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CORTIS: A clinical trial of a correlate of risk targeted screen and treat strategy to impact TB control

Existing tests for M.tb infection have poor specificty for incident TB disease, more specific tests would allow more efficient targeting of preventive therpay. The CORTIS trial will evaluate the performance of an 11-gene signature (COR) for identifying prevalent TB disease, predicting incident TB disease and the impact of preventive therapy among COR-positive individuals on TB incidence. Mathematical modelling will be used to explore the potential population level effect of COR based screen and treat strategies.

Project dates: October 2015 - December 2019

Project lead and staff: Richard White and Tom Sumner

Collaborating institution: University of Cape Town

Funder: Bill & Melinda Gates Foundation

Determining the importance of different locations to Mycobacterium tuberculosis transmission in high tuberculosis burden settings

Currently, little is known about where M.tb. transmission occurs in high incidence settings, limiting the potential effectiveness of infection control interventions. The aim of this study is to estimate the proportion of M.tb. transmission that occurs in different locations in Cape Town and other high incidence, sub-Saharan African settings, and to investigate the implications for TB control.

Project dates: February 2017 - January 2020

Project lead and staff: Richard White, Nicky McCreesh, Arminder Deol

Collaborating institution: University of Cape Town

Funder: Medical Research Council (MRC)

Development of an RNA based vaccine against Mycobacterium tuberculosis

Tuberculosis (TB) now ranks as the leading infectious killer worldwide, surpassing HIV/AIDS and malaria for the last several years in a row. The bacterium that causes TB disease, Mycobacterium tuberculosis (Mtb), is typically transmitted by inhaling the bacteria from infected people. These bacteria infect one-quarter of the world’s population, causing disease in ~10.4 million people and resulting in ~1.6 million deaths each year. Therefore, new TB vaccines represent a critical, unmet global public health need.  

A new vaccine technology, based on the delivery of self-replicating RNA molecules has gained attention worldwide but there has been limited exploration of this vaccine technology in protection against TB. IDRI has adapted their ID93 vaccine antigen into a self-replicating RNA molecule formulated in a state-of-the-art nanostructured lipid carrier. This enables the RNA vaccine candidate to be compared head-to-head with the classical ID93 protein with adjuvant vaccine, currently in phase 2b trials. Comparison of the nucleic acid based ID93 with the classical protein adjuvant formulation of ID93 will accelerate the development of the RNA based vaccine and provide insight into the breadth and magnitude of immune response induced by nucleic acid versus protein based vaccines.

We will evaluate ability of these vaccine candidates to reduce bacterial burden in the mouse model along with the accompanying immune responses. Recent clinical trial data have uncovered sets of host biomarkers that identify people who are more likely to advance to active disease states. This proposal aims to evaluate these clinically defined host markers (post-Mtb challenge) in a preclinical model of TB and to determine if immunization with two different types of vaccine candidates influences these host risk signatures. Successful completion of this proposal would significantly advance the TB vaccine pipeline and has the potential to streamline efforts and resources for the most promising candidates.

Project dates: 2019 - 2020

Project lead: Helen Fletcher

Collaborating institutions: Infectious Disease Research Insititute (Seattle, USA)

Funder: MRC GCRF

Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment?

Diabetes mellitus is now prominent on the global agenda and its association with TB is the next great challenge for global TB control. Its prevalence has been rising more rapidly in middle and low-income countries, where the burden of TB is greatest.  TB control programmes should target patients with diabetes for any intervention that may have an impact on TB outcomes. Drug induced liver injury (DILI) is a major concern in TB treatment. Diabetes is associated with a number of co-morbidities that can cause hepatic damage. Thus, it is important to understand whether diabetes is an important independent risk factor for DILI or an important co-factor for DILI due to other hepatotoxic co-morbidities or indeed not actually a condition for which heightened vigilance for DILI is necessary. Those are the questions that our study set out to address.  

