A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus

Abstract

A therapy for dengue is still elusive. We describe the neutralizing and protective capacity of a dengue serotype-cross-reactive antibody isolated from the plasmablasts of a patient. Antibody SIgN-3C neutralized all four dengue virus serotypes at nano to picomolar concentrations and significantly decreased viremia of all serotypes in adult mice when given 2 days after infection. Moreover, mice were protected from pathology and death from a lethal dengue virus-2 infection. To avoid potential Fc-mediated uptake of immune complexes and ensuing enhanced infection, we introduced a LALA mutation in the Fc part. SIgN-3C-LALA was as efficient as the non-modified antibody in neutralizing dengue virus and in protecting mice while antibody-dependent enhancement was completely abrogated. The epitope of the antibody includes conserved amino acids in all three domains of the glycoprotein, which can explain its cross-reactivity. SIgN-3C-LALA neutralizes dengue virus both pre and post-attachment to host cells. These attributes likely contribute to the remarkable protective capacity of SIgN-3C.

Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys

“…Of note, prevention of dengue infection with monoclonal Abs (mAbs) was previously achieved in immunodeficient mouse models of dengue. [30][31][32] However, murine models are artificially constrained by the reduced permissiveness of mouse cells, and the extent that these findings will be translatable to humans remains unclear. 39 In contrast, nonhuman primate (NHP) models have been useful in predicting human clinical trial outcomes during dengue vaccine development.…”

“…24,25 Several monoclonal Abs with different neutralization characteristics have been isolated. [26][27][28][29][30] Some of these Abs can prevent viral replication in mouse models, when administered prior to infection. [30][31][32] These studies highlight the concerns and potential of nAb-mediated prophylaxis against DENV.…”

Antibody-Dependent Enhancement of Viral Infections

“…Use of serotype-specific mAbs or high dose administration of cross-reactive mAbs has demonstrated reduced risk of ADE in vitro and in animal models. Further, antibodies with modifications in the Fc region such as deletion of nine amino acids (at positions 231-239) in the N terminus, mutation of asparagine to glutamine at position 297 (N297Q), or mutation of leucine to alanine at positions 234 and 235 (LALA mutants) have also shown reduced risk of ADE and exhibited prophylactic and therapeutic efficacy in animal models (Balsitis et al 2010;Shi et al 2016;Xu et al 2017;Injampa et al 2017;Lu et al 2018). Fc region modifications that extend the antibody half-life also help minimize ADE by maintaining the mAbs at high levels.…”

Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

“…In recent years, advances in high-throughput B-cell technologies have revealed a plethora of potent nAbs for different pathogens which have resisted the traditional means of vaccine development for several decades, including HIV-1 ( 3 ), influenza ( 4 ), respiratory syncytial virus (RSV) ( 5, 6 ), zika ( 7, 8 ), dengue ( 9 ) and others ( 10-12 ). A major target of these nAb responses is the pathogens fusion protein, which drives the viral and host cell membrane fusion while undergoing a conformational rearrangement from a prefusion to a postfusion state ( 13 ).…”