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1.
Elife ; 112022 05 19.
Article in English | MEDLINE | ID: covidwho-1856224

ABSTRACT

The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies , Antibodies, Viral , Humans , Killer Cells, Natural , Proteomics
2.
Infect Dis Rep ; 14(1): 56-62, 2022 Jan 12.
Article in English | MEDLINE | ID: covidwho-1771175

ABSTRACT

There is limited evidence to guide successful treatment of recurrent Campylobacter infection in patients with common variable immunodeficiency (CVID) already managed on regular immunoglobulin therapy. The role of faecal microbiota transplant (FMT) is uncertain. We report a case of recurrent Campylobacter jejuni infection in a patient with CVID treated with repeated FMT with 18 months of symptom resolution prior to relapse.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316696

ABSTRACT

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia was associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). In longitudinal comparisons, COVID-19 ICU patients had a distinct proteomic trajectory associated with RNAemia and mortality. Among COVID-19-enriched proteins, galectin-3 binding protein (LGALS3BP) and proteins of the complement system were identified as interaction partners of SARS-CoV-2 spike glycoprotein. Finally, machine learning identified ‘Age, RNAemia’ and ‘Age, pentraxin-3 (PTX3)’ as the best binary signatures associated with 28-day ICU mortality.

4.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295726

ABSTRACT

Background Rapid antigen lateral flow devices (LFDs) are set to become a cornerstone of SARS-CoV-2 mass community testing. However, their reduced sensitivity compared to PCR has raised questions of how well they identify infectious cases. Understanding their capabilities and limitations is therefore essential for successful implementation. To address this, we evaluated six commercial LFDs on the same collection of clinical samples and assessed their correlation with infectious virus culture and cycle threshold (Ct) values. Methods A head-to-head comparison of specificities and sensitivities was performed on six commercial rapid antigen tests using combined nasal/oropharyngeal swabs, and their limits of detection determined using viral plaque forming units (PFU). Three of the LFDs were selected for a further study, correlating antigen test result with RT-PCR Ct values and positive viral culture in Vero-E6 cells. This included sequential swabs and matched serum samples obtained from four infected individuals with varying disease severities. Detection of antibodies was performed using an IgG/IgM Rapid Test Cassette, and neutralising antibodies by infectious virus assay. Finally, the sensitivities of selected rapid antigen LFTs were assessed in swabs with confirmed B.1.1.7 variant, currently the dominant genotype in the UK. Findings Most of the rapid antigen LFDs showed a high specificity (>98%), and accurately detected 50 PFU/test (equivalent N1 Ct of 23.7 or RNA copy number of 3×10 6 /ml). Sensitivities of the LFDs performed on clinical samples ranged from 65 to 89%. These sensitivities increased in most tests to over 90% for samples with Cts lower than 25. Positive virus culture was achieved for 57 out of 141 samples, with 80% of the positive cultures from swabs with Cts lower than 23. Importantly, sensitivity of the LFDs increased to over 95% when compared with the detection of infectious virus alone, irrespective of Ct. Longitudinal studies of PCR-positive samples showed that most of the tests identified all infectious samples as positive, but differences in test sensitivities can lead to missed cases in the absence of repeated testing. Finally, test performance was not impacted when re-assessed against swabs positive for the dominant UK variant B.1.1.7. Interpretation In this comprehensive comparison of antigen LFD and virus infectivity, we demonstrate a clear relationship between Ct values, quantitative culture of infectious virus and antigen LFD positivity in clinical samples. Our data support regular testing of target groups using LFDs to supplement the current PCR testing capacity, to rapidly identify infected individuals in situations where they would otherwise go undetected. Funding King’s Together Rapid COVID-19, Medical Research Council, Wellcome Trust, Huo Family Foundation.

5.
Cardiovasc Res ; 118(2): 461-474, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1510904

ABSTRACT

AIMS: Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. METHODS AND RESULTS: We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. CONCLUSION: Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.


