New Hope in the Century-Old Fight Against Tuberculosis
October 2024
In the ongoing battle against infectious diseases, tuberculosis (TB) remains a formidable foe. Despite being preventable and curable, TB claims 1.5 million lives annually and stands as the leading infectious cause of death worldwide 1 6 . For over a century, the Bacille Calmette-Guérin (BCG) vaccine has been our only defense against TB. While it protects children from severe forms of the disease, its performance in adults has been disappointing—offering virtually no protection against pulmonary TB in adolescents and adults 2 5 . This critical gap in our arsenal has fueled scientific efforts to develop next-generation vaccines, with nucleic acid vaccines (DNA and RNA) emerging as promising candidates in this century-old fight.
1.5 million deaths annually
10 million new cases each year
¼ of the world's population has latent TB
100 years since BCG vaccine introduction
The recent success of mRNA vaccines against COVID-19 has demonstrated the potential of nucleic acid technology to respond rapidly to global health threats. Scientists are now harnessing this same technology to tackle one of humanity's oldest pathogens—Mycobacterium tuberculosis 3 8 . This article explores the exciting developments in DNA and RNA vaccines against TB, examining the current state of research and what these technological advances might mean for controlling a disease that has plagued humanity for millennia.
Nucleic acid vaccines represent a revolutionary approach to immunization. Unlike traditional vaccines that introduce weakened or inactivated pathogens into the body, or subunit vaccines that deliver specific viral proteins, nucleic acid vaccines provide our cells with the genetic instructions to produce key pathogen proteins themselves 3 . This elegant strategy harnesses our own cellular machinery to generate an immune response without exposure to the actual pathogen.
Use plasmid DNA to encode antigenic proteins
Use mRNA molecules to encode antigenic proteins
DNA vaccines typically use circular DNA molecules called plasmids that have been engineered to contain genes encoding antigenic proteins from the target pathogen. These plasmids are injected into the body, usually intramuscularly, where they're taken up by cells. Once inside the cell, the genetic information is transcribed and translated into protein antigens, which are then displayed on the cell surface, triggering an immune response 3 .
RNA vaccines function similarly but use messenger RNA (mRNA) molecules instead of DNA. The mRNA is encapsulated in lipid nanoparticles that protect the fragile RNA molecules and help them enter cells. Once inside the cell cytoplasm, the mRNA is directly translated into protein antigens without needing to enter the nucleus 3 8 . This makes the process more efficient and eliminates any theoretical risk of genetic integration.
| Characteristic | DNA Vaccines | RNA Vaccines |
|---|---|---|
| Stability | High (can be stored at room temperature) | Low (requires cold chain storage) |
| Delivery Method | Often naked DNA or with simple adjuvants | Requires lipid nanoparticles for protection |
| Cellular Mechanism | Must enter nucleus for transcription | Direct translation in cytoplasm |
| Development Speed | Moderate | Very rapid |
| Manufacturing | Bacterial fermentation required | Cell-free chemical synthesis |
| Immune Response | Strong T-cell and antibody responses | Strong T-cell and antibody responses |
A comprehensive scoping review published in Frontiers in Immunology in October 2024 analyzed the entire landscape of nucleic acid vaccine research for tuberculosis 1 4 6 . The researchers identified an impressive 18,157 records through systematic searches of multiple databases and registries, eventually narrowing these down to 345 animal studies that met their inclusion criteria.
The review revealed a striking imbalance: 99.1% of studies focused on DNA vaccines, while only three studies investigated mRNA vaccines 1 6 . This reflects the historical development trajectory of nucleic acid vaccines.
