Tuberculosis Vaccine Programme
Programme Leader: Prof Helen McShane
Tuberculosis (TB) is a disease caused by the bacterium, Mycobacterium tuberculosis. Worldwide, TB is second only to HIV as the greatest global infectious killer; in 2013 9 million people were infected with TB and 1.5 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 have been shown to be safe and immunogenic in healthy adult volunteers (e.g. McShane H et al 2004). MVA85A has been further studied in M.tb latently infected individuals, and HIV-infected individuals, and the vaccine is 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 (Satti I et al 2014).
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). An ongoing trial in Uganda with the UVRI, Entebbe, is investigating the effect of helminth infection on vaccine immunogenicity.
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 has taken 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.
This trial started in 2011 and the 650 adults completed follow up in late 2014. Results are expected shortly.
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 will enable us to conduct a comprehensive analysis of the function and phenotype of these cells using flowcytometry, functional growth inhibition assays and transcriptomics.
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 BCG challenge model that could facilitate more effective downstream selection of candidate TB vaccines (Harris SA et al 2014).
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.
Helen McShane, Programme Leader
Paulo Bettencourt, Postdoc
Lucia Biffar, Jenner Fellow
Naomi Bull, DPhil student
Stephanie Harris, Research Assistant
Raquel Lopez Ramon, Research Nurse
Julia Marshall, Clinical Research Fellow
Jenny McNulty, PA to Helen McShane
Janet Pasricha, Clinical Research Fellow