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1.
Eur Rev Med Pharmacol Sci ; 25(24): 8019-8022, 2021 12.
Article in English | MEDLINE | ID: covidwho-1605687

ABSTRACT

Recently a new variant of SARS-CoV-2 was reported from South Africa. World Health Organization (WHO) named this mutant as a variant of concern - Omicron (B.1.1.529) on 26th November 2021. This variant exhibited more than thirty amino acid mutations in the spike protein. This mutation rate is exceeding the other variants by approximately 5-11 times in the receptor-binding motif of the spike protein. Omicron (B.1.1.529) variant might have enhanced transmissibility and immune evasion. This new variant can reinfect individuals previously infected with other SARS-CoV-2 variants. Scientists expressed their concern about the efficacy of already existing COVID-19 vaccines against Omicron (B.1.1.529) infections. Some of the crucial mutations that are detected in the receptor-binding domain of the Omicron variant have been shared by previously evolved SARS-CoV-2 variants. Based on the Omicron mutation profile in the receptor-binding domain and motif, it might have collectively enhanced or intermediary infectivity relative to its previous variants. Due to extensive mutations in the spike protein, the Omicron variant might evade the immunity in the vaccinated individuals.


Subject(s)
COVID-19/epidemiology , Reinfection/epidemiology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , COVID-19/immunology , COVID-19/transmission , COVID-19/virology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , Immune Evasion/genetics , Immunogenicity, Vaccine , Mutation , Reinfection/immunology , Reinfection/transmission , Reinfection/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Vaccine Potency
2.
Viruses ; 13(12)2021 12 19.
Article in English | MEDLINE | ID: covidwho-1580420

ABSTRACT

Rapid molecular surveillance of SARS-CoV-2 S-protein variants leading to immune escape and/or increased infectivity is of utmost importance. Among global bottlenecks for variant monitoring in diagnostic settings are sequencing and bioinformatics capacities. In this study, we aimed to establish a rapid and user-friendly protocol for high-throughput S-gene sequencing and subsequent automated identification of variants. We designed two new primer pairs to amplify only the immunodominant part of the S-gene for nanopore sequencing. Furthermore, we developed an automated "S-Protein-Typer" tool that analyzes and reports S-protein mutations on the amino acid level including a variant of concern indicator. Validation of our primer panel using SARS-CoV-2-positive respiratory specimens covering a broad Ct range showed successful amplification for 29/30 samples. Restriction to the region of interest freed sequencing capacity by a factor of 12-13, compared with whole-genome sequencing. Using either the MinION or Flongle flow cell, our sequencing strategy reduced the time required to identify SARS-CoV-2 variants accordingly. The S-Protein-Typer tool identified all mutations correctly when challenged with our sequenced samples and 50 deposited sequences covering all VOCs (December 2021). Our proposed S-protein variant screening offers a simple, more rapid, and low-cost entry into NGS-based SARS-CoV-2 analysis, compared with current whole-genome approaches.


Subject(s)
High-Throughput Nucleotide Sequencing/methods , Nanopore Sequencing/methods , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , COVID-19/epidemiology , COVID-19/virology , Epidemiological Monitoring , Genotype , Humans , Immune Evasion/genetics , Mutation , SARS-CoV-2/immunology
3.
PLoS Comput Biol ; 17(12): e1009664, 2021 12.
Article in English | MEDLINE | ID: covidwho-1571973

ABSTRACT

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise.


