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1.
Cell ; 185(3): 467-484.e15, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35081335

RESUMEN

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

2.
Cell ; 184(16): 4220-4236.e13, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34242578

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.


Asunto(s)
Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Complejo Antígeno-Anticuerpo/química , COVID-19/patología , COVID-19/terapia , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Chlorocebus aethiops , Cristalografía por Rayos X , Humanos , Inmunización Pasiva , Pruebas de Neutralización , Dominios Proteicos/inmunología , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero , Sueroterapia para COVID-19
3.
Clin Exp Immunol ; 212(3): 249-261, 2023 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-36807499

RESUMEN

T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established 'Protective Immunity from T Cells in Healthcare workers' (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Estudios Transversales , Ensayos de Liberación de Interferón gamma , Vacunación , Anticuerpos Antivirales
4.
Mol Ther ; 30(10): 3209-3225, 2022 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-35614857

RESUMEN

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson's disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Animales , Ingeniería Genética , Terapia Genética , Células Madre Hematopoyéticas/metabolismo , Ratones , Distribución Tisular
5.
Health Promot Int ; 30 Suppl 2: ii116-25, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26420807

RESUMEN

The role of social innovations in transforming the lives of individuals and communities has been a source of popular attention in recent years. This article systematically reviews the available evidence of the relationship between social innovation and its promotion of health equity. Guided by Fair Foundations: The VicHealth framework for health equity and examining four types of social innovation--social movements, service-related social innovations, social enterprise and digital social innovations--we find a growing literature on social innovation activities, but inconsistent evaluative evidence of their impacts on health equities, particularly at the socio-economic, political and cultural level of the framework. Distinctive characteristics of social innovations related to the promotion of health equity include the mobilization of latent or unrealised value through new combinations of (social, cultural and material) resources; growing bridging social capital and purposeful approaches to linking individual knowledge and experience to institutional change. These have implications for health promotion practice and for research about social innovation and health equity.


Asunto(s)
Equidad en Salud , Promoción de la Salud , Justicia Social , Política de Salud , Humanos
6.
Lancet ; 391(10123): 883-910, 2018 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-28987452
7.
ACS Synth Biol ; 13(2): 466-473, 2024 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-38266181

RESUMEN

We engineered HEK293T cells with a transgene encoding tetracycline-inducible expression of a Staphylococcus aureus nuclease incorporating a translocation signal. We adapted the unmodified and nuclease-engineered cell lines to grow in suspension in serum-free media, generating the HEK293TS and NuPro-2S cell lines, respectively. Transient transfection yielded 1.19 × 106 lentiviral transducing units per milliliter (TU/mL) from NuPro-2S cells and 1.45 × 106 TU/mL from HEK293TS cells. DNA ladder disappearance revealed medium-resident nuclease activity arising from NuPro-2S cells in a tetracycline-inducible manner. DNA impurity levels in lentiviral material arising from NuPro-2S and HEK293TS cells were undetectable by SYBR Safe agarose gel staining. Direct measurement by PicoGreen reagent revealed DNA to be present at 636 ng/mL in lentiviral material from HEK293TS cells, an impurity level reduced by 89% to 70 ng/mL in lentiviral material from NuPro-2S cells. This reduction was comparable to the 23 ng/mL achieved by treating HEK293TS-derived lentiviral material with 50 units/mL Benzonase.


Asunto(s)
Fluoruro de Fosfato Acidulado , Vectores Genéticos , Lentivirus , Animales , Humanos , Lentivirus/genética , Vectores Genéticos/genética , Células HEK293 , Transfección , ADN/genética , Tetraciclina , Mamíferos/genética
8.
BMC Evol Biol ; 13: 174, 2013 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-23962342

RESUMEN

BACKGROUND: Sex in higher diploids carries a two-fold cost of males that should reduce its fitness relative to cloning, and result in its extinction. Instead, sex is widespread and clonal species face early obsolescence. One possible reason is that sex is an adaptation that allows organisms to respond more effectively to endless changes in their environment. The purpose of this study was to model mutation and selection in a diploid organism in an evolving environment and ascertain their support for sex. RESULTS: We used a computational approach to model finite populations where a haploid environment subjects a diploid host to endlessly evolving change. Evolution in both populations is primarily through adoption of novel advantageous mutations within a large allele space. Sex outcompetes cloning by two complementary mechanisms. First, sexual diploids adopt advantageous homozygous mutations more rapidly than clonal ones under conditions of lag load (the gap between the actual adaptation of the diploid population and its theoretical optimum). This rate advantage can offset the higher fecundity of cloning. Second, a relative advantage to sex emerges where populations are significantly polymorphic, because clonal polymorphism runs the risk of clonal interference caused by selection on numerous lines of similar adaptation. This interference extends allele lifetime and reduces the rate of adaptation. Sex abolishes the interference, making selection faster and elevating population fitness. Differences in adaptation between sexual and clonal populations increase markedly with the number of loci under selection, the rate of mutation in the host, and a rapidly evolving environment. Clonal interference in these circumstances leads to conditions where the greater fecundity of clones is unable to offset their poor adaptation. Sexual and clonal populations then either co-exist, or sex emerges as the more stable evolutionary strategy. CONCLUSIONS: Sex can out-compete clones in a rapidly evolving environment, such as that characterized by pathogens, where clonal interference reduces the adaptation of clonal populations and clones adopt advantageous mutations more slowly. Since all organisms carry parasitic loads, the model is of potentially general applicability.


