AUTHOR=Gary Ebony N. , Tursi Nicholas J. , Warner Bryce M. , Cuismano Gina , Connors Jennifer , Parzych Elizabeth M. , Griffin Bryan D. , Bell Matthew R. , Ali Ali R. , Frase Drew , Hojecki Casey E. , Canziani Gabriela A. , Chaiken Irwin , Kannan Toshitha , Moffat Estella , Embury-Hyatt Carissa , Wooton Sarah K. , Kossenkov Andrew , Patel Ami , Kobasa Darwyn , Kutzler Michele A. , Haddad Elias K. , Weiner David B. 

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1138609

DOI=10.3389/fimmu.2023.1138609

ISSN=1664-3224

ABSTRACT=<p>Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of T<sub>H</sub>2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased T<sub>H</sub>2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting T<sub>H</sub>1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a T<sub>H</sub>1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.</p>