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in category allergy and immunology

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1: A serological assay to detect SARS-CoV-2 seroconversion in humans
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Posted 18 Mar 2020

A serological assay to detect SARS-CoV-2 seroconversion in humans
92,699 downloads medRxiv allergy and immunology

Fatima Amanat, Daniel Stadlbauer, Shirin Strohmeier, Thi HO Nguyen, Veronika Chromikova, Meagan McMahon, Kaijun Jiang, Guha Asthagiri Arunkumar, Denise Jurczyszak, Jose Polanco, Maria Bermudez-Gonzalez, Giulio Kleiner, Teresa Aydillo, Lisa Miorin, Daniel Fierer, Luz Amarilis Lugo, Erna Milunka Kojic, Jonathan Stoever, Sean T.H. Liu, Charlotte Cunningham-Rundles, Philip L. Felgner, Thomas Moran, Adolfo Garcia-Sastre, Daniel Caplivski, Allen Cheng, Katherine Kedzierska, Olli Vapalahti, J Hepojoki, Viviana Simon, Florian Krammer

IntroductionSARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. MethodsHere we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. These assays were developed with negative control samples representing pre-COVID 19 background immunity in the general population and samples from COVID19 patients. ResultsThe assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as 3 days post symptom onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. ConclusionSerological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of Coronavirus SARS-Cov-2 antibody titers will also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.

2: Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine
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Posted 01 Feb 2021

Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine
32,455 downloads medRxiv allergy and immunology

Florian Krammer, Komal Srivastava, PARIS team, Viviana Simon

As COVID-19 vaccines are getting rolled out, an important question is arising: Should individuals who already had a SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines. In this short report, we are providing evidence that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naive individuals after the second dose. We also show that the reactogenicity is significantly higher in individuals who already have been infected with SARS-CoV-2 in the past. Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.

3: The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
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Posted 26 Feb 2020

The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
26,302 downloads medRxiv allergy and immunology

Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, Lei Liu, Shuye Zhang, Zheng Zhang

The novel coronavirus SARS-CoV-2, etiological agent of recently named Coronavirus infected disease (COVID-19) by WHO, has caused more than 2, 000 deaths worldwide since its emergency in Wuhan City, Hubei province, China, in December, 2019. The symptoms of COVID-19 varied from modest, mild to acute respiratory distress syndrome (ARDS), and the latter of which is generally associated with deregulated immune cytokine production; however, we currently know little as to the interplay between the extent of clinical symptoms and the compositions of lung immune microenvironment. Here, we comprehensively characterized the lung immune microenvironment with the bronchoalveolar lavage fluid (BALF) from 3 severe and 3 mild COVID-19 patients and 8 previously reported healthy lung controls through single-cell RNA sequence (scRNA-seq) combined with TCR-seq. Our data shows that monocyte-derived FCN1+ macrophages, whereas notFABP4+ alveolar macrophages that represent a predominant macrophage subset in BALF from patients with mild diseases, overwhelm in the severely damaged lungs from patients with ARDS. These cells are highly inflammatory and enormous chemokine producers implicated in cytokine storm. Furthermore, the formation of tissue resident, highly expanded clonal CD8+ T cells in the lung microenvironment of mild symptom patients suggests a robust adaptive immune response connected to a better control of COVID-19. This study first reported the cellular atlas of lung bronchoalveolar immune microenvironment in COVID-19 patients at the single-cell resolution, and unveiled the potential immune mechanisms underlying disease progression and protection in COVID-19. HighlightsO_LIImmune microenvironment of SARS-CoV-2-infected lungs revealed by scRNA/TCR seq C_LIO_LIIncreased inflammatory FCN1+ macrophages are replacing FABP4+ macrophages in the BALF from severe COVID-19 patients C_LIO_LIHighly expanded and functional competent tissue resident clonal CD8+ T cells in mild COVID-19 patients C_LI

4: Pre-existing T cell memory as a risk factor for severe 1 COVID-19 in the elderly
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Posted 18 Sep 2020

Pre-existing T cell memory as a risk factor for severe 1 COVID-19 in the elderly
8,859 downloads medRxiv allergy and immunology

