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1.
J Med Virol ; 94(4): 1633-1640, 2022 04.
Article in English | MEDLINE | ID: covidwho-1568204

ABSTRACT

The coronavirus disease 2019 (COVID-19) is outbreaking all over the world. To help fight this disease, it is necessary to establish an effective and rapid detection method. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is involved in viral replication, assembly, and immune regulation and plays an important role in the viral life cycle. Moreover, the N protein also could be a diagnostic factor and potential drug target. Therefore, by synthesizing the N gene sequence of SARS-CoV-2, constructing the pET-28a (+)-N recombinant plasmid, we expressed the N protein in Escherichia coli and obtained 15 monoclonal antibody (mAbs) against SARS-CoV-2-N protein by the hybridomas and ascites, then an immunochromatographic test strip method detecting N antigen was established. In this study, we obtained 14 high-titer and high-specificity monoclonal antibodies, and the test strips exclusively react with the SARS-CoV-2-N protein and no cross-reactivity with other coronavirus and also recognize the recombinant N protein of Delta (B.1.617.2) variant. These mAbs can be used for the early and rapid diagnosis of SARS-CoV-2 infection through serological antigen.


Subject(s)
Antibodies, Monoclonal/immunology , COVID-19 Serological Testing/instrumentation , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/isolation & purification , Animals , COVID-19/blood , COVID-19/diagnosis , COVID-19 Serological Testing/methods , Coronavirus Nucleocapsid Proteins/blood , Coronavirus Nucleocapsid Proteins/genetics , Humans , Immunoassay , Mice , Mutation , Phosphoproteins/blood , Phosphoproteins/genetics , Phosphoproteins/immunology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sensitivity and Specificity
2.
STAR Protoc ; 2(4): 100906, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1458864

ABSTRACT

Nucleocapsid proteins are essential for SARS-CoV-2 life cycle. Here, we describe protocols to gather domain-specific insights about essential properties of nucleocapsids. These assays include dynamic light scattering to characterize oligomerization, fluorescence polarization to quantify RNA binding, hydrogen-deuterium exchange mass spectrometry to map RNA binding regions, negative-stain electron microscopy to visualize oligomeric species, interferon reporter assay to evaluate interferon signaling modulation, and a serology assay to reveal insights for improved sensitivity and specificity. These assays are broadly applicable to RNA-encapsidated nucleocapsids. For complete details on the use and execution of this protocol, please refer to Wu et al. (2021).


Subject(s)
COVID-19/blood , Coronavirus Nucleocapsid Proteins/blood , Interferons/metabolism , Nucleocapsid/metabolism , RNA, Viral/metabolism , SARS-CoV-2/isolation & purification , Antiviral Agents/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Humans , Nucleocapsid/genetics , Phosphoproteins/blood , Phosphoproteins/genetics , Protein Binding , RNA, Viral/genetics
3.
Clin Chem ; 68(1): 204-213, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1450383

ABSTRACT

BACKGROUND: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antigen in blood has been described, but the diagnostic and prognostic role of antigenemia is not well understood. This study aimed to determine the frequency, duration, and concentration of nucleocapsid antigen in plasma and its association with coronavirus disease 2019 (COVID-19) severity. METHODS: We utilized an ultrasensitive electrochemiluminescence immunoassay targeting SARS-CoV-2 nucleocapsid antigen to evaluate 777 plasma samples from 104 individuals with COVID-19. We compared plasma antigen to respiratory nucleic acid amplification testing (NAAT) in 74 individuals with COVID-19 from samples collected ±1 day of diagnostic respiratory NAAT and in 52 SARS-CoV-2-negative individuals. We used Kruskal-Wallis tests, multivariable logistic regression, and mixed-effects modeling to evaluate whether plasma antigen concentration was associated with disease severity. RESULTS: Plasma antigen had 91.9% (95% CI 83.2%-97.0%) clinical sensitivity and 94.2% (84.1%-98.8%) clinical specificity. Antigen-negative plasma samples belonged to patients with later respiratory cycle thresholds (Ct) when compared with antigen-positive plasma samples. Median plasma antigen concentration (log10 fg/mL) was 5.4 (interquartile range 3.9-6.0) in outpatients, 6.0 (5.4-6.5) in inpatients, and 6.6 (6.1-7.2) in intensive care unit (ICU) patients. In models adjusted for age, sex, diabetes, and hypertension, plasma antigen concentration at diagnosis was associated with ICU admission [odds ratio 2.8 (95% CI 1.2-6.2), P=.01] but not with non-ICU hospitalization. Rate of antigen decrease was not associated with disease severity. CONCLUSIONS: SARS-CoV-2 plasma nucleocapsid antigen exhibited comparable diagnostic performance to upper respiratory NAAT, especially among those with late respiratory Ct. In addition to currently available tools, antigenemia may facilitate patient triage to optimize intensive care utilization.


