Clinical Development of New TB Vaccines: Recent Advances and Next Steps

Abstract

Mycobacterium tuberculosis (Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01 _E provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01 _E with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01 _E and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will.

Keywords: Bacille Calmette Guerin; Mycobacterium tuberculosis; development; tuberculosis; vaccine.

FIGURE 1

Target populations for new TB vaccines include Mtb-uninfected (pre-exposure) and Mtb-infected, TB diseased, and treated individuals (post-exposure). Risk of Mtb infection and progression to TB disease increases with age (time at risk). Pre-exposure strategies for TB vaccination of Mtb-uninfected individuals include both prevention of infection (POI) and prevention of disease (POD). Post-exposure strategies include vaccination of Mtb-infected individuals to prevent progression to TB disease (POD); vaccination of TB patients to improve treatment outcomes (therapeutic); and vaccination of treated TB patients to prevent recurrent disease (POR). Therapeutic vaccination might also confer POR benefit.