Profiling Antibody Response Patterns in COVID-19: Spike S1-Reactive IgA Signature in the Evolution of SARS-CoV-2 Infection

Abstract

This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies.

Keywords: COVID-19; SARS-CoV-2; VOC; clinical outcome; neutralizing antibodies.

Figure 1

SARS-CoV-2 antibody levels (A) and neutralizing antibody titers (IC₅₀) (B) in prepandemic (n = 14), asymptomatic (n = 19), and symptomatic subjects (n = 122). The latter were grouped based on days PSO and color coded according to the severity of the disease: green (mild), yellow (moderate), and red (severe). (C) Spearman’s correlations between IC₅₀ and SARS-CoV-2 antibodies in the symptomatic subjects with onset of symptoms of less or equal to 7 days (n = 23) and between 8 and 30 days (n = 31). (D) IC₅₀ of IgA- and IgG-purified fractions and IgA/IgG-depleted fractions from five randomly selected patients. The dashed lines represent the cutoff of the ELISA tests (10 AU) or the lowest dilution (1:40) of the neutralization assay.

Figure 2

SARS-CoV-2 antibodies (A) and IC₅₀ (B) in symptomatic nonhospitalized (n = 50) and hospitalized subjects (n = 72). Decision tree for the classification of the hospital admission in symptomatic subjects (n = 122) (C).

Figure 3

Spearman’s correlations between IC₅₀ and SARS-CoV-2 antibodies in symptomatic (A) nonhospitalized (n = 50) and (B) hospitalized subjects (n = 72).

Figure 4

Decision tree for the classification of the WHO score in symptomatic subjects (n = 122).

Figure 5

Graphical sketch of CART analyses showing relevant cutoff values of S1-IgA, allowing discrimination of the broad variety of COVID-19 clinical manifestations.

Figure 6

Dynamic of SARS-CoV-2 antibodies in nonhospitalized (n = 35) (A) and hospitalized subjects (n = 37) (B).

Figure 7

Neutralizing antibody titers in convalescent patients (n = 54) against the D614G spike and the spike protein of the variant B.1.1.7 and B.1.351. Friedman test followed by Dunn’s multiple comparison test was applied.