Subject(s)
Evolution, Molecular , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Animals , Antibodies, Viral/biosynthesis , Antigens, Viral/chemistry , Antigens, Viral/genetics , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Influenza, Human/immunology , Influenza, Human/virology , Models, Immunological , Molecular Dynamics Simulation , Mutation , Pandemics , Spike Glycoprotein, Coronavirus/chemistry , Viral Envelope Proteins/chemistry
4.
J Clin Invest ; 131(18)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1533156

ABSTRACT

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Evolution, Molecular , Immune Evasion/genetics , Mutation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , New York City , Protein Domains , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
5.
Front Immunol ; 12: 742167, 2021.
Article in English | MEDLINE | ID: covidwho-1528818

ABSTRACT

COVID-19 pandemic remains an on-going global health and economic threat that has amassed millions of deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of this disease and is constantly under evolutionary pressures that drive the modification of its genome which may represent a threat to the efficacy of current COVID-19 vaccines available. This article highlights the pressures that facilitate the rise of new SARS-CoV-2 variants and the key mutations of the viral spike protein - L452R, E484K, N501Y and D614G- that promote immune escape mechanism and warrant a cautionary point for clinical and public health responses in terms of re-infection, vaccine breakthrough infection and therapeutic values.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immune Evasion/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Evolution, Molecular , Humans , Mutation
6.
Eur Rev Med Pharmacol Sci ; 25(18): 5857-5864, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1451044

ABSTRACT

OBJECTIVE: The current study reviewed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) variants for their effects on infection, transmission and neutralization by vaccine-induced antibodies. MATERIALS AND METHODS: The research articles for the current study were searched over PubMed, Google Scholar, EMBASE and Web of Science online databases. The keywords used were: (("SARS-CoV-2" OR "COVID-19") AND ("mutation" OR "variant") AND ("death" OR "hospitalization" OR "infection" OR "transmission") AND ("antibody" OR "neutralize" OR "vaccine")). A total of 333 research articles were retrieved through online-database search. These articles were further scrutinized for their relevancy. Additionally, searches were performed to find the latest relevant information over Google search engine and relevant news browsers. Finally, around 35 germane articles were considered for scripting the current report. RESULTS: The mutations have changed amino acids at key positions in spike protein viz. S477N, E484K, Q677H, E484Q, L452R, K417T, K417N and N501Y. These mutations are relevant for different characteristics and are present in newly evolved strains of SARS-CoV-2 like E484K in B.1.526, B.1.525, P.2, B.1.1.7, P.1 and B.1.351. Mutations have increased the immune escape potential leading to 3.5-6.5-folds decrease in neutralization of antibodies (Pfizer and Moderna vaccines). The variant, B.1.617 circulating in India and many other countries (double variant) having E484Q and L452R mutations, has raised the infection rate and decreased the neutralization capacity of the vaccine-induced antibodies. Deadly K417N+E484K+N501Y triplet mutations found in B.1.351 and P.1 have increased the transmission ability of these strains by 50% leading to greater COVID-19 hospitalization, ICU admissions and deaths. CONCLUSIONS: The new SARS-CoV-2 variants have compromised the neutralization potential of the currently used vaccines, but still, they have considerable efficacy to reduce infection and mortality. Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract.jpg.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , COVID-19/prevention & control , COVID-19/transmission , Humans , Immune Evasion/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/classification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
7.
Nat Commun ; 12(1): 5769, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1447305

ABSTRACT

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Δ, Y144Δ, and LLA241/243Δ. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers.


Subject(s)
COVID-19/transmission , COVID-19/virology , SARS-CoV-2/genetics , Africa, Central/epidemiology , Antibodies, Neutralizing/immunology , COVID-19/epidemiology , Europe/epidemiology , Humans , Immune Evasion/genetics , Mutation , Phylogeny , Phylogeography , SARS-CoV-2/classification , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Travel/statistics & numerical data
8.
Nat Commun ; 12(1): 5730, 2021 09 30.
Article in English | MEDLINE | ID: covidwho-1447303

ABSTRACT

Viral reproduction of SARS-CoV-2 provides opportunities for the acquisition of advantageous mutations, altering viral transmissibility, disease severity, and/or allowing escape from natural or vaccine-derived immunity. We use three mathematical models: a parsimonious deterministic model with homogeneous mixing; an age-structured model; and a stochastic importation model to investigate the effect of potential variants of concern (VOCs). Calibrating to the situation in England in May 2021, we find epidemiological trajectories for putative VOCs are wide-ranging and dependent on their transmissibility, immune escape capability, and the introduction timing of a postulated VOC-targeted vaccine. We demonstrate that a VOC with a substantial transmission advantage over resident variants, or with immune escape properties, can generate a wave of infections and hospitalisations comparable to the winter 2020-2021 wave. Moreover, a variant that is less transmissible, but shows partial immune-escape could provoke a wave of infection that would not be revealed until control measures are further relaxed.


