Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 35
Filter
1.
Bioengineering & Translational Medicine ; 7(2), 2022.
Article in English | ProQuest Central | ID: covidwho-1848906

ABSTRACT

There is clinical need for a quantifiable point‐of‐care (PoC) SARS‐CoV‐2 neutralizing antibody (nAb) test that is adaptable with the pandemic's changing landscape. Here, we present a rapid and semi‐quantitative nAb test that uses finger stick or venous blood to assess the nAb response of vaccinated population against wild‐type (WT), alpha, beta, gamma, and delta variant RBDs. It captures a clinically relevant range of nAb levels, and effectively differentiates prevaccination, post first dose, and post second dose vaccination samples within 10 min. The data observed against alpha, beta, gamma, and delta variants agrees with published results evaluated in established serology tests. Finally, our test revealed a substantial reduction in nAb level for beta, gamma, and delta variants between early BNT162b2 vaccination group (within 3 months) and later vaccination group (post 3 months). This test is highly suited for PoC settings and provides an insightful nAb response in a postvaccinated population.

2.
Am J Respir Crit Care Med ; 2022 May 17.
Article in English | MEDLINE | ID: covidwho-1846615

ABSTRACT

RATIONALE: Uncertainty regarding the natural history of coronavirus disease 2019 (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized COVID-19 patients. OBJECTIVES: Evaluate 90-day clinical course of patients hospitalized with COVID-19 comparing three distinct definitions of recovery. METHODS: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach 2) the Therapeutics for Inpatients with COVID-19 (TICO) trials "sustained recovery" approach, and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-intensive care unit setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. MEASUREMENTS AND MAIN RESULTS: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age 68 vs. 59 years; p<0.001) and more had a comorbidity (84% vs. 70%; p<0.001). Of 170 discordant participants, 106 (62%) had post-discharge events captured by the TICO approach. CONCLUSIONS: Among patients hospitalized with COVID-19, 20% had clinically significant post-discharge events within 90 days after randomization, in patients that would be considered "recovered" using the hospital discharge approach. Employing the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should employ follow-up times up to 90 days to assess clinical recovery more accurately.

3.
Clin Infect Dis ; 2022 May 11.
Article in English | MEDLINE | ID: covidwho-1840043

ABSTRACT

BACKGROUND: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity has raised the need for booster vaccinations. However, which combination of COVID-19 vaccines offers the strongest immune response against Omicron variant is unknown. METHODS: This randomized, subject-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. 100 BNT162b2-vaccinated individuals were enrolled and randomized 1: 1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB') or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and VOCs at Day 28. RESULTS: 51 participants were allocated to BBB and 49 to BBM; 50 and 48 respectively were analyzed for safety and immunogenicity outcomes. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382  IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751  IU/mL 95% CI, 25,281 to 35,011, p = 0.034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97.9 to 99.3%) vs BBM 99.3% (IQR 98.8 to 99.5%, p = 0.021). On sub-group analysis, significant differences in mean spike antibody titer and live Omicron neutralization titer was only observed in older adults. Median surrogate neutralizing antibody level against all VOCs was also significantly higher with BBM in older adults, and against Omicron was BBB 72.8% (IQR 54.0 to 84.7%) vs BBM 84.3% (IQR 78.1 to 88.7%, p = 0.0073). Both vaccines were well tolerated. CONCLUSIONS: Heterologous mRNA-1273 booster vaccination induced a stronger neutralizing response against the Omicron variant in older individuals compared with homologous BNT123b2.