Petra Bacher, Elisa Rosati, Daniela Esser, Gabriela Rios Martini, Carina Saggau, Esther Schiminsky, Justina Dargvainiene, Ina Schr&oumlder, Imke Wieters, Fabian Eberhardt, Holger Neb, Yascha Khodamoradi, Michael Sonntagbauer, Maria J.G.T. Vehreschild, Claudio Conrad, Florian Tran, Philip Rosenstiel, Robert Markewitz, Klaus-Peter Wandinger, Jan Rybniker, Matthias Kochanek, Frank Leypoldt, Oliver A. Cornely, Philipp Koehler, Andre Franke, Alexander Scheffold

Coronavirus disease 2019 (COVID-19) displays high clinical variability but the parameters that determine disease severity are still unclear. Pre-existing T cell memory has been hypothesized as a protective mechanism but conclusive evidence is lacking. Here we demonstrate that all unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses. They display low functional avidity and broad protein target specificities and their frequencies correlate with the overall size of the CD4+ memory compartment reflecting the immunological age of an individual. COVID-19 patients have strongly increased SARS-CoV-2-specific inflammatory T cell responses that are correlated with severity. Strikingly however, patients with severe COVID-19 displayed lower TCR functional avidity and less clonal expansion. Our data suggest that a low avidity pre-existing T cell memory negatively impacts on the T cell response quality against neoantigens such as SARS-CoV-2, which may predispose to develop inappropriate immune reactions especially in the elderly. We propose the immunological age as an independent risk factor to develop severe COVID-19.

5: Characterization of anti-viral immunity in recovered individuals infected by SARS-CoV-2
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Posted 20 Mar 2020

Characterization of anti-viral immunity in recovered individuals infected by SARS-CoV-2
8,623 downloads medRxiv allergy and immunology

Ling Ni, Fang Ye, Meng-Li Chen, Yu Feng, Yong-Qiang Deng, Hui Zhao, Peng Wei, Jiwan Ge, Xiaoli Li, Lin Sun, Pengzhi Wang, Peng Liang, Han Guo, Xinquan Wang, Cheng-Feng Qin, Fang Chen, Chen Dong

The WHO has declared SARS-CoV-2 outbreak a public health emergency of international concern. However, to date, there was hardly any study in characterizing the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. In this study, we collected blood from COVID-19 patients who have recently become virus-free and therefore were discharged, and analyzed their SARS-CoV-2-specific antibody and T cell responses. We observed SARS-CoV-2-specific humoral and cellular immunity in the patients. Both were detected in newly discharged patients, suggesting both participate in immune-mediated protection to viral infection. However, follow-up patients (2 weeks post discharge) exhibited high titers of IgG antibodies, but with low levels of virus-specific T cells, suggesting that they may enter a quiescent state. Our work has thus provided a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It has also implications in designing an effective vaccine to protect and treat SARS-CoV-2 infection.

6: SARS-CoV-2 seroconversion in health care workers
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Posted 19 May 2020

SARS-CoV-2 seroconversion in health care workers
7,899 downloads medRxiv allergy and immunology

Adrian M Shields, Sian E Faustini, Marisol Perez-Toledo, Sian Jossi, Erin L Aldera, Joel D Allen, Saly Al-Taei, Claire Backhouse, Andrew Bosworth, Lyndsey Dunbar, Daniel Ebanks, Beena Emmanuel, Joanne Grey, I Michael Kidd, Golaeh McGinnell, Dee McLoughlin, Gabriella Morley, Joanne O'Neill, Danai Papakonstantinou, Oliver Pickles, Charlotte Poxon, Megan Richter, Eloise Walker, Kasun Wanigasooriya, Yasunori Watanabe, Celina Whalley, Agnieszka E Zielinska, Max Crispin, David C. Wraith, Andrew D Beggs, Adam F. Cunningham, Mark T Drayson, Alex G Richter

