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3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332958

ABSTRACT

As SARS-CoV-2 Omicron and other variants of concern continue spreading around the world, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with exceptional breadth and potency against diverse sarbecoviruses including SARS-CoV-1, Omicron BA.1, and BA.2. Crystal structure analysis of one representative nanobody, 3-2A2-4, revealed a highly conserved epitope between the cryptic and the outer face of the receptor binding domain (RBD). The epitope is readily accessible regardless of RBD in up or down conformation and distinctive from the receptor ACE2 binding site. Passive delivery of 3-2A2-4 protected K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. This group of nanobodies and the epitope identified should provide invaluable reference for the development of next generation antibody therapies and vaccines against wide varieties of SARS-CoV-2 infection and beyond.

4.
Cell Discov ; 7(1): 123, 2021 Dec 18.
Article in English | MEDLINE | ID: covidwho-1768807

ABSTRACT

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently needed to tackle the COVID-19 global pandemic. Here, we describe the development of chimpanzee adenovirus serotypes 6 and 68 (AdC6 and AdC68) vector-based vaccine candidates expressing the full-length transmembrane spike glycoprotein. We assessed the vaccine immunogenicity, protective efficacy, and immune cell profiles using single-cell RNA sequencing in mice. Mice were vaccinated via the intramuscular route with the two vaccine candidates using prime-only regimens or heterologous prime-boost regimens. Both chimpanzee adenovirus-based vaccines elicited strong and long-term antibody and T cell responses, balanced Th1/Th2 cell responses, robust germinal center responses, and provided effective protection against SARS-CoV-2 infection in mouse lungs. Strikingly, we found that heterologous prime-boost immunization induced higher titers of protective antibodies, and more spike-specific memory CD8+ T cells in mice. Potent neutralizing antibodies produced against the highly transmissible SARS-CoV-2 variants B.1.1.7 lineage (also known as N501Y.V1) and B.1.351 lineage (also known as N501Y.V2) were detectable in mouse sera over 6 months after prime immunization. Our results demonstrate that the heterologous prime-boost strategy with chimpanzee adenovirus-based vaccines is promising for further development to prevent SARS-CoV-2 infection.

5.
iScience ; 25(4): 104043, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1734555

ABSTRACT

With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor-binding domain (RBD trimer) and showed its robust capability in inducing broad and protective immune responses against wild-type and major variants of concern (VOCs) in the mouse model of SARS-CoV-2 infection. The protectivity was correlated with RBD-specific B cell responses especially the long-lived plasma B cells in bone marrow, strong ability in triggering BCR clustering, and downstream signaling. Monoclonal antibodies isolated from vaccinated animals demonstrated broad and potent neutralizing activity against VOCs tested. Structure analysis of one representative antibody identified a novel epitope with a high degree of conservation among different variants. Collectively, these results demonstrate that the RBD trimer mRNA vaccine serves as a promising vaccine candidate against SARS-CoV-2 variants and beyond.

6.
Proc Natl Acad Sci U S A ; 119(11): e2122954119, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1721790

ABSTRACT

SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.


Subject(s)
Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/pharmacology , COVID-19 Vaccines/immunology , Complementarity Determining Regions , Deep Learning , Epitopes/immunology , Humans , Immunotherapy/methods , Neutralization Tests/methods , Protein Domains , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325084

ABSTRACT

The development of an effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we present three chimpanzee adenovirus vaccines that express either the full-length spike (ChAdTS-S), or receptor-binding domain (RBD) with two different signal sequences (ChAdTS-RBD and ChAdTS-RBDs). Single-dose intranasal or intramuscular immunization induced robust and sustained neutralizing antibody responses in BALB/c mice, with ChAdTS-S being superior to ChAdTS-RBD and ChAdTS-RBDs. Intranasal immunization appeared to induce a predominately Th2-based response whereas intramuscular administration resulted in a predominately Th1 response. The neutralizing activity against several circulating SARS-CoV-2 variants remained unaffected for mice serum but reduced for rhesus macaque serum. Importantly, immunization with ChAdTS-S via either route induced protective immunity against high-dose challenge with live SARS-CoV-2 in rhesus macaques. Vaccinated macaques demonstrated dramatic decreases in viral RNA in the lungs and nasal swabs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in a golden Syrian hamster model of SARS-CoV-2 infection. Taken together, these results confirm that ChAdTS-S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315683

