Antibodies capable of neutralizing SARS-CoV-2 are well studied, but
Fc receptor-dependent antibody activities that can also significantly impact the course of
infection have not been studied in such depth. Since most
SARS-CoV-2 vaccines induce only anti-spike
antibodies, here we investigated spike-specific antibody-dependent cellular cytotoxicity (ADCC). Vaccination produced
antibodies that weakly induced ADCC; however,
antibodies from individuals who were infected prior to vaccination (hybrid immunity) elicited strong anti-spike ADCC. Quantitative and qualitative aspects of humoral immunity contributed to this capability, with
infection skewing
IgG antibody production toward S2, vaccination skewing toward S1, and hybrid immunity evoking strong responses against both domains. A combination of
antibodies targeting both spike domains support strong antibody-dependent NK cell activation, with 3 regions of antibody reactivity outside the receptor-binding domain (RBD) corresponding with potent anti-spike ADCC. Consequently, ADCC induced by hybrid immunity with ancestral
antigen was conserved against variants containing neutralization escape mutations in the RBD. Induction of
antibodies recognizing a broad range of spike
epitopes and eliciting strong and durable ADCC may partially explain why hybrid immunity provides superior protection against
infection and disease compared with vaccination alone, and it demonstrates that spike-only
subunit vaccines would benefit from strategies that induce combined anti-S1 and anti-S2 antibody responses.