Subject(s)
COVID-19/mortality , MicroRNAs/blood , SARS-CoV-2 , Adult , Aged , Biomarkers , COVID-19/complications , COVID-19/genetics , Cardiometabolic Risk Factors , Female , High-Throughput Nucleotide Sequencing , Humans , Intensive Care Units , Male , Middle Aged , Patient Acuity
6.
Nat Microbiol ; 6(11): 1433-1442, 2021 11.
Article in English | MEDLINE | ID: covidwho-1469971

ABSTRACT

COVID-19 vaccine design and vaccination rollout need to take into account a detailed understanding of antibody durability and cross-neutralizing potential against SARS-CoV-2 and emerging variants of concern (VOCs). Analyses of convalescent sera provide unique insights into antibody longevity and cross-neutralizing activity induced by variant spike proteins, which are putative vaccine candidates. Using sera from 38 individuals infected in wave 1, we show that cross-neutralizing activity can be detected up to 305 days pos onset of symptoms, although sera were less potent against B.1.1.7 (Alpha) and B1.351 (Beta). Over time, despite a reduction in overall neutralization activity, differences in sera neutralization potency against SARS-CoV-2 and the Alpha and Beta variants decreased, which suggests that continued antibody maturation improves tolerance to spike mutations. We also compared the cross-neutralizing activity of wave 1 sera with sera from individuals infected with the Alpha, the Beta or the B.1.617.2 (Delta) variants up to 79 days post onset of symptoms. While these sera neutralize the infecting VOC and parental virus to similar levels, cross-neutralization of different SARS-CoV-2 VOC lineages is reduced. These findings will inform the optimization of vaccines to protect against SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines , Female , Humans , Immunization, Passive , Immunoglobulin G , Immunoglobulin M , Male , Middle Aged , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Young Adult
7.
Clin Microbiol Infect ; 28(1): 93-100, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1356178

ABSTRACT

OBJECTIVES: To analyse nosocomial transmission in the early stages of the coronavirus 2019 (COVID-19) pandemic at a large multisite healthcare institution. Nosocomial incidence is linked with infection control interventions. METHODS: Viral genome sequence and epidemiological data were analysed for 574 consecutive patients, including 86 nosocomial cases, with a positive PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first 19 days of the pandemic. RESULTS: Forty-four putative transmission clusters were found through epidemiological analysis; these included 234 cases and all 86 nosocomial cases. SARS-CoV-2 genome sequences were obtained from 168/234 (72%) of these cases in epidemiological clusters, including 77/86 nosocomial cases (90%). Only 75/168 (45%) of epidemiologically linked, sequenced cases were not refuted by applying genomic data, creating 14 final clusters accounting for 59/77 sequenced nosocomial cases (77%). Viral haplotypes from these clusters were enriched 1-14x (median 4x) compared to the community. Three factors implicated unidentified cases in transmission: (a) community-onset or indeterminate cases were absent in 7/14 clusters (50%), (b) four clusters (29%) had additional evidence of cryptic transmission, and (c) in three clusters (21%) diagnosis of the earliest case was delayed, which may have facilitated transmission. Nosocomial cases decreased to low levels (0-2 per day) despite continuing high numbers of admissions of community-onset SARS-CoV-2 cases (40-50 per day) and before the impact of introducing universal face masks and banning hospital visitors. CONCLUSION: Genomics was necessary to accurately resolve transmission clusters. Our data support unidentified cases-such as healthcare workers or asymptomatic patients-as important vectors of transmission. Evidence is needed to ascertain whether routine screening increases case ascertainment and limits nosocomial transmission.


Subject(s)
COVID-19 , Cross Infection , SARS-CoV-2/genetics , COVID-19/epidemiology , COVID-19/transmission , Cross Infection/epidemiology , Disease Outbreaks , Genome, Viral , Genomics , Hospitals , Humans , Pandemics
8.
Lancet Microbe ; 2(9): e461-e471, 2021 09.
Article in English | MEDLINE | ID: covidwho-1294386