ABSTRACT

Background: The widespread pandemic of novel coronavirus disease 2019 (COVID-19) poses an unprecedented global health crisis. In the United States (US), different state governments have adopted various combinations of non-pharmaceutical public health interventions (NPIs), such as non-essential business closures and gathering bans, to mitigate the epidemic from February to April, 2020. Quantitative assessment on the effectiveness of NPIs is greatly needed to assist in guiding individualized decision making for adjustment of interventions in the US and around the world. However, the impacts of these approaches remain uncertain. Methods: Based on the reported cases, the effective reproduction number (B) of COVID-19 epidemic for 50 states in the US was estimated. Measurements on the effectiveness of nine different NPIs were conducted by assessing risk ratios (RRs) between a and NPIs through a generalized linear model (GLM). Results: Different NPIs were found to have led to different levels of reduction in c. Stay-at-home contributed approximately 51% (95% CI 46%-57%), wearing (face) masks 29% (15%-42%), gathering ban (more than 10 people) 19% (14%-24%), non-essential business closure 16% (10%-21%), declaration of emergency 13% (8%-17%), interstate travel restriction 11% (5%-16%), school closure 10% (7%-14%), initial business closure 10% (6%-14%), and gathering ban (more than 50 people) 7% (2%-11%). Conclusions: : This retrospective assessment of NPIs on k has shown that NPIs played critical roles on epidemic control in the US in the past several months. The quantitative results could guide individualized decision making for future adjustment of NPIs in the US and other countries for COVID-19 and other similar infectious diseases.

9.
Front Immunol ; 12: 766821, 2021.
Article in English | MEDLINE | ID: covidwho-1581335

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge and spread around the world, antibodies and vaccines to confer broad and potent neutralizing activity are urgently needed. Through the isolation and characterization of monoclonal antibodies (mAbs) from individuals infected with SARS-CoV-2, we identified one antibody, P36-5D2, capable of neutralizing the major SARS-CoV-2 variants of concern. Crystal and electron cryo-microscopy (cryo-EM) structure analyses revealed that P36-5D2 targeted to a conserved epitope on the receptor-binding domain of the spike protein, withstanding the three key mutations-K417N, E484K, and N501Y-found in the variants that are responsible for escape from many potent neutralizing mAbs, including some already approved for emergency use authorization (EUA). A single intraperitoneal (IP) injection of P36-5D2 as a prophylactic treatment completely protected animals from challenge of infectious SARS-CoV-2 Alpha and Beta. Treated animals manifested normal body weight and were devoid of infection-associated death up to 14 days. A substantial decrease of the infectious virus in the lungs and brain, as well as reduced lung pathology, was found in these animals compared to the controls. Thus, P36-5D2 represents a new and desirable human antibody against the current and emerging SARS-CoV-2 variants.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , HEK293 Cells , Humans , Immunization, Passive , Mice
10.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-296272

ABSTRACT

New SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

11.
Cell Rep Med ; 2(11): 100448, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1492754

ABSTRACT

Activation of nucleic acid sensing Toll-like receptors (TLRs) in B cells is involved in antiviral responses by promoting B cell activation and germinal center responses. In order to take advantage of this natural pathway for vaccine development, synthetic pathogen-like antigens (PLAs) constructed of multivalent antigens with encapsulated TLR ligands can be used to activate B cell antigen receptors and TLRs in a synergistic manner. Here we report a PLA-based coronavirus disease 2019 (COVID-19) vaccine candidate designed by combining a phage-derived virus-like particle carrying bacterial RNA as TLR ligands with the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein as the target antigen. This PLA-based vaccine candidate induces robust neutralizing antibodies in both mice and non-human primates (NHPs). Using a NHP infection model, we demonstrate that the viral clearance is accelerated in vaccinated animals. In addition, the PLA-based vaccine induces a T helper 1 (Th1)-oriented response and a durable memory, supporting its potential for further clinical development.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , B-Lymphocytes/immunology , COVID-19 Vaccines/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Cell Line , Female , Lymphocyte Activation , Macaca mulatta/immunology , Male , Mice , SARS-CoV-2/metabolism
12.
Nat Commun ; 12(1): 250, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1387324

ABSTRACT

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Disease Models, Animal , Epitopes , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Binding , Protein Conformation , Receptors, Virus/immunology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
13.
Front Immunol ; 12: 697074, 2021.
Article in English | MEDLINE | ID: covidwho-1311376

ABSTRACT

The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.


