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

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  • Alexander Rouvinski

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie
    Present address: Department of Microbiology and Molecular Genetics, Kuvin Center for the Study of Infectious and Tropical Diseases, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel)

  • Wanwisa Dejnirattisai

    (Hammersmith Hospital Campus, Imperial College London)

  • Pablo Guardado-Calvo

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie)

  • Marie-Christine Vaney

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie)

  • Arvind Sharma

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie)

  • Stéphane Duquerroy

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie
    Université Paris-Sud, Faculté des Sciences)

  • 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
    CNRS UMR 3569 Virologie)

  • Juthathip Mongkolsapaya

    (Hammersmith Hospital Campus, Imperial College London
    Dengue Haemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University)

  • Félix A. Rey

    (Institut Pasteur, Unité de Virologie Structurale
    CNRS UMR 3569 Virologie)

  • Gavin R. Screaton

    (Hammersmith Hospital Campus, Imperial College London)

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.

Suggested Citation

  • Alexander Rouvinski & Wanwisa Dejnirattisai & Pablo Guardado-Calvo & Marie-Christine Vaney & Arvind Sharma & Stéphane Duquerroy & Piyada Supasa & Wiyada Wongwiwat & Ahmed Haouz & Giovanna Barba-Spaeth, 2017. "Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15411
    DOI: 10.1038/ncomms15411
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    1. Antonio Santos-Peral & Fabian Luppa & Sebastian Goresch & Elena Nikolova & Magdalena Zaucha & Lisa Lehmann & Frank Dahlstroem & Hadi Karimzadeh & Julia Thorn-Seshold & Elena Winheim & Ev-Marie Schuste, 2024. "Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Summa Bibby & James Jung & Yu Shang Low & Alberto A. Amarilla & Natalee D. Newton & Connor A. P. Scott & Jessica Balk & Yi Tian Ting & Morgan E. Freney & Benjamin Liang & Timothy Grant & Fasséli Couli, 2025. "A single residue in the yellow fever virus envelope protein modulates virion architecture and antigenicity," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    3. Yimeng Wang & Andrey Galkin & Xiaoran Shang & Alexander Marin & Shaohua Jin & Ting-Juan Ye & Shridhar Bale & Chi-I Chiang & Ananda Chowdhury & Agnes L. Chenine & Ashley Turonis & Jack Greenhouse & Reb, 2025. "Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk," Nature Communications, Nature, vol. 16(1), pages 1-22, December.

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