Subject(s)
Antigens, Viral/blood , COVID-19 Testing/methods , COVID-19 , Coronavirus Nucleocapsid Proteins/blood , COVID-19/diagnosis , Electrochemical Techniques , Hospitalization , Humans , Immunoassay , Luminescent Measurements , Nucleocapsid , Phosphoproteins/blood , SARS-CoV-2 , Sensitivity and Specificity
4.
J Med Virol ; 94(1): 222-228, 2022 01.
Article in English | MEDLINE | ID: covidwho-1372751

ABSTRACT

The current study aimed at characterizing the dynamics of SARS-CoV-2 nucleocapsid (N) antigenemia in a cohort of critically ill adult COVID-19 patients and assessing its potential association with plasma levels of biomarkers of clinical severity and mortality. Seventy-three consecutive critically ill COVID-19 patients (median age, 65 years) were recruited. Serial plasma (n = 340) specimens were collected. A lateral flow immunochromatography assay and reverse-transcription polymerase chain reaction (RT-PCR) were used for SARS-CoV-2 N protein detection and RNA quantitation and in plasma, respectively. Serum levels of inflammatory and tissue-damage biomarkers in paired specimens were measured. SARS-CoV-RNA N-antigenemia and viral RNAemia were documented in 40.1% and 35.6% of patients, respectively at a median of 9 days since symptoms onset. The level of agreement between the qualitative results returned by the N-antigenemia assay and plasma RT-PCR was moderate (k = 0.57; p < 0.0001). A trend towards higher SARS-CoV-2 RNA loads was seen in plasma specimens testing positive for N-antigenemia assay than in those yielding negative results (p = 0.083). SARS-CoV-2 RNA load in tracheal aspirates was significantly higher (p < 0.001) in the presence of concomitant N-antigenemia than in its absence. Significantly higher serum levels of ferritin, lactose dehydrogenase, C-reactive protein, and D-dimer were quantified in paired plasma SARS-CoV-2 N-positive specimens than in those testing negative. Occurrence of SARS-CoV-2 N-antigenemia was not associated with increased mortality in univariate logistic regression analysis (odds ratio, 1.29; 95% confidence interval, 0.49-3.34; p = 0.59). In conclusion, SARS-CoV-2 N-antigenemia detection is relatively common in ICU patients and appears to associate with increased serum levels of inflammation and tissue-damage markers. Whether this virological parameter may behave as a biomarker of poor clinical outcome awaits further investigations.


Subject(s)
COVID-19/virology , Coronavirus Nucleocapsid Proteins/blood , Critical Illness , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Antigens, Viral/blood , Biomarkers/analysis , Biomarkers/blood , COVID-19/mortality , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Inflammation , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Prospective Studies , RNA, Viral/analysis , RNA, Viral/blood , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Trachea/virology , Young Adult
5.
Clin Chem ; 68(1): 240-248, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1345724

