SARS-CoV-2, the causative agent of COVID-19, has imposed a major public health threat, which needs effective therapeutics and vaccination strategies. Several potential candidate vaccines being rapidly developed are in clinical evaluation. Considering the crucial role of SARS-CoV-2 spike (S) glycoprotein in virus attachment, entry, and induction of neutralizing antibodies, S protein is being widely used as a target for vaccine development. Based on advances in techniques for vaccine design, inactivated, live-vectored, nucleic acid, and recombinant COVID-19 vaccines are being developed and tested for their efficacy. Phase3 clinical trials are underway or will soon begin for several of these vaccines. Assuming that clinical efficacy is shown for one or more vaccines, safety is a major aspect to be considered before deploying such vaccines to the public. The current review focuses on the recent advances in recombinant COVID-19 vaccine research and development and associated issues.

Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor-␣ (TNF-␣) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF-␣ and IL-12. Although TNF-␣ production was markedly decreased, IL-12 expression was increased by 2-3-fold in GPI-stimulated MK2 ؊/؊ macrophages compared with wild type (WT) cells. MK2؊/؊ macrophages produced markedly decreased levels of TNF-␣ than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2 ؊/؊ macrophages than WT. This enhanced production is due to increased NF-B binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2 ؊/؊ macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF-␣ and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.

Rationale The cytosolic protease calpain has been recently implicated in the vascular remodeling of angiotensin II (AngII) type-1 receptor (AT1r) signaling. The role of AngII/AT1r/calpain signaling on endothelial function, an important and early determinant of vascular pathology, remains though totally unknown. Accordingly, we investigated the role of calpain in the endothelial dysfunction of AngII. Objective To demonstrate a mechanistic role for calpain in the endothelial dysfunction induced by AngII/AT1r signaling. To establish endothelial-expressed calpains as an important target of AT1r signaling. Methods and Results Subchronic administration of nonpressor doses of AngII to rats and mice significantly increased vascular calpain activity via AT1r signaling. Intravital microscopy studies revealed that activation of vascular expressed calpains causes endothelial dysfunction with increased leukocyte-endothelium interactions and albumin permeability in the microcirculation. Western blot and immunohistochemistry studies confirmed that AngII/AT1r signaling preferentially activates the constitutively expressed μ-calpain isoform and demonstrated a calpain-dependent degradation of IκBα, along with upregulation of NF-κB-regulated endothelial cell adhesion molecules (eCAMs). These physiological and biochemical parameters were nearly normalized following inhibition of AT1r or calpain in vivo. Antisense depletion studies in microvascular endothelial cells along with knockout and transgenic mouse studies further confirmed the role of μ-calpain in the endothelial adhesiveness induced by AngII. Conclusions This study uncovers a novel role for calpain in the endothelial dysfunction of AngII/AT1r signaling and establishes the calpain system as a novel molecular target of the vascular protective action of RAS inhibition. Our results may have significant clinical implications in vascular disease.

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