Tuberculosis Vaccines

2.1

History

Mtb was first recognized as the cause of TB in 1882, an achievement for which Robert Koch received the Nobel prize. The pathogen may have coexisted with humans for up to 70,000 years, suggested by a recent report of the global distribution and variability among Mtb strains, which indicated that Mtb migrated out of Africa with humans during the Neolithic period. This also points to the first and perhaps main roadblock in developing effective vaccines against TB: our understanding of the coevolution of the human and Mtb remains limited; in particular, we do not fully comprehend how humans control the infection.

2.2

Epidemiology

Although the global public health threat of TB remains significant, some changes in the epidemiology of the disease have been encouraging. TB mortality has fallen by 47% since 1990; it is estimated that effective diagnosis and treatment of TB has saved 43 million lives between 2000 and 2014. The millennium development goal of halting and reversing TB incidence has been achieved: globally, this incidence has decreased by 1.5% per year since 2000, and in 2014 was 18% lower than the level of 2000. The global TB prevalence rate in 2015 was 42% lower than in 1990.

Regardless, the rate of decline in global incidence is slow, and even if the entire world could achieve a decline of 5% shown in some endemic countries, it is not nearly possible to reach the World Health Organization’s (WHO) goal of a global incidence of 20/100,000/year in 2030. This is the major argument for developing a more effective preventive TB vaccine, as a tool to complement current tools for intervention.

The majority of the world’s TB cases occur in the Southeast Asia and Western Pacific Regions, while Africa has the highest incidence: southern Africa is the most severely affected. Here, HIV infection is common and the immune compromise caused by this infection has been a driver of the epidemic. TB disease occurs in men at a frequency that is about double of that in women, while <10% of cases manifest in children. TB is overwhelmingly a disease of the socioeconomically disposed.

Therefore, ideally, a vaccine should be able to target all ages and persons with all comorbidities, but if not possible, an effective vaccine that targets adults without comorbidities such as HIV infection will still have a massive impact (see later).

2.3

Bacteriology

Mtb is one of nine mycobacterial species that are collectively classified as the Mycobacterium tuberculosis complex: M. tuberculosis , M. africanum , M. canettii , M. bovis , M. caprae , M. pinnipedii , M. microti , M. mungi , and M. orygis . Each can cause clinical TB disease in humans, although Mtb is by far the most common. More than 140 additional nontuberculous mycobacterial (NTM) species are found worldwide, often present in soil and water reservoirs. BCG is an attenuated strain of M. bovis . Multiple NTMs, and even modified Mtb, are currently in clinical development as vaccine candidates (see later).

Some of the approximately 3800 proteins of Mtb are immunodominant, meaning that most infected persons’ immune systems have developed a detectable immune response to these proteins. Examples include early secretory antigen target-6 (ESAT-6) and culture filtrate protein 10 (CFP-10). New candidate vaccines classically contain immunodominant proteins (see later). This may be a concern, as very limited variation among these proteins has been shown in Mtb strains from across the globe; our assumption would have been that tens of thousands of years of immune pressure from humans on the pathogen would have resulted in significant changes in these proteins. Rather, nonimmunodominant proteins of Mtb show greater variation. These observations suggest human immune responses to immunodominant proteins may hold evolutionary advantage to the pathogen. Overall, it is not known which particular protein our immune systems should target for protection against TB—a gap in our knowledge that compromises vaccine development.

Mtb has a capsule, the very outer layer of the cell wall. Current procedures for growing Mtb in the laboratory involves detergents in the growth medium, as well as shaking, both of which result in destruction of the capsule. Capsular components are likely to be encountered first by the human immune system following inhalation, and may contain components that should be targeted with vaccination. Multiple efforts are currently underway to grow Mtb in vitro while retaining the capsule; success is likely to enhance vaccine discovery and development efforts.

