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Chen Y, Luo G, Song F, Wang X, Zhang S, Ge S, Li T, Zhang J, Xia N. Truncated rotavirus VP4 proteins induce stronger protective immunity compared to P2 - VP8 in animal models. Antiviral Res 2025; 238:106156. [PMID: 40194664 DOI: 10.1016/j.antiviral.2025.106156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/17/2025] [Accepted: 04/05/2025] [Indexed: 04/09/2025]
Abstract
Group A rotavirus (RVA) is the primary causative agent of acute gastroenteritis (AGE) in children under five years of age, resulting in over 120,000 deaths annually. In previous studies, we identified truncated VP4∗ as a potentially more promising vaccine candidate compared to VP8∗ and VP5∗. This study aimed to compare the immunogenicity and protective efficacy of VP4∗ and P2-VP8, the most advanced recombinant rotavirus vaccine undergoing phase 3 clinical trial in various animal models, including mice, guinea pigs, rabbits, and piglets. The results indicated that the binding antibodies and neutralizing antibodies induced by VP4∗ were significantly higher levels compared to P2-VP8. Immunization with VP4∗ provided 100 % protection for mice against challenges with EDIM and LLR strains. Additionally, we were intrigued to discover that the VP4∗ antibody not only inhibited virus adsorption but also prevented the virus from entering cells following pre-adsorption. In summary, VP4∗ demonstrates greater immunogenicity and protective efficacy compared to P2-VP8, making it a more promising candidate antigen for recombinant rotavirus vaccines.
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MESH Headings
- Animals
- Rotavirus Infections/prevention & control
- Rotavirus Infections/immunology
- Rotavirus Infections/virology
- Capsid Proteins/immunology
- Capsid Proteins/genetics
- Rotavirus Vaccines/immunology
- Rotavirus Vaccines/administration & dosage
- Rotavirus Vaccines/genetics
- Antibodies, Viral/blood
- Antibodies, Viral/immunology
- Rotavirus/immunology
- Rotavirus/genetics
- Mice
- Antibodies, Neutralizing/blood
- Antibodies, Neutralizing/immunology
- Disease Models, Animal
- Rabbits
- Guinea Pigs
- Swine
- Vaccines, Synthetic/immunology
- Vaccines, Synthetic/administration & dosage
- Immunogenicity, Vaccine
- Mice, Inbred BALB C
- Antigens, Viral/immunology
- Antigens, Viral/genetics
- Female
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Affiliation(s)
- Yaling Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
| | - Guoxing Luo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China; Novel Product R&D Department, Xiamen Innovax Biotech Co., Ltd., Xiamen, 361022, Fujian, China
| | - Feibo Song
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
| | - Xuechun Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
| | - Shiyin Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
| | - Shengxiang Ge
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China.
| | - Tingdong Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China.
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University. Xiamen, 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, 361102, China
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Ghonaim AH, Rouby SR, Nageeb WM, Elgendy AA, Xu R, Jiang C, Ghonaim NH, He Q, Li W. Insights into recent advancements in human and animal rotavirus vaccines: Exploring new frontiers. Virol Sin 2025; 40:1-14. [PMID: 39672271 PMCID: PMC11962973 DOI: 10.1016/j.virs.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 12/10/2024] [Indexed: 12/15/2024] Open
Abstract
Rotavirus infections cause severe gastroenteritis and dehydration in young children and animals worldwide, leading to high rates of morbidity and mortality, predominantly in low- and middle-income countries. In the past decade, substantial progress has been made in the development and implementation of rotavirus vaccines, which have been essential in alleviating the global burden of this disease, not only in human being but also in livestock species like calves and piglets, where these infections can cause significant economic losses. By synthesizing the latest research and real-world evidence, this review article is designated to provide deep insights into the current state of rotavirus vaccine technology and its global implementation as well as the application of rotavirus vaccines in veterinary settings and their importance in controlling zoonotic transmission and maintaining food security.
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Affiliation(s)
- Ahmed H Ghonaim
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China; Desert Research Center, Cairo 11435, Egypt
| | - Sherin R Rouby
- Department of Veterinary Medicine, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Wedad M Nageeb
- Medical Microbiology and Immunology Department, Faculty of Medicine, Suez Canal University, Ismailia 41111, Egypt
| | - Ashraf Ahmed Elgendy
- Department of Immunology, Faculty of Medicine, New Kaser Al-Aini Teaching Hospital, Cairo University, 11435, Egypt
| | - Rong Xu
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
| | - Changsheng Jiang
- Anhui Provincial Key Laboratory of Animal Nutritional Regulation and Health, College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Noha H Ghonaim
- Family Medicine Department, Faculty of Medicine, Suez Canal University, Ismailia 41111, Egypt
| | - Qigai He
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Wentao Li
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan 430070, China.
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Song F, Zeng Y, Sheng R, Lin Y, Wang X, Hong C, Luo G, Wang Y, Fang M, He S, Zhang S, Zheng Q, Li T, Ge S, Zhang J, Xia N. VP8 Mosaic Nanoparticles Elicit Cross-Neutralizing Immune Responses and Provide Protection Against Heterotypic Rotavirus Challenge in Mice. ACS NANO 2024; 18:31809-31822. [PMID: 39497609 DOI: 10.1021/acsnano.4c07061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
Group A rotaviruses (RVA) remain one of the dominant pathogens causing diarrhea in children under 5 years of age worldwide, despite a sharp decrease of RVA-associated diarrhea and mortality since the introduction of rotavirus vaccines. The decreased effectiveness of live attenuated rotavirus vaccines, coupled with the emergence of new rotavirus genotypes and the risk of cross-species virus transmission, underscores the necessity to develop more effective and broad-spectrum rotavirus vaccines. In this study, we utilized nanoparticles coupled with the SpyCatcher-SpyTag system to effectively display the truncated VP8-1 protein. The modular display of the monovalent VP8-1 proteins markedly increased the immunogenicity of VP8-1. Furthermore, the bivalent display of VP8-1 proteins from simian rotavirus SA11 and lamb rotavirus LLR on the same particle not only increased immunogenicity against homotypic antigens but also elicited robust heterotypic immune responses and conferred effective protection against a distant heterotypic rotavirus with sequence identities of only 62%-66% in an adult mouse model. Therefore, mosaic VP8 nanoparticles could be considered as a viable strategy for the development of the next-generation broad-spectrum rotavirus vaccine.
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Affiliation(s)
- Feibo Song
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yuanjun Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Roufang Sheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yunyun Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xuechun Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Congming Hong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Guoxing Luo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yingbin Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Mujin Fang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Shuizhen He
- Haicang Hospital of Xiamen, Xiamen 361026, China
| | - Shiyin Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Qingbing Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Tingdong Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Shengxiang Ge
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
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Strachan M, Mashapa T, Gildenhuys S. Spectroscopic analysis of the bacterially expressed head domain of rotavirus VP6. Biosci Rep 2024; 44:BSR20232178. [PMID: 38592735 PMCID: PMC11065646 DOI: 10.1042/bsr20232178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/10/2024] Open
Abstract
The rotavirus capsid protein VP6 forms the middle of three protein layers and is responsible for many critical steps in the viral life cycle. VP6 as a structural protein can be used in various applications including as a subunit vaccine component. The head domain of VP6 (VP6H) contains key sequences that allow the protein to trimerize and that represent epitopes that are recognized by human antibodies in the viral particle. The domain is rich in β-sheet secondary structures. Here, VP6H was solubilised from bacterial inclusion bodies and purified using a single affinity chromatography step. Spectral (far-UV circular dichroism and intrinsic tryptophan fluorescence) analysis revealed that the purified domain had native-like secondary and tertiary structures. The domain could maintain structure up to 44°C during thermal denaturation following which structural changes result in an intermediate forming and finally irreversible aggregation and denaturation. The chemical denaturation with urea and guanidinium hydrochloride produces intermediates that represent a loss in the cooperativity. The VP6H domain is stable and can fold to produce its native structure in the absence of the VP6 base domain but cannot be defined as an independent folding unit.
