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1.
Front Immunol ; 12: 728021, 2021.
Article in English | MEDLINE | ID: covidwho-1538370

ABSTRACT

As the COVID-19 pandemic continues, the authorization of vaccines for emergency use has been crucial in slowing down the rate of infection and transmission of the SARS-CoV-2 virus that causes COVID-19. In order to investigate the longitudinal serological responses to SARS-CoV-2 natural infection and vaccination, a large-scale, multi-year serosurveillance program entitled SPARTA (SARS SeroPrevalence and Respiratory Tract Assessment) was initiated at 4 locations in the U.S. The serological assay presented here measuring IgG binding to the SARS-CoV-2 receptor binding domain (RBD) detected antibodies elicited by SARS-CoV-2 infection or vaccination with a 95.5% sensitivity and a 95.9% specificity. We used this assay to screen more than 3100 participants and selected 20 previously infected pre-immune and 32 immunologically naïve participants to analyze their antibody binding to RBD and viral neutralization (VN) responses following vaccination with two doses of either the Pfizer-BioNTech BNT162b2 or the Moderna mRNA-1273 vaccine. Vaccination not only elicited a more robust immune reaction than natural infection, but the level of neutralizing and anti-RBD antibody binding after vaccination is also significantly higher in pre-immune participants compared to immunologically naïve participants (p<0.0033). Furthermore, the administration of the second vaccination did not further increase the neutralizing or binding antibody levels in pre-immune participants (p=0.69). However, ~46% of the immunologically naïve participants required both vaccinations to seroconvert.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , COVID-19 Serological Testing , COVID-19 Vaccines/immunology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Time Factors , United States , Young Adult
4.
Lancet Respir Med ; 9(5): 522-532, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537199

ABSTRACT

BACKGROUND: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. METHODS: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. FINDINGS: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1·7 [-9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [-6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI -7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. INTERPRETATION: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FUNDING: Sanofi and Regeneron Pharmaceuticals.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , International Cooperation , Male , Middle Aged , Mortality , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
5.
Lancet Respir Med ; 9(5): 511-521, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537197

ABSTRACT

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , India , Male , Middle Aged , Mortality , Respiration, Artificial/methods , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
7.
J Clin Invest ; 131(18)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1533156

ABSTRACT

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Evolution, Molecular , Immune Evasion/genetics , Mutation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , New York City , Protein Domains , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
8.
Emerg Microbes Infect ; 10(1): 2141-2150, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1532382

ABSTRACT

BACKGROUND: We studied humoral and cellular responses against SARS-CoV-2 longitudinally in a homogeneous population of healthy young/middle-aged men of South Asian ethnicity with mild COVID-19. METHODS: In total, we recruited 994 men (median age: 34 years) post-COVID-19 diagnosis. Repeated cross-sectional surveys were conducted between May 2020 and January 2021 at six time points - day 28 (n = 327), day 80 (n = 202), day 105 (n = 294), day 140 (n = 172), day 180 (n = 758), and day 280 (n = 311). Three commercial assays were used to detect anti-nucleoprotein (NP) and neutralizing antibodies. T cell response specific for Spike, Membrane and NP SARS-CoV-2 proteins was tested in 85 patients at day 105, 180, and 280. RESULTS: All serological tests displayed different kinetics of progressive antibody reduction while the frequency of T cells specific for different structural SARS-CoV-2 proteins was stable over time. Both showed a marked heterogeneity of magnitude among the studied cohort. Comparatively, cellular responses lasted longer than humoral responses and were still detectable nine months after infection in the individuals who lost antibody detection. Correlation between T cell frequencies and all antibodies was lost over time. CONCLUSION: Humoral and cellular immunity against SARS-CoV-2 is induced with differing kinetics of persistence in those with mild disease. The magnitude of T cells and antibodies is highly heterogeneous in a homogeneous study population. These observations have implications for COVID-19 surveillance, vaccination strategies, and post-pandemic planning.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Antibodies, Neutralizing/blood , Cross-Sectional Studies , Humans , Male , Nucleocapsid Proteins/immunology
9.
Lancet Oncol ; 22(6): 765-778, 2021 06.
Article in English | MEDLINE | ID: covidwho-1531901

