A recent Npj Vaccines study discussed the success and challenges of developing different tuberculosis (TB) vaccine types.

Study: Key advances in vaccine development for tuberculosis—success and challenges. Image Credit: Creativa Images/Shutterstock.com

Effectiveness of BCG vaccine against TB

In 1982, Robert Koch first identified the TB-causing bacterial pathogen Mycobacterium tuberculosis.

TB treatment is costly and lengthy and could require 6-9 months of antibiotic therapy. The emergence of a multidrug-resistant strain of M. tuberculosis has increased the urgency to develop a TB eradication program. Vaccination could be the most effective tool to protect the global population from TB manifestations.

Bacille Calmette-Guérin (BCG) is the most common and only licensed TB vaccine. This vaccine is safe for all age groups and communities except for immunocompromised people or those who have contracted human immunodeficiency virus (HIV).

BCG vaccination protects against meningeal TB when administered soon after birth. This protection sustains for up to ten years. 

The efficacy of the BCG vaccine against pulmonary TB varies significantly in adults and adolescents. This reduced efficacy could be attributed to a decline in immune protection with age. Another reason linked to the variable efficacy of BCG in tropical regions is the prevalence and exposure to environmental non-tuberculous mycobacteria (NTM).

The genetic inconsistencies due to mutations in BCG stains used and differential culture preparation are other factors that contribute to the variable efficacy of this vaccine. Host genetics and environmental exposures are other important factors that influence vaccine effectiveness.

Effectiveness of different types of TB vaccines

Twenty-one vaccine candidates are at various stages of clinical and preclinical development.

Different types of vaccines are developed following differential approaches, such as live whole-cell vaccines, inactivated whole-cell vaccines, subunit vaccines, viral-vectored vaccines, and mRNA vaccines.

BCG is a live whole-cell vaccine, i.e., an attenuated form of Mycobacterium bovis. A key advantage of this type of vaccine is that it is genetically related to M. tuberculosis, and offers antigenic conservation. BCG vaccination induces CD4 and CD8 T cell responses and triggers antibody production.

The advancements in gene engineering or modification tools have enabled the manipulation of the BCG genome, ensuring improved efficacy against TB disease.

A newly developed VPM1002 vaccine, based on modified BCG, has demonstrated significant efficacy in Phase 3 clinical trials. The new vaccine contains a gene encoding listeriolysin O (LLO) from Listeria monocytogenes and the removal of the BCG urease C gene. 

The DAR-901 vaccine is the inactivated vaccine type that was designed using inactivated M. obuense. This vaccine has been developed to be used in a heterologous vaccination approach, i.e., adolescents who received BCG as infants were provided with DAR-91 as a booster dose to enhance immune protection.

It must be noted that in a phase 2b clinical trial, the DAR-91 vaccine failed to protect BCG-vaccinated adolescents in Tanzania from TB occurrence.

Other inactivated whole-cell vaccines are RUTU (completed phase 2 trial successfully) and oral V7 vaccine (completed a phase III clinical trial). Both these vaccines exhibited tolerance and safety in clinical trials. 

Subunit TB vaccines typically target specific proteins from M. tuberculosis and induce immune response. TB subunit vaccines, namely, H56:IC31, H4:IC31, and M72/AS01, have completed phase 2 clinical trials and demonstrated effective immunogenicity and safety in human volunteers.

Viral-vectored vaccines are designed using both whole-cell vaccines and subunit vaccine approaches. AdHu85A and AdHu35 are two viral-vectored TB vaccines that have completed Phase I clinical trials. The MVA85A has recently completed a large-scale phase II trial in South Africa.

Developing an mRNA-based TB vaccine is difficult because selecting an appropriate vaccine target is extremely difficult, mainly due to the lack of sufficient genomic data. Recently, ID91 fusion protein has demonstrated promise for its use in developing mRNA TB vaccines.

Animal models helped overcome challenges in the development of new TB vaccines 

Scientists worldwide have encountered multiple hurdles to developing universally effective TB vaccines. Insufficient research funds and investments have significantly attributed to this failure.

Ineffective mouse, guinea pigs, cattle, rabbit, and non-human primates (NHP) TB models that failed to replicate the pathological features observed in humans precisely limited preclinical studies. However, it must be noted that all these models have provided important insights into TB pathogenesis and treatment development.

NHP models most closely resemble human TB. However, these models are extremely resource-intensive and are highly expensive. Although mouse models are not resource-intensive, cost-effective, and easy to handle, they are not as efficient as NHP models. 

Addressing the lack of genetic diversity in mouse models, the mouse genetics community created two distinct mouse resources: Diversity Outbred (DO) mice and Collaborative Cross (CC) mice.

Furthermore, low and ultra-low-dose M. tuberculosis infection mouse TB models have exhibited increased infection diversity and formation of well-defined granulomatous structures.

Conclusions

Recently, two different TB vaccine clinical trials, M72/AS01 and BCG revaccination, have demonstrated a significant reduction in M. tuberculosis disease in high-risk populations.

These vaccines have effectively protected this population from contracting the disease. Both the vaccine candidates performed exceptionally well in achieving sterilizing immunity in NHP models of TB.