title: Inclusion of a universal tetanus toxoid CD4(+) T cell epitope P2 significantly enhanced the immunogenicity of recombinant rotavirus ΔVP8* subunit parenteral vaccines.
abstract: Currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]ΔVP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4(+) T cell epitope P2 was introduced into P[8] or P[6]ΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 μg/dose) of the P2-P[8]ΔVP8* vaccine or P2-P[6]ΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]ΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 μg/dose) of the P2-P[8]ΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P[8]) strain. The P2-P[8]ΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4(+) T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance.
authors: Rotavirus Vaccine Development Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
authors: Xiaobo
authors: X
authors: Wen
authors: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Integrated Life Science Building, Blacksburg, VA 24061, United States.
authors: Ke
authors: K
authors: Wen
authors: Rotavirus Vaccine Development Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Integrated Life Science Building, Blacksburg, VA 24061, United States.
authors: Dianjun
authors: D
authors: Cao
authors: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Integrated Life Science Building, Blacksburg, VA 24061, United States.
authors: Guohua
authors: G
authors: Li
authors: Rotavirus Vaccine Development Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
authors: Ronald W
authors: RW
authors: Jones
authors: Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
authors: Jianping
authors: J
authors: Li
authors: Laboratory of Developmental and Molecular Immunity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
authors: Shousun
authors: S
authors: Szu
authors: Rotavirus Vaccine Development Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States. Electronic address: thoshino@niaid.nih.gov.
authors: Yasutaka
authors: Y
authors: Hoshino
authors: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Integrated Life Science Building, Blacksburg, VA 24061, United States. Electronic address: lyuan@vt.edu.
authors: Lijuan
authors: L
authors: Yuan
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D017607:Aluminum Compounds / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003967:Diarrhea / Q000276:immunology / Q000517:prevention & control; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D007074:Immunoglobulin G / Q000097:blood; D007273:Injections, Intramuscular; D010710:Phosphates / Q000008:administration & dosage; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012400:Rotavirus Infections / Q000276:immunology / Q000517:prevention & control*; D022243:Rotavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013552:Swine; D013745:Tetanus Toxoid / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D010710:Phosphates; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D022243:Rotavirus Vaccines; D013745:Tetanus Toxoid; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D017361:Viral Nonstructural Proteins; C079234:NS35 protein, rotavirus; C012714:aluminum phosphate
keywords: Diarrhea; Gnotobiotic pigs; Human rotavirus; Immunogenicity; Protective efficacy; Subunit vaccine; T cell epitope