Orthoflavivirus Vaccine Platforms: Current Strategies and Challenges

The orthoflaviviruses genus belongs to the Flaviviridae family. Orthoflaviviruses include major clinically relevant arthropod-borne human viruses such as Dengue, Zika, yellow fever, West Nile and tick-borne encephalitis virus. These viruses pose an increasing threat to global health due to the expansion of arthropod habitats, urbanization, and climate change. While vaccines have been developed for certain orthoflaviviruses with varying levels of success, critical challenges remain in achieving broadly deployable vaccines that combine a robust safety profile with durable immunity against many current and emerging orthoflaviviruses. This review provides a snapshot of established and emerging vaccine platforms against orthoflaviviruses, with a particular emphasis on those leveraging the envelope glycoprotein E as the primary antigen. We examine the strengths and disadvantages of these different platforms in eliciting safe, durable, and robust orthoflavivirus immunity, and discuss how specific attributes such as multivalency, authentic epitope presentations, and logistical practicality can enhance their value in preventing orthoflavivirus infection and disease.