Heterologous Vaccination with SARS-CoV-2 Spike saRNA Prime followed by DNA Dual-Antigen Boost Induces Robust Antibody and T-Cell Immunogenicity against both Wild Type and Delta Spike as well as Nucleocapsid Antigens

Rice, A.; Verma, M.; Voigt, E.; Battisti, P.; Beaver, S.; Reed, S.; Dinkins, K.; Mody, S.; Zakin, L.; Sieling, P.; Tanaka, S.; Morimoto, B.; Higashide, W.; Olson, C. A.; Gabitzsch, E. R.; Safrit, J. T.; Spilman, P. R.; Casper, C.; Soon-Shiong, P.

doi:10.1101/2021.11.29.470440

bioRxiv · 10.1101/2021.11.29.470440

Heterologous Vaccination with SARS-CoV-2 Spike saRNA Prime followed by DNA Dual-Antigen Boost Induces Robust Antibody and T-Cell Immunogenicity against both Wild Type and Delta Spike as well as Nucleocapsid Antigens

Rice, A.·Verma, M.·Voigt, E.·Battisti, P.·Beaver, S.·Reed, S.·Dinkins, K.·Mody, S.·Zakin, L.·Sieling, P.·Tanaka, S.·Morimoto, B.·Higashide, W.·Olson, C. A.·Gabitzsch, E. R.·Safrit, J. T.·Spilman, P. R.·Casper, C.·Soon-Shiong, P.

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Abstract

We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (SASA S) delivered by a nano-lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression. The N antigen is modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the SASA S vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to increase cross-reactivity across variants. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen including the SASA S vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AdS+N boost of an SASA S prime particularly enhanced both CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving SASA S homologous or heterologous vaccination were found to be highly neutralizing of all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strain. The findings here support the clinical testing of heterologous vaccination by an SASA S > AdS+N regimen to provide increased protection against emerging SARS-CoV-2 variants.

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Rice, A., Verma, M., Voigt, E., Battisti, P., Beaver, S., Reed, S., Dinkins, K., Mody, S., Zakin, L., Sieling, P., Tanaka, S., Morimoto, B., Higashide, W., Olson, C. A., Gabitzsch, E. R., Safrit, J. T., Spilman, P. R., Casper, C., Soon-Shiong, P.. 2021-11-30. Heterologous Vaccination with SARS-CoV-2 Spike saRNA Prime followed by DNA Dual-Antigen Boost Induces Robust Antibody and T-Cell Immunogenicity against both Wild Type and Delta Spike as well as Nucleocapsid Antigens. https://doi.org/10.1101/2021.11.29.470440

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