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. 2021 May 11;12(1):2670.
doi: 10.1038/s41467-021-22958-8.

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

Stefania Dispinseri  1 , Massimiliano Secchi  2   3 , Maria Franca Pirillo  4 , Monica Tolazzi  1 , Martina Borghi  5 , Cristina Brigatti  2 , Maria Laura De Angelis  6 , Marco Baratella  1 , Elena Bazzigaluppi  2 , Giulietta Venturi  5 , Francesca Sironi  1 , Andrea Canitano  4 , Ilaria Marzinotto  2 , Cristina Tresoldi  7 , Fabio Ciceri  8   9 , Lorenzo Piemonti  2   9 , Donatella Negri  5 , Andrea Cara  4 , Vito Lampasona  2 , Gabriella Scarlatti  10
Affiliations

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

Stefania Dispinseri et al. Nat Commun. .

Abstract

Understanding how antibody responses to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches and vaccination for COVID-19. Here we profile the antibody responses of 162 COVID-19 symptomatic patients in the COVID-BioB cohort followed longitudinally for up to eight months from symptom onset to find SARS-CoV-2 neutralization, as well as antibodies either recognizing SARS-CoV-2 spike antigens and nucleoprotein, or specific for S2 antigen of seasonal beta-coronaviruses and hemagglutinin of the H1N1 flu virus. The presence of neutralizing antibodies within the first weeks from symptoms onset correlates with time to a negative swab result (p = 0.002), while the lack of neutralizing capacity correlates with an increased risk of a fatal outcome (p = 0.008). Neutralizing antibody titers progressively drop after 5-8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities, with IgG to spike antigens providing the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporarily boosted, and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Our results thus suggest compromised immune responses to the SARS-CoV-2 spike to be a major trait of COVID-19 patients with critical conditions, and thereby inform on the planning of COVID-19 patient care and therapy prioritization.

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Conflict of interest statement

V.L., M.S., and L.P. have a patent pending that refers to polypeptides, nucleic acids, vectors, and host cells and their use to detect SARS-CoV-2 antibodies with LIPS. All other authors have no competing interests.

