Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern: A Perspective for Emerging More Transmissible and Vaccine-Resistant Strains

Abstract

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) are constantly threatening global public health. With no end date, the pandemic persists with the emergence of novel variants that threaten the effectiveness of diagnostic tests and vaccines. Mutations in the Spike surface protein of the virus are regularly observed in the new variants, potentializing the emergence of novel viruses with different tropism from the current ones, which may change the severity and symptoms of the disease. Growing evidence has shown that mutations are being selected in favor of variants that are more capable of evading the action of neutralizing antibodies. In this context, the most important factor guiding the evolution of SARS-CoV-2 is its interaction with the host's immune system. Thus, as current vaccines cannot block the transmission of the virus, measures complementary to vaccination, such as the use of masks, hand hygiene, and keeping environments ventilated remain essential to delay the emergence of new variants. Importantly, in addition to the involvement of the immune system in the evolution of the virus, we highlight several chemical parameters that influence the molecular interactions between viruses and host cells during invasion and are also critical tools making novel variants more transmissible. In this review, we dissect the impacts of the Spike mutations on biological parameters such as (1) the increase in Spike binding affinity to hACE2; (2) bound time for the receptor to be cleaved by the proteases; (3) how mutations associate with the increase in RBD up-conformation state in the Spike ectodomain; (4) expansion of uncleaved Spike protein in the virion particles; (5) increment in Spike concentration per virion particles; and (6) evasion of the immune system. These factors play key roles in the fast spreading of SARS-CoV-2 variants of concern, including the Omicron.

Keywords: SARS-CoV-2 variants; sensitivity to antisera; transmissibility; viral load.

Figure 1

Structural features of SARS-CoV-2 Spike protein. (a) Genomic organization of SARS-CoV-2 based on the sequence of locus NC_045512.2 in the NCBI. (b) Domains in the Spike sequence. The SARS-CoV-2 Spike protein has two main subunits: S1 and S2, the first is related to the binding to the host cellular receptor, whereas the last allows the fusion of the viral and cellular membranes. During the infection process, the Spike protein is processed by a human serine protease, TMPRSS2, at the S1/S2 and the S2’sites to activate virus entry [10,11,12,13]. The total length of SARS-CoV-2 Spike is ~1273 amino acids and consists of a signal peptide (SP) located at the N-terminus followed by the S1 subunit composed of a N-terminal domain (NTD), a receptor binding domain (RBD) and SD1 and SD2 domains. The S2 subunit is composed of the fusion peptide (FP), the heptapeptide repeat sequences 1 (HR1) and 2 (HR2), a transmembrane domain (TM) and a cytoplasm domain (CT) [5,6]. The percentage of mutations in each domain of the Spike protein in relation to the Alpha, Beta, Gamma, Delta, and Omicron variants is shown. There are more mutations in the S1 (6.8%) than in the S2 domain (2%). Deletions and insertions have been observed in the NTD. Significant mutations have accumulated in the interface of interaction between the RBD Spike protein and ACE2. The S1/S2 protease cleavage site has 25% mutations, whilst no mutation was observed in the S2’ site. (c) Structural representation of the trimeric form of the Spike protein. (d) Monomeric Spike protein structure. (e) Conservation profile of the Spike protein among VOCs (Alpha, Beta, Gamma, Delta and Omicron) was performed using ClustalW server [14] followed by the ConSurf Server [15,16] (Table S1). Surface of absolutely conserved residues are shown in only one subunit of the trimeric form of the Spike protein in dark blue and those less conserved in cyan, blue or green as shown in the bar (PDB ID 7DF4 [17]). ACE2 structure surface is colored in salmon, while the chains A and C in the trimeric form of the Spike protein are colored in grey.

Figure 2

The kinetics of SARS-CoV-2 infection. The SARS-CoV-2 infection involves contact with the virus, viral incubation (days of presymptomatic viral replication), period of viral transmission (viral shedding, shown in the red line in the graphs), which is associated with increased viral loads in the infected person, the symptomatic period, from symptoms onset to recovery and the window for detection of viral RNA by diagnostic tests (viral RNA shedding, gray dashed lines in the graphs).

Figure 3

Number of COVID-19 cases and death rates, the effect of vaccination rate and prevalence of SARS-CoV-2 Delta and Omicron in the UK, Japan, USA and Germany. The (left) side shows the number of cases (red line), the number of deaths (blue line), the rate of vaccinated individuals with the first dose (gray line), second dose (fully vaccinated, brown line) and additional dose (green line). The (right) side shows the graph of the number of cases (blue line) and the percentage of the Delta variant (green line) and Omicron variant (red line) as a function of time. All data were obtained from World in Data, WHO, CDC, UK Gov and Outbreak [1,148,149,150,151].

Figure 4

Hypothesis to explain the emergence of novel SARS-CoV-2 variants. Currently, the world population is composed of three groups: those who do not have neutralizing antibodies to fight infection by the virus (susceptible) and those who acquired it either because they were infected by the virus or because they had taken the vaccine. In scenario 1, in which society does not make any kind of restriction to prevent the spread of the virus, the emergence of VOC should occur faster than in scenario 2, in which society maintains measures to reduce the virus spread. These two scenarios are independent of population immunization, since the virus mutates its genetic information randomly, and selection for variants with more successful infection should prevail in the population. This natural selection seems to be directed towards variants that are able to evade the immune system and spread the virus faster. The SARS-CoV-2 neutralizing antibodies of completely immunized and previously infected individuals kept high until 6 months after immunization or virus infection [152].