scholarly journals Inferring effects of mutations on SARS-CoV-2 transmission from genomic surveillance data

Author(s):  
Brian Lee ◽  
Muhammad Saqib Sohail ◽  
Elizabeth Finney ◽  
Syed Faraz Ahmed ◽  
Ahmed Abdul Quadeer ◽  
...  

New and more transmissible variants of SARS-CoV-2 have arisen multiple times over the course of the pandemic. Rapidly identifying mutations that affect transmission could facilitate outbreak control efforts and highlight new variants that warrant further study. Here we develop an analytical epidemiological model that infers the transmission effects of mutations from genomic surveillance data. Applying our model to SARS-CoV-2 data across many regions, we find multiple mutations that strongly affect the transmission rate, both within and outside the Spike protein. We also quantify the effects of travel and competition between different lineages on the inferred transmission effects of mutations. Importantly, our model detects lineages with increased transmission as they arise. We infer significant transmission advantages for the Alpha and Delta variants within a week of their appearances in regional data, when their regional frequencies were only around 1%. Our model thus enables the rapid identification of variants and mutations that affect transmission from genomic surveillance data.

2020 ◽  
Author(s):  
Motoaki Utamura ◽  
Makoto Koizumi ◽  
Seiichi Kirikami

BACKGROUND COVID-19 currently poses a global public health threat. Although Tokyo, Japan, is no exception to this, it was initially affected by only a small-level epidemic. Nevertheless, medical collapse nearly happened since no predictive methods were available to assess infection counts. A standard susceptible-infectious-removed (SIR) epidemiological model has been widely used, but its applicability is limited often to the early phase of an epidemic in the case of a large collective population. A full numerical simulation of the entire period from beginning until end would be helpful for understanding COVID-19 trends in (separate) counts of inpatient and infectious cases and can also aid the preparation of hospital beds and development of quarantine strategies. OBJECTIVE This study aimed to develop an epidemiological model that considers the isolation period to simulate a comprehensive trend of the initial epidemic in Tokyo that yields separate counts of inpatient and infectious cases. It was also intended to induce important corollaries of governing equations (ie, effective reproductive number) and equations for the final count. METHODS Time-series data related to SARS-CoV-2 from February 28 to May 23, 2020, from Tokyo and antibody testing conducted by the Japanese government were adopted for this study. A novel epidemiological model based on a discrete delay differential equation (apparent time-lag model [ATLM]) was introduced. The model can predict trends in inpatient and infectious cases in the field. Various data such as daily new confirmed cases, cumulative infections, inpatients, and PCR (polymerase chain reaction) test positivity ratios were used to verify the model. This approach also derived an alternative formulation equivalent to the standard SIR model. RESULTS In a typical parameter setting, the present ATLM provided 20% less infectious cases in the field compared to the standard SIR model prediction owing to isolation. The basic reproductive number was inferred as 2.30 under the condition that the time lag <i>T</i> from infection to detection and isolation is 14 days. Based on this, an adequate vaccine ratio to avoid an outbreak was evaluated for 57% of the population. We assessed the date (May 23) that the government declared a rescission of the state of emergency. Taking into consideration the number of infectious cases in the field, a date of 1 week later (May 30) would have been most effective. Furthermore, simulation results with a shorter time lag of <i>T</i>=7 and a larger transmission rate of α=1.43α0 suggest that infections at large should reduce by half and inpatient numbers should be similar to those of the first wave of COVID-19. CONCLUSIONS A novel mathematical model was proposed and examined using SARS-CoV-2 data for Tokyo. The simulation agreed with data from the beginning of the pandemic. Shortening the period from infection to hospitalization is effective against outbreaks without rigorous public health interventions and control.


Author(s):  
Tarun Mishra ◽  
M. Sreepadmanabh ◽  
Pavitra Ramdas ◽  
Amit Kumar Sahu ◽  
Atul Kumar ◽  
...  

