title: Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates.
abstract: Influenza virus can cause life-threatening infections in neonates and young infants. Although vaccination is a major countermeasure against influenza, current vaccines are not approved for use in infants less than 6 months of age, in part due to the weak immune response following vaccination. Thus, there is a strong need to develop new vaccines with improved efficacy for this vulnerable population. To address this issue, we established a neonatal African green monkey (AGM) nonhuman primate model that could be used to identify effective influenza vaccine approaches for use in young infants. We assessed the ability of flagellin, a Toll-like receptor 5 (TLR5) agonist, to serve as an effective adjuvant in this at-risk population. Four- to 6-day-old AGMs were primed and boosted with inactivated PR8 influenza virus (IPR8) adjuvanted with either wild-type flagellin or inactive flagellin with a mutation at position 229 (m229), the latter of which is incapable of signaling through TLR5. Increased IgG responses were observed following a boost, as well as at early times after challenge, in infants vaccinated with flagellin-adjuvanted IPR8. Inclusion of flagellin during vaccination also resulted in a significantly increased number of influenza virus-specific T cells following challenge compared to the number in infants vaccinated with the m229 adjuvant. Finally, following challenge infants vaccinated with IPR8 plus flagellin exhibited a reduced pathology in the lungs compared to that in infants that received IPR8 plus m229. This study provides the first evidence of flagellin-mediated enhancement of vaccine responses in nonhuman primate neonates.
  
  
  OBJECTIVE
  Young infants are particularly susceptible to severe disease as a result of influenza virus infection. Compounding this is the lack of effective vaccines for use in this vulnerable population. Here we describe a vaccine approach that results in improved immune responses and protection in young infants. Incorporation of flagellin during vaccination resulted in increased antibody and T cell responses together with reduced disease following virus infection. These results suggest that flagellin may serve as an effective adjuvant for vaccines targeted to this vulnerable population.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Jong R
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Beth C
authors.initials: BC
authors.lastname: Holbrook
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hayward
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Lance K
authors.initials: LK
authors.lastname: Blevins
authors.affiliation: Department of Pathology, Section of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Jorgensen
authors.affiliation: Department of Pathology, Section of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: De Paris
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: D'Agostino
authors.affiliation: Animal Resources Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: S Tyler
authors.initials: ST
authors.lastname: Aycock
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Mizel
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Griffith D
authors.initials: GD
authors.lastname: Parks
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA marthaam@wakehealth.edu.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Alexander-Miller
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral / Q000097:blood; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005408:Flagellin / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000097:blood; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated; D005408:Flagellin