Next-Generation TB Vaccines: Progress, Challenges, and Prospects

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a prevalent global infectious disease and a leading cause of mortality worldwide. Currently, the only available vaccine for TB prevention is Bacillus Calmette-Guérin (BCG). However, BCG demonstrates limited efficacy, particularly in adults. Efforts to develop effective TB vaccines have been ongoing for nearly a century. In this review, we have examined the current obstacles in TB vaccine research and emphasized the significance of understanding the interaction mechanism between MTB and hosts in order to provide new avenues for research and establish a solid foundation for the development of novel vaccines. We have also assessed various TB vaccine candidates, including inactivated vaccines, attenuated live vaccines, subunit vaccines, viral vector vaccines, DNA vaccines, and the emerging mRNA vaccines as well as virus-like particle (VLP)-based vaccines, which are currently in preclinical stages or clinical trials. Furthermore, we have discussed the challenges and opportunities associated with developing different types of TB vaccines and outlined future directions for TB vaccine research, aiming to expedite the development of effective vaccines. This comprehensive review offers a summary of the progress made in the field of novel TB vaccines.

Keywords: Mycobacterium tuberculosis (MTB); clinical trials; deep learning; tuberculosis (TB); vaccines.

Figure 1

Innate and adaptive immune responses induced by the MTB. Upon entering the pulmonary alveoli via the respiratory tract, MTB is first recognized by resident immune cells such as alveolar macrophages, immature dendritic cells (iDCs), and natural killer (NK) cells. Following capture by iDCs, which migrate from the site of infection to the lymph nodes, the bacteria induces their differentiation into mature dendritic cells (mDCs) with enhanced antigen-presenting and MHC expression capacity. Through the assistance of CD28-CD80 and CD40-CD40L, MHC I and MHC II molecules on dendritic cells recognize and activate CD4⁺ and CD8⁺ T lymphocytes. CD4⁺ T lymphocytes differentiate into Th1, Th2, or Th17 subsets depending on the microenvironmental cytokines and contribute to the control of MTB infection. Th1 and Th2 immunity counterbalance each other and maintain immune homeostasis. CD8⁺ T lymphocytes further differentiate into cytotoxic T lymphocytes (CTLs) that produce granzyme, perforin, Fas-FasL, IFN-γ, TNF-α, and other molecules to activate macrophages and eliminate the bacteria. Depending on the interplay between innate and adaptive immune responses and the virulence of MTB, infection can lead to either recovery, latent tuberculosis infection (LTBI), or active tuberculosis (ATB).

Figure 2

Interplay and balance of CD4⁺ T cell subtypes in MTB infection. APCs, such as macrophages, present MTB antigen peptides to naive T cells (Th0 cells) through MHC II molecules, inducing the differentiation of T cells into different subtypes depending on the cytokine microenvironment. Upon stimulation with IL-12 and IFN-γ secreted by macrophages, Th0 cells activate STAT4 and T-bet, differentiate into Th1 subtype, and release cytokines such as IFN-γ and TNF-α to combat MTB infection. Similarly, macrophages can facilitate the differentiation of Th0 cells into Th2, Th17, and Treg subtypes by secreting different cytokines, including IL-2 and IL-4, IL-6, IL-23, and TGF-β, as well as IL-10 and TGF-β. The interplay among Th1, Th2, Th17, and Treg subtypes is complex and balanced, and they work together to exert immune responses and maintain the host defense against MTB infection.

Figure 3

TB vaccine clinical pipeline. The current pipeline delivers data pertinent to vaccine candidates undergoing clinical development, while information on candidates in preclinical development remains uncollected. Abbreviations: RIBSP, Research Institute for Biological Safety Problems; SRII, Smorodintsev Research Institute of Influenza; NIAID, National Institute of Allergy and Infectious Diseases; NIH, National Institutes of Health; SSI, Statens Serum Institut; IAVI, International AIDS Vaccine Initiative; ICMR, Indian Council of Medical Research; CADILA, Cadila Pharmaceuticals Ltd.; DHMC, Dartmouth Hitchcock Medical Center; SIIPL, Serum Institute of India Private Limited; VPM, Vakzine Projekt Management GmbH; Gates MRI, Bill & Melinda Gates Medical Research Institute; GSK, GlaxoSmithKline.

Figure 4

Efficacy of M72/AS01E subunit vaccine against confirmed cases of PTB in individuals without HIV infection. The analysis utilized an unadjusted Cox regression model in the efficacy cohort as per the protocol. The data used in this figure were obtained from the previous study [79]. Copyright ^© 2019 Massachusetts Medical Society.

Figure 5

Illustrates the generation of mRNA TB vaccines and VLP-based TB vaccines. In (A), the DNA encoding the target protein of MTB is obtained and transcribed into mRNA. The mRNA is then loaded with lipid nanoparticles and other carriers to create a TB mRNA vaccine for intramuscular immunization. When these mRNA vaccines are injected into the human body, ribosomes in bystander cells assist in translating the target protein. Bystander cells engulf the produced protein, activating both innate and adaptive immune responses to eliminate MTB. In (B), a coat protein from a virus is cloned into an expression vector. The expression vector is then modified to include the MTB protein, such as ESAT-6 or CFP-10. The resulting expression vector contains both the coat protein and the MTB protein. It is transformed or transfected into an expression system to produce the proteins. Finally, the MTB protein assembles into VLPs, resulting in a VLP-based TB vaccine.