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Affiliation(s)
- Milaan Simone Strachan
- Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X6, Florida, Roodepoort 1710, South Africa
| | - Tshepo Mashapa
- Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X6, Florida, Roodepoort 1710, South Africa
| | - Samantha Gildenhuys
- Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X6, Florida, Roodepoort 1710, South Africa
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Kostina LV, Filatov IE, Eliseeva OV, Latyshev OE, Chernoryzh YY, Yurlov KI, Lesnova EI, Khametova KM, Cherepushkin SA, Savochkina TE, Tsibezov VV, Kryshen KL, Alekseeva LI, Zaykova ON, Grebennikova TV. [Study of the safety and immunogenicity of VLP-based vaccine for the prevention of rotavirus infection in neonatal minipig model]. Vopr Virusol 2023; 68:415-427. [PMID: 38156575 DOI: 10.36233/0507-4088-194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Indexed: 12/30/2023]
Abstract
INTRODUCTION In Russia, almost half of the cases of acute intestinal infections of established etiology in 2022 are due to rotavirus infection (RVI). There is no specific treatment for rotavirus gastroenteritis. There is a need to develop modern, effective and safe vaccines to combat rotavirus infection that are not capable of multiplying (replicating) in the body of the vaccinated person. A promising approach is to create vaccines based on virus-like particles (VLPs). OBJECTIVE Study of the safety and immunogenicity of a vaccine against rotavirus infection based on virus-like particles of human rotavirus A in newborn minipigs with multiple intramuscular administration. MATERIALS AND METHODS Newborn minipigs were used as an animal model in this study. The safety of the tested vaccine was assessed based on thermometry data, clinical examination, body weight gain, clinical and biochemical blood parameters, as well as necropsy and histological examination. When studying the immunogenic properties of the Gam-VLP-rota vaccine in doses of 30 and 120 µg, the cellular, humoral and secretory immune response was studied. RESULTS The results of assessing the general condition of animals during the immunization period, data from clinical, laboratory and pathomorphological studies indicate the safety of the vaccine against human rotavirus infection based on VLP (Gam-VLP-rota) when administered three times intramuscularly. Good local tolerance of the tested vaccine was demonstrated. The results of the assessment of humoral immunity indicate the formation of a stable immune response after three-time immunization with Gam-VLP-rota, stimulation of the production of antigen-specific IgG antibodies and their functional activity to neutralize human rotavirus A. It was shown that following the triple immunization with the minimum tested concentration of 30 µg/dose, animals developed a cell-mediated immune response. The results of the IgA titer in blood serum and intestinal lavages indicate the formation of both a systemic immunological response and the formation of specific secretory immunity to human rotavirus A. CONCLUSION Thus, three-time intramuscular immunization of minipigs with the Gam-VLP-rota vaccine forms stable protective humoral and cellular immunity in experimental animals. Evaluated vaccine is safe and has good local tolerability.
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Affiliation(s)
- L V Kostina
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - I E Filatov
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - O V Eliseeva
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - O E Latyshev
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - Y Y Chernoryzh
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - K I Yurlov
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - E I Lesnova
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - K M Khametova
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - S A Cherepushkin
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - T E Savochkina
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - V V Tsibezov
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | | | | | - O N Zaykova
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
| | - T V Grebennikova
- National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
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Tian Q, Huo X, Liu Q, Yang C, Zhang Y, Su J. VP4/VP56/VP35 Virus-like Particles Effectively Protect Grass Carp ( Ctenopharyngodon idella) against GCRV-II Infection. Vaccines (Basel) 2023; 11:1373. [PMID: 37631941 PMCID: PMC10458301 DOI: 10.3390/vaccines11081373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/31/2023] [Accepted: 08/10/2023] [Indexed: 08/29/2023] Open
Abstract
Grass carp reovirus (GCRV) seriously threatens the grass carp (Ctenopharyngodon idella) industry. Prophylactic GCRV vaccines prepared by virus-like particle (VLP) assembly biotechnology can improve effectiveness and safety. The highly immunogenic candidate antigens of GCRV vaccines that have been generally considered are the outer capsid proteins VP4, VP56, and VP35. In this study, VP4, VP56, and VP35 were expressed in an Escherichia coli expression system and a Pichia pastoris expression system. The successful assembly of uniform, stable, and non-toxic VP4/VP56/VP35 VLPs was confirmed through various assays. After vaccination and GCRV infection, the survival rate in the VLPs + adjuvant Astragalus polysaccharide (APS) group was the highest (62%), 40% higher than that in control group (22%). Through the antibody levels, tissue viral load, and antioxidant immunity assays, the P. pastoris VLP vaccine effectively improved IgM levels, alleviated tissue virus load, and regulated antioxidant immune-related indicators. The treatment with P. pastoris VLPs enhanced the mRNA expression of important immune-related genes in the head kidney, as measured by qRT-PCR assay. Upon hematoxylin-eosin staining examination, relatively reduced tissue pathological damage was observed in the VLPs + APS group. The novel vaccine using P. pastoris VLPs as an effective green biological agent provides a prospective strategy for the control of fish viral diseases.
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Affiliation(s)
- Qingqing Tian
- Hubei Hongshan Laboratory, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Q.T.); (X.H.); (Q.L.); (Y.Z.)
- Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Xingchen Huo
- Hubei Hongshan Laboratory, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Q.T.); (X.H.); (Q.L.); (Y.Z.)
| | - Qian Liu
- Hubei Hongshan Laboratory, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Q.T.); (X.H.); (Q.L.); (Y.Z.)
| | - Chunrong Yang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430000, China;
| | - Yongan Zhang
- Hubei Hongshan Laboratory, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Q.T.); (X.H.); (Q.L.); (Y.Z.)
| | - Jianguo Su
- Hubei Hongshan Laboratory, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (Q.T.); (X.H.); (Q.L.); (Y.Z.)
- Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, China
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Asensio-Cob D, Rodríguez JM, Luque D. Rotavirus Particle Disassembly and Assembly In Vivo and In Vitro. Viruses 2023; 15:1750. [PMID: 37632092 PMCID: PMC10458742 DOI: 10.3390/v15081750] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Rotaviruses (RVs) are non-enveloped multilayered dsRNA viruses that are major etiologic agents of diarrheal disease in humans and in the young in a large number of animal species. The viral particle is composed of three different protein layers that enclose the segmented dsRNA genome and the transcriptional complexes. Each layer defines a unique subparticle that is associated with a different phase of the replication cycle. Thus, while single- and double-layered particles are associated with the intracellular processes of selective packaging, genome replication, and transcription, the viral machinery necessary for entry is located in the third layer. This modular nature of its particle allows rotaviruses to control its replication cycle by the disassembly and assembly of its structural proteins. In this review, we examine the significant advances in structural, molecular, and cellular RV biology that have contributed during the last few years to illuminating the intricate details of the RV particle disassembly and assembly processes.