Background The correlates of protection against SARS-CoV-2 and their longevity remain unclear. Studies in severely ill individuals have identified robust cellular and humoral immune responses against the virus. Asymptomatic infection with SARS-CoV-2 has also been described, but it is unknown whether this is sufficient to produce antibody responses. Methods We performed a cross-sectional study recruiting 554 health care workers from University Hospitals Birmingham NHS Foundation Trust who were at work and asymptomatic. Participants were tested for current infection with SARS-CoV-2 by nasopharyngeal swab for real-time polymerase chain reaction and for seroconversion by the measurement of anti-SARS-CoV-2 spike glycoprotein antibodies by enzyme linked immunosorbent assay. Results were interpreted in the context of previous, self-reported symptoms of illness consistent with COVID-19. Results The point prevalence of infection with SARS-CoV-2, determined by the detection of SARS-CoV-2 RNA on nasopharnygeal swab was 2.39% (n=13/544). Serum was available on 516 participants. The overall rate of seroconversion in the cohort was 24.4% (n=126/516). Individuals who had previously experienced a symptomatic illness consistent with COVID-19 had significantly greater seroconversion rates than those who had remained asymptomatic (37.5% vs 17.1%, {chi}2 =21.1034, p<0.0001). In the week preceding peak COVID-19-related mortality at UHBFT, seroconversion rates amongst those who were suffering from symptomatic illnesses peaked at 77.8%. Prior symptomatic illness generated quantitatively higher antibody responses than asymptomatic seroconversion. Seroconversion rates were highest amongst those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%) with lower rates observed in participants working in intensive care (14.8%) and emergency medicine (13.3%). Conclusions In a large cross-sectional seroprevalence study of health-care workers, we demonstrate that asymptomatic seroconversion occurs, however prior symptomatic illness is associated with quantitatively higher antibody responses. The identification that the potential for seroconversion in health-care workers can associate differentially with certain hospital departments may inform future infection control and occupational health practices.

7: ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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Posted 07 Feb 2020

ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
6,566 downloads medRxiv allergy and immunology

Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, Zhanghua Chen, Fan Bai, Jun Cui, Andrew M Lew, Jincun Zhao, Yan Zhang, Hai-Bin Luo, Yuxia Zhang

Respiratory disease caused by the 2019 novel coronavirus (2019-nCoV) pneumonia first emerged in Wuhan, Hubei Province, China, in December 2019 and spread rapidly to other provinces and other countries. Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV and has been suggested to be also the receptor for 2019-nCoV. Paradoxically, ACE2 expression in the lung protects mice from SARS-CoV spike protein induced lung injury by attenuating the renin-angiotensin system. In the intestine, ACE2 also suppresses intestinal inflammation by maintaining amino acid homeostasis, antimicrobial peptide expression and ecology of the gut microbiome. Upon analysis of single cell-RNA sequencing data from control subjects and those with colitis or inflammatory bowel disease (IBD), we found that ACE2 expression in the colonocytes was positively associated with genes regulating viral infection, innate and cellular immunity, but was negatively associated with viral transcription, protein translation, humoral immunity, phagocytosis and complement activation. In summary, we suggest that ACE2 may play dual roles in mediating the susceptibility and immunity of 2019-nCoV infection.

8: Systems-level immunomonitoring from acute to recovery phase of severe COVID-19
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Posted 05 Jun 2020

Systems-level immunomonitoring from acute to recovery phase of severe COVID-19
4,527 downloads medRxiv allergy and immunology

Lucie Rodriguez, Pirkka Pekkarinen, Lakshmi Kanth Tadepally, Ziyang Tan, Camila Rosat Consiglio, Christian Pou, Yang Chen, Constantin Habimana Mugabo, Anh Nguyen Quoc, Kirsten Nowlan, Tomas Strandin, Lev Levanov, Jaromir Mikes, Jun Wang, Anu Kantele, Jussi Hepojoki, Olli Vapalahti, Santtu Heinonen, Eliisa Kekalainen, Petter Brodin

The immune response to SARS-CoV2 is under intense investigation, but not fully understood att this moment. Severe disease is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome, rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Systems-level analyses are required to simultaneously capture all immune cell populations and the many protein mediators by which cells communicate. Since every patient analyzed will be captured at different stages of his or her infection, longitudinal monitoring of the immune response is critical. Here we report on a systems-level blood immunomonitoring study of 39 adult patients, hospitalized with severe COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNg-Eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

9: Evidence for sustained mucosal and systemic antibody responses to SARS-CoV-2 antigens in COVID-19 patients
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Posted 04 Aug 2020

