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Published on: June 25, 2015
Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates
Jong R Kim1, Beth C Holbrook1, Sarah L Hayward1
1Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Insights
Flagellin enhances infant influenza vaccine responses. This adjuvant improved antibody and T cell immunity, and reduced lung disease in a neonatal primate model, offering hope for vulnerable infants.
Area of Science:
- Immunology
- Vaccinology
- Virology
Background:
- Infants under 6 months are highly susceptible to severe influenza infections.
- Current influenza vaccines are not approved for infants due to weak immune responses.
- There is a critical need for effective influenza vaccines for this population.
Purpose of the Study:
- To evaluate flagellin as an adjuvant for influenza vaccines in a neonatal nonhuman primate model.
- To assess the impact of flagellin on immune responses and protection against influenza in young infants.
Main Methods:
- Established a neonatal African green monkey (AGM) model.
- Vaccinated 4- to 6-day-old AGMs with inactivated PR8 influenza virus (IPR8) plus either wild-type flagellin or inactive mutant flagellin (m229).
- Assessed antibody (IgG) and T cell responses post-vaccination and post-challenge, along with lung pathology.
Main Results:
- Flagellin-adjuvanted IPR8 induced higher IgG responses after boost and early post-challenge.
- Significantly more influenza virus-specific T cells were observed in flagellin-vaccinated infants post-challenge.
- Vaccination with IPR8 plus flagellin led to reduced lung pathology after influenza challenge.
Conclusions:
- Flagellin acts as an effective adjuvant, enhancing both humoral and cellular immune responses to influenza vaccination in neonatal nonhuman primates.
- These findings support flagellin's potential as a key component in developing improved influenza vaccines for young infants.
- This study validates a novel neonatal primate model for evaluating infant vaccine strategies.
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.
