Understanding B cell immunity to Dengue Virus infection and vaccination

• Grant number: 25/15195-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: June 01, 2026
• End date: May 31, 2031
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Flavio Lemos Matassoli
• Grantee: Flavio Lemos Matassoli
• Host Institution: Instituto Butantan. São Paulo , SP, Brazil
• City of the host institution: São Paulo

Abstract

Dengue is a widespread mosquito-borne viral disease caused by four related serotypes (DENV1-4), resulting in approximately 400 million infections annually-100 million symptomatic and 500,000 severe. In Brazil, dengue is hyperendemic, with all serotypes circulating simultaneously. A primary dengue infection induces serotype-specific neutralizing antibodies that recognize quaternary structures on the virus surface, providing long-lasting protection against the same serotype. These antibodies are central to long-term immunity and can persist for decades. However, infection also produces low-affinity, weakly cross-reactive antibodies against other three remaining serotypes but wane over time. These antibodies mainly target the fusion loop or the prM protein on immature virus particles and are associated with antibody-dependent enhancement (ADE), potentially increasing viral entry into Fc receptor-bearing cells during subsequent infections. While polyclonal serum antibody responses to dengue are well documented, relatively few studies have characterized monoclonal antibodies (mAbs) derived from human B cells. Some mAbs, particularly those targeting the fusion loop, show limited neutralization breadth. In contrast, broadly neutralizing antibodies (bNAbs) targeting the E dimer epitope (EDE) can neutralize all four DENV serotypes by binding mature virions, suggesting a key role in cross-serotype protection. However, it remains unclear whether infection or vaccination consistently induces EDE-targeting antibodies, how the B cell repertoire differs between the two, and what proportion of memory B cells targets these epitopes. Instituto Butantan has developed a live attenuated tetravalent dengue vaccine currently in Phase 3 trials in Brazil. It has demonstrated high efficacy and a favorable safety profile in both dengue-naïve and previously exposed individuals, including children. Despite its success in preventing symptomatic infection, a detailed immunological analysis-especially distinguishing between vaccine- and infection-induced responses at the level of B cells and antibodies-remains to be done. This research project aims to address that gap by analyzing, at the single-cell level, the activation, dynamics, evolution, and repertoire of DENV-specific memory B cells and the monoclonal antibodies they produce in both vaccinated and naturally infected individuals. The objectives are to improve our understanding of immune correlates of protection, distinguish vaccine-induced from infection-induced immunity, inform next-generation dengue vaccine design, and isolate potent bNAbs capable of cross-flavivirus neutralization for potential use as therapeutic agents and diagnostic tools. (AU)