Tuberculosis Vaccine: Dual delivery of antigens shows promise

The simultaneous delivery of protein and lipid antigens via nanoparticles may help efforts to develop a new vaccine for tuberculosis.
  1. Jose L Luque-García
  2. Rafael Prados-Rosales  Is a corresponding author
  1. Department of Analytical Chemistry, School of Chemistry, Universidad Complutense of Madrid, Spain
  2. Department of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autonoma de Madrid, Spain

The BCG vaccine was first used in 1921 and, remarkably, over 100 years later it is the only licensed vaccine for use against tuberculosis. While the BCG vaccine provides protection against tuberculosis that has spread beyond the lungs in young children, its efficacy against lung infections in adults – the main form of the disease – is variable (Trunz et al., 2006). Tuberculosis is caused by a bacterium called Mycobacterium tuberculosis (M. tb), and one reason for the lack of more effective vaccines is that we still do not know which M. tb antigens are able to induce protective immunity (Guinn and Rubin, 2017).

Almost 20 vaccine candidates are currently being evaluated in clinical trials. Most of these aim to induce a response from immune cells called type 1 helper T cells by exposing them to protein antigens from M. tb, although other approaches are also being explored. Now, in eLife, Evan Scott and Chyung-Ru Wang from Northwestern University and colleagues – including Eva Morgun as first author – report a new approach that involves using protein antigens and long-chain fatty acids called mycolic acids, found in the M. tb cell envelope, to induce an immune response (Morgun et al., 2023).

Previous studies have shown that the immune system generates a protective response when exposed to mycolic acids: this response is mediated by a subset of “unconventional” T cells, but the details of the response are not fully understood (Shang et al., 2018; Zhao et al., 2015). Moreover, there have been very few attempts to explore the use of mycolic acids as alternative antigens for a tuberculosis vaccine, partly because most vaccine delivery systems are designed for hydrophilic cargoes (such as proteins), whereas mycolic acids are hydrophobic. Morgun et al. have overcome this problem by developing a system that can deliver hydrophobic and hydrophilic cargoes at the same time.

Building upon evidence that vaccine formulations including M. tb lipids encapsulated in liposomes – hollow spherical structures made of lipid bilayers – provide protection (Dascher et al., 2003; Larrouy-Maumus et al., 2017), Morgun et al. developed structures called bicontinuous nanospheres. These self-assembled polymer-based structures can carry both hydrophobic and hydrophilic components because they possess an organized internal cubic structure including hydrophobic bilayers and hydrophilic aqueous channels (Figure 1). Furthermore, the nanospheres retain antigens more efficiently than other lipid nanostructures, and only release their contents when they reach the target compartment within antigen-presenting cells. These features increase the persistence of the antigens within cells and stimulate the immune system for longer periods of time, which leads to a more robust immune response (Correia-Pinto et al., 2013).

Bicontinuous nanospheres can be loaded with both protein and lipid antigens.

Structure of a bicontinuous nanosphere. Hydrophilic (blue) regions contain protein antigens and hydrophobic (green) regions contain mycolic acids, represented by tentative structures. Figure based on image from Allen et al., 2018.

Morgun et al. used a mouse model that allowed them to observe the immune response to dual vaccination with mycolic acids and proteins. This showed that T cells responded to both antigens: however, only mycolic acid remained detectable inside immune cells after vaccination. It remains unclear if this differential antigen persistence is due to the nanosphere delivery system, the protein itself, or a distinct mechanism of antigen capture and maintenance by immune cells.

It is worth noting that the persistence of mycolic acids likely occurs during in vivo infection and, therefore, the dual vaccination strategy may mimic a previously overlooked feature of the infection process. Supporting this notion, Morgun et al. found that vaccination with an attenuated M. tb strain resulted in a persistence of mycolic acids similar to that observed with the dual approach. These results suggest that vaccines using live attenuated strains of M. tb likely provide protection via mycolic acid-specific T cells. This raises the question of whether the persistence of lipid antigens is a key aspect of the protective immune response: this is something that needs to be considered when developing tuberculosis vaccines in the future.

Although definitive proof of protective immunity induced by dual-loaded bicontinuous nanospheres remains elusive, this approach allowing combinations of antigens – both hydrophobic and hydrophilic – can be used as an alternative strategy to live attenuated vaccines. Moreover, the ability to test combinations of alternative antigens will aid the development of vaccines for tuberculosis more generally. Future work with this system could also investigate the role of lipid persistence in other overlooked aspects of tuberculosis immunity, such as antibody responses, which might have an important contribution to protective immunity.

References

Article and author information

Author details

  1. Jose L Luque-García

    Jose L Luque-García is in the Department of Analytical Chemistry, School of Chemistry, Universidad Complutense of Madrid, Madrid, Spain

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6273-0349
  2. Rafael Prados-Rosales

    Rafael Prados-Rosales in the Department of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain

    For correspondence
    rafael.prados@uam.es
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5964-0166

Publication history

  1. Version of Record published:

Copyright

© 2023, Luque-García and Prados-Rosales

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 642
    views
  • 57
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jose L Luque-García
  2. Rafael Prados-Rosales
(2023)
Tuberculosis Vaccine: Dual delivery of antigens shows promise
eLife 12:e90407.
https://doi.org/10.7554/eLife.90407

Further reading

    1. Immunology and Inflammation
    Xiaoyu Meng, Yezhang Zhu ... Lie Wang
    Research Article

    FOXP3-expressing regulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in Treg cells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC-finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition. Cxxc1 deletion in Treg cells leads to severe inflammatory disease and spontaneous T cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key Treg functional markers under steady-state conditions, which are essential for the maintenance of Treg cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of Treg program genes in mouse Treg cells, overlapping with FOXP3-binding sites. Given its critical role in Treg cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.

    1. Immunology and Inflammation
    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.