ABSTRACT

BACKGROUND: Lateral flow devices (LFDs) for rapid antigen testing are set to become a cornerstone of SARS-CoV-2 mass community testing, although their reduced sensitivity compared with PCR has raised questions of how well they identify infectious cases. Understanding their capabilities and limitations is, therefore, essential for successful implementation. We evaluated six commercial LFDs and assessed their correlation with infectious virus culture and PCR cycle threshold (Ct) values. METHODS: In a single-centre, laboratory evaluation study, we did a head-to-head comparison of six LFDs commercially available in the UK: Innova Rapid SARS-CoV-2 Antigen Test, Spring Healthcare SARS-CoV-2 Antigen Rapid Test Cassette, E25Bio Rapid Diagnostic Test, Encode SARS-CoV-2 Antigen Rapid Test Device, SureScreen COVID-19 Rapid Antigen Test Cassette, and SureScreen COVID-19 Rapid Fluorescence Antigen Test. We estimated the specificities and sensitivities of the LFDs using stored naso-oropharyngeal swabs collected at St Thomas' Hospital (London, UK) for routine diagnostic SARS-CoV-2 testing by real-time RT-PCR (RT-rtPCR). Swabs were from inpatients and outpatients from all departments of St Thomas' Hospital, and from health-care staff (all departments) and their household contacts. SARS-CoV-2-negative swabs from the same population (confirmed by RT-rtPCR) were used for comparative specificity determinations. All samples were collected between March 23 and Oct 27, 2020. We determined the limit of detection (LOD) for each test using viral plaque-forming units (PFUs) and viral RNA copy numbers of laboratory-grown SARS-CoV-2. Additionally, LFDs were selected to assess the correlation of antigen test result with RT-rtPCR Ct values and positive viral culture in Vero E6 cells. This analysis included longitudinal swabs from five infected inpatients with varying disease severities. Furthermore, the sensitivities of available LFDs were assessed in swabs (n=23; collected from Dec 4, 2020, to Jan 12, 2021) confirmed to be positive (RT-rtPCR and whole-genome sequencing) for the B.1.1.7 variant, which was the dominant genotype in the UK at the time of study completion. FINDINGS: All LFDs showed high specificity (≥98·0%), except for the E25Bio test (86·0% [95% CI 77·9-99·9]), and most tests reliably detected 50 PFU/test (equivalent SARS-CoV-2 N gene Ct value of 23·7, or RNA copy number of 3 × 106/mL). Sensitivities of the LFDs on clinical samples ranged from 65·0% (55·2-73·6) to 89·0% (81·4-93·8). These sensitivities increased to greater than 90% for samples with Ct values of lower than 25 for all tests except the SureScreen fluorescence (SureScreen-F) test. Positive virus culture was identified in 57 (40·4%) of 141 samples; 54 (94·7%) of the positive cultures were from swabs with Ct values lower than 25. Among the three LFDs selected for detailed comparisons (the tests with highest sensitivity [Innova], highest specificity [Encode], and alternative technology [SureScreen-F]), sensitivity of the LFDs increased to at least 94·7% when only including samples with detected viral growth. Longitudinal studies of RT-rtPCR-positive samples (tested with Innova, Encode, and both SureScreen-F and the SureScreen visual [SureScreen-V] test) showed that most of the tests identified all infectious samples as positive. Test performance (assessed for Innova and SureScreen-V) was not affected when reassessed on swabs positive for the UK variant B.1.1.7. INTERPRETATION: In this comprehensive comparison of antigen LFDs and virus infectivity, we found a clear relationship between Ct values, quantitative culture of infectious virus, and antigen LFD positivity in clinical samples. Our data support regular testing of target groups with LFDs to supplement the current PCR testing capacity, which would help to rapidly identify infected individuals in situations in which they would otherwise go undetected. FUNDING: King's Together Rapid COVID-19, Medical Research Council, Wellcome Trust, Huo Family Foundation, UK Department of Health, National Institute for Health Research Comprehensive Biomedical Research Centre.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , COVID-19 Testing , Humans , RNA, Viral/genetics
9.
Nat Commun ; 12(1): 3406, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1260941

ABSTRACT

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.