Evidence for sustained mucosal and systemic antibody responses to SARS-CoV-2 antigens in COVID-19 patients
4,281 downloads medRxiv allergy and immunology

Baweleta Isho, Kento T Abe, Michelle Zuo, Alainna J Jamal, Bhavisha Rathod, Jenny H. Wang, Zhijie Li, Gary Chao, Olga L Rojas, Yeo Myong Bang, Annie Pu, Natasha Christie-Holmes, Christian Gervais, Derek Ceccarelli, Payman Samavarchi-Tehrani, Furkan Guvenc, Patrick Budylowski, Angel Li, Aimee Paterson, Yue Feng Yun, Lina M Marin, Lauren Caldwell, Jeffrey L Wrana, Karen Colwill, Frank Sicheri, Samira Mubareka, Scott D. Gray-Owen, Steven J. Drews, Walter L Siqueira, Miriam Barrios-Rodiles, Mario Ostrowski, James M Rini, Yves Durocher, Allison J McGeer, Jennifer L Gommerman, Anne-Claude Gingras

While the antibody response to SARS-CoV-2 has been extensively studied in blood, relatively little is known about the mucosal immune response and its relationship to systemic antibody levels. Since SARS-CoV-2 initially replicates in the upper airway, the antibody response in the oral cavity is likely an important parameter that influences the course of infection, but how it correlates to the antibody response in serum is not known. Here, we profile by enzyme linked immunosorbent assays (ELISAs) IgG, IgA and IgM responses to the SARS-CoV-2 spike protein (full length trimer) and its receptor binding domain (RBD) in serum (n=496) and saliva (n=90) of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3-115 days post-symptom onset (PSO), compared to negative controls. Anti-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16-30 days PSO. Whereas anti-CoV-2 IgA and IgM antibodies rapidly decayed, IgG antibodies remained relatively stable up to 105 days PSO in both biofluids. In a surrogate neutralization ELISA (snELISA), neutralization activity peaks by 31-45 days PSO and slowly declines, though a clear drop is detected at the last blood draw (105-115 days PSO). Lastly, IgG, IgM and to a lesser extent IgA responses to spike and RBD in the serum positively correlated with matched saliva samples. This study confirms that systemic and mucosal humoral IgG antibodies are maintained in the majority of COVID-19 patients for at least 3 months PSO. Based on their correlation with each other, IgG responses in saliva may serve as a surrogate measure of systemic immunity.

10: Critically ill SARS-CoV-2 patients display lupus-like hallmarks of extrafollicular B cell activation
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Posted 03 May 2020

Critically ill SARS-CoV-2 patients display lupus-like hallmarks of extrafollicular B cell activation
4,244 downloads medRxiv allergy and immunology

Matthew Woodruff, Richard Ramonell, Kevin Cashman, Doan Nguyen, Ankur Saini, Natalie Haddad, Ariel Ley, Shuya Kyu, J. Christina Howell, Tugba Ozturk, Saeyun Lee, Weirong Chen, Jacob Estrada, Andrea Morrison-Porter, Andrew Derrico, Fabliha Anam, Monika Sharma, Henry Wu, Sang Le, Scott Jenks, Christopher M Tipton, Wiliam Hu, F. Eun-Hyung Lee, Ignacio Sanz

A wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody secreting cell expansion and early production of high levels of SARS-CoV-2-specific antibodies. Yet, these patients fared poorly with elevated inflammatory biomarkers, multi-organ failure, and death. Combined, the findings strongly indicate a major pathogenic role for immune activation in subsets of COVID-19 patients. Our study suggests that, as in autoimmunity, targeted immunomodulatory therapy may be beneficial in specific patient subpopulations that can be identified by careful immune profiling.

