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

Abstract

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-onlyimmunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptorbinding domainspecific memory B cells, and SARS-CoV-2specific 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.

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

“…ADA1 expression identifies GC T FH cells ( 11 ). We previously reported that co-delivery of pADA enhanced anti-SARS-CoV-2 humoral responses in young mice and supported single-dose protection from challenge at acute and memory timepoints ( 13 ). We confirmed that a single pADA co-immunization robustly increases SARS-CoV-2 serum antibodies ( Supplementary Figures 2A, B ) however, following two immunizations, pS-only and pADA co-immunized young mice had similar quantities of binding antibodies in their sera ( Supplementary Figures 2A, C ).…”

“…Adenosine deaminase-1 (ADA1) deaminates adenosine to produce inosine and is essential for lymphocyte homeostasis ( 17 ). Recently we reported that co-immunization with plasmid-encoded adenosine deaminase (pADA) enhanced cellular responses to pS in young mice ( 13 ). Therefore, we quantified SARS-CoV-2 spike-specific cell-mediated immunity by both IFNγ fluorospot assay and intracellular cytokine staining (ICS) following pADA co-administration in aged mice.…”

“…Pseudoviruses neutralization assays were performed as previously described ( 13 ). For live virus neutralization, isolates were received from BEI resources.…”

“…Furthermore, ADA1 mutation causes severe-combined immunodeficiency in humans, characterized by broad T cell dysfunction. We have reported the ability of plasmid-encoded adenosine deaminase-1 (pADA) to enhance T FH cell function and improve humoral responses to synthetic DNA (synDNA) antigens targeting HIV-1 ( 12 ) and SARS-CoV-2 ( 13 ). We recently reported that in young mice addition of pADA to a single DNA immunization supported increased antibody production and long-lived protection that was equal to two immunizations with unadjuvanted spike DNA vaccine ( 13 ).…”

“…We have reported the ability of plasmid-encoded adenosine deaminase-1 (pADA) to enhance T FH cell function and improve humoral responses to synthetic DNA (synDNA) antigens targeting HIV-1 ( 12 ) and SARS-CoV-2 ( 13 ). We recently reported that in young mice addition of pADA to a single DNA immunization supported increased antibody production and long-lived protection that was equal to two immunizations with unadjuvanted spike DNA vaccine ( 13 ). Additionally, ADA levels have been negatively correlated with age in human patients ( 14 ) and aged cultured human cells ( 15 ).…”