4.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-330621

ABSTRACT

Background: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity has raised the need for booster vaccinations. However, which combination of COVID-19 vaccines offers the strongest immune response against Omicron variant is unknown. Methods: This randomized, subject-blinded, controlled trial assess the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. 100 BNT162b2-vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2+BNT162b2+BNT162b2;‘BBB’) or heterologous mRNA booster vaccine (BNT162b2+BNT162b2+mRNA-1273;‘BBM’). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and VOCs at Day 28. Results: 51 participants were allocated to BBB and 49 to BBM;50 and 48 respectively were analyzed for safety and immunogenicity outcomes. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382 IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751 IU/mL 95% CI, 25,281 to 35,011, p=0·034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97·9 to 99·3%) vs BBM 99.3% (IQR 98·8 to 99·5%, p=0·021). On sub-group analysis, significant differences in mean spike antibody titer and live Omicron neutralization titer was only observed in older adults. Median surrogate neutralizing antibody level against all VOCs was also significantly higher with BBM in older adults, and against Omicron was BBB 72·8% (IQR 54·0 to 84·7%) vs BBM 84·3% (IQR 78·1 to 88·7%, p=0·0073). Both vaccines were well tolerated. Conclusions: Heterologous mRNA-1273 booster vaccination induced a stronger neutralizing response against the Omicron variant in older individuals compared with homologous BNT123b2.

5.
Antibiotics (Basel) ; 11(3)2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1731895

ABSTRACT

Data on use of monoclonal antibodies (mAbs) in hospitalized patients are limited. In this cross-sectional study, we evaluated the use of mAbs for early treatment of unvaccinated hospitalized patients with mild-to-moderate COVID-19. All inpatients at our center were screened on 27 October 2021. Primary outcome was in-hospital deterioration as defined by a composite of oxygen requirement, intensive care unit (ICU) admission, or mortality within 28 days of admission. Ninety-four out of 410 COVID-19 inpatients were included in the final analysis, of whom 19 (20.2%) received early treatment with sotrovimab. The median age was 73 years (IQR 61-83), and 35 (37.2%) were female. Although the treatment group was significantly older and had more comorbidities, there was a lower proportion of progression to oxygen requirement (31.6% vs. 54.7%), ICU admission (10.5% vs. 24.0%), or mortality (5.3% vs. 13.3%). Kaplan-Meier curves showed a significant difference in time to in-hospital deterioration (log-rank test, p = 0.043). Cox proportional hazards model for in-hospital deterioration showed that sotrovimab treatment was protective (hazard ratio, 0.41; 95% CI, 0.17-0.99; p = 0.047) after adjustment for baseline ISARIC deterioration score. Our findings support the use of sotrovimab for early treatment in hospitalized patients with mild-to-moderate COVID-19 at a high risk of disease progression.

6.
Antibiotics (Basel) ; 11(2)2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-1667025

ABSTRACT

BACKGROUND: COVID-19 imposes challenges in antibiotic decision-making due to similarities between bacterial pneumonia and moderate to severe COVID-19. We evaluated the effects of antibiotic therapy on the clinical outcomes of COVID-19 pneumonia patients and diagnostic accuracy of key inflammatory markers to inform antibiotic decision-making. METHODS: An observational cohort study was conducted in patients hospitalised with COVID-19 at the National Centre for Infectious Diseases and Tan Tock Seng Hospital, Singapore, from January to April 2020. Patients were defined as receiving empiric antibiotic treatment for COVID-19 if started within 3 days of diagnosis. RESULTS: Of 717 patients included, 86 (12.0%) were treated with antibiotics and 26 (3.6%) had documented bacterial infections. Among 278 patients with COVID-19 pneumonia, those treated with antibiotics had more diarrhoea (26, 34.7% vs. 24, 11.8%, p < 0.01), while subsequent admissions to the intensive care unit were not lower (6, 8.0% vs. 10, 4.9% p = 0.384). Antibiotic treatment was not independently associated with lower 30-day (adjusted odds ratio, aOR 19.528, 95% confidence interval, CI 1.039-367.021) or in-hospital mortality (aOR 3.870, 95% CI 0.433-34.625) rates after adjusting for age, co-morbidities and severity of COVID-19 illness. Compared to white cell count and procalcitonin level, the C-reactive protein level had the best diagnostic accuracy for documented bacterial infections (area under the curve, AUC of 0.822). However, the sensitivity and specificity were less than 90%. CONCLUSION: Empiric antibiotic use in those presenting with COVID-19 pneumonia did not prevent deterioration or mortality. More studies are needed to evaluate strategies to diagnose bacterial co-infections in these patients.