11: SARS-CoV-2 serology in 4000 health care and administrative staff across seven sites in Lombardy, Italy
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Posted 26 May 2020

SARS-CoV-2 serology in 4000 health care and administrative staff across seven sites in Lombardy, Italy
4,105 downloads medRxiv allergy and immunology

Maria Teresa Sandri, Elena Azzolini, Valter Torri, Sara Carloni, Chiara Pozzi, Michela Salvatici, Michele Tedeschi, Massimo Castoldi, Alberto Mantovani, Maria Rescigno

Lombardy is the Italian region most affected by COVID-19. We tested the presence of plasma anti-SARS-CoV-2 IgG antibodies in 3985 employees across 7 healthcare facilities in areas of Lombardy with different exposure to the SARS-CoV-2 epidemic. Subjects filled a questionnaire to self-report on COVID-19 symptoms, co-morbidities, smoking, regular or smart-working, and the exposure to COVID-infected individuals. We show that the number of individuals exposed to the virus depended on the geographical location of the facility, ranging between 3 and 43%, consistent with the spatial variation of COVID-19 incidence in Lombardy, and correlated with family contacts. We observed a higher prevalence of females than males positive for IgG, however the level of antibodies was similar, suggesting a comparable magnitude of the response. IgG positivity among smokers was lower (7.4% vs 13.5%) although without difference in IgG plasma levels. We observed 11.9% of IgG positive asymptomatic individuals and another 23.1% with one or two symptoms. Interestingly, among the IgG positive population, 81.2% of subjects with anosmia/dysgeusia and fever were SARS-CoV-2 infected, indicating that these symptoms are strongly associated to COVID-19. The plasma level of IgG inversely correlated with anti-pneumococcal vaccination. In conclusion, the frequency of IgG positivity and SARS-CoV-2 infection is dependent on the geographical exposure to the virus and primarily to family rather than hospital exposure.

12: Kinetics of antibody responses dictate COVID-19 outcome
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Posted 22 Dec 2020

Kinetics of antibody responses dictate COVID-19 outcome
3,891 downloads medRxiv allergy and immunology

Carolina Lucas, Jon Klein, Maria Sundaram, Feimei Liu, Patrick Wong, Julio Silva, Tianyang Mao, Ji Eun Oh, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Benjamin Israelow, Anne L Wyllie, Chantal B. F. Vogels, M. Catherine Muenker, Arnau Casanovas-Massana, Wade L. Schulz, Joseph Zell, Melissa Campbell, John B. Fournier, Yale IMPACT Research Team, Nathan D. Grubaugh, Shelli Farhadian, Adam V Wisnewski, Charles Dela Cruz, Saad Omer, Albert I. Ko, Aaron Ring, Akiko Iwasaki

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). Yet, the exact feature of antibody responses that governs COVID-19 disease outcomes remain unclear. Here, we analysed humoral immune responses in 209 asymptomatic, mild, moderate and severe COVID-19 patients over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-Spike (S) IgG levels, length of hospitalization and clinical parameters associated with worse clinical progression. While high anti-S IgG levels correlated with worse disease severity, such correlation was time-dependent. Deceased patients did not have higher overall humoral response than live discharged patients. However, they mounted a robust, yet delayed response, measured by anti-S, anti-RBD IgG, and neutralizing antibody (NAb) levels, compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, while sera from 89% of patients displayed some neutralization capacity during their disease course, NAb generation prior to 14 days of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se, but rather with the delayed kinetics of NAb production.

13: The production of antibodies for SARS-CoV-2 and its clinical implication
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Posted 24 Apr 2020

The production of antibodies for SARS-CoV-2 and its clinical implication
3,595 downloads medRxiv allergy and immunology

Qianfang Hu, Xiaoping Cui, Xinzhu Liu, Bin Peng, Jinyue Jiang, Xiaohui Wang, Yan Li, Wenhui Hu, Zhi Ao, Jun Duan, Xue Wang, Linxiao Zhu, Shuliang Guo, Guicheng Wu

