Combination of Modified NS1 and NS3 as a Novel Vaccine Strategy against Dengue Virus Infection

Dengue virus (DENV) causes a range of illness, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. DENV nonstructural protein (NS) 1 has been considered to be a desirable vaccine candidate for its ability to induce Ab and complement-dependent cytolysis of DENV-infected cells...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2019-10, Vol.203 (7), p.1909-1917
Main Authors: Kao, Yu-San, Yu, Chia-Yi, Huang, Hong-Jyun, Tien, Sen-Mao, Wang, Wan-Yu, Yang, Martyr, Anderson, Robert, Yeh, Trai-Ming, Lin, Yee-Shin, Wan, Shu-Wen
Format: Article
Language:English
Subjects:
Animals
Antibodies, Viral - immunology
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cross Reactions
Dengue - immunology
Dengue - pathology
Dengue - prevention & control
Dengue Vaccines - immunology
Dengue Virus - immunology
Epitopes - immunology
Immunity, Cellular
Immunization
Male
Mice
Viral Nonstructural Proteins - immunology
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Summary:Dengue virus (DENV) causes a range of illness, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. DENV nonstructural protein (NS) 1 has been considered to be a desirable vaccine candidate for its ability to induce Ab and complement-dependent cytolysis of DENV-infected cells as well as to block the pathogenic effects of NS1. However a potential drawback of NS1 as a vaccine is that anti-DENV NS1 Abs can lead to endothelial cell damage and platelet dysfunction by antigenic cross-reactivity. Therefore, we modified the DENV NS1 by replacing the C-terminal cross-reactive epitopes with the corresponding region of Japanese encephalitis virus NS1 to generate a chimeric DJ NS1 protein. Active immunization with DJ NS1 induced a strong Ab response. To enhance cellular immunity, we further combined DJ NS1 with DENV NS3 to immunize mice and showed activation of Ag-specific CD4 and CD8 T cells in addition to Ab responses. We further detected NS3-specific CTL activities as well as CD107a expression of effector cells. Importantly, the protective effects attributed by DJ NS1 and NS3 immunization were demonstrated in a DENV-infected mouse model by reduced viral titers, soluble NS1 levels, mouse tail bleeding time, and vascular leakage at skin injection sites. Collectively, the results from this study reveal the humoral and cellular immune responses and the protective effects conferred by DJ NS1 and NS3 immunization in the mouse model of DENV infection and provide a potential strategy for dengue vaccine design.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1900136