Immune-mediated approaches against COVID-19

Abstract

The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The long incubation period of this new virus, which is mostly asymptomatic yet contagious, is a key reason for its rapid spread across the world. Currently, there is no worldwide-approved treatment for COVID-19. Therefore, the clinical and scientific communities have joint efforts to reduce the severe impact of the outbreak. Research on previous emerging infectious diseases have created valuable knowledge that is being exploited for drug repurposing and accelerated vaccine development. Nevertheless, it is important to generate knowledge on SARS-CoV-2 mechanisms of infection and its impact on host immunity, to guide the design of COVID-19 specific therapeutics and vaccines suitable for mass immunization. Nanoscale delivery systems are expected to play a paramount role in the success of these prophylactic and therapeutic approaches. This Review provides an overview of SARS-CoV-2 pathogenesis and examines immune-mediated approaches currently explored for COVID-19 treatments, with an emphasis on nanotechnological tools.

Fig. 1

Schematic representation of SARS-CoV-2 structure. This is an enveloped, positive-sense RNA virus with four main structural proteins, including spike (S) and membrane (M) glycoproteins, as well as envelope (E) and nucleocapsid (N) proteins.

Fig. 2

Summary of COVID-19 trials first posted on ClinicalTrials.gov per month (30 June 2020). The search terms COVID-19, 2019-nCOV, SARS-CoV-2 or 2019 novel coronavirus resulted in 2,351 trials, including 185 with hydroxycholoroquine/chloroquine, 25 with remdesivir, 375 with other repurposed drugs, 48 with vaccines, 217 with immune-modulatory approaches, 118 with convalescent plasma, 202 with diagnostic tests and 41 with dietary supplements.

Fig. 3. SARS-CoV-2 entry and mechanism of infection.

a–d, SARS-CoV-2 is internalized by the cell via (i) membrane fusion or (ii) endocytosis. The SARS-CoV-2 spike binds to the angiotensin-converting enzyme 2 (ACE2) via its receptor-binding domain (RBD) and further releases its RNA (b), which will be translated into viral proteins (c,d). e–h, These proteins will form a replication complex to create additional RNA (e) that will further assemble with the viral proteins into a new virus (f), which will be released (g,h). The transmembrane protease serine 2 (TMPRSS2) is a protease shown to affect virus entry, even though its knockout does not inhibit cell infection by SARS-CoV-2. TMPRSS2, transmembrane protease serine 2; ACE2, angiotensin-converting enzyme 2.

Fig. 4. Potential targets for vaccine development to SARS-CoV-2.

Bioinformatics-assisted prediction of SARS-CoV-2 T cell and B cell epitope candidates given the similarity of the SARS-CoV and SARS-CoV-2 genomic structure. Potential antigen epitope sequences are represented for N protein (PBD: 6VYO) and for S protein (PBD: 6VXX). Potential antigen epitope sequences are not presented for membrane (M) and envelope (E) proteins, as the crystallographic structures of these proteins are not yet available at Protein Data Bank.

Fig. 5. Diverse systems used for vaccine delivery.

Proteins, fragments of proteins and peptides, RNAi or DNA- and mRNA-coding antigens can be stabilized while entrapped in different delivery systems, including lipid and polymeric nanoparticles, or conjugated to lipids or polymers. Viral-vectored vaccines and virus-like particles also constitute an active area of research for vaccine development.

Fig. 6. Schematic representation of key methodologies to characterize the immune response and related anti-SARS-CoV-2 effect induced by vaccine candidates.

These assays include the evaluation of dendritic cell (DC) and T cell function upon immunization by flow cytometry and quantification of levels of antigen-specific binding and neutralizing antibodies at different time-points. These studies are still limited by the mouse models of SARS disease currently available, but different options are emerging as potentially useful for the study of SARS-CoV-2 infection mechanisms and COVID-19 vaccine development. DC, dendritic cell; FACS, fluorescence-activated cell sortin; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulins (Ig); hACE2, human angiotensin-converting enzyme 2; HLA, human leukocyte antigen; PBMC, peripheral blood mononuclear cell.