Oxford University Clinical Academic Graduate School

Women in Science interview

The HIV epidemic and the emergence of multi and extensively drug-resistant strains of Mycobacterium tuberculosis (M.tb) mean that global control of tuberculosis (TB), particularly adult pulmonary TB, remains inadequate. 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. The current vaccine, BCG confers protection against disseminated disease in childhood, but does not reliably protect against pulmonary disease. A strong cell mediated immune response is essential for protective immunity. It is known that Class II-restricted CD4+ T cells are essential for protective immunity and that class I-restricted CD8+ T lymphocytes may play a role in maintaining the latent state. Other cell types, including gamma delta cells and Th17 cells may also play a role. Antibodies may have some role, particularly in prevention of infection.

Since 2002, my group has conducted a series of clinical trials in the UK, The Gambia, South Africa, Senegal and Uganda, to investigate the safety, immunogenicity and efficacy 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. 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. Successful healthy adult clinical trials were followed by age de-escalation studies that demonstrated safety in children and infants.

MVA85A was the first new TB candidate vaccine to be evaluated in an efficacy trial since BCG was last tested in infants in the 1960s. The first efficacy trial, conducted from 2009-2012 in collaboration with the South African TB Vaccine Initiative (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.

 A second randomised, double-blind, placebo-controlled, efficacy trial has taken place in South Africa and Senegal in HIV-infected adults, with the collaboration of the University of Cape Town 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.

A current 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. Other current projects within my group include the development of a BCG challenge model in humans, evaluating the effect of helminth infection on vaccine induced immune responses, and the evaluation of the protective efficacy of new antigens in viral vectors.

IMPAc-TB

The Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) program is an initiative established by NIAID in 2019 to elucidate the immune responses needed to protect against infection with Mycobacterium tuberculosis (M.tb). The program will lead to a better understanding of tuberculosis (TB) immunology, which is critical to guide the design and development of new and improved TB vaccines, and it aligns with the goals of the NIAID Strategic Plan for Tuberculosis Research.

Visit IMPAc-TB Site