7.
Front Immunol ; 12: 710217, 2021.
Article in English | MEDLINE | ID: covidwho-1555700

ABSTRACT

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of "long COVID-19", and defines key cells and cytokines that delineate true and quasi-convalescent states.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , COVID-19/complications , Cohort Studies , Convalescence , Female , Humans , Male , Middle Aged
8.
Clin Infect Dis ; 73(9): e2932-e2942, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500989

ABSTRACT

BACKGROUND: Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. METHODS: We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years; 56% male; 38% with comorbidities). Respiratory samples (n = 74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n = 30), and plasma samples for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. RESULTS: Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9-18) days for IgM and 15.0 (12-20) days for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. CONCLUSIONS: We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials.


Subject(s)
COVID-19 , Pneumonia, Viral , Antibodies, Viral , Female , Humans , Immunoglobulin M , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Seroconversion
9.
Clin Trials ; 19(1): 52-61, 2022 02.
Article in English | MEDLINE | ID: covidwho-1463193

ABSTRACT

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.


Subject(s)
Antiviral Agents , COVID-19 , Adult , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Hospitalization , Humans , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Treatment Outcome
10.
J Clin Invest ; 131(17)2021 09 01.
Article in English | MEDLINE | ID: covidwho-1463086

ABSTRACT

Defining the correlates of protection necessary to manage the COVID-19 pandemic requires the analysis of both antibody and T cell parameters, but the complexity of traditional tests limits virus-specific T cell measurements. We tested the sensitivity and performance of a simple and rapid SARS-CoV-2 spike protein-specific T cell test based on the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2-vaccinated individuals (n = 112), convalescent asymptomatic and symptomatic COVID-19 patients (n = 130), and SARS-CoV-1-convalescent individuals (n = 12). The sensitivity of this rapid test is comparable to that of traditional methods of T cell analysis (ELISPOT, activation-induced marker). Using this test, we observed a similar mean magnitude of T cell responses between the vaccinees and SARS-CoV-2 convalescents 3 months after vaccination or virus priming. However, a wide heterogeneity of the magnitude of spike-specific T cell responses characterized the individual responses, irrespective of the time of analysis. The magnitude of these spike-specific T cell responses cannot be predicted from the neutralizing antibody levels. Hence, both humoral and cellular spike-specific immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 , Immunity, Cellular/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes , Adult , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
12.
N Engl J Med ; 385(15): 1401-1406, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1361670

ABSTRACT

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.).


Subject(s)
Antibodies, Viral/blood , Broadly Neutralizing Antibodies/blood , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/immunology , B-Lymphocytes , Humans , Immunogenicity, Vaccine , Phylogeny , SARS Virus/genetics , SARS-CoV-2/genetics , Survivors
13.
Front Immunol ; 12: 680188, 2021.
Article in English | MEDLINE | ID: covidwho-1311374

ABSTRACT

A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokines/blood , Hospitalization , SARS-CoV-2/genetics , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/therapeutic use , Antibodies, Viral/blood , Antibodies, Viral/immunology , Becaplermin/blood , Brain-Derived Neurotrophic Factor/blood , COVID-19/blood , COVID-19/immunology , Case-Control Studies , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Male , Membrane Proteins/blood , Middle Aged , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Treatment Outcome
14.
PLoS One ; 16(6): e0253487, 2021.
Article in English | MEDLINE | ID: covidwho-1280634

ABSTRACT

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , COVID-19/therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/metabolism , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Chemokines/genetics , Chlorocebus aethiops , Convalescence , Cricetinae , Cytokines/blood , Cytokines/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Immunoglobulin G/isolation & purification , Macaca mulatta , Male , Mice, Transgenic , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Load
15.
Front Immunol ; 12: 674279, 2021.
Article in English | MEDLINE | ID: covidwho-1266662

ABSTRACT

An accurate depiction of the convalescent COVID-19 immunome will help delineate the immunological milieu crucial for disease resolution and protection. Using mass cytometry, we characterized the immune architecture in patients recovering from mild COVID-19. We identified a virus-specific immune rheostat composed of an effector T (Teff) cell recall response that is balanced by the enrichment of a highly specialized regulatory T (Treg) cell subset. Both components were reactive against a peptide pool covering the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. We also observed expansion of IFNγ+ memory CD4+ T cells and virus-specific follicular helper T (TFH) cells. Overall, these findings pinpoint critical immune effector and regulatory mechanisms essential for a potent, yet harmless resolution of COVID-19 infection.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , CD4-Positive T-Lymphocytes/immunology , Child , Child, Preschool , Female , Humans , Male , Spike Glycoprotein, Coronavirus/immunology , T Follicular Helper Cells/immunology , T-Lymphocytes, Regulatory/immunology , Young Adult
16.
EBioMedicine ; 66: 103319, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1174196

ABSTRACT

BACKGROUND: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. METHODS: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth's logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. FINDINGS: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades 'O' were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. INTERPRETATION: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility.


