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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332787

ABSTRACT

Omicron B.1.1.529 became the predominant SARS-CoV-2 variant in early 2022, causing a new wave of public anxiety. Compared to the ancestral strain, Omicron has 50 mutations, with over 30 mutations in the spike protein. These differences likely underlie the changes in Omicron biology noted in other studies, including an attenuation in the lung parenchyma, compared to the ancestral SARS-CoV-2 strain and other variants, as well as a preference for endosomal entry, in place of the TMPRSS2-mediated membrane fusion pathway. This raises questions on Omicron tropism and infectivity in various target organ systems, including the gastrointestinal (GI) tract. Up to 70% of COVID-19 patients report GI symptoms, including nausea, vomiting, and diarrhea. Here, we show that in the context of donor intrinsic genetic heterogeneity, the SARS-CoV-2 Omicron variant infects human colonoids similarly, if not less effectively, than the ancestral WT (WA1) strain or the Delta variant. Additionally, we note a higher ratio of viral RNA to infectious virus titer, which may suggest that Omicron is potentially less infectious in the intestine. This study lays the foundation for further work defining mechanisms mediating intestinal infection and pathogenesis by Omicron.

3.
Science ; 373(6556)2021 Aug 13.
Article in English | MEDLINE | ID: covidwho-1559379

ABSTRACT

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Antigen-Antibody Reactions , COVID-19/virology , Humans , Immune Evasion , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/metabolism , Mutation , Neutralization Tests , Protein Domains , Receptors, Coronavirus/antagonists & inhibitors , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
5.
Science ; 373(6556)2021 Aug 13.
Article in English | MEDLINE | ID: covidwho-1295159

ABSTRACT

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/metabolism , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Antigen-Antibody Reactions , COVID-19/virology , Humans , Immune Evasion , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/metabolism , Mutation , Neutralization Tests , Protein Domains , Receptors, Coronavirus/antagonists & inhibitors , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
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