The review also shed light on the antigenic strategies employed by researchers:
The most frequently targeted antigens were immunodominant secretory proteins (Ag85A, Ag85B, ESAT6), heat shock proteins, and cell wall proteins 1 6 . These antigens were selected based on their known ability to trigger strong immune responses during natural infection.
| Antigen | Function | Percentage of Studies |
|---|---|---|
| Ag85A | Secretory protein involved in cell wall biosynthesis | ~32% |
| Ag85B | Secretory protein involved in cell wall biosynthesis | ~28% |
| ESAT6 | Early secreted antigenic target | ~25% |
| HSP65 | Heat shock protein | ~15% |
| MPT64 | Secretory protein | ~10% |
Animal studies for TB vaccines typically follow a standardized protocol. Researchers use various animal models, with mice being the most common due to their practicality and well-characterized immune systems 2 . The general experimental approach involves:
Intramuscular
Intradermal
Intranasal
Aerosol
The scoping review revealed that nucleic acid vaccines show promise but face significant challenges. When compared to BCG—the current gold standard—only 4 out of 17 studies demonstrated superior protection in terms of bacterial load reduction 1 6 . However, some vaccine variants did show better efficacy compared to BCG, suggesting that with further optimization, nucleic acid vaccines could outperform the century-old BCG vaccine.
The immune response generated by these vaccines typically includes both CD4+ and CD8+ T cell activation, which is crucial for combating intracellular pathogens like M. tuberculosis 5 . Some studies also reported strong antibody responses, though cellular immunity is considered more important for TB protection.
The route of administration emerged as a critical factor influencing vaccine efficacy. While most studies used intramuscular injection, some explored alternative routes such as intradermal, intranasal, or aerosol delivery 2 . Mucosal administration routes showed particular promise for generating lung-resident T cells that could provide first-line defense against respiratory pathogens.
Developing effective nucleic acid vaccines against tuberculosis requires a sophisticated array of research tools and reagents. These materials enable scientists to design, produce, and evaluate potential vaccine candidates.
Engineered DNA circles used to express mycobacterial antigens in host cells
In vitro transcribed mRNA molecules encoding TB antigens
Delivery systems that protect mRNA from degradation
Substances that enhance the immune response to vaccines
Well-characterized bacterial strains used to test vaccine efficacy
Tools for measuring antigen-specific T cell responses
Despite the promising results from animal studies, nucleic acid vaccines for TB face several challenges before they can become clinical reality:
The future of nucleic acid vaccines for TB likely lies in combination approaches. Prime-boost strategies, where nucleic acid vaccines are used alongside other platforms (such viral vectors or protein subunits), may elicit more robust and durable immunity 7 . Additionally, multiantigen cocktails that target different stages of the bacterial life cycle could overcome the limitations of single-antigen vaccines 1 6 .
The mRNA platform, though less explored, holds particular promise due to its rapid development timeline and flexibility. Once optimized for TB, mRNA vaccines could be quickly adapted to address different strains or target specific antigen combinations 3 8 . The success of mRNA COVID-19 vaccines has accelerated technological advances in RNA stability, delivery, and manufacturing, which will benefit TB vaccine development 3 8 .
From a global health perspective, any new TB vaccine must not only be effective but also accessible and affordable. Nucleic acid vaccines, particularly DNA platforms, offer advantages in terms of manufacturing scalability and thermostability, which could facilitate distribution in resource-limited settings 3 .
The development of nucleic acid vaccines against tuberculosis represents an exciting frontier in the century-long battle against this devastating disease. While the BCG vaccine has served an important role in protecting children from severe TB, its limitations in adults have left a critical gap in our global defense system. Nucleic acid vaccines—with their ability to elicit potent T-cell responses and their flexibility in antigen selection—offer hope for filling this gap.
The extensive body of animal research, comprehensively reviewed in the 2024 scoping review, provides a solid foundation for future clinical development. The predominance of DNA vaccine studies reflects the historical trajectory of the field, while the emerging RNA technology offers new opportunities for innovation 1 3 6 .
As scientists continue to optimize antigen selection, delivery systems, and vaccination strategies, we move closer to a world where tuberculosis no longer claims millions of lives each year. The path forward will require sustained investment, international collaboration, and continued scientific creativity. But with the powerful tools of nucleic acid technology now at our disposal, we have renewed reason for hope in the fight against one of humanity's oldest and deadliest infectious diseases.
This article was based on current scientific literature available as of 2025, with particular reference to the comprehensive scoping review published in Frontiers in Immunology (2024) and other recent advances in the field.