Combined anti-S1 and anti-S2 antibodies from hybrid immunity elicit potent cross-variant ADCC against SARS-CoV-2

Abstract

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.

SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis

“…Taken together, these results support the established ( 20 , 43 , 44 ) idea that pre-exposure to SARS-CoV-2 Ags, whether by natural infection or heterologous vaccination (e.g., Janssen or AstraZeneca), confers a more rapid and robust response to the mRNA primary vaccine series with the following adaptive immunological features: 1) increased circulating anti-RBD Abs ( Fig. 1A, 1D ); 2) increased frequency of anti-RBD IgG-producing B cells ( Fig.…”

“…To assess the dynamic range of humoral response to vaccination, we also compared matched subject anti-RBD responses across time ranges and found that pre-exposed subjects demonstrated a significantly higher differential response over the prevaccination to the 4- to 11-wk interval ( Fig. 1B , gMFI: unexposed 5.11e4, pre-exposed 10.1e4, p = 0.033), consistent with the observation that pre-exposure confers the capacity to mount a more dynamic increase in anti-RBD IgG upon subsequent vaccination ( 20 , 43 , 44 ). Supporting the specificity of our Ab response measurement platform, Ab levels to related endemic coronavirus variants (OC43 and HKU) did not change in response to SARS-CoV-2 vaccination ( Supplemental Fig.…”

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

“…In addition, the antibody-mediated Fc effector functions such as antibody dependent cellular cytotoxicity (ADCC) are important components of immunological protection. 87 , 88 , 89 Unfortunately, ADCC activity was not detected withe the current IgG-scFv bispecific antibodies Bis-Beb ( Figure S7 ). Furthermore, there are concerns regarding in vivo efficacy of the IgG-scFv formatted bispecific antibody.…”

Characteristics of Vaccine- and Infection-Induced Systemic IgA Anti-SARS-CoV-2 Spike Responses

“…Working plasma dilutions for assessing IgG and IgA antibody levels were 1:100 and 1:50, respectively, and conjugate dilutions were 1:50,000 for anti-IgG*HRP and 1:25,000 for anti-IgA*HRP. Variability and reproducibility of this assay format have been described [ 12 , 15 , 17 ]. All between-group comparisons shown were run in the same assay.…”

“…While it is mucosal IgA that is most likely to contribute protection from respiratory infections, for ease and simplicity, vaccine-induced Ab production studies primarily focus on the capacity of circulating IgG to neutralize SARS-CoV-2 variants [ 7 , 8 , 9 , 10 , 11 ]. Vaccine-induced anti-SARS-CoV-2 IgG responses are optimized with sufficient time intervals between doses, yet fall short of responses seen with hybrid immunity [ 12 , 13 , 14 , 15 ]. Furthermore, subjects who experience an infection with SARS-CoV-2 variants following vaccination with ancestral-S-based vaccines continue to display preferential IgG responses against ancestral S. This favouring of an immune response toward previously encountered, closely related versions of an extant antigen is known as original antigenic sin or immune imprinting [ 16 ].…”