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Affiliation(s)
- Dunia Asensio-Cob
- Department of Molecular Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G0A4, Canada;
| | - Javier M. Rodríguez
- Department of Structure of Macromolecules, Centro Nacional de Biotecnología/CSIC, Cantoblanco, 28049 Madrid, Spain
| | - Daniel Luque
- Electron Microscopy Unit UCCT/ISCIII, 28220 Majadahonda, Spain
- School of Biomedical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
- Electron Microscope Unit, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW 2052, Australia
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8
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Cheng K, Ma N, Liang J, Ma X, Feng Q, Liu G, Xu C, Tang M, Zhang L, Gao X, Xu J, Wang C, Zhu F, Wang X, Li X, Zhao X, Nie G. Site-Specific Modification of Virus-Like Particles for Exogenous Tumor Antigen Display and Minimizing Preexisting Immunity. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2300125. [PMID: 36879481 DOI: 10.1002/smll.202300125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/08/2023] [Indexed: 06/08/2023]
Abstract
The widespread preexisting immunity against virus-like particles (VLPs) seriously limits the applications of VLPs as vaccine vectors. Enabling technology for exogenous antigen display should not only ensure the assembly ability of VLPs and site-specific modification, but also consider the effect of preexisting immunity on the behavior of VLPs in vivo. Here, combining genetic code expansion technique and synthetic biology strategy, a site-specific modification method for hepatitis B core (HBc) VLPs via incorporating azido-phenylalanine into the desired positions is described. Through modification position screening, it is found that HBc VLPs incorporated with azido-phenylalanine at the main immune region can effectively assemble and rapidly conjugate with the dibenzocycolctyne-modified tumor-associated antigens, mucin-1 (MUC1). The site-specific modification of HBc VLPs not only improves the immunogenicity of MUC1 antigens but also shields the immunogenicity of HBc VLPs themselves, thereby activating a strong and persistent anti-MUC1 immune response even in the presence of preexisting anti-HBc immunity, which results in the efficient tumor elimination in a lung metastatic mouse model. Together, these results demonstrate the site-specific modification strategy enabled HBc VLPs behave as a potent antitumor vaccine and this strategy to manipulate immunogenicity of VLPs may be suitable for other VLP-based vaccine vectors.
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Affiliation(s)
- Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Nana Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Xiaotu Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Qingqing Feng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Guangna Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Chen Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Ming Tang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Lizhuo Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Xiaoyu Gao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Jiaqi Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Chufan Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Fei Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Xinwei Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
| | - Xiang Li
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, P. R. China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, P. R. China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing, 100190, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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9
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Luo G, Zeng Y, Yang H, Li Y, Yang L, Li C, Song F, Zhang S, Li T, Ge S, Zhang J, Xia N. Bivalent rotavirus VP4∗ stimulates protective antibodies against common genotypes of human rotaviruses. iScience 2022; 25:105099. [PMID: 36185383 PMCID: PMC9519587 DOI: 10.1016/j.isci.2022.105099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/18/2022] [Accepted: 09/04/2022] [Indexed: 12/01/2022] Open
Abstract
Non-replicating rotavirus vaccines are an alternative strategy to improve the efficacy and safety of rotavirus vaccines. The spike protein VP4, which could be enzymatically cleaved into VP8∗ and VP5∗, is an ideal target for the development of recombinant rotavirus vaccine. In our previous studies, we demonstrated that the truncated VP4 (aa26-476, VP4∗) could be a more viable vaccine candidate compared to VP8∗ and VP5∗. Here, to develop a human rotavirus vaccine, the VP4∗ proteins of P[4], P[6], and P[8] genotype rotaviruses were expressed. All VP4∗ proteins can stimulate high levels of neutralizing antibodies in both guinea pigs and rabbits when formulated in aluminum adjuvant. Furthermore, bivalent VP4∗-based vaccine (P[8] + P[6]-VP4∗) can stimulate high levels of neutralizing antibodies against various genotypes of rotavirus with no significant difference as compared to the trivalent vaccines. Therefore, bivalent VP4∗ has the potential to be a viable rotavirus vaccine candidate for further development.
Purified rotavirus VP4∗ proteins form homogenic and stable trimers VP4∗ stimulated high levels of homotypic and heterotypic neutralizing antibodies The immunogenicity of different genotype VP4∗ is not influenced by each other Bivalent VP4∗ (P[8]+P[6]) stimulated protective immunity against most prevalent rotaviruses
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10
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Shoja Z, Jalilvand S, Latifi T, Roohvand F. Rotavirus VP6: involvement in immunogenicity, adjuvant activity, and use as a vector for heterologous peptides, drug delivery, and production of nano-biomaterials. Arch Virol 2022; 167:1013-1023. [PMID: 35292854 PMCID: PMC8923333 DOI: 10.1007/s00705-022-05407-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 01/26/2022] [Indexed: 12/15/2022]
Abstract
The first-generation, live attenuated rotavirus (RV) vaccines, such as RotaTeq and Rotarix, were successful in reducing the number of RV-induced acute gastroenteritis (AGE) and child deaths globally. However, the low efficacy of these first-generation oral vaccines, coupled with safety concerns, required development of improved RV vaccines. The highly conserved structural protein VP6 is highly immunogenic, and it can generate self-assembled nano-sized structures, including tubes and spheres (virus-like particles; VLPs). Amongst the RV proteins, only VP6 shows these features. Interestingly, VP6-assembled structures, in addition to being highly immunogenic, have several other useful characteristics that could allow them to be used as adjuvants, immunological carriers, and drug-delivery vehicles as well as acting a scaffold for production of valuable nano-biomaterials. This review provides an overview of the self-assembled nano-sized structures of VP6-tubes/VLPs and their various functions.
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Affiliation(s)
- Zabihollah Shoja
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran.
| | - Somayeh Jalilvand
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Latifi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzin Roohvand
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
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11
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Li C, Luo G, Zeng Y, Song F, Yang H, Zhang S, Wang Y, Li T, Ge S, Xia N. Establishment of Sandwich ELISA for Quality Control in Rotavirus Vaccine Production. Vaccines (Basel) 2022; 10:243. [PMID: 35214701 PMCID: PMC8876306 DOI: 10.3390/vaccines10020243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 12/04/2022] Open
Abstract
Non-replicating rotavirus vaccines are alternative strategies that may improve the protective efficacy of rotavirus vaccines in low- and middle-income countries. The truncated spike protein VP4 (aa26-476, VP4*)was a candidate antigen for the development of recombinant rotavirus vaccines, with higher immunogenicity and protective efficacy compared to VP8* and VP5* alone. This article describes the development of three genotype-specific sandwich ELISAs for P[4], P[6], and P[8]-VP4*, which are important for quality control in rotavirus vaccine production. Our results showed that the detection systems had good specificity for the different genotype VP4* and were not influenced by the E. coli host proteins. Moreover, the detection systems play an important role in determining whether the target protein was contaminated by VP4* proteins of other genotypes. They can also detect the adsorption rate of the adjuvant to the P[4], P[6], P[8]-VP4* protein during the process development. The three detection systems will play an important role in the quality control and process development of VP4* based rotavirus vaccines and facilitate the development of recombinant rotavirus vaccines.
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Affiliation(s)
- Cao Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Guoxing Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Yuanjun Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Feibo Song
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, China;
| | - Han Yang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Shiyin Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Yingbin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Tingdong Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Shengxiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; (C.L.); (G.L.); (Y.Z.); (H.Y.); (S.Z.); (Y.W.); (N.X.)
