ADCC Protection

"Neutralizing activity was not upregulated in slow responders, despite the fact that prolonged antigen exposure can enhance antibody affinity and neutralization. Neutralization titers in COVID-19 patients with long-term infections have been reported as modest, with approximately 20% of patients lacking neutralizing activity entirely. Therefore, extended antigen persistence in slow responders does not consistently confer elevated neutralizing activity. In contrast, ADCC activity was positively associated with slow SARS-CoV-2 clearance. Similar to findings that prolonged exposure enhances binding affinity and recognition of pan-SARS-CoV-2 variants, ADCC activity may be promoted by somatic hypermutation and affinity maturation. Repeated SARS-CoV-2 vaccination has been shown to increase ADCC activity. Furthermore, prophylactic treatment with the 5SB12 mAb, a high-ADCC antibody identified from a slow responder, reduced viral burden. These findings suggest that upregulated ADCC activity in slow responders results from greater antigen exposure and serves a protective role without delaying viral clearance. Individuals with prolonged viral replication or delayed early cytolytic responses may experience longer antigen exposure, allowing more time to develop higher-affinity antibodies with stronger ADCC activity. However, it remains possible that the association of high ADCC with high viral RNA levels arises from enhanced Fc-mediated lysis, in which cytotoxic clearance releases viral genomic RNA and debris into the airway lumen. This scenario requires further experimental validation. The diversity of NK-cell receptors was previously found to be negatively correlated with the SARS-CoV-2 clearance rate. NK cells can directly lyse virus-infected cells through the release of lytic granules and can also kill infected cells through engagement of virus-specific antibodies. The significance of antibody effector functions, mediated at least in part through NK cells, has also been demonstrated in SARS-CoV-2 infection. Mutations that disrupt antibody effector functions, such as LALA or GRLR mutations in the Fc domain of RBD-binding neutralizing monoclonal antibodies, resulted in weaker protection, loss of therapeutic effects, and failure in viral clearance or mitigation of lung inflammation. Bulk RNA-seq results validated the robust in vivo protection of 5SB12: SARS-CoV-2-infected mice treated with 5SB12 ADCC mAb exhibited a transcriptional profile closely resembling that of uninfected mice. Upregulated genes in infected mice with ADCC mAb pretreatment suggested that ADCC-inducing antibodies facilitate viral clearance. Trim13 may halt or inhibit viral transcription, while Zfp36 destabilizes mRNA involved in viral replication and may suppress viral activities. Foxp1 may play a role in monocyte differentiation and repair of damaged epithelial tissue in the lung, and Dysf may induce monocyte activation and monocyte interaction with damaged alveolar endothelial cells during SARS-CoV-2 infection. Taken together, these results suggest that the ADCC mAb may induce a tissue-repair mechanism after suppressing viral activities, leading to quick recovery."