Inhibition of elastase enhances the adjuvanticity of alum and promotes anti–SARS-CoV-2 systemic and mucosal immunity

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.

A novel bacterial protease inhibitor adjuvant in RBD-based COVID-19 vaccine formulations increases neutralizing antibodies, specific germinal center B cells and confers protection against SARS-CoV-2 infection

“…The copyright holder for this preprint this version posted December 9, 2021. ; https://doi.org/10.1101/2021.12.07.471590 doi: bioRxiv preprint antibody function by U-Omp19 addition to formulations could also be due to its protease inhibitor activity. U-Omp19 can inhibit neutrophil elastase 18 and Kim et al have recently shown that coadministration of a neutrophil elastase inhibitor enhances the affinity and function of antibodies induced by alum as adjuvant 55 . In the same work, Kim et al showed that neutrophil elastase inhibitor supplementation can improve the efficacy of alum-adsorbed anti-SARS-CoV-2 vaccines by promoting the induction of IgA in the serum and mucosal secretions 55 .…”

“…U-Omp19 can inhibit neutrophil elastase 18 and Kim et al have recently shown that coadministration of a neutrophil elastase inhibitor enhances the affinity and function of antibodies induced by alum as adjuvant 55 . In the same work, Kim et al showed that neutrophil elastase inhibitor supplementation can improve the efficacy of alum-adsorbed anti-SARS-CoV-2 vaccines by promoting the induction of IgA in the serum and mucosal secretions 55 . Of note, U-Omp19 adjuvanted group presented the highest levels of RBD specific IgA in serum and BAL and the highest neutralizing activity against SARS-CoV-2 Spike-pseudotyped virions in BAL.…”

“…We have previously demonstrated that U-Omp19 increases antigen half-life in antigen presenting cells 19,62 , and thus may increase GC reactions and CD4 + T cell activation. Also, it has been shown that neutrophil elastase inhibitor supplementation to alum formulations increases the frequency of GC B cells and the size of GC 55 , suggesting that enrichment of RBD-specific GC B cells induced by U-Omp19 could be related to its ability to inhibit neutrophil elastase. U-Omp19 ability to increase GC B cell reactions was also demonstrated in the context of a rabies vaccine, in which the addition of U-Omp19 resulted in enhanced immunogenicity through increasing dendritic cells activation and germinal center formation 63 .…”

A Perspective on the Roles of Adjuvants in Developing Highly Potent COVID-19 Vaccines

“…It also has a higher affinity for uptake by DCs, which leads to an efficient delivery of antigens and an enhanced cross presentation. This results in strong humoral and cellular immune responses [19]. PAPE may provide potential insights into a safe and effective COVID-19 vaccine adjuvant platform.…”

“…Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by the pathogen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2019, the first known case was identified in Hubei Province, China [1].…”