Subject(s)
COVID-19/transmission , Immune Evasion/genetics , Models, Biological , Pandemics/statistics & numerical data , SARS-CoV-2/pathogenicity , Adolescent , Adult , COVID-19/epidemiology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Computer Simulation , Forecasting/methods , Humans , Middle Aged , Mutation , Pandemics/prevention & control , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Stochastic Processes , United Kingdom/epidemiology , Vaccination/statistics & numerical data , Young Adult
9.
Biochem Biophys Res Commun ; 574: 14-19, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1446453

ABSTRACT

Following the initial surges of the Alpha (B.1.1.7) and the Beta (B.1.351) variants, a more infectious Delta variant (B.1.617.2) is now surging, further deepening the health crises caused by the pandemic. The sharp rise in cases attributed to the Delta variant has made it especially disturbing and is a variant of concern. Fortunately, current vaccines offer protection against known variants of concern, including the Delta variant. However, the Delta variant has exhibited some ability to dodge the immune system as it is found that neutralizing antibodies from prior infections or vaccines are less receptive to binding with the Delta spike protein. Here, we investigated the structural changes caused by the mutations in the Delta variant's receptor-binding interface and explored the effects on binding with the ACE2 receptor as well as with neutralizing antibodies. We find that the receptor-binding ß-loop-ß motif adopts an altered but stable conformation causing separation in some of the antibody binding epitopes. Our study shows reduced binding of neutralizing antibodies and provides a possible mechanism for the immune evasion exhibited by the Delta variant.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , Immune Evasion/immunology , Mutation/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acids/genetics , Amino Acids/immunology , Amino Acids/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , Binding Sites/genetics , Binding Sites/immunology , COVID-19/metabolism , COVID-19/virology , Humans , Immune Evasion/genetics , Molecular Dynamics Simulation , Mutation/genetics , Neutralization Tests , Protein Binding , Protein Domains , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
12.
Nature ; 592(7853): 277-282, 2021 04.
Article in English | MEDLINE | ID: covidwho-1387425

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , COVID-19/virology , Evolution, Molecular , Mutagenesis/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Chronic Disease , Genome, Viral/drug effects , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing , Humans , Immune Evasion/drug effects , Immune Evasion/genetics , Immune Evasion/immunology , Immune Tolerance/drug effects , Immune Tolerance/immunology , Immunization, Passive , Male , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/immunology , Mutation , Phylogeny , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Viral Load/drug effects , Virus Shedding
13.
Front Immunol ; 12: 700184, 2021.
Article in English | MEDLINE | ID: covidwho-1365542

ABSTRACT

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Subject(s)
COVID-19/immunology , Host Microbial Interactions/genetics , Immunity, Innate/genetics , RNA, Long Noncoding/metabolism , Thrombosis/immunology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biomarkers/analysis , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , COVID-19 Testing/methods , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/immunology , Host Microbial Interactions/drug effects , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Pandemics/prevention & control , RNA, Long Noncoding/analysis , RNA, Long Noncoding/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/genetics , Signal Transduction/immunology , Thrombosis/genetics , Thrombosis/virology , Virus Replication/drug effects , Virus Replication/genetics , Virus Replication/immunology
14.
J Med Virol ; 93(9): 5376-5389, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363676

