Anti-SARS-CoV-2 Vaccines and Monoclonal Antibodies Facing Viral Variants

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is genetically variable, allowing it to adapt to various hosts including humans. Indeed, SARS-CoV-2 has accumulated around two mutations per genome each month. The first relevant event in this context was the occurrence of the mutant D614G in the Spike gene. Moreover, several variants have emerged, including the well-characterized 20I/501Y.V1, 20H/501Y.V2, and 20J/501Y.V3 strains, in addition to those that have been detected within clusters, such as 19B/501Y or 20C/655Y in France. Mutants have also emerged in animals, including a variant transmitted to humans, namely, the Mink variant detected in Denmark. The emergence of these variants has affected the transmissibility of the virus (for example, 20I/501Y.V1, which was up to 82% more transmissible than other preexisting variants), its severity, and its ability to escape natural, adaptive, vaccine, and therapeutic immunity. In this respect, we review the literature on variants that have currently emerged, and their effect on vaccines and therapies, and, in particular, monoclonal antibodies (mAbs). The emergence of SARS-CoV-2 variants must be examined to allow effective preventive and curative control strategies to be developed.

Keywords: SARS-CoV-2; antibody; emergence; immunity; mutations; vaccine; variant.

Figure 1

Percentage of three suspected variants of concern (20I/501Y.V1, 20H/501Y.V2, and 20J/501Y.V3) according to screening tests undertaken in France (7 April 2021), and percentage of 19B/501Y, 20C/655Y, and 20A.EU2 according to #5 Flash survey sequencing results (17 March 2021) [34]. (Designed by comersis).

Figure 2

The history of SARS-CoV-2 and its variants subject to vaccine immunity and neutralization by monoclonal antibodies. (1) The localization of immune escape mutations in the SARS-CoV-2 genome. (2) Emerging variant mutations involved in vaccine immunity escape and/or monoclonal antibody neutralization escape. (3) Measures taken to control variants and the potential emergence of others. (Designed by biorender).

Figure 3

The development of viral quasi-species can modulate viral interaction with cell receptors in several tissues (type II pneumocytes, cholangiocytes, cardiomyocytes, tubular and podocyte cells, olfactory and neuronal cells, and enterocyte and parietal cells), particularly ubiquitous CD147 and ACE2R. This is, at least in part, due to the development of certain mutations, which may be associated with some clinical symptoms, and the elevation of certain biochemical markers in patients. Acute cerebrovascular disease (ACD); acute kidney injury (AKI); aspartate transaminase (AST); alanine transaminase (ALT); angiotensin-converting enzyme 2 receptor (ACE2R); differentiation cluster 147 (CD147) [48]. (Designed by biorender).

Figure 4

Tridimensional structure of Spike protein trimer in complex with host cell receptor ACE2. (a) 3D structure of Wuhan Strain Spike protein trimer; (b) 3D structure of Spike protein trimer of 20I/501Y.V1; (c) 3D structure of Spike protein trimer of 20H/501Y.V2; (d) 3D structure of Spike protein trimer of 20J/501Y.V3. S1 (Subunit 1); S2 (Subunit 2) [51].

Figure 5

Mechanism of the immune response during SARS-CoV-2 infection. (a) SARS-CoV-2 penetrates the host cell by endocytosis through the Spike binding to the ACE2R present in alveolar epithelial cells. The active replication of the virus and the release of virions lead to pyroptosis, and, therefore, the release of pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors (PRRs) of neighboring alveolar epithelial cells, alveolar macrophages, and endothelial cells. This leads to the production of pro-inflammatory cytokines/chemokines, which in turn attract other immune cells to the infection site. (b) In the case of a normal immune system, CD4 + LTs recognize antigen-MHCII complexes of antigen-presenting cells (APCs). This induces the differentiation of CD4 + LTs into Th1, which is the producer of INFγ. CD4 + LTs can also differentiate into Th2, the producer of IL-4, which activates the LBs into plasma cells that produce neutralizing antibodies; these antibodies target several virus antigens and promote viral phagocytosis through the opsonization phenomenon. The CD8 + LTs recognize the antigens presented by the infected cells through the interaction of their TCRs with the CMHI of the infected cells, thus leading to cell death by cytotoxicity. (c) In the case of a defective immune system, a high level of pyroptosis induces a cytokine storm; non-neutralizing antibodies are produced, which are responsible for the antibody-dependent enhancement (ADE) phenomenon. In addition, inhibition of the production of INFγ occurs due to the involvement of certain viral proteins responsible for immune escape. This unbalanced immune response leads to multiorgan lesions, acute-respiratory-distress-syndrome (ARDS), and alveolar and vascular lesions [7,57]. (Designed by biorender).