Subject(s)
COVID-19/prevention & control , Critical Care/statistics & numerical data , Proteomics/methods , RNA, Viral/genetics , SARS-CoV-2/genetics , Adult , Animals , Antibodies, Neutralizing/immunology , Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Kaplan-Meier Estimate , Male , Middle Aged , RNA, Viral/blood , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serum Amyloid P-Component/metabolism , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Viral Load/immunology
10.
PLoS One ; 16(4): e0249791, 2021.
Article in English | MEDLINE | ID: covidwho-1171455

ABSTRACT

During the first wave of the global COVID-19 pandemic the clinical utility and indications for SARS-CoV-2 serological testing were not clearly defined. The urgency to deploy serological assays required rapid evaluation of their performance characteristics. We undertook an internal validation of a CE marked lateral flow immunoassay (LFIA) (SureScreen Diagnostics) using serum from SARS-CoV-2 RNA positive individuals and pre-pandemic samples. This was followed by the delivery of a same-day named patient SARS-CoV-2 serology service using LFIA on vetted referrals at central London teaching hospital with clinical interpretation of result provided to the direct care team. Assay performance, source and nature of referrals, feasibility and clinical utility of the service, particularly benefit in clinical decision-making, were recorded. Sensitivity and specificity of LFIA were 96.1% and 99.3% respectively. 113 tests were performed on 108 participants during three-week pilot. 44% participants (n = 48) had detectable antibodies. Three main indications were identified for serological testing; new acute presentations potentially triggered by recent COVID-19 e.g. pulmonary embolism (n = 5), potential missed diagnoses in context of a recent COVID-19 compatible illness (n = 40), and making infection control or immunosuppression management decisions in persistently SARS-CoV-2 RNA PCR positive individuals (n = 6). We demonstrate acceptable performance characteristics, feasibility and clinical utility of using a LFIA that detects anti-spike antibodies to deliver SARS-CoV-2 serology service in adults and children. Greatest benefit was seen where there is reasonable pre-test probability and results can be linked with clinical advice or intervention. Experience from this pilot can help inform practicalities and benefits of rapidly implementing new tests such as LFIAs into clinical service as the pandemic evolves.


Subject(s)
COVID-19 Serological Testing , COVID-19 , Pandemics , SARS-CoV-2/metabolism , Adult , COVID-19/blood , COVID-19/complications , COVID-19/diagnosis , COVID-19/epidemiology , Female , Humans , Male , Syndrome
12.
Ther Adv Infect Dis ; 8: 2049936120981526, 2021.
Article in English | MEDLINE | ID: covidwho-1058224

ABSTRACT

Faecal microbiota transplantation (FMT) is the transfer of screened and minimally processed faecal material from a 'healthy' donor to 'diseased' recipient. It has an established role, and is recommended as a therapeutic strategy, in the management of recurrent Clostridioides difficile infection (CDI). Recognition that gut dysbiosis is associated with, and may contribute to, numerous disease states has led to interest in exploiting FMT to 'correct' this microbial imbalance. Conditions for which it is proposed to be beneficial include inflammatory bowel disease, irritable bowel syndrome, liver disease and hepatic encephalopathy, neuropsychiatric conditions such as depression and anxiety, systemic inflammatory states like sepsis, and even coronavirus disease 2019. To understand what role, if any, FMT may play in the management of these conditions, it is important to consider the potential risks and benefits of the therapy. Regardless, there are several barriers to its more widespread adoption, which include incompletely understood mechanism of action (especially outside of CDI), inability to standardise treatment, disagreement on its active ingredients and how it should be regulated, and lack of long-term outcome and safety data. Whilst the transfer of faecal material from one individual to another to treat ailments or improve health has a history dating back thousands of years, there are fewer than 10 randomised controlled trials supporting its use. Moving forward, it will be imperative to gather as much data from FMT donors and recipients over as long a timeframe as possible, and for trials to be conducted with rigorous methodology, including appropriate control groups, in order to best understand the utility of FMT for indications beyond CDI. This review discusses the history of FMT, its appreciable mechanisms of action with reference to CDI, indications for FMT with an emerging evidence base above and beyond CDI, and future perspectives on the field.

