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Antiviral Res. 2018 Oct 30;161:10-19. doi: 10.1016/j.antiviral.2018.10.027. [Epub ahead of print]

The optimized fusion protein HA1-2-FliCΔD2D3 promotes mixed Th1/Th2 immune responses to influenza H7N9 with low induction of systemic proinflammatory cytokines in mice.

Author information

1
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China.
2
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China; Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT 06269, USA.
3
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China. Electronic address: jiao@yzu.edu.cn.
4
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Yangzhou, Jiangsu 225009, China. Electronic address: zmpan@yzu.edu.cn.

Abstract

H7N9 influenza virus has an unusually high fatality rate of approximately 40%, and a safe and effective vaccine against this subtype is urgently needed. Flagellin, a Toll-like receptor (TLR) 5 agonist, has been deemed as a potent adjuvant candidate. However, its high antigenicity and potential for causing inflammatory injury might restrict its clinical application. Previously, we demonstrated that a fusion protein, HA1-2-FliC, comprising the hemagglutinin globular head protein (HA1-2) of H7N9 influenza virus and the full-length Salmonella typhimurium flagellin protein (FliC), had high efficiency against H7N9 in mouse and chicken models. Here, we constructed an improved fusion protein, HA1-2-FliCΔD2D3, with HA1-2 fused to the FliCΔD2D3 (lacking the hypervariable-region domains D2 and D3 of FliC). HA1-2-FliCΔD2D3 exhibited efficient immunoreactivity and TLR5 agonist efficacy, and promoted innate immune-response activation in mouse macrophages, peripheral blood mononuclear cells, and splenocytes, based on cytokine- and chemokine-expression profiles. Mice immunized with HA1-2-FliCΔD2D3 showed significantly lower systemic inflammatory responses (compared with HA1-2-FliC) and highly reduced flagellin-specific antibody production, without affecting HA1-2-specific antibody production and cellular immune responses. Enhanced IFN-γ/IL-4 generation suggested that HA1-2-FliCΔD2D3 maintained balanced Th1/Th2 immune responses. Furthermore, virus challenge was performed in a chicken model. The results showed that chickens receiving FliCΔD2D3 adjuvant vaccine induced high levels of serum neutralizing antibodies, and exhibited a significant reduction of viral loads in throat and cloaca compared to chickens receiving only HA1-2. In conclusion, we constructed the H7N9 influenza subunit vaccine candidate HA1-2-FliCΔD2D3, with reduced immunogenicity against FliC and lower adverse events. The improved adjuvant FliCΔD2D3 can potentially help in developing safe and effective universal protein-based influenza vaccines for humans.

KEYWORDS:

Adjuvanticity; Flagellin; H7N9 influenza virus; Hemagglutinin globular head; Hypervariable region; Immune response

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