Anti-Idiotypic Antibodies Specific to prM Monoantibody Prevent Antibody Dependent Enhancement of Dengue Virus Infection

Abstract

Dengue virus (DENV) co-circulates as four serotypes (DENV1-4). Primary infection only leads to self-limited dengue fever. But secondary infection with another serotype carries a higher risk of increased disease severity, causing life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Serotype cross-reactive antibodies facilitate DENV infection in Fc-receptor-bearing cells by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody dependent enhancement (ADE). Most studies suggested that enhancing antibodies were mainly specific to the structural premembrane protein (prM) of DENV. However, there is still no effective drugs or vaccines to prevent ADE. In this study, we firstly confirmed that both DENV-2 infected human sera (anti-DENV-2) and DENV-2 prM monoclonal antibody (prM mAb) could significantly enhance DENV-1 infection in K562 cells. Then we developed anti-idiotypic antibodies (prM-AIDs) specific to prM mAb by immunizing of Balb/c mice. Results showed that these polyclonal antibodies can dramatically reduce ADE phenomenon of DENV-1 infection in K562 cells. To further confirm the anti-ADE effect of prM-AIDs in vivo, interferon-α and γ receptor-deficient mice (AG6) were used as the mouse model for DENV infection. We found that administration of DENV-2 prM mAb indeed caused a higher DENV-1 titer as well as interleukin-10 (IL-10) and alaninea minotransferase (ALT) in mice infected with DENV-1, similar to clinical ADE symptoms. But when we supplemented prM-AIDs to DENV-1 challenged AG6 mice, the viral titer, IL-10 and ALT were obviously decreased to the negative control level. Of note, the number of platelets in peripheral blood of prM-AIDs group were significantly increased at day 3 post infection with DENV-1 compared that of prM-mAb group. These results confirmed that our prM-AIDs could prevent ADE not only in vitro but also in vivo, suggested that anti-idiotypic antibodies might be a new choice to be considered to treat DENV infection.

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

“…In an AG6 mice model, the administration of prM-AIDs reduced ADE and decreased levels of IL-10 and ALT. This suggests that instead of using prM mAb, using prM-AIDs may be a better choice to prevent ADE during DENV infection ( 119 ). The human mAb HM14c10, obtained from a DENV patient who recovered, showed strong neutralization of DENV1 in an AG129 mouse model.…”

Antibody dependent enhancement: Unavoidable problems in vaccine development

“…Wang produced anti-idiotypic antibodies against prM antibodies that can cause ADE, and found that they can prevent ADE not only in vitro but also in vivo ( Wang et al, 2017 ). After mice immunized with prM mAb-specific anti-idiotypic antibodies (prM-AID) were infected with DENV-1, interleukin 10 (IL-10) and alanine aminotransferase (ALT) were as low as the negative control level, and the number of platelets increased significantly compared with the control group.…”

Role of the complement system in antibody-dependent enhancement of flavivirus infections

“…Notably, the antibody repertoire after natural infection with DENV and WNV includes poorly neutralizing antibodies associated with the immature conformation (Beltramello et al, 2010;Dejnirattisai et al, 2010;Lai et al, 2008;Throsby et al, 2006). Antibodies against two such epitopes play an important role in enhancement; anti-prM antibodies are poorly neutralizing and enhance infection over a wide range of concentrations (Dejnirattisai et al, 2010;Rodenhuis-Zybert et al, 2010;Wang et al, 2017). Likewise, fusion loop epitopes, which recognize a hydrophobic pocket between DII and DIII that is exposed in immature virions but is buried in mature virions (de Alwis et al, 2014;Barba-Spaeth et al, 2016;Rey et al, 2018) are also strong mediators of ADE.…”