Subject(s)
Adenovirus Vaccines/administration & dosage , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunization Schedule , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccination/methods , Adenovirus Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Cricetinae , Disease Models, Animal , Female , HEK293 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Pan troglodytes , RNA, Viral/blood , Spike Glycoprotein, Coronavirus/immunology , Transfection , Treatment Outcome
14.
Nat Commun ; 12(1): 4210, 2021 07 09.
Article in English | MEDLINE | ID: covidwho-1303772

ABSTRACT

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Receptors, Virus/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites/immunology , COVID-19/immunology , Cricetinae , Disease Models, Animal , Epitopes/immunology , Female , Humans , Male , Neutralization Tests , Receptors, Antigen, B-Cell/immunology , Spike Glycoprotein, Coronavirus/immunology
15.
BMJ Open ; 11(7): e045886, 2021 07 07.
Article in English | MEDLINE | ID: covidwho-1301642

ABSTRACT

OBJECTIVES: This study quantified how the efficiency of testing and contact tracing impacts the spread of COVID-19. The average time interval between infection and quarantine, whether asymptomatic cases are tested or not, and initial delays to beginning a testing and tracing programme were investigated. SETTING: We developed a novel individual-level network model, called CoTECT (Testing Efficiency and Contact Tracing model for COVID-19), using key parameters from recent studies to quantify the impacts of testing and tracing efficiency. The model distinguishes infection from confirmation by integrating a 'T' compartment, which represents infections confirmed by testing and quarantine. The compartments of presymptomatic (E), asymptomatic (I), symptomatic (Is), and death with (F) or without (f) test confirmation were also included in the model. Three scenarios were evaluated in a closed population of 3000 individuals to mimic community-level dynamics. Real-world data from four Nordic countries were also analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: Simulation result: total/peak daily infections and confirmed cases, total deaths (confirmed/unconfirmed by testing), fatalities and the case fatality rate. Real-world analysis: confirmed cases and deaths per million people. RESULTS: (1) Shortening the duration between Is and T from 12 to 4 days reduces infections by 85.2% and deaths by 88.8%. (2) Testing and tracing regardless of symptoms reduce infections by 35.7% and deaths by 46.2% compared with testing only symptomatic cases. (3) Reducing the delay to implementing a testing and tracing programme from 50 to 10 days reduces infections by 35.2% and deaths by 44.6%. These results were robust to sensitivity analysis. An analysis of real-world data showed that tests per case early in the pandemic are critical for reducing confirmed cases and the fatality rate. CONCLUSIONS: Reducing testing delays will help to contain outbreaks. These results provide policymakers with quantitative evidence of efficiency as a critical value in developing testing and contact tracing strategies.


Subject(s)
COVID-19 , Pandemics , Contact Tracing , Humans , Pandemics/prevention & control , SARS-CoV-2 , Scandinavian and Nordic Countries
16.
Immunity ; 54(7): 1611-1621.e5, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1260761

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/immunology , Immune Evasion , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/chemistry , Antigenic Variation/genetics , COVID-19/immunology , COVID-19/virology , Host Specificity , Humans , Immune Evasion/genetics , Mice , Mink , Mutation , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
17.
BMC Public Health ; 21(1): 965, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1238713

