In the battle against infectious diseases, vaccines are the most powerful allies for building immune responses. In line with this, a recent study indicates that Bacille Calmette-Guérin (BCG) boosters reveal new and existing populations of memory cells, highlighting their protective role against tuberculosis (TB) infection.
The work, published in Nature Communications last month, entitled “Adolescent BCG revaccination induces a phenotypic shift in CD4+ T cell responses to Mycobacterium tuberculosis,” shows how BCG revaccination in adolescents boosts the identification of CD4+ T cell subsets, which may play a crucial role in immune protection against TB infection.
TB is a common disease that causes a high rate of mortality and morbidity in countries around the world. The recent increase in TB rates is due to the evolution of drug-resistant strains, mostly in South Africa. Mycobacterium tuberculosis (M. tb) bypasses the immune system by using components of the defense mechanism as a Trojan horse, allowing it to replicate. Its rapid adaptation to environmental factors makes it highly dangerous.
High rate of mortality and morbidity
New approaches, including vaccines, are urgently needed. BCG is a major vaccine for TB prevention, but while the vaccine is effective in infants, it has questionable efficacy in adults who respond differently to BCG because their immune systems are more established, and they are more likely to be exposed to environmental M. tb. The main function of BCG is to activate T cells, which are important for both long-term defense and rapid response. In the event of a re-exposure, BCG may not be as effective in preventing the initial infection.
The authors note that BCG revaccination in young adults shows potential for reducing the sustained infection rate because adolescents are more susceptible to TB infection during this period. Reducing the overall burden of the disease and improving long-term health outcomes are critical benefits of this reduction in persistent infection, making this high-risk age group perfect for optimizing vaccine strategies.
Eighty-four South African adolescent volunteers who were vaccinated as children participated in the revaccination study. The study compares a placebo to the single dose BCG (live-attenuated) vaccine with other vaccine candidates, including H4:IC31 (subunit vaccine), administered in two doses.
Blood drawn following revaccination was analyzed utilizing Intracellular Cytokine Staining (ICS) for measuring T-cell responses versus mycobacterial antigens, together with high-dimensional flow cytometry and single-cell CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). This approach allowed for an “in-depth analysis” of different T cell subsets, unraveling their polyfunctional or migratory potentials.
Surface marker expression
The authors showed that BCG revaccination had a more sustained effect on preventing the infection in adolescent subjects, compared to revaccination with H4:IC31. However, it is important to note that neither vaccine was effective in preventing the initial infection; it positively impacted individuals who were already infected. Despite this, the induced surface marker expression such as CD103 (integrin alpha E protein involved in T cells with epithelial cells in tissue interaction) indicates the presence of resident memory cells that protect the lungs, which are the main site of TB infection.
“This finding enhances our understanding of managing M. tb with BCG revaccination boosts. Precise cellular response analysis could help define biomarkers related to these responses,” said Dintwe.
Applying these findings is not only relevant to TB. A better understanding of memory formation and T cell variation informs new treatment options for other infectious diseases. The importance of immune responses was hypothesized as part of a prior phase Ib study, which was conducted by EMA-CRS for vaccine development against human immunodeficiency virus (HIV). HIV is well-known for its ability to weaken the immune system, providing conditions for infection by other organisms, especially M. tb that cause TB disease.
Identifying specific T cell subsets activated by BCG revaccination points to the development of new therapies and vaccines that could help control TB virulence, mainly in high-risk adolescent populations. Additionally, this strategy could lower the chance of co-infections in individuals with weakened immune systems, such as those who also have HIV. “Despite the anti-retroviral therapy, people living with HIV are still susceptible to TB, which creates serious rates in high-risk countries,” the authors wrote.
This research underlines the importance of new technological applications in solving the complexities of the immune system. Continued research and clinical trials are crucial for validating these findings and developing effective public health strategies.
Dintwe and colleagues conclude that their results “suggest that BCG revaccination-dependent protection, involving different T cell populations to prevent sustained infection, could be a promising strategy in the future.”
Bilge Elif Bozokluoğlu ([email protected]) studied molecular biology and genetics at Bahçeşehir University in Istanbul. She is the co-founder of HBT R&D Technologies, a new startup.
