Tuberculosis (TB) is responsible for more deaths than any other single organism – an estimated 1.5 million people died from TB in 2018 and 10 million people fell ill. More than a quarter of TB deaths occur in sub-Saharan Africa.

For many decades, prevention of infection has relied on the BCG vaccine, which is only partially effective and has multiple drawbacks. Now, however, innovative new approaches are being used to create more powerful vaccines with much greater potential to prevent infection with Mycobacterium tuberculosis (Mtb) and the spread of disease.

EDCTP is funding three TB vaccine trials. The MTBVAC-Newborns and priMe projects are focusing on alternatives to BCG to prevent infection in infants – precisely engineered vaccines based, respectively, on Mtb and M. bovis (from which BCG was originally derived). By contrast, the POR-TB project is aiming to prevent recurrence of disease in patients supposedly cured of Mtb by antibiotic treatment – typically, one in ten patients will relapse.

Although the projects are focused on different kinds of vaccine, there is great potential to improve efficiencies and impact by strengthening the links between them and with other global TB vaccine endeavours. To achieve this, in 2019 EDCTP provided dedicated funding to the Tuberculosis Vaccine Initiative (TBVI), a non-profit foundation set up to accelerate the development of TB vaccines. The project will provide additional resources and coordination to the three EDCTP projects, helping them to draw on further technical support and expertise, and to share experience, in order to achieve their goals.

Given these exciting developments, it is important that the pathway to impact is as smooth as possible – so that people rapidly benefit from effective new vaccines. To achieve this, early and coordinated attention needs to be given to the clinical evaluation of candidate vaccines and the pathways of licensing and implementation.

In 2019, EDCTP therefore awarded a one-year grant to the Amsterdam Institute of Global Health and Development (AIGHD) to support a global consultation and drafting of a new global TB vaccine R&D roadmap. Working in close collaboration with the World Health Organisation (WHO), AIGHD will consult with TB vaccine stakeholders globally, to map out the current state of play, key obstacles and enablers, and priority areas for R&D. It will cover the entire R&D chain, including TB vaccine research, product development, and product licensing and implementation.

The project will ensure that the interests and perspectives of all key groups – including researchers, product developers, funders, regulatory agencies, and national and global bodies focused on TB control – have a shared understanding of challenges at each stage and how they can be collaboratively addressed. The final roadmap will therefore be a vital strategic tool to guide their decision-making and activities, and ultimately accelerate the delivery of new TB vaccines to populations in need

The POR TB project aims to prevent latent TB infections from reactivating. Why is this important?

The prevention of recurrence (POR) TB project aims to prevent recurrence of pulmonary TB through vaccination with H56:IC31 at the end of treatment of an episode of uncomplicated TB. Clinical development of new TB vaccines requires large trials to demonstrate vaccine efficacy. Because the incidence of recurrent TB disease following completed TB treatment is 2–8% within the first year, a POR trial can be smaller, shorter and more cost-effective than a trial in the general population.

What progress was made in 2019?

As of July 2020, we have recruited and randomised 391 participants across the five clinical sites in South Africa and Tanzania. At the same time, the POR consortium has supported community engagement and capacity development to expand TB vaccine clinical trial and laboratory expertise in sub-Saharan Africa through (1) technology transfer of immunologic assays from the University of Cape Town to the Mbeya Medical Research Programme in Tanzania and (2) supporting the doctoral studies of Maria Mwakatima from the National Institute for Medical Research in Tanzania.

What comes next?

The current focus of the POR consortium is to continue recruiting a total of 900 trial participants, with follow up so that the pre-specified number of 23 recurrent episodes of pulmonary TB, the clinical endpoint of the trial, is reached. Lockdown measures to contain the spread of COVID-19 in South Africa have had a serious impact on participant recruitment. In close contact with regulatory authorities at local and national levels, the POR consortium has implemented mitigation measures to enhance enrolment and randomisation to get back on track.

When the trial is completed, carefully collected clinical data coupled with an extensive biologic repository will enable us to differentiate between reinfection and relapse among recurring cases of pulmonary TB, and identify correlates of protection.