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. 2022 Jul 4;11(13):3870.
doi: 10.3390/jcm11133870.

Preexisting Humoral Immunity Cross-Reacting with SARS-CoV-2 Might Prevent Death Due to COVID-19 in Critical Patients

Taro Yamashita  1 , Tetsuro Shimakami  2 , Kouki Nio  3 , Takeshi Terashima  3 , Masaki Okajima  4 , Takumi Taniguchi  5 , Takashi Wada  6 , Masao Honda  3 , Toshifumi Gabata  7 , Kenji Ota  8 , Katsunori Yanagihara  8 , Shuichi Kaneko  3
Affiliations

Preexisting Humoral Immunity Cross-Reacting with SARS-CoV-2 Might Prevent Death Due to COVID-19 in Critical Patients

Taro Yamashita et al. J Clin Med. .

Abstract

The preexistence of humoral immunity, which cross-reacts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein due to prior endemic low-pathogenic human coronavirus infection, has been reported, but its role in coronavirus disease 2019 (COVID-19) outcomes remains elusive. We evaluated serum samples obtained from 368 patients before the pandemic and 1423 independent serum samples from patients during the pandemic. We found that approximately 6~13% and 1.5% of patients had IgG cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins in both cohorts. We evaluated the IgG cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins in 48 severe or critical COVID-19 patients to evaluate if the elevation of IgG was evoked as a primary response (IgG elevation from 10 days after antigen exposure) or boosted as a secondary response (IgG elevation immediately after antigen exposure). Approximately 50% of patients showed humoral immune responses to the nucleocapsid protein of SARS-CoV-2. Importantly, none of the critically ill patients with this humoral immunity died, whereas 40% of patients without this immunity did. Taken together, subjects had humoral immunity to SARS-CoV-2 nucleocapsid but not spike before the pandemic, which might prevent critically ill COVID-19 patients from dying.

Keywords: COVID-19; SARS-CoV-2; humoral immune memory; mortality.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multi-alignment analysis of the nucleocapsid RNA-binding domain of SARS-CoV-2, SARS-CoV, and alpha (229E and NL63) and beta (OC43 and HKU1) human coronaviruses. Similarity and identity are indicated as orange boxes and red boxes, respectively.
Figure 2
Figure 2
Multi-alignment analysis of the spike S2 domain of SARS-CoV-2, SARS-CoV, and alpha (229E and NL63) and beta (OC43 and HKU1) human coronaviruses. Similarity and identity are indicated as orange boxes and red boxes, respectively.
Figure 2
Figure 2
Multi-alignment analysis of the spike S2 domain of SARS-CoV-2, SARS-CoV, and alpha (229E and NL63) and beta (OC43 and HKU1) human coronaviruses. Similarity and identity are indicated as orange boxes and red boxes, respectively.
Figure 3
Figure 3
Multi-alignment analysis of the spike S1 receptor-binding domain of SARS-CoV-2, SARS-CoV, and alpha (229E and NL63) and beta (OC43 and HKU1) human coronaviruses. Similarity and identity are indicated as orange boxes and red boxes, respectively.
Figure 4
Figure 4
Humoral immunity to SARS-CoV-2 N and S proteins in sera obtained before and during pandemic. (a) IgG N and S titers of serum samples obtained before the COVID-19 pandemic (n = 368). X and Y axes indicate the OD values at 450 nm absorbance evaluated by the Quo Research ELISA system. (b) IgG N titers of serum samples obtained before the COVID-19 pandemic according to season (n = 368). Serum samples obtained from March to May, June to August, September to November, and December to February were regarded as samples obtained in spring, summer, autumn, and winter, respectively. (c) Neutralizing activity of serum samples regarded as IgG S (+) before and during the pandemic on S1 RBD and ACE2 binding. (d) IgG N and S titers of serum samples obtained during the COVID-19 pandemic (n = 1423). X and Y axes indicate the OD values at 450 nm absorbance evaluated by the Quo Research ELISA system.
Figure 5
Figure 5
Heatmap images of IgG NC titers of serial serum samples from the same cases obtained before and during the COVID-19 pandemic (n = 219). One hundred sixty-eight serum samples (76.7% of tested cases) had no IgG N before and in 2020 (not depicted here). A total of 32 of 35 patients that were positive for IgG N before 2020 became negative in 2020 (indicated as group A), whereas 16 of 184 patients that were negative for IgG N before 2020 became positive in 2020 (group B). Yellow and blue cells depict high and low IgG NC titers (OD values at 450 nm absorbance), respectively.
Figure 6
Figure 6
Humoral Immunity to SARS-CoV-2 in hospitalized COVID-19 patients. (a) IgG N titers of COVID-19 patients diagnosed with severe (green circles) or critical (red circles) disease. (b) IgG S titers of COVID-19 patients diagnosed with severe (green circles) or critical (red circles) disease. (c) Kaplan–Meier survival curves of critical COVID-19 patients according to age (blue bar; age < 65, red bar; age ≥ 65). (d) Kaplan–Meier survival curves of critical COVID-19 patients with (red bar) or without (blue bar) humoral immune responses to SARS-CoV-2 N.
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