## 1 The New Coronavirus: Molecular Proofs
More than one year after the first confirmed case of COVID-19, SARS-CoV-2 infection around the world is maintained by several lineages, such as B.1, B.2, B.3, B.4, and VOCs (i.e., B.1.1.7, B.1.351, P.1, B.1.617.2, and so on) (Table 1). \begin{table}
\begin{tabular}{c c c c c} \hline \hline \multicolumn{1}{c}{WHO _Label_} & _First Identified_ & _Pango Lineage_ & _Spike Protein_ & _ORF1a/b Protein_ \\ \hline \multicolumn{5}{c}{_VOCs (Variants of Concern)_} \\ \hline \multirow{2}{*}{**Alpha**} & United Kingdom & B.1.1.7 & 69 del, 70 del, 144 del, E484K, S494P, N501Y, A570D, & \multirow{2}{*}{None} \\  & D614G, P681H, T716I, S982A, D1118H K1191N & & \\ \hline
**Beta** & South Africa & B.1.351 & K417N, E484K, N501Y & None \\ \hline
**Gamma** & Japan/Brazil & P.1 & K417T, E484K, N501Y & None \\ \hline
**Delta** & India & B.1.617.2 & 19R, G142D, 156 del, 157 del, R158G, L452R, T478K, & \multirow{2}{*}{None} \\  & & D614G, P681R, D950N & \\ \hline
**Epsilon** & California & B.1.427, B.1.429 & S13I, W152C, L452R, Q677H & \multirow{2}{*}{
\begin{tabular}{c} I4205V (ORF1a); \\ D1183Y (ORF1b) \\ \end{tabular} } \\ \hline \multicolumn{5}{c}{_VOIs (Variants of Interest)_} \\ \hline \multirow{2}{*}{**Eta**} & United Kingdom/Nigeria & B.1.525 & E484K, D614G, Q677H & None \\ \hline
**Theta** & The Philippines & P.3 & E484K, N501Y, D614G, P681H & None \\ \hline
**Iota** & \
\begin{tabular}{c} United States \\ (New York) \\ \end{tabular} & B.1.526 &
\begin{tabular}{c} L5F, D80G, T95I, Y144-, F1575, D253G, L452R, S477N, \\ E484K, D614G, A701V, T859N, D950H, Q957R \\ \end{tabular} & \multirow{2}{*}{None} \\ \hline
**Kappa** & India & B.1.617.1 &
\begin{tabular}{c} T95I, G142D, E154K, L452R, E484Q, D614G, \\ P681R, Q1071H \\ \end{tabular} & \multirow{2}{*}{None} \\ \hline
**Lambda** & Peru & C.37 & L452Q, F490S, D614G & None \\ \hline
**Mu** & Colombia & B.1.621 &
\begin{tabular}{c} T95I, Y144S, Y148N, 146N insertion, R346K, E484K, \\ N501Y, D614G, P681H, D950N \\ \end{tabular} & \multirow{2}{*}{None} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: SARS-CoV-2 variants and related substitutions. VOCs harbor substitutions at the receptor-binding site (RBD) of the S protein that impact on viral fitness, transmissibility, and immunity [12]. According to the latest European Centre for Disease Prevention and Control (ECDC) report released on 3 June 2021, VOCs are all more transmissible than the wild-type strain. The emergence of novel variants and their spread into new countries must be constantly monitored. The B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma) variants possess substitutions, such as N501Y, E484K, and K417N/T capable of increasing transmissibility, pathogenicity, and ability to escape immunity [13]. B.1.617.1 (kappa) and B.1.617.2 (delta), first detected in India, carry the main substitutions, L452R, E484Q, D614G, and P681R [14] (Table 1). In particular, P681R, which facilitates spike protein cleavage and enhances viral fusogenicity, was reported as responsible for increased spread and pathogenicity [15]. However, the B.1.617.1 (kappa) variant is less efficient at infecting host cells [16]. Adaptive evolution of SARS-CoV-2 suggests that specific patterns of changes in the RBD domain, N and S proteins confer a selective advantage within a broader epistatic context [17]. In particular, B.1.351 (beta) and B.1.617.2 (delta) variants clearly escape neutralization by convalescent plasma and vaccines are likely to be less effective against them [18]. B.1.1.7 (alpha) and B.1.617.2 (delta) variants previously linked to limited cases or outbreaks have become more widespread due to genomic substitutions influencing cellular binding and viral replication [12]. Currently, according to epidemiological data, B.1.617.2 (delta) is the most prevalent variant worldwide and at least 40% more transmissible than B.1.1.7 (alpha) [9]. Very recently, the B.1.621 (mu) variant was identified for the first time in Colombia, South America. On 30 August 2021, it was classified as a VOI by the WHO.