Detrimental Effects of Anti-Nucleocapsid Antibodies in SARS-CoV-2 Infection, Reinfection, and the Post-Acute Sequelae of COVID-19.

Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies enhance subsequent viral infections rather than preventing them. Sub-optimal levels of neutralizing antibodies in individuals infected with dengue virus are known to be associated with severe disease upon reinfection with a different dengue virus serotype. For Severe Acute Respiratory Syndrome Coronavirus type-2 infection, three types of ADE have been proposed: (1) Fc receptor-dependent ADE of infection in cells expressing Fc receptors, such as macrophages by anti-spike antibodies, (2) Fc receptor-independent ADE of infection in epithelial cells by anti-spike antibodies, and (3) Fc receptor-dependent ADE of cytokine production in cells expressing Fc receptors, such as macrophages by anti-nucleocapsid antibodies. This review focuses on the Fc receptor-dependent ADE of cytokine production induced by anti-nucleocapsid antibodies, examining its potential role in severe COVID-19 during reinfection and its contribution to the post-acute sequelae of COVID-19, i.e., prolonged symptoms lasting at least three months after the acute phase of the disease. We also discuss the protective effects of recently identified anti-spike antibodies that neutralize Omicron variants.