Non-neutralizing functions in anti-SARS-CoV-2 IgG antibodies

Most individuals infected with or vaccinated against COVID-19 develop antigenic neutralizing immunoglobulin G (IgG) antibodies against the SARS-CoV-2 spike protein. Although neutralizing antibodies are biomarkers of the adaptive immune response, their mere presence is insufficient to explain the protection afforded against the disease or its pathology. IgG exhibits other secondary effector functions that activate innate immune components, including complement, natural killer cells, and macrophages. The affinity for effector cells depends on the isotypes and glycosylation of IgG antibodies. The anti-spike IgG titer should be sufficient to provide significant Fc-mediated effects in severe COVID-19, mRNA, and protein subunit vaccinations. In combination with aberrant effector cells, pro-inflammatory afucosylated IgG1 and IgG3 may be detrimental in severe COVID-19. The antibody response of mRNA vaccines leads to higher fucosylation and a less inflammatory IgG profile, with a long-term shift to IgG4, which is correlated with protection from disease.