Asunto(s)
Evolución Biológica , Modelos Biológicos , Reproducción , Sexo , Animales , Simulación por Computador , Diploidia , Femenino , Humanos , Masculino , Mutación , Tasa de Mutación
10.
Biochem Eng J ; 77(100): 246-257, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23956681

RESUMEN

The use of embryonic stem cells (ESCs) and their progeny in high throughput drug discovery and regenerative medicine will require production at scale of well characterized cells at an appropriate level of purity. The adoption of automated bioprocessing techniques offers the possibility to overcome the lack of consistency and high failure rates seen with current manual protocols. To build the case for increased use of automation this work addresses the key question: "can an automated system match the quality of a highly skilled and experienced person working manually?" To answer this we first describe an integrated automation platform designed for the 'hands-free' culture and differentiation of ESCs in microwell formats. Next we outline a framework for the systematic investigation and optimization of key bioprocess variables for the rapid establishment of validatable Standard Operating Procedures (SOPs). Finally the experimental comparison between manual and automated bioprocessing is exemplified by expansion of the murine Oct-4-GiP ESC line over eight sequential passages with their subsequent directed differentiation into neural precursors. Our results show that ESCs can be effectively maintained and differentiated in a highly reproducible manner by the automated system described. Statistical analysis of the results for cell growth over single and multiple passages shows up to a 3-fold improvement in the consistency of cell growth kinetics with automated passaging. The quality of the cells produced was evaluated using a panel of biological markers including cell growth rate and viability, nutrient and metabolite profiles, changes in gene expression and immunocytochemistry. Automated processing of the ESCs had no measurable negative effect on either their pluripotency or their ability to differentiate into the three embryonic germ layers. Equally important is that over a 6-month period of culture without antibiotics in the medium, we have not had any cases of culture contamination. This study thus confirms the benefits of adopting automated bioprocess routes to produce cells for therapy and for use in basic discovery research.

11.
Heliyon ; 9(6): e17067, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37484388

RESUMEN

At present lentiviral vector production for cell and gene therapy commonly involves transient plasmid transfection of mammalian cells cultivated in serum-containing media and addition of exogenous nuclease to reduce host cell and plasmid DNA impurities. Switching from serum-containing media to chemically-defined, serum free media, and minimising the number of process additions, are both increasingly regarded as necessary steps for simplifying and potentially automating lentiviral vector bioprocessing in future. Here we adapted human embryonic kidney 293T (HEK293T) cells to grow in serum-free media and also modified these cells with transgenes designed to encode a secreted nuclease activity. Stable transfection of HEK293T cells with transgenes encoding the Staphylococcus aureus nuclease B (NucB) open reading frame with either its native secretion signal peptide, the murine Igκ chain leader sequence or a novel viral transport fusion protein, all resulted in qualitatively detectable nuclease activity in serum-free media. Serum-free transient transfection of human embryonic kidney HEK293T cells stably harbouring the transgene for NucB with its native secretion signal produced active lentivirus in the presence of medium-resident nuclease activity. This lentivirus material was able to transduce the AGF-T immortal T cell line with a green fluorescent protein reporter payload at a level of 2.05 × 105 TU/mL (±3.34 × 104 TU/mL). Sufficient nuclease activity was present in 10 µL of this unconcentrated lentivirus material to degrade 1.5 µg DNA within 2 h at 37 °C, without agitation - conditions compatible with lentivirus production. These observations demonstrate that lentiviral vector production, by transient transfection, is compatible with host cells harbouring a nuclease transgene and evidencing nuclease activity in their surrounding growth media. This work provides a solid basis for future investigations, beyond the scope of this present study, in which commercial and academic groups can apply this approach to therapeutic payloads and potentially omit exogenous nuclease bioprocess additions.

12.
Biotechnol Lett ; 34(12): 2307-15, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22983716

RESUMEN

The commercialisation of human embryonic stem cell derived cell therapies for large patient populations is reliant on both minimising expensive and variable manual-handling methods whilst realising economies of scale. The Quantum Cell Expansion System, a hollow fibre bioreactor (Terumo BCT), was used in a pilot study to expand 60 million human embryonic stem cells to 708 million cells. Further improvements can be expected with optimisation of media flow rates throughout the run to better control the cellular microenvironment. High levels of pluripotency marker expression were maintained on the bioreactor, with 97.7 % of cells expressing SSEA-4 when harvested.