ABSTRACT

BACKGROUND: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer. METHODS: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 µg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 µg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031). FINDINGS: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported. INTERPRETATION: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine. FUNDING: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/immunology , Neoplasms/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/blood , COVID-19/complications , COVID-19/virology , COVID-19 Vaccines/immunology , Dose-Response Relationship, Immunologic , Female , Humans , Immunogenicity, Vaccine/immunology , London/epidemiology , Male , Middle Aged , Neoplasms/blood , Neoplasms/complications , Neoplasms/virology , Prospective Studies , SARS-CoV-2 , Wales
10.
Curr Opin Immunol ; 71: 111-116, 2021 08.
Article in English | MEDLINE | ID: covidwho-1531148

ABSTRACT

COVID-19 is a pandemic of unprecedented proportions in recent human history. Less than 18 months since the onset of the pandemic, there are close to two hundred million confirmed cases and four million deaths worldwide. There have also been massive efforts geared towards finding safe and effective vaccines. By July 2021 there were 184 COVID-19 vaccine candidates in pre-clinical development, 105 in clinical development, and 18 vaccines approved for emergency use by at least one regulatory authority. These vaccines include whole virus live attenuated or inactivated, protein-based, viral vector, and nucleic acid vaccines. By mid-2021 three billion doses of COVID-19 vaccine have been administered around the world, mostly in high-income countries. COVID-19 vaccination provides hope for an end to the pandemic, if and only if there would be equal access and optimal uptake in all countries around the world.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Humans , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccines, DNA/immunology , Vaccines, Inactivated/immunology
11.
Curr Opin Immunol ; 71: 13-20, 2021 08.
Article in English | MEDLINE | ID: covidwho-1531147

ABSTRACT

Vaccines developed in high-income countries have been enormously successful in reducing the global burden of infectious diseases, saving perhaps 2.5 million lives per year, but even for successful cases, like the rotavirus vaccine, global implementation may take a decade or more. For unincentivized vaccines, the delays are even more profound, as both the supply of a vaccine from developing country manufacturers and vaccine demand from countries with the high disease burdens have to be generated in order for impact to be manifest. A number of poverty-associated infectious diseases, whose burden is greatest in low-income and middle-income countries, would benefit from appropriate levels of support for vaccine development such as Group A Streptococcus, invasive non-typhoid salmonella, schistosomiasis, shigella, to name a few. With COVID-19 vaccines we will hopefully be able to provide novel vaccine technology to all countries through a unique collaborative effort, the COVAX facility, led by the World Health Organization (WHO), Gavi, and the Coalition for Epidemic Preparedness Innovations (CEPI). Whether this effort can deliver vaccine to all its participating countries remains to be seen, but this ambitious effort to develop, manufacture, distribute, and vaccinate 60-80% of the world's population will hopefully be a lasting legacy of COVID-19.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/immunology , Global Health , Humans , SARS-CoV-2/immunology
13.
J Med Virol ; 93(12): 6813-6817, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530183

ABSTRACT

Vaccination for SARS-CoV-2 is necessary to overcome coronavirus disease 2019 (COVID-19). However, the time-dependent vaccine-induced immune response is not well understood. This study aimed to investigate the dynamics of SARS-CoV-2 antispike immunoglobulin G (IgG) response. Medical staff participants who received two sequential doses of the BNT162b2 vaccination on days 0 and 21 were recruited prospectively from the Musashino Red Cross Hospital between March and May 2021. The quantitative antispike receptor-binding domain (RBD) IgG antibody responses were measured using the Abbott SARS-CoV-2 IgGII Quant assay (cut off ≥50 AU/ml). A total of 59 participants without past COVID-19 history were continuously tracked with serum samples. The median age was 41 (22-75) years, and 14 participants were male (23.7%). The median antispike RBD IgG and seropositivity rates were 0 (0-31.1) AU/ml, 0.3 (0-39.5) AU/ml, 529.1 (48.3-8711.4) AU/ml, 18,836.9 (742.2-57,260.4) AU/ml, and 0%, 0%, 98.3%, and 100% on days 0, 3, 14, and 28 after the first vaccination, respectively. The antispike RBD IgG levels were significantly increased after day 14 from vaccination (p < 0.001) The BNT162b2 vaccination led almost all participants to obtain serum antispike RBD IgG 14 days after the first dose.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/virology , Female , Humans , Immunologic Tests/methods , Male , Middle Aged , Prospective Studies , Vaccination/methods , Young Adult
14.
J Med Virol ; 93(12): 6798-6802, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530182

