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1.
Sci Transl Med ; 14(646): eabn6859, 2022 May 25.
Article in English | MEDLINE | ID: covidwho-1794534

ABSTRACT

The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Humans , Immunoglobulin Isotypes , Spike Glycoprotein, Coronavirus
2.
Front Psychol ; 13: 804635, 2022.
Article in English | MEDLINE | ID: covidwho-1785403

ABSTRACT

Public health emergencies can trigger individual death anxiety. Most previous studies focus on the negative effects of death anxiety via the Western materialistic view, neglecting both the positive aspects of death anxiety within the Chinese cultural background and the positive effects of death anxiety upon environmental consumption. By implementing the unique Chinese cultural background for the concepts of justice and interests, this study explores the positive influence of individual death anxiety on altruistic environmental consumption during the COVID-19 crisis by analyzing personal life reviews and other sources. The results show that (1) under the guidance of the correct concept of justice and benefit, individuals with high death anxiety during the epidemic period not only enhance their self-esteem through positive self-perception and social evaluation, but they are more inclined to benefit from other environmental consumption behaviors and attain a symbolic self-survival; and (2) during the epidemic period, mental resilience, as a transformation mechanism of external defense and the internal growth of death psychology, can directly affect altruistic environmental consumption by consumers without relying on external standards. In the context of the Chinese culture's concept of justice and interests, this study enriches the knowledge of fear management theory and the positive impact of death anxiety on environmental consumption. The introduction of mental resilience as a boundary condition has important theoretical and practical significance within the study of consumer behavior in public health emergencies and post-epidemic economic recovery.

3.
Nature ; 604(7906): 553-556, 2022 04.
Article in English | MEDLINE | ID: covidwho-1721546

ABSTRACT

The identification of the Omicron (B.1.1.529.1 or BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Botswana in November 20211 immediately caused concern owing to the number of alterations in the spike glycoprotein that could lead to antibody evasion. We2 and others3-6 recently reported results confirming such a concern. Continuing surveillance of the evolution of Omicron has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K alteration (BA.1+R346K, also known as BA.1.1) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike alterations and lacking 13 spike alterations found in BA.1. Here we extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 (refs. 2,3,5,6). These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)7, which had retained appreciable activity against BA.1 and BA.1+R346K (refs. 2-4,6). This finding shows that no authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant, except for the recently authorized LY-CoV1404 (bebtelovimab).


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316984

ABSTRACT

We developed and validated serologic assays to determine SARS-CoV-2 seroprevalence in select patient populations in greater New York City area early during the epidemic. We tested “discarded” serum samples from February 24 to March 29 for antibodies against SARS-CoV-2 spike trimer and nucleocapsid protein. Using known durations for antibody development, incubation period, serial interval, and reproductive ratio for this pandemic, we determined that introduction of SARS-CoV-2 into New York likely occurred between January 23 and February 4, 2020. SARS-CoV-2 spread silently for 4–5 weeks before the first community acquired infection was reported. A novel coronavirus emerged in December 2019 in Wuhan, China 1,2 and devasted Hubei Province in early 2020 before spreading to every province within China and nearly every country in the world 3 . This pathogen, now termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic, with ~ 10 million cases and over 500,000 deaths reported through June 30, 2020 3 . The first case of SARS-CoV-2 infection in the United States was identified on January 19, 2020 in a man who returned to the State of Washington from Wuhan 4 . In the ensuing months, the U.S. has become a hotspot of the pandemic, presently accounting for almost one third of the total caseload and over one fourth of the deaths 3 . The first confirmed case in New York was reported on March 1 in a traveler recently returned from Iran. The first community-acquired SARS-CoV-2 infection was diagnosed on March 3 in a 50-year-old male who lived in New Rochelle and worked in New York City (https://www1.nyc.gov/site/doh/covid/covid-19-data-archive.page.) In the ensuing 18 weeks, New York City has suffered a peak daily infection number of ~ 4,500 (Fig. 1a) and a cumulative caseload of ~ 400,000 to date. The time period when SARS-CoV-2 gained entry into this epicenter of the pandemic remains unclear.

5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327483

ABSTRACT

The identification of the Omicron variant (B.1.1.529.1 or BA.1) of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in Botswana in November 2021 1 immediately raised alarms due to the sheer number of mutations in the spike glycoprotein that could lead to striking antibody evasion. We 2 and others 3–6 recently reported results in this Journal confirming such a concern. Continuing surveillance of Omicron evolution has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K mutation (BA.1+R346K) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike mutations while lacking 13 spike mutations found in BA.1. We therefore extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 2,3,5,6 . These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab) 7 , which had retained appreciable activity against BA.1 and BA.1+R346K 2–4,6 . This new finding shows that no presently approved or authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant.

