Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients
TL;DR: This study observed a significant expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay, and found that Sars-Cov-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS -CoV -2-neutralizing antibody titers.
Abstract: COVID-19, caused by SARS-CoV-2, emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. We observed a significant expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of sampling. Additionally, we found that SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers. This study constitutes a detailed description of B cell and antibody responses to SARS-CoV-2 in COVID-19, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.
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TL;DR: In this paper, a systematic review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 1/01/2020-26/06/2020.
Abstract: Introduction
Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020.
Methods
Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised.
Results
150 papers were included. Most studies (75%) were observational in design, and included papers were generally of moderate quality based on hospitalised patients. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, and up to around 3 months from disease onset, although inconsistencies remain concerning clinical correlates. Development of neutralising antibodies following SARS-CoV-2 infection is typical, although titres may be low. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross reactivity but limited cross neutralisation occurs with other HCoVs. Evidence for protective immunity in vivo is limited to small, short-term animal studies, which show promising initial results in the immediate recovery phase.
Interpretation
Published literature on immune responses to SARS-CoV-2 is of variable quality with considerable heterogeneity with regard to methods, study participants, outcomes measured and assays used. Antibody dynamics have been evaluated thoroughly in the acute phase but longer follow up and a comprehensive assessment of the role of demographic characteristics and disease severity is needed. The role of protective neutralising antibodies is emerging, with implications for therapeutics and vaccines. Large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.
172 citations
Cites background from "Expansion of SARS-CoV-2-specific An..."
...Most studies, including all those considered high quality, suggested that neutralisation ability broadly correlated with total virus-specific IgG.29,49,67,74,87,99–101 Specifically, high quality studies found that neutralisation ability correlated positively with anti-S IgG49,72,87,99 or anti-RBD IgG.72,74,87,102 There was more limited evidence for correlation with anti-RBD IgM, including one high quality study,51,84 and IgA.93,99 A number of basic science studies also identified specific neutralising antibodies....
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...There was more limited evidence for correlation with anti-RBD IgM, including one high quality study,(51,84) and IgA.(93,99)...
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TL;DR: This review will discuss the performance of different laboratory diagnostic tests and platforms, as well as suitable clinical samples for testing, and related biosafety protection, for the diagnosis of COVID-19 caused by SARS-CoV-2.
95 citations
Cites background from "Expansion of SARS-CoV-2-specific An..."
...These studies indicating that SARS-CoV-2 antibody titers in COVID- 19 patients may reflect the capacity of serum to neutralize SARS-CoV-2 [95]....
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TL;DR: The results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination, and examine the immunity induced by either prime and boost with the adenoviral vectored vaccine ChAd Ox1 or prime with ChAdOx1 andBoost with a messenger RNA (mRNA) vaccine.
Abstract: Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy. We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–boosted participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relative to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination. Description Enhancing the immune response Many lives have been saved by the vaccines that were rapidly developed against severe acute respiratory syndrome coronavirus 2. As the pandemic continues, we are faced with waning vaccine-induced immunity and variants of the virus that partly evade this immunity, and thus there are questions regarding boosting strategies. Kaku et al. examined the immunity induced by either prime and boost with the adenoviral vectored vaccine ChAdOx1 or prime with ChAdOx1 and boost with a messenger RNA (mRNA) vaccine. Whereas ChAdOx1 expresses wild-type viral spike, the mRNA vaccines express spike stabilized in the prefusion conformation. Boosting with the mRNA vaccine focuses the response on epitopes in the prefusion conformation and results in overall higher neutralizing activity and increased breadth against variants of concern. —VV ChAdOx1 followed by mRNA-1273 vaccination induces higher-quality memory B cell responses relative to two doses of ChAdOx1.
50 citations
TL;DR: Clinical evidence suggests that migration of immune cells to the affected organs can produce an exacerbated release of proinflammatory mediators that contribute to disease and render the immune response as a major player during the development of the COVID-19 disease.
