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

Date Published: December 9, 2015

Publisher: Public Library of Science

Author(s): Antônio J. S. Gonçalves, Edson R. A. Oliveira, Simone M. Costa, Marciano V. Paes, Juliana F. A. Silva, Adriana S. Azevedo, Marcio Mantuano-Barradas, Ana Cristina M. A. Nogueira, Cecília J. Almeida, Ada M. B. Alves, Eva Harris.

Abstract: 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.

Partial Text: Dengue represents the most important human mosquito-borne disease worldwide. Each year, an estimated 96 million people present clinical signs of the disease [1], resulting in about 20000 deaths [2]. The illness is caused by the dengue virus (DENV), which consists of four distinct serotypes (DENV1-4) present in tropical and subtropical regions of the globe. Infection may be asymptomatic or can be manifested as a non-differentiate febrile, marked mainly by myalgia, headache and retroorbital pain. The most severe forms of the disease are characterized by plasma leakage, thrombocytopenia and hemorrhage, which can evolve to hypovolemic shock [3–4].

In this report we investigated the contribution of the humoral and cellular immune responses induced by a DNA vaccine (pcTPANS1) encoding the NS1 protein in Balb/c mice challenged with DENV2. We observed that both responses were important for protection against dengue. In fact, results revealed that an effective protection against virus challenge was not achieved with antibody or T cells only, but rather with the combination of both responses.



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