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. 2021 Nov 1;131(21):e150613.
doi: 10.1172/JCI150613.

Seasonal coronavirus-specific B cells with limited SARS-CoV-2 cross-reactivity dominate the IgG response in severe COVID-19

Muriel Aguilar-Bretones  1 , Brenda M Westerhuis  1 , Matthijs P Raadsen  1 , Erwin de Bruin  1 , Felicity D Chandler  1 , Nisreen Ma Okba  1 , Bart L Haagmans  1 , Thomas Langerak  1 , Henrik Endeman  2 , Johannes Pc van den Akker  2 , Diederik Ampj Gommers  2 , Eric Cm van Gorp  1 , Corine H GeurtsvanKessel  1 , Rory D de Vries  1 , Ron Am Fouchier  1 , Barry Hg Rockx  1 , Marion Pg Koopmans  1 , Gijsbert P van Nierop  1
Affiliations

Seasonal coronavirus-specific B cells with limited SARS-CoV-2 cross-reactivity dominate the IgG response in severe COVID-19

Muriel Aguilar-Bretones et al. J Clin Invest. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between preexisting immunity to endemic seasonal coronaviruses and the development of a SARS-CoV-2-specific IgG response. We investigated the kinetics, breadth, magnitude, and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in patients with mild or severe COVID-19 as well as in disease control patients. We assessed antibody reactivity to nucleocapsid and spike antigens and correlated this IgG response to SARS-CoV-2 neutralization. Patients with COVID-19 mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against a seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings indicate a boost of poorly protective CoV-specific antibodies in patients with COVID-19 that correlated with disease severity, revealing "original antigenic sin."

Keywords: Immunoglobulins; Immunology; Imprinting; Virology.

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Figures

Figure 1
Figure 1. Patients with severe COVID-19 generate a strong serum SARS-CoV-2 IgG response and have an increasingly stronger IgG response to other coronaviruses.
Longitudinal serum IgG titers (x axis) for 6 disease control donors (green boxes), 12 patients with mild COVID-19 (blue boxes), and 20 patients with severe COVID-19 (red boxes), grouped by week number after the onset of symptoms (y axis), against a panel of coronavirus nucleocapsid proteins (N, left column), the ecto (SECTO, middle column) and head domains (S1, right column) of S protein, and the SARS-CoV-2 SRBD and HA of the H1N1 (2009) influenza virus (listed along the y axis). A SARS-CoV-2–specific response was mounted in all patients with COVID-19, together with a boost of seasonal human 229E, NL63, HKU1, OC43, and epidemic MERS, SARS, and SARS2 coronavirus antigens. Dotted line shows the assay background. Boxes represent the median, upper, and lower quartiles, and whiskers show the range. P values calculated using a 2-way ANOVA with Tukey’s multiple-comparison test (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001) are shown in black (significant intergroup differences) and red (significant intragroup differences).
Figure 2
Figure 2. Patients with severe COVID-19 exhibit a prominent expansion of SARS-CoV-2 and OC43-SECTO–specific IgG B cells.
Normalized enumeration of in vitro–stimulated peripheral blood–derived IgG B cells from patients with mild COVID-19 (blue boxes) and patients with severe COVID-19 (red boxes) with reactivity to N, SECTO, and S1 coronavirus antigens and SARS-CoV-2 SRBD. Relative OC43-SECTO–, SARS-SECTO SARS2-SECTO/S1–, and SRBD-specific IgG B cell clones showed a highly significant outgrowth in the first 4 weeks after SARS-CoV-2 infection in patients with severe COVID-19. In patients with mild COVID-19, a highly significant increase was only seen for 229E-S1–specific IgG clones 3 weeks after the onset of symptoms. Boxes represent the median, upper, and lower quartiles, and whiskers show the range. P values calculated using a 2-way ANOVA with Tukey’s multiple-comparison test (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001) are shown in black (intergroup significant differences), blue (significant mild COVID-19 intragroup differences), and red (severe COVID-19 intragroup significant differences).
Figure 3
Figure 3. In vitro–stimulated B cells from a representative disease control, a patient with mild COVID-19, and a patient with severe COVID-19 show different patterns of clonal IgG cross-reactivity to human coronavirus strains.
B cells were isolated from peripheral blood samples and stimulated in vitro in oligoclonal cultures at limiting dilution to analyze IgG reactivity at the clonal level. The representative patients were analyzed on the indicated day or week after the onset of symptoms. (A) Heatmaps show the MFI of clonal IgG reactivity to N of different human coronaviruses. The number of single- and cross-reactive N-specific B cell clones (x axis) remained stable in the disease control (green) but increased over time after SARS-CoV-2 infection in the patients with mild (blue) or severe (red) COVID-19. (B) Heatmaps show the MFI of clonal IgG reactivity to SECTO, S1, and SRBD antigens from the same representative patients. The disease control showed stable reactivity. By contrast, the patient with severe COVID-19 showed the strongest response to OC43-SECTO, and this response poorly cross-reacted with SARS-CoV-2 antigens.
Figure 4
Figure 4. Combined analysis of reactive IgG clones from patients with mild or severe COVID-19 shows major differences in cross-reactivity patterns.
Pearson’s correlation analysis of (A) N- and (B) S-reactive IgG clones identified in patients with mild COVID-19 (n = 6) in week 1 and week 3 after the onset of symptoms, and in patients with severe COVID-19 in week 1 (n = 3) and week 3 (n = 11) after the onset of symptoms. Heatmaps show the R value of Pearson’s regression (red to blue shades, range –0.2–1) and the significant P value (*P < 0.05, **P < 0.01, and ***P < 0.001) of these correlations.
Figure 5
Figure 5. OC43-SECTO–reactive clones show limited yet antigenically evolving cross-reactivity with SARS-CoV-2.
All OC43-SECTO–reactive clones (n = 920) from 17 patients with severe COVID-19 were stratified by week number after the onset of clinical symptoms. The proportion of single OC43-SECTO (blue) and SARS-CoV-2 cross-reactive clones (gray) is shown (left pie). The cross-reactivity with 1 (green colors), 2 (yellow and orange colors), and 3 SARS-CoV-2 antigens (red) is depicted (right pie). The number of patients analyzed per week is indicated on the left. The frequency and number of contributing clones for each cluster are shown inside and adjacent to each part, respectively.
Figure 6
Figure 6. IgG titers and normalized counts of B cells reactive to SARS-CoV-2 S, but not OC43-SECTO, correlate with serum SARS-CoV-2 virus neutralization titers.
(A) Linear regression between log2-transformed serum IgG and SARS-CoV-2 virus neutralization (PRNT50) titers show that only SARS-CoV and SARS-CoV-2 S–reactive IgG correlated with neutralization titers. Horizontal dotted lines show the background of the PMA. (B) Normalized counts of B cells specific for the SARS-CoV-2 antigens OC43-S1 and SARS-S1 selectively correlated with PRNT50 titers. Serum samples from 20 patients and B cell analysis for 17 patients with severe COVID-19 were included in these analyses. Solid line in A and B depicts the best-fit regression coefficient. Curved lines in A and B show the 95% confidence of the best-fit line.
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