Antibody avidity maturation favors SARS-CoV-2 convalescents over vaccinated individuals granting breadth in neutralizability and tolerance against variants

BackgroundThe durability and cross-neutralizability of protective antibodies against evolving SARS-CoV-2 variants are primary concerns in mitigating (re-)exposures. The role of antibody maturation, the process whereby selection of higher avidity antibodies augments host immunity, to determine SARS-CoV-2 neutralizability was investigated.MethodsSera collected from SARS-CoV-2 convalescent individuals at 2- or 10-months after recovery, and BNT162b2 vaccine recipients at 3 or 25 weeks post-vaccination, were analyzed. Anti-spike IgG avidity was measured on a urea-treated ELISA platform. Neutralizing ability of antibodies was assessed by surrogate virus neutralization. Fold change between variant and wild-type antigen neutralizability was calculated to infer breadth of neutralizability.ResultsCompared with early-convalescence, the avidity index of late-convalescent sera was significantly higher (median 37.7 (interquartile range 28.4–45.1) vs. 64.9 (57.5–71.5), p < 0.0001), indicative of progressive antibody maturation extending months beyond acute-phase illness. The urea-resistant, high-avidity fraction of IgG was best predictive of neutralizability (Spearman’s r = 0.49 vs. 0.67 for wild-type; 0.18–0.52 vs. 0.48–0.83 for variants). Higher-avidity convalescent sera showed greater cross-neutralizability against SARS-CoV-2 variants (p < 0.001 for Alpha; p < 0.01 for Delta and Omicron). Vaccinees experienced delayed maturation kinetics, translating to limited breadth of neutralizability at week-25 post-vaccination which was only comparable to that of early-convalescence.ConclusionsAvidity maturation grants broader neutralizability that is resilient against emerging SARS-CoV-2 variants. With immunopotentiation through repeat vaccinations becoming a pivotal strategy to accomplish herd immunity, understanding the variable longitudinal evolutions of the two building blocks of ‘hybrid immunity’ is crucial.