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Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.

ABSTRACT: Encouraging protection results from current mRNA-based SARS-CoV-2 vaccine platforms are primarily due to the induction of SARS- CoV-2- specific B cell antibody and CD4 + T cell. Even though, current mRNA vaccine platforms are adept in inducing SARS-CoV2-specific CD8 + T cell, much less is known about CD8 T cells contribution to the overall vaccine protection. Our allogeneic cellular vaccine, based on a secreted form of the heat-shock protein gp96-Ig, achieves high frequencies of polyclonal CD8 + T cell responses to tumor and infectious antigens through antigen cross-priming in vivo. We and others have shown that gp96-Ig, in addition to antigen-specific CD8 + T cell anti-tumor and anti-pathogen immunity, primes antibody responses as well. Here, we generated a cell-based vaccine that expresses SARS-Cov-2 Spike (S) protein and simultaneously secretes gp96-Ig and OX40L-Fc fusion proteins. We show that co-secretion of gp96-Ig-S peptide complexes and the OX40L-Fc costimulatory fusion protein in allogeneic cell lines results in enhanced activation of S protein-specific IgG antibody responses. These findings were further strengthened by the observation that this vaccine platform induces T follicular helper cells (TFH) and protein-S -specific CD8 + T cells. Thus, a cell-based gp96-Ig vaccine/OX40-L fusion protein regimen provides encouraging translational data that this vaccine platform induces pathogen-specific CD8+, CD4 + T and B cell responses, and may cohesively work as a booster for FDA-approved vaccines. Our vaccine platform can be rapidly engineered and customized based on other current and future pathogen sequences.

SUBMITTER: Padula L

PROVIDER: S-EPMC9347141 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.

Padula Laura L Fisher Eva E Rivas Katelyn K Podack Kristin K Frasca Daniela D Kupritz Jonah J Seavey Matthew M MM Jayaraman Padmini P Dixon Eric E Jasuja Rahul R Strbo Natasa N

Vaccine: X 20220803

Encouraging protection results from current mRNA-based SARS-CoV-2 vaccine platforms are primarily due to the induction of SARS- CoV-2- specific B cell antibody and CD4 + T cell. Even though, current mRNA vaccine platforms are adept in inducing SARS-CoV2-specific CD8 + T cell, much less is known about CD8 T cells contribution to the overall vaccine protection. Our allogeneic cellular vaccine, based on a secreted form of the heat-shock protein gp96-Ig, achieves high frequencies of polyclonal CD8 + ...[more]

PMID: 35936992

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Project description:The extracellular form of the abundant heat-shock protein, gp96, is involved in human autoimmune pathologies. In patients with type 1 diabetes, circulating gp96 is found to be elevated, and is bound to the acute-phase protein, α1-antitrypsin (AAT). The two molecules also engage intracellularly during the physiological folding of AAT. AAT therapy promotes pancreatic islet survival in both transplantation and autoimmune diabetes models, and several clinical trials are currently examining AAT therapy for individuals with type 1 diabetes. However, its mechanism of action is yet unknown. Here, we examine whether the protective activity of AAT is related to binding of extracellular gp96. Primary mouse islets, macrophages, and dendritic cells were added recombinant gp96 in the presence of clinical-grade human AAT (hAAT, Glassia™, Kamada Ltd., Israel). Islet function was evaluated by insulin release. The effect of hAAT on IL-1β/IFNγ-induced gp96 cell-surface levels was also evaluated. In vivo, skin transplantation was performed for examination of robust immune responses, and systemic inflammation was induced by cecal puncture. Endogenous gp96 was inhibited by gp96-inhibitory peptide (gp96i, Compugen Ltd., Israel) in an allogeneic islet transplantation model. Our findings indicate that hAAT binds to gp96 and diminishes gp96-induced inflammatory responses; e.g., hAAT-treated gp96-stimulated islets released less pro-inflammatory cytokines (IL-1β by 6.16-fold and TNFα by 2.69-fold) and regained gp96-disrupted insulin release. hAAT reduced cell activation during both skin transplantation and systemic inflammation, as well as lowered inducible surface levels of gp96 on immune cells. Finally, inhibition of gp96 significantly improved immediate islet graft function. These results suggest that hAAT is a regulator of gp96-mediated inflammatory responses, an increasingly appreciated endogenous damage response with relevance to human pathologies that are exacerbated by tissue injury.

Dataset Information

Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.

Publications

Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.

Similar Datasets

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