Current efforts and future prospects in the development of live mycobacteria as vaccines

Abstract

The development of more effective vaccines against Mycobacterium tuberculosis (Mtb) remains a major goal in the effort to reduce the enormous global burden of disease caused by this pathogen. Whole-cell vaccines based on live mycobacteria with attenuated virulence represent an appealing approach, providing broad antigen exposure and intrinsic adjuvant properties to prime durable immune responses. However, designing vaccine strains with an optimal balance between attenuation and immunogenicity has proven to be extremely challenging. Recent basic and clinical research efforts have broadened our understanding of Mtb pathogenesis and created numerous new vaccine candidates that have been designed to overcome different aspects of immune evasion by Mtb. In this review, we provide an overview of the current efforts to create improved vaccines against tuberculosis based on modifications of live attenuated mycobacteria. In addition, we discuss the use of such vaccine strains as vectors for stimulating protective immunity against other infectious diseases and cancers.

Keywords:

• attenuation
• autophagy
• auxotroph
• immune evasion
• live vaccine
• mycobacterial antigens
• Mycobacterium tuberculosis
• phagosome
• pro-apoptotic

Financial & competing interests disclosure

The authors were supported by grants from the US Department of Health and Human Services-National Institutes of Health (P01AI063537, R01AI093649) and the US Department of Health and Human Services-National Institutes of Health-National Institute of General Medical Sciences (UO1GM111849). LJ Carreño received a fellowship from the Pew Charitable Trusts. SA Porcelli is paid as a consultant for Vaccinex, a biotechnology company with commercial interest in modified live bacterial vaccines. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The costs and efforts required for clinical trials impose severe limitations on the number of vaccines that can be tested. This issue is compounded by the lack of clearly predictive animal models for testing the protective efficacy of candidate vaccines against Mycobacterium tuberculosis (Mtb) challenge.

• Basic research to better understand the pathogenesis of Mtb and its mechanisms for evading host immunity remains critically important for refining vaccine design and selecting the best vaccine candidates for clinical trials.

• Research development in recent years, including identification of mycobacterial antigens, improved methods for genetic modification of mycobacteria, rational approaches to attenuation and new understanding of adjuvants, have all contributed to new concepts in vaccine design. These advances have accelerated the creation of new candidate vaccine strains that show promise in various animal models.

• Live mycobacterial vaccines provide a broad antigen exposure and intrinsic adjuvant properties to prime durable immune responses. However, due to the complexity of Mtb pathogenesis, it is often difficult to achieve a balance between attenuation and immunogenicity for improved vaccine efficacy.

• Efforts to improve live mycobacterial cell vaccines against tuberculosis can be applied to other infections and diseases such as HIV, malaria and cancer, further consolidating the efforts in designing vaccines against various diseases.

Notes