Abstract: The World Health Organization (WHO) announced in March a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This new infectious disease was named Coronavirus Disease 19 (COVID-19), and at October 2020, more than 39,000,000 cases of SARS-CoV-2 have been detected worldwide leading to near 1,100,000 deaths. Clinically, COVID-19 is characterized by clinical manifestations, such as fever, dry cough, headache, and in more severe cases, respiratory distress. Moreover, neurological-, cardiac-, and renal-related symptoms have also been described. Clinical evidence suggests that migration of immune cells to the affected organs can produce an exacerbated release of proinflammatory mediators that contribute to disease and render the immune response as a major player during the development of the COVID-19 disease. Due to the current sanitary situation, the development of vaccines is imperative. Up to the date, 42 prototypes are being tested in humans in different clinical stages, with 10 vaccine candidates undergoing evaluation in phase III clinical trials. In the same way, the search for an effective treatment to approach the most severe cases is also in constant advancement. Several potential therapies have been tested since COVID-19 was described, including antivirals, antiparasitic and immune modulators. Recently, clinical trials with hydroxychloroquine-a promising drug in the beginning-were suspended. In addition, the Food and Drug Administration (FDA) approved convalescent serum administration as a treatment for SARS-CoV-2 patients. Moreover, monoclonal antibody therapy is also under development to neutralize the virus and prevent infection. In this article, we describe the clinical manifestations and the immunological information available about COVID-19 disease. Furthermore, we discuss current therapies under study and the development of vaccines to prevent this disease.
33 citations
Cites background from "Expansion of SARS-CoV-2-specific An..."
...Also, in severe cases, ASCs levels are elevated compared to healthy controls, with a 31% expansion 7 days after the onset of the symptoms (109)....
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TL;DR: A randomised Phase-1/2 trial followed by a Phase-2 trial were conducted to assess the safety and immunogenicity of the COVID-19 vaccine Corbevax and select to an optimum formulation as discussed by the authors .
31 citations
References
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TL;DR: The epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of patients with laboratory-confirmed 2019-nCoV infection in Wuhan, China, were reported.
36,578 citations
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
21,455 citations
"Expansion of SARS-CoV-2-specific An..." refers background in this paper
...Characterizing immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is an important step towards understanding correlates of protection (Zhu et al. 2020)....
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TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.
16,857 citations
"Expansion of SARS-CoV-2-specific An..." refers background in this paper
...3 Introduction 50 Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 51 coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic 52 (1)....
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TL;DR: A validated diagnostic workflow for 2019-nCoV is presented, its design relying on close genetic relatedness of 2019- nCoV with SARS coronavirus, making use of synthetic nucleic acid technology.
Abstract: Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
6,229 citations
"Expansion of SARS-CoV-2-specific An..." refers background or methods in this paper
...5 (9-30) Duration of hospitalization, days, median (range) 7....
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...To analyze for possible SARS-CoV-2 viremia, we screened all serum samples by real time RT-PCR (Corman et al. 2020)....
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...5 (3-25) Intensive care unit (ICU) treatmenta, n (%) 3 (15) Fatal outcome, n (%) 1 (5) Comorbidities n (%) Overweight (BMI >25), n/N (%) 14/14 (100)b Diabetes mellitus type II 4 (20) Hypertension 3 (15) Asthma 2 (10) Cardiovascular disease 1 (5) Symptoms n (%) Fever (>38°C) 20 (100) Cough 20 (100) Respiratory difficulties (SpO2 ≤ 93% on room air) 20 (100) Myalgia 9 (45) Chest pain 6 (30) Diarrhea 4 (20) Treatment n (%) Supplemental oxygenc 20 (100) High flow nasal oxygen 4 (20) Inhaled bronchodilators 2 (10) Low molecular weight heparin 17 (85) Antibiotics 14 (70) Immunomodulatory drugsd (given before sampling) 3 (15)...
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...Red asterisks represent patients with detectable levels of SARS-CoV-2 RNA in serum....
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...Detection of SARS-CoV-2 RNA in Serum of COVID-19 Patients An important aspect of neutralizing antibodies is to limit viral spread....
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TL;DR: Investigation of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19 and shows the novel coronavirus might mainly act on lymphocytes, especially T lymphocytes.
Abstract: BACKGROUND: In December 2019, coronavirus 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from 10 January to 12 February 2020 were collected and analyzed. The data on laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between patients with severe and nonsevere infection. RESULTS: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as having severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough, and myalgia. Severe cases tend to have lower lymphocyte counts, higher leukocyte counts and neutrophil-lymphocyte ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and were more impaired in severe cases. Both helper T (Th) cells and suppressor T cells in patients with COVID-19 were below normal levels, with lower levels of Th cells in the severe group. The percentage of naive Th cells increased and memory Th cells decreased in severe cases. Patients with COVID-19 also have lower levels of regulatory T cells, which are more obviously decreased in severe cases. CONCLUSIONS: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis, and treatment of COVID-19.
3,532 citations
"Expansion of SARS-CoV-2-specific An..." refers background in this paper
...Increased T cell Activation and Inflammatory Response in COVID-19 Patients According to the latest reports, COVID-19 patients generally present with decreased lymphocyte numbers in peripheral blood (Wang et al. 2020; Qin et al. 2020; Zhang et al. 2020)....
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