Fig. 2: Different vaccination strategies and the resulting immune responses.

Various delivery systems currently used to administer vaccines are shown on the far left. Vaccine delivery routes and devices are depicted in the middle, and the resulting immune pathway after intranasal inoculation is shown on the right. Intranasal delivery of vaccine is achieved by using an inhaler, nebulizer, or spray method. Vaccination via the mucosal route can mount an immune response both in the upper (URT) and lower (LRT) respiratory tract (indicated by green arrows). Microfold cells present on the nasal mucosa actively transport antigens to the dendritic cells (DCs) and macrophages in the subepithelial space. Additionally, DCs situated in the lamina propria or interspersed among epithelial cells sample the mucosal environment using extensions. Activated DCs and macrophages migrate to regional draining lymph nodes or tertiary lymphoid follicles and present antigens to T and B cells. Resulting effector T cells may traffic to the respiratory tract as tissue-resident memory T cells (TRM). Activated B cells either differentiate into low-affinity IgG or IgA-producing plasma cells, which traffic to the respiratory tract, or move to the germinal center, undergo class-switching and somatic hypermutation, and differentiate into long-lived plasma or memory B cells, secreting high-affinity immunoglobulins. These memory B cells may traffic to the respiratory tract. Here, IgA is mainly produced in its polymeric form (pIgA), predominantly dimeric, and transported across the epithelium of the respiratory tract by polymeric Immunoglobulin receptor (pIgR). The pIgR-pIgA complex is cleaved at the apical surface of the epithelium. Thereby, IgA gains part of the pIgR named the secretory component and is released as secretory IgA (sIgA). The secretory component increases the stability of sIgA. Intramuscular immunization can mount robust systemic and LRT immune responses (indicated by red arrows). Circulating IgG antibody levels are generally higher upon vaccination via the intramuscular route in comparison with the intranasal route. NALT Nasal-associated lymphoid tissue. Created with BioRender.com.