13.
ERJ Open Res ; 6(4)2020 Oct.
Article in English | MEDLINE | ID: covidwho-917915

ABSTRACT

BACKGROUND: The use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in severe hypoxaemic respiratory failure from coronavirus disease 2019 (COVID-19) has been described, but reported utilisation and outcomes are variable, and detailed information on patient characteristics is lacking. We aim to report clinical characteristics, management and outcomes of COVID-19 patients requiring VV-ECMO, admitted over 2 months to a high-volume centre in the UK. METHODS: Patient information, including baseline characteristics and clinical parameters, was collected retrospectively from electronic health records for COVID-19 VV-ECMO admissions between 3 March and 2 May 2020. Clinical management is described. Data are reported for survivors and nonsurvivors. RESULTS: We describe 43 consecutive patients with COVID-19 who received VV-ECMO. Median age was 46 years (interquartile range 35.5-52.5) and 76.7% were male. Median time from symptom onset to VV-ECMO was 14 days (interquartile range 11-17.5). All patients underwent computed tomography imaging, revealing extensive pulmonary consolidation in 95.3%, and pulmonary embolus in 27.9%. Overall, 79.1% received immunomodulation with methylprednisolone for persistent maladaptive hyperinflammatory state. Vasopressors were used in 86%, and 44.2% received renal replacement therapy. Median duration on VV-ECMO was 13 days (interquartile range 8-20). 14 patients died (32.6%) and 29 survived (67.4%) to hospital discharge. Nonsurvivors had significantly higher d-dimer (38.2 versus 9.5 mg·L-1, fibrinogen equivalent units; p=0.035) and creatinine (169 versus 73 µmol·L-1; p=0.022) at commencement of VV-ECMO. CONCLUSIONS: Our data support the use of VV-ECMO in selected COVID-19 patients. The cohort was characterised by high degree of alveolar consolidation, systemic inflammation and intravascular thrombosis.

14.
Nat Microbiol ; 5(12): 1598-1607, 2020 12.
Article in English | MEDLINE | ID: covidwho-892039

ABSTRACT

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/pathology , Female , Humans , Kinetics , Longitudinal Studies , Male , Middle Aged , Seroconversion , Severity of Illness Index , Young Adult
15.
PLoS Pathog ; 16(9): e1008817, 2020 09.
Article in English | MEDLINE | ID: covidwho-793175

ABSTRACT

There is a clear requirement for an accurate SARS-CoV-2 antibody test, both as a complement to existing diagnostic capabilities and for determining community seroprevalence. We therefore evaluated the performance of a variety of antibody testing technologies and their potential use as diagnostic tools. Highly specific in-house ELISAs were developed for the detection of anti-spike (S), -receptor binding domain (RBD) and -nucleocapsid (N) antibodies and used for the cross-comparison of ten commercial serological assays-a chemiluminescence-based platform, two ELISAs and seven colloidal gold lateral flow immunoassays (LFIAs)-on an identical panel of 110 SARS-CoV-2-positive samples and 50 pre-pandemic negatives. There was a wide variation in the performance of the different platforms, with specificity ranging from 82% to 100%, and overall sensitivity from 60.9% to 87.3%. However, the head-to-head comparison of multiple sero-diagnostic assays on identical sample sets revealed that performance is highly dependent on the time of sampling, with sensitivities of over 95% seen in several tests when assessing samples from more than 20 days post onset of symptoms. Furthermore, these analyses identified clear outlying samples that were negative in all tests, but were later shown to be from individuals with mildest disease presentation. Rigorous comparison of antibody testing platforms will inform the deployment of point-of-care technologies in healthcare settings and their use in the monitoring of SARS-CoV-2 infections.


