Naturally Acquired SARS-CoV-2 Immunity Persists for Up to 11 Months Following Infection

Abstract

Background: Characterizing the kinetics of the antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to developing strategies that may mitigate the public health burden of coronavirus disease 2019 (COVID-19). We conducted a prospective, longitudinal analysis of COVID-19 convalescent plasma donors at multiple time points over an 11-month period to determine how circulating antibody levels change over time following natural infection.

Methods: From April 2020 to February 2021, we enrolled 228 donors. At each study visit, subjects either donated plasma or had study samples drawn only. Anti-SARS-CoV-2 donor testing was performed using the VITROS Anti-SARS-CoV-2 Total and IgG assays and an in-house fluorescence reduction neutralization assay.

Results: Anti-SARS-CoV-2 antibodies were identified in 97% of COVID-19 convalescent donors at initial presentation. In follow-up analyses, of 116 donors presenting at repeat time points, 91.4% had detectable IgG levels up to 11 months after symptom recovery, while 63% had detectable neutralizing titers; however, 25% of donors had neutralizing levels that dropped to an undetectable titer over time.

Conclusions: Our data suggest that immunological memory is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients for up to 11 months after recovery. Clinical Trials Registration. NCT04360278.

Keywords: COVID-19; convalescent plasma; immunological memory; neutralizing; serology.

Figure 1.

COVID-19 convalescent plasma donor characteristics. A, Age distribution of COVID-19 convalescent plasma (CCP) donors (blue; n = 228) relative to the US population (red). Dotted lines represent a Gaussian distribution and the coefficient of determination (R²) was calculated for the CCP goodness of fit. B, Sex distribution of CCP donors (blue; n = 228) relative to the US population (red). Binomial test was not significant relative to the US population. C, Blood type distribution of CCP donors (blue; n = 218) relative to the US population (red). Binomial tests performed relative to US population, all comparisons were not significant following Bonferroni correction for multiple comparisons.

Figure 2.

SARS-CoV-2 seroconversion and neutralizing activity at initial donation. A, Percent of CCP donors testing positive or negative for the presence of total Ab, IgG Ab, or neutralizing Ab. B, Correlation of total antibody levels with IgG antibody levels (n = 228). Line represents a linear fit of the data including 95% confidence interval (dotted lines). Pearson correlation coefficient (r) is displayed along with P value. C, Distribution of IgG antibody levels based on FRNA₅₀ neutralizing antibody titers (n = 228). Boxplots indicate median value with 1st and 3rd quartiles, and bars span minimum and maximum values. Individual patient values are indicated by dots. A statistically significant difference between groups was determined via Kruskal-Wallis test (P value < .0001). Post hoc comparisons were calculated using Dunn multiple comparison test, with significant pairwise comparisons indicated on the graph. * P < .05, ** P < .01, *** P < .001, **** P < .0001. Abbreviations: Ab, antibodies; CCP, COVID-19 convalescent plasma; FRNA₅₀, fluorescence reduction neutralization assay at 50% reduction; IgG, immunoglobulin G; Neg, negative; Neu, neutralizing; Pos, positive; S/Co, signal to cutoff ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

Correlation of serology tests and neutralizing activity with clinical characteristics. Total antibody levels, IgG antibody levels, and neutralizing antibody titers (FRNA₅₀) in CCP donors are shown based on (A) clinical disease course (asymptomatic, n = 4; mild, n = 205; moderate, n = 16; severe, n = 3); (B) donor age (19–34 years, n = 55; 35–54 years, n = 89; 55–79 years, n = 84); and (C) donor BMI (<18.5, n = 1; 18.5–24.9, n = 87; 25–29.9, n = 84; ≥30, n = 55; missing data for n = 1 donor). For all graphs, boxplots display the median with 1st and 3rd quartiles, and bars span minimum and maximum values. Individual patient values are indicated by dots. Statistically significant differences between groups were determined via Kruskal-Wallis test (A) for total Ab levels and IgG Ab levels based on disease course (P = <.0001 and .0003, respectively); (B) for IgG Ab levels and neutralizing titers based on age (P value = .0073 and .0191, respectively); and (C) for IgG Ab levels and neutralizing titers based on BMI (P value = .0006 and .0012, respectively). Post hoc comparisons were calculated using Dunn multiple comparison test, with significant pairwise comparisons indicated on graphs. * P < .05, ** P < .01. Abbreviations: Ab, antibody; Asympt, asymptomatic; BMI, body mass index; CCP, COVID-19 convalescent plasma; FRNA₅₀, fluorescence reduction neutralization assay at 50% reduction; IgG, immunoglobulin G; S/Co, signal to cutoff ratio.

Figure 4.

SARS-CoV-2 antibody levels in CCP donors over time. A, Boxplots indicate the interval between consecutive donations and between first and final donation. B, Boxplots display median number of days after symptom resolution at indicated donations. A and B, Boxplots indicate median value with 1st and 3rd quartiles, and bars span minimum and maximum values. Individual patient values indicated by dots. C, IgG antibody outcomes over time for repeat CCP donors are quantified in the pie chart, and individual antibody levels are plotted relative to days after symptom resolution (n = 114; n = 2 asymptomatic donors not plotted). Only first and last CCP donation values are plotted. Samples from the same donor connected by lines. Colors indicate antibody level outcomes over time: increase (green), decrease (red), no change (percent change <1%; purple), and negative (levels consistently below or falling below cutoff threshold S/Co < 1; black). The S/Co threshold of 1 indicated by the dashed line. Values below this threshold are represented by an “x.” D, Neutralizing titer outcomes over time for repeat CCP donors are quantified. Outcome categories are the same as in (C) except no change/level off indicates donors whose titers remained unchanged or leveled off to a detectable titer (≥1:40) for their last 2 or more donations, and negative indicates donors with consistently undetectable activity or whose titers fell to an undetectable level (<1:40). E, Outcomes from (D) stratified based on the titer at first donation. Abbreviations: CCP, COVID-19 convalescent plasma; IgG, immunoglobulin G; S/Co, signal to cutoff ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.