Project dates: December 2017 - October 2019

Project lead: Ivanice Freire (L), David Moore and Katherine Fielding

Collaborating institutions: Porto Alegre Municipal Health Department; Sanatório Partenon Hospital

Evaluation of ultrasound for first-line adult tuberculosis screening 

Proof-of-concept pilot evaluation of point of care ultrasound for detection of pulmonary TB.

Project dates: June 2019 - May 2020

Project lead and staff: Alison Grant, Aaron Karat

Collaborating institution: AHRI

Funder: Bill & Melinda Gates Foundation

Exploring mechanisms of paediatric immunity to M. tuberculosis infection in children

Some children exposed to tuberculosis bacteria become ill, whilst others look well but their immune system has mounted a memory response to the bacteria. This is called latent infection. Children with latent infection have a higher risk of developing tuberculosis than those who also appear well but are uninfected.

If we could understand why some children who have been exposed to tuberculosis become infected, whilst others do not, it would help to design a better tuberculosis vaccine.

Project dates: August 2018 - July 2020

Project lead and staff: Robin Basu Roy, Beate Kampmann

Collaborating institutions: MRC Unit The Gambia at LSHTM, Oxford Vaccine Group

Funder: Academy of Medical Sciences

Exposed but not ignored: An e-registry of MDR TB exposed household contacts

This study aims to determine if there is a more streamlined way of screening MDRTB HHC to detect TB than the current World Health Organisation (WHO) algorithm. We will achieve this by identifying when TB occurs in contacts and which exposures carry such low risk that contacts do not require follow up beyond initial screening. MDRTB patients and their HHC will be prospectively recruited into a cohort study with up to two years of follow up with the aim to identify when TB occurs in contacts.Two case control studies partially nested within the cohort will assess exposure risk factors within households and individuals. The first case control study will compare household level risks. The second case control study nested in the case household of the first study will compare individual level risks.

Project dates: March 2019 - March 2023

Project lead and staff: Kate Gaskell, Dave Moore, Chrissy Roberts, Tansy Edwards, Katharina Kranzer

Collaborating institution: UPCH

Funder: Wellcome

How can we incentive Lady Health Workers to engage in TB Case Finding in Pakistan

Many interventions to motivate community health workers to perform better rely on financial incentives, even though it is not clear that monetary gain is the main motivational driver. In Pakistan, Lady Health Workers (LHW) are responsible for delivering community level primary healthcare, focusing on rural and urban slum populations. Our study qualitatively investigated how to most effectively motivate LHW to engage more actively in tuberculosis case-finding. The study was embedded within a pilot intervention that provided financial and other incentives to LHW who refer the highest number of tuberculosis cases in three districts in Sindh province.

Picture looking at buildings across an empty landscape in Pakistan

Project dates: January 2018 - July 2019

Project lead: Mishal Khan

Collaborating institutions: Mercy Corps Pakistan

Funder: TB Reach via Mercy Corps

Immunostimulation/Immunodynamic modelling to optimise vaccine dose

Though vaccination is one of the most effective forms of life preservation, development of vaccines is expensive and vaccine dose is often not well optimised. Immunostimulation/Immunodynamic modelling aims to optimise dose through translation of techniques from pharmacokinetic/pharmacodynamic (PK/PD) modelling of drugs, namely a combination in-silico modelling and simulation informed by in-vitro experiments, animal experiments, and small scale human trials. Our aim is to reduce the impact of disease in humans by improving vaccine dosing using IS/ID mathematical modelling, optimising a novel prime boost vaccinatation as a case study.

Project dates: September 2018 - September 2022

Project lead and staff: Richard White, Sophie Rhodes and Steven Smith

Collaborating institution: Vaccitech

Funder: Biotechnology and Biological Sciences Research Council (BBSRC)

Impact of potential novel TB vaccines on MDR-TB

This project aims to model the epidemiologic and health economic impacts of potential novel TB vaccines on MDR-TB epidemic.

Project dates: October 2017

Project lead and staff: Richard White, Chathika Weerasuriya, Rebecca Harris, Fiammetta Bozzani, Tom Sumner and Gabriela Gomez

Funder: Medical Research Council (MRC)/IAVI