2  Overview of antibody and immunization
In response to pathogens including viruses, human body has evolved its immune system to protect it from invasion. Following the virus invasion, antibodies (Abs) are produced after a series of immune signaling and these Abs are able to recognize a diverse array of antigens (Ag) [2]. More specifically, the paratopes (Ag-binding sites) of Abs bind epitopes on virion-associated Ags. During an Ab response, B-cells which express Ag receptors are clonally expanded [3]. Antibodies structurally are composed of heavy (μ, α, γ, δ, ε) chains that are linked by disulfide bonds with light chains (κ, λ). In the progress of B-cell development, immunoglobulin heavy (IgH) chain gene recombination typically occurs before immunoglobulin light (IgL) chain gene recombination [4].
Neutralizing antibodies (nAbs) can inhibit the viral infection via following the viral replication cycle. Attachment is the first critical step blocked by Abs by interfering with the virion-receptor binding. Moreover, Abs may induce the aggregation of viral particles which cause a reduction of individual penetration. In post-attachment step, Abs on the virion possibly dampen virus endocytosis internalization leading to the lysosomal degradation. The Abs also block fusion of virion when they intercalate between viruses and cell membrane. The next stage of interference is to uncoat or appropriate intracellular localization of core or capsid. Lastly, Abs might bind virion surface then inhibit the metabolic events that blocks the replication of viruses even after internalization [3,5,6].
The approach to nAbs design relies on the identification of antigens; in other words, the epitopes are the central of quests. However, the variable regions of the antigen induce the largest fraction of the antibodies whereas broadly nAbs represent only a minor proportion of the response. The major challenges related to both sides were previously described: viral antigen and the generation of antibodies to these sites. In the detail, the antigen concerns are (1) epitope masking or shielding by glycans or protein loops; (2) transient exposure during the entry process or via other mechanisms such as viral “breathing;” (3) the size of conserved epitopes is small resulting in the limitation of interaction, (4) epitopes are constrainedly accessible, (5) the mutability of epitopes. Regarding antibody production, (1) the need for extensive somatic mutations and focused evolution; (2) the use of specific germline allelic variants and HCDR3s of particular length and structure; and (3) the molecular mimicry of host molecules are mentioned [6].