Subject(s)
Antibodies, Viral/analysis , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Point-of-Care Systems , Serologic Tests/methods , Adult , Aged , Betacoronavirus , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Community Health Services , Coronavirus Nucleocapsid Proteins , Enzyme-Linked Immunosorbent Assay , Female , Hospitals , Humans , Immunoassay , Luminescent Measurements , Male , Middle Aged , Nucleocapsid Proteins/immunology , Pandemics , Phosphoproteins , SARS-CoV-2 , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology
16.
Infect Prev Pract ; 2(3): 100069, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-640118

ABSTRACT

From its origins as a left-field, experimental, and even "maverick" intervention, faecal microbiota transplantation (FMT) is now a well-recognised, accepted, and potentially life-saving therapeutic strategy, for the management of recurrent Clostridiodes difficile infection (rCDI). It is being investigated as a treatment for a growing number of diseases including hepatic encephalopathy and eradication of antimicrobial resistant organisms, and the list of indications will likely expand in the future. There is no universally accepted definition of what FMT is, and its mechanism of action remains incompletely understood; this has likely contributed to the breadth of approaches to regulation depending on interpretation. In the UK FMT is considered a medicinal product, in North America, a biological product, whereas in parts of Europe, it is considered a human cell/tissue product. Regulation seeks to improve quality and safety, however, lack of standardisation creates confusion, and overly restrictive regulation may hamper widespread access and discourage research using FMT. FMT is generally considered safe, especially if rigorous donor screening and testing is conducted. Most short-term risks are associated with the delivery method (e.g. colonoscopy). Longer term risks are less well described but longitudinal follow-up of treated cohorts is in place to assess for this, and no signal towards harm has been found to date. Rarely it has been associated with adverse outcomes including the transmission of antibiotic resistant bacteria, and even death. It is vital patients undergoing FMT are well informed to the currently appreciated risks and benefits before proceeding.

17.
Nat Med ; 26(10): 1623-1635, 2020 10.
Article in English | MEDLINE | ID: covidwho-717130

ABSTRACT

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Dendritic Cells/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Aged , B-Lymphocyte Subsets/immunology , Basophils/immunology , Betacoronavirus , COVID-19 , Case-Control Studies , Cell Cycle , Chemokine CXCL10/immunology , Chemokines/immunology , Cohort Studies , Coronavirus Infections/blood , Disease Progression , Female , Flow Cytometry , Hospitalization , Humans , Immunologic Memory , Immunophenotyping , Interleukin-10/immunology , Interleukin-6/immunology , Leukocyte Count , Lymphocyte Activation/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Prognosis , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Up-Regulation
18.
Analyst ; 145(16): 5638-5646, 2020 Aug 21.
Article in English | MEDLINE | ID: covidwho-637680

ABSTRACT

An evaluation of a rapid portable gold-nanotechnology measuring SARS-CoV-2 IgM, IgA and IgG antibody concentrations against spike 1 (S1), spike 2 (S) and nucleocapsid (N) was conducted using serum samples from 74 patients tested for SARS-CoV-2 RNA on admission to hospital, and 47 historical control patients from March 2019. 59 patients were RNA(+) and 15 were RNA(-). A serum (±) classification was derived for all three antigens and a quantitative serological profile was obtained. Serum(+) was identified in 30% (95% CI 11-48) of initially RNA(-) patients, in 36% (95% CI 17-54) of RNA(+) patients before 10 days, 77% (95% CI 67-87) between 10 and 20 days and 95% (95% CI 86-100) after 21 days. The patient-level diagnostic accuracy relative to RNA(±) after 10 days displayed 88% sensitivity (95% CI 75-95) and 75% specificity (95% CI 22-99), although specificity compared with historical controls was 100% (95%CI 91-100). This study provides robust support for further evaluation and validation of this novel technology in a clinical setting and highlights challenges inherent in assessment of serological tests for an emerging disease such as COVID-19.


Subject(s)
Antibodies, Viral/analysis , Betacoronavirus/immunology , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Serologic Tests/methods , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Cohort Studies , Coronavirus Infections/blood , Coronavirus Nucleocapsid Proteins , False Negative Reactions , Female , Gold/chemistry , Humans , Immunoglobulin A/analysis , Immunoglobulin A/immunology , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Immunoglobulin M/analysis , Immunoglobulin M/immunology , Male , Metal Nanoparticles/chemistry , Middle Aged , Nucleocapsid Proteins/immunology , Pandemics , Phosphoproteins , Pneumonia, Viral/blood , SARS-CoV-2 , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology , Young Adult
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