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The UFAW 3Rs Liaison Group Research Studentship

Rachel Tanner, University of Oxford

'Development of mycobacterial growth inhibition assays for early evaluation and gating of novel TB vaccine candidates'.

Tuberculosis (TB) continues to pose a serious global health threat, with an estimated 9 million new cases and 1.5 million deaths annually. The current vaccine, BCG, is not always protective - particularly in areas where TB is most prevalent. Developing a new vaccine is extremely difficult because it is not clear which parts of the immune response should be measured to demonstrate protection. Without any alternative, candidate vaccines are currently tested using animal models such as mice and non-human primates. Large numbers of animals are required and must be infected with M.tb (the causative agent of TB): a procedure classified as ‘Moderate’ in severity by the Home Office. As TB disease progresses, animals may experience loss of body weight, fever and respiratory distress.

Rachel Tanner, under the supervision of Professor Helen McShane, University of Oxford, was awarded a 3Rs Liaison Group Studentship in 2012 to carry out a PhD project concerned with the optimisation and evaluation of an in vitro alternative to infecting animals with M.tb to test TB vaccines.

Blood or cells can be infected with M.tb (or BCG as a safer surrogate) in a test tube, and the amount by which the blood or cells inhibit growth of the bacteria quantified. If inhibition is measured before and after vaccination, vaccine protection may be estimated. The first step involved ensuring the assay had acceptable levels of reproducibility, and many different parameters were compared and tweaked to offer the best chance of detecting differences. Secondly, proof-of-concept was required to show that, where a vaccine was known to be protective, a corresponding response could be demonstrated with the assay. This was achieved using samples from BCG-vaccination studies in UK adults, macaques and mice. Finally, the assay underwent biological validation (to demonstrate that it is a meaningful representation of what would happen in live animals or people). Encouragingly, a correlation was observed between the in vitro response and in vivo protection from challenge in the mouse and macaque models. There was also concordance between the assay and epidemiological data or in vivo outcome in humans.

This work has generated considerable interest including inclusion of the assay in TB biomarker consortia packages, workshops and transfer of the technology to other laboratories worldwide. With further development, the in vitro assay represents a potential correlate of protection that may be game-changing in preclinical vaccine testing, reducing the number of animals used in challenge experiments and accelerating the development of an effective vaccine. 

Dr Tanner was awarded her PhD in 2015.

Published papers arising from Rachel’s work supported by UFAW:

Tanner R, O’Shea MK, White AD, Müller J, Harrington-Kandt R, Matsumiya M, Dennis MJ, Parizotto EA, Harris S, Stylianou E, Naranbhai V, Bettencourt P, Drakesmith H, Sharpe S, Fletcher HA, McShane H. 2017. The influence of haemoglobin and iron on in vitro mycobacterial growth inhibition assays. Nature Scientific Reports 7, Article number: 43478. Doi:10.1038/srep43478

Tanner R, O'Shea MK, Fletcher HA, McShane H. 2016. In vitro mycobacterial growth inhibition assays: A tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy. Vaccine. 34(39): 4656-4665. https://doi.org/10.1016/j.vaccine.2016.07.058  

Tanner R, and McShane H. 2016. Review Article: Replacing, reducing and refining the use of animals in tuberculosis vaccine research. ALTEX Online, first published 26 Sept 2016. http://dx.doi.org/10.14573/altex.1607281.

Harris S, White A, Stockdale L, Tanner R, Dennis M, Sibley L, Sarfas C, Meyer J, Peter J, Satti I, Manjaly Z, Hamidi A, McShane H, Sharpe H. “Optimisation of a non-human primate BCG challenge model for selection of candidate tuberculosis vaccines.” (submitted to Journal of Infectious Diseases).

Pepponi I, Katri B, Tanner R, Villarreal-Ramos B, Vordermeier M, McShane H. “A mycobacterial growth inhibition assay (MGIA) for bovine TB vaccine development.” (submitted to Transboundary and Emerging Diseases).