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1.
Nature ; 2021 Nov 10.
Article in English | MEDLINE | ID: covidwho-1510600

ABSTRACT

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24-11, would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, suggesting abortive infection. RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA-polymerase was preferentially targeted (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. Enriched pre-existing RNA-polymerase-specific T-cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.

2.
Lancet Microbe ; 2(10): e508-e517, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1475189

ABSTRACT

Background: We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. Methods: We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity. Findings: We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27-47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91-0·99), sensitivity 0·84 (0·70-0·93), and specificity 0·95 (0·85-0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91-0·95). Interpretation: Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge. Funding: Barts Charity, Wellcome Trust, and National Institute of Health Research.

3.
Lancet Microbe ; 2(10): e508-e517, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1305340

ABSTRACT

Background: We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. Methods: We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity. Findings: We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27-47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91-0·99), sensitivity 0·84 (0·70-0·93), and specificity 0·95 (0·85-0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91-0·95). Interpretation: Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge. Funding: Barts Charity, Wellcome Trust, and National Institute of Health Research.

4.
JACC Cardiovasc Imaging ; 14(11): 2155-2166, 2021 11.
Article in English | MEDLINE | ID: covidwho-1225278

ABSTRACT

OBJECTIVES: The purpose of this study was to detect cardiovascular changes after mild severe acute respiratory syndrome-coronavirus-2 infection. BACKGROUND: Concern exists that mild coronavirus disease 2019 may cause myocardial and vascular disease. METHODS: Participants were recruited from COVIDsortium, a 3-hospital prospective study of 731 health care workers who underwent first-wave weekly symptom, polymerase chain reaction, and serology assessment over 4 months, with seroconversion in 21.5% (n = 157). At 6 months post-infection, 74 seropositive and 75 age-, sex-, and ethnicity-matched seronegative control subjects were recruited for cardiovascular phenotyping (comprehensive phantom-calibrated cardiovascular magnetic resonance and blood biomarkers). Analysis was blinded, using objective artificial intelligence analytics where available. RESULTS: A total of 149 subjects (mean age 37 years, range 18 to 63 years, 58% women) were recruited. Seropositive infections had been mild with case definition, noncase definition, and asymptomatic disease in 45 (61%), 18 (24%), and 11 (15%), respectively, with 1 person hospitalized (for 2 days). Between seropositive and seronegative groups, there were no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T1, T2, extracellular volume fraction mapping, late gadolinium enhancement) or biomarkers (troponin, N-terminal pro-B-type natriuretic peptide). With abnormal defined by the 75 seronegatives (2 SDs from mean, e.g., ejection fraction <54%, septal T1 >1,072 ms, septal T2 >52.4 ms), individuals had abnormalities including reduced ejection fraction (n = 2, minimum 50%), T1 elevation (n = 6), T2 elevation (n = 9), late gadolinium enhancement (n = 13, median 1%, max 5% of myocardium), biomarker elevation (borderline troponin elevation in 4; all N-terminal pro-B-type natriuretic peptide normal). These were distributed equally between seropositive and seronegative individuals. CONCLUSIONS: Cardiovascular abnormalities are no more common in seropositive versus seronegative otherwise healthy, workforce representative individuals 6 months post-mild severe acute respiratory syndrome-coronavirus-2 infection.


Subject(s)
COVID-19 , Cardiovascular Abnormalities , Adolescent , Adult , Artificial Intelligence , Case-Control Studies , Contrast Media , Female , Gadolinium , Health Personnel , Humans , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Myocardium , Predictive Value of Tests , Prospective Studies , SARS-CoV-2 , Ventricular Function, Left , Young Adult
5.
EBioMedicine ; 65: 103259, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1116568

ABSTRACT

BACKGROUND: SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. METHODS: Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. FINDINGS: A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16-18 weeks, r = 0.57, p<0.0001). By 21 weeks' follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). INTERPRETATION: Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity. FUNDING: Charitable donations via Barts Charity, Wellcome Trust, NIHR.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/diagnosis , Health Personnel/statistics & numerical data , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Phosphoproteins/immunology , Protein Domains/immunology
6.
Wellcome Open Res ; 5: 179, 2020.
Article in English | MEDLINE | ID: covidwho-1068028

ABSTRACT

Background: Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-up sampling to evaluate the quality and duration of immune memory. Methods: We conducted a prospective study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later (recruitment still ongoing, target n=1,000). Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swab (for SARS-CoV-2 RNA by RT-PCR tests) and blood samples (mononuclear cells, serum, plasma, RNA and DNA are biobanked) at 16 weekly study visits, and at 6 and 12 months. Results: Preliminary baseline results for the first 731 HCWs (400 single-centre, 331 multicentre extension) are presented. Mean age was 38±11 years; 67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities; 18% smokers; 13% obesity; 11% asthma; 7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396 (7.1%, 95% CI 4.9-10.0%) and 15 of 385 (3.9%, 2.4-6.3%) had circulating IgG antibodies. Conclusions: This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application  https://covid-consortium.com/application-for-samples/.

7.
Sci Immunol ; 5(54)2020 12 23.
Article in English | MEDLINE | ID: covidwho-999191

ABSTRACT

Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.


Subject(s)
Antibodies, Neutralizing/immunology , Asymptomatic Infections , COVID-19/immunology , T-Lymphocytes/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , Case-Control Studies , Cross-Sectional Studies , Humans , SARS-CoV-2/immunology
8.
Preprint in English | ProQuest Central | ID: ppcovidwho-2091

ABSTRACT

Background: Most biomedical research has focused on sampling COVID-19 patients presenting to hospital with advanced disease, with less focus on the asymptomatic or paucisymptomatic. We established a bioresource with serial sampling of health care workers (HCWs) designed to obtain samples before and during mainly mild disease, with follow-usampling to evaluate the quality and duration of immune memory. Methods: We conducted a prospective observational study on HCWs from three hospital sites in London, initially at a single centre (recruited just prior to first peak community transmission in London), but then extended to multiple sites 3 weeks later (recruitment still ongoing, target n=1,000). Asymptomatic participants attending work complete a health questionnaire, and provide a nasal swa(for SARS-CoV-2 RNA by RT-PCR tests) and blood samples (mononuclear cells, serum, plasma, RNA and DNA are biobanked) at 16 weekly study visits, and at 6 and 12 months. Results: Preliminary baseline results for the first 731 HCWs (400 single-centre, 331 multicentre extension) are presented. Mean age was 38±11 years;67% are female, 31% nurses, 20% doctors, and 19% work in intensive care units. COVID-19-associated risk factors were: 37% black, Asian or minority ethnicities;18% smokers;13% obesity;11% asthma;7% hypertension and 2% diabetes mellitus. At baseline, 41% reported symptoms in the preceding 2 weeks. Preliminary test results from the initial cohort (n=400) are available: PCR at baseline for SARS-CoV-2 was positive in 28 of 396 (7.1%, 95% C4.9-10.0%) and 15 of 385 (3.9%, 2.4-6.3%) had circulating IgG antibodies. Conclusions: This COVID-19 bioresource established just before the peak of infections in the UK will provide longitudinal assessments of incident infection and immune responses in HCWs through the natural time course of disease and convalescence. The samples and data from this bioresource are available to academic collaborators by application https://covid-consortium.com/application-for-samples/.

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