Immunological Strategies for Tuberculosis Vaccination

Tuberculosis (TB) remains one of the leading causes of infectious mortality worldwide, driving the development of vaccines that elicit both robust innate defences and durable adaptive immunity. Contemporary strategies focus on optimising antigen selection and delivery to promote Th1-skewed CD4+ T-helper responses and potent CD8+ cytotoxic responses, which are critical for interferon-γ–mediated activation of infected macrophages. Live-attenuated and subunit vaccine platforms incorporate key mycobacterial antigens—sometimes absent from the century-old BCG vaccine—to broaden antigenic coverage and improve immunogenicity. Adjuvant systems and targeted routes, including aerosol or mucosal administration, aim to enhance lung-resident memory and local antibody responses. Cutting-edge immunoprofiling methods, such as single-cell RNA sequencing and functional mycobacterial growth inhibition assays, are being used to identify correlates of protection and guide the rational design of next-generation TB vaccines with global applicability.

Research from Nature Portfolio

Recent studies have identified considerable heterogeneity in human responses to BCG vaccination in healthy adults, revealing that only a subset of individuals develop newly acquired control of mycobacterial growth, while others exhibit preexisting control or remain non-responsive. Single-cell transcriptomics has delineated distinct cellular pathways and gene expression programmes associated with these responder phenotypes, offering novel targets for vaccine optimisation. Another seminal investigation has demonstrated that incorporation of antigens such as ESAT6 and CFP10—absent in current BCG formulations—into live-attenuated vaccine candidates markedly enhances antigen-specific immune activation and correlates with superior protection in preclinical models. These findings underscore the critical importance of antigen repertoire and individual immunoprofiling in next-generation vaccine development.

Immunological Strategies for Tuberculosis Vaccination publication trend

The graph below shows the total number of articles in immunological strategies for tuberculosis vaccination across all publications each year (not limited to Nature Index journals).

Technical terms

Antigen-specific reactogenicity: the innate and adaptive immune activation observed in response to defined mycobacterial antigens, reflecting the magnitude of vaccine-induced immune recognition.
Polyfunctional T cells: T lymphocytes capable of producing multiple cytokines concurrently, often associated with enhanced control of intracellular pathogens.
Live-attenuated vaccine: a vaccine composed of live pathogens that have been genetically or chemically modified to reduce virulence while retaining immunogenicity.
Single-cell RNA sequencing: a high-resolution technique that profiles gene expression in individual cells, revealing cellular heterogeneity and activation states within complex immune populations.
Correlates of protection: measurable immune parameters (for example, specific cytokine profiles or functional assays) that associate with vaccine-induced immunity and predict protective efficacy.

References

1. Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial. The Lancet Infectious Diseases (2024).
2. BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination. Nature Communications (2024).
3. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nature Communications (2017).
4. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. The Lancet Respiratory Medicine (2015).
5. In vitro mycobacterial growth inhibition assays: A tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy. Vaccine (2016).