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

• Main Authors: 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, Gavin R. Screaton
• Other Authors: Institut Pasteur, Paris
• Format: Article
• Published: 2018
• Subjects: Biochemistry, Genetics and Molecular Biology; Chemistry
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/41884
• Institution: Mahidol University

© The Author(s) 2017. 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.