Targeting dengue through mucosal vaccination: the potential of NS1 and bacterial spore-based delivery platforms

Severe dengue is characterized by marked vascular leakage, hemorrhagic manifestations, and organ impairment, largely driven by immunopathological mechanisms. Traditional vaccine approaches focusing on inducing neutralizing antibodies against DENV structural antigens have shown limitations and, under certain conditions, may also worsen infection through antibody-dependent enhancement (ADE) of infection. More recently, increasing evidence has highlighted the importance of T cell-mediated immunity and anti-non-structural protein 1 (NS1)-specific responses in suppressing DENV replication and reducing disease severity. DENV NS1, however, is known to be associated with severe dengue pathologies. In this context, immunization against NS1 offers a strategic advantage by eliciting immune responses that may contribute to early control of virus replication while simultaneously mitigating NS1-mediated vascular pathology. A vaccine delivery platform that would stimulate protective immune responses yet avoid the potential pathologic effects of NS1, hence, is needed. Bacillus subtilis spores antigen delivery platform stands out as a promising platform for its safety, stability, and inherent adjuvant properties. This review summarizes current advances in NS1-based dengue vaccine development and progress in the Bacillus subtilis spore-based immunization strategy against severe dengue.