Promising breakthroughs ignite hope for a novel and effective Tuberculosis vaccine

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 expensive and lengthy and will 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 possibly be essentially the most effective tool to guard the worldwide population from TB manifestations.

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

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

The efficacy of the BCG vaccine against pulmonary TB varies significantly in adults and adolescents. This reduced efficacy could possibly be attributed to a decline in immune protection with age. One more 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 as a consequence of mutations in BCG stains used and differential culture preparation are other aspects that contribute to the variable efficacy of this vaccine. Host genetics and environmental exposures are other vital aspects that influence vaccine effectiveness.

Effectiveness of several types of TB vaccines

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

Several types of vaccines are developed following differential approaches, reminiscent of 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 type of Mycobacterium bovis. A key advantage of the sort of vaccine is that it’s 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 brand new vaccine incorporates 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 utilized in a heterologous vaccination approach, i.e., adolescents who received BCG as infants were supplied with DAR-91 as a booster dose to boost immune protection.

It should be noted that in a phase 2b clinical trial, the DAR-91 vaccine didn’t protect BCG-vaccinated adolescents in Tanzania from TB occurrence.

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

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

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

Developing an mRNA-based TB vaccine is difficult because choosing an appropriate vaccine goal is incredibly difficult, mainly as a consequence of the shortage 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 event of latest 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 copy the pathological features observed in humans precisely limited preclinical studies. Nonetheless, it should be noted that every one these models have provided vital insights into TB pathogenesis and treatment development.

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

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

Moreover, 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 major reduction in M. tuberculosis disease in high-risk populations.

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