Use of Adeno-associated viral vectors to improve delivery of a DNA vaccine against dengue virus.

Dengue virus (DENV) remains a significant healthcare and socioeconomic burden for endemic countries. Attempts to produce a safe and effective vaccine have been unsuccessful so far, making this task one of the top priorities in the field. We have previously shown that an EDIII-based DNA vaccine is able to induce neutralizing, long-lasting and highly specific antibody responses for all four DENV serotypes in mice using gene-gun delivery technology.

Dengue virus capsid anchor modulates the efficiency of polyprotein processing and assembly of viral particles.

The assembly and secretion of flaviviruses are part of an elegantly regulated process. During maturation, the viral polyprotein undergoes several co- and post-translational cleavages mediated by both viral and host proteases. Among these, sequential cleavage at the N and C termini of the hydrophobic capsid anchor (Ca) is crucial in deciding the fate of viral infection.

A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.

Infections with dengue virus (DENV) and Zika virus (ZIKV) can induce cross-reactive antibody responses. Two immunodominant epitopes-one to precursor membrane protein and one to the fusion loop epitope on envelope (E) protein-are recognized by cross-reactive antibodies that are not only poorly neutralizing, but can also promote increased viral replication and disease severity via Fcγ receptor-mediated infection of myeloid cells-a process termed antibody-dependent enhancement (ADE). ADE is a significant concern for both ZIKV and DENV vaccines as the induction of poorly neutralizing cross-reactive antibodies may prime an individual for ADE on natural infection.

The immune response against flaviviruses.

Arthropod-borne flaviviruses are important human pathogens that cause a diverse range of clinical conditions, including severe hemorrhagic syndromes, neurological complications and congenital malformations. Consequently, there is an urgent need to develop safe and effective vaccines, a process requiring better understanding of the immunological mechanisms involved during infection. Decades of research suggest a paradoxical role of the immune response against flaviviruses: although the immune response is crucial for the control, clearance and prevention of infection, poor clinical outcomes are commonly associated with virus-specific immunity and immunopathogenesis.

Role of Capsid Anchor in the Morphogenesis of Zika Virus.

The flavivirus capsid protein (C) is separated from the downstream premembrane (PrM) protein by a hydrophobic sequence named capsid anchor (Ca). During polyprotein processing, Ca is sequentially cleaved by the viral NS2B/NS3 protease on the cytosolic side and by signal peptidase on the luminal side of the endoplasmic reticulum (ER). To date, Ca is considered important mostly for directing translocation of PrM into the ER lumen.