Dengue virus (DV) is the most common mosquito-borne virus, with 4 billion people living at risk for infection by its four serotypes (DV1-4). Infection by DV and its related flavivirus Zika virus (ZV) may clinically manifest as mild flu-like symptoms and arthralgia. Severe DV cases can progress into hemorrhagic fever and shock syndrome, while severe complications of ZV infection include Guillain-Barre syndrome and neonatal microcephaly. Severe dengue is associated with antibody-dependent enhancement (ADE) of infection, a potentially fatal phenomenon. In response to a primary DV infection, the immune system produces antibodies that can bind and neutralize that serotype to resolve infection. However, during a subsequent infection by a homologous DV serotype or ZV, antibodies are re-elicited but may be non- or weakly-neutralizing; thus, instead of eliminating infection, these antibodies promote uptake of <i>active</i> virus into Fcγ receptor-expressing immune cells and increase viremia and inflammation. Currently, there is a need for vaccines for DV and ZV that do not carry the risk of inducing ADE. We determined E glycoprotein as a favorable candidate for immunogen design. Neutralizing, protective antibodies have shown to target domain III (DIII) of E glycoprotein, which is critical for viral entry and cell attachment. However, non-neutralizing, ADE-inducing antibodies were also identified to bind to other DIII motifs. This proposal will investigate structure-based methods to display DIII immunogen multivalently and to increase the immunodominance of heterologous favorable epitopes found on the lateral ridge (LR) of DIII, while masking unfavorable ones on, to induce broad humoral protection and mitigate severity of disease. We previously demonstrated strong immunoprotecting potential of a homotypic ZV immunization strategy, which involved the multivalent display of a LR-focused DIII mutant onto nanoparticles. We will study the effectiveness of cocktail and mosaic nanoparticles as heterotypic immunization strategies against ZV and DV and characterize underlying humoral responses to the immunizations in mice. Sera of vaccinated mice will undergo neutralization assays against DV-ZV. B cells will be evaluated for sequence and lineage diversity of the resulting antibody repertoire. These studies will further our understanding of the adaptive immune response to flavivirus infections and may provide a framework for developing novel vaccines and antibody-based therapeutics.

Strategies for next-generation flavivirus vaccine development

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ACS Fall 2022

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