Background: Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), a novel betacoronavirus, has caused an outburst of pneumonia cases in Wuhan, China. We report the production of specific IgM and IgG antibodies after the infection of SARS-CoV-2 and its implication for the diagnosis, pathology and the course of the disease as well as the recurrence of positive nucleic acid tests after discharge. Methods: Test results for SARS-CoV-2 IgM and IgG antibodies of 221 confirmed COVID-19 patients were retrospectively examined, and their clinical data were collected and analyzed based on various subgroups. SARS-CoV-2 IgM and IgG antibodies were determined with the chemiluminescence method. Findings: The concentration (S/CO) of SARS-CoV-2 IgM and IgG antibodies peaked on day 19-21 after symptom onset, with a median of 17.38 (IQR 4.39-36.4) for IgM and 5.59 (IQR 0.73-13.65) for IgG. Detection rates reached highest on day 16-18 and day 19-21 for IgM and IgG, which were 73.6% and 98.6%, respectively, with significantly higher concentration of IgG in critically ill patients than in those with mild to moderate disease (P=0.027). The concentration of the antibodies on day 16-21 is not correlated with the course or outcome of the disease (Spearman r < 0.20, P > 0.05). Nasopharyngeal swabs revealed positive SARS-CoV-2 RNA in up to 52.7% of recovered patients after discharge, whose IgG proved to be significantly lower than that of those with negative RNA results (P = 0.009). IgG and IgM were tested twice within 14 days after discharge with a 7-day interval, and the second testing of these antibodies displayed a decrease in concentration of 21.2% (IQR, 11.2%34.48%) for IgG and 23.05% (IQR, -27.96%46.13%) for IgM, without statistical significance between the patients with re-detectable positive RNA results and those with negative RNA results after discharge. However, those with positive results experienced a count decrease in lymphocyte subsets. Interpretation: The concentration of SARS-CoV-2 IgM and IgG antibodies peaked on day 19-21 after symptom onset, and antibody testing on day 16-21 is associated with increased detection rates, but the antibody concentration does not affect the course and outcome of the infection. Recovering patients with re-detectable positive SARS-CoV-2 RNA displayed lower concentration of IgG, but the downward trend of IgG during recovery indicated its limited duration of protection, and the protective effect of IgG remains to be investigated.

14: Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19
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Posted 08 Jul 2020

Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19
3,308 downloads medRxiv allergy and immunology

Mikail Dogan, Lina Kozhaya, Lindsey Placek, Courtney L Gunter, Mesut Yigit, Rachel Hardy, Matt Plassmeyer, Paige Coatney, Kimberleigh Lillard, Zaheer Bukhari, Michael Kleinberg, Chelsea Hayes, Moshe A Arditi, Ellen Klapper, Noah Merin, Bruce T Liang, Raavi Gupta, Oral Alpan, Derya Unutmaz

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n=115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

15: A possible role of immunopathogenesis in COVID-19 progression
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Posted 02 May 2020

A possible role of immunopathogenesis in COVID-19 progression
3,170 downloads medRxiv allergy and immunology

Moritz Anft, Krystallenia Paniskaki, Arturo Blazquez-Navarro, Adrian Atila Nicolas Doevelaar, Felix Seibert, Bodo Hoelzer, Sarah Skrzypczyk, Eva Kohut, Julia Kurek, Jan Zapka, Patrizia Wehler, Sviatlana Kaliszczyk, Sharon Bajda, Constantin Thieme, Toralf Roch, Margarethe Justine Konik, Thorsten Brenner, Clemens Tempfer, Carsten Watzl, Sebastian Dolff, Ulf Dittmer, Timm Westhoff, Oliver Witzke, Ulrik Stervbo, Nina Babel

Background: The efficacy of the humoral and cellular immunity determines the outcome of viral infections. An appropriate immune response mediates protection, whereas an overwhelming immune response has been associated with immune-mediated pathogenesis in viral infections. The current study explored the general and SARS-CoV-2 specific cellular and humoral immune status in patients with different COVID-19 severities. Methods: In this prospective study, we included 53 patients with moderate, severe, and critical COVID-19 manifestations comparing their quantitative, phenotypic, and functional characteristics of circulating immune cells, SARS-CoV-2 antigen specific T-cells, and humoral immunity. Results: Significantly diminished frequencies of CD8+T-cells, CD4+ and CD8+T-cell subsets with activated differentiated memory/effector phenotype and migratory capacity were found in circulation in patients with severe and/or critical COVID-19 as compared to patients with moderate disease. Importantly, the improvement of the clinical courses from severe to moderate was accompanied by an improvement in the T-cell subset alterations. Furthermore, we surprisingly observed a detectable SARS-CoV-2-reactive T-cell response in all three groups after stimulation with SARS-CoV-2 S-protein overlapping peptide pool already at the first visit. Of note, patients with a critical COVID-19 demonstrated a stronger response of SARS-CoV-2-reactive T-cells producing Th1 associated inflammatory cytokines. Furthermore, clear correlation between antibody titers and SARS-CoV-2-reactive CD4+ frequencies underscore the role of specific immunity in disease progression. Conclusion: Our data demonstrate that depletion of activated memory phenotype circulating T-cells and a strong SARS-CoV-2-specific cellular and humoral immunity are associated with COVID-19 disease severity. This counter-intuitive finding may have important implications for diagnostic, therapeutic and prophylactic COVID-19 management.

