Immune protection against coronavirus disease 2019 (COVID-19) relies, along with cellular immunity, on anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. We studied the effect of IgG avidity, the average antibody binding strength, on anti-SARS-CoV-2 neutralizing antibodies (nAbs), often considered the hallmark of effective immunity. Prior studies estimating the significance of avidity for nAb-mediated immunity have been complicated by the fact that not only the quality but also the quantity of antibodies impacts the results. Here we provide means for quantifying the impact of IgG avidity on neutralization, irrespective of antibody titer.MethodsWe introduce for anti-SARS-CoV-2 spike protein (S) and nucleoprotein (N) antibodies, IgG avidity assays shown to be unaffected by the IgG concentration. Hospitalized (n = 14) and nonhospitalized (n = 14) COVID-19 patients and vaccinees (n = 20) of early 2020 were assayed for Wuhan S-IgM, S-IgA, S-IgG, and S-IgG avidity; Wuhan N-IgG and N-IgG avidity; and Wuhan, Beta, and Delta nAbs, to identify the factors contributing to neutralization efficiency.ResultsN-IgG avidity was superior to S-avidity in pinpointing the time of SARS-CoV-2 primary infection. Both Wuhan nAb and Delta nAb correlated, expectedly, with Wuhan S-IgG level (P < .0001 each). Wuhan S-IgG avidity intensified homologous (Wuhan; P = .001) but not significantly heterologous (Delta; P = .053) neutralization. Accordingly, along with postinfection time, the average neutralization efficiency of S-IgG molecules increased while their concentration decreased. Quantitatively, doubling of Wuhan S-IgG avidity, at constant S-IgG quantity, augmented Wuhan neutralization 1.58- to 1.68-fold.ConclusionsComprehensive serological profiles of early SARS-CoV-2 primary infections and immunizations provided a model showing that the antiviral neutralization potency is enhanced by anti-spike IgG avidity. The methodology presented is applicable widely beyond COVID-19.

September 20 – 23, 2025, Saint-Raphaël, France

September 20 – 23, 2025, Saint-Raphaël, France

September 20 – 23, 2025, Saint-Raphaël, France