Efficacy of a stable broadly protective subunit vaccine platform against SARS-CoV-2 variants of concern.

The emergence and ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the need for rapid vaccine development platforms that can be updated to counteract emerging variants of currently circulating and future emerging coronaviruses. Here we report the development of a "train model" subunit vaccine platform that contains a SARS-CoV-2 Wuhan S1 protein (the "engine") linked to a series of flexible receptor binding domains (RBDs; the "cars") derived from SARS-CoV-2 variants of concern (VOCs). We demonstrate that these linked subunit vaccines when combined with Sepivac SWE™, a squalene in water emulsion (SWE) adjuvant, are immunogenic in Syrian hamsters and subsequently provide protection from infection with SARS-CoV-2 VOCs Omicron (BA.1), Delta, and Beta. Importantly, the bivalent and trivalent vaccine candidates offered protection against some heterologous SARS-CoV-2 VOCs that were not included in the vaccine design, demonstrating the potential for broad protection against a range of different VOCs. Furthermore, these formulated vaccine candidates were stable at 2-8 °C for up to 13 months post-formulation, highlighting their utility in low-resource settings. Indeed, our vaccine platform will enable the development of safe and broadly protective vaccines against emerging betacoronaviruses that pose a significant health risk for humans and agricultural animals.

ASK1 inhibitors are potential pan-antiviral drugs, which dampen replication of diverse viruses including SARS-CoV2.

Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38- Mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) that are reactive oxygen species (ROS)-induced kinases. Accumulating evidence show that ROS accumulate in virus-infected cells. Here, we investigated the relationship between viruses and ASK1/p38MAPK or ASK1/JNK pathways. Our findings suggest that virus infection activates ASK1 related pathways. In parallel, ASK1 inhibition led to a remarkable reduction in the replication of a broad range of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccinia virus (VV), vesicular stomatitis virus (VSV), Herpes Simplex Virus (HSV), and Human Immunodeficiency virus (HIV) in different human cell lines. Our work demonstrates the potential therapeutic use of Selonsertib, an ASK1 inhibitor, as a pan-antiviral drug in humans. Surprisingly, we observed differential effects of Selonsertib in in vitro and in vivo hamster models, suggesting caution in using rodent models to predict clinical and therapeutic outcomes in humans.