Until recently, virtually all the efforts to develop a TB vaccine have been focused on conventional T cell-mediated immunity. However, there is no direct correlation between increased T-cell responses and protection against TB. Thus, it is not surprising that the results from clinical trials of T cell-based vaccine approaches have been disappointing.106,107 These studies collectively challenge the current dogma that conventional T cells are predominantly engaged in host resistance against TB, but rather indicate the critical role of T cells in disease tolerance and containment of infection.108
Contrary to focusing on the adaptive immune response, epidemiological data show that among close household contacts of highly infectious TB patients, up to 50% of exposed individuals do not convert their TST response from negative to positive, suggesting many of these individuals are intrinsically resistant to infection by M. tuberculosis,109,110 These studies support the idea that perhaps the best window of opportunity to eradicate M. tuberculosis is during the early phase of infection, when the bacteria are still in the airway and have not initiated adaptive immunity and granuloma formation. These studies indicate that developing a vaccine targeting innate immunity may prevent TB.111 However, designing such a vaccine will require a better understanding of innate immunity, especially the memory capacity of innate cells. Simple organisms such as plants and invertebrates, which only possess innate immune defenses, have demonstrated immunological memory (ie, the primary exposure to a pathogen resulted in more efficient immunity to a subsequent challenge with the same pathogen).112 Similarly, innate immune cells in vertebrates can generate a memory-like response (termed trained immunity), which is more efficient in preventing subsequent infection by a broad spectrum of pathogens and that is largely driven by epigenetic modifications.113–115 Therefore, identifying the key determinants of trained immunity and their protective function will lead to new targets and vaccine strategies against M. tuberculosis.
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