The establishment of SARS CoV-2 spike-pseudotyped lentiviral (LV) systems has enabled the rapid identification of entry inhibitors and neutralizing agents, alongside allowing for the study of this emerging pathogen in BSL-2 level facilities. While such frameworks recapitulate the cellular entry process in ACE2+ cells, they are largely unable to factor in supplemental contributions by other SARS CoV-2 genes. To address this, we performed an unbiased ORF screen and identified the nucleoprotein (N) as a potent enhancer of spike-pseudotyped LV particle infectivity. We further demonstrate that the spike protein is better enriched in virions when the particles are produced in the presence of N protein. This enrichment of spike renders LV particles more infectious as well as less vulnerable to the neutralizing effects of a human IgG-Fc fused ACE2 microbody. Importantly, this improvement in infectivity is observed with both wild-type spike protein as well as the D614G mutant. Our results hold important implications for the design and interpretation of similar LV pseudotyping-based studies.


2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Nilotinib and Imatinib bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


2021 ◽  
Author(s):  
Meet Parmar ◽  
Ritik Thumar ◽  
Jigar Sheth ◽  
Dhaval Patel

Since the SARS-CoV-2 outbreak in 2019, millions of people have been infected with the virus, and due to its high human-to-human transmission rate, there is a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging variants of concern is B1.1.529 (Omicron), which carries ~30 mutations in the Spike protein of SARS-CoV-2 is predicted to evade antibodies recognition even from vaccinated people. We used a structure-based approach along with an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity were used for designing and predicting vaccine construct features and structure models. The MESV construct In-silico cloning in pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. The proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern.


2021 ◽  
Vol 15 (10) ◽  
pp. 1376-1383
Author(s):  
Samina Naz Mukry ◽  
Shariq Ahmed ◽  
Ali Raza Bukhari ◽  
Aneeta Shahni ◽  
Gul Sufaida ◽  
...  

Introduction: The first case of severe acute respiratory syndrome 2 (SARS-CoV-2) was imported to Pakistan in February 2020, since then 8,260 deaths have been witnessed. The virus has been constantly mutating and local transmission cases from different countries vary due to host dependent viral adaptation. Many distinct clusters of variant SARS-CoV-2 have been defined globally. In this study, the epidemiology of SARS-CoV-2 was studied and locally transmitted SARS-CoV-2 isolates from Karachi were sequenced to compared and identify any possible variants. Methodology: The real time PCR was performed on nasopharyngeal specimen to confirm SARS-CoV-2 with Orf 1ab and E gene as targets. The virus isolates were sequenced through oxford nanopore technology MinION platform. Isolates from the first and second wave of COVID-19 outbreak in Karachi were compared. Results: The overall positivity rate for PCR was 26.24% with the highest number of positive cases in June. Approximately, 37.45% PCR positive subjects aged between 19-40 years. All the isolates belonged to GH clade and shared missense mutation D614G in spike protein linked to increased transmission rate worldwide. Another spike protein mutation A222V coexisted with D614G in the virus from the second wave of COVID-19. Conclusions: Based on the present findings it is suggested that the locally transmitted virus from Karachi varies from those reported from other parts of Pakistan. Slight variability was also observed between viruses from the first and second wave. Variability in any potential vaccine target may result in failed trials, therefore information on any local viral variants is always useful for effective vaccine design and/or selection.


2021 ◽  
Author(s):  
Tanner Roy Wiegand ◽  
Aidan McVey ◽  
Anna Nemudraia ◽  
Artem Nemudryi ◽  
Blake Wiedenheft

In late December of 2019, high throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we analyze a subset (n=87,032) of all publicly available SARS-CoV-2 genomes (n=~5.6 million) that were randomly selected, but equally distributed over the course of the pandemic. We plot the appearance of new variants of concern (VOCs) over time and show that the mutation rates in Omicron viruses are significantly greater than those in previously identified SARS-CoV-2 variants. Mutations in Omicron are primarily restricted to the spike protein, while 25 other viral proteins—including those involved in SARS-CoV-2 replication—are highly conserved. Collectively, this suggests that the genetic distinction of Omicron primarily arose from selective pressures on the spike, and that the fidelity of replication of this variant has not been altered.


