Study of binding characteristics of human monoclonal antibodies to differentially matured dengue virus particles (VIR2P.1172)

Abstract

Abstract Dengue virus (DENV) is the leading cause of arboviral disease. The ectodomain of envelope protein, containing three domains, DI, DII and DIII, is the major target of DENV vaccine. Studies on monoclonal antibodies (mAbs) showed that DIII mAbs are more potent neutralizing (NT) than those mAbs binding DII fusion-loop (FL). Due to the inefficiency of furin protease activity, produced DENV is a mixture of mature, immature and partially immature virions. It remains unknown regarding the epitope accessibility, avidity and NT potency of different mAbs on different maturation status of DENV. Immature and mature virions were generated from DENV1 infected BHK cells with treatment of NH4Cl and transfected with furin, respectively. Capture ELISA were performed to examine human anti-FL and anti-DIII mAbs (kindly provided by Dr. J. Mongkolsapaya and Dr. F. Sallusto). Anti-FL mAbs had higher maximum binding (Bmax) to immature than mature virions (P=0.0015) and no difference in dissociation constant (Kd) to both virions, suggesting that they have more accessible epitopes on immature virions and bind both with similar avidity. Anti-DIII mAbs showed no difference in Bmax or Kd to both virions but had lower Kd to mature virions than Anti-FL mAbs (P=0.04). Considering the greater infectivity of mature than immature virions, our findings of higher avidity of Anti-DIII mAbs to mature virions compared with Anti-FL mAbs provide a mechanistically explanation for stronger NT potency of Anti-DIII mAbs.