Mucosal chemokine adjuvant supports heterologous protection against Delta and Omicron VOCs in the context of a SARS-CoV-2 wild-type DNA vaccine

Abstract Emerging variants of concern (VOCs) and waning vaccine-induced immunity challenge SARS-CoV-2 control. Directing vaccine-induced humoral and cell-mediated responses to mucosal surfaces could enhance vaccine efficacy and potentially reduce transmission. We immunized mice with DNA plasmids expressing a wild-type SARS-CoV-2 spike protein (pS) alone, or with the DNA-encoded mucosal chemokine adjuvant cutaneous T cell-attracting chemokine (pCTACK). Mice co-immunized with pS and pCTACK exhibited increased spike specific IFNy T cell responses compared to those receiving the pS alone. While both groups showed similar levels of spike receptor binding domain (RBD)-specific IgG in their serum, in the mucosa, co-immunization with pCTACK enhanced RBD-specific IgA, and cecal extracts from pCTACK co-immunized animals neutralized pseudotyped viruses. When ACE2 transgenic mice were immunized, rested for 3 months, and challenged with a heterologous SARS-CoV-2 Delta variant, co-immunization with pCTACK supported 100% survival while immunization with wild-type pS antigen alone supported 60% survival. Enhanced protection from morbidity was also observed as 100% of pCTACK co-immunized animals did not exhibit infection-induced weight loss. When animals were immunized similarly and challenged with Omicron BA.2, pCTACK co-delivery resulted insignificantly decreased viral loads compared to pS-only immunization. These studies demonstrate that mucosal chemokine adjuvants can direct vaccine-induced responses to specific immunological sites with significant impact on heterologous challenge. These data have significant implications for the design of improved vaccines targeting SARS-CoV-2. This work was supported by NIH NCI award T32 CA09171 (ENG) and NIH NIAID award T32-AI-055400 (EMP) and The Wistar Institute coronavirus discovery fund with additional support from CEPI/Inovio Pharmaceuticals.