Trained immunity-based mucosal immunotherapies for preventing respiratory infections: a translational, evidence-graded appraisal of platforms, populations, and the protection–immunopathology balance
Abstract
Conventional respiratory vaccines protect through antigen-specific immunity, leaving broad gaps against antigenically diverse and emerging pathogens and inducing little protection at the airway surface itself. Trained immunity, the durable epigenetic and metabolic reprogramming of innate immune cells and their bone marrow progenitors, offers antigen-agnostic, heterologous protection and can be induced directly at the respiratory mucosa, providing a mechanistic rationale for a new class of prophylactic immunotherapies. Here we appraise this field from a clinical-translational, evidence-graded standpoint, integrating three interdependent axes. We first compare the principal inducer platforms (bacille Calmette-Guérin, β-glucan and other pattern-recognition-receptor ligands, inactivated polybacterial preparations, and viral vectors) together with the intranasal, sublingual, and inhaled routes through which they deposit innate memory, showing that platform and route jointly govern the quality, location, and durability of protection. We then grade the clinical evidence population by population, which forms a gradient rather than a uniform endorsement: strongest for sublingual MV130 in childhood recurrent wheeze, moderate for bacille Calmette-Guérin in older adults and for MV130 in chronic obstructive pulmonary disease, and preliminary but promising in immunocompromised hosts. Throughout, we apply the protection-vs.-immunopathology balance as a critical lens, distinguishing host resistance from disease tolerance and highlighting the biomarkers and patient-selection strategies needed to steer benefit over harm. We conclude that trained immunity-based mucosal immunotherapy is best advanced not as a uniform promise but as a disciplined program aligning standardized interventions, mechanism-matched trial endpoints, and prospective biomarkers, positioning it as a credible complement to antigen-specific respiratory vaccines.