A high burden of TB mortality persists despite the long-term availability of the bacillus Calmette-Guérin (BCG) vaccine, whose efficacy has been highly variable across populations. Innovative and alternative approaches to TB prevention are urgently needed while optimal biomedical tools continue to be developed. We call for new interdisciplinary collaborations to expand and integrate our understanding of how social determinants influence the biological processes that lead to TB disease, how this translates into differential BCG efficacy and, ultimately, how social protection interventions can play a role in reducing the global burden of TB. After providing an overview of the immune pathways important for the establishment of a response to the BCG vaccine, we outline how social determinants and psychosocial stressors can contribute to the observed variation in BCG efficacy above and beyond these biological factors. We conclude by proposing a new interdisciplinary research model based on the integration of social epidemiology theories with biomedical knowledge.