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

Aged patients suffer disproportionately increased morbidity and mortality associated with SARS-CoV-2 infection. Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, the aged patient population has suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterize vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in 18-month-old mice and interrogate protection. Aged mice have 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 of humoral responses in aged mice. pADA co-delivery also altered the gene expression profiles of lymph node lymphocytes in aged animals. Upon challenge pADA co-immunization modestly decreased age-associated morbidity and mortality in ACE2 transgenic and mouse-adapted SARS-CoV-2 challenge models. These data support the use of aged mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 and provide further support of the use of adenosine deaminase as a molecular adjuvant. single cell RNA-seq in young and aged treated and naïve mice