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Tuberculosis

Tuberculosis (TB) is a disease caused by the bacterium, Mycobacterium tuberculosis. Prior to the COVID-19 pandemic, TB was the greatest global infectious killer; in 2019, 10 million people were infected with TB and 1.4 million died from the disease. The emergence of drug resistance makes it harder to treat this disease and co-infection with HIV increases susceptibility. There is an urgent need for better control measures, and the most cost-effective way to control any infectious disease epidemic is with effective vaccination.

Clinical Trial Programme

Phase I clinical trials in the UK

Since 2002, we have run a series of clinical trials to investigate the safety and immunogenicity of candidate TB vaccines, including MVA85A (recombinant modified vaccinia Ankara expressing antigen 85A) and ChAdOx1 85A (chimp adenovirus expressing antigen 85A) (both developed at the Jenner), and a number of industry partners’ vaccines. MVA85A and ChAdOx1 85A are used as boost vaccines for BCG-primed subjects; heterologous prime-boost vaccination regimens provide an effective way to induce high levels of cellular immunity, while the inclusion of BCG in a new regimen allows the retention of the protective effects of BCG in childhood against severe disease. Both vaccines were shown to be safe and immunogenic in healthy adult volunteers (e.g. McShane H et al. 2004, Wilkie M et al. 2020). MVA85A was further studied in M.tb latently infected individuals and HIV-infected individuals, and was safe and immunogenic in these groups (Sander R et al. 2009; Minassian AM et al. 2011).

An area of interest to our group is whether delivering a TB vaccine via the aerosol route (through nebulisation directly into the lungs) is a more effective method of vaccination. In the last few years we have started clinical trials investigating aerosol delivery of MVA85A and have shown this route to be both safe and immunogenic, including in M.tb-infected adults (Satti I et al. 2014, Thomas ZRM et al. 2016, Riste M et al. 2021).

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Photo Credit: John Cairns

Phase I and II clinical trials in Africa

As a result of our successful UK trials, we have been working closely with African collaborators to run clinical trials of MVA85A in target populations in Africa. Successful healthy adult studies in South Africa, in collaboration with SATVI, were followed by age de-escalation studies that demonstrated safety in children and infants (Scriba TJ et al. 2010), while a trial in The Gambia, with the MRC Laboratories, Fajara, showed that co-administration of MVA85A and routine EPI vaccinations did not result in interference of the EPI vaccines (Ota MO et al. 2011).

In Senegal, with CHU Le Dantec, Dakar, MVA85A vaccination of HIV-infected adults on and off antiretroviral therapy (ART) demonstrated that subjects on ART had higher responses than ART naïve subjects, but that responses were comparable after a second dose of MVA85A 6-12 months later (Dieye TN et al. 2013). A trial in Uganda with the UVRI, Entebbe, investigated the effect of helminth infection on vaccine immunogenicity (Wajja A et al. 2017).

efficacy trials

1st vaccinee in efficacy trials, August 2011, Dakar, Senegal1st vaccinee in efficacy trials, August 2011, Dakar, Senegal

MVA85A was the first new TB candidate vaccine to reach efficacy trial since BCG over 100 years ago. The first efficacy trial, from 2009-2012, in collaboration with SATVI and supported by Aeras and the Wellcome Trust, enrolled 2797 South African infants who were randomised to receive BCG alone at birth or BCG followed by MVA85A boost at 4-6 months of age. MVA85A vaccination was safe but did not improve upon BCG-induced protection (Tameris MD et al. 2013).

A second double-blind, placebo-controlled, randomised efficacy trial took place in South Africa and Senegal in HIV-infected adults, with the collaboration of UCT and CHU Le Dantec and support from Aeras and EDCTP. MVA85A was well-tolerated and immunogenic but no efficacy was detected against M.tb infection (Ndiaye BP et al. 2015).

Our main immunological readout in all of the clinical trials outlined above is the ex-vivo interferon gamma ELISpot assay. However, we have cryopreserved PBMC from all subjects at all time points in all of these clinical trials. This enables us to conduct a comprehensive analysis of the function and phenotype of these cells using flow cytometry, functional assays and transcriptomics to better understand immune correlates of risk of M.tb infection and TB disease. In one such analysis using samples from the phase 2b MVA85A efficacy trial, we identified activated HLA-DR+ CD4+ T cells as a correlate of TB disease risk, and found that BCG-specific T cells secreting IFN-γ and 85A-specific IgG antibodies associate with reduced risk of TB (Fletcher HA et al. 2016). We identified cytomegalovirus (CMV) infection as a microbial driver of T cell activation and found that a CMV-specific IFN-γ response was associated with increased risk of developing TB disease (Müller J et al. 2019).

controlled human infection models and ex-vivo mgias 

TB has no known immune correlate of protection, making it difficult to decide which candidate TB vaccines should be taken forward to efficacy trials. We are developing a human challenge model using attenuated Mycobacterium bovis as a surrogate for M.tb, as it is not ethical to infect humans with virulent M.tb. We have demonstrated that an intradermal (ID) BCG challenge model is able to detect differences in anti-mycobacterial immunity induced by vaccination (Harris SA et al. 2014), and are currently developing an aerosol BCG challenge model to better represent the natural route of M.tb infection. A CHIM could facilitate more effective downstream selection of candidate TB vaccines.

A complementary model which may be applied as a surrogate of protective efficacy is the ex-vivo mycobacterial growth inhibition assay (MGIA). We have developed a cross-species direct MGIA in which cells and serum from vaccinated individuals or animals are co-cultured with mycobacteria to assess control of mycobacterial growth. This has been optimised, standardised and biologically validated (Tanner R et al. 2018, 2020, 2021), and represents a 3Rs refinement to TB vaccine testing (Tanner R et al. 2017).

Preclinical Programme

There are several preclinical models of human tuberculosis and we have an active programme of research, both in house and through collaborations with other institutions, in working on evaluating new vaccines in these models. We have identified and evaluated novel protective antigens, with promising results for PPE15 (Stylianou et al. 2018). We are also using cutting-edge immunopeptidomics and whole-proteome array approaches to identify novel antigens which are then assessed in the murine model (Bettencourt et al. 2020).

Our team