Flaviviruses are a large group of viruses spread mainly by mosquitoes and ticks, causing major global health problems. Well-known examples include dengue, Zika, yellow fever, and West Nile virus. Dengue infects around 100 million people each year, and Zika’s 2015 outbreak was linked to birth defects. These viruses are mostly found in tropical and subtropical areas, but as the climate warms, their mosquito carriers are spreading northward, bringing local outbreaks to parts of the U.S. and Europe.
Other related viruses, such as Japanese encephalitis and tick-borne encephalitis, also threaten many regions. These viruses often infect the brain and can be deadly. While vaccines exist for yellow fever and Japanese encephalitis, safe and effective vaccines for dengue and other flaviviruses remain a major challenge. One reason is that antibodies from a previous infection or vaccination can sometimes worsen disease instead of preventing it—a phenomenon called antibody-dependent enhancement (ADE).
A key viral protein, called the Envelope (E) glycoprotein, is the main target for neutralizing antibodies. Some antibodies strongly block infection by recognizing specific parts of the E protein, while others bind more weakly and can actually promote infection through ADE. However, most current studies focus on isolated antibodies, not the complex mix of (polyclonal) antibodies found in blood. Understanding this broader response could greatly improve vaccine and antibody design.
The proposed project, FLAVIR, aims to develop new ways to display and study the E protein, allowing detailed analysis of how antibodies recognize and neutralize flaviviruses. Using advanced techniques in mass spectrometry, electron microscopy, and glycoproteomics, the project will reveal how different antibodies and sugar modifications affect immune recognition. These methods will also help design better vaccines and diagnostic tools by stabilizing and presenting E proteins in forms that mimic real viruses.
Ultimately, FLAVIR will build a flexible platform for studying many flaviviruses, helping to uncover how our immune system fights these infections—and how we can use that knowledge to prevent them.