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, China;
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12
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Kurokawa N, Lavoie PO, D'Aoust MA, Couture MMJ, Dargis M, Trépanier S, Hoshino S, Koike T, Arai M, Tsutsui N. Development and characterization of a plant-derived rotavirus-like particle vaccine. Vaccine 2021; 39:4979-4987. [PMID: 34325930 DOI: 10.1016/j.vaccine.2021.07.039] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Virus-like particles (VLPs) are unable to replicate in the recipient but stimulate the immune system through recognition of repetitive subunits. Parenterally delivered rotavirus-VLP (Ro-VLP) vaccine could have the potential to overcome the weaknesses of licensed oral live-attenuated rotavirus vaccines, namely, low efficacy in low-income and high mortality settings and a potential risk of intussusception. METHODS A monovalent Ro-VLP composed of viral protein (VP) 7, VP6 and VP2 of G1 genotype specificity was produced in Nicotiana benthamiana using Agrobacterium tumefaciens infiltration-based transient recombinant expression system. Plants expressing recombinant G1 Ro-VLP were harvested, then the resultant biomass was processed through a series of clarification and purification steps including standard extraction, filtration, ultrafiltration and chromatography. The purified G1 Ro-VLP was subsequently examined for its immunogenicity and toxicological profile using animal models. RESULTS G1 Ro-VLP had a purity of ≥90% and was structurally similar to triple-layered rotavirus particles as determined by cryogenic transmission electron microscopy. Two doses of aluminum hydroxide-adjuvanted G1 Ro-VLP (1 μg, 5 μg or 30 μg), administered intramuscularly, elicited a robust homotypic neutralizing antibody response in rats. Also, rabbits administered G1 Ro-VLP (10 μg or 30 μg) four times intramuscularly with aluminum hydroxide adjuvant did not show any significant toxicity. CONCLUSIONS Plant-derived Ro-VLP composed of VP7, VP6 and VP2 structural proteins would be a plausible alternative to live-attenuated oral rotavirus vaccines currently distributed worldwide.
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Affiliation(s)
- Natsuki Kurokawa
- Mitsubishi Tanabe Pharma Corporation, 17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo 103-8405, Japan.
| | | | | | - Manon M-J Couture
- Medicago Inc., 1020 route de l'Église office 600, Québec, QC, Canada
| | - Michèle Dargis
- Medicago Inc., 1020 route de l'Église office 600, Québec, QC, Canada
| | - Sonia Trépanier
- Medicago Inc., 1020 route de l'Église office 600, Québec, QC, Canada
| | - Shigeki Hoshino
- Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
| | - Tomohiro Koike
- Mitsubishi Tanabe Pharma Corporation, Shonan Health Innovation Park, 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan
| | - Masaaki Arai
- Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan
| | - Naohisa Tsutsui
- Mitsubishi Tanabe Pharma Corporation, 17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo 103-8405, Japan
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13
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Wang Y, Li J, Liu P, Zhu F. The performance of licensed rotavirus vaccines and the development of a new generation of rotavirus vaccines: a review. Hum Vaccin Immunother 2021; 17:880-896. [PMID: 32966134 DOI: 10.1080/21645515.2020.1801071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Rotavirus, which causes acute gastroenteritis and severe diarrhea, has posed a great threat to children worldwide over the last 30 y. Since no specific drugs and therapies against rotavirus are available, vaccination is considered the most effective method of decreasing the morbidity and mortality related to rotavirus-associated gastroenteritis. To date, six rotavirus vaccines have been developed and licensed by local governments. Notably, Rotarix™ and RotaTeq™ have been recommended as universal agents against rotavirus infection by the World Health Organization; however, lower efficacies were found in less-developed and developing regions with medium and high child mortality than well-developed ones with low child mortality. For now, two promising novel vaccines, Rotavac™ and RotaSiil™ were pre-qualified by the World Health Organization in 2018. Other rotavirus vaccines in the pipeline including neonatal strain (RV3-BB) and several non-replicating rotavirus vaccines with a parenteral delivery strategy are currently undergoing investigation, with the potential to improve the performance of, and eliminate the safety concerns associated with, previous live oral rotavirus vaccines. This paper reviews the important developments in rotavirus vaccines in the last 20 y and discusses problems and challenges that require investigation in the future.
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Affiliation(s)
- Yuxiao Wang
- School of Public Health, Southeast University, Nanjing, China
| | - Jingxin Li
- Vaccine Clinical Evaluation Department, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Pei Liu
- School of Public Health, Southeast University, Nanjing, China
| | - Fengcai Zhu
- Vaccine Clinical Evaluation Department, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
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14
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Highly secretory expression of recombinant cowpea chlorotic mottle virus capsid proteins in Pichia pastoris and in-vitro encapsulation of ruthenium nanoparticles for catalysis. Protein Expr Purif 2020; 174:105679. [PMID: 32534017 DOI: 10.1016/j.pep.2020.105679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/17/2022]
Abstract
The applications of viral protein cages have expanded rapidly into the fields of bionanotechnology and materials science. However, the low-cost production of viral capsid proteins (CPs) on a large scale is always a challenge. Herein, we develop a highly efficient expression system by constructing recombinant Pichia pastoris cells as a "factory" for the secretion of soluble cowpea chlorotic mottle virus (CCMV) CPs. Under optimal induction conditions (0.9 mg/mL of methanol concentration at 30 °C for 96 h), a high yield of approximately 95 mg/L of CCMV CPs was harvested from the fermentation supernatant with CPs purity >90%, which has significantly simplified the rest of the purification process. The resultant CPs are employed to encapsulate Ruthenium (Ru) nanoparticles (NPs) via in-vitro self-assembly to prepare hybrid nanocatalyst, i.e. Ru@virus-like particles (VLPs). The catalytic activity over Ru@VLPs was evaluated by reducing 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). The results indicate that, with the protection of protein cages, Ru NPs were highly stabilized during the catalytic reaction. This results in enhanced catalytic activity (reaction rate constant k = 0.14 min-1) in comparison with unsupported citrate-stabilized Ru NPs (Ru-CA) (k = 0.08 min-1). Additionally, comparatively lower activation energy over Ru@VLPs (approximately 32 kJ/mol) than that over Ru-CA (approximately 39 kJ/mol) could be attributed to the synergistic effect between Ru NPs and some functional groups such as amino groups (-NH2) on CPs that weakened the activation barrier of 4-NP reduction. Therefore, enhanced activity and decreased activation energy over Ru@VLPs demonstrated the superiority of Ru@VLPs to unsupported Ru-CA.