ABSTRACT

Viral infections have been on the rise for the past decades. The impact of the viruses worsened amidst the pandemic burdening the already overwhelmed health care system in African countries. This article sheds light on how the coronavirus together with the already existing viral infections, some of which re-emerged, impacted the continent. The strategies in place such as immunization, education, will have to be strengthened in all African countries to reduce the burden. Furthermore, governments can further collaborate with other countries in creating guidelines to reduce co-infection of the diseases.


Subject(s)
COVID-19/enzymology , COVID-19/virology , Coinfection/epidemiology , Coinfection/virology , Virus Diseases/epidemiology , Africa/epidemiology , COVID-19/immunology , Coinfection/immunology , Humans , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Virus Diseases/immunology , Virus Diseases/virology
15.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1529016

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
17.
Int J Biol Sci ; 17(1): 20-31, 2021.
Article in English | MEDLINE | ID: covidwho-1526974

ABSTRACT

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global infection, and is seriously threatening human life, especially cancer patients. Thus, we sought to determine the clinical roles of ACE2 (the cell entry receptor of SARS-CoV-2) in ccRCC (clear cell renal cell carcinoma). TCGA, GEO and TIP datasets, and immunohistochemistry and western blot results were used to determine the prognostic and clinicopathological characteristics of ACE2. ACE2 expression was down-regulated in ccRCC tissues and cell lines. The multivariate Cox regression analysis results indicated that increased ACE2 expression was independent predictor of longer OS (HR: 0.8259, 95%CI: 0.7734-0.8819, P<0.0001) and RFS (HR: 0.8023, 95%CI: 0.7375-0.8729, P<0.0001) in ccRCC patients. Lower ACE2 expression was also associated with advanced tumor stage, higher histological grade and pathological stage, and metastasis. Besides, ACE2 expression was significantly positively and negatively correlated with CD4 Naïve infiltration and CD4 Memory infiltration, respectively. Moreover, higher CD4 Naïve and lower CD4 Memory infiltration levels were associated with better pathological features and longer OS and RFS. Furthermore, high ACE2 expression group in decreased CD4 Naïve, enriched CD4 Naïve and enriched CD4 memory cohort had favorable prognosis. These findings identified that AEC2 was significantly reduced in ccRCC, and decreased ACE2 was related to worse pathological features and poor prognosis. Low ACE2 expression in ccRCC may partially affect the prognosis due to altered immune cells infiltration levels.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Carcinoma, Renal Cell/immunology , Humans , Kidney Neoplasms/immunology , Prognosis , SARS-CoV-2/isolation & purification
18.
mSphere ; 6(5): e0075221, 2021 10 27.
Article in English | MEDLINE | ID: covidwho-1526451

