B-cell and antibody responses to SARS-CoV-2: infection, vaccination, and hybrid immunity

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- and vaccine-induced immune responses in the context of this pathogen. B-cell and antibody responses are at the center of these investigations, as neutralizing antibodies (nAbs) are an important correlate of protection (COP) from infection and the primary target of SARS-CoV-2 vaccine modalities. In addition to absolute levels, nAb longevity, neutralization breadth, immunoglobulin isotype and subtype composition, and presence at mucosal sites have become important topics for scientists and health policy makers. The recent pandemic was and still is a unique setting in which to study de novo and memory B-cell (MBC) and antibody responses in the dynamic interplay of infection- and vaccine-induced immunity. It also provided an opportunity to explore new vaccine platforms, such as mRNA or adenoviral vector vaccines, in unprecedented cohort sizes. Combined with the technological advances of recent years, this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected findings. In this review, we summarize the key findings of the last 2.5 years regarding infection- and vaccine-induced B-cell immunity, which we believe are of significant value not only in the context of SARS-CoV-2 but also for future vaccination approaches in endemic and pandemic settings.

Keywords: IgG4; SARS-CoV-2; memory responses; neutralizing antibodies; vaccines.

Fig. 1. Mucosal antibody responses following infection or vaccination.

Systemic SARS-CoV-2 vaccination results in mucosal antibody responses dominated by IgG, whereas IgM and secretory dimeric IgA (sIgA) responses are low and very transient (left). After breakthrough infection, vaccinees display elevated IgG levels and a robust induction of sIgA in the respiratory mucosa (center). SARS-CoV-2 convalescent patients display moderate levels of IgG, IgM, and sIgA responses, and vaccination reinvigorates levels of sIgA and IgG in the respiratory tract (right). Antibody kinetics and relative levels are simplified for ease of interpretation. Created with BioRender.com

Fig. 2. Distinct features of germinal center (GC) reactions after infection or vaccination.

Mild COVID-19 leads to extrafollicular (EF) and GC responses (left), whereas severe cases result in defective GC reactions and a shift toward pronounced EF responses (center). In contrast, mRNA vaccines elicit only minimal EF responses but persistent and pronounced GC reactions. Continuous B-cell maturation may cause consecutive class-switch recombination (CSR), which may explain the increased IgG4 levels after repeated mRNA vaccinations. Created with BioRender.com

Fig. 3. Systemic IgG subtype kinetics following vaccination.

S-specific humoral responses induced by the basic immunization cycle with mRNA vaccines are dominated by IgG1 and IgG3, which possess proinflammatory Fc functionalities. Late after the second vaccination, and especially after the booster dose, IgG1 is still dominant, but the fraction of noninflammatory IgG3 and IgG4 is substantially increased. Antibody kinetics and relative levels are simplified for ease of interpretation. Created with BioRender.com