T cell repertoires associated with control of TB progression in new study

Researchers at the South African Tuberculosis Vaccine Initiative (SATVI), a major research grouping at the IDM, together with colleagues, recently published a paper in Nature Medicine. This seminal study has identified a set of high-priority targets for tuberculosis (TB) vaccine development.

The paper is co-led by SATVI Research Officer and new IDM Fellow, Dr Munyaradzi Musvosvi, and deputy director of immunology and IDM member Professor Thomas Scriba. This paper is a collaboration with other SATVI colleagues, director Professor Mark Hatherill and Senior Research Officer, Dr Virginie Rozot who are also members of the institute, and colleagues from Stanford University, the Adolescent Cohort Study group, and the Gates Grand Challenge 6-74 consortium.

The paper leveraged and combined the best parts of clinical science and cutting-edge molecular biology to reveal which TB proteins the immune response targets in people who successfully controlled TB infection compared to those who did not, and thus developed TB disease. By doing so, the research looked at the role that T cells, an essential component of the immune system, play in controlling TB infection.

“We showed that compared to those who didn’t, people who controlled infection appear to have an enrichment of a unique set of T cells in their blood. The team determined which parts of the TB bacterium these unique T cells recognised,” said Dr Musvosvi.

South Africa has a particularly high TB burden, Prof Scriba explained: “There are 23 000 South Africans dying from TB each year. Many more, who manage to survive this disease, suffer from the catastrophic consequences of protracted illness.”

“The importance of developing more effective vaccines against TB cannot be overstated. TB is a devastating disease that affects millions of people around the world. This disease, caused by the bacterium Mycobacterium tuberculosis, has caused the highest human mortality among infectious agents for centuries.”

Selection of the correct target antigens for TB vaccine development has been an ongoing challenge. According to the researchers, unlike with TB, for the COVID-19 vaccine it was clear that the spike protein should be the target antigen. But the TB bacterium makes about 4 000 proteins, and it is not at all obvious which ones may make the best targets for TB vaccine development.

The study assessed T cell responses by sequencing the T cell receptor, which determines what part of bacterial proteins a particular T cell can recognise. This was done for many thousands of T cells that were isolated from 166 individuals with TB infection, enrolled in the Western Cape, and followed carefully over a period of two years. Among these individuals, 48 progressed to TB disease, while 118 controlled the TB infection and remained healthy.

“The data from our study suggests that having T cell responses to bacterial proteins targeted by T cells, in people who control the TB infection, may be important in preventing progression to TB disease,” Musvosvi said.

Speaking of the impact of the work he added: “It has informed the design of candidate mRNA vaccines that are being developed through a collaboration between researchers at the IDM, UCT and the Wits/SA-MRC AGTRU [University of Witwatersrand and the South African Medical Research Council Antiviral Gene Therapy Research Unit].”

This follow-up work to develop new candidate TB vaccines is funded by the SA-MRC.

Read the paper here.