Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope

Alexander Rouvinski, Wanwisa Dejnirattisai, Pablo Guardado-Calvo, Marie-Christine Vaney, Arvind Sharma, Stéphane Duquerroy, Piyada Supasa, Wiyada Wongwiwat, Ahmed Haouz, Giovanna Barba-Spaeth, Juthathip Mongkolsapaya (), Félix A. Rey () and Gavin R. Screaton ()
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Alexander Rouvinski: Institut Pasteur, Unité de Virologie Structurale
Wanwisa Dejnirattisai: Hammersmith Hospital Campus, Imperial College London
Pablo Guardado-Calvo: Institut Pasteur, Unité de Virologie Structurale
Marie-Christine Vaney: Institut Pasteur, Unité de Virologie Structurale
Arvind Sharma: Institut Pasteur, Unité de Virologie Structurale
Stéphane Duquerroy: Institut Pasteur, Unité de Virologie Structurale
Piyada Supasa: Hammersmith Hospital Campus, Imperial College London
Wiyada Wongwiwat: Hammersmith Hospital Campus, Imperial College London
Ahmed Haouz: Institut Pasteur, Protéopôle, CNRS UMR 3528
Giovanna Barba-Spaeth: Institut Pasteur, Unité de Virologie Structurale
Juthathip Mongkolsapaya: Hammersmith Hospital Campus, Imperial College London
Félix A. Rey: Institut Pasteur, Unité de Virologie Structurale
Gavin R. Screaton: Hammersmith Hospital Campus, Imperial College London

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic ‘breathing’ of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.

Date: 2017
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DOI: 10.1038/ncomms15411

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