SARS-CoV-2: Targeted managements and vaccine development

Abstract

Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) results in diverse outcomes. The symptoms appear to be more severe in males older than 65 and people with underlying health conditions; approximately one in five individuals could be at risk worldwide. The virus's sequence was rapidly established days after the first cases were reported and identified an RNA virus from the Coronaviridae family closely related to a Betacoronavirus virus found in bats in China. SARS-CoV-2 is the seventh coronavirus known to infect humans, and with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), the only ones to cause severe diseases. Lessons from these two previous outbreaks guided the identification of critical therapeutic targets such as the spike viral proteins promoting the virus's cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor expressed on the surface of multiple types of eukaryotic cells. Although several therapeutic agents are currently evaluated, none seems to provide a clear path for a cure. Also, various types of vaccines are developed in record time to address the urgency of efficient SARS-CoV-2 prevention. Currently, 58 vaccines are evaluated in clinical trials, including 11 in phase III, and 3 of them reported efficacy above 90 %. The results so far from the clinical trials suggest the availability of multiple effective vaccines within months.

Keywords: ACE2; COVID-19; Chemokines; Cytokines; Immunity; Spike protein; Vaccines.

Graphical abstract

Fig. 1

Genome organization, protein function, and structure of SARS-CoV-2. (A) Genome organization and protein function of SARS-CoV-2. ORF1a and 1b at the 5ʹ untranslated region are coding for polyproteins (pp1a/ab) cleaved in several nonstructural proteins (nsps) required for virus replication, followed by structural proteins for spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. At the 3ʹ terminus, accessory genes (3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14) are located. The putative functions of these proteins are mentioned in the tables. (B) Structure of the SARS-CoV-2. The viral structural proteins S, M, E, and N are embedded in the membrane, while N proteins package the RNA. IFN, interferon; nsps, nonstructural proteins; ORF, open reading frame; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, RdRp, RNA-dependent RNA polymerase. Adapted from [3,[170], [171], [172], [173], [174]].

Fig. 2

Infection of the alveolar epithelial type II cells by the SARS-CoV-2. (A) SARS-CoV-2 targets cells expressing angiotensin-converting enzyme 2 (ACE2). (B) The virus is endocytosed. The transmembrane serine protease 2 (TMPRSS2) cleaved the S proteins to allow the viral RNA into the host cell cytoplasm. The replication of the virus triggers pyroptosis and the release of DNA, ATP, IL-1β, and other factors. (C) The factors are recognized by the neighboring cells and resident alveolar macrophages, promoting the secretion of pro-inflammatory cytokines and chemokines, including IL-6, IL-8, TNF-α, IP10, MCP-1, and RANTES. These factors attract monocytes and dendritic cells, amplifying the signal. (D) These signals lure T-cells and more immune cells that, in a defective immune response, trigger a cytokine storm damaging the lungs and affecting other organs. IL, interleukin; IP10, interferon-γ-inducible protein; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein 1α; GCSF, granulocyte colony-stimulating factor; TNF, tumor necrosis factor; RANTES, regulated on activation, normal T-cell expressed and secreted.

Fig. 3

Therapeutics trialed for the treatment of SARS-CoV-2. Repurposed and investigational drugs were assessed in various clinical trials, either as single-drug treatment or combinations. ACE2: angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; nsps, nonstructural proteins; pp1a; polyprotein 1a; pp1ab; polyprotein 1ab; RdRp, RNA-dependent RNA polymerase; IL-6, interleukin-6.

Fig. 4

Number and types of vaccines currently in the preclinical phase and the different clinical trial phases. Data were adapted from the COVID-19 vaccine tracker [133].