SUMMARY Arthropod vector-borne flaviviruses threaten the health of people in nearly all countries of the world. Over the past 30 years, the epidemiology of flaviviruses has been characterized by intense year-round transmission in some areas, abrupt and permanent expansion of the range of viruses to new regions and continents, and severe epidemics caused by viral species previously considered to be a minor nuisance. FLARE Center Project 2 is based on our recent discovery of a structure-based method, broadly applicable to flaviviruses, for producing highly stable, secreted envelope (E) protein homodimers displaying quaternary structure epitopes recognized by human antibodies that strongly neutralize flaviviruses. The goal of Project 2 is to build on this discovery and establish ‘plug and play’ modular protein subunit and mRNA vaccine platforms to counter currently circulating and future epidemic flaviviruses. The prototype flavivirus selected for Project 2 is dengue virus type 2 (DENV2) because this serotype, which is widely distributed, is one of the most studied flaviviruses. Lessons learned and vaccine platforms developed for DENV2 will be applicable to closely related pathogenic flaviviruses (e.g., other DENV serotypes and Zika virus) as well as more distantly related flaviviruses. Project 2 has three independent Aims, where each Aim is based on a single design concept for developing a modular vaccine platform. In Aim 1, we will further improve the E homodimer technology and obtain critical non-human primate immunogenicity and protection data required for advancement of the platform to clinical trials with our industry partner, Moderna. Aims 2 and 3 explore new and exciting vaccine design approaches for induction of flavivirus cross-protective immunity using antigens that display complex structural epitopes on E that require assembly of higher order E homodimers. Project 2 is closely linked to other Projects and Cores in the FLARE Center. Project 2 will use animal models available through Core D, up-to-date immunological assays developed by Core E, and engage with Core C to solve the structure of vaccine antigens and explore alternate nanoparticle vaccine delivery platforms. Project 2 also will collaborate with Project 1 to design and test E homodimer vaccines for flaviviruses that are distantly related to the DENV complex, and Project 5 to develop DENV serotype cross-protective therapeutic mAbs.