Acquired structural remnants in flaviviruses: Exploring structural targets for developing rational non-ADE inducing vaccines

The goal of this project is to better understand the complex structural mechanisms of antibody-dependent enhancement (ADE) caused by dengue viruses (DENVs) and their monoclonal antibodies (mAbs).

ADE is a major consideration in developing safe and rational vaccines and therapeutic mAbs against the DENVs; however, our understanding of its mechanisms remains limited.

This is mainly because of the lack of methods to predict which structural epitopes of the DENVs cause ADE and how to generate ADE-inducing mAbs. Hence, I together with participating researchers will employ a novel reasoning-based approach to tackle this problem.

The approach is based on my hypothesis that vertebrate flaviviruses, such as DENVs, have acquired structures for eluding the host antibody neutralization, whereas invertebrate flaviviruses have not. The project has three phases for three years.

In phase 1, the structure of the as yet unknown invertebrate flaviviruses will be determined to discover the acquired structures of the DENVs.

In phase 2, using hybridoma technology and a newly developing in-silico method, I will generate mAbs that target acquired structural epitopes of the DENVs and are potential candidates to induce ADE.

In phase 3, the generated mAbs will be tested by ADE/neutralization assay to discover ADE-inducing mAbs, to prove my hypothesis, and to eventually determine the first-ever complex structure of DENV and the ADE-inducing mAb to reveal the structural mechanisms of ADE.