title: The level of protection against rotavirus shedding in mice following immunization with a chimeric VP6 protein is dependent on the route and the coadministered adjuvant.
abstract: Intranasal (i.n.) immunization of BALB/c mice with chimeric murine rotavirus EDIM (epizootic diarrhea of infant mice) VP6 and attenuated E. coli heat-labile toxin (LT), LT(R192G), stimulated >99% protection against rotavirus shedding after EDIM challenge. Here, we evaluated other potential adjuvants with chimeric VP6 administered by two mucosal routes: i.n. and oral. Besides LT(R192G), the adjuvants examined included Adjumer, CpG oligodeoxynucleotides (CpG ODN), chimeric A1 subunit of cholera toxin (CTA1)-DD, and QS-21. All except QS-21 significantly (P<0.05) increased VP6-specific serum IgG responses after i.n. immunization, but none significantly increased these responses when administered orally. The i.n. delivery of chimeric VP6 alone induced both rotavirus IgG1 and IgG2a whose relative titers suggested a skewed Th2-like response. Inclusion of Adjumer greatly increased Th2-like responses, while CpG ODN shifted the response to a less Th2-like response. The adjuvants CTA1-DD, LT(R192G), QS-21 had no significant effect on ratios of IgG1/IgG2a titers. Following EDIM challenge of mice immunized i.n. with chimeric VP6 and either LT(R192G), CTA1-DD, Adjumer or CpG ODN, shedding was reduced >99, 95, 80, 74, respectively, relative to that found in unimmunized mice (P<0.05). QS-21 induced less protection (43%, not significant (N.S.)) while immunization with chimeric VP6 alone reduced shedding by only 16% (N.S.). Oral immunization with chimeric VP6 and all selected adjuvants except QS-21 was less effective than after i.n. immunization, with protection levels of 94 (P<0.05), 71 (P<0.05), 55, 35 and 28% for LT(R192G), QS-21, CpG ODN, CTA1-DD, and Adjumer, respectively, while immunization with chimeric VP6 alone gave no protection. Thus, different adjuvants induced different degrees of protection and oral immunization was generally less effective then the i.n. route.
authors.affiliation: Division of Infectious Diseases, Children's Hospital Medical Center, The Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. anthony.choi@chmcc.org
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Choi
authors.forename: Monica M
authors.initials: MM
authors.lastname: McNeal
authors.forename: Jason A
authors.initials: JA
authors.lastname: Flint
authors.forename: Mitali
authors.initials: M
authors.lastname: Basu
authors.forename: Nils Y
authors.initials: NY
authors.lastname: Lycke
authors.forename: John D
authors.initials: JD
authors.lastname: Clements
authors.forename: Judy A
authors.initials: JA
authors.lastname: Bean
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCluskie
authors.forename: John L
authors.initials: JL
authors.lastname: VanCott
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ward
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000956:Antigens, Viral; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology; D002213:Capsid / Q000276:immunology*; D036022:Capsid Proteins; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D029968:Escherichia coli Proteins; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D012401:Rotavirus / Q000276:immunology* / Q000302:isolation & purification; D012400:Rotavirus Infections / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D001427:Bacterial Toxins; C408982:CPG-oligonucleotide; C440610:CTA1-DD protein, recombinant; D036022:Capsid Proteins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; C061332:VP6 protein, Rotavirus; D014765:Viral Vaccines; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli