Transfer of a non-human primate (NHP) in vitro functional assay for the early evaluation of TB vaccine candidates and the associated immune response

Why did we fund this project?

This award aims to refine tuberculosis (TB) vaccine studies by avoiding the challenge tests in monkeys that are used to assess the protective efficacy of vaccine candidates.

TB vaccine candidates are tested in macaques after initial preclinical evaluation. The studies involve the challenge of naïve and vaccinated animals with Mycobacterium tuberculosis (M.tb), the infectious agent. Although relatively small numbers of animals are used, they can experience clinical signs such as a raised temperature, respiratory distress and weight loss, necessitating humane end-points. Dr Rachel Tanner has developed a functional in vitro assay that could be used to refine the tests by avoiding the need for the in vivo M.tb challenge. The assay – the direct mycobacterial growth inhibition assay (MGIA) – uses peripheral blood mononuclear cells (PBMCs) from naïve and vaccinated animals. Cells are co-cultured with mycobacteria and the control of mycobacterial growth is used as a measure of protective immunity.

Rachel had previously worked to optimise the MGIA for a range of species include the macaque. With NC3Rs funding, Rachel will work with researchers at Public Health England (PHE) and the Biomedical Primate Research Centre (BPRC) in the Netherlands to facilitate the adoption of the MGIA into their TB vaccine programmes.

What was achieved?

Rachel and her collaborators at PHE and BPRC have shown that the assay is reproducible between tests, laboratories and operators. The primary paper from this project is currently under review and will be followed by an associated methods paper on the NC3Rs gateway. Further validation work is being undertaken at the institutions to allow the MGIA to be fully adopted. Ultimately this could lead to a reduction in the use of around 45 macaques (30% of the total used in TB vaccine studies) annually across the two institutions as the PBMCs from a single group of animals can be used to screen multiple clinical isolates, as well as investigate immune mechanisms mediating mycobacterial control.

The grant has stimulated further interested in the MGIA by the TB research community and as a result Rachel has worked with collaborators at 13 institutions in Europe, North America and Asia to help set up the assay for various species. Rachel has received various accolades for her research including the 2019 Woman of the Future award for Science. She is the lead author of a paper published in Frontiers in Immunology in January 2020 that describes the validation of the human direct MGIA for measuring vaccine efficacy and exploring immune mechanisms with the assay, also providing an opportunity to replace animal studies in some settings. Rachel has previously published a paper on the 3Rs in Frontiers for Young Minds, a science journal for children and teenagers.

This award was featured as a case study in the 2019 Research review.

• 2019 Research Review: TB challenge in vitro