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15
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Zhu J, Lu X, Li Y, Li T, Yang L, Yang K, Ji L, Lu M, Li M. A Rotavirus Virus-Like Particle Confined Palladium Nanoreactor and Its Immobilization on Graphene Oxide for Catalysis. Catal Letters 2020; 150:3542-3552. [PMID: 32421047 PMCID: PMC7223084 DOI: 10.1007/s10562-020-03252-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/03/2020] [Indexed: 12/18/2022]
Abstract
Abstract In this work, a new viral protein cage based nanoreactor was successfully constructed via encapsulating Tween 80 stabilized palladium nanoparticles (NPs) into rotavirus capsid VP2 virus-like particles (i.e. Pd@VP2). The effects of stabilizers including CTAB, SDS, Tween 80 and PVP on controlling the particle size of Pd NPs were investigated. They were further immobilized on graphene oxide (i.e. Pd@VP2/GO) by a simple mixing method. Some characterizations including FT-IR and XPS were conducted to study adsorption mode of Pd@VP2 on GO sheets. Their catalytic performance was estimated in the reduction of 4-nitrophenol (4-NP). Results showed that Tween 80 stabilized Pd NPs with the molar ratio of Pd to Tween 80 at 1:0.1 possessed the smallest size and the best stability as well. They were encapsulated into viral protein cages (mean size 49 ± 0.26 nm) to assemble confined nanoreactors, most of which contained 1-2 Pd NPs (mean size 8.15 ± 0.26 nm). As-prepared Pd@VP2 indicated an enhanced activity (apparent reaction rate constant k app = (3.74 ± 0.10) × 10-3 s-1) for the reduction of 4-NP in comparison to non-confined Pd-Tween80 colloid (k app = (2.20 ± 0.06) × 10-3 s-1). It was logically due to confinement effects of Pd@VP2 including high dispersion of Pd NPs and high effective concentration of substrates in confined space. Pd@VP2 were further immobilized on GO surface through C-N bond. Pd@VP2/GO exhibited good reusability after recycling for four runs, confirming the strong anchoring effects of GO on Pd@VP2. Graphic Abstract
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Affiliation(s)
- Jie Zhu
- 1National-Local Joint Engineering Research Center of Biomass Refining and High-Quality Utilization, Changzhou University, Changzhou, 213164 China.,2Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou, 213164 China
| | - Xiaoxue Lu
- 1National-Local Joint Engineering Research Center of Biomass Refining and High-Quality Utilization, Changzhou University, Changzhou, 213164 China
| | - Yijian Li
- 3State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, 361102 China
| | - Tingdong Li
- 3State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, 361102 China
| | - Linsong Yang
- 1National-Local Joint Engineering Research Center of Biomass Refining and High-Quality Utilization, Changzhou University, Changzhou, 213164 China
| | - Kun Yang
- 1National-Local Joint Engineering Research Center of Biomass Refining and High-Quality Utilization, Changzhou University, Changzhou, 213164 China
| | - Liang Ji
- 1National-Local Joint Engineering Research Center of Biomass Refining and High-Quality Utilization, Changzhou University, Changzhou, 213164 China
| | - Mohong Lu
- 2Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou, 213164 China
| | - Mingshi Li
- 2Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou, 213164 China
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16
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Velasquez DE, Jiang B. Evolution of P[8], P[4], and P[6] VP8* genes of human rotaviruses globally reported during 1974 and 2017: possible implications for rotavirus vaccines in development. Hum Vaccin Immunother 2019; 15:3003-3008. [PMID: 31124743 DOI: 10.1080/21645515.2019.1619400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Non-replicating parenteral rotavirus (RV) vaccine candidates are in development in an attempt to overcome the lower efficacy and effectiveness of oral RV vaccines in low-income countries. One of the leading candidates is a truncated recombinant VP8* protein, expressed in Escherichia coli from original sequences of the prototype RV genotypes P[8], P[4], or P[6] isolated before 1983. Since VP8* is highly variable, it was considered useful to examine the evolutionary changes of RV strains reported worldwide over time in relation to the three P2-VP8 vaccine strains. Here, we retrieved from the GenBank 6,366 RV VP8* gene sequences of P[8], P[4], or P[6] strains isolated between 1974 and 2017, in 77 countries, and compared them with those of the three P2-VP8 vaccine strains: Wa (USA, 1974, G1P[8]), DS-1 (USA, 1976, G2P[4]), and 1076 (Sweden, 1983, G2P[6]). Phylogenetic analysis showed that 94.9% (4,328/4,560), 99.8% (1,141/1,143), and 100% (663/663) of the P[8], P[4], and P[6] strains, respectively, reported globally between 1974 and 2018 belong to non-vaccine lineages. These P[8], P[4], and P[6] RV strains have a mean of 9%, 5%, and 6% amino acid difference from the corresponding vaccine strains. Additionally, in the USA, the mean percentage difference between all the P[8] RV strains and the original Wa strain increased over time: 4% (during 1974-1980), 5% (1988-1991), and 9% (2005-2013). Our analysis substantiated high evolutionary changes in VP8* of the P[8], P[4], and P[6] major RV strains and their increasing variations from the candidate subunit vaccine strains over time. These findings may have implications for the development of new RV vaccines.
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Affiliation(s)
- Daniel E Velasquez
- Division of Viral Diseases, Centers for Diseases Control and Prevention, Atlanta, GA, USA
| | - Baoming Jiang
- Division of Viral Diseases, Centers for Diseases Control and Prevention, Atlanta, GA, USA
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17
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Afchangi A, Jalilvand S, Mohajel N, Marashi SM, Shoja Z. Rotavirus VP6 as a potential vaccine candidate. Rev Med Virol 2019; 29:e2027. [DOI: 10.1002/rmv.2027] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Atefeh Afchangi
- Virology Department, School of Public Health; Tehran University of Medical Sciences; Tehran Iran
| | - Somayeh Jalilvand
- Virology Department, School of Public Health; Tehran University of Medical Sciences; Tehran Iran
| | - Nasir Mohajel
- Virology Department; Pasteur Institute of Iran; Tehran Iran
| | - Sayed Mahdi Marashi
- Virology Department, School of Public Health; Tehran University of Medical Sciences; Tehran Iran
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18
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Li Y, Xue M, Yu L, Luo G, Yang H, Jia L, Zeng Y, Li T, Ge S, Xia N. Expression and characterization of a novel truncated rotavirus VP4 for the development of a recombinant rotavirus vaccine. Vaccine 2018; 36:2086-2092. [DOI: 10.1016/j.vaccine.2018.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 02/27/2018] [Accepted: 03/05/2018] [Indexed: 12/28/2022]
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Abstract
Virus-like particle (VLP) technologies are based on virus-inspired artificial structures and the intrinsic ability of viral proteins to self-assemble at controlled conditions. Therefore, the basic knowledge about the mechanisms of viral particle formation is highly important for designing of industrial applications. As an alternative to genetic and chemical processes, different physical methods are frequently used for VLP construction, including well characterized protein complexes for introduction of foreign molecules in VLP structures.This chapter shortly discusses the mechanisms how the viruses form their perfectly ordered structures as well as the principles and most interesting application examples, how to exploit the structural and assembly/disassembly properties of viral structures for creation of new nanomaterials.
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Affiliation(s)
- Andris Zeltins
- Latvian Biomedical Research and Study Centre, Riga, Latvia.
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20
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Velasquez DE, Parashar U, Jiang B. Decreased performance of live attenuated, oral rotavirus vaccines in low-income settings: causes and contributing factors. Expert Rev Vaccines 2017; 17:145-161. [PMID: 29252042 DOI: 10.1080/14760584.2018.1418665] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Numerous studies have shown that the oral rotavirus vaccines are less effective in infants born in low income countries compared to those born in developed countries. Identifying the specific factors in developing countries that decrease and/or compromise the protection that rotavirus vaccines offer, could lead to a path for designing new strategies for the vaccines' improvement. AREAS COVERED We accessed PubMed to identify rotavirus vaccine performance studies (i.e., efficacy, effectiveness and immunogenicity) and correlated performance with several risk factors. Here, we review the factors that might contribute to the low vaccine efficacy, including passive transfer of maternal rotavirus antibodies, rotavirus seasonality, oral polio vaccine (OPV) administered concurrently, microbiome composition and concomitant enteric pathogens, malnutrition, environmental enteropathy, HIV, and histo blood group antigens. EXPERT COMMENTARY We highlight two major factors that compromise rotavirus vaccines' efficacy: the passive transfer of rotavirus IgG antibodies to infants and the co-administration of rotavirus vaccines with OPV. We also identify other potential risk factors that require further research because the data about their interference with the efficacy of rotavirus vaccines are inconclusive and at times conflicting.
