Improved Durability to SARS-CoV-2 Vaccine Immunity following Coimmunization with Molecular Adjuvant Adenosine Deaminase-1.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have demonstrated strong immunogenicity and protection against severe disease, concerns about the duration and breadth of these responses remain. In this study, we show that codelivery of plasmid-encoded adenosine deaminase-1 (pADA) with SARS-CoV-2 spike glycoprotein DNA enhances immune memory and durability in vivo. Coimmunized mice displayed increased spike-specific IgG of higher affinity and neutralizing capacity as compared with plasmid-encoded spike-only-immunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptor-binding domain-specific memory B cells, and SARS-CoV-2-specific T follicular helper cells. Increased spike-specific T cell polyfunctionality was also observed. Notably, animals coimmunized with pADA had significantly reduced viral loads compared with their nonadjuvanted counterparts in a SARS-CoV-2 infection model. These data suggest that pADA enhances immune memory and durability and supports further translational studies.

Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals.

Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines.