The DHVI Dengue Program team is working to apply a structure-based vaccine approach to develop new vaccines for dengue types 1-4. New approaches and techniques need to be developed because of the variability of the dengue envelope. The team has developed a new strategy by combining single-cell B cell sorting with high-throughput recombinant antibody technology to generate human monoclonal antibodies to find broadly reactive antibodies from dengue-infected patients. The team has now produced over 100 new human monoclonal antibodies that bind to dengue proteins, 25 of which neutralize dengue viruses. Those antibodies that broadly neutralize all four types of dengue viruses will be mapped to define the common neutralizing epitope. In collaboration with Sheemei Lok at Duke-NUS in Singapore, the dengue neutralization epitopes will be further explored and defined by studying the interaction between dengue-specific neutralizing antibodies and dengue envelope antigens using x-ray crystallography and cryoEM image reconstruction.
Reverted unmutated ancestors (i.e., the putative germline naive B cell receptors) and/or intermediate antibodies can be inferred, and testing can determine the strength of reactivity of the dengue envelopes with the putative naive B cell receptors or intermediate B cell receptors. These studies will lead to improved immunogen design for the induction of broadly protective immune responses against all four types of dengue viruses. In collaboration with Stephen Harrison at Harvard University, a structural-based vaccine approach is being undertaken to design envelope proteins that best interact with the germline B cell receptors to make a vaccine that will drive broad neutralizing antibody responses. The dengue team has established collaborations with Sheemei Lok at Duke-NUS in Singapore, Eva Harris at UC Berkeley, and Stephen Harrison at Harvard University for these studies.