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Affiliation(s)
- Daniel E Velasquez
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
| | - Umesh Parashar
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
| | - Baoming Jiang
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
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21
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Changotra H, Vij A. Rotavirus virus-like particles (RV-VLPs) vaccines: An update. Rev Med Virol 2017; 27. [DOI: 10.1002/rmv.1954] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/17/2017] [Accepted: 09/18/2017] [Indexed: 01/24/2023]
Affiliation(s)
- Harish Changotra
- Department of Biotechnology and Bioinformatics; Jaypee University of Information Technology; Solan Himachal Pradesh India
| | - Avni Vij
- Department of Biotechnology and Bioinformatics; Jaypee University of Information Technology; Solan Himachal Pradesh India
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22
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Blazevic V, Malm M, Arinobu D, Lappalainen S, Vesikari T. Rotavirus capsid VP6 protein acts as an adjuvant in vivo for norovirus virus-like particles in a combination vaccine. Hum Vaccin Immunother 2017; 12:740-8. [PMID: 26467630 PMCID: PMC4964741 DOI: 10.1080/21645515.2015.1099772] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Rotavirus (RV) and norovirus (NoV) are the 2 leading causes of acute viral gastroenteritis worldwide. We have developed a non-live NoV and RV vaccine candidate consisting of NoV virus-like particles (VLPs) and recombinant polymeric RV VP6 protein produced in baculovirus-insect cell expression system. Both components have been shown to induce strong potentially protective immune responses. As VP6 nanotubes are highly immunogenic, we investigated here a possible adjuvant effect of these structures on NoV-specific immune responses in vivo. BALB/c mice were immunized intramuscularly with a suboptimal dose (0.3 μg) of GII.4 or GI.3 VLPs either alone or in a combination with 10 μg dose of VP6 and induction of NoV-specific antibodies in sera of experimental animals were measured. Blocking assay using human saliva or synthetic histo-blood group antigens was employed to test NoV blocking antibodies. Suboptimal doses of the VLPs alone did not induce substantial anti-NoV antibodies. When co-administered with the VP6, considerable titers of not only type-specific but also cross-reactive IgG antibodies against NoV VLP genotypes not included in the vaccine composition were induced. Most importantly, NoV-specific blocking antibodies, a surrogate for neutralizing antibodies, were generated. Our results show that RV VP6 protein has an in vivo adjuvant effect on NoV-specific antibody responses and support the use of VP6 protein as a part of the NoV-RV combination vaccine, especially when addition of external adjuvants is not desirable.
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Affiliation(s)
- Vesna Blazevic
- a Vaccine Research Center, University of Tampere Medical School , Tampere , Finland
| | - Maria Malm
- a Vaccine Research Center, University of Tampere Medical School , Tampere , Finland
| | - Daisuke Arinobu
- b R&D Project Office, UMN Pharma Inc. , Yokohama , Kanagawa , Japan
| | - Suvi Lappalainen
- a Vaccine Research Center, University of Tampere Medical School , Tampere , Finland
| | - Timo Vesikari
- a Vaccine Research Center, University of Tampere Medical School , Tampere , Finland
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23
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Malm M, Heinimäki S, Vesikari T, Blazevic V. Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co-delivered with norovirus VLPs. Clin Exp Immunol 2017; 189:331-341. [PMID: 28407442 PMCID: PMC5543502 DOI: 10.1111/cei.12977] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2017] [Indexed: 01/19/2023] Open
Abstract
A subunit protein vaccine candidate based on norovirus (NoV) virus‐like particles (VLPs) and rotavirus (RV) VP6 protein against acute childhood gastroenteritis has been proposed recently. RV VP6 forms different oligomeric nanostructures, including tubes and spheres when expressed in vitro, which are highly immunogenic in different animal models. We have shown recently that recombinant VP6 nanotubes have an adjuvant effect on immunogenicity of NoV VLPs in mice. In this study, we investigated if the adjuvant effect is dependent upon a VP6 dose or different VP6 structural assemblies. In addition, local and systemic adjuvant effects as well as requirements for antigen co‐delivery and co‐localization were studied. The magnitude and functionality of NoV GII.4‐specific antibodies and T cell responses were tested in mice immunized with GII.4 VLPs alone or different combinations of VLPs and VP6. A VP6 dose‐dependent adjuvant effect on GII.4‐specific antibody responses was observed. The adjuvant effect was found to be strictly dependent upon co‐administration of NoV GII.4 VLPs and VP6 at the same anatomic site and at the same time. However, the adjuvant effect was not dependent on the types of oligomers used, as both nanotubes and nanospheres exerted adjuvant effect on GII.4‐specific antibody generation and, for the first time, T cell immunity. These findings elucidate the mechanisms of VP6 adjuvant effect in vivo and support its use as an adjuvant in a combination NoV and RV vaccine.
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Affiliation(s)
- M Malm
- Vaccine Research Center, University of Tampere, Tampere, Finland
| | - S Heinimäki
- Vaccine Research Center, University of Tampere, Tampere, Finland
| | - T Vesikari
- Vaccine Research Center, University of Tampere, Tampere, Finland
| | - V Blazevic
- Vaccine Research Center, University of Tampere, Tampere, Finland
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24
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Kirkwood CD, Ma LF, Carey ME, Steele AD. The rotavirus vaccine development pipeline. Vaccine 2017; 37:7328-7335. [PMID: 28396207 PMCID: PMC6892263 DOI: 10.1016/j.vaccine.2017.03.076] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/23/2017] [Indexed: 01/12/2023]
Abstract
Rotavirus disease is a leading global cause of mortality and morbidity in children under 5 years of age. The effectiveness of the two globally used oral rotavirus vaccines quickly became apparent when introduced into both developed and developing countries, with significant reductions in rotavirus-associated mortality and hospitalizations. However, the effectiveness and impact of the vaccines is reduced in developing country settings, where the burden and mortality is highest. New rotavirus vaccines, including live oral rotavirus candidates and non-replicating approaches continue to be developed, with the major aim to improve the global supply of rotavirus vaccines and for local implementation, and to improve vaccine effectiveness in developing settings. This review provides an overview of the new rotavirus vaccines in development by developing country manufacturers and provides a rationale why newer candidates continue to be explored. It describes the new live oral rotavirus vaccine candidates as well as the non-replicating rotavirus vaccines that are furthest along in development.
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Affiliation(s)
- Carl D Kirkwood
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA.
| | - Lyou-Fu Ma
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Megan E Carey
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - A Duncan Steele
- Enteric & Diarrheal Diseases, Global Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
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25
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Meier AF, Suter M, Schraner EM, Humbel BM, Tobler K, Ackermann M, Laimbacher AS. Transfer of Anti-Rotavirus Antibodies during Pregnancy and in Milk Following Maternal Vaccination with a Herpes Simplex Virus Type-1 Amplicon Vector. Int J Mol Sci 2017; 18:E431. [PMID: 28212334 PMCID: PMC5343965 DOI: 10.3390/ijms18020431] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/01/2017] [Accepted: 02/09/2017] [Indexed: 11/16/2022] Open
Abstract
Rotaviruses (RVs) are important enteric pathogens of newborn humans and animals, causing diarrhea and in rare cases death, especially in very young individuals. Rotavirus vaccines presently used are modified live vaccines that lack complete biological safety. Previous work from our laboratory suggested that vaccines based on in situ produced, non-infectious rotavirus-like particles (RVLPs) are efficient while being entirely safe. However, using either vaccine, active mucosal immunization cannot induce protective immunity in newborns due to their immature immune system. We therefore hypothesized that offspring from vaccinated dams are passively immunized either by transfer of maternal antibodies during pregnancy or by taking up antibodies from milk. Using a codon optimized polycistronic gene expression cassette packaged into herpesvirus particles, the simultaneous expression of the RV capsid genes led to the intracellular formation of RVLPs in various cell lines. Vaccinated dams developed a strong RV specific IgG antibody response determined in sera and milk of both mother and pups. Moreover, sera of naïve pups nursed by vaccinated dams also had RV specific antibodies suggesting a lactogenic transfer of antibodies. Although full protection of pups was not achieved in this mouse model, our observations are important for the development of improved vaccines against RV in humans as well as in various animal species.
