Antibody response to SARS-CoV-2 for more than one year - kinetics and persistence of detection are predominantly determined by avidity progression and test design

Abstract

Background: Antibody detection of SARS-CoV-2 requires an understanding of its variation, course, and duration.

Methods: Antibody response to SARS-CoV-2 was evaluated over 5-430 days on 828 samples across COVID-19 severity levels, for total antibody (TAb), IgG, IgA, IgM, neutralizing antibody (NAb), antibody avidity, and for receptor-binding-domain (RBD), spike (S), or nucleoprotein (N). Specificity was determined on 676 pre-pandemic samples.

Results: Sensitivity at 30-60 days post symptom onset (pso) for TAb-S/RBD, TAb-N, IgG-S, IgG-N, IgA-S, IgM-RBD, and NAb was 96.6%, 99.5%, 89.7%, 94.3%, 80.9%, 76.9% and 92.8%, respectively. Follow-up 430 days pso revealed: TAb-S/RBD increased slightly (100.0%); TAb-N decreased slightly (97.1%); IgG-S and IgA-S decreased moderately (81.4%, 65.7%); NAb remained positive (94.3%), slightly decreasing in activity after 300 days; there was correlation with IgG-S (Rs = 0.88) and IgA-S (Rs = 0.71); IgG-N decreased significantly from day 120 (15.7%); IgM-RBD dropped after 30-60 days (22.9%). High antibody avidity developed against S/RBD steadily with time in 94.3% of patients after 430 days. This correlated with persistent antibody detection depending on antibody-binding efficiency of the test design. Severe COVID-19 correlated with earlier and higher antibody response, mild COVID-19 was heterogeneous with a wide range of antibody reactivities. Specificity of the tests was ≥99%, except for IgA (96%).

Conclusion: Sensitivity of anti-SARS-CoV-2 assays was determined by test design, target antigen, antibody avidity, and COVID-19 severity. Sustained antibody detection was mainly determined by avidity progression for RBD and S. Testing by TAb and for S/RBD provided the highest sensitivity and longest detection duration of 14 months so far.

Keywords: Antibody avidity; COVID-19; Persistence SARS-CoV-2 antibodies; Sensitivity; Specificity; neutralization.

Fig. 1

Spearman rank correlation of COVID-19 severity scores with SARS-CoV-2 antibody response. Footnotes: Spearman rank correlation of COVID-19 severity (x) with (y) IgG-S titer, neutralizing antibodies (NAb), IgA-S titer and antibody avidity (Avi). P value for significance of correlation: for all COVID-19 severity scores 0–8 = large bracket; within severity scores 1–3 small bracket.

Fig. 2

Time course and duration of SARS-CoV-2 antibody detection. A: Mild COVID-19, B: Severe COVID-19. Footnotes: Days post symptom onset (pso) of patient sample (x) plotted against test signal (s/co = sample to cutoff ratio) of the respective tests (y), and (y2) AU/ml in IgG-S for the Liaison test. Group (A) samples of patients with mild COVID-19 and (B) severe COVID-19. Trend lines are polynomial.

Fig. 2

Time course and duration of SARS-CoV-2 antibody detection. A: Mild COVID-19, B: Severe COVID-19. Footnotes: Days post symptom onset (pso) of patient sample (x) plotted against test signal (s/co = sample to cutoff ratio) of the respective tests (y), and (y2) AU/ml in IgG-S for the Liaison test. Group (A) samples of patients with mild COVID-19 and (B) severe COVID-19. Trend lines are polynomial.

Fig. 3

Correlation of neutralizing antibodies vs quantitative IgG-S and vs IgA antibody titers. Footnote: Spearman rank correlation (Rs): neutralizing antibodies (NAb) (x) plotted against quantitative IgG-S titer and IgA titer (y).

Fig. 4

Correlation of avidity vs quantitative IgG-S titers and vs neutralizing antibodies. Footnote: Spearman rank correlation (Rs): Avidity (x) plotted against quantitative IgG-S titer and NAb activity (y).

Fig. 5

Endpoint titers in different SARS-CoV-2 antibody test designs depending on antibody avidity and time. Footnotes: Fig. 5A: Endpoint titers (y) of TAb-RBD vs TAb-N and IgG-S vs IgG-N against avidity (x1) and days after symptom onset (x2) of the neat samples. Shown as polynomial trend line order 2. Fig. 5B: Avidity for RBD and N versus time used in Fig. 5A and Fig. 5B. Fig. 5C: Analogous to (A) endpoint titers for NAb, IgG-S and IgA-S. Data table 1 to Fig. 5.