Abstract | UNLABELLED: 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.
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Authors | Jong 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 |
Journal | Journal of virology
(J Virol)
Vol. 89
Issue 14
Pg. 7291-303
(Jul 2015)
ISSN: 1098-5514 [Electronic] United States |
PMID | 25948746
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015, American Society for Microbiology. All Rights Reserved. |
Chemical References |
- Adjuvants, Immunologic
- Antibodies, Viral
- Immunoglobulin G
- Influenza Vaccines
- Vaccines, Inactivated
- Flagellin
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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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