title: Mice develop effective but delayed protective immune responses when immunized as neonates either intranasally with nonliving VP6/LT(R192G) or orally with live rhesus rotavirus vaccine candidates.
abstract: Rotavirus vaccines are delivered early in life, when the immune system is immature. To determine the effects of immaturity on responses to candidate vaccines, neonatal (7 days old) and adult mice were immunized with single doses of either Escherichia coli-expressed rotavirus VP6 protein and the adjuvant LT(R192G) or live rhesus rotavirus (RRV), and protection against fecal rotavirus shedding following challenge with the murine rotavirus strain EDIM was determined. Neonatal mice immunized intranasally with VP6/LT(R192G) were unprotected at 10 days postimmunization (dpi) and had no detectable rotavirus B-cell (antibody) or CD4(+) CD8(+) T-cell (rotavirus-inducible, Th1 [gamma interferon and interleukin-2 {IL-2}]-, Th2 [IL-5 and IL-4]-, or ThIL-17 [IL-17]-producing spleen cells) responses. However, by 28 and 42 dpi, these mice were significantly (P >or= 0.003) protected and contained memory rotavirus-specific T cells but produced no rotavirus antibody. In contrast, adult mice were nearly fully protected by 10 dpi and contained both rotavirus immunoglobulin G and memory T cells. Neonates immunized orally with RRV were also less protected (P=0.01) than adult mice by 10 dpi and produced correspondingly less rotavirus antibody. Both groups contained few rotavirus-specific memory T cells. Protection levels by 28 dpi for neonates or adults were equal, as were rotavirus antibody levels. This report introduces a neonatal mouse model for active protection studies with rotavirus vaccines. It indicates that, with time, neonatal mice develop full protection after intranasal immunization with VP6/LT(R192G) or oral immunization with a live heterologous rotavirus and supports reports that protection depends on CD4(+) T cells or antibody, respectively.
authors.affiliation: Division of Infectious Diseases and Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: VanCott
authors.forename: Anne E
authors.initials: AE
authors.lastname: Prada
authors.forename: Monica M
authors.initials: MM
authors.lastname: McNeal
authors.forename: Susan C
authors.initials: SC
authors.lastname: Stone
authors.forename: Mitali
authors.initials: M
authors.lastname: Basu
authors.forename: Bert
authors.initials: B
authors.lastname: Huffer
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Smiley
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Shao
authors.forename: Judy A
authors.initials: JA
authors.lastname: Bean
authors.forename: John D
authors.initials: JD
authors.lastname: Clements
authors.forename: Anthony H-C
authors.initials: AH
authors.lastname: Choi
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; D000831:Animals, Newborn; D000956:Antigens, Viral / Q000008:administration & dosage / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000008:administration & dosage / Q000276:immunology*; D002478:Cells, Cultured; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051381:Rats; D012401:Rotavirus / Q000276:immunology*; D022243:Rotavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000956:Antigens, Viral; D001427:Bacterial Toxins; D036022:Capsid Proteins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022243:Rotavirus Vaccines; C061332:VP6 protein, Rotavirus; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated; C052014:rhesus rotavirus vaccine; C027538:heat-labile enterotoxin, E coli