress in macrophage polarisation during Mycobacterium tuberculosis infection

This is a travel award to facilitate longer term collaboration between LSHTM and Chungnam University, to develop our overlapping interests in macrophage cell biology in TB. Macrophages are one of the prominent cell types to contribute protective immune responses against Mycobacterium tuberculosis infection. Macrophages exhibit plasticity and can be commonly polarised to M1 (inflammatory) and M2 (anti-inflammatory) phenotypes by the surrounding environment. Understanding dynamics of M1/M2 polarisation during Mtb infection may provide clues for TB therapeutic targets.

Project dates: April 2019 - September 2020

Project lead and staff: Jackie Cliff, JiSook Lee, Steve Smith, Theresa Ward and John Raynes

Collaborating institution: Chungnam National University

Funder: MRC-KHIDI

Causes of death in patients admitted to a TB ward in the Philippines

In phase 1 of this project we investigated the role of undernutriiton and diabetes as risk factors for inpatient death in acutely unwell patients admitted to the TB ward at San Lazaro Hospital, Manila, The Philippines, which has previously reported a very high rate of mortality. We also attempted to trace post-discharge outcomes. We observed that undernutrition assessed using mid-upper arm circumference (MUAC), predictive of BMI<17 kg/m2, in this population was a significant risk factor for inpatient mortality, regardless of TB status and with a significant interaction by sex, such that the risk was greatest in men. Phase 2 of the study is enrolling further patients in a simplified/refined protocol to further investigate causes of death and poor outcomes, with a plan to develop interventions. 

Project dates: May 2016 - March 2020

Project lead and staff: Sharon Cox, Tansy Edwards

Collaborating institutions: San Lazaro Hospital, Manila, Philippines; Nagasaki University

Funder: Nagasaki University & Sysmex Inc, Japan 

CD8 cells, treatment and QuantiFERON-Plus - a pilot study

Reports suggest that the CD8 T cell response can be used to track treatment responses, even in latent TB.  This is a pilot study to confirm or refute these earlier reports.

Project dates: August 2019 - August 2020

Project lead: Graham Bothamley

Collaborating institutions: Homerton University Hospital/QMUL

Funder: National Institute of Health Research (NIHR)

Clinical correlations of the macrophage-lymphocyte ratio

The diagnostic indices of a raised macrophage-lymphocyte ratio are poor.  Have the recent reports of significance been compromised by patient selection?  Can the ratio aid clinic-decision making?

Project dates: April 2018 - April 2020

Project lead: Graham Bothamley

Collaborating institution: Homerton University Hospital/QMUL

Funder: Audit-HUH

Concurrent adult pulmonary tuberculosis prevalence survey using digital radiography and Xpert MTB/RIF Ultra and child interferon-gamma release assay infection survey in Karachi

Zero TB Cities Initiative endorses the implementation of integrated evidence-based interventions at the community-level to tackle the global TB epidemic.  The aim of the initiative is to create “islands of tuberculosis elimination” through (i) active case-finding (ACF) using systematic and evidence-based diagnostic algorithms (‘search’), (ii) early and effective treatment (‘treat’) and (iii) a reduction in M. tuberculosis exposure and provision of preventive therapy for high risk groups (‘prevent’).

This ‘Search-Treat-Prevent’ strategy has been adopted by key stakeholders including the Stop TB Partnership and a number of non-governmental organisations - Partners in Health, Advance Access & Delivery, Interactive Research and Development (IRD), underpinned by academic input from the Centre for Global Health Delivery-Dubai, Harvard Medical School, in a number of cities, namely Chennai, Lima and Karachi. However there is currently no evidence for the effectiveness of this comprehensive ‘Search-Treat-Prevent’ approach in reducing M. tuberculosis transmission at a population-level in high tuberculosis burden settings. The rationale for this concurrent adult pulmonary tuberculosis prevalence survey and child IGRA survey in Karachi is to primarily provide a baseline measure of the burden of infectious tuberculosis (culture-confirmed adult pulmonary tuberculosis) and an estimate of annual risk of tuberculosis infection in young children, in 2018 – 2019, at the start of the implementation of Zero TB Karachi initiative.

Project dates: August 2017 - September 2019

Project lead and staff: Katherine Fielding, Palwasha Khan

Collaborating institution: IRD and The Indus Hospital

Funder: Global Fund