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A Human PrM Antibody That Recognizes a Novel Cryptic Epitope on Dengue E Glycoprotein

Dengue virus (DENV) is a major mosquito-borne pathogen infecting up to 100 million people each year; so far no effective treatment or vaccines are available. Recently, highly cross-reactive and infection-enhancing pre-membrane (prM)-specific antibodies were found to dominate the anti-DENV immune response in humans, raising concern over vaccine candidates that contain native dengue prM sequences. In this study, we have isolated a broadly cross-reactive prM-specific antibody, D29, during a screen with a non-immunized human Fab-phage library against the four serotypes of DENV. The antibody is capable of restoring the infectivity of virtually non-infectious immature DENV (imDENV) in FcγR-bearing K562 cells. Remarkably, D29 also cross-reacted with a cryptic epitope on the envelope (E) protein located to the DI/DII junction as evidenced by site-directed mutagenesis. This cryptic epitope, while inaccessible to antibody binding in a native virus particle, may become exposed if E is not properly folded. These findings suggest that generation of anti-prM antibodies that enhance DENV infection may not be completely avoided even with immunization strategies employing E protein alone or subunits of E proteins

Nicole J Moreland

Subhash G Vasudevan

Paul A MacAry

Brendon J Hanson

Directory of Open Access Journals

A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein.

<div><p>Dengue virus (DENV) is a major mosquito-borne pathogen infecting up to 100 million people each year; so far no effective treatment or vaccines are available. Recently, highly cross-reactive and infection-enhancing pre-membrane (prM)-specific antibodies were found to dominate the anti-DENV immune response in humans, raising concern over vaccine candidates that contain native dengue prM sequences. In this study, we have isolated a broadly cross-reactive prM-specific antibody, D29, during a screen with a non-immunized human Fab-phage library against the four serotypes of DENV. The antibody is capable of restoring the infectivity of virtually non-infectious immature DENV (imDENV) in FcγR-bearing K562 cells. Remarkably, D29 also cross-reacted with a cryptic epitope on the envelope (E) protein located to the DI/DII junction as evidenced by site-directed mutagenesis. This cryptic epitope, while inaccessible to antibody binding in a native virus particle, may become exposed if E is not properly folded. These findings suggest that generation of anti-prM antibodies that enhance DENV infection may not be completely avoided even with immunization strategies employing E protein alone or subunits of E proteins.</p> </div

Annie Hoi Yi Chan (175355)

Hwee Cheng Tan (175358)

Angelia Yee Chow (175362)

Angeline Pei Chiew Lim (175369)

Shee Mei Lok (175374)

Nicole J. Moreland (175379)

Subhash G. Vasudevan (175384)

Paul A. MacAry (175388)

Eng Eong Ooi (56879)

Brendon J. Hanson (175393)

The Francis Crick Institute

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https://figshare.com/articles/A_Human_PrM_Antibody_That_Recognizes_a_Novel_Cryptic_Epitope_on_Dengue_E_Glycoprotein/127149

A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein

A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein

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