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Affiliation(s)
- Anita F Meier
- Institute of Virology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
| | - Mark Suter
- Immunology Division, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
| | - Elisabeth M Schraner
- Institutes of Veterinary Anatomy and Virology, University of Zurich, 8057 Zurich, Switzerland.
| | - Bruno M Humbel
- Electron Microscopy Facility, University of Lausanne, 1015 Lausanne, Switzerland.
| | - Kurt Tobler
- Institute of Virology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
| | - Mathias Ackermann
- Institute of Virology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
| | - Andrea S Laimbacher
- Institute of Virology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
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26
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Xue M, Yu L, Jia L, Li Y, Zeng Y, Li T, Ge S, Xia N. Immunogenicity and protective efficacy of rotavirus VP8* fused to cholera toxin B subunit in a mouse model. Hum Vaccin Immunother 2016; 12:2959-2968. [PMID: 27435429 PMCID: PMC5137547 DOI: 10.1080/21645515.2016.1204501] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 06/09/2016] [Accepted: 06/17/2016] [Indexed: 12/25/2022] Open
Abstract
In attempts to develop recombinant subunit vaccines against rotavirus disease, it was previously shown that the N-terminal truncated VP8* protein, VP8-1 (aa26-231), is a good vaccine candidate when used for immunization in combination with Freund's adjuvant. However, this protein stimulated only weak immune response when aluminum hydroxide was used as an adjuvant. In this study, the nontoxic B subunit of cholera toxin (CTB) was employed as intra-molecular adjuvant to improve the immunogenicity of VP8-1. Both, the N-terminal and C-terminal fusion proteins, were purified to homogeneity, at which stage they formed pentamers, and showed significantly higher immunogenicity and protective efficacy than a VP8-1/aluminum hydroxide mixture in a mouse model. Compared to VP8-1-CTB, CTB-VP8-1 showed higher binding activity to both, GM1 and the conformation sensitive neutralizing monoclonal antibodies specific to VP8. More importantly, CTB-VP8-1 elicited higher titers of neutralizing antibodies and conferred higher protective efficacy than VP8-1-CTB. Therefore, the protein CTB-VP8-1, with enhanced immunogenicity and immunoprotectivity, could be considered as a viable candidate for further development of an alternative, replication-incompetent, parenterally administered vaccine against rotavirus disease.
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MESH Headings
- Adjuvants, Immunologic/genetics
- Adjuvants, Immunologic/metabolism
- Animals
- Antibodies, Neutralizing/blood
- Antibodies, Viral/blood
- Cholera Toxin/genetics
- Cholera Toxin/metabolism
- Disease Models, Animal
- Mice, Inbred BALB C
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/immunology
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/immunology
- Recombinant Fusion Proteins/metabolism
- Rotavirus Infections/prevention & control
- Rotavirus Vaccines/administration & dosage
- Rotavirus Vaccines/genetics
- Rotavirus Vaccines/immunology
- Vaccines, Subunit/administration & dosage
- Vaccines, Subunit/genetics
- Vaccines, Subunit/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Vaccines, Synthetic/immunology
- Viral Nonstructural Proteins/genetics
- Viral Nonstructural Proteins/immunology
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Affiliation(s)
- Miaoge Xue
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Linqi Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Lianzhi Jia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Yijian Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Yuanjun Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Tingdong Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Shengxiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen, China
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27
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Pan XX, Zhao BX, Teng YM, Xia WY, Wang J, Li XF, Liao GY, Yang C, Chen YD. Immunoreactivity of chimeric proteins carrying poliovirus epitopes on the VP6 of rotavirus as a vector. Mol Biol 2016. [DOI: 10.1134/s0026893316030092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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28
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Li JT, Wei J, Guo HX, Han JB, Ye N, He HY, Yu TT, Wu YZ. Development of a human rotavirus induced diarrhea model in Chinese mini-pigs. World J Gastroenterol 2016; 22:7135-7145. [PMID: 27610023 PMCID: PMC4988310 DOI: 10.3748/wjg.v22.i31.7135] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/26/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a new animal model for the research of human rotavirus (HRV) infection, its pathogenesis and immunity and evaluation of potential vaccines.
METHODS: 5-d, 30-d and 60-d-old Chinese mini-pigs, Guizhou and Bamma, were inoculated with a single oral dose of attenuated strain Wa, G1, G3 of HRV, and PBS (control), respectively, and fecal samples of pigs from 0 to 7 d post infection (DPI) were collected individually. Enzyme linked immunosorbent assay was used to detect HRV antigen in feces. The HRV was tested by real-time PCR (RT-PCR). The sections of the intestinal tissue were stained with hematoxylin and eosin to observe the morphologic variation by microscopy. Immunofluorescence was used to determine the HRV in intestinal tissue. HRV particles in cells of the ileum were observed by electron micrography.
RESULTS: When inoculated with HRV, mini-pigs younger than 30 d developed diarrhea in an age-dependent manner and shed HRV antigen of the same inoculum, as demonstrated by RT-PCR. Histopathological changes were observed in HRV inoculated mini-pigs including small intestinal cell tumefaction and necrosis. HRV that was distributed in the small intestine was restricted to the top part of the villi on the internal wall of the ileum, which was observed by immunofluorescence and transmission electron microscopy. Virus particles were observed in Golgi like follicles in HRV-infected neonatal mini-pigs. Guizhou mini-pigs were more sensitive to HRV than Bamma with respect to RV antigen shedding and clinical diarrhea.
CONCLUSION: These results indicate that we have established a mini-pig model of HRV induced diarrhea. Our findings are useful for the understanding of the pathogenic mechanisms of HRV infection.
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29
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Simple and efficient ultrafiltration method for purification of rotavirus VP6 oligomeric proteins. Arch Virol 2016; 161:3219-23. [DOI: 10.1007/s00705-016-2991-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 07/17/2016] [Indexed: 02/01/2023]
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30
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Scalable chromatography-based purification of virus-like particle carrier for epitope based influenza A vaccine produced in Escherichia coli. J Virol Methods 2016; 232:8-11. [DOI: 10.1016/j.jviromet.2016.02.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/14/2016] [Accepted: 02/18/2016] [Indexed: 01/06/2023]
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31
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López-Sagaseta J, Malito E, Rappuoli R, Bottomley MJ. Self-assembling protein nanoparticles in the design of vaccines. Comput Struct Biotechnol J 2015; 14:58-68. [PMID: 26862374 PMCID: PMC4706605 DOI: 10.1016/j.csbj.2015.11.001] [Citation(s) in RCA: 263] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 11/10/2015] [Indexed: 01/09/2023] Open
Abstract
For over 100 years, vaccines have been one of the most effective medical interventions for reducing infectious disease, and are estimated to save millions of lives globally each year. Nevertheless, many diseases are not yet preventable by vaccination. This large unmet medical need demands further research and the development of novel vaccines with high efficacy and safety. Compared to the 19th and early 20th century vaccines that were made of killed, inactivated, or live-attenuated pathogens, modern vaccines containing isolated, highly purified antigenic protein subunits are safer but tend to induce lower levels of protective immunity. One strategy to overcome the latter is to design antigen nanoparticles: assemblies of polypeptides that present multiple copies of subunit antigens in well-ordered arrays with defined orientations that can potentially mimic the repetitiveness, geometry, size, and shape of the natural host-pathogen surface interactions. Such nanoparticles offer a collective strength of multiple binding sites (avidity) and can provide improved antigen stability and immunogenicity. Several exciting advances have emerged lately, including preclinical evidence that this strategy may be applicable for the development of innovative new vaccines, for example, protecting against influenza, human immunodeficiency virus, and respiratory syncytial virus. Here, we provide a concise review of a critical selection of data that demonstrate the potential of this field. In addition, we highlight how the use of self-assembling protein nanoparticles can be effectively combined with the emerging discipline of structural vaccinology for maximum impact in the rational design of vaccine antigens.
