Intranasal Immunization with Influenza Virus-Like Particles Containing Membrane-Anchored Cholera Toxin B or Ricin Toxin B Enhances Adaptive Immune Responses and Protection against an Antigenically Distinct Virus.
Vaccination is the most effective means to prevent influenza virus infection, although current approaches are associated with suboptimal efficacy. Here, we generated virus-like particles (VLPs) composed of the hemagglutinin (HA), neuraminidase (NA) and matrix protein (M1) of A/Changchun/01/2009 (H1N1) with or without either membrane-anchored cholera toxin B (CTB) or ricin toxin B (RTB) as molecular adjuvants. The intranasal immunization of mice with VLPs containing membrane-anchored CTB or RTB elicited stronger humoral and cellular immune responses when compared to mice immunized with VLPs alone. Administration of VLPs containing CTB or RTB significantly enhanced virus-specific systemic and mucosal antibody responses, hemagglutination inhibiting antibody titers, virus neutralizing antibody titers, and the frequency of virus-specific IFN-γ and IL-4 secreting splenocytes. VLPs with and without CTB or RTB conferred complete protection against lethal challenge with a mouse-adapted homologous virus. When challenged with an antigenically distinct H1N1 virus, all mice immunized with VLPs containing CTB or RTB survived whereas mice immunized with VLPs alone showed only partial protection (80% survival). Our results suggest that membrane-anchored CTB and RTB possess strong adjuvant properties when incorporated into an intranasally-delivered influenza VLP vaccine. Chimeric influenza VLPs containing CTB or RTB may represent promising vaccine candidates for improved immunological protection against homologous and antigenically distinct influenza viruses.
College of Veterinary Medicine, Inner Mongolia Agricultural University, Huhhot 010018, China. jixianliang2011@126.com.|Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. jixianliang2011@126.com.
Xianliang
X
Ji
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. renzhiguang66@126.com.|Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing 100730, China. renzhiguang66@126.com.|Key Lab of Cellular and Molecular Immunology, Henan University School of Medicine, Kaifeng 475001, China. renzhiguang66@126.com.
Zhiguang
Z
Ren
Jilin Medical University, Changchun 132013, China. doudou7756@126.com.
Na
N
Xu
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. meng13843191452@163.com.|College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China. meng13843191452@163.com.
Lingnan
L
Meng
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. zhijun0215@gmail.com.|Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing 100730, China. zhijun0215@gmail.com.
Zhijun
Z
Yu
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. fengna0308@126.com.
Na
N
Feng
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. xysang2012@163.com.
Xiaoyu
X
Sang
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. 18626656520@126.com.|College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China. 18626656520@126.com.
Shengnan
S
Li
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. liyuanguo0520@163.com.
Yuanguo
Y
Li
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. wgcha@163.com.
Tiecheng
T
Wang
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. zhaoyongkun1976@126.com.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Nanjing 210009, China. zhaoyongkun1976@126.com.
Yongkun
Y
Zhao
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. wangh25@hotmail.com.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Nanjing 210009, China. wangh25@hotmail.com.
Hualei
H
Wang
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. zhengxx2513@163.com.|School of Public Health, Shandong University, Jinan 250110, China. zhengxx2513@163.com.
Xuexing
X
Zheng
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. jin8616771@163.com.
Hongli
H
Jin
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. linan226@126.com.
Nan
N
Li
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. yst62041@163.com.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Nanjing 210009, China. yst62041@163.com.
Songtao
S
Yang
College of Veterinary Medicine, Inner Mongolia Agricultural University, Huhhot 010018, China. jinshancao@imau.edu.cn.
Jinshan
J
Cao
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. liuws85952@163.com.
Wensen
W
Liu
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. gaoyuwei@gmail.com.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Nanjing 210009, China. gaoyuwei@gmail.com.
Yuwei
Y
Gao
Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130122, China. xiaxzh@cae.cn.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Nanjing 210009, China. xiaxzh@cae.cn.
Xianzhu
X
Xia
D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D002772:Cholera Toxin / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D004195:Disease Models, Animal; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D007111:Immunity, Cellular; D018928:Immunity, Mucosal / Q000276:immunology; D007114:Immunization; D009980:Influenza A virus / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D012276:Ricin / Q000235:genetics / Q000276:immunology*; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*; D019562:Viral Load
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007252:Influenza Vaccines; D058425:Vaccines, Virus-Like Particle; D012276:Ricin; D002772:Cholera Toxin
cross-protection; influenza; intranasal administration; membrane-anchored cholera toxin B; ricin toxin B; virus-like particles