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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

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

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

Impact of a conditional cash transfer programme on HIV/AIDS and tuberculosis in Brazil and forecast of effectiveness scenarios

Project dates: 2016 - 2020

Project lead and staff: Davide Rasella, Richard White

Funder: Wellcome Trust

Infection prevention and control for drug-resistant tuberculosis in South Africa in the era of decentralised care: a whole systems approach.

In this project we are using a whole systems approach to understand drivers of drug-resistant TB transmission in primary healthcare clinics in South Africa, and modelling potential interventions to reduce transmission.

Project dates:  August 2017 - January 2021

Project lead and staff: Alison Grant, Anna Vassall, Aaron Karat and Fiammetta Bozzani

Collaborating institution: QMU Edinburgh, IDS, AHRI, UZKN, UCT

Funder: Economic and Social Research Council via UKRI

Integration of TB services into a peer-led community based HIV support program (CATS) to increase TB case detection and uptake of IPT among adolescents living with HIV

The developmental period of adolescence is challenging for adolescents, health providers and caregivers. Adolescents often prioritise short-term social benefits over potential long-term health gains. Engagement in care and adherence to HIV treatment drops in adolescence resulting in low viral suppression rates. This in turn increases the risk of immunosuppression and with it the risk of developing TB. In addition the risk of acquiring Mycobacterium tuberculosis infection and developing infectious TB each markedly increase during adolescence as compared to children. Thus in high TB burden settings adolescents living with HIV (ALWH) experience an extremely high TB risk compounded by delayed diagnosis. Uptake of isoniazid preventive therapy (IPT) has been low across all age-groups and particularly low among ALWH. 

Africaid-Zvandiri has established a peer-to-peer support program delivered by community adolescent treatment supporters (CATS) providing adherence support to ALWH in Zimbabwe, a high TB and HIV-TB burden country. CATS are trained HIV-positive peer-counselors aged 18-24 receiving regular mentorship and supervision. One CATS typically supports 40-50 ALWH. They conduct regular home visits to check on their clients and provide psychosocial and adherence support. This study aims to integrated TB services into the existing program and will assess the feasibility, uptake and yield of active TB case finding and screening as well as uptake of IPT among ALWH. The activities will be delivered by CATS who will also support ALWH in adherence to TB treatment and IPT once initiated. 

Picture of two people sitting on chairs in a garden

Project dates: June 2019 - June 2020

Project lead and staff: Katharina Kranzer

Collaborating institution: Africaid

Funder: Internal Africaid Funding