Persistence of Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 in Relation to Symptoms in a Nationwide Prospective Study

Abstract

Background: Assessing the duration of immunity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a first priority to gauge the degree of protection following infection. Such knowledge is lacking, especially in the general population. Here, we studied changes in immunoglobulin isotype seropositivity and immunoglobulin G (IgG) binding strength of SARS-CoV-2-specific serum antibodies up to 7 months following onset of symptoms in a nationwide sample.

Methods: Participants from a prospective representative serological study in the Netherlands were included based on IgG seroconversion to the spike S1 protein of SARS-CoV-2 (N = 353), with up to 3 consecutive serum samples per seroconverted participant (N = 738). Immunoglobulin M (IgM), immunoglobulin A (IgA), and IgG antibody concentrations to S1, and increase in IgG avidity in relation to time since onset of disease symptoms, were determined.

Results: While SARS-CoV-2-specific IgM and IgA antibodies declined rapidly after the first month after disease onset, specific IgG was still present in 92% (95% confidence interval [CI], 89%-95%) of the participants after 7 months. The estimated 2-fold decrease of IgG antibodies was 158 days (95% CI, 136-189 days). Concentrations were sustained better in persons reporting significant symptoms compared to asymptomatic persons or those with mild upper respiratory complaints only. Similarly, avidity of IgG antibodies for symptomatic persons showed a steeper increase over time compared with persons with mild or no symptoms (P = .022).

Conclusions: SARS-CoV-2-specific IgG antibodies persist and show increasing avidity over time, indicative of underlying immune maturation. These data support development of immune memory against SARS-CoV-2, providing insight into protection of the general unvaccinated part of the population.

Clinical trials registration: NL8473 (the Dutch trial registry).

Keywords: COVID-19; avidity/maturation; decay; immunoglobulin G; symptoms.

Figure 1.

A, Flow diagram of number of participants throughout the study. B, The availability of consecutive samples from the 3 Pienter corona (PICO) rounds relative time since onset of disease to days since onset of symptoms (x-axis). Each line represents a participant, with the dot indicating the days since onset of disease and the lines the availability of consecutive samples.

Figure 2.

A, The proportion of immunoglobulin M (IgM), immunoglobulin A (IgA), and immunoglobulin G (IgG) and 95% confidence intervals (CIs) of positive samples in relation to months since onset of symptoms. The proportion of individuals positive for IgM (B), IgA (C), and IgG (D) with symptoms, or with mild or no symptoms.

Figure 3.

The concentrations of immunoglobulin M (IgM, A), immunoglobulin A (IgA, B), and immunoglobulin G (IgG, C) are shown relative to days since onset of symptoms for individuals having symptoms (colored lines) or those without or only mild symptoms (black lines). D, Development of IgG avidity for persons with or without symptoms. Data were fitted using generalized estimating equations and show 95% CIs around the fit, with an exponential decay over time for IgA and a linear relationship for IgM, IgG, and avidity. The fit was adjusted for age, sex, symptoms, and the duration of symptoms where appropriate (Supplementary Table 3). For IgM, univariable regression analysis did not show an association between symptoms and IgM levels (ie, P > .10; see Methods) but results by group are shown here for consistency. Transparent dots and connected lines represent (repeated) measures per individual.