Protective Immunity to Dengue Virus Induced by DNA Vaccines Encoding Nonstructural Proteins in a Lethal Challenge Immunocompetent Mouse Model.

Rúbens Prince Dos Santos Alves,Jaime Henrique Amorim,Denicar Lina Nascimento Fabris-Maeda,Lennon Ramos Pereira,Mônica Josiane Rodrigues-Jesus,Natiely Silva Sales,Alexia Adrianne Venceslau Brito Carvalho,Luís Carlos De Souza Ferreira,Carla Longo De Freitas,Robert Andreata-Santos,Samuel Santos Pereira,Jean Pierre Schatzmann Peron

doi:10.3389/fmedt.2020.558984

Rúbens Prince Dos Santos Alves, Jaime Henrique Amorim + Show 10 more

Open Access

https://doi.org/10.3389/fmedt.2020.558984

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Abstract

Dengue virus represents the main arbovirus affecting humans, but there are no effective drugs or available worldwide licensed vaccine formulations capable of conferring full protection against the infection. Experimental studies and results generated after the release of the licensed anti-DENV vaccine demonstrated that induction of high-titer neutralizing antibodies does not represent the sole protection correlate and that, indeed, T cell-based immune responses plays a relevant role in the establishment of an immune protective state. In this context, this study aimed to further demonstrate protective features of immune responses elicited in immunocompetent C57BL/6 mice immunized with three plasmids encoding DENV2 nonstructural proteins (NS1, NS3, and NS5), which were subsequently challenged with a DENV2 strain naturally capable of inducing lethal encephalitis in immunocompetent mouse strains. The animals were immunized intramuscularly with the DNA vaccine mix and complete protection was observed among vaccinated mice. Vaccine induced protection correlated with the cytokine profiles expressed by spleen cells and brain-infiltrating mononuclear cells. The results confirm the pivotal role of cellular immune responses targeting nonstructural DENV proteins and validate the experimental model based on a DENV2 strain capable of infecting and killing immunocompetent mice as a tool for the evaluation of protective immunity induced by anti-DENV vaccines.

Highlights

Dengue fever is an acute disease caused by dengue virus (DENV), an arbovirus belonging to the Flaviviridae family transmitted by Aedes mosquitoes [1,2,3,4]
We developed an immunocompetent mouse model using the non-adapted DENV2 JHA1 strain originally isolated from a symptomatic patient in Brazil for testing the protective immunity induced by antiDENV vaccines [51]
Dengvaxia R, the only DENV vaccine approved for use in humans, has multiple drawbacks, including lack of efficacy in DENV-naïve individuals and higher incidence of severe dengue disease cases in some vaccinated subjects relative to in unvaccinated individuals, which supports a role for Abs in DENV pathogenesis (ADE) [25,26,27,28,29,30,31]

Summary

Introduction

Dengue fever is an acute disease caused by dengue virus (DENV), an arbovirus belonging to the Flaviviridae family transmitted by Aedes mosquitoes [1,2,3,4]. It is estimated that 3.9 billion people in 128 countries are at risk of infection [6]. 96 million DENV-infected people develop symptoms with sufficient severity to change their routine [7], and previous studies showed that ∼500,000 individuals develop severe forms of disease, which may include hemorrhagic shock syndrome [8]. The mortality rate in this group reaches 10% in hospitalized patients and 30% in nonhospitalized DENV-infected individuals [9]. Regardless of the high epidemiological importance of dengue fever, there is no effective drug against the virus or a completely safe and widely available vaccine capable of preventing viral infection when used in endemic areas [10]

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