Importance of adjuvant selection in tuberculosis vaccine development: Exploring basic mechanisms and clinical implications

The global emergency of unexpected pathogens, exemplified by SARS-CoV-2, has emphasized the importance of vaccines in thwarting infection and curtailing the progression of severe disease. The scourge of tuberculosis (TB), emanating from the Mycobacterium tuberculosis (Mtb) complex, has inflicted a more profound toll in terms of mortality and morbidity than any other infectious agents prior to the SARS-CoV-2 pandemic. Despite the existence of Bacillus Calmette-Guérin (BCG), the only licensed vaccine developed a century ago, its efficacy against TB remains unsatisfactory, particularly in preventing pulmonary Mtb infections in adolescents and adults. However, collaborations between academic and industrial entities have led to a renewed impetus in the development of TB vaccines, with numerous candidates, particularly subunit vaccines with specialized adjuvants, exhibiting promising outcomes in recent clinical studies. Adjuvants are crucial in modulating optimal immunological responses, by endowing immune cells with sufficient antigen and immune signals. As exemplified by the COVID-19 vaccine landscape, the interplay between vaccine efficacy and adverse effects is of paramount importance, particularly for the elderly and individuals with underlying ailments such as diabetes and concurrent infections. In this regard, adjuvants hold the key to optimizing vaccine efficacy and safety. This review accentuates the pivotal roles of adjuvants and their underlying mechanisms in the development of TB vaccines. Furthermore, we expound on the prospects for the development of more efficacious adjuvants and their synergistic combinations for individuals in diverse states, such as aging, HIV co-infection, and diabetes, by examining the immunological alterations that arise with aging and comparing them with those observed in younger cohorts.