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.
Highlights
Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses
Since alum promotes neutrophil infiltration through stimulation of IL-1α and interleukin 1β (IL-1β) [15], we investigated whether inhibition of neutrophil elastase could regulate antibody (Ab) responses induced by alum
Groups of mice were immunized by intraperitoneal injection (i.p.) of a combination of antigens either alone, adsorbed to alum as adjuvant (Ag + alum), or Ag + alum supplemented with alvelestat, a highly selective and reversible neutrophil elastase (NEI) (Ag + alum + NEI)
Summary
Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. 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). Our results show that neutrophil elastase limits the breadth of CD4+ T cell response and the production of high-affinity serum IgG antibodies Consistent with this notion, suppression of elastase activity promotes antigen-specific mucosal immunity, including SIgA. We report that suppression of the serine protease elastase reshapes innate responses induced by injected vaccines containing alum adjuvant This reprogramming improves the induction of protective antibodies in the bloodstream and stimulates innate signals, which support the development of antibody responses in mucosal tissues. This strategy could help in the development of future protein-based vaccines against SARS-CoV-2
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