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. 2021 Oct 28;224(8):1305-1315.
doi: 10.1093/infdis/jiab333.

Detection of Serum Cross-Reactive Antibodies and Memory Response to SARS-CoV-2 in Prepandemic and Post-COVID-19 Convalescent Samples

Khalid Shrwani  1 , Ravi Sharma  2 , Madhan Krishnan  2 , Terry Jones  3 , Martin Mayora-Neto  4 , Diego Cantoni  4 , Nigel J Temperton  4 , Susan L Dobson  1 , Krishanthi Subramaniam  1 , Paul S McNamara  5 , Nigel A Cunliffe  1 , Lance Turtle  1 , Qibo Zhang  1
Affiliations

Detection of Serum Cross-Reactive Antibodies and Memory Response to SARS-CoV-2 in Prepandemic and Post-COVID-19 Convalescent Samples

Khalid Shrwani et al. J Infect Dis. .

Abstract

Background: A notable feature of coronavirus disease 2019 (COVID-19) is that children are less susceptible to severe disease. Children are known to experience more infections with endemic human coronaviruses (HCoVs) compared to adults. Little is known whether HCoV infections lead to cross-reactive anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies.

Methods: We investigated the presence of cross-reactive anti-SARS-CoV-2 IgG antibodies to spike 1 (S1), S1-receptor-binding domain (S1-RBD), and nucleocapsid protein (NP) by enzyme-linked immunosorbent assays, and neutralizing activity by a SARS-CoV-2 pseudotyped virus neutralization assay, in prepandemic sera collected from children (n = 50) and adults (n = 45), and compared with serum samples from convalescent COVID-19 patients (n = 16).

Results: A significant proportion of children (up to 40%) had detectable cross-reactive antibodies to SARS-CoV-2 S1, S1-RBD, and NP antigens, and the anti-S1 and anti-S1-RBD antibody levels correlated with anti-HCoV-HKU1 and anti-HCoV-OC43 S1 antibody titers in prepandemic samples (P < .001). There were marked increases of anti-HCoV-HKU1 and - OC43 S1 (but not anti-NL63 and -229E S1-RBD) antibody titers in serum samples from convalescent COVID-19 patients (P < .001), indicating an activation of cross-reactive immunological memory to β-coronavirus spike.

Conclusions: We demonstrated cross-reactive anti-SARS-CoV-2 antibodies in prepandemic serum samples from children and young adults. Promoting this cross-reactive immunity and memory response derived from common HCoV may be an effective strategy against SARS-COV-2 and future novel coronaviruses.

Keywords: 19; 2; COVID; CoV; HCoV; NL63; SARS; common human coronavirus (HCoV)-HKU1; cross; immunological memory; reactive immunity; serum antibody.

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Figures

Figure 1.
Figure 1.
A, Detection of anti–SARS-CoV-2 spike 1, S1-RBD, and NP antibodies in convalescent sera from COVID-19 patients (n = 16) as compared to age-matched prepandemic healthy control samples (n = 22). ****P < .0001. Horizontal bars represent geometric mean antibody titers in each group. Dashed lines indicate the antibody positivity cutoff for anti-S1, S1-RBD, and NP IgG antibodies. B, Correlations between the antigen-specific anti–SARS-CoV-2 IgG antibodies to S1, S-RBD, and NP antigens in the convalescent samples (Pearson r = 0.85, 0.86, and 0.78, respectively). Abbreviations: COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; NP, nucleocapsid protein; RBD, receptor-binding domain; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Detection of preexisting cross-reactive antibodies to SARS-CoV-2 in prepandemic samples from children (n = 50) and adults (n = 45) undergoing elective adenotonsillectomy due to upper airway obstruction, as compared with convalescent COVID-19 patient samples (n = 16). Horizontal bars represent geometric mean antibody titers of antibody in each group, and dashed lines indicate the antibody positivity cutoff for anti-S1, S-RBD, and NP IgG antibodies. ** P < .01, ***P < .001, ****P < .0001. Abbreviations: COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; NP, nucleocapsid protein; RBD, receptor-binding domain; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 3.
Figure 3.
Association between the cross-reactive anti–SARS-CoV-2 S1 (A), S-RBD (B), and NP (C) antibody titers and age in prepandemic serum samples from children and adults. Dashed lines indicate the antibody positivity cutoff for anti-S1, S-RBD, and NP IgG antibodies. Abbreviations: IgG, immunoglobulin G; NP, nucleocapsid protein; RBD, receptor-binding domain; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 4.
Figure 4.
Correlations (Pearson r) between preexisting cross-reactive anti–SARS-CoV-2 IgG antibodies (to S1, S-RBD, and NP) and anti-HKU1 S-RBD, anti-NL63 S-RBD, anti-OC43 S1, and anti-229E S-RBD antibodies in prepandemic samples from children and adults (n = 110). Antibody titers expressed as original OD values were preferred in this correlation analysis as many samples have undetectable antibody titers (units/mL). Abbreviations: IgG, immunoglobulin G; NP, nucleocapsid protein; OD, optical density; RBD, receptor-binding domain; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 5.
Figure 5.
Correlations between age and anti-HCoV (HKU1 S1-RBD, NL63 S1-RBD, OC43 S1, and 229E S1-RBD) IgG antibody titers in prepandemic samples from children and adults undergoing adeotonsillectomy. The regression lines and P values are shown for children (red) and adults (blue). Abbreviations: HCoV, human coronavirus; IgG, immunoglobulin G; NS, not significant; RBD, receptor-binding domain; S, spike.
Figure 6.
Figure 6.
Enhancement of anti-HKU1 S1-RBD and anti-OC43 S1 antibody levels following COVID-19 suggests cross-reactive antibody memory response. Anti-HCoV (HKU1 S1-RBD, NL63 S1-RBD, OC43 S1, and 229E S1-RBD) antibody titers were compared between post–COVID-19 (n = 16) and prepandemic samples from children (n = 50) and adults (n = 67). Horizontal bars represent geometric mean antibody titer in each group. *P < .05, ***P < .001, ****P < .0001. Abbreviations: COVID-19, coronavirus disease 2019; HCoV, human coronavirus; IgG, immunoglobulin G; NS, not significant; RBD, receptor-binding domain; S, spike.
Figure 7.
Figure 7.
Detection of anti–SARS-CoV-2 neutralizing antibody titers by pseudotyped SARS-COV-2 virus in convalescent COVID-19 and prepandemic samples from children and adults. Dashed horizontal line represents the detection limit of neutralizing activity. Abbreviations: COVID-19, coronavirus disease 2019; IC50, 50% inhibitory concentration; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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