16: Hydroxychloroquine inhibits trained immunity - implications for COVID-19
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Posted 09 Jun 2020

Hydroxychloroquine inhibits trained immunity - implications for COVID-19
3,153 downloads medRxiv allergy and immunology

Nils Rother, Cansu Yanginlar, Rik G.H. Lindeboom, Siroon Bekkering, Mandy M.T. van Leent, Baranca Buijsers, Inge Jonkman, Mark de Graaf, Marijke Baltissen, Lieke A. Lamers, Niels P. Riksen, Zahi A. Fayad, Willem J.M. Mulder, Luuk B. Hilbrands, Leo AB Joosten, Mihai G Netea, Michiel Vermeulen, Johan van der Vlag, Raphaël Duivenvoorden

SARS-CoV-2 infection can cause severe disease for which currently no specific therapy is available. The use of hydroxychloroquine to prevent or treat SARS-CoV-2 infection is controversial and its mode of action poorly understood. We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by profound changes in the cellular lipidome as well as reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response. Our findings therefore suggest that hydroxychloroquine may not have a beneficial effect on the anti-viral immune response to SARS-CoV-2.

17: Long-term Co-existence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) with Antibody Response in Non-severe Coronavirus Disease 2019 (COVID-19) Patients
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Posted 17 Apr 2020

Long-term Co-existence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) with Antibody Response in Non-severe Coronavirus Disease 2019 (COVID-19) Patients
3,115 downloads medRxiv allergy and immunology

Bin Wang, Li Wang, Xianggen Kong, Jin Geng, Di Xiao, Chunhong Ma, Xuemei Jiang, Pei-Hui Wang

Severe acute respiratory syndrome coronavirus 2 infection causing coronavirus disease 2019 has spread worldwide. Whether antibodies are important for the adaptive immune responses against SARS-CoV-2 infection needs to be determined. Here, 26 cases of COVID-19 in Jinan, China, were examined and shown to be mild or with common clinical symptoms and no cases of severe symptoms were found among these patients. A striking feature of some patients is that SARS-CoV-2 could exist in patients who have virus-specific IgG antibodies for a very long period, with one case for up to 36 days. One COVID-19 patient who did not produce any SARS-CoV-2-bound IgG successfully cleared SARS-CoV-2 after 46 days of illness, revealing that without antibody-mediated adaptive immunity, innate immunity may still be powerful enough to eliminate SARS-CoV-2. Overall, this report may provide a basis for further analysis of both innate and adaptive immunity in SARS-CoV-2 clearance, especially in non-severe cases. This study also has implications for understanding the pathogenesis and treatment of SARS-CoV-2.

18: Evaluation of Nucleocapsid and Spike Protein-based ELISAs for detecting antibodies against SARS-CoV-2
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Posted 20 Mar 2020

Evaluation of Nucleocapsid and Spike Protein-based ELISAs for detecting antibodies against SARS-CoV-2
2,987 downloads medRxiv allergy and immunology

Wanbing Liu, Lei Liu, Guomei Kou, Yaqiong Zheng, Yinjuan Ding, Wenxu Ni, Qiongshu Wang, Li Tan, Wanlei Wu, Shi Tang, Zhou Xiong, Shangen Zheng

