scholarly journals Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Science ◽  
2020 ◽  
Vol 369 (6506) ◽  
pp. 1010-1014 ◽  
Author(s):  
Johanna Hansen ◽  
Alina Baum ◽  
Kristen E. Pascal ◽  
Vincenzo Russo ◽  
Stephanie Giordano ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Selective Pressure ◽  
Three Dimensional ◽  
Spike Protein ◽  
Humanized Mice ◽  
Dimensional Structure ◽  
Antibody Treatment ◽  
Virus Escape ◽  
Escape Mutants ◽  
Antibody Cocktail

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola—one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

scholarly journals Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants

2014 ◽  
Vol 211 (12) ◽  
pp. 2361-2372 ◽  
Author(s):  
Florian Klein ◽  
Lilian Nogueira ◽  
Yoshiaki Nishimura ◽  
Ganesh Phad ◽  
Anthony P. West ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Humanized Mice ◽  
Broadly Neutralizing Antibodies ◽  
Virus Escape ◽  
Immunodeficiency Virus ◽  
Shiv Infection ◽  
Hiv 1

Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian–human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants.

scholarly journals Structures of SARS-CoV-2 B.1.351 neutralizing antibodies provide insights into cocktail design against concerning variants

2021 ◽  
Author(s):  
Shuo Du ◽  
Pulan Liu ◽  
Zhiying Zhang ◽  
Tianhe Xiao ◽  
Ayijiang Yasimayi ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Antibody Responses ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Humoral Antibody ◽  
Cryo Electron Microscopy ◽  
Antibody Cocktail

The spread of the SARS-CoV-2 variants could seriously dampen the global effort to tackle the COVID-19 pandemic. Recently, we investigated the humoral antibody responses of SARS-CoV-2 convalescent patients and vaccinees towards circulating variants, and identified a panel of monoclonal antibodies (mAbs) that could efficiently neutralize the B.1.351 (Beta) variant. Here we investigate how these mAbs target the B.1.351 spike protein using cryo-electron microscopy. In particular, we show that two superpotent mAbs, BD-812 and BD-836, have non-overlapping epitopes on the receptor-binding domain (RBD) of spike. Both block the interaction between RBD and the ACE2 receptor; and importantly, both remain fully efficacious towards the B.1.617.1 (Kappa) and B.1.617.2 (Delta) variants. The BD-812/BD-836 pair could thus serve as an ideal antibody cocktail against the SARS-CoV-2 VOCs.

scholarly journals A Rare Deletion in SARS-CoV-2 ORF6 Dramatically Alters the Predicted Three-Dimensional Structure of the Resultant Protein

2020 ◽  
Author(s):  
Marco A. Riojas ◽  
Andrew M. Frank ◽  
Nikhita P. Puthuveetil ◽  
Beth Flores ◽  
Michael Parker ◽  
...  
Keyword(s):  
Selective Pressure ◽  
Type I Interferon ◽  
Clinical Sample ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Type I ◽  
Three Dimensional Structure ◽  
Clinical Patient ◽  
N Terminus ◽  
Functional Implications

AbstractThe function of the SARS-CoV-2 accessory protein p6, encoded by ORF6, is not fully known. Based upon its similarity to p6 from SARS-CoV, it may play a similar role, namely as an antagonist of type I interferon (IFN) signaling. Here we report the sequencing of a SARS-CoV-2 strain passaged six times after original isolation from a clinical patient in Hong Kong. The genome sequence shows a 27 nt in-frame deletion (Δ27,264-27,290) within ORF6, predicted to result in a 9 aa deletion (ΔFKVSIWNLD) from the central portion of p6. This deletion is predicted to result in a dramatic alteration in the three-dimensional structure of the resultant protein (p6Δ22-30), possibly with significant functional implications. Analysis of the original clinical sample indicates that the deletion was not present, while sequencing of subsequent passages of the strain identifies the deletion as a majority variant. This suggests that the deletion originated ab initio during passaging and subsequently propagated into the majority, possibly due to the removal of selective pressure through the IFN-deficient Vero E6 cell line. The specific function of the SARS-CoV-2 p6 N-terminus, if any, has not yet been determined. However, this deletion is predicted to cause a shift from N-endo to N-ecto in the transmembrane localization of the SARS-CoV-2 p6Δ22-30 N-terminus, possibly leading to the ablation of its native function.

scholarly journals REGN-COV2 antibody cocktail prevents and treats SARS-CoV-2 infection in rhesus macaques and hamsters

