Fig. 4: Comparison of parenteral and intranasal vaccination strategies.

Following parenteral immunization, dendritic cells (DC) rapidly uptake the vaccine’s antigens and migrate to draining lymph nodes. Here, DC prime antigen-specific CD4 + and CD8 + T cells. Contemporary, antigen-specific B cells activate and differentiate in memory B cells and Ig-secreting plasma cells. CD4 + T cells, CD8 + T cells, B cells, and plasma cells egress the lymph node into the bloodstream. CD4 + T cells, CD8 + T cells, and B cells enter the pool of recirculating lymphocytes, while plasma cells will home to bone marrow niches, where they will continue to secrete antigen-specific IgG. In case of a secondary response (SARS-CoV-2 encounter), in addition to the presence of specific IgG, CD4 + and CD8 + T cells will be recruited to the airways. The infection is limited to upper airways, with no involvement of lower airways and no systemic inflammation. In the case of intranasal vaccination, in addition to the response occurring in draining lymph nodes, a mucosal response occurs in the NALT. B cells differentiate in plasma cells secreting IgA, while CD4 + and CD8 + T cells migrating in the airway mucosa develop a tissue-resident phenotype, thus do not recirculate but reside in tissues. In the case of SARS-CoV-2 encounter, specific T cells and IgA are immediately available in the upper airways to fight the virus and are subsequently assisted by IgG and the recruitment of T cells from the bloodstream. Thus, a faster immune response occurs, with rapid elimination of the virus and no infection of upper airways.