Therapeutic Antibodies for Mosquito‐Borne Orthoflavivirus Infections: Discovery, Engineering Approaches, and Advances in mRNA‐Based Delivery Systems

Abstract Mosquito‐borne orthoflaviviruses such as Zika virus (ZIKV), dengue (DENV), yellow fever (YFV), West Nile (WNV), and Japanese encephalitis virus (JEV) are major public health concerns worldwide due to their epidemic potential, immune evasion mechanisms, and the absence of specific antiviral treatments. While vaccines exist for JEV, DENV, and Yellow Fever, their use is limited by safety concerns in vulnerable populations. In this context, monoclonal antibodies (mAbs) gain attention as potent and specific therapeutic tools. A central focus of recent research is the orthoflavivirus envelope (E) protein, particularly the fusion loop (FL), which is a highly conserved region within domain II that plays a critical role in viral membrane fusion and entry. The FL is a structural conservation across orthoflavivirus species, making it a target for the development of neutralizing antibodies (NAbs). This review highlights the key mechanisms of mAb‐mediated neutralization, with a focus on FL‐targeting strategies, and discusses how rational antigen design and antibody engineering are overcoming challenges related to epitope accessibility and antibody‐dependent enhancement. Strategies for antibody discovery, such as phage display and Fc engineering are explored. Finally, mRNA‐based platforms for in vivo antibody expression, offering an approach to rapid antibody expression to combat orthoflavivirus infections are discussed.