ABSTRACT

During the progression of coronavirus disease 2019 (COVID-19), immune response and inflammation reactions are dynamic events that develop rapidly and are associated with the severity of disease. Here, we aimed to develop a predictive model based on the immune and inflammatory response to discriminate patients with severe COVID-19. COVID-19 patients were enrolled, and their demographic and immune inflammatory reaction indicators were collected and analyzed. Logistic regression analysis was performed to identify the independent predictors, which were further used to construct a predictive model. The predictive performance of the model was evaluated by receiver operating characteristic curve, and optimal diagnostic threshold was calculated; these were further validated by 5-fold cross-validation and external validation. We screened three key indicators, including neutrophils, eosinophils, and IgA, for predicting severe COVID-19 and obtained a combined neutrophil, eosinophil, and IgA ratio (NEAR) model (NEU [109/liter] - 150×EOS [109/liter] + 3×IgA [g/liter]). NEAR achieved an area under the curve (AUC) of 0.961, and when a threshold of 9 was applied, the sensitivity and specificity of the predicting model were 100% and 88.89%, respectively. Thus, NEAR is an effective index for predicting the severity of COVID-19 and can be used as a powerful tool for clinicians to make better clinical decisions. IMPORTANCE The immune inflammatory response changes rapidly with the progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is responsible for clearance of the virus and further recovery from the infection. However, the intensified immune and inflammatory response in the development of the disease may lead to more serious and fatal consequences, which indicates that immune indicators have the potential to predict serious cases. Here, we identified both eosinophils and serum IgA as prognostic markers of COVID-19, which sheds light on new research directions and is worthy of further research in the scientific research field as well as clinical application. In this study, the combination of NEU count, EOS count, and IgA level was included in a new predictive model of the severity of COVID-19, which can be used as a powerful tool for better clinical decision-making.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , COVID-19/immunology , Clinical Decision Rules , Severity of Illness Index , Adult , Aged , Biomarkers/blood , COVID-19/blood , Clinical Decision-Making/methods , Disease Progression , Eosinophils/metabolism , Female , Humans , Immunoglobulin A/blood , Inflammation/blood , Inflammation/diagnosis , Inflammation/virology , Logistic Models , Male , Middle Aged , Neutrophils/metabolism , Predictive Value of Tests , Prognosis , Sensitivity and Specificity
19.
Blood Coagul Fibrinolysis ; 32(7): 427-433, 2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1526210

ABSTRACT

Immune thrombocytopenia is a haematological, autoimmune disorder characterized by elevated platelet demolition due to the presence of antiplatelet autoantibodies derived from B cells and to an irregular, deficient process of platelets production in bone marrow. In this review, after a brief presentation of 'old' strategies used nowadays yet, we focused on new drugs used in the treatment of immune thrombocytopenia and their mechanism of action and posology, basing on the last scientific literature. The observation that CoViD-19 can be associated with immune thrombocytopenia is also put in evidence. Particular attention will be dedicated on the concept that the ideal treatment should represent a solution not only for the failure of normal processes of production and survival of platelets, but also it should improve quality of life of patients, with minimum adverse events. Anyway, despite enormous advances of the last years, further investigations are necessary in order to define scrupulously long-term efficacy of new molecules proposed.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Aminopyridines/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , COVID-19/immunology , Histocompatibility Antigens Class I , Humans , Immunosuppressive Agents/therapeutic use , Morpholines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/immunology , Pyrimidines/therapeutic use , Receptors, Fc/antagonists & inhibitors , Receptors, Thrombopoietin/agonists , SARS-CoV-2/immunology , Syk Kinase/antagonists & inhibitors , Thiazoles/therapeutic use , Thiophenes/therapeutic use
20.
Expert Rev Anticancer Ther ; 21(12): 1371-1383, 2021 12.
Article in English | MEDLINE | ID: covidwho-1526146

ABSTRACT

INTRODUCTION: For the clinical treatment of cancer patients, coronavirus (SARS-CoV-2) can cause serious immune-related problems. Cancer patients, who experience immunosuppression due to the pathogenesis and severity of disease, may become more aggressive due to multiple factors such as age, comorbidities, and immunosuppression. In this pandemic era, COVID-19 causes lymphopenia, cancer cell awakening, inflammatory diseases, and a cytokine storm that worsens disease-related morbidity and prognosis. AREAS COVERED: We discuss all the risk factors of COVID-19 associated with cancer patients and propose new strategies to use antiviral and anticancer drugs for therapeutic purposes. We bring new drugs, cancers and COVID-19 treatment strategies together to address the immune system challenges faced by oncologists. EXPERT OPINION: The chronic inflammatory microenvironment caused by COVID-19 awakens dormant cancer cells through inflammation and autoimmune activation. Drug-related strategies to ensure that clinical treatment can reduce the susceptibility of cancer patients to COVID-19, and possible counter-measures to minimize the harm caused by the COVID-19 have been outlined. The response to the pandemic and recovery has been elaborated, which can provide information for long-term cancer treatment and speed up the optimization process.


Subject(s)
COVID-19/complications , Inflammation/drug therapy , Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammation/immunology , Inflammation/virology , Neoplasms/immunology , Neoplasms/virology , Prognosis , Risk Factors , Severity of Illness Index
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