ABSTRACT

BACKGROUND: Biomarkers have been widely explored for coronavirus disease 2019 diagnosis. Both viral RNA or antigens (Ag) in the respiratory system and antibodies (Ab) in blood are used to identify active infection, transmission risk, and immune response but have limitations. This study investigated the diagnostic utility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-Ag) in serum. METHODS: We retrospectively studied 208 randomly selected cases with SARS-CoV-2 infection confirmed by viral RNA test in swabs. N-Ag concentrations were measured in remnant serum samples, compared to viral RNA or Ab results, and correlated to electronic health records for clinical value evaluation. RESULTS: Serum N-Ag was detected during active infection as early as day 2 from symptom onset with a diagnostic sensitivity of 81.5%. Within 1 week of symptom onset, the diagnostic sensitivity and specificity reached 90.9% (95% CI, 85.1%-94.6%) and 98.3% (95% CI, 91.1%-99.9%), respectively. Moreover, serum N-Ag concentration closely correlated to disease severity, reflected by highest level of care, medical interventions, chest imaging, and the length of hospital stays. Longitudinal analysis revealed the simultaneous increase of Abs and decline of N-Ag. CONCLUSIONS: Serum N-Ag is a biomarker for SARS-CoV-2 acute infection with high diagnostic sensitivity and specificity compared to viral RNA in the respiratory system. There is a correlation between serum N-Ag concentrations and disease severity and an inverse relationship of N-Ag and Abs. The diagnostic value of serum N-Ag, as well as technical and practical advantages it could offer, may meet unsatisfied diagnostic and prognostic needs during the pandemic.


Subject(s)
COVID-19 Testing/methods , COVID-19 , Coronavirus Nucleocapsid Proteins/blood , Antibodies, Viral/blood , COVID-19/diagnosis , Humans , Nucleocapsid Proteins , Phosphoproteins/blood , RNA, Viral , Retrospective Studies , SARS-CoV-2 , Sensitivity and Specificity
6.
PLoS One ; 16(7): e0254367, 2021.
Article in English | MEDLINE | ID: covidwho-1304472

ABSTRACT

COVID-19 serological test must have high sensitivity as well as specificity to rule out cross-reactivity with common coronaviruses (HCoVs). We have developed a quantitative multiplex test, measuring antibodies against spike (S) proteins of SARS-CoV-2, SARS-CoV, MERS-CoV, and common human coronavirus strains (229E, NL63, OC43, HKU1), and nucleocapsid (N) protein of SARS-CoV viruses. Receptor binding domain of S protein of SARS-CoV-2 (S-RBD), and N protein, demonstrated sensitivity (94% and 92.5%, respectively) in COVID-19 patients (n = 53), with 98% specificity in non-COVID-19 respiratory-disease (n = 98), and healthy-controls (n = 129). Anti S-RBD and N antibodies appeared five to ten days post-onset of symptoms, peaking at approximately four weeks. The appearance of IgG and IgM coincided while IgG subtypes, IgG1 and IgG3 appeared soon after the total IgG; IgG2 and IgG4 remained undetectable. Several inflammatory cytokines/chemokines were found to be elevated in many COVID-19 patients (e.g., Eotaxin, Gro-α, CXCL-10 (IP-10), RANTES (CCL5), IL-2Rα, MCP-1, and SCGF-b); CXCL-10 was elevated in all. In contrast to antibody titers, levels of CXCL-10 decreased with the improvement in patient health suggesting it as a candidate for disease resolution. Importantly, anti-N antibodies appear before S-RBD and differentiate between vaccinated and infected people-current vaccines (and several in the pipeline) are S protein-based.


Subject(s)
Antibodies, Viral , COVID-19 , Chemokines , Coronavirus Nucleocapsid Proteins , Immunoglobulin G , Immunoglobulin M , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , Chemokines/blood , Chemokines/immunology , Coronavirus Nucleocapsid Proteins/blood , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Macaca mulatta , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Rabbits , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology
7.
J Med Virol ; 93(4): 2262-2269, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217377

ABSTRACT

This study assesses the clinical performance of three anti-SARS-CoV-2 assays, namely EUROIMMUN anti-SARS-CoV-2 nucleocapsid (IgG) ELISA, Elecsys anti-SARS-CoV-2 nucleocapsid (total antibodies) assay, and LIAISON anti-SARS-CoV-2 spike proteins S1 and S2 (IgG) assay. One hundred and thirty-seven coronavirus disease 2019 (COVID-19) samples from 96 reverse-transcription polymerase chain reaction confirmed patients were chosen to perform the sensitivity analysis. Non-SARS-CoV-2 sera (n = 141) with a potential cross-reaction to SARS-CoV-2 immunoassays were included in the specificity analysis. None of these tests demonstrated a sufficiently high clinical sensitivity to diagnose acute infection. Fourteen days since symptom onset, we did not find any significant difference between the three techniques in terms of sensitivities. However, Elecsys performed better in terms of specificity. All three anti-SARS-CoV-2 assays had equivalent sensitivities 14 days from symptom onset to diagnose past-COVID-19 infection. We also confirmed that anti-SARS-CoV-2 determination before Day 14 is of less clinical interest.


