Tuberculosis Vaccine Development: Progress in Clinical Evaluation.
Sable Suraj B,Posey James E,Scriba Thomas J
Clinical microbiology reviews
Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the bacille Calmette-Guérin (BCG) vaccine. A safer and more effective vaccine than BCG is urgently required. More than a dozen TB vaccine candidates are under active evaluation in clinical trials aimed to prevent infection, disease, and recurrence. After decades of extensive research, renewed promise of an effective vaccine against this ancient airborne disease has recently emerged. In two innovative phase 2b vaccine clinical trials, one for the prevention of infection in healthy adolescents and another for the prevention of TB disease in -infected adults, efficacy signals were observed. These breakthroughs, based on the greatly expanded knowledge of the infection spectrum, immunology of TB, and vaccine platforms, have reinvigorated the TB vaccine field. Here, we review our current understanding of natural immunity to TB, limitations in BCG immunity that are guiding vaccinologists to design novel TB vaccine candidates and concepts, and the desired attributes of a modern TB vaccine. We provide an overview of the progress of TB vaccine candidates in clinical evaluation, perspectives on the challenges faced by current vaccine concepts, and potential avenues to build on recent successes and accelerate the TB vaccine research-and-development trajectory.
Robust IgM responses following intravenous vaccination with Bacille Calmette-Guérin associate with prevention of Mycobacterium tuberculosis infection in macaques.
Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette-Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, but the antibody response it elicits remains incompletely defined. Here we show that i.v. BCG drives superior antibody responses in the plasma and the lungs of rhesus macaques compared to traditional intradermal BCG administration. While i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma and lungs of immunized macaques are among the strongest markers of reduced bacterial burden. IgM was also enriched in macaques that received protective vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and mediator of protection against TB.
The status of tuberculosis vaccine development.
Schrager Lewis K,Vekemens Johan,Drager Nick,Lewinsohn David M,Olesen Ole F
The Lancet. Infectious diseases
Tuberculosis represents the leading global cause of death from an infectious agent. Controlling the tuberculosis epidemic thus represents an urgent global public health priority. Epidemiological modelling suggests that, although drug treatments for tuberculosis continue to improve, WHO timelines to control the spread of the disease require a new vaccine capable of preventing tuberculosis, particularly in adolescents and adults. The spread of strains resistant to multiple drugs adds additional urgency to the vaccine development effort yet attempts to develop new vaccines with wider applicability and better, longer-lasting efficacy than BCG-the only tuberculosis vaccine licensed for use globally-have proven challenging. Results from clinical efficacy trials, particularly a completed, phase 2b trial for preventing tuberculosis disease in people infected with Mycobacterium tuberculosis using the adjuvanted protein subunit vaccine M72/AS01E give hope. We review the current status of tuberculosis vaccine candidates and outline the diversified vaccine development that are underway.
Insights and challenges in tuberculosis vaccine development.
The Lancet. Respiratory medicine
Tuberculosis kills more people than any other pathogen and the need for a universally effective vaccine has never been greater. An effective vaccine will be a key tool in achieving the targets set by WHO in the End TB Strategy. Tuberculosis vaccine development is difficult and slow. Substantial progress has been made in research and development of tuberculosis vaccines in the past 20 years, and two clinical trial results from 2018 provide reason for optimism. However, many challenges to the successful licensure and deployment of an effective tuberculosis vaccine remain. The development of new tools for vaccine evaluation might facilitate these processes, and continued collaborative working and sustained funding will be essential.