Antibody and B cell responses to SARS-CoV-2 infection and vaccination

Abstract

Antibodies, and the B cell and plasma cell populations responsible for their production, are key components of the human immune system's response to SARS-CoV-2, which has caused the coronavirus disease 2019 (COVID-19) pandemic. Here, we review findings addressing the nature of antibody responses against SARS-CoV-2 and their role in protecting from infection or modulating COVID-19 disease severity. In just over a year, much has been learned, and replicated in independent studies, about human immune responses to this pathogen, contributing to the development of effective vaccines. Nevertheless, important questions remain about the duration and effectiveness of antibody responses, differences between immunity derived from infection compared to vaccination, the cellular basis for serological findings, and the extent to which viral variants will escape from current immunity.

Figure 1

Overview of the humoral immune response to SARS-CoV-2 SARS-CoV-2 antigen recognition initiates a cascade of immune responses, including the activation of naive B cells. Activated B cells can differentiate rapidly into extrafollicular, short-lived plasma cells (SL PCs) and memory B cells (MBCs) with low rates of somatic hypermutation (SHM) (1), or they can enter germinal centers of secondary lymphoid organs such as lymph nodes, where they undergo rounds of SHM and affinity maturation, resulting in long-lived plasma cells (LL PCs) and MBCs (2). Antibody-secreting plasma cells and MBCs can enter the blood and (potentially) mucosa, where they help to fight viral infection and protect from reinfection. LL PCs also transit to the bone marrow and potentially to other anatomical sites. Schematic created with biorender.com.

Figure 2

Anti-SARS-CoV-2 B cell responses B cell responses to SARS-CoV-2 infection are initiated primarily by the stimulation of naive B cells and potentially some HCoV cross-reactive memory B cells. The time frames for the development of extrafollicular (EF) responses, which produce short-lived antibody-secreting cells (plasmablasts and SL PCs) and memory B cells (MBCs), and germinal center (GC) responses, which provide somatically hypermutated long-lived plasma cells (LL PCs) and class-switched memory B cells, are not well described for human tissues and may take place simultaneously. The duration of these responses, as well as the longevity of memory B cells formed in different microanatomical sites, is still unclear. Signs of impaired GC function have been identified in deceased COVID-19 patients. PSO, post symptom onset. Schematic created with biorender.com.

Figure 3

Anti-SARS-CoV-2 antibody responses SARS-CoV-2 infection elicits robust antibody responses to the S protein. (A and B) Patients with severe COVID-19 develop significantly higher anti-S IgM, IgG, and IgA titers than do patients with mild manifestations. (C) Individuals vaccinated with two doses of S protein-encoding mRNA vaccines develop IgG antibody titers comparable to those of severely ill patients, but lower concentrations of IgM and IgA. ^∗Anti-RBD antibody responses show similar patterns but are in general lower than those against S and decline more rapidly. Schematic created with biorender.com.

Figure 4

S variant emergence and impact on antibody recognition (A) The S protein consists of two subdomains: S1 (shaded blue, contains the NTD and RBD) and S2 (shaded gray). (B) S protein structure (PDB: 6ZGG; Wrobel et al., 2020), showing the RBD (dark red) and NTD (salmon) domains. (C) S protein structure (PDB: 6MOJ; Lan et al., 2020) showing key surface residues in RBD (sphere representation, dark red) that have been reported in variants of concern. Amino acid residues highlighted with a colored box decreased neutralization by polyclonal sera from COVID-19 convalescent patients (Greaney et al., 2021). (D) S protein structure (PDB: 6ZGG) showing key surface residues in NTD (sphere representation, salmon) reported in variants of concern. Amino acid residues highlighted with a colored box are part of the NTD “supersite,” a region that is involved in binding by at least eight reported neutralizing antibodies (Cerutti et al., 2021). (E) Table of amino acid changes reported in currently circulating viral variants of concern (source: CDC, WHO). ^∗Detected in some sequences but not all. The protein and domain structures were visualized with PyMOL.