Abstract
Tuberculosis (TB) is the global leading cause of death from an infectious agent with approximately 10 million new cases of TB and 1.45 million deaths in 2018. Bacille Calmette-Guérin (BCG) remains the only approved vaccine for Mycobacterium tuberculosis (M. tb, causative agent of TB), however clinical studies have shown BCG has variable effectiveness ranging from 0–80% in adults. With 1.7 billion people latently infected, it is becoming clear that vaccine regimens aimed at both post-exposure and pre-exposure to M. tb will be crucial to end the TB epidemic. The two main strategies to improve or replace BCG are subunit and live attenuated vaccines. However, following the failure of the MVA85A phase IIb trial in 2013, more varied and innovative approaches are being developed. These include recombinant BCG strains, genetically attenuated M. tb and naturally attenuated mycobacteria strains, novel methods of immunogenic antigen discovery including for hypervirulent M. tb strains, improved antigen recognition and delivery strategies, and broader selection of viral vectors. This article reviews preclinical vaccine work in the last 5 years with focus on those tested against M. tb challenge in relevant animal models.
Highlights
Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is the global leading cause of death from an infectious agent and one of the top 10 overall causes of death [1]
In addition to the recombinant Bacille Calmette-Guérin (BCG) that expresses antigens encoded in region of difference 1 (RD1) (e.g., ESAT-6 and CFP-10) as discussed in great detail in [23], there have been several new rBCG constructions tested in more recent years that will be discussed here (Table 1)
Guinea pigs: intradermal boost had the most reduced bacterial burden 6 weeks post infection compared to BCG alone; intramuscular boost had the most reduced bacterial burden while intranasal boost had no improvement Rhesus macaques: greatest reduced bacterial burden up to 20 weeks post infection and increased survival following intramuscular boost compared to unvaccinated macaques Mice: greater Th1 type specific response and antibody response compared to recombinant MVA (rMVA) without the tissue plasminogen activator signal sequence Mice: reduced bacterial loads 4 weeks post infection compared to BCG alone regardless of vaccination route; better protection than either viral vector boost alone Mice: retained protective immunity in mice previously exposed to human adenovirus Mice: greatest specific Th1 immunity compared to either vector alone or an modified vaccinia virus Ankara (MVA)-Ad prime boost regime
Summary
Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is the global leading cause of death from an infectious agent and one of the top 10 overall causes of death [1]. Bacille Calmette-Guérin (BCG) is the only approved vaccine for prevention of TB. It was developed in 1921 from a strain of virulent M. bovis, which was attenuated by 230 in vitro passages over 13 years [2]. The results were disappointing as MVA85A was unsuccessful in providing significantly improved protection against TB or M. tb infection than in BCG-vaccinated South African infants [15]. This failure has raised questions regarding plausibility of the subunit vaccine approach and further emphasizes the importance of more diversified vaccine research [16]. Many recent vaccine candidates are being tested in animal models of TB; we will focus on those that examined protective efficacy against M. tb
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