Mucosal vaccines: Immunological basis, challenges and emerging strategies

Mucosal surfaces represent the principal entry points for numerous pathogens responsible for respiratory, gastrointestinal, and sexually transmitted infections. Despite major advances in parenteral vaccine development, protection against pathogens initiating infection at mucosal interfaces remains suboptimal. The global impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic underscored the vulnerability of mucosal tissues and renewed interest in vaccine strategies capable of inducing robust local immunity. Mucosal vaccination aims to generate protective immune responses at sites of pathogen entry, including secretory immunoglobulin A (IgA), tissue-resident memory T (TRM) cells, and specialized antigen-presenting cell activation, thereby limiting colonization, transmission, and disease progression. This review examines the global burden of mucosal infections, the immunological foundations of mucosal immunity, and the biological challenges posed by mucosal tolerance. It further evaluates antigen design considerations, adjuvant strategies, and emerging platforms such as viral vectors and nucleic acid-based vaccines. Particular emphasis is placed on the structural and functional characteristics of mucosal inductive and effector sites, the importance of particulate antigen delivery, and the role of innovative biomaterial and nanocarrier systems. Advancing mucosal vaccine development requires integrated approaches that address immunological, physiological, and translational barriers to achieve durable and protective immunity at mucosal surfaces.