Asunto(s)
Reactores Biológicos , Técnicas de Cultivo de Célula/métodos , Células Madre Embrionarias/fisiología , Expresión Génica , Humanos , Antígenos Embrionarios Específico de Estadio/biosíntesis
13.
Biomedicines ; 10(2)2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35203513

RESUMEN

Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology.

14.
Mol Ther Methods Clin Dev ; 27: 464-487, 2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36419467

RESUMEN

Pompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and central nervous system (CNS), risks recombinant enzyme immunogenicity, and requires high doses and frequent infusions. Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy was investigated in a Pompe mouse model using a clinically relevant promoter driving nine engineered GAA coding sequences incorporating distinct peptide tags and codon optimizations. Vectors solely including glycosylation-independent lysosomal targeting tags enhanced secretion and improved reduction of glycogen, myofiber, and CNS vacuolation in key tissues, although GAA enzyme activity and protein was consistently lower compared with native GAA. Genetically modified microglial cells in brains were detected at low levels but provided robust phenotypic correction. Furthermore, an amino acid substitution introduced in the tag reduced insulin receptor-mediated signaling with no evidence of an effect on blood glucose levels in Pompe mice. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation.

15.
Cell Host Microbe ; 30(1): 53-68.e12, 2022 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-34921776

RESUMEN

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.


Asunto(s)
Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Células Cultivadas , Chlorocebus aethiops , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Transgénicos , Pruebas de Neutralización/métodos , Unión Proteica/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Células Vero
17.
Int J Surg Pathol ; 29(6): 648-652, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33345669

RESUMEN

Phyllodes tumors (PTs) represent a spectrum of rare, fibroepithelial neoplasms of the breast, which can be subcategorized as benign, borderline, or malignant based on their histological appearance. Accessory breast tissue may present anywhere along the embryological mammary ridge, and at distant locations as aberrant breast tissue. We present the case of a 56-year-old lady with an umbilical mass, thought to represent a strangulated hernia. Sections showed a fibroepithelial tumor with leaf-like ducts, conspicuous mitotic activity (up to 8 per 10 high-power fields), and focal infiltration into fat. Immunohistochemical studies showed diffuse positivity of epithelial cells for estrogen receptor, mammaglobin, GCDFP-15, and CK7. These findings were consistent with a borderline PT. This is the first case report of PT presenting as an umbilical mass, and the first extramammary borderline PT described.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Coristoma/diagnóstico , Tumor Filoide/diagnóstico , Ombligo/patología , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Coristoma/patología , Coristoma/cirugía , Femenino , Humanos , Persona de Mediana Edad , Tumor Filoide/patología , Tumor Filoide/cirugía , Ombligo/cirugía
18.
Mol Ther Methods Clin Dev ; 20: 312-323, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33511245

RESUMEN

Gaucher disease type 1 (GD1) is an inherited lysosomal disorder with multisystemic effects in patients. Hallmark symptoms include hepatosplenomegaly, cytopenias, and bone disease with varying degrees of severity. Mutations in a single gene, glucosidase beta acid 1 (GBA1), are the underlying cause for the disorder, resulting in insufficient activity of the enzyme glucocerebrosidase, which in turn leads to a progressive accumulation of the lipid component glucocerebroside. In this study, we treat mice with signs consistent with GD1, with hematopoietic stem/progenitor cells transduced with a lentiviral vector containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the genome encodes for functional human glucocerebrosidase. Five months after gene transfer, a highly significant reduction in glucocerebroside accumulation with subsequent reversal of hepatosplenomegaly, restoration of blood parameters, and a tendency of increased bone mass and density was evident in vector-treated mice compared to non-treated controls. Furthermore, histopathology revealed a prominent reduction of Gaucher cell infiltration after gene therapy. The vector displayed an oligoclonal distribution pattern but with no sign of vector-induced clonal dominance and a typical lentiviral vector integration profile. Cumulatively, our findings support the initiation of the first clinical trial for GD1 using the lentiviral vector described here.

19.
Nat Commun ; 12(1): 5406, 2021 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-34518533

RESUMEN

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.


Asunto(s)
Neoplasias de la Mama/genética , Metilación de ADN , Epigénesis Genética , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica , Estudios de Cohortes , Islas de CpG/genética , Replicación del ADN/genética , Femenino , Genoma Humano/genética , Inestabilidad Genómica/genética , Genómica/métodos , Humanos , Células MCF-7 , Mutación , Regiones Promotoras Genéticas/genética , Análisis de Supervivencia
20.
bioRxiv ; 2021 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-34981049

RESUMEN

On the 24 th November 2021 the sequence of a new SARS CoV-2 viral isolate spreading rapidly in Southern Africa was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.

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