Figures

Fig. 1
Fig. 1. Higher incorporation of truncated Spike on LV pseudovirions improves infectivity in ACE2 + cell lines.
a Evaluation of SARS-CoV-2 spike expression in 293T Lenti-X cells transfected with pSpike and pSpike-C3 plasmid by flow cytometry. Data from one representative experiment of three independent experiments are shown. b Western blot (WB) of lysates from concentrated preparations of LV-Luc pseudotyped with wild-type spike (LV-Luc/Spike) or spike truncated (21aa) at the cytoplasmic tail (LV-Luc/Spike-C3). Low dose: 1 × 105 reverse transcriptase (RT) units; High dose: 6 × 105 RT Units. Control vector included LV-Luc pseudotyped with VSV.G envelope (LV-Luc/VSV.G). Data from one representative of three independent experiments are shown. c Infection of human and macaque epithelial cell lines and the control B cell line Raji incubated with decreasing concentrations of LV-Luc pseudotyping the full length (LV-Luc/Spike) or the truncated form (LV-Luc/Spike-C3) of the SARS-CoV-2 spike. Data are expressed as mean luciferase activity (RLU) of duplicates. Nd = not done. Source data are provided as a Source Data file.
Fig. 2
Fig. 2. Kinetics of the anti-Spike antibody response.
Scatterplots of each patient anti-spike neutralizing (a), S1 + S2 IgG (b), RDB IgG (c), S2 (d) IgG antibodies over time from symptoms onset. Antibody levels correspond to the reciprocal of the ID50 for nAbs or to arbitrary units for all other reactivities. Sampling during hospital attendance (ER or ward) or at post-discharge outpatient follow-up visits is shown by the indicated color code. The moving average of data + SE (black curve line + gray band), as obtained by a LOESS curve fitting polynomial regression, is displayed. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Anti-SARS-CoV-2 Spike neutralizing and binding antibody profile.
a Indicated is the percent of 150 COVID-19 patients tested at the in-hospital visit, that had IgG, IgM, and IgA to SARS-CoV-2 antigens detected with LIPS, when sampled during the first or second two weeks from symptoms onset. b, c Sera of COVID-19 patients, collected at the indicated timepoints from symptoms onset, were measured by LV-based-neutralization assay and the LIPS indicated in gray labels above each row/column. In (b) are Ig to RBD and in (c) Ig to S1 + S2. Boxes under the diagonal show each correlation plot of the reciprocal of ID50 and arbitrary units after log1p conversion. Dots correspond to individual measurements, the black line represents the regression line and the gray area is 95%CI. Boxes on the diagonal show as histograms the distribution of values in each assay. Boxes above the diagonal show the corresponding Pearson correlation analysis coefficients. Asterisks correspond to the following p values: ***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05. d Correlation matrix of the indicated variables in weeks 1–2. For each pair, Pearson’s correlation coefficient is shown as number and on a color scale. Statistically non-significant correlations are crossed. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Early development of the nAb response correlates with viral control and survival.
Cox regression survival estimates for 150 patients with COVID-19 sampled for nAb response to SARS-CoV-2 during in-hospital visit. The analysis was adjusted for sex and age and stratified for the time from symptoms onset at serum sampling. In (a) the time to a SARS-CoV-2 negative naso-pharyngeal swab (HR 2.238, 95%CI 1.342–3.734; p = 0.002) and in (b) the survival rate (HR 2.918, 95%CI 1.321–6.449; p = 0.008) was estimated by the presence or absence of a nAb response. Dots represent the Hazard Ratio (HR), filled dots stand for p < 0.05 (two-sided). Wald statistics were used for comparison. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Development and kinetics of the nAb response according to age or co-morbidities.
Raincloud plot of each patient’s nAb response (circles) expressed as the reciprocal of the ID50 titer. Patients are stratified by time from symptoms onset at sampling (vertical panels, weeks) and clinical outcome (recovered or deceased). Patients are further stratified as below or above the median age of the overall study population (<63 years = blue, >63 years = red) or according to the presence of any co-morbidity (present = red, absent = blue). Shown are the probability density estimate (with the half violin plot upscaled to maximum width for better visualization) and box plots displaying median, IQR, and whiskers extending to 1.96 times the IQR. Source data are provided as a Source Data file.
Fig. 6
Fig. 6. NAbs and antibody (IgG) to S2 HCOV-OC43 and HKU1 and SARS-CoV-2.
Sera of COVID-19 patients, collected at the indicated timepoint from symptoms onset, were measured by LV-based-neutralization assay and the LIPS to SARS-CoV-2 and HCoV S2 spike antigen as indicated. a Boxes under the diagonal show each correlation plot of the reciprocal of the ID50 and arbitrary units after log1p transformation. Dots correspond to individual measurements, the black line represents the regression line and the gray area its 95%CI. Boxes on the diagonal show as histograms the distribution of values in each assay. Boxes above the diagonal show the corresponding Pearson correlation analysis coefficients. Asterisks correspond to the following p values: ***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05. b Shown are box plot displaying median of each antibody response as indicated, IQR, and whiskers extending to 1.96 times the IQR, stratified by sampling at the indicated week from symptoms onset and a negative or positive nAb response. c Development and kinetics of nAb responses to SARS-CoV-2 during follow-up of patients with negative or positive nAb score at the in-hospital sampling. Each colored dot corresponds to the reciprocal of the ID50 of a serum of a given infected individual stratified for low, medium or high IgG to HCoV S2 antigens. Shown is the moving average of data + SE (black curve line + gray band) as obtained by a LOESS curve fitting polynomial regression. Source data are provided as a Source Data file.
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