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Review
. 2021 Mar 15;54(5):e10725.
doi: 10.1590/1414-431X202010725. eCollection 2021.

Immunity, virus evolution, and effectiveness of SARS-CoV-2 vaccines

J E Belizário  1
Affiliations
Review

Immunity, virus evolution, and effectiveness of SARS-CoV-2 vaccines

J E Belizário. Braz J Med Biol Res. .

Abstract

Phylogenetic and pathogenesis studies of the severe acute respiratory syndrome-related coronaviruses (SARS-CoVs) strains have highlighted some specific mutations that could confer the RNA genome fitness advantages and immunological resistance for their rapid spread in the human population. The analyses of 30 kb RNA SARS-CoVs genome sequences, protein structures, and functions have provided us a perspective of how host-virus protein-protein complexes act to mediate virus infection. The open reading frame (ORF)1a and ORF1b translation yields 16 non-structural (nsp1-16) and 6 accessory proteins (p6, p7a, p8ab, p9b) with multiple functional domains. Viral proteins recruit over 300 host partners forming hetero-oligomeric complexes enabling the viral RNA synthesis, packing, and virion release. Many cellular host factors and the innate immune cells through pattern-recognition receptors and intracellular RNA sensor molecules act to inhibit virus entry and intracellular replication. However, non-structural ORF proteins hijack them and suppress interferon synthesis and its antiviral effects. Pro-inflammatory chemokines and cytokines storm leads to dysfunctional inflammation, lung injury, and several clinical symptoms in patients. During the global pandemic, COVID-19 patients were identified with non-synonymous substitution of G614D in the spike protein, indicating virus co-evolution in host cells. We review findings that suggest that host RNA editing and DNA repair systems, while carrying on recombination, mutation, and repair of viral RNA intermediates, may facilitate virus evolution. Understanding how the host cell RNA replication process may be driven by SARS-CoV-2 RNA genome fitness will help the testing of vaccines effectiveness to multiple independent mutated coronavirus strains that will emerge.

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Figures

Figure 1
Figure 1. The severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) and its life cycle and host immune response to viral infection. ACE2 is a cellular receptor in the lungs, arteries, heart, kidneys, and the intestine that binds to the viral (S) protein and is cleaved into S1 and S2 subunits by an extracellular protease. S2 is further cleaved and activated by TMPRSS2. The SARS-CoV is a large enveloped, single-stranded, positive-sense RNA virus (∼30 kb) in which 5' two-thirds encodes the two large open reading frames (ORFs) and is transcribed and translated into two polyproteins (pp1a and pp1ab) collectively termed the replicase. The 3' one-third of the SARS-CoV-2 genome encodes four essential structural proteins (S, spike, M, membrane, N, nucleocapsid, and E, envelope) and a set of functional non-structural (Nsp) and accessory proteins (ORFs), which are essential for evading immune response. SARS-CoV-2 is detected by various intercellular sensors, such as RIG I and TLR-3, -7/8, and -9. Viral peptides are presented via MHC I and II to tissue-residing APCs, such as dendritic cells and macrophages, which, in turn, can produce pro-inflammatory cytokines, including interleukin-6, (IL-6), IL-1, IL-17, TNF-α, etc. Cytokines modulate the adaptive immune response by recruiting and activating CD4+ T cells, CD8+ T cells, and B cells that orchestrate the production of antibodies IgM, IgA, IgG, and cytotoxic factors (perforin and granzymes) for killing the virus-infected cells. However, an unbalanced immune response can lead to hyper-inflammation and cytokine storm, causing ARDS and other clinical symptoms of severe COVID-19 patients. Cytoplasmic APOBECs by introducing cytosine to uracil changes and potential mutation of SARS-CoV genomic RNA may be conferring advantage to viral adaptation and transmissibility. ACE2: angiotensin-converting enzyme 2; TMPRSS2: type II transmembrane protease serine; MCP-1: monocyte chemoattractant protein-1; IP-10: IFN-γ-induced protein 10; TNF-α: tumor necrosis factor; MHC: major histocompatibility complex; TCR: T cell receptor; PMN: polymorphonuclear leukocytes; NK: natural killer; APC: antigen-presenting cells; TLR: toll-like receptor; RIG-I: retinoic-acid-inducible protein 1; ARDS: acute respiratory distress syndrome; ds-RNA: double‐stranded RNA; ORF: open reading frame. Partially adapted from Azkur et al. 2020 (40).
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