6.
Cell Rep ; 38(9): 110428, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1670282

ABSTRACT

The recently reported B.1.1.529 Omicron variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 34 mutations in the spike protein relative to the Wuhan strain, including 15 mutations in the receptor-binding domain (RBD). Functional studies have shown Omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here, we report a 3.1 Å-resolution cryoelectron microscopy (cryo-EM) structure of the Omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with high mobility of RBD. Many mutations cause steric clashes and/or altered interactions at antibody-binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the Omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies.


Subject(s)
Cryoelectron Microscopy , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Humans , Immune Evasion/genetics , Models, Molecular , Mutation , Neutralization Tests , Protein Binding , Protein Structure, Quaternary , SARS-CoV-2/genetics , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/genetics
7.
Nature ; 602(7898): 676-681, 2022 02.
Article in English | MEDLINE | ID: covidwho-1616993

ABSTRACT

The B.1.1.529/Omicron variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally1. It is expected to become dominant in the coming weeks2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies4. This concern is amplified by the findings of our study. Here we found that B.1.1.529 is markedly resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals who were vaccinated with one of the four widely used COVID-19 vaccines. Even serum from individuals who were vaccinated and received a booster dose of mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies against all known epitope clusters on the spike protein, we noted that the activity of 17 out of the 19 antibodies tested were either abolished or impaired, including ones that are currently authorized or approved for use in patients. Moreover, we also identified four new spike mutations (S371L, N440K, G446S and Q493R) that confer greater antibody resistance on B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Immune Evasion/immunology , SARS-CoV-2/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Cell Line , Convalescence , Evolution, Molecular , Humans , Immune Sera/immunology , Inhibitory Concentration 50 , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/chemistry , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296805

ABSTRACT

The Omicron (B.1.1.529) variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally1. It is expected to become dominant in the coming weeks2, probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies4. This concern is amplified by the findings from our study. We found B.1.1.529 to be markedly resistant to neutralization by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 18 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296804

ABSTRACT

The devastation caused by SARS-CoV-2 has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses and thus its promise as an agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses, but also uncovered a new antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.

11.
Open forum infectious diseases ; 8(Suppl 1):S373-S373, 2021.
Article in English | EuropePMC | ID: covidwho-1564195

ABSTRACT

Background Molnupiravir (MOV, MK-4482, EIDD-2801) is an orally administered prodrug of N-hydroxycytidine (NHC, EIDD-1931), a nucleoside with broad antiviral activity against a range of RNA viruses. MOV acts by driving viral error catastrophe following its incorporation by the viral RdRp into the viral genome. Given its mechanism of action, MOV activity should not be affected by substitutions in the spike protein present in SARS-CoV-2 variants of concern which impact efficacy of therapeutic neutralizing antibodies and vaccine induced immunity. We characterized MOV activity against variants by assessing antiviral activity in vitro and virologic response from the Phase 2/3 clinical trials (MOVe-In, MOVe-Out) for treatment of COVID-19. Methods MOV activity against several SARS-CoV-2 variants, was evaluated in an in vitro infection assay. Antiviral potency of NHC (IC50) was determined in Vero E6 cells infected with virus at MOI ~0.1 by monitoring CPE. Longitudinal SARS-CoV-2 RNA viral load measures in participants enrolled in MOVe-In and MOVe-Out were analyzed based on SARS-CoV-2 genotype. Sequences of SARS-CoV-2 from study participants were amplified from nasal swabs by PCR and NGS was performed on samples with viral genome RNA of >22,000 copies/ml amplified by primers covering full length genome with Ion Torrent sequencing to identify clades represented in trial participants. SARS-CoV-2 clades were assigned using clade.nextstrain.org. Results In vitro, NHC was equally effective against SARS-CoV-2 variants B.1.1.7 (20I), B.1351 (20H), and P1 (20J), compared with the original WA1 (19B) isolate. In clinical trials, no discernable difference was observed in magnitude of viral response measured by change from baseline in RNA titer over time across all clades represented including 20A through 20E and 20G to 20I. No participants at the time of the study presented with 20F, 20J, or 21A. Conclusion Distribution of clades in participants in MOVe-In and MOVe-Out was representative of those circulating globally at the time of collection (Oct 2020 – Jan 2021). Both in vitro and clinical data suggest that spike protein substitutions do not impact antiviral activity of MOV and suggest its potential use for the treatment of SARS-CoV-2 variants. Disclosures Jay Grobler, PhD, Merck & Co., Inc. (Employee, Shareholder) Julie Strizki, PhD, Merck & Co., Inc. (Employee, Shareholder) Nicholas Murgolo, PhD, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Youfang Cao, PhD, Merck & Co. (Employee) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Manoj Nair, PhD, Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Yaoxing Huang, PhD, Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Yang Luo, PhD, Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Daria Hazuda, PhD, Merck & Co., Inc. (Employee, Shareholder) David D. Ho, MD, Merck & Co., Inc. (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) David D. Ho, MD, Brii Biosciences (Individual(s) Involved: Self): Consultant;Merck (Individual(s) Involved: Self): Research Grant or Support;RenBio (Individual(s) Involved: Self): Consultant, Founder, Other Financial or Material Support, Shareholder;WuXi Biologics (Individual(s) Involved: Self): Consultant

