A DENV-2-type-specific monoclonal antibody binds to the DENV-complex-reactive antigenic site on envelope protein domain 3

Sarathy, Vanessa V.; Pitcher, Trevor; Gromowski, Gregory D.; Roehrig, John T.; Barrett, Alan D.T.

doi:10.1099/jgv.0.000785

Cited by 4 publications

(3 citation statements)

References 20 publications

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“…DIII was identified as the dominant epitope for the mouse antibodies but not for human antibodies [42]. Mouse antibodies elicited by DENV1-4 immunization target DIII and exhibit potent neutralization [38,61–63]. Epitope mapping of these antibodies, with random recombinant DIII mutants, identified the lateral ridge in DIII as the target of strongly neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…The mAb d182 recognizes V300 in the I-III linker (E299-304) and the T329 in DIII. A panel of mouse DIII-neutralizing antibodies also targets this region [38]. The I-III linker is essential for dengue virus particle assembly in the cell and interaction of E protein with the heparin receptor [57].…”

Section: Discussionmentioning

confidence: 99%

“…Their neutralization capacity and specificity vary between DENV serotypes. [36–38]. The lateral ridge (loops between the β-sheets) of DIII, fully accessible on the intact virion, is an epitope hotspot for mouse neutralizing antibodies.…”

Section: Introductionmentioning

confidence: 99%

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Potent neutralizing antibodies elicited by dengue vaccine in rhesus macaque target diverse epitopes

Meng

Horton

et al. 2019

PLoS Pathog

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There is still no safe and effective vaccine against dengue virus infection. Epidemics of dengue virus infection are increasingly a threat to human health around the world. Antibodies generated in response to dengue infection have been shown to impact disease development and effectiveness of dengue vaccine. In this study, we investigated monoclonal antibody responses to an experimental dengue vaccine in rhesus macaques. Variable regions of both heavy chain (VH) and light chain (VL) were cloned from single antibody-secreting B cells. A total of 780 monoclonal antibodies (mAbs) composed of paired VH and VL were characterized. Results show that the vaccination induces mAbs with diverse germline sequences and a wide range of binding affinities. Six potent neutralizing mAbs were identified among 130 dengue envelope protein binders. Critical amino acids for each neutralizing antibody binding to the dengue envelope protein were identified by alanine scanning of mutant libraries. Diverse epitopes were identified, including epitopes on the lateral ridge of DIII, the I-III hinge, the bc loop adjacent to the fusion loop of DII, and the β-strands and loops of DI. Significantly, one of the neutralizing mAbs has a previously unknown epitope in DII at the interface of the envelope and membrane protein and is capable of neutralizing all four dengue serotypes. Taken together, the results of this study not only provide preclinical validation for the tested experimental vaccine, but also shed light on a potential application of the rhesus macaque model for better dengue vaccine evaluation and design of vaccines and immunization strategies.

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