Researchers Exploring a Possible Path to a New TB Vaccine

There is no highly effective vaccine against tuberculosis (TB), which remains an infection of global concern. Charles Kyriakos Vorkas, MD, an infectious diseases physician-scientist at the Renaissance School of Medicine (RSOM) at Stony Brook University, and colleagues identified a novel population of immune cells that could serve as an alternative target for TB vaccines and immune-directed therapy. Their findings are detailed in a paper published in Scientific Reports.

According to the World Health Organization, more than 10 million people fall ill with TB each year. TB remains the top cause of infectious disease morbidity and mortality worldwide due to a single pathogen (Mycobacterium tuberculosis).

The research team demonstrated that innate immune cells called Natural Killer (NK) cells that express CD8a on the cell surface (a receptor usually associated with T cells) are reactive to human tuberculosis exposure and infection within a high-risk TB household contact cohort.

The clinical cohort that had close exposure to individuals with active TB was recruited in Port-au-Prince, Haiti, at the GHESKIO Centers during the years 2015 to 2018 as part of a National Institutes of Health (NIH) funded TB Research Unit (Tri-I TBRU). Biobanked blood samples from the TB contact cohort were used to analyze immune responses during asymptomatic household exposure to tuberculosis.

“Our research shows a specialized role for these CD8a⁺ NK cells, including progressive depletion from blood during asymptomatic infection and active TB disease, enhanced responsiveness to cytokines and surface expression dependent on a ubiquitously expressed antigen-presenting molecule, called major histocompatibility complex (MHC) Class I,” said Vorkas, senior author and assistant professor in the Departments of Medicine and Microbiology and Immunology.

He said the findings from this new study may provide a roadmap to the use of NK cells in the development of a new type of TB vaccine.

According to Vorkas, the findings are particularly relevant to informing a new generation of TB immune-directed therapy as they accompany recently published 2025 data in the Journal of Experimental Medicine, highlighting the essential role for CD8aa⁺ lymphocytes in BCG-induced protection against tuberculosis in a non-human primate model. This model shows that a significant proportion of these protective CD8aa⁺ lymphocytes are NK cells.

Importantly, he also noted the team found that CD8a protein is ubiquitously expressed intracellularly in most human NK cells, yet it marks a distinct functional population when expressed at the cell surface.

Current experimental TB vaccines

The only approved TB vaccine to date is Bacille-Calmette Guérin (BCG), an attenuated strain of Mycobacterium bovis. This vaccine is administered to children in endemic regions to prevent severe TB disease, but it does not have long-lasting effects in adults.

Current experimental TB vaccines in adults are designed to target conventional peptide-specific CD4⁺ and CD8⁺ T cells. However, this strategy does not appear to be promising, as these vaccines have fallen short of efficacy margins for wide-spread roll-out. The reason for this may be because the expansion of conventional T cells after experimental TB vaccination does not clearly correlate with prevention of primary tuberculosis infection.

The study team also highlights that their work parallels findings of NK cell depletion from blood during disease progression in other infectious and non-infectious pathology. This may be a clue to a specialized role of NK cells in the protection against chronic inflammatory diseases such as cancer and multiple sclerosis.

Future directions of the research seek to identify mechanisms by which NK cells can specifically recognize TB-derived proteins through MHC I via a specialized group of receptors called Killer immunoglobulin-like Receptors (KIRs).

Vorkas believes that if NK cells can recognize specific epitopes (antigens that trigger the immune response) through KIRs, this biology would parallel that of T cell receptors, thereby leading to a transformation in the design of vaccine and immune-directed therapies, including for TB.

The study was performed in collaboration with the Hsu and Cheung labs at Memorial Sloan Kettering Cancer Center.

Federal support for the research included grants from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), such as NIAID K08AI132739, R21SI171578, and R21AI83259, and a Potts Memorial Foundation Award.