12.
Biomed Res Int ; 2021: 3178796, 2021.
Article in English | MEDLINE | ID: covidwho-1541947

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously affected public health and social stability. The main route of the transmission is droplet transmission, where the oral cavity is the most important entry point to the body. Due to both the direct harmful effects of SARS-CoV-2 and disordered immune responses, some COVID-19 patients may progress to acute respiratory distress syndrome or even multiple organ failure. Genetic variants of SARS-CoV-2 have been emerging and circulating around the world. Currently, there is no internationally approved precise treatment for COVID-19. Mesenchymal stem cells (MSCs) can traffic and migrate towards the affected tissue, regulate both the innate and acquired immune systems, and participate in the process of healing. Here, we will discuss and investigate the mechanisms of immune disorder in COVID-19 and the therapeutic activity of MSCs, in particular human gingiva mesenchymal stem cells.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , SARS-CoV-2/genetics , COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Variation , Gingiva/cytology , Humans , Mesenchymal Stem Cell Transplantation , SARS-CoV-2/immunology
13.
Cell Rep ; 37(1): 109771, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1439919

ABSTRACT

Understanding mechanisms of protective antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We report a monoclonal antibody, 910-30, targeting the SARS-CoV-2 receptor-binding site for ACE2 as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. Sequence and structural analyses of 910-30 and related antibodies explore how class recognition features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer reveal binding interactions and its ability to disassemble spike. Despite heavy-chain sequence similarity, biophysical analyses of IGHV3-53/3-66-encoded antibodies highlight the importance of native heavy:light pairings for ACE2-binding competition and SARS-CoV-2 neutralization. We develop paired heavy:light class sequence signatures and determine antibody precursor prevalence to be ∼1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These class signatures reveal genetic, structural, and functional immune features that are helpful in accelerating antibody-based medical interventions for SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Aged , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/ultrastructure , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation , B-Lymphocytes/immunology , Binding Sites , Chlorocebus aethiops , Cryoelectron Microscopy , HEK293 Cells , Humans , Immunoglobulin Heavy Chains/chemistry , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Immunoglobulin Heavy Chains/ultrastructure , Immunoglobulin Light Chains/chemistry , Immunoglobulin Light Chains/genetics , Immunoglobulin Light Chains/immunology , Immunoglobulin Light Chains/ultrastructure , Male , Protein Binding , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
14.
J Adolesc Health ; 69(2): 199-210, 2021 08.
Article in English | MEDLINE | ID: covidwho-1364146

ABSTRACT

PURPOSE: Adolescent mental illness often goes undetected. Youth and teen Mental Health First Aid (MHFA) are variations of adult MHFA that aims to help adults and adolescents recognize the signs and provide help where appropriate. We conducted a systematic review to summarize the current evidence for youth and teen MHFA, providing direction for future training and research. METHODS: A systematic search was performed on September 12, 2020 on PubMed, Embase, PsycINFO, ERIC, and Cochrane using keywords related to teen or youth MHFA, adolescents, and mental health. A narrative synthesis was then carried out. RESULTS: Of the 695 articles identified, 14 studies were included. All studies were from the U.S. and Australia. All studies demonstrated significant improvements in knowledge, recognition, stigmatizing attitudes, confidence, helping intentions, and helping behavior in both adult and youth participants. Improvement in knowledge and confidence was most reported, and improvement in helping behavior was the least reported. There is encouraging evidence of long-term benefits after the training. CONCLUSIONS: More studies need to be conducted in non-Western countries, high-risk populations, and different professional settings. Future interventions could also consider different modes of learning, longer-term follow-up, and the measurement of outcomes that evaluate the quality of helping behavior.


