Adenoviral Vector Reuse in Respiratory Mucosal Vaccination: Immune Barriers, Transduction, and Memory Recall

Respiratory mucosal vaccination with adenoviral vectors can induce secretory IgA and tissue-resident memory B and T cells, yet immune responses to the vector may compromise subsequent administrations. Antibodies recognizing adenoviral capsid proteins can interfere with receptor engagement and cellular entry, whereas cytosolic TRIM21 promotes the proteasomal degradation of antibody-coated virions. Cross-reactive adenovirus-specific T cells can accelerate the clearance of transduced cells, while innate DNA sensing through cGAS and STING influences antigen presentation and antiviral restriction. The consequences of these mechanisms vary across respiratory compartments according to epithelial receptor accessibility, vector deposition, and the distribution of local immune effectors. This Review examines how these factors determine the mucosal transduction reserve, defined as the residual capacity for productive antigen delivery and expression after previous vector exposure. Effective homologous boosting depends on whether the remaining antigen expression is sufficient to reactivate local immunological memory, a requirement conceptualized as the antigen recall threshold. The relationship between residual transduction and memory reactivation provides a mechanistic basis for the proposed mucosal reusability window. Preclinical evidence suggests that detectable immunity against adenovirus does not necessarily prevent subsequent boosting. Capsid engineering, targeted respiratory deposition and optimization of dosing intervals may preserve vector function, but their effects on repeated mucosal administration require longitudinal evaluation of local vector immunity, early transgene expression and tissue-resident immune recall.