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.

A guide to vaccinology: from basic principles to new developments

“…However, for much of history, vaccines have been developed through empirical research without the involvement of immunologists. There is a great need today for improved understanding of the immunological basis for vaccination to develop vaccines for hard-to-target pathogens (such as Mycobacterium tuberculosis , the bacterium that causes tuberculosis (TB)) 3 and antigenically variable pathogens (such as HIV) 4 , to control outbreaks that threaten global health security (such as COVID-19 or Ebola) 5 , 6 and to work out how to revive immune responses in the ageing immune system 7 to protect the growing population of older adults from infectious diseases.…”

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination

“… 17 Thus, TB continues to be a major threat to global human health, and a better vaccination strategy is urgently needed to relieve the burden of TB. 18 , 19 While intradermal injection is the standard route for BCG vaccination, historical data in rhesus macaques have shown that mucosal or intravenous administration provided superior signals of protection against experimental infection. 20 We have recently demonstrated that pulmonary mucosal BCG vaccination reduced disease in a cohort of rhesus macaques in which intradermal BCG failed to show any protective effect.…”

Rescuing ESAT-6 Specific CD4 T Cells From Terminal Differentiation Is Critical for Long-Term Control of Murine Mtb Infection

“…Conversely, Mtb establish life-long chronic infections and a significant proportion of the population living in TB endemic regions have an already acquired Mtb infection thereby harboring a pre-existing memory response to Mtb ( 6 , 7 ). A few of the more recent vaccine strategies have already been implemented to target individuals with active TB or latent tuberculosis infection (LTBI) ( 8 ) but it has proven more difficult to obtain vaccine-protection in animal models of post-exposure vaccination. The mechanisms behind protection in sensitized individuals is still debated ( 9 ).…”