Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) responses to viral infection are a form of antibody regulated immune responses mediated through the Fc fragment. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered ADCC responses contributes to COVID-19 disease development is currently not well understood. To understand the potential correlation between ADCC responses and COVID-19 disease development, we analyzed the ADCC activity and neutralizing antibody response in 255 individuals ranging from asymptomatic to fatal infections over 1 year post disease. ADCC was elicited by 10 days post-infection, peaked by 11-20 days, and remained detectable until 400 days post-infection. In general, patients with severe disease had higher ADCC activities. Notably, patients who had severe disease and recovered had higher ADCC activities than patients who had severe disease and deceased. Importantly, ADCC activities were mediated by a diversity of epitopes in SARS-COV-2-infected mice and induced to comparable levels against SARS-CoV-2 variants of concern (VOCs) (B.1.1.7, B.1.351, and P.1) as that against the D614G mutant in human patients and vaccinated mice. Our study indicates anti-SARS-CoV-2 ADCC as a major trait of COVID-19 patients with various conditions, which can be applied to estimate the extra-neutralization level against COVID-19, especially lethal COVID-19.

Fig. 1

Antibody-dependent cellular cytotoxicity (ADCC) in COVID-19 patients over time. a Total patients (n = 255). b Patients stratified by age groups (97 patients were <40 years old; 74 patients were 40–60 years old; 84 patients were ≥60 years old). c Patients stratified by sex (164 males and 91 females). d Patients stratified by clinical phenotype (21 asymptomatic, 58 mild, 94 moderate, and 82 severe). e Patients stratified by clinical outcomes (30 survived and 19 fatal). Dots represent values for individual detection, and lines and error bars indicate the median and interquartile range, respectively. In a, c, e, Mann–Whitney U test was performed. In b, d, the multiple comparisons among the groups were made using Kruskal–Wallis test followed by Bonferroni post hoc correction; *P < 0.05, **P < 0.01, ****P < 0.0001. COVID-19 coronavirus disease 2019

Fig. 2

Neutralization antibodies in COVID-19 patients over time. a Total patients (n = 255). b Patients stratified by age groups (97 patients were <40 years old; 74 patients were 40–60 years old; 84 patients were ≥60 years old). c Patients stratified by sex (164 males and 91 females). d Patients stratified by clinical phenotype (21 asymptomatic, 58 mild, 94 moderate, and 82 severe). e Patients stratified by clinical outcomes (30 survived and 19 fatal). Dots represent values (log₁₀-transformed) for individual detection, and lines and error bars indicate the median and interquartile range, respectively. In a, c, e, Mann–Whitney U test was performed. In b, d, the multiple comparisons among the groups were made using Kruskal–Wallis test followed by Bonferroni post hoc correction; *P < 0.05, ***P < 0.001, ****P < 0.0001. COVID-19 coronavirus disease 2019

Fig. 3

Antibody and ADCC activities mediated by different domains of SARS-COV-2 spike (S) protein in mice. The SARS-COV-2 N-terminal domain (NTD), receptor-binding domain (RBD), and S2 subunit were analyzed. a ADCC fold induction in the three domains. b Neutralization ED50 (log10-transformed) in the three domains. c Binding IgG (log10-transformed) in the three domains. The mean and standard deviation are shown. Comparisons among the three groups were performed by one-way analysis of variance; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. ADCC antibody-dependent cell-mediated cytotoxicity, SARS-COV-2 severe acute respiratory syndrome coronavirus 2

Fig. 4

ADCC activity in human patients and mice infected with SARS-COV-2 variants or inoculated with various vaccines. Four SARS-COV-2 strains, which included D614G, B.1.1.7, B.1.351, and P.1, were used. Four vaccines, which included inactivated vaccine, recombination protein vaccine, mRNA vaccine, and adenovirus vector vaccine, were used. a ADCC activity in patients against D614G, B.1.1.7, B.1.351, and P.1. b ADCC activity in BALB/c mice infected with SARS-COV-2 pseudoviruses D614G, B.1.1.7, B.1.351, and P.1. c ADCC activity in the BALB/c mice inoculated with inactivated vaccine. d ADCC activity in BALB/c mice inoculated with the mRNA vaccine. e ADCC activity in BALB/c mice inoculated with the recombination protein vaccine. f ADCC fold induction in BALB/c mice inoculated with the adenovirus vector vaccine. g ADCC fold induction in BALB/c mice immunized with the SARS-COV-2 RBD proteins. h ADCC fold induction in the BALB/c mice immunized with SARS-COV-2 S2 protein. The mean and standard deviation are shown. Comparisons among the three groups were performed by one-way analysis of variance. ADCC antibody-dependent cell-mediated cytotoxicity, SARS-COV-2 severe acute respiratory syndrome coronavirus 2