Subject(s)
COVID-19 Testing/methods , COVID-19/blood , COVID-19/virology , Coronavirus Nucleocapsid Proteins/blood , Immunoassay/methods , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/blood , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Cross Reactions , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Retrospective Studies , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/immunology
8.
J Med Virol ; 93(4): 2262-2269, 2021 04.
Article in English | MEDLINE | ID: covidwho-986249

ABSTRACT

This study assesses the clinical performance of three anti-SARS-CoV-2 assays, namely EUROIMMUN anti-SARS-CoV-2 nucleocapsid (IgG) ELISA, Elecsys anti-SARS-CoV-2 nucleocapsid (total antibodies) assay, and LIAISON anti-SARS-CoV-2 spike proteins S1 and S2 (IgG) assay. One hundred and thirty-seven coronavirus disease 2019 (COVID-19) samples from 96 reverse-transcription polymerase chain reaction confirmed patients were chosen to perform the sensitivity analysis. Non-SARS-CoV-2 sera (n = 141) with a potential cross-reaction to SARS-CoV-2 immunoassays were included in the specificity analysis. None of these tests demonstrated a sufficiently high clinical sensitivity to diagnose acute infection. Fourteen days since symptom onset, we did not find any significant difference between the three techniques in terms of sensitivities. However, Elecsys performed better in terms of specificity. All three anti-SARS-CoV-2 assays had equivalent sensitivities 14 days from symptom onset to diagnose past-COVID-19 infection. We also confirmed that anti-SARS-CoV-2 determination before Day 14 is of less clinical interest.


Subject(s)
COVID-19 Testing/methods , COVID-19/blood , COVID-19/virology , Coronavirus Nucleocapsid Proteins/blood , Immunoassay/methods , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/blood , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Cross Reactions , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Retrospective Studies , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/analysis , Spike Glycoprotein, Coronavirus/immunology
9.
Bioanalysis ; 13(1): 13-28, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-977787

ABSTRACT

Aim: Coronavirus disease 2019 antibody testing often relies on venous blood collection, which is labor-intensive, inconvenient and expensive compared with finger-stick capillary dried blood spot (DBS) collection. The purpose of our work was to determine if two commercially available anti-severe acute respiratory syndrome coronavirus 2 enzyme-linked immunosorbent assays for IgG antibodies against spike S1 subunit and nucleocapsid proteins could be validated for use with DBS. Materials & methods: Kit supplied reagents were used to extract DBS, and in-house DBS calibrators were included on every run. Results: Positive/negative concordance between DBS and serum was 100/99.3% for the spike S1 subunit assay and 100/98% for the nucleocapsid assay. Conclusion: Validation of the DBS Coronavirus disease 2019 IgG antibody assays demonstrated that serum and DBS can produce equivalent results with minimal kit modifications.


Subject(s)
COVID-19 Testing/standards , COVID-19/diagnosis , Dried Blood Spot Testing/standards , Enzyme-Linked Immunosorbent Assay/standards , SARS-CoV-2/immunology , Antibodies, Viral/chemistry , Antigens, Viral/blood , Antigens, Viral/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Coronavirus Nucleocapsid Proteins/blood , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunoglobulin G/chemistry , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Reagent Kits, Diagnostic/standards , Reproducibility of Results , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology
10.
Clin Chem ; 66(12): 1562-1572, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-748361

