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

Azevedo, Adriana de Souza; Gonçalves, Antônio José; Archer, Marcia; Freire, Marcos S.; Galler, Ricardo; Alves, Ada M. B.

doi:10.1371/journal.pone.0058357

Cited by 20 publications

(17 citation statements)

References 45 publications

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“…Immunocompetent mice, in turn, are still an alternative, in particular with the use of neuroadapted viral samples. In fact, the most traditional immunocompetent mouse model for testing vaccines against DENV is the use of a brain-adapted virus inoculated by the intracerebral route, which provides a straightforward readout parameter because the infection is usually lethal 25,27,33 . Albeit protection in these animals is normally reduced to evaluation of morbidity and/or survival rates after virus challenge, we have recently shown the systemic effect of the DENV2 inoculation in BALB/c mice by the i.c.…”

Section: Discussionmentioning

confidence: 99%

Dengue infection in mice inoculated by the intracerebral route: neuropathological effects and identification of target cells for virus replication

Amorim

Azevedo

Costa

et al. 2019

Sci Rep

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Dengue is an important arboviral infection, causing a broad range symptom that varies from lifethreatening mild illness to severe clinical manifestations. Recent studies reported the impairment of the central nervous system (CNS) after dengue infection, a characteristic previously considered as atypical and underreported. However, little is known about the neuropathology associated to dengue. Since animal models are important tools for helping to understand the dengue pathogenesis, including neurological damages, the aim of this work was to investigate the effects of intracerebral inoculation of a neuroadapted dengue serotype 2 virus (DENV2) in immunocompetent BALB/c mice, mimicking some aspects of the viral encephalitis. Mice presented neurological morbidity after the 7 th day post infection. At the same time, histopathological analysis revealed that DENV2 led to damages in the CNS, such as hemorrhage, reactive gliosis, hyperplastic and hypertrophied microglia, astrocyte proliferation, Purkinje neurons retraction and cellular infiltration around vessels in the pia mater and in neuropil. Viral tropism and replication were detected in resident cells of the brain and cerebellum, such as neurons, astrocyte, microglia and oligodendrocytes. Results suggest that this classical mice model might be useful for analyzing the neurotropic effect of DENV with similarities to what occurs in human. Dengue is one of the most important diseases caused by an arbovirus, the dengue virus (DENV), which affects 96 million people annually worldwide, with 396 million estimated infections 1. The disease has a broad range manifestation, varying from a life-threatening mild flu-like illness, known as dengue fever, to severe dengue 2. The virus belongs to the family Flaviviridae, genus Flavivirus, and consists of four antigenically distinct serotypes (DENV 1-4) 3. Although DENV is classically characterized as a non-neurotropic virus, in the last decades several studies led to a different understanding of the clinical profile of the dengue disease. In addition to a variety of non-specific signs and symptoms, the disease may also present manifestations including neurological involvements 4. The emergence of neurological signs in human patients infected with DENV was first reported in 1976 5. Nowadays, encephalitis and encephalopathy stand out as the most common neurological signs resulting from DENV infection 6 .

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Section: Discussionmentioning

confidence: 99%

Dengue infection in mice inoculated by the intracerebral route: neuropathological effects and identification of target cells for virus replication

Amorim

Azevedo

Costa

et al. 2019

Sci Rep

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“…DNA immunization may be an interesting approach for the development of a vaccine against dengue, since it is recognized as a useful tool to induce both arms of the immune system. Different DNA vaccines have been tested against DENV, most of them based on the dengue virus envelope protein [ 47 – 49 ]. However, several reports have shown that the E protein is also involved in the phenomena of antibody dependent enhancement (ADE), where instead of protection by neutralization, antibodies against this protein may lead to an increase of virus replication [ 50 – 52 ].…”