Subject(s)
COVID-19/etiology , COVID-19/transmission , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Adult , Age Factors , Aged , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Female , Humans , Hypoxia/therapy , Hypoxia/virology , Male , Middle Aged , Singapore/epidemiology , Viral Load
17.
Elife ; 102021 03 23.
Article in English | MEDLINE | ID: covidwho-1146275

ABSTRACT

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Endothelium, Vascular/pathology , Lymphocyte Activation , Adult , Aged , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/pathology , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelium, Vascular/immunology , Female , Humans , Male , Middle Aged , Risk Factors
18.
Nat Biotechnol ; 38(9): 1073-1078, 2020 09.
Article in English | MEDLINE | ID: covidwho-1023948

ABSTRACT

A robust serological test to detect neutralizing antibodies to SARS-CoV-2 is urgently needed to determine not only the infection rate, herd immunity and predicted humoral protection, but also vaccine efficacy during clinical trials and after large-scale vaccination. The current gold standard is the conventional virus neutralization test requiring live pathogen and a biosafety level 3 laboratory. Here, we report a SARS-CoV-2 surrogate virus neutralization test that detects total immunodominant neutralizing antibodies targeting the viral spike (S) protein receptor-binding domain in an isotype- and species-independent manner. Our simple and rapid test is based on antibody-mediated blockage of the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor protein and the receptor-binding domain. The test, which has been validated with two cohorts of patients with COVID-19 in two different countries, achieves 99.93% specificity and 95-100% sensitivity, and differentiates antibody responses to several human coronaviruses. The surrogate virus neutralization test does not require biosafety level 3 containment, making it broadly accessible to the wider community for both research and clinical applications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2 , Antibodies/immunology , Antibodies/pharmacology , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Neutralization Tests , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
19.
Ann Acad Med Singap ; 49(11): 857-869, 2020 11.
Article in English | MEDLINE | ID: covidwho-1001259

ABSTRACT

INTRODUCTION: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore. METHODS: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission. RESULTS: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia; one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days; one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive >11 weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal samples taken at birth were negative; placenta and cord histology showed non-specific inflammation; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5). CONCLUSION: The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection; this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta.


Subject(s)
COVID-19/epidemiology , Pregnancy Complications, Infectious/epidemiology , Pregnancy Outcome/epidemiology , Abortion, Spontaneous/epidemiology , Adult , COVID-19/physiopathology , COVID-19/transmission , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Cohort Studies , Disease Transmission, Infectious/statistics & numerical data , Female , Fetal Blood/immunology , Humans , Infectious Disease Transmission, Vertical/statistics & numerical data , Live Birth/epidemiology , Maternal Age , Milk, Human/chemistry , Milk, Human/virology , Obesity, Maternal/epidemiology , Placenta/pathology , Pregnancy , Pregnancy Complications, Infectious/physiopathology , Pregnancy Trimester, First , Pregnancy Trimester, Second , Prospective Studies , RNA, Viral/analysis , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Singapore/epidemiology , Umbilical Cord/pathology , Young Adult
20.
medRxiv ; 2021 Apr 08.
Article in English | MEDLINE | ID: covidwho-939615

ABSTRACT

BACKGROUND: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership initiated the Therapeutics for Inpatients with COVID-19 (TICO). TICO is a multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. Four agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. PROTOCOL DESIGN AND IMPLEMENTATION: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. TICO utilizes a MAMS design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo as well as the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and DSMB schedule was developed for the study of agents with limited in-human data. CHALLENGES: Challenges included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff, and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the TICO protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required.

SELECTION OF CITATIONS
SEARCH DETAIL