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Nat Commun. 2017 May 23;8:15411. doi: 10.1038/ncomms15411.

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

Author information

Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France.
CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, w12 0NN London, UK.
Université Paris-Sud, Faculté des Sciences, 91405 Orsay, France.
Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
Dengue Haemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.


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.

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