ABSTRACT

The suppression of types I and III interferon (IFN) responses by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to the pathogenesis of coronavirus disease 2019 (COVID-19). The strategy used by SARS-CoV-2 to evade antiviral immunity needs further investigation. Here, we reported that SARS-CoV-2 ORF9b inhibited types I and III IFN production by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of types I and III IFNs by Sendai virus and poly (I:C). SARS-CoV-2 ORF9b inhibited the activation of types I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKKε, rather than IRF3-5D, which is the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of types I and III IFNs by TRIF and STING, which are the adaptor protein of the endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of the cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. A mechanistic analysis revealed that the SARS-CoV-2 ORF9b protein interacted with RIG-I, MDA-5, MAVS, TRIF, STING, and TBK1 and impeded the phosphorylation and nuclear translocation of IRF3. In addition, SARS-CoV-2 ORF9b facilitated the replication of the vesicular stomatitis virus. Therefore, the results showed that SARS-CoV-2 ORF9b negatively regulates antiviral immunity and thus facilitates viral replication. This study contributes to our understanding of the molecular mechanism through which SARS-CoV-2 impairs antiviral immunity and provides an essential clue to the pathogenesis of COVID-19.


Subject(s)
DEAD Box Protein 58/immunology , Immune Evasion/genetics , Interferons/immunology , Nucleotidyltransferases/immunology , Receptors, Immunologic/immunology , SARS-CoV-2/immunology , Toll-Like Receptor 3/immunology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Adaptor Proteins, Vesicular Transport/genetics , Adaptor Proteins, Vesicular Transport/immunology , Animals , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/immunology , DEAD Box Protein 58/genetics , Gene Expression Regulation , HEK293 Cells , HeLa Cells , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/immunology , Immunity, Innate , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/immunology , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/immunology , Interferons/genetics , Membrane Proteins/genetics , Membrane Proteins/immunology , Nucleotidyltransferases/genetics , Phosphoproteins/genetics , Phosphoproteins/immunology , Plasmids/chemistry , Plasmids/metabolism , /immunology , Receptors, Immunologic/genetics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction/genetics , Signal Transduction/immunology , Toll-Like Receptor 3/genetics , Transfection , Vero Cells , Virus Replication/immunology
16.
mSphere ; 6(4): e0024421, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1329039

ABSTRACT

Recent studies have shown that persistent SARS-CoV-2 infections in immunocompromised patients can trigger the accumulation of an unusual high number of mutations with potential relevance at both biological and epidemiological levels. Here, we report a case of an immunocompromised patient (non-Hodgkin lymphoma patient under immunosuppressive therapy) with a persistent SARS-CoV-2 infection (marked by intermittent positivity) over at least 6 months. Viral genome sequencing was performed at days 1, 164, and 171 to evaluate SARS-CoV-2 evolution. Among the 15 single-nucleotide polymorphisms (SNPs) (11 leading to amino acid alterations) and 3 deletions accumulated during this long-term infection, four amino acid changes (V3G, S50L, N87S, and A222V) and two deletions (18-30del and 141-144del) occurred in the virus Spike protein. Although no convalescent plasma therapy was administered, some of the detected mutations have been independently reported in other chronically infected individuals, which supports a scenario of convergent adaptive evolution. This study shows that it is of the utmost relevance to monitor the SARS-CoV-2 evolution in immunocompromised individuals, not only to identify novel potentially adaptive mutations, but also to mitigate the risk of introducing "hyper-evolved" variants in the community. IMPORTANCE Tracking the within-patient evolution of SARS-CoV-2 is key to understanding how this pandemic virus shapes its genome toward immune evasion and survival. In the present study, by monitoring a long-term COVID-19 immunocompromised patient, we observed the concurrent emergence of mutations potentially associated with immune evasion and/or enhanced transmission, mostly targeting the SARS-CoV-2 key host-interacting protein and antigen. These findings show that the frequent oscillation in the immune status in immunocompromised individuals can trigger an accelerated virus evolution, thus consolidating this study model as an accelerated pathway to better understand SARS-CoV-2 adaptive traits and anticipate the emergence of variants of concern.


