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Two mAbs take a stab at influenza's NActive site

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Science Immunology  06 Nov 2020:
Vol. 5, Issue 53, eabf4907
DOI: 10.1126/sciimmunol.abf4907

Abstract

Two human-derived recombinant mAbs specific for IBV bind the neuraminidase active site by emulating the enzymatic substrate, which results in broad protection.

Seasonal influenza remains an ongoing threat to global human health because the virus constantly mutates. Influenza A (IAV) is the most prevalent and currently the only influenza type to have instigated pandemics. At the same time, influenza B (IBV) is estimated to account for the remaining 25% of seasonal influenza infections. Despite the lower incidence, IBV-infected patients have shown similar morbidity and mortality rates to that of IAV, and recent epidemics caused by IBVs are responsible for more than half of influenza-associated pediatric mortality. Existing therapies are more effective for IAV than IBV. Current vaccine strategies include both IAV and IBV representative strains, mainly eliciting host antibody responses against influenza’s primary surface antigen, hemagglutinin (HA). The secondary surface antigen of influenza, neuraminidase (NA), represents an appealing target for further improving vaccines and therapeutic strategies, given that conserved epitopes with critical residues are present in the enzyme’s active site.

Madsen et al. spotlighted the promising potential of antibodies against NA. The authors isolated and cloned seven IBV-NA–specific recombinant monoclonal antibodies (mAbs) from an infected patient’s plasmablast repertoire. They showed that two of the mAbs were broadly reactive; capable of inhibiting NA; and neutralized various strains of IBV, including those resistant to current treatment and some dating back to 1940. These results suggest that the two mAbs specifically bind to conserved residues on NA, and accordingly, the authors constructed cryo-EM structures of these antibodies bound to NA. Interestingly, they discovered long CDR-H3 loops that protrude into the active site pocket of the NA enzyme. Epitope analysis demonstrated that the mAbs engaged in tight biochemical interactions with key conserved NA residues, thus emulating the structure of the enzymatic substrate and robustly neutralizing its activity.

Due to antigenic drift, influenza virus vaccines require repeated reformulation. Thus, humanity’s current endeavors against influenza imitate a continuous “cat and mouse game.” To obtain the ultimate advantage, all approaches must be considered. This study comprehensively demonstrates the importance of NA as a target for the development of vaccines and therapeutics designed to provide broad and durable antibody-mediated protection against IBVs.

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