Heavy-chain-only antibodies for protection against MERS-CoV

Autor: Okba, Nisreen M. A., Stalin Raj, V., Gutierrez-Alvarez, Francisco J., Drabek, Dubravka, Dieren, Brenda van, Widagdo, W., Lamers, Mart M., Widjaja, Ivy, Fernandez-Delgado, Raúl, Solá Gurpegui, Isabel, Bensaid, Albert, Koopmans, Marion P., Segalés, Joaquim, Osterhaus, Albert D. M. E., Bosch, Berend Jan, Enjuanes Sánchez, Luis, Haagmans, Bart L.
Rok vydání: 2019
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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Popis: Trabajo presentado en el European Congress of Virology, celebrado en Rotterdam (Países Bajos), del 28 de abril al 1 de mayo de 2019
Introduction: With the ongoing outbreaks and 35% case fatality rate, Middle East respiratory syndrome coronavirus (MERS-CoV), continues to pose a global threat. However, licensed vaccines and therapeutics for MERS-CoV, including monoclonal antibodies, are not currently available. Camelids have unique heavy-chain-only antibodies with long finger-like complementary determining regions allowing accessibility to epitopes inaccessible to conventional antibodies. The variable domain of these antibodies (VHHs), known as nanobodies, have small size, high antigen affinity and high homology to human counterparts, making them potential candidates for clinical use. Aim: We aimed at generating MERS-CoV-specific VHHs targeting different epitopes within the MERS-CoV spike protein to prevent viral neutralization escape and provide efficient protection against viral infection. Methods: Using bone marrow from MERS-CoV vaccinated dromedary camels, we cloned and expressed the VHH repertoire in E. coli. From this library, we screened for and characterized MERS-CoV-specific VHHs targeting different domains on the vial spike protein. We selected potent VHHs and fused them to a human Fc, generating camel/human monoand bi-specific chimeric heavy-chain-only antibodies (cHCAbs). Results: We identified several potent MERS-CoV-specific VHHs targeting the viral spike receptor binding domain (RBD) and the sialic acid binding (S1A ) domain, thereby blocking virus entry and attachment, respectively. Those with the highest potencies were selected and fused to human Fc to extend their half-life in vivo. The cHCAbs directed against the RBD were capable of blocking MERS-CoV entry in vitro and in vivo. S1A -directed cHCAbs blocked virus attachment to sialic acids and reduced infection in vitro. Different combinations of cHCAbs and bi-specific cHCAbs were evaluated for their protective efficacy against different virus variants and escape mutants. Conclusion: The pathogenesis of a viral disease is the biological mechanism, or mechanisms, that lead to the diseased state. There are several possibilities for comparing the pathogenesis of viral diseases among host species: a viral disease, e.g. rabies, that naturally infects different host species; a viral disease in an experimentally infected laboratory animal species, e.g. avian influenza in ferrets, as a model for the disease in humans; an emerging viral disease, e.g. Marburg haemorrhagic fever, in its reservoir species and its new host species. We here focus on the latter possibility. Many emerging viral diseases in a given host species originate from another host species, which acts as a reservoir. While the clinical outcome of emerging virus infections ranges from subclinical to fatal, we usually focus on those virus infections that cause severe disease in the new host species. Currently, research concentrates on the pathogenesis of such a viral disease in its new host species or, if that is not possible, in a laboratory animal species acting as a model. However, research on the pathogenesis of emerging viral diseases in their reservoir host species is neglected. This is a pity, because there are several good reasons to compare the pathogenesis of emerging viral diseases between the new host species and the reservoir species. First, pathogenesis in the reservoir host species may predict several types of virus-host interaction in the new host species. Second, differences in the pathogenesis between reservoir host species and new host species may provide clues for the mechanism of increased severity of disease in the new host species. Third, pathogenesis in the reservoir host species may predict the future evolution of the emerging virus in the new host species. Therefore, we advocate an increased emphasis on understanding the pathogenesis of emerging viral diseases in their reservoir species.
Databáze: OpenAIRE
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