Advances in Tuberculosis Vaccine Research

Background of Tuberculosis Vaccine Research

Tuberculosis is one of the major challenges facing global public health and is the world's second-largest single infectious disease cause of death, second only to COVID-19 infection. Following the basic principles and guidelines for infectious disease control, early detection, diagnosis, treatment, and management, along with effective control of the source of infection, vaccination stands as one of the most successful and effective public health interventions for reducing or even eradicating infectious diseases. An effective tuberculosis vaccine is crucial for protecting susceptible populations, interrupting tuberculosis transmission, and reducing the incidence of tuberculosis disease among latent Mycobacterium tuberculosis infection carriers. However, the currently globally widely-used tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), has limited efficacy in preventing the spread of Mycobacterium tuberculosis. BCG is primarily administered to newborns to reduce the incidence of childhood tuberculous meningitis and disseminated pulmonary tuberculosis, with a protection rate ranging from 54% to 82%. Its protective efficacy decreases with age, failing to prevent most adult tuberculosis infections and diseases or to prevent the progression of latent infections to active disease, which is a primary source of tuberculosis transmission in communities.

A picture of the vaccine.

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Protection Mechanism of Tuberculosis Vaccine

The primary purpose of vaccine administration is to establish long-lasting effective immune memory to rapidly control Mycobacterium tuberculosis infection. Tuberculosis vaccines involve immune responses from CD4+ T cells, CD8+ T cells, B cells, and other immune cells (such as NK cells and unconventional T cells). The efficacy of the vaccine largely depends on immune memory mediated by memory T cells. CD4+ T cells are generally considered crucial for controlling tuberculosis, and to prevent tuberculosis, CD4+ T cells differentiate into four main types:

• T Central Memory Cells (TCM): Primarily located in lymphoid organs and maintain high proliferative capacity.
• T Effector Memory Cells (TEM): Mainly present in circulation and peripheral sites, differentiate from TCM cells upon antigen re-exposure.
• T Tissue-Resident Memory Cells (TRM): Some TEM cells remain in the lungs.
• T Effector Cells (TEFF): Newly recruited immune cells after infection.

T Stem Cell Memory (TSCM) cells and TCM cells play a central role in the immune response to chronic Mycobacterium tuberculosis infection. The responsive memory is mediated by TCM, which exists in the T cell zones of secondary lymphoid organs and has minimal effector function. However, when exposed to foreign antigens, these cells can proliferate and rapidly differentiate into effector cells. Therefore, TCM can provide long-term protection against pathogen invasion, while TEM cells can only provide short-term protection. TRM cells reside in peripheral tissues (such as the lungs), providing local protection against reinfection.

Types of Tuberculosis Vaccine Candidates

Currently, numerous candidate vaccines are in clinical trial phases, encompassing candidates aimed at preventing tuberculosis infection and disease, as well as those designed to enhance tuberculosis treatment outcomes. These candidates can be categorized based on their design approaches into attenuated Mycobacterium tuberculosis live vaccines, inactivated Mycobacterium tuberculosis vaccines, adjuvanted subunit vaccines, viral vector vaccines, and messenger RNA (mRNA) vaccines.

Attenuated Mycobacterium Tuberculosis Live Vaccines

The Bacille Calmette-Guérin (BCG) vaccine is an attenuated strain derived from bovine tuberculosis. Due to the similar cellular biology of intracellular infection, BCG and Mycobacterium tuberculosis both elicit CD4 and CD8 T-cell responses and stimulate antibody production. During its attenuation process, deletions in genomic regions result in the loss of its major virulence factors, rendering BCG safe in hosts with robust immune systems. However, over the past three decades, BCG has shown partial ineffectiveness and instability in certain populations, providing immunity to only up to 60% of adult pulmonary tuberculosis cases. The prevalence of multidrug-resistant strains of Mycobacterium tuberculosis and the existence of a large population with latent infections underscore the urgent and critical need for the development of novel tuberculosis vaccines to replace BCG. Currently, there is considerable interest in the development of recombinant BCG (rBCG) candidate vaccines as potential alternatives to BCG. Because live vaccines can induce more diverse immune responses, strategies to enhance the efficacy of rBCG include gene deletions from BCG and the insertion of Mycobacterium tuberculosis-encoded genes into the BCG genome.

Inactivated Mycobacterium Tuberculosis Vaccines

Mycobacterium vaccae, also known as Mycobacterium Vaccae, is a specific lysate product obtained by culturing bovine Mycobacterium tuberculosis and collecting the bacterial bodies. After undergoing high-pressure homogenization, it is inactivated and lyophilized with the addition of stabilizers. The primary active ingredient is the bacterial body protein of bovine Mycobacterium tuberculosis. Pharmacological studies have shown that it possesses bidirectional immune-regulating functions. Phase III clinical studies of Mycobacterium vaccae as a preventive tuberculosis vaccine have been completed. Multiple research findings indicate that injection of Mycobacterium vaccae, combined with anti-tuberculosis treatment, results in higher sputum smear conversion rates and sputum culture conversion rates in newly diagnosed, retreated, and multidrug-resistant pulmonary tuberculosis patients compared to control groups. Additionally, it can promote the absorption of pulmonary lesions and closure of cavities.

Subunit Adjuvanted Vaccines

The development of subunit adjuvanted tuberculosis vaccines largely relies on identifying novel tuberculosis antigens involved in protective immunity and selecting appropriate adjuvant systems. Most subunit tuberculosis vaccines target specific proteins of Mycobacterium tuberculosis, resulting in a much narrower breadth of immune response. Therefore, the selection of antigen targets is particularly crucial.

Viral Vector Vaccines

Viral vector vaccines mimic the process of pathogen invasion and induce immune responses, possessing the ability to establish long-lasting immune memory. In addition, recombinant live viral vector vaccines typically have the following advantages:

• They can accommodate relatively long antigenic segments.
• Stable efficiency in expressing foreign genes.
• They can induce both high-level T cell-mediated immune responses and humoral immune responses simultaneously.
• The inherent immune responses induced by the vector itself can enhance adaptive immune responses to some extent.
• They do not require adjuvants.
• They are easy to prepare, with mature methods for expansion culture and production.
• They use attenuated or replication-defective viruses with clear infection mechanisms, ensuring strong safety.
• Generally, a single immunization can induce robust immune memory, requiring no or fewer repeated doses.

For tuberculosis vaccines, since Mycobacterium tuberculosis can infect cells and persist intracellularly, the specific ability of live viral vector vaccines to induce high-level cytotoxic T lymphocyte responses can aid in the clearance of intracellular mycobacteria.

mRNA Vaccines

Inspired by the tremendous success of mRNA vaccines against COVID-19, the development of mRNA vaccines for other infectious diseases such as monkeypox (mpox) and tuberculosis has garnered unprecedented attention. The protective effect of RNA vaccines against tuberculosis has been validated, although its efficacy is not as high as that of the BCG vaccine.