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2.
Cell Host Microbe ; 2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2240051

ABSTRACT

Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.

3.
Antib Ther ; 6(1): 49-58, 2023 Jan.
Article in English | MEDLINE | ID: covidwho-2212700

ABSTRACT

Background: Neutralising antibodies against SARS-CoV-2 are a vital component in the fight against COVID-19 pandemic, having the potential of both therapeutic and prophylactic applications. Bispecific antibodies (BsAbs) against SARS-CoV-2 are particularly promising, given their ability to bind simultaneously to two distinct sites of the receptor-binding domain (RBD) of the viral spike protein. Such antibodies are complex molecules associated with multi-faceted mechanisms of action that require appropriate bioassays to ensure product quality and manufacturing consistency. Methods: We developed procedures for biolayer interferometry (BLI) and a cell-based virus neutralisation assay, the focus reduction neutralisation test (FRNT). Using both assays, we tested a panel of five BsAbs against different spike variants (Ancestral, Delta and Omicron) to evaluate the use of these analytical methods in assessing binding and neutralisation activities of anti-SARS-CoV-2 therapeutics. Results: We found comparable trends between BLI-derived binding affinity and FRNT-based virus neutralisation activity. Antibodies that displayed high binding affinity against a variant were often followed by potent neutralisation at lower concentrations, whereas those with low binding affinity also demonstrated reduced neutralisation activity. Conclusion: The results support the utility of BLI and FRNT assays in measuring variant-specific binding and virus neutralisation activity of anti-SARS-CoV-2 antibodies.

4.
DNA Cell Biol ; 41(1): 34-37, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1577529

ABSTRACT

Monoclonal antibodies are coming of age as powerful tools for the prevention of infectious diseases. In recent years, the rate of antibody discovery has accelerated, and the coronavirus disease 2019 (COVID-19) pandemic has shone a spotlight on the role of these antibodies in combating pathogens. However, questions remain about the utility of monoclonal antibodies, especially when effective vaccines are also available. In this article, I discuss the role of monoclonal antibodies and briefly describe the effort to identify potent human monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including our study on bispecific antibodies that neutralize SARS-CoV-2 variants of concern.


Subject(s)
SARS-CoV-2 , Antibodies, Monoclonal
5.
Science ; 377(6607): 728-735, 2022 08 12.
Article in English | MEDLINE | ID: covidwho-1968212

ABSTRACT

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.


Subject(s)
Antibodies, Monoclonal , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19 , Epitopes , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Epitopes/chemistry , Epitopes/immunology , Humans , Peptides/immunology , Protein Conformation, alpha-Helical , Protein Domains , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
6.
Front Psychiatry ; 12: 755059, 2021.
Article in English | MEDLINE | ID: covidwho-1551544

ABSTRACT

Background: The COVID-19 pandemic brought about great transformation to medical education mode. Although mobile communication devices played a crucial role in online learning among quarantined university students, the potential smartphone addition problems, negative health behaviors, and psychological symptoms need considerable attention. This study examined the relationship of problematic smartphone use (PSU), sleep quality, and daytime fatigue among medical students. Methods: A web-based survey was conducted in six polyclinic hospitals in Beijing between February and May 2020. 1016 participants (26.01 ± 2.46 years, 65.16% female) completed self-report measurements including Short Version Smartphone Addiction Scale (SAS-SV), Athens Insomnia Scale (AIS), and Subjective Fatigue Scale (FS). Spearman correlation coefficients and multiple regression models were used to analyze the association among PSU, sleep quality, and daytime fatigue. We used structural equation modeling to test the mediating effect of sleep quality between PSU and daytime fatigue. Results: 49.70% of the participants had PSU. Significant positive correlations were found among SAS-SV, AIS, and FS scores (r = 0.35-0.61, P S < 0.001). Subjects with PSU were more likely to report sleep disturbance (ß = 1.07, P < 0.001, OR = 2.91, 95%CI = 2.17-3.91), physical fatigue (ß = 1.16, P < 0.001, OR = 3.18, 95%CI = 2.45-4.15), and mental fatigue (ß = 0.88, P < 0.001, OR = 2.42, 95%CI = 1.86-3.14). The indirect effect of PSU on physical fatigue and mental fatigue mediated by sleep quality accounted for 50.03 and 45.43% of the total effect, respectively. Conclusions: PSU was significantly associated with sleep disturbance and fatigue among medical students during the COVID-19 pandemic. Sleep quality mediated the relationship between PSU and daytime fatigue. Our results provide valuable information for maintaining medical students' health status and constructing online education structures.

7.
Sci Transl Med ; 13(616): eabj5413, 2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1406601

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain­RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.


Subject(s)
Antibodies, Bispecific , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Bispecific/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 , Humans , SARS-CoV-2
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