ABSTRACT

BACKGROUND: The widespread pandemic of novel coronavirus disease 2019 (COVID-19) poses an unprecedented global health crisis. In the United States (US), different state governments have adopted various combinations of non-pharmaceutical public health interventions (NPIs), such as non-essential business closures and gathering bans, to mitigate the epidemic from February to April, 2020. Quantitative assessment on the effectiveness of NPIs is greatly needed to assist in guiding individualized decision making for adjustment of interventions in the US and around the world. However, the impacts of these approaches remain uncertain. METHODS: Based on the reported cases, the effective reproduction number (Rt) of COVID-19 epidemic for 50 states in the US was estimated. Measurements on the effectiveness of nine different NPIs were conducted by assessing risk ratios (RRs) between Rt and NPIs through a generalized linear model (GLM). RESULTS: Different NPIs were found to have led to different levels of reduction in Rt. Stay-at-home contributed approximately 51% (95% CI 46-57%), wearing (face) masks 29% (15-42%), gathering ban (more than 10 people) 19% (14-24%), non-essential business closure 16% (10-21%), declaration of emergency 13% (8-17%), interstate travel restriction 11% (5-16%), school closure 10% (7-14%), initial business closure 10% (6-14%), and gathering ban (more than 50 people) 7% (2-11%). CONCLUSIONS: This retrospective assessment of NPIs on Rt has shown that NPIs played critical roles on epidemic control in the US in the past several months. The quantitative results could guide individualized decision making for future adjustment of NPIs in the US and other countries for COVID-19 and other similar infectious diseases.


Subject(s)
COVID-19 , Public Health , Humans , Pandemics , Retrospective Studies , SARS-CoV-2 , United States/epidemiology
18.
J Biomed Inform ; 118: 103800, 2021 06.
Article in English | MEDLINE | ID: covidwho-1219083

ABSTRACT

OBJECTIVE: As the potential spread of COVID-19 sparked by imported cases from overseas will pose continuous challenges, it is essential to estimate the effects of control measures on reducing the importation risk of COVID-19. Our objective is to provide a framework of methodology for quantifying the combined effects of entry restrictions and travel quarantine on managing the importation risk of COVID-19 and other pandemics by leveraging different sets of parameters. METHODS: Three major categories of control measures on controlling importation risk were parameterized and modelled by the framework: 1) entry restrictions, 2) travel quarantine, and 3) domestic containment measures. Integrating the parameterized intensity of control measures, a modified SEIR model was developed to simulate the case importation and local epidemic under different scenarios of global epidemic dynamics. A web-based tool was also provided to enable interactive visualization of epidemic simulation. RESULTS: The simulated number of case importation and local spread modelled by the proposed framework of methods fitted well to the historical epidemic curve of China and Singapore. Based on the simulation results, the total numbers of infected cases when reducing 30% of visitor arrivals would be 88·4 (IQR 87·5-89·6) and 58·8 (IQR 58·3-59·5) times more than those when reducing 99% of visitor arrivals in mainland China and Singapore respectively, assuming actual time-varying Rt and travel quarantine policy. If the number of global daily new infections reached 100,000, 85%-91% of inbound travels should be reduced to keep the daily new infected number below 100 for a country with a similar travel volume as Singapore (daily 52,000 tourist arrivals in 2019). Whereas if the number was lower than 10,000, the daily new infected case would be less than 100 even with no entry restrictions. DISCUSSIONS: We proposed a framework that first estimated the intensity of travel restrictions and local containment measures for countries since the first overseas imported case. Our approach then quantified the combined effects of entry restrictions and travel quarantine using a modified SEIR model to simulate the potential epidemic spread under hypothetical intensities of these control measures. We also developed a web-based system that enables interactive simulation, which could serve as a valuable tool for health system administrators to assess policy effects on managing the importation risk. By leveraging different sets of parameters, it could adapt to any specific country and specific type of epidemic. CONCLUSIONS: This framework has provided a valuable tool to parameterize the intensity of control measures, simulate both the case importation and local epidemic, and quantify the combined effects of entry restrictions and travel quarantine on managing the importation risk.


Subject(s)
COVID-19/prevention & control , Quarantine , Travel , China/epidemiology , Humans , Singapore/epidemiology
19.
Cell Research ; 31(5):517-525, 2021.
Article in English | ProQuest Central | ID: covidwho-1210136

ABSTRACT

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.

20.
Cell Res ; 31(5): 517-525, 2021 05.
Article in English | MEDLINE | ID: covidwho-1139736

ABSTRACT

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/ultrastructure , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibodies, Viral/ultrastructure , Host-Pathogen Interactions , Humans , Immunoglobulin G/chemistry , Immunoglobulin G/ultrastructure , Models, Molecular , Protein Conformation , Protein Multimerization , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/ultrastructure
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