# Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials
## 1 Introduction  
Tuberculosis (TB) is an infectious disease caused by the bacillus _Mycobacterium tuberculosis (M. tuberculosis)_. M. tuberculosis in inhaled droplets enters the alveolar passages of exposed humans, contacting resident cells, and is ingested by the alveolar macrophages [1]. Within host macrophages, _M. tuberculosis_ resides in a phagosome (Figure 1) where the bacteria is exposed to a hostile environment consisting of an acidic pH, lysosomal enzymes, toxic peptides, and reactive oxygen intermediates [2]. However, _M. tuberculosis_ has evolved mechanisms to avoid this hostile vacuolar microenvironment and evade the host defense mechanisms [2, 3]. With the progression of the disease, the infected macrophages produce chemokines that attract neutrophils, lymphocytes, and inactivated monocytes, leading to the formation of granulomatous focal lesions to contain the spread of the bacteria [4]. Depending on the host immune response, the infection may arrest here, referred to as latent TB, and persist in an asymptomatic nontransmissible state [1, 3]. In those with effective cell-mediated immunity, the infection may arrest permanently, with the granulomas healing and resulting in fibrous-calcified lesions [2, 3]. When the initial infection in the lung cannot be controlled, or when the host with latent infection has a suppressed immune system, the granuloma center can become liquefied, serving as a medium for the newly revived bacteria to replicate in an uncontrolled manner and progress to later stages of the disease, including dissemination to other parts of the body [1, 2, 4]. TB is a disease that humanity has faced for millennia. In ancient Greece, [PERSON] accurately defined its symptoms and characteristic lung lesions, while [PERSON] was the first to suppose its infectious nature [5]. By the eighteenth-century, TB had become epidemic in Western Europe, but was only recognized as a disease that not only affects the lungs in 1810 [5]. Further progress and insight into the disease was garnered throughout the nineteenth century, highlighted by the first successful remedy against TB in 1854, and in 1882, the successful attempt, by [PERSON], at isolating the tubercle bacillus and reproducing the disease in inoculated animals [5]. This laid the foundation for the subsequent discoveries of tuberculin skin tests (1890), and for the development of the bacillus Calmette-Guerin (BCG) vaccine (1921) [5]. Nowadays, BCG is widely used and prevents TB in children, but has an immuno-protective effect only lasting 10 to 15 years, and is not effective in preventing TB in adults [5; 6; 7; 8]. According to the 2020 World Health Organization (WHO) global TB report, TB remains one of the top 10 causes of death worldwide, with an estimated ten million people newly diagnosed in 2019 [9]. Globally, within the same period, over 1.2 million deaths were reported, reaffirming that, since 2007, TB has been the principal cause of death from a single infectious agent [9]. While effective drug treatments exist, the only licensed vaccine available for TB prevention remains the BCG vaccine, developed 100 years ago [5; 6; 7; 9]. To fulfil the need for an effective vaccine for the adult population, provide longer lasting immunity in children, and ensure we meet the End TB Strategy target of 2035 (95% reduction in the absolute number of TB deaths per year) as set out by the WHO, it is of paramount importance to continue the research and development of new TB vaccines [4; 9]. In the last decade, novel vaccines using nanoparticles (NPs) have been widely developed. These nauvaccines utilize particles smaller than 1000 nm, which can be biological or synthetic, in combination with pathogen-specific antigens [8; 10]. The use of nauvaccines as a preventative option is being investigated for a host of infectious diseases, including acquired immunodeficiency syndrome (AIDS), malaria, influenza, and TB.