Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses

A cell-based vaccine co-secreting gp96-Ig, protein S1 and OX40L-Fc leads to activation of dendritic cells (DC) and cross-presentation of gp96-chaperoned protein S peptides to CD8+ T cells. Co-secretion of OX40L-Fc further augments CD8+T cell activity through OX40/OX40L axis. Secreted protein S1 is endocytosed by activated DC and S1 peptides are presented within the MHC class II molecules to TFH cells that also receive co-stimulatory signals through OX40L-Fc. In addition, B cells recognize secreted protein S1 through BCR and present S1 peptides within the MHC class II molecules to TFH cells. TFH cells through OX40/OX40L axis provide essential signals to promote B cell differentiation into memory B cells and long-lived plasma cells, and secretion of high-affinity specific antibodies. Local modulation of the gp96-Ig vaccine microenvironment by OX40L-Fc has the advantage to enhance immunological protection through providing additional support to CD8+ T cell and immunoglobulin antiviral response in the lungs and simplifying the clinical translation of such combination immunotherapies into humans.