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 21 million people worldwide since August 16, 2020. Compared to PCR and serology tests, SARS-CoV-2 antigen assays are underdeveloped, despite their potential to identify active infection and monitor disease progression. METHODS: We used Single Molecule Array (Simoa) assays to quantitatively detect SARS-CoV-2 spike, S1 subunit, and nucleocapsid antigens in the plasma of patients with coronavirus disease (COVID-19). We studied plasma from 64 patients who were COVID-19 positive, 17 who were COVID-19 negative, and 34 prepandemic patients. Combined with Simoa anti-SARS-CoV-2 serological assays, we quantified changes in 31 SARS-CoV-2 biomarkers in 272 longitudinal plasma samples obtained for 39 patients with COVID-19. Data were analyzed by hierarchical clustering and were compared to longitudinal RT-PCR test results and clinical outcomes. RESULTS: SARS-CoV-2 S1 and N antigens were detectable in 41 out of 64 COVID-19 positive patients. In these patients, full antigen clearance in plasma was observed a mean ± 95% CI of 5 ± 1 days after seroconversion and nasopharyngeal RT-PCR tests reported positive results for 15 ± 5 days after viral-antigen clearance. Correlation between patients with high concentrations of S1 antigen and ICU admission (77%) and time to intubation (within 1 day) was statistically significant. CONCLUSIONS: The reported SARS-CoV-2 Simoa antigen assay is the first to detect viral antigens in the plasma of patients who were COVID-19 positive to date. These data show that SARS-CoV-2 viral antigens in the blood are associated with disease progression, such as respiratory failure, in COVID-19 cases with severe disease.


Subject(s)
Antibodies, Viral/blood , Antigens, Viral/blood , COVID-19/diagnosis , Disease Progression , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/blood , COVID-19 Serological Testing , Coronavirus Nucleocapsid Proteins/blood , Female , Hospitalization , Humans , Intensive Care Units , Intubation , Limit of Detection , Male , Middle Aged , Phosphoproteins/blood , Prognosis , Protein Subunits/blood , Spike Glycoprotein, Coronavirus/blood
11.
Pediatrics ; 146(6)2020 12.
Article in English | MEDLINE | ID: covidwho-745069

ABSTRACT

OBJECTIVES: We aimed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological responses in children hospitalized with multisystem inflammatory syndrome in children (MIS-C) compared with those with coronavirus disease 2019 (COVID-19), those with Kawasaki disease (KD), and hospitalized pediatric controls. METHODS: From March 17, 2020, to May 26, 2020, we prospectively identified hospitalized children with MIS-C (n = 10), symptomatic COVID-19 (n = 10), and KD (n = 5) and hospitalized controls (n = 4) at Children's Healthcare of Atlanta. With institutional review board approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike receptor-binding domain (RBD) immunoglobulin M and immunoglobulin G (IgG), full-length spike IgG, and nucleocapsid protein antibodies using quantitative enzyme-linked immunosorbent assays and SARS-CoV-2 neutralizing antibodies using live-virus focus-reduction neutralization assays. We statistically compared the log-transformed antibody titers among groups and performed linear regression analyses. RESULTS: All children with MIS-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated with full-length spike IgG antibodies (R 2 = 0.956; P < .001), nucleocapsid protein antibodies (R 2 = 0.846; P < .001), and neutralizing antibodies (R 2 = 0.667; P < .001). Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer 6800; 95% confidence interval 3495-13 231) than children with COVID-19 (geometric mean titer 626; 95% confidence interval 251-1563; P < .001), children with KD (geometric mean titer 124; 95% confidence interval 91-170; P < .001), and hospitalized controls (geometric mean titer 85; P < .001). All children with MIS-C also had detectable RBD immunoglobulin M antibodies, indicating recent SARS-CoV-2 infection. RBD IgG titers correlated with the erythrocyte sedimentation rate (R 2 = 0.512; P < .046) and with hospital (R 2 = 0.548; P = .014) and ICU lengths of stay (R 2 = 0.590; P = .010). CONCLUSIONS: Quantitative SARS-CoV-2 serology may have a role in establishing the diagnosis of MIS-C, distinguishing it from similar clinical entities, and stratifying risk for adverse outcomes.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Mucocutaneous Lymph Node Syndrome/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Antibodies, Neutralizing/blood , Blood Sedimentation , COVID-19/blood , COVID-19/diagnosis , COVID-19 Serological Testing , Case-Control Studies , Child , Child, Preschool , Coronavirus Nucleocapsid Proteins/blood , Diagnosis, Differential , Female , Hospitalization , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Infant , Infant, Newborn , Length of Stay , Male , Mucocutaneous Lymph Node Syndrome/blood , Mucocutaneous Lymph Node Syndrome/diagnosis , Neutralization Tests , Phosphoproteins/blood , Phosphoproteins/immunology , Prospective Studies , Regression Analysis , Spike Glycoprotein, Coronavirus/blood , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Young Adult
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