Potent neutralizing human monoclonal antibodies preferentially target mature dengue virus particles: implication for novel strategy of dengue vaccine

Journal article

The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (DI, DII and DIII). Recent studies reported that human monoclonal antibodies (mAbs) recognizing the DIII, D1/DII hinge, the E-dimer epitope or a quaternary epitope involving DI/DII/DIII are more potently neutralizing compared with those recognizing the fusion-loop (FL) of DII. Due to inefficient cleavage of premembrane protein, DENV suspensions consist of a mixture of mature, immature and partially immature particles. We investigated the neutralization and binding of 22 human mAbs to DENV1 virions with differential maturation status. Compared with FL mAbs, DIII, DI/DII hinge and E-dimer epitope mAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such mAbs. FL-specific mAbs required 57 to 87% occupancy on mature particles to achieve half maximal neutralization (NT50), whereas the potently neutralizing mAbs achieved NT50 states at 20 to 38% occupancy. Analysis of the mAbs repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing mAbs. Taken together, these findings suggest that the use of homogenous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than immature or mixed particles. IMPORTANCE With an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine, Dengvaxia, was licensed, however its low efficacy among dengue-naïve individuals and increased risk of severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions contain mature, immature and partially immature particles. We investigated the binding of 22 human monoclonal antibodies (mAbs) to DENV envelope protein on particles with differing maturation status. Compared with weakly neutralizing mAbs, potently neutralizing mAbs had higher relative maximum binding and avidity to mature particles. This was supported by analysis of mAbs repertoires and polyclonal sera from patients with primary DENV infection. Together, these findings suggest that mature particles may be the optimal form of presenting envelope protein to induce more potent neutralizing antibodies against DENV.

Authors: Tsai, W; Chen, H; Tsai, J; Dejnirattisai, W; Jumnainsong, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Microbiology
• Journal: Journal of Virology
• Volume: 92
• Issue: 23
• Article number: e00556-18
• Publication date: 2018-09-05
• Acceptance date: 2018-08-22
• DOI: 10.1128/jvi.00556-18
• EISSN: 1098-5514
• ISSN: 0022-538X
• Pmid: 30185598
• Language: English
• Keywords: Journal Article