2021 ◽  
Author(s):  
Tarun Mishra ◽  
M Sreepadmanabh ◽  
Pavitra Ramdas ◽  
Amit K Sahu ◽  
Atul Kumar ◽  
...  

AbstractThe establishment of SARS CoV-2 spike-pseudotyped lentiviral (LV) systems has enabled the rapid identification of entry inhibitors and neutralizing agents, alongside allowing for the study of this emerging pathogen in BSL-2 level facilities. While such frameworks recapitulate the cellular entry process in ACE2+ cells, they are largely unable to factor in supplemental contributions by other SARS CoV-2 genes. To address this, we performed an unbiased ORF screen and identified the nucleoprotein (N) as a potent enhancer of spike-pseudotyped LV particle infectivity. We further demonstrate that this augmentation by N renders LV spike particles less vulnerable to the neutralizing effects of a human IgG-Fc fused ACE2 microbody. Biochemical analysis revealed that the spike protein is better enriched in virions when the particles are produced in the presence of SARS CoV-2 nucleoprotein. Importantly, this improvement in infectivity is achieved without a concomitant increase in sensitivity towards RBD binding-based neutralization. Our results hold important implications for the design and interpretation of similar LV pseudotyping-based studies.


2021 ◽  
Author(s):  
Stefano Pascarella ◽  
Massimo Ciccozzi ◽  
Davide Zella ◽  
Martina Bianchi ◽  
Francesca Benedetti ◽  
...  

Lineage B.1.617+, also known as G/452R.V3, is a recently described SARS-CoV-2 variant under investigation (VUI) firstly identified in October 2020 in India. As of May 2021, three sublineages labelled as B.1.617.1, B.1.617.2 and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R and P681R. Here we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the Receptor Binding Domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 sublineage, which shows multiple replacements of neutral or negatively-charged amino acids with positively-charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+ RBD and the negatively-charged ACE2 thus conferring a potential increase in the virus transmission.


Author(s):  
Chek Meng Poh ◽  
Guillaume Carissimo ◽  
Bei Wang ◽  
Siti Naqiah Amrun ◽  
Cheryl Yi-Pin Lee ◽  
...  

AbstractThe ongoing SARS-CoV-2 pandemic demands rapid identification of immunogenic targets for the design of efficient vaccines and serological detection tools. In this report, using pools of overlapping linear peptides and functional assays, we present two immunodominant regions on the spike glycoprotein that were highly recognized by neutralizing antibodies in the sera of COVID-19 convalescent patients. One is highly specific to SARS-CoV-2, and the other is a potential pan-coronavirus target.


2021 ◽  
Author(s):  
Samina Naz Mukry ◽  
Shariq Ahmed ◽  
Ali Raza Bukhari ◽  
Aneeta Shahni ◽  
Gul Sufaida ◽  
...  

The first case of severe acute respiratory syndrome 2 (SARS CoV2) was imported to Pakistan in February 2020 since then 8,260 deaths have been witnessed. The virus has been mutating and local transmission cases from different countries vary due to host dependent viral adaptation. Many distinct clusters of variant SARS CoV2 have been defined globally. In this study, the epidemiology of SARS CoV2 was studied and locally transmitted SARS CoV2 isolates from Karachi were sequenced to compared and identify any possible variants.The real time PCR was performed on nasopharyngeal specimen to confirm SARSCoV2 with Orf 1ab and E gene as targets. The viral sequencing was performed through oxford nanopore technology MinION platform. Isolates from first and second wave of COVID-19 outbreak in Karachi were compared. The overall positivity rate for PCR was 26.24% with highest number of positive cases in June. Approximately, 37.45% PCR positive subjects aged between 19-40 years. All the isolates belonged to GH clade and shared missense mutation D614G in spike protein linked to increased transmission rate worldwide. Another spike protein mutation A222V coexisted with D614G in the virus from second wave of COVID-19. Based on the present findings it is suggested that the locally transmitted virus from Karachi vary from those reported from other parts of Pakistan. Slight variability was also observed between viruses from first and second wave. Variability in any potential vaccine target may result in failed trials therefore information on any local viral variants is always useful for effective vaccine design and/or selection.


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