Subject(s)
Mental Disorders , Mental Health , Adolescent , Adult , Australia , First Aid , Humans , Mental Disorders/therapy , Social Stigma
15.
Small ; 17(29): e2101508, 2021 07.
Article in English | MEDLINE | ID: covidwho-1263125

ABSTRACT

Abnormal elevated levels of cytokines such as interferon (IFN), interleukin (IL), and tumor necrosis factor (TNF), are considered as one of the prognosis biomarkers for indicating the progression to severe or critical COVID-19. Hence, it is of great significance to develop devices for monitoring their levels in COVID-19 patients, and thus enabling detecting COVID-19 patients that are worsening and to treat them before they become critically ill. Here, an intelligent aptameric dual channel graphene-TWEEN 80 field effect transistor (DGTFET) biosensing device for on-site detection of IFN-γ, TNF-α, and IL-6 within 7 min with limits of detection (LODs) of 476 × 10-15 , 608 × 10-15 , or 611 × 10-15 m respectively in biofluids is presented. Using the customized Android App together with this intelligent device, asymptomatic or mild COVID-19 patients can have a preliminary self-detection of cytokines and get a warning reminder while the condition starts to deteriorate. Also, the device can be fabricated on flexible substrates toward wearable applications for moderate or even critical COVID-19 cases for consistently monitoring cytokines under different deformations. Hence, the intelligent aptameric DGTFET biosensing device is promising to be used for point-of-care applications for monitoring conditions of COVID-19 patients who are in different situations.


Subject(s)
COVID-19 , Graphite , Biomarkers , Cytokine Release Syndrome , Cytokines , Humans , Interleukin-6 , SARS-CoV-2
16.
Nature ; 595(7866): 278-282, 2021 07.
Article in English | MEDLINE | ID: covidwho-1258586

ABSTRACT

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1-3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.


Subject(s)
Antibodies, Neutralizing/immunology , Camelids, New World/immunology , SARS-CoV-2/immunology , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/isolation & purification , CRISPR-Cas Systems , Camelids, New World/genetics , Female , Gene Editing , Humans , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Single-Domain Antibodies/genetics , Single-Domain Antibodies/isolation & purification , Somatic Hypermutation, Immunoglobulin/genetics
17.
Nature ; 593(7857): 130-135, 2021 05.
Article in English | MEDLINE | ID: covidwho-1120052

ABSTRACT

The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/therapy , Immune Evasion/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Drug Resistance, Viral/immunology , HEK293 Cells , Humans , Immune Evasion/genetics , Immunization, Passive , Middle Aged , Models, Molecular , Mutation , Neutralization Tests , Protein Domains/immunology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Synthetic/immunology , Vero Cells
19.
Front Psychiatry ; 11: 565098, 2020.
Article in English | MEDLINE | ID: covidwho-970836

ABSTRACT

Background: The twenty-first century viral respiratory epidemics have taught us valuable lessons. Our systematic review examined the impact of these epidemics, including coronavirus disease 2019 (COVID-19), on mental health among different population groups, drawing on their insights for recommendations for the current COVID-19 pandemic. Methods: Searches were performed on PubMed, Embase, PsycINFO, Web of Science, Scopus, CINAHL, and Cochrane on April 4, 2020. Studies that had undefined mental health outcomes or did not use a validated scale for measure were excluded. Quality assessment was carried out via the Newcastle-Ottawa Scale. Results: We included 95 studies, most of which were conducted in Hong Kong (31.6%) and China (21.4%). A total of 30 (30.9%) studies are on the general public, 41 (42.2%) on healthcare workers, and 26 (26.6%) on patients and quarantined individuals. Furthermore, 36 (37.1%) of the studies are of high quality, 48 (49.5%) are of moderate quality, and 13 (13.4%) are of low quality. The most significant mental health outcomes reported include anxiety, depression, and post-traumatic stress disorder symptoms. The subgroups identified to have a higher risk of psychiatric symptoms among the general public include females, the elderly, individuals with chronic illness, migrant workers, and students. Long-term mental health impact was reported in some healthcare workers and epidemic patients, even up to 3 years in the former. Interestingly, when compared to non-quarantined groups, quarantine was not significantly associated with worse mental health outcomes. Conclusion: Important implications for the COVID-19 pandemic were highlighted. Respiratory epidemics pose a significant psychological morbidity onto many population groups. Psychological support for vulnerable groups, including healthcare workers and patients, should be implemented to prevent them from spiraling into clinical psychiatric conditions.

20.
Chinese Journal of Nosocomiology ; 30(17):2595-2602, 2020.
Article in Chinese | GIM | ID: covidwho-923146

ABSTRACT

Early and rapid laboratory test of Corona Virus Disease 2019(COVID-19) is crucial to the treatment of viral infection and monitoring of prognosis and is one of the most important means to improve the therapeutic effects. The traditional nucleic acid test based on polymerase chain reaction(PCR) and the protein test based on immune reaction are the main approaches for early and rapid tests. Each technique has its own advantages and disadvantages due to the limitations of the methodologies. Nonspecific laboratory indexes also have important value in the clinical diagnosis and treatment of patients with COVID-19. The approaches and strategies for COVID-19 test were explored in detail by focusing on nucleic acid, protein and routine laboratory indexes, and the joint detection of nucleic acid, protein and serological indexes is expected to be an important mean for clinical diagnosis of infectious diseases.

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