Tuberculosis (TB) remains a major global health problem, and has recently surpassed HIV as the biggest killer due to an infectious disease. In 2016 there were 10.4m new cases of TB and 1.7m deaths. Given the rise of drug-resistant and multi-drug resistant TB, an efficacious vaccine would be the most effective intervention strategy. The only currently available vaccine, BCG, has variable efficacy against pulmonary TB. Efficacy is high in the UK (~80%), but very poor in regions with the greatest burden of TB, such as sub-Saharan Africa. A more effective vaccine is desperately needed.
Due to the intracellular nature of Mycobacterium tuberculosis (M.tb), TB immunology studies and vaccine development to date have focussed on the cellular immune response. Indeed, the Th1 cytokine IFN-γ has been shown to be necessary (though not sufficient) for protection, and a recent study of BCG-vaccinated South African infants conducted by our group demonstrated that BCG-specific IFN-γ ELISpot responses were associated with reduced risk of TB disease. However, an additional and perhaps surprising finding from this study was that specific IgG antibodies were also associated with reduced risk of disease.
The role of antibodies in TB has been largely neglected, but this and other emerging evidence suggests they may constitute an important component of a protective host immune response. There is very little literature on the antibody response to BCG vaccination, which has not been well-characterised. Given the benefits of BCG vaccination in protection from leprosy and disseminated TB in infants, a novel TB vaccine will most likely be given as a boost to BCG, and as such it is critical to understand the nature of the immune response to BCG to direct future vaccine design.
Here we propose to explore and characterise the humoral immune response to BCG and other novel TB candidates and determine how it relates to protection, including the mechanisms involved. Samples are available following vaccination across relevant species including mice, non-human primates, cattle and humans. The isotype and specificity of the antibodies will be determined, and functional activity measured using two novel in vitro assays that have been developed in out group: the mycobacterial growth inhibition assay (MGIA) and a macrophage uptake assay using BCG genetically engineered to express green fluorescent protein (GFP). The role of opsonisation and the Fcγ receptor will also be explored. The in vivo murine M.tb challenge model will also be applied in exploratory studies. This work aims to feed in to the design of more effective novel TB vaccine candidates which is ongoing in our group.
This project is most suited to candidates with a strong background and competence in practical laboratory techniques. In addition to standard immunological methods such as ELISA and flow cytometry, the student will be trained in and apply technically complex assays such as the functional MGIA. Further training will be provided at Biosafety Level 3 for work with M.tb in addition to Home Office Modular Training to gain a licence for conducting animal research. The student will also be trained in relevant data analysis and statistical methods.
Project reference number: 977
|Professor Helen McShane||Jenner Institute||Oxford University, Old Road Campus Research Building||GBRfirstname.lastname@example.org|
|Dr Rachel Tanner||The Jenner Institute||University of Oxford||GBRemail@example.com|
Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN-γ) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-γ enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines. Hide abstract
Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case-control analysis to identify immune correlates of TB disease risk in Bacille Calmette-Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR(+) CD4(+) T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25-2.68, P=0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis-infected adolescents, activated HLA-DR(+) CD4(+) T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068-1.801, P=0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29-0.86, P=0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations. Hide abstract