Section: Discussionmentioning

confidence: 99%

Cooperation between CD4+ T Cells and Humoral Immunity Is Critical for Protection against Dengue Using a DNA Vaccine Based on the NS1 Antigen

et al. 2015

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Dengue virus (DENV) is spread through most tropical and subtropical areas of the world and represents a serious public health problem. At present, the control of dengue disease is mainly hampered by the absence of antivirals or a vaccine, which results in an estimated half worldwide population at risk of infection. The immune response against DENV is not yet fully understood and a better knowledge of it is now recognized as one of the main challenge for vaccine development. In previous studies, we reported that a DNA vaccine containing the signal peptide sequence from the human tissue plasminogen activator (t-PA) fused to the DENV2 NS1 gene (pcTPANS1) induced protection against dengue in mice. In the present work, we aimed to elucidate the contribution of cellular and humoral responses elicited by this vaccine candidate for protective immunity. We observed that pcTPANS1 exerts a robust protection against dengue, inducing considerable levels of anti-NS1 antibodies and T cell responses. Passive immunization with anti-NS1 antibodies conferred partial protection in mice infected with low virus load (4 LD50), which was abrogated with the increase of viral dose (40 LD50). The pcTPANS1 also induced activation of CD4+ and CD8+ T cells. We detected production of IFN-γ and a cytotoxic activity by CD8+ T lymphocytes induced by this vaccine, although its contribution in the protection was not so evident when compared to CD4+ cells. Depletion of CD4+ cells in immunized mice completely abolished protection. Furthermore, transfer experiments revealed that animals receiving CD4+ T cells combined with anti-NS1 antiserum, both obtained from vaccinated mice, survived virus infection with survival rates not significantly different from pcTPANS1-immunized animals. Taken together, results showed that the protective immune response induced by the expression of NS1 antigen mediated by the pcTPANS1 requires a cooperation between CD4+ T cells and the humoral immunity.

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“…Animals developed neutralizing antibodies and the combined immunization protected against a lethal dose of DENV-2, when compared to each vaccine administered alone. Results also revealed that immunization with the DNA vaccine and the combination with the chimeric virus induced a robust production of IFNγ by CD8+ T lymphocytes (83). Unfortunately, these authors did not evaluate this combination in non-human primates.…”

Section: Complementary Prime-boost Immunization Strategies For the Dementioning

confidence: 99%

Can Complementary Prime-Boost Immunization Strategies Be an Alternative and Promising Vaccine Approach Against Dengue Virus?

et al. 2019

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Dengue is one of the most important diseases transmitted by mosquitoes. Dengvaxia®, a vaccine registered in several countries, cannot be administered to non-immune individuals and children younger than 9 years old, due to safety reasons. There are two vaccine candidates in phase 3 efficacy trials, but their registration date is completely unknown at this moment. So, the development of new vaccines or vaccine strategies continues to be a priority for the WHO. This work reviews some complementary prime-boost immunization studies against important human pathogens. Additionally, it reviews the results obtained using this regimen of immunization against dengue virus as a potential alternative approach for finding a safe and efficient vaccine. Finally, the main elements associated with this strategy are also discussed. The generation of new strategies of vaccination against dengue virus, must be directed to reduce the risk of increasing viral load through sub-neutralizing antibodies and it must be also directed to induce a polyfunctional T cell response. Complementary prime-boost immunization strategies could emerge as an interesting approach to induce solid immunity or at least to reduce viral load after natural infection, avoiding severe dengue. Subunit vaccine could be safe and attractive antigens for this strategy, especially proteins including B, and T-cells epitopes for inducing humoral and cellular immune responses, which can play an important role controlling the disease.

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

Cited by 20 publications

References 45 publications

Dengue infection in mice inoculated by the intracerebral route: neuropathological effects and identification of target cells for virus replication

Dengue infection in mice inoculated by the intracerebral route: neuropathological effects and identification of target cells for virus replication

Cooperation between CD4+ T Cells and Humoral Immunity Is Critical for Protection against Dengue Using a DNA Vaccine Based on the NS1 Antigen

Can Complementary Prime-Boost Immunization Strategies Be an Alternative and Promising Vaccine Approach Against Dengue Virus?

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