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

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Rouvinski, Alexander | Dejnirattisai, Wanwisa | Guardado-Calvo, Pablo | Vaney, Marie-Christine | Sharma, Arvind | Duquerroy, Stéphane | Supasa, Piyada | Wongwiwat, Wiyada | Haouz, Ahmed | Barba-Spaeth, Giovanna | Mongkolsapaya, Juthathip | Rey, Félix A. | Screaton, Gavin R.

Edité par CCSD ; Nature Publishing Group -

International audience. 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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