Rational Repurposing of Drugs, Clinical Trial Candidates, and Natural Products for SARS-CoV-2 Therapy

In the last 20 years, the world has been threatened with coronavirus (CoV) pandemic threats from severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 and finally COVID-19 due to SARS-CoV-2 in 2019. These viruses posed serious global pandemic threats, with estimated case fatality rates of 15% for SARS-CoV, 34% for MERS-CoV, and 1-3% for SARS-CoV-2. With the current pandemic still far from over there is an urgent need to find new drug treatments for COVID-19. We can assume that this will not be the last coronavirus to threaten humanity, so we need better tools to identify drugs active against past but also future coronavirus threats. In this Chapter we describe in silico computer modeling and screening approaches that can rapidly identify drugs from existing drug libraries that could be repurposed to treat COVID-19 infections. We also describe how this computational screening pipeline can be expanded in the future to identify drugs with broad spectrum activity against a wide diversity of coronaviruses. A significant concern is that the protection against CoVs provided by single drugs protection may be short-lived because viruses rapidly mutate to develop drug resistance. We know from other viruses such as HIV that drugs hitting multiple targets within the virus provide better protection against the development of resistance. This Chapter describes the current state of development of in silico CoV drug repurposing, the challenges and pitfalls of these approaches, and our predictions of how these methods could be used to develop drugs for future pandemics before they occur. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Covax-19/Spikogen: The first exclusively Australian-developed human vaccine in four decades

Introduction/Aim: The development of safe and effective vaccines is crucial to conquering the COVID-19 pandemic. Recombinant proteins represent the best understood and reliable approach to pandemic vaccine delivery with well-established safety;however, they face challenges in design, structural characterisation, manufacture, potency testing and ensuring adequate immunogenicity. Method(s): Our team used in silico structural modelling to design a vaccine based on a stabilised spike protein extracellular domain (ECD). The insect cell expressed recombinant spike ECD was formulated with Vaxine's proprietary Advax-CpG55.2 adjuvant. Result(s): The vaccine known as Covax-19 or SpikoGen induced high titers of antibody and memory T-cells which translated to protection against SARS-CoV-2 infection in hamsters, ferrets, and aged monkeys. Despite numerous challenges along the journey, clinical trials in Iran during a major wave of delta variant infection confirmed SpikoGen vaccine was 78% effective in reducing risk of severe disease and with no evidence of vaccine-associated thrombosis, myocarditis, or sudden death, receiving marketing approval under emergency use authorisation in Iran on 6 October 2021. This made it the first recombinant spike-protein vaccine in the world to be approved, and the first Australian-developed human vaccine to receive marketing approval in four decades. Since approval millions of doses have been administered and additional trials in Australia and Iran have confirmed its effectiveness as a booster to prevent waning immunity, as well as its safety and effectiveness in children from the age of 5 years. The ongoing Australian and overseas clinical trial program is focussed on gaining better understanding the effect of dosing intervals on vaccine immunogenicity, gathering additional data on use as a booster, and development of new variant formulations. Conclusion(s): Covax-19/Spikogen is safe and effective adjuvanted recombinant protein vaccine.

SARS coronavirus infections of the lower respiratory tract and their prevention

The Severe Acute Respiratory Syndrome (SARS) coronavirus was first identified in 2003 when it caused an epidemic of fatal human pneumonia cases that rapidly spread to multiple countries from an epicenter in Hong Kong. The outbreak was eventually controlled by quarantine measures but not before it had caused many fatalities. The original zoonotic source of the SARS virus that caused the outbreak is still unknown but is suspected to be bats. Attempts were made to develop a prophylactic vaccine but the SARS epidemic was over before any vaccines could be tested for human efficacy. As will be discussed in this chapter, coronavirus vaccines present many challenges including low and rapidly waning immunity and the fact that coronavirus vaccines, particularly when formulated with Th2-biased alum adjuvants, can exacerbate coronavirus infection-associated eosinophilic lung immunopathology. Fortunately, this problem can be avoided by formulation of coronavirus vaccines with Th1-type adjuvants that enhance T cell IFN-γ responses, such as, delta inulin or TLR agonists. Hence, appropriate adjuvant selection is vitally important for the development of safe and effective coronavirus vaccines. This chapter will describe the current state of development of SARS vaccines, the issue of coronavirus-associated eosinophilic lung immunopathology and how adjuvants can be used to reduce the risk of this complication. FAU - Petrovsky, N.