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Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates.

AbstractUNLABELLED:
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.
IMPORTANCE:
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.
AuthorsJong R Kim, Beth C Holbrook, Sarah L Hayward, Lance K Blevins, Matthew J Jorgensen, Nancy D Kock, Kristina De Paris, Ralph B D'Agostino Jr, S Tyler Aycock, Steven B Mizel, Griffith D Parks, Martha A Alexander-Miller
JournalJournal of virology (J Virol) Vol. 89 Issue 14 Pg. 7291-303 (Jul 2015) ISSN: 1098-5514 [Electronic] United States
PMID25948746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015, American Society for Microbiology. All Rights Reserved.
Chemical References
  • Adjuvants, Immunologic
  • Antibodies, Viral
  • Immunoglobulin G
  • Influenza Vaccines
  • Vaccines, Inactivated
  • Flagellin
Topics
  • Adjuvants, Immunologic (administration & dosage)
  • Animals
  • Animals, Newborn
  • Antibodies, Viral (blood)
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Flagellin (administration & dosage)
  • Immunoglobulin G (blood)
  • Influenza Vaccines (administration & dosage, immunology)
  • Orthomyxoviridae Infections (immunology, prevention & control)
  • T-Lymphocytes (immunology)
  • Vaccination (methods)
  • Vaccines, Inactivated (administration & dosage, immunology)

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