BackgroundAt present, PCR-based nucleic acid detection cannot meet the demands for coronavirus infectious disease (COVID-19) diagnosis. Methods214 confirmed COVID-19 patients who were hospitalized in the General Hospital of Central Theater Command of the Peoples Liberation Army between January 18 and February 26, 2020, were recruited. Two Enzyme-Linked Immunosorbent Assay (ELISA) kits based on recombinant SARS-CoV-2 nucleocapsid protein (rN) and spike protein (rS) were used for detecting IgM and IgG antibodies, and their diagnostic feasibility was evaluated. ResultsAmong the 214 patients, 146 (68.2%) and 150 (70.1%) were successfully diagnosed with the rN-based IgM and IgG ELISAs, respectively; 165 (77.1%) and 159 (74.3%) were successfully diagnosed with the rS-based IgM and IgG ELISAs, respectively. The positive rates of the rN-based and rS-based ELISAs for antibody (IgM and/or IgG) detection were 80.4% and 82.2%, respectively. The sensitivity of the rS-based ELISA for IgM detection was significantly higher than that of the rN-based ELISA. We observed an increase in the positive rate for IgM and IgG with an increasing number of days post-disease onset (d.p.o.), but the positive rate of IgM dropped after 35 d.p.o. The positive rate of rN-based and rS-based IgM and IgG ELISAs was less than 60% during the early stage of the illness 0-10 d.p.o., and that of IgM and IgG was obviously increased after 10 d.p.o. ConclusionsELISA has a high sensitivity, especially for the detection of serum samples from patients after 10 d.p.o, it can be an important supplementary method for COVID-19 diagnosis.

19: The phenotypic changes of γδ T cells in COVID-19 patients
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Posted 07 Apr 2020

The phenotypic changes of γδ T cells in COVID-19 patients
2,893 downloads medRxiv allergy and immunology

Lei Lei, Hongbo Qian, Xiaofang Yang, Xiaobo Zhou, Xingzhe Zhang, Dan Zhang, Tongxin Dai, Rui Guo, Lin Shi, Yanbin Cheng, Baojun Zhang, Jinsong Hu, Yaling Guo

A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which caused by SARS-CoV-2 and broken in Wuhan, China in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. Also, information regarding the immunological characteristics in COVID-19 patients remains limited. Here we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes in {gamma}{delta} T cells. In comparison to HD, the {gamma}{delta} T cells percentage was decreased. {gamma}{delta} T cells are able to immediately respond to SARS-CoV-2 infection and upregulate the activation marker CD25. In addition, the increased expression of CD4 in {gamma}{delta} T cells may serve as a biomarker for the assessment of SARS-CoV-2 infection.

20: A Streamlined CyTOF Workflow To Facilitate Standardized Multi-Site Immune Profiling of COVID-19 Patients
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Posted 28 Jun 2020

A Streamlined CyTOF Workflow To Facilitate Standardized Multi-Site Immune Profiling of COVID-19 Patients
2,815 downloads medRxiv allergy and immunology

Daniel Geanon, Brian Lee, Geoffrey Kelly, Diana Handler, Bhaskar Upadhyaya, John Leech, Manon Herbinet, Diane Del Valle, Sacha Gnjatic, Seunghee Kim-Schulze, Miriam Merad, Adeeb H Rahman

Mass cytometry (CyTOF) represents one of the most powerful tools in immune phenotyping, allowing high throughput quantification of over 40 single parameters at single-cell resolution. However, wide deployment of CyTOF-based immune phenotyping studies are limited by complex experimental workflows and the need for specialized CyTOF equipment and technical expertise. Furthermore, differences in cell isolation and enrichment protocols, antibody reagent preparation, sample staining and data acquisition protocols can all introduce technical variation that can potentially confound integrative analyses of large data-sets of samples processed across multiple labs. Here, we present a streamlined whole blood CyTOF workflow which addresses many of these sources of experimental variation and facilitates wider adoption of CyTOF immune monitoring across sites with limited technical expertise or sample-processing resources or equipment. Our workflow utilizes commercially available reagents including the Fluidigm MaxPar Direct Immune Profiling Assay (MDIPA), a dry tube 30-marker immunophenotyping panel, and SmartTube Proteomic Stabilizer, which allows for simple and reliable fixation and cryopreservation of whole blood samples. We validate a workflow that allows for streamlined staining of whole blood samples with minimal processing requirements or expertise at the site of sample collection, followed by shipment to a central CyTOF core facility for batched downstream processing and data acquisition. We further demonstrate the application of this workflow to characterize immune responses in a cohort of hospitalized COVID-19 patients, highlighting key disease-associated changes in immune cell frequency and phenotype.

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