A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus

Dejnirattisai W, Wongwiwat W, Supasa S, Zhang X, Dai X, Rouvinski A, Jumnainsong A, Edwards C, Quyen NT, Duangchinda T, Grimes JM, Tsai WY, Lai CY, Wang WK, Malasit P, Farrar J, Simmons CP, Zhou ZH, Rey FA, Mongkolsapaya J, Screaton GR.

Nat Immunol. (2015) 16(2): 170–177

Speaker: Martyr Yang （楊俊常）                             Time: 13:00~14:00, May. 18, 2016

Commentator: Dr. Tzong-Shiann Ho (何宗憲醫師) Place: Room 601

Abstract:

Dengue virus (DENV) is a positive-sense, single-stranded RNA virus with four serotypes (DENV-1 to 4), which infects about 400 million people per year. The cellular and humoral responses generated after a primary DENV infection can be either protective against or enhancing of a subsequent (secondary) infec­tion with a different serotype due to antibody-dependent enhancement (ADE). The surface of immature, non-infectious DENV is covered with 180 envelope (E) proteins and pre-membrane/membrane (prM/M) proteins which form 60 trimeric spikes. As the virus exits the cell, the host protease furin cleaves the prM protein, which results in structural alterations wherein the E proteins rearrange into 90 antiparallel dimers and the virus becomes mature and infectious. However, the cleavage of prM is frequently incomplete, immature viruses containing large amounts of prM are not infectious, but partially mature viruses with lower levels of prM are still infectious. It has been postulated that these partially mature viruses can still be driven to infect by ADE ^[1]. In this study, the authors characterized 145 human monoclonal antibodies (mAbs) that target DENV E protein from plas­mablasts isolated from seven Vietnamese patients with mostly secondary acute DENV infection. They identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were highly potent and broadly reactive that can neutralize multiple DENV serotypes produced in either human dendritic cells or insect cells, with neutralizing titers in the picomolar range. Furthermore, EDE mAbs bind to and neutralize both partially immature and mature virions. In addition, EDE mAbs are four- to eight­-fold less enhancing of infection than are mAbs directed against FLE (fusion loop epitope). Overall, this new class of strongly neutralizing, serotype-cross-reactive mAbs may provide a path for subunit vaccine design as well as the evaluation of vaccines.

Reference:

1) Dejnirattisai W, et al. (2010) Cross-reacting antibodies enhance dengue virus infection in humans. Science. 328:745–748.