Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity.
TL;DR: A combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects suggested roles for both CD4 plus T cells in protective immunity in COVID-19.
About: This article is published in Cell.The article was published on 2020-11-12 and is currently open access. It has received 1298 citations till now. The article focuses on the topics: Acquired immune system & Immune system.
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01 Jan 2020
TL;DR: Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
4,408 citations
TL;DR: It is shown that neutralization level is highly predictive of immune protection, and an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic is provided.
Abstract: Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic. Estimates of the levels of neutralizing antibodies necessary for protection against symptomatic SARS-CoV-2 or severe COVID-19 are a fraction of the mean level in convalescent serum and will be useful in guiding vaccine rollouts.
2,705 citations
TL;DR: This article analyzed multiple compartments of circulating immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months after infection.
Abstract: Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
1,980 citations
TL;DR: In this article, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ Tcells, and neutralizing antibodies all contribute to control SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19.
1,092 citations
TL;DR: In this paper, the authors investigated the degree to which infection with SARS-CoV-2 confers protection against subsequent reinfection, and estimated protection against repeat infection.
523 citations
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TL;DR: Wang et al. as discussed by the authors used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death, including older age, high SOFA score and d-dimer greater than 1 μg/mL.
20,189 citations
TL;DR: The epidemiological and clinical characteristics of novel coronavirus (2019-nCoV)-infected pneumonia in Wuhan, China, and hospital-associated transmission as the presumed mechanism of infection for affected health professionals and hospitalized patients are described.
Abstract: Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.
16,635 citations
"Antigen-Specific Adaptive Immunity ..." refers background in this paper
...…titers were associated with protection against SARS-CoV-2 in non-human primate infection and rechallenge studies (Chandrashekar et al., 2020; Gao et al., 2020), as well as in three candidate COVID-19 vaccine studies in non-human primates (Gao et al., 2020; Wang et al., 2020c; Yu et al., 2020)....
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...The detrimental effects of fewer naive T cells may also be amplified by the well-characterized total lymphopenia (Wang et al., 2020a) and general T cell cytopenia observed in severe COVID-19 (Wang et al., 2020b)....
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TL;DR: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area and assesses outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death.
Abstract: Importance There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.
7,282 citations
"Antigen-Specific Adaptive Immunity ..." refers background or result in this paper
...…increased rates of severe and fatal disease among older individuals (> 65 years old) (Docherty et al., 2020; Grasselli et al., 2020) and those with pre-existing medical conditions like cardiovascular disease, obesity, and type 2 diabetes mellitus (Docherty et al., 2020; Richardson et al., 2020)....
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...Severe cases can progress to respiratory failure associated with diffuse alveolar damage and acute respiratory distress syndrome (ARDS) (Grasselli et al., 2020; Richardson et al., 2020), similar to what was observed for SARS (Rockx et al., 2020)....
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TL;DR: Detailed virological analysis of nine cases of coronavirus disease 2019 (COVID-19) provides proof of active replication of the SARS-CoV-2 virus in tissues of the upper respiratory tract.
Abstract: Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity—but also aided in the control—of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6–8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples—in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19. Detailed virological analysis of nine cases of coronavirus disease 2019 (COVID-19) provides proof of active replication of the SARS-CoV-2 virus in tissues of the upper respiratory tract.
5,840 citations
TL;DR: The data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
Abstract: Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducte...
5,532 citations