2.4

Pathogenesis

TB is spread by aerosols, following coughing. About a third of exposed persons become infected following inhalation. Infection is detected by a positive tuberculin skin test (TST) or a positive interferon-γ release assay (IGRA). Interestingly, a small fraction of exposed persons appear to resist infection, as demonstrated by persistently negative TSTs or IGRAs following repeated exposure. Studying these individuals may reveal clues for development of vaccines to prevent infection.

Only 10% of untreated persons infected with Mtb will develop active TB disease in a lifetime, which implies that most humans have immune mechanisms that control the pathogen and prevent disease manifestations. Intensive investigation is ongoing to delineate these mechanisms in prospective cohort studies of humans (see later).

Approximately 50% of disease occurs within 2 years of infection, while disease manifests much later in life in the other 50%—so-called reactivation disease. Disease commonly occurs in persons with relative immune compromise, associated with poor nutrition, other conditions that are linked to poverty, or diabetes mellitus, for example. More overt immune compromise, including that caused by HIV infection, increases the risk of progression to TB disease following infection dramatically: Mtb and HIV coinfected persons not on antiretrovirals have a 10% annual risk of developing active TB disease, while the risk decreases significantly on antiretroviral therapy.

Age is also a determinant of progression to active disease following infection. Infants appear to have a 5–10-fold increased risk of progressing to TB disease following infection, compared with adults ; their relatively immature immune systems may be responsible. Relative immune compromise in the elderly is also likely responsible for the rise in incidence of TB disease in this age group. Remarkably, prepubescent children between the ages of 5 and 10 years appear to have the lowest lifetime risk of developing TB disease following infection —their host responses to mycobacteria, when compared with other ages, may hold clues to successful vaccination strategies to prevent disease.

The host response to Mtb infection and associated with TB disease is complex. Briefly, inhaled Mtb is taken up by cells that patrol the airways, called macrophages. These cells commonly need help to kill or control growth of the pathogen inside the cell. The immune system provides this assistance by activating other immune cells, called T lymphocytes, which deploy strategies to help the macrophages. Most TB vaccines are designed to induce T lymphocytes, which would then be ready to help fight off the pathogen when infection occurs. Acute TB disease occurs when these immune responses fail, or become excessive, resulting in widespread inflammation. Therefore, a vaccination approach should induce sufficient immunity to protect; a disproportionately large vaccine-mediated response could be detrimental.

Mtb is known to induce a wide range of immune responses beyond those mediated by T lymphocytes. Unfortunately, it is not known what constitutes an essential and sufficient immune response to protect against TB; this lack of information hampers TB vaccine development, and is an area of investigation. This also focuses on many mechanisms that Mtb uses to subvert or avoid the immune response, and on the excessive inflammation that characterizes development of clinical disease.

2.5

Clinical Manifestations

As mentioned earlier, the lung is by far the most common site of symptomatic disease. Early symptoms include loss of appetite, malaise, and fatigue, often lasting for weeks. Classical symptoms include chronic cough, low-grade fever, weight loss or failure to thrive, night sweats, and chest pain. Symptoms develop insidiously; patients often present to health-care facilities following an acute bacterial pulmonary superinfection (an infection on top of TB). TB may also affect virtually any organ of the body. Disease manifestations vary between prepubescent children and adolescents/adults, suggesting possible differential mechanisms of protection, which may therefore require differential vaccination approaches. Children with active TB classically have milder lung disease, compared with adults. Pulmonary cavities (holes in the lung) are rare in children, while lymph node enlargement in the thorax is common. In contrast, adolescents/adults often have more severe lung disease with cavitation and much higher bacterial loads, compared with children. Children are at higher risk of disease in other organs, such as neck lymph node disease, or severe disease such as meningitis or miliary disease, when bacteria have disseminated to all organs, compared with adults. HIV-infected persons not controlled on antiretrovirals are also at risk of disseminated TB disease; their lung disease presentation may be atypical.

2.6