CONSERVED ANTIGENIC SITE IN DENGUE/ZIKA VIRUSES AS A TARGET FOR REVERSE VACCINOLOGY

Alexander Rouvinski ¹ Giovanna Barba-Spaeth ² Pablo Guardado-Calvo ² Marie-Christine Vaney ² Stéphane Duquerroy ² Wanwisa Dejnirattisai ^3,9 Arvind Sharma ² Iris Medits ⁶ Ahmed Haouz ⁴ Xiaokang Zhang ² Carlos Kikuti ² Etienne Simon-Lorière ⁵ Erika Navarro Sanchez ² Wiyada Wongwiwat ^3,9 William Shepard ⁷ Christine Girard-Blanc ⁴ Stéphane Petres ⁴ Anavaj Sakuntabhai ⁵ Patrick England ⁴ Hong Zhou ⁸ Karin Stiasny ⁶ Juthathip Mongkolsapaya ^3,9 Franz Heinz ⁶ Gavin Screaton ³ Félix Rey ²

¹Microbiology and Molecular Genetics, Faculty of Medicine, Institute for Medical Research, Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem
²Département de Virologie, Institut Pasteur, Paris
³Department of Medicine, Division of Immunology and Inflammation, Hammersmith Campus, London
⁴Citec, Institut Pasteur, Paris
⁵Functional Genetics of Infectious Diseases Unit, Institut Pasteur, Paris
⁶Department of Virology, Medical University of Vienna, Vienna
⁷PX2, L’ Orme des Merisiers, Synchrotron SOLEIL, Saint Aubin
⁸Department of Microbiology, Immunology and Molecular Genetics, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California
⁹Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok

Flaviviruses are positive single stranded, RNA enveloped viruses of extraordinary human health importance. Many of them are constantly emerging and have shown a remarkable tendency to invade new geographical niches, such as mosquito-borne Zika, West Nile, and Dengue viruses. Dengue disease is caused by four different serotypes, which infect 390 million people yearly with 25% symptomatic cases. Zika virus had not been associated with severe disease in humans until the recent outbreaks, when it was linked to microcephaly in newborns in Brazil and to Guillain-Barré syndrome in adults in French Polynesia. Zika virus is related to dengue virus and their natural history of infection is complicated by the adverse phenomenon of antibody dependent enhancement (ADE), challenging the classical vaccinology approach. We have recently described human broadly neutralizing Dengue Abs (bnAbs) that also potently neutralize Zika virus with 50% neutralization in the low picomolar range. Crystal structures the bnAbs in complex with the envelope glycoproteins E from dengue and Zika viruses reveal that they target a conformational epitope at a serotype-invariant site at the E-dimer interface. This `E-dimer-dependent epitope` (EDE) overlaps with the site of interaction with the precursor membrane (prM) protein during virus maturation, explaining its conservation across dengue serotypes and Zika. Structural comparison of the Zika and dengue virus immunocomplexes provides a lead for rational, epitope-focused design of a recombinant subunit vaccine capable of eliciting potent cross-neutralizing antibodies. Such universal immunogen would aim to protect simultaneously against Zika and dengue virus infections.

Alexander Rouvinski

The Hebrew University of Jerusalem