2020 ◽  
Author(s):  
Alina Baum ◽  
Richard Copin ◽  
Dharani Ajithdoss ◽  
Anbo Zhou ◽  
Kathryn Lanza ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Potential ◽  
Rhesus Macaques ◽  
Upper Airway ◽  
Spike Protein ◽  
In Vivo Efficacy ◽  
Virus Load ◽  
Golden Hamsters ◽  
Antibody Cocktail

AbstractAn urgent global quest for effective therapies to prevent and treat COVID-19 disease is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987+REGN10933) targeting non-overlapping epitopes on the SARS-CoV-2 spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques and golden hamsters and demonstrate that REGN-COV-2 can greatly reduce virus load in lower and upper airway and decrease virus induced pathological sequalae when administered prophylactically or therapeutically. Our results provide evidence of the therapeutic potential of this antibody cocktail.

scholarly journals REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters

Science ◽  
2020 ◽  
Vol 370 (6520) ◽  
pp. 1110-1115 ◽  
Author(s):  
Alina Baum ◽  
Dharani Ajithdoss ◽  
Richard Copin ◽  
Anbo Zhou ◽  
Kathryn Lanza ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Potential ◽  
Rhesus Macaques ◽  
Severe Disease ◽  
Spike Protein ◽  
Upper Airways ◽  
In Vivo Efficacy ◽  
Mild Disease ◽  
Antibody Cocktail

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.

scholarly journals SARS-CoV-2 mutations and where to find them: An in silico perspective of structural changes and antigenicity of the Spike protein

2020 ◽  
Author(s):  
Ricardo Lemes Gonçalves ◽  
Túlio César Rodrigues Leite ◽  
Bruna de Paula Dias ◽  
Camila Carla da Silva Caetano ◽  
Ana Clara Gomes de Souza ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Changes ◽  
Three Dimensional ◽  
Specific Treatment ◽  
Spike Protein ◽  
Dimensional Structure ◽  
Structural Protein ◽  
Worldwide Distribution ◽  
Recent Emergence ◽  
Novel Coronavirus

The recent emergence of a novel coronavirus (SARS-CoV-2) is causing a severe global health threat characterized by severe acute respiratory syndrome (Covid-19). At the moment, there is no specific treatment for this disease, and vaccines are still under development. The structural protein Spike is essential for virus infection and has been used as the main target for vaccine and serological diagnosis test development. We analysed 2363 sequences of the Spike protein from SARS-CoV-2 isolates and identified variability in 44 amino acid residues and their worldwide distribution in all continents. We used the three-dimensional structure of the homo-trimer model to predict conformational epitopes of B-cell, and sequence of Spike protein Wuhan-Hu-1 to predict linear epitopes of T-Cytotoxic and T-Helper cells. We identified 45 epitopes with amino acid variations. Finally, we showed the distribution of mutations within the epitopes. Our findings can help researches to identify more efficient strategies for the development of vaccines, therapies, and serological diagnostic tests based on the Spike protein of Sars-Cov-2.

scholarly journals L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England

2021 ◽  
Author(s):  
Frederic Grabowski ◽  
Marek Kochańczyk ◽  
Tomasz Lipniacki
Keyword(s):  
Molecular Evolution ◽  
South African ◽  
Receptor Binding ◽  
Growth Rates ◽  
Neutralizing Antibodies ◽  
Spike Protein ◽  
Binding Motif ◽  
Viral Genomes ◽  
African Strain ◽  
Escape Mutants

AbstractThe Variant of Concern (VOC)-202012/01 (also known as B.1.1.7) is a rapidly growing lineage of SARS-CoV-2. In January 2021, VOC-202012/01 constituted about 80% of SARS-CoV-2 genomes sequenced in England and was present in 27 out of 29 countries that reported at least 50 viral genomes. As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. Based on GISAID data we systematically estimated growth rates of mutations acquired by the VOC lineage to find that L18F substitution in viral spike protein has initiated a substrain characterized by replicative advantage of 1.70 [95% CI: 1.56–1.96] in relation to the remaining VOC-202012/01 substrains. The L18F mutation is of significance because when recently analyzed in the context of the South African strain 501Y.V2 it has been found to compromise binding of neutralizing antibodies. We additionally indicate three mutations that were acquired by VOC-202012/01 in the receptor binding motif of spike, specifically E484K, F490S, and S494P, that may also give rise to escape mutants. Such mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.

scholarly journals Structure of antigenic sites on the haemagglutinin molecule of H5 avian influenza virus and phenotypic variation of escape mutants