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Affiliation(s)
| | - Enrico Malito
- GlaxoSmithKline Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy
| | - Rino Rappuoli
- GlaxoSmithKline Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy
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32
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Zhao B, Pan X, Teng Y, Xia W, Wang J, Wen Y, Chen Y. Rotavirus VP7 epitope chimeric proteins elicit cross-immunoreactivity in guinea pigs. Virol Sin 2015; 30:363-70. [PMID: 26459269 PMCID: PMC8200902 DOI: 10.1007/s12250-015-3620-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/28/2015] [Indexed: 10/23/2022] Open
Abstract
VP7 of group A rotavirus (RVA) contains major neutralizing epitopes. Using the antigenic protein VP6 as the vector, chimeric proteins carrying foreign epitopes have been shown to possess good immunoreactivity and immunogenicity. In the present study, using modified VP6 as the vector, three chimeric proteins carrying epitopes derived from VP7 of RVA were constructed. The results showed that the chimeric proteins reacted with anti-VP6 and with SA11 and Wa virus strains. Antibodies from guinea pigs inoculated with the chimeric proteins recognized VP6 and VP7 of RVA and protected mammalian cells from SA11 and Wa infection in vitro. The neutralizing activities of the antibodies against the chimeric proteins were significantly higher than those against the vector protein VP6F. Thus, development of chimeric vaccines carrying VP7 epitopes using VP6 as a vector could be a promising alternative to enhance immunization against RVAs.
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Affiliation(s)
- Bingxin Zhao
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Xiaoxia Pan
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming, 650500, China
| | - Yumei Teng
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Wenyue Xia
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Jing Wang
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Yuling Wen
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Yuanding Chen
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China.
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Rodrigues AF, Soares HR, Guerreiro MR, Alves PM, Coroadinha AS. Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology. Biotechnol J 2015. [PMID: 26212697 PMCID: PMC7161866 DOI: 10.1002/biot.201400387] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus‐like particles, vectored vaccines and chimeric vaccines requires the use – and often the development – of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture.
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Affiliation(s)
- Ana F Rodrigues
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
| | - Hugo R Soares
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.,Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Miguel R Guerreiro
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.,Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Paula M Alves
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.,Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Ana S Coroadinha
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal. .,Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
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34
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Jalilvand S, Marashi SM, Shoja Z. Rotavirus VP6 preparations as a non-replicating vaccine candidates. Vaccine 2015; 33:3281-7. [PMID: 26021725 DOI: 10.1016/j.vaccine.2015.05.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/05/2015] [Accepted: 05/13/2015] [Indexed: 01/03/2023]
Abstract
Rotavirus (RV) structural proteins VP4 and VP7, located on the surface of viral particles, elicit neutralizing antibodies (Abs) and are therefore considered to be important components of RV vaccines. However, despite inducing neutralizing Abs, limits of cross-neutralizing activity and lack of full correlation with protection limit the usefulness of these proteins as protective agents against RV disease. VP6 protein, which forms the middle layer of RV particles, is discussed as an alternative vaccine candidate since it can induce cross-protective immune responses against different RV strains although the Ab raised is not neutralizing. This report reviews different functions of VP6 that can lead to considering it as an alternative vaccine against RV disease.
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Affiliation(s)
- Somayeh Jalilvand
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed Mahdi Marashi
- Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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35
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Effio CL, Hubbuch J. Next generation vaccines and vectors: Designing downstream processes for recombinant protein-based virus-like particles. Biotechnol J 2015; 10:715-27. [PMID: 25880158 DOI: 10.1002/biot.201400392] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 02/11/2015] [Accepted: 03/19/2015] [Indexed: 12/28/2022]
Abstract
In recent years, the development of novel recombinant virus-like particles (VLPs) has been generating new perspectives for the prevention of untreated and arising infectious diseases. However, cost-reduction and acceleration of manufacturing processes for VLP-based vaccines or vectors are key challenges for the global health system. In particular, the design of rapid and cost-efficient purification processes is a critical bottleneck. In this review, we describe and evaluate new concepts, development strategies and unit operations for the downstream processing of VLPs. A special focus is placed on purity requirements and current trends, as well as chances and limitations of novel technologies. The discussed methods and case studies demonstrate the advances and remaining challenges in both rational process development and purification tools for large biomolecules. The potential of a new era of VLP-based products is highlighted by the progress of various VLPs in clinical phases.
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Affiliation(s)
- Christopher Ladd Effio
- Karlsruhe Institute of Technology, Institute of Process Engineering in Life Sciences, Section IV: Biomolecular Separation Engineering, Karlsruhe, Germany
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36
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Xue M, Yu L, Che Y, Lin H, Zeng Y, Fang M, Li T, Ge S, Xia N. Characterization and protective efficacy in an animal model of a novel truncated rotavirus VP8 subunit parenteral vaccine candidate. Vaccine 2015; 33:2606-13. [PMID: 25882173 DOI: 10.1016/j.vaccine.2015.03.068] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 03/14/2015] [Accepted: 03/23/2015] [Indexed: 11/17/2022]
Abstract
The cell-attachment protein VP8* of rotavirus is a potential candidate parenteral vaccine. However, the yield of full-length VP8 protein (VP8*, residues 1-231) expressed in Escherichia coli was low, and a truncated VP8 protein (ΔVP8*, residues 65-231) cannot elicit efficient protective immunity in a mouse model. In this study, tow novel truncated VP8 proteins, VP8-1 (residues 26-231) and VP8-2 (residues 51-231), were expressed in E. coli and evaluated for immunogenicity and protective efficacy, compared with VP8* and ΔVP8*. As well as ΔVP8*, the protein VP8-1 and VP8-2 were successfully expressed in high yield and purified in homogeneous dimeric forms, while the protein VP8* was expressed with lower yield and prone to aggregation and degradation in solution. Although the immunogenicity of the protein VP8*, VP8-1, VP8-2 and ΔVP8* was comparable, immunization of VP8* and VP8-1 elicited significantly higher neutralizing antibody titers than that of VP8-2 and ΔVP8* in mice. Furthermore, when assessed using a mouse maternal antibody model, the efficacy of VP8-1 to protect against rotavirus-induced diarrhea in pups was comparable to that of VP8*, both were dramatically higher than that of VP8-2 and ΔVP8*. Taken together, the novel truncated protein VP8-1, with increased yield, improved homogeneity and high protective efficacy, is a viable candidate for further development of a parenterally administrated prophylactic vaccine against rotavirus infection.
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MESH Headings
- Animals
- Antibodies, Neutralizing/blood
- Antibodies, Viral/blood
- Diarrhea/prevention & control
- Disease Models, Animal
- Escherichia coli/genetics
- Female
- Immunity, Maternally-Acquired
- Injections, Subcutaneous
- Mice, Inbred BALB C
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/immunology
- Rotavirus/immunology
- Rotavirus Infections/prevention & control
- Rotavirus Vaccines/administration & dosage
- Rotavirus Vaccines/immunology
- Vaccines, Subunit/administration & dosage
- Vaccines, Subunit/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/immunology
- Viral Nonstructural Proteins/genetics
- Viral Nonstructural Proteins/immunology
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Affiliation(s)
- Miaoge Xue
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Linqi Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China; School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Yaojian Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Haijun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Yuanjun Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Mujin Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China; School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Tingdong Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China; School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China.
| | - Shengxiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China; School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China.
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, PR China; School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
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