Adenosine deaminase augments SARS-CoV-2 specific cellular and humoral responses in aged mouse models of immunization and challenge

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Abstract Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity and mortality. Furthermore, the aged patient population has suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mouse models. Aged mice had altered cellular responses, including decreased IFNγ secretion and increased TNFα secretion as compared to young mice. Aged mice had significantly decreased binding and neutralizing antibodies in their serum compared to their young counterparts. Co-immunization with the plasmid-encoded molecular adjuvant adenosine deaminase-1 (pADA) enhanced cellular responses and expanded the breadth and affinity of humoral responses in aged mice. pADA co-delivery also altered the gene expression profiles of lymph node lymphocytes in aged animals. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a strong TH1 gene profile and decreased FoxP3 gene expression. Upon challenge pADA co-immunization decreased viral loads and age-associated morbidity and mortality in mouse-adapted and ACE2 transgenic SARS-CoV-2 challenge models. These data support the use of aged mice as a model for age-associated decreases in vaccine immunogenicity and increased in infection-mediated morbidity and mortality in the context of SARS-CoV-2. These studies provide further support for the use of adenosine deaminase as a molecular adjuvant in the elderly. 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.

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