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A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.

ABSTRACT: Severe acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants D614G, B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, B.1.617.1, and B.1.617.2 by a receptor binding domain (RBD)–specific human antibody, DH1047. Prophylactic and therapeutic treatment with DH1047 was protective against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B.1.351 infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among sarbecoviruses. Thus, DH1047 is a broadly protective antibody that can prevent infection and mitigate outbreaks caused by SARS-related strains and SARS-CoV-2 variants. Our results also suggest that the conserved RBD epitope bound by DH1047 is a rational target for a universal sarbecovirus vaccine.

SUBMITTER: Martinez DR

PROVIDER: S-EPMC8899823 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.

Martinez David R DR Schäfer Alexandra A Gobeil Sophie S Li Dapeng D De la Cruz Gabriela G Parks Robert R Lu Xiaozhi X Barr Maggie M Stalls Victoria V Janowska Katarzyna K Beaudoin Esther E Manne Kartik K Mansouri Katayoun K Edwards Robert J RJ Cronin Kenneth K Yount Boyd B Anasti Kara K Montgomery Stephanie A SA Tang Juanjie J Golding Hana H Shen Shaunna S Zhou Tongqing T Kwong Peter D PD Graham Barney S BS Mascola John R JR Montefiori David C DC Alam S Munir SM Sempowski Gregory G Sempowski Gregory D GD Khurana Surender S Wiehe Kevin K Saunders Kevin O KO Acharya Priyamvada P Haynes Barton F BF Baric Ralph S RS

Science translational medicine 20220126 629

Severe acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants ...[more]

PMID: 34726473

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Project description:The incidence of infections attributed to antimicrobial-resistant (AMR) pathogens has increased exponentially over the recent decades reaching 1.27 million deaths worldwide in 2019. Without intervention, these infections are predicted to cause up to 10 million deaths a year and incur costs of up to 100 trillion US dollars globally by 2050. The emergence of AMR bacteria such as the ESKAPEE pathogens, and in particular Pseudomonas aeruginosa and species from the genus Burkholderia, underscores an urgent need for new therapeutic strategies. Monoclonal antibody (mAb) therapy offers a promising alternative to treat and prevent bacterial infections. In this study, we used peptides from highly conserved areas of the bacterial flagellin to generate monoclonal antibodies capable of broad binding to flagellated Gram-negative bacteria. We generated a broadly reactive IgG2bĸ mAb (WVDC-2109) that recognizes P. aeruginosa, Burkholderia sp., and other Gram-negative pathogens of interest. Characterization of the therapeutic potential of this antibody was determined using P. aeruginosa as model. In vitro characterization of WVDC-2109 demonstrated complement-mediated bactericidal activity and enhanced opsonophagocytosis of P. aeruginosa. Prophylactic administration of WVDC-2109 markedly improved survival and outcome in a lethal sepsis model and a sub-lethal murine pneumonia model of P. aeruginosa infection, reducing bacterial burden and inflammation. These findings suggest that WVDC-2109 and similar FliC-targeting antibodies could be valuable in preventing or treating diseases caused by P. aeruginosa as well as other life-threatening diseases of concern.IMPORTANCEAntimicrobial resistance (AMR) costs hundreds of thousands of lives and billions of dollars annually. To protect the population against these infections, it is imperative to develop new medical countermeasures targeting AMR pathogens like P. aeruginosa and Burkholderia sp. The administration of broadly reactive monoclonal antibodies can represent an alternative to treat and prevent infections caused by multi-drug-resistant bacteria. Unlike vaccines, antibodies can provide protection regardless of the immune status of the infected host. In this study, we generated an antibody capable of recognizing flagellin from P. aeruginosa and B. pseudomallei along with other Gram-negative pathogens of concern. Our findings demonstrate that the administration of the monoclonal antibody WVDC-2109 enhances survival rates and outcomes in different murine models of P. aeruginosa infection. These results carry significant implications in the field given that there are no available vaccines for P. aeruginosa.

Dataset Information

A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.

Publications

A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.

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