The Synergistic Effect of Combined Immunization with a DNA Vaccine and Chimeric Yellow Fever/Dengue Virus Leads to Strong Protection against Dengue

Adriana S Azevedo,Marcos S Freire,Ada M B Alves,Ricardo Galler,Marcia Archer,Antônio J S Gonçalves,Anil Kumar Tyagi

doi:10.1371/journal.pone.0058357

Abstract

The dengue envelope glycoprotein (E) is the major component of virion surface and its ectodomain is composed of domains I, II and III. This protein is the main target for the development of a dengue vaccine with induction of neutralizing antibodies. In the present work, we tested two different vaccination strategies, with combined immunizations in a prime/booster regimen or simultaneous inoculation with a DNA vaccine (pE1D2) and a chimeric yellow fever/dengue 2 virus (YF17D-D2). The pE1D2 DNA vaccine encodes the ectodomain of the envelope DENV2 protein fused to t-PA signal peptide, while the YF17D-D2 was constructed by replacing the prM and E genes from the 17D yellow fever vaccine virus by those from DENV2. Balb/c mice were inoculated with these two vaccines by different prime/booster or simultaneous immunization protocols and most of them induced a synergistic effect on the elicited immune response, mainly in neutralizing antibody production. Furthermore, combined immunization remarkably increased protection against a lethal dose of DENV2, when compared to each vaccine administered alone. Results also revealed that immunization with the DNA vaccine, regardless of the combination with the chimeric virus, induced a robust cell immune response, with production of IFN-γ by CD8+ T lymphocytes.

Highlights

Dengue is an important viral disease, consisting of a global public health problem in tropical and subtropical regions of the world including the Americas, where the main vector is the mosquito Aedes aegypti
Serum samples from mice inoculated with the different immunization protocols (Table 1), as well as control animals, were collected 24 h before virus challenge and titrated for neutralizing antibodies (PRNT50%), performed with a DENV2 isolate different from that used for vaccine constructions
Immunization with two doses of the DNA vaccine elicits a slight increase of neutralizing antibody levels when compared to inoculation with one dose (PRNT median of 67 and 40, respectively), while two doses of the chimeric virus induced significant higher plaque reduction neutralization tests (PRNT) comparing to what it was observed with one dose of this vaccine (Fig. 1)

Summary

Introduction

Dengue is an important viral disease, consisting of a global public health problem in tropical and subtropical regions of the world including the Americas, where the main vector is the mosquito Aedes aegypti. The E glycoprotein is the major component of virion surface and it is associated with several biological activities. It acts as a binding protein, interacting with receptors present on host cell surface and leading to endocytosis of the virus particle. It mediates fusion of envelope and host cell membranes, which culminates with the nucleocapsid disassemble and release of virus genome for polyprotein synthesis [5], [6]. The virus particle contains 90 homodimers of the E protein and its ectodomain is composed of the domain I, II and III [6]

Methods

Results

Conclusion