Subject(s)
COVID-19/immunology , Immune Evasion/immunology , Immunocompromised Host/immunology , Lymphoma, Non-Hodgkin/immunology , SARS-CoV-2/immunology , Amino Acids/genetics , Amino Acids/immunology , Animals , COVID-19/virology , Cell Line , Chlorocebus aethiops , Female , Genome, Viral/genetics , Genome, Viral/immunology , Humans , Immune Evasion/genetics , Immunization, Passive/methods , Lymphoma, Non-Hodgkin/virology , Middle Aged , Mutation/genetics , Mutation/immunology , Pandemics/prevention & control , SARS-CoV-2/genetics , Vero Cells , Virus Replication/genetics , Virus Replication/immunology
17.
Nature ; 597(7874): 103-108, 2021 09.
Article in English | MEDLINE | ID: covidwho-1316713

ABSTRACT

The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/prevention & control , SARS-CoV-2/classification , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Broadly Neutralizing Antibodies/chemistry , COVID-19/immunology , COVID-19/virology , Cross Reactions/immunology , Disease Models, Animal , Female , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Mesocricetus/immunology , Mesocricetus/virology , Mutation , Neutralization Tests , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Viral Zoonoses/immunology , Viral Zoonoses/prevention & control , Viral Zoonoses/virology
18.
Nature ; 597(7874): 97-102, 2021 09.
Article in English | MEDLINE | ID: covidwho-1309448

ABSTRACT

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse sarbecoviruses4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.


Subject(s)
Broadly Neutralizing Antibodies/immunology , COVID-19/virology , Cross Reactions/immunology , Immune Evasion , SARS-CoV-2/classification , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibody Affinity , Broadly Neutralizing Antibodies/chemistry , COVID-19/drug therapy , COVID-19/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Cell Line , Cricetinae , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Female , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Male , Mesocricetus , Middle Aged , Models, Molecular , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccinology
19.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1307383

ABSTRACT

Understanding the trends in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution is paramount to control the COVID-19 pandemic. We analyzed more than 300,000 high-quality genome sequences of SARS-CoV-2 variants available as of January 2021. The results show that the ongoing evolution of SARS-CoV-2 during the pandemic is characterized primarily by purifying selection, but a small set of sites appear to evolve under positive selection. The receptor-binding domain of the spike protein and the region of the nucleocapsid protein associated with nuclear localization signals (NLS) are enriched with positively selected amino acid replacements. These replacements form a strongly connected network of apparent epistatic interactions and are signatures of major partitions in the SARS-CoV-2 phylogeny. Virus diversity within each geographic region has been steadily growing for the entirety of the pandemic, but analysis of the phylogenetic distances between pairs of regions reveals four distinct periods based on global partitioning of the tree and the emergence of key mutations. The initial period of rapid diversification into region-specific phylogenies that ended in February 2020 was followed by a major extinction event and global homogenization concomitant with the spread of D614G in the spike protein, ending in March 2020. The NLS-associated variants across multiple partitions rose to global prominence in March to July, during a period of stasis in terms of interregional diversity. Finally, beginning in July 2020, multiple mutations, some of which have since been demonstrated to enable antibody evasion, began to emerge associated with ongoing regional diversification, which might be indicative of speciation.


Subject(s)
Adaptation, Physiological/genetics , Evolution, Molecular , SARS-CoV-2/genetics , Amino Acid Substitution , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Testing , Coronavirus Nucleocapsid Proteins/genetics , Epistasis, Genetic , Genome, Viral/genetics , Humans , Immune Evasion/genetics , Mutation , Nuclear Localization Signals/genetics , Phosphoproteins/genetics , Phylogeny , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/classification , Selection, Genetic , Spike Glycoprotein, Coronavirus/genetics , Vaccination
20.
Nat Commun ; 12(1): 4196, 2021 07 07.
Article in English | MEDLINE | ID: covidwho-1301167

ABSTRACT

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.


Subject(s)
Antibodies, Viral/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19/immunology , Epitopes , HLA Antigens/immunology , Humans , Immune Evasion/genetics , Models, Molecular , Mutation , Neutralization Tests , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
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