ABSTRACT
Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity.
Subject(s)
Adjuvants, Immunologic/pharmacology , Alum Compounds/pharmacology , COVID-19/immunology , COVID-19/therapy , Enzyme Inhibitors/pharmacology , Leukocyte Elastase/antagonists & inhibitors , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/drug effects , COVID-19/metabolism , HEK293 Cells , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , Immunity, Mucosal/drug effects , Immunity, Mucosal/immunology , Immunoglobulin A/immunology , Leukocyte Elastase/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Swine , Th1 Cells/immunology , COVID-19 Drug TreatmentABSTRACT
WHAT IS KNOWN AND OBJECTIVE: This article summarizes the effects of sivelestat on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or ARDS with coagulopathy, both of which are frequently seen in patients with COVID-19. COMMENT: COVID-19 patients are more susceptible to thromboembolic events, including disseminated intravascular coagulation (DIC). Various studies have emphasized the role of neutrophil elastase (NE) in the development of DIC in patients with ARDS and sepsis. It has been shown that NE inhibition by sivelestat mitigates ALI through amelioration of injuries in alveolar epithelium and vascular endothelium, as well as reversing the neutrophil-mediated increased vascular permeability. WHAT IS NEW AND CONCLUSIONS: Sivelestat, a selective NE inhibitor, has not been evaluated for its possible therapeutic effects against SARS-CoV-2 infection. Based on its promising beneficial effects in underlying complications of COVID-19, sivelestat could be considered as a promising modality for better management of COVID-19-induced ALI/ARDS or coagulopathy.