The Duration, Dynamics, and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Responses in Individual Healthcare Workers

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary.

Methods: We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning.

Results: Anti-spike IgG levels remained stably detected after a positive result, for example, in 94% (95% credibility interval [CrI] 91-96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% CrI 19-31) days post first polymerase chain reaction (PCR)-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titer, the mean estimated antibody half-life was 85 (95% CrI 81-90) days. Higher maximum observed anti-nucleocapsid titers were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity, and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives.

Conclusions: SARS-CoV-2 anti-nucleocapsid antibodies wane within months and fall faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.

Keywords: COVID-19; SARS-CoV-2; antibody; longitudinal; serology.

Figure 1.

SARS-CoV-2 antibody trajectory cohorts. Abbreviations: IgG, immunoglobulin G; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

SARS-CoV-2 anti-nucleocapsid (A–D) and anti-spike (E–H) IgG antibody trajectories. Panels A and B show anti-nucleocapsid trajectories for HCWs with a positive result (≥1.40 arbitrary units) at some time. A, Those whose first measurement was positive (n = 466, only data from 100 randomly sampled individuals is shown to assist visualization). B, Remainder (n = 56) in whom seroconversion was observed. C, Those with a maximum titer that was equivocal (0.50–1.39, n = 90). D, Results from HCWs with a maximum titer that was negative (<0.50, n = 2605, 100 randomly sampled individuals are shown). Dashed and dotted lines indicate the thresholds for a positive and equivocal result; note the different y-axis scales in panels A and B vs panels C and D. Similarly, panels E–H show anti-spike trajectories in million net normalized units for individuals who start positive (≥8 million units, n = 457), seroconvert (n = 103), have a maximum equivocal result (4.0–7.9 million units, n = 209, 100 shown), and only negative results (<4 million units, n = 2354, 100 shown). Anti-spike assay values above the upper limited of quantification, ie, >9 million, are plotted as 9 million. Abbreviations: HCW, healthcare worker; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

SARS-CoV-2 anti-nucleocapsid IgG antibody trajectories in 452 SARS-CoV-2 seropositive HCWs. A, Overall mean trajectory of anti-nucleocapsid IgG antibody levels from the maximum observed level (ie, model fixed effect). Posterior mean and 95% CrI are shown as a solid line and shaded area. Dashed line represents the diagnostic threshold of 1.40 arbitrary units. B, Estimated anti-nucleocapsid IgG half-life with 95% CrI by days for all participants, ranked by its value. Solid horizontal line indicates the overall mean. CrIs exceeding 500 days are truncated at 500 days. C, Estimated maximum anti-nucleocapsid IgG antibody level with 95% CrI for all participants, ranked by its value. Solid horizontal line indicates the overall mean. D, Comparison of maximum observed anti-nucleocapsid IgG antibody level and the estimated anti-nucleocapsid IgG half-life per individual. Abbreviations: CrI, credibility interval; HCW, healthcare worker; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 4.

Comparison of SARS-CoV-2 anti-nucleocapsid IgG antibody levels following a positive PCR test and the maximum IgG level per individual in those with a positive PCR test. A, Those with a positive PCR undertaken for symptoms; B, those with a positive PCR for asymptomatic screening. The x-axis value for the model starting from the maximum IgG level is aligned to the maximum point from the model starting with a positive PCR test. Model starting from a positive PCR is fitted with a 5-knot spline (3 interior knots at t = 10, t = 30, and t = 50, locations chosen based on model fit). Abbreviations: IgG, immunoglobulin G; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 5.

Proportion of HCWs remaining anti-nucleocapsid IgG (A–B) and anti-spike IgG (C–D) antibody positive by days following their maximum antibody level. Panels A and C show the observed proportion in 30-day intervals with binomial 95% confidence intervals. Number of individuals tested and the number of individuals remaining antibody positive is shown at the base of each bar. Panels B and D show the results of Bayesian interval censored survival analyses, the posterior mean and 95% credibility interval are shown. Abbreviations: HCW, healthcare worker; IgG, immunoglobulin G; PCR, polymerase chain reaction.