COVID-19 therapeutics: Challenges and directions for the future

Abstract

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.

Keywords: epidemiology; immunology; virology.

Fig. 1.

Established therapies and future opportunities for intervention early in disease. Following infection with SARS-CoV-2, there are specific time points in the disease trajectory where different therapies could be optimally administered. At this time, the majority of treatments have been targeted during hospitalization and particularly at late stages of acute disease during ICU admission. Additionally, many of the therapies trialed are antibody therapies and are cost prohibitive, especially in low- to middle-income countries. There is currently a window of missed opportunity early in disease to reduce progression to hospitalization.

Fig. 2.

Major immunologic and coagulatory factors implicated in COVID-19 pathology. Viral infection leads to type I IFN, inflammatory mediator, and alarmin release from the respiratory epithelium/endothelium and resident immune cells setting-up a chemotactic gradient pulling cells from circulation into the lung. An emergency myelopoietic state occurs and neutrophils and monocytes display abnormalities in the blood in this state of high inflammation. Lymphocytes concurrently become depleted in circulation. Activated monocytes and macrophages can be an important source of cytokines, including IL-6. Enhanced by complement, clusters of neutrophils and activated platelets occur and neutrophil NETosis in blood and tissue directly augments thrombosis by supporting platelet activation. Size for each cell indicates its relative abundance in each compartment.