2002 ◽  
Vol 83 (10) ◽  
pp. 2497-2505 ◽  
Author(s):  
Nikolai V. Kaverin ◽  
Irina A. Rudneva ◽  
Natalia A. Ilyushina ◽  
Natalia L. Varich ◽  
Aleksandr S. Lipatov ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Haemagglutination Inhibition ◽  
Three Dimensional ◽  
Glycosylation Site ◽  
Dimensional Structure ◽  
Mouse Serum ◽  
Antigenic Sites ◽  
Escape Mutants ◽  
Influenza Virus Haemagglutinin

To elucidate the structure of the antigenic sites of avian H5 influenza virus haemagglutinin (HA) we analysed escape mutants of a mouse-adapted variant of the H5N2 strain A/Mallard/Pennsylvania/10218/84. A panel of five anti-H5 monoclonal antibodies (mAbs) was used to select 16 escape mutants. The mutants were tested by ELISA and haemagglutination inhibition with this panel of anti-H5 mAbs and the HA genes of the mutants were sequenced. The sequencing demonstrated that the amino acid changes were grouped in two antigenic sites. One corresponded to site A in the H3 HA. The other contained areas that are separated in the amino acid sequence but are topographically close in the three-dimensional structure and partially overlap in the reactions with mAbs. This site corresponds in part to site B in the H3 structure; it also includes a region not involved in site B that partially overlaps site Sa in the H1 HA and an antigenic area in H2 HA. Mutants with the amino acid change K152N, as well as those with the change D126N, showed reduced lethality in mice. The substitution D126N, creating a new glycosylation site, was accompanied by an increase in the sensitivity of the mutants to normal mouse serum inhibitors. Several amino acid changes in the H5 escape mutants occurred at the positions of reported changes in H2 drift variants. This coincidence suggests that the antigenic sites described and analysed here may be important for drift variation if H5 influenza virus ever appears as a pathogen circulating in humans.

scholarly journals Structural Differences among Hemagglutinins of Influenza A Virus Subtypes Are Reflected in Their Antigenic Architecture: Analysis of H9 Escape Mutants

2004 ◽  
Vol 78 (1) ◽  
pp. 240-249 ◽  
Author(s):  
Nikolai V. Kaverin ◽  
Irina A. Rudneva ◽  
Natalia A. Ilyushina ◽  
Aleksandr S. Lipatov ◽  
Scott Krauss ◽  
...  
Keyword(s):  
Hong Kong ◽  
Amino Acid ◽  
Influenza A ◽  
Three Dimensional ◽  
Antigenic Site ◽  
Dimensional Structure ◽  
Three Dimensional Structure ◽  
Equivalent Site ◽  
Escape Mutants ◽  
Phenotypic Variations

ABSTRACT We used a panel of monoclonal antibodies to H9 hemagglutinin to select 18 escape mutants of mouse-adapted influenza A/Swine/Hong Kong/9/98 (H9N2) virus. Cross-reactions of the mutants with the antibodies and the sequencing of hemagglutinin genes revealed two minimally overlapping epitopes. We mapped the amino acid changes to two areas of the recently reported three-dimensional structure of A/Swine/Hong Kong/9/98 hemagglutinin. The grouping of the antigenically relevant amino acid positions in H9 hemagglutinin differs from the pattern observed in H3 and H5 hemagglutinins. Several positions in site B of H3 hemagglutinin are distributed in two sites of H9 hemagglutinin. Unlike any subtype analyzed so far, H9 hemagglutinin does not contain an antigenic site corresponding to site A in H3 hemagglutinin. Positions 145 and 193 (H3 numbering), which in H3 hemagglutinin belong to sites A and B, respectively, are within one site in H9 hemagglutinin. This finding is consistent with the peculiarity of the three-dimensional structure of the H9 molecule, that is, the absence from H9 hemagglutinin of the lateral loop that forms site A in H3 and the equivalent site in H5 hemagglutinins. The escape mutants analyzed displayed phenotypic variations, including decreased virulence for mice and changes in affinity for sialyl substrates. Our results demonstrate a correlation between intersubtype differences in three-dimensional structure and variations among subtypes in the distribution of antigenic areas. Our findings also suggest that covariation and pleiotropic effects of antibody-selected mutations may be important in the evolution of H9 influenza virus, a possible causative agent of a future pandemic.

scholarly journals Structure-guided antibody cocktail for prevention and treatment of COVID-19

2021 ◽  
Vol 17 (10) ◽  
pp. e1009704
Author(s):  
Shih-Chieh Su ◽  
Tzu-Jing Yang ◽  
Pei-Yu Yu ◽  
Kang-Hao Liang ◽  
Wan-Yu Chen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Spike Protein ◽  
Great Promise ◽  
Cryo Electron Microscopy ◽  
Control Disease ◽  
Antibody Cocktail ◽  
Potent Neutralization

Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance.

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