Peripheral co-immunization with CCL27 drives robust mucosal responses to SARS-CoV-2 synDNA antigens and provides heterologous protection against Delta variant challenge

Abstract

Abstract SARS-CoV-2, which causes COVID-19 has caused a global pandemic which has claimed over 5 million lives to date. Emerging variants of concern and waning vaccine-induced immunity continually challenge viral control measures. We previously reported on the immunogenicity of a DNA vaccine encoding the spike glycoprotein of SARS-CoV-2, however directing vaccine-induced humoral and cell-mediated responses to mucosal surfaces such as the respiratory mucosa remains a challenge. We immunized mice with synthetic DNA (synDNA) plasmids expressing the wild-type SARS-CoV-2 spike protein (pS) alone, or with the DNA-encoded molecular adjuvant cutaneous T cell-attracting chemokine (pCTACK) Mice co-immunized with pS and pCTACK had increased spike-specific IFNy T cell responses compared to those receiving pS alone. While groups had 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 only the cecal extract from pCTACK co-immunized animals neutralized pseudotyped viruses. When ACE2 transgenic mice were immunized, rested, and challenged with the heterologous SARS-CoV-2 Delta variant, co-immunization with pCTACK supported 100% survival while immunization with wild-type spike DNA antigens supported 60% survival. Importantly 100% of pCTACK co-immunized animals were protected from infection-induced weight loss. These studies demonstrate that chemokine adjuvants can direct vaccine-induced responses to specific immunological sites and that such responses can have significant impact on heterologous challenge outcomes and support the continued study of molecular chemokine adjuvants in the context of SARS-CoV-2 vaccines. We would like to thank the Animal Facility staff at the Wistar Institute and the Public Health agency of Canada for providing care to the animals used in these studies and for additional financial support. We would also like to thank the flow cytometry core facility at the Wistar Institute. This work was supported by NIH NCI award T32 CA09171 (ENG) and NIH NIAID award T32-AI-055400 (EMP) with additional support from CEPI/Inovio Pharmaceuticals.