An article in Scientific reports in July 2024 describes the “pressing need” for novel and safe vaccines that provide “robust immune defence and have various applications” against tuberculosis. The authors apply an immunoinformatic strategy to generate an adequate multi-epitope immunisation against Mycobacterium tuberculosis (Mtb). Their analysis suggests that the vaccine could induce specific immune responses, indicating potential against Mtb, but they recognise the need for validation through in-vivo research.
A persistent threat and an old vaccine
Tuberculosis (TB) is “one of the most ancient diseases” but is still considered a global threat to human morbidity. Although identification and treatment solutions are evolving, TB remains the second-highest fatal infectious disease. Therapeutic options are “limited” and only one approved vaccine exists: BCG. The BCG vaccine has existed for over 80 years and is “one of the most widely used of all current vaccines”. However, it does not prevent primary infection or reactivation of latent pulmonary infection, the “principal source of bacillary spread in the community”.
There are “several” TB vaccines at various stages of clinical trials, but safety issues “remain a concern”, with nearly 50% of the candidates using a live, attenuated Mtb strain. Contrasting with “most of the past research”, which relies on exosome vesicles or known antigenic proteins to identify epitopes, the authors of this study integrate highly antigenic, non-allergenic, and non-toxic epitopes from novel immunogenic proteins for an in silico multi-epitope vaccine.
The study
In a literature study the authors identified five antigenic proteins that could serve as vaccine targets: probable transcriptional regulatory protein, possible exported protein, PPE family protein PPE41, conserved threonine-rich protein, and Phospholipase C A. These proteins were found to be antigenic and could induce an immune response in the host but have not been explored in the context of vaccine development against Mtb, providing a “novel avenue for investigation”.
The selection is also grounded in a “comprehensive antigenicity, non-allergenicity, and non-homology analysis”. The proteins were targeted to develop a potential vaccine against Mtb, and specific epitopes that can bind with Toll-Like Receptors (TLRs) were selected.
“The evolution of sequencing and immunoinformatics has revolutionised drug and vaccine design, replacing traditional, time-consuming approaches with efficient, epitope-based strategies utilising in silico tools.”
The study framework is centred on the development of a subunit vaccine through the analysis of five antigenic proteins derived from Mtb. This resulted in a chimeric vaccine, comprising 15 cytotoxic T lymphocytes (CTL), 5 interferon-gamma (IFN- γ) inducing helper T lymphocytes (HTL), and 5 B-cell epitopes. By linking these epitopes, the authors intended to “optimise protein folding and enhance flexibility”.
“This multiepitope vaccine, grounded in immunogenic antigens, has been conceived in response to the global tuberculosis pandemic, addressing the imperative for effective TB treatment. The envisaged assessment profile of the vaccine design provides insights into its immunogenicity, laying the foundation for subsequent experimental evaluation.”
The vaccine design elicited “robust” primary and secondary immune responses. A primary response was characterised by an elevation in IgM antibodies, manifesting after a “lag time” of five to seven days after antigen exposure. Following this, the secondary immune response was marked by elevated expression of IgM, IgG1, and IgM-IgG antibodies as well as increased B-cell proliferation. Furthermore, the population of cytotoxic (Tc) and helper (Th) cells demonstrated a “clear increase” post-immunisation and the enhanced production of IFN- γ and IL-2 observed after immunisation “underscores the activation of essential immune effectors”.
An assessment of clonal specificity with the Simpson index, D, indicates a “potentially diverse” immunological response. Earlier research has highlighted the role of innate immune cells like NK cells and DCs in “combatting” Mtb. Analysis revealed a “potent” activation of these cells, notably a “rapid and sustained increase” in NK cell production. Resting DC cells influenced the total counts of DCs, increasing from 150 to approximately 200 cells/mm 3 while inducing “limited” proliferation of presenting-1 and presenting-2 DCs.
“These results collectively signify a substantial and comprehensive immune response against Mtb, validating the efficacy of our vaccine design.”
The authors conclude that “more attention” should be directed to the development of innovative vaccine targets to control TB at all phases of infection with the goal of improving TB care. They also call for research on novel pharmacological targets to shorten the drug regimen, addressing the issue of treatment resistance. Their work, using immunoinformatic methods to extract immunodominant and non-allergic peptides from antigenic proteins, promises to produce an “adequate immune response”. However, an animal model will be “essential” to validate immunogenicity.
We look forward to considering TB vaccine progress at the Congress in Barcelona this October, welcoming experts from IAVI and BioNTech among others – you can get your tickets to join us here! Don’t forget to subscribe for more vaccine development updates.
