Nonhuman primate infants have an impaired respiratory but not systemic IgG antibody response following influenza virus infection

Holbrook, Beth C.; Hayward, Sarah L.; Blevins, Lance K.; Kock, Nancy D.; Aycock, Tyler; Parks, Griffith D.; Alexander-Miller, Martha A.

doi:10.1016/j.virol.2014.12.007

Cited by 20 publications

(37 citation statements)

References 45 publications

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“…The selection of R848 was made based on the potential to stimulate DC, B cells, and T cells (34, 47–50) as well as to suppress T regulatory cells (through TLR8) (35). The last is of particular interest given reports showing increased function and/or differentiation of T regulatory cells in neonates (26, 27, 51). Further, while TLR responsiveness is impaired in neonates, in myeloid neonate derived DC there is evidence that TLR8 responsiveness is less diminished than that of TLR7 (34).…”

Section: Discussionmentioning

confidence: 99%

“…Further, there are data in mice (15–18), human cord blood (19), and nonhuman primates (our unpublished data) showing a propensity for differentiation of CD4 + T cells into Th2 cells. Finally, in human neonates there is evidence supporting a generalized defect in T cell responsiveness (14, 20–25) as well as a heightened T reg response (26, 27). …”

Section: Introductionmentioning

confidence: 99%

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A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

Holbrook

Kim

Blevins

et al. 2016

The Journal of Immunology

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Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. Here we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist (R848) conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design as it provides multiple antigenic targets allowing for elicitation of a broad immune response. Our results show that this vaccine induces high level virus-specific antibody and cell mediated responses in neonates that result in increased virus clearance and reduced lung pathology following challenge compared to the non-adjuvanted virus vaccine. Surprisingly, the addition of a second TLR agonist (flagellin) did not enhance vaccine protection, suggesting combinations of TLR that provide increased efficacy must be determined empirically. These data support further exploration of this new conjugate influenza vaccine approach as a platform for use in the at-risk neonate population.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

Holbrook

Kim

Blevins

et al. 2016

The Journal of Immunology

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“…Holbrook et al studied antibody responses in infant African green monkeys (AGM) infected with influenza [38]. They found similar systemic influenza-specific IgG responses in infants and adults, yet infants had lower influenza-specific IgG and demonstrated less neutralizing activity in upper respiratory tract secretions.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, while adult AGM showed robust generation of bronchus associated lymphoid tissue (BALT) following infection, infants demonstrated a near absence of these tertiary lymphoid tissues. This may be due to increased levels of Tregs, which may inhibit BALT formation, in the lungs of AGM infants[38]. Further studies on the dynamics of immune responses in the lung specifically will help elucidate potential mechanisms of suppression, and may suggest approaches for generating local immune responses to effectively counter respiratory pathogens.…”

Section: Introductionmentioning

confidence: 99%

Determinants of early life immune responses to RSV infection

Ruckwardt

Morabito

Graham

2016

Current Opinion in Virology

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Respiratory syncytial virus causes significant morbidity and mortality in both developed and developing countries, and a vaccine that adequately protects from severe disease remains an important unmet need. RSV disease has an inordinate impact on the very young, and the physical and immunological immaturity of early life complicates vaccine design. Defining and targeting the functional capacities of early life immune responses and controlling responses during primary antigen exposure with selected vaccine delivery approaches will be important for protecting infants by active immunization. Alternatively, vaccination of older children and pregnant mothers may ameliorate disease burden indirectly until infants reach about six months of age,when they can generate more effective anti-RSV immune responses.

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“…In addition, survival of plasmablasts and differentiation into long-lived antibody-secreting cells in the neonate are likely hampered by decreased levels of APRIL (27). Finally, neonates appear to have increases in regulatory B and T cell populations (28)(29)(30)(31)(32).…”

mentioning

confidence: 99%

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

Kim

Holbrook

Hayward

et al. 2015

J Virol

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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. Influenza virus remains one of the leading causes of morbidity and mortality worldwide. Infants less than 6 months of age are particularly vulnerable to development of severe disease following infection (1). Diseases associated with influenza virus infection in children include otitis media, pneumonia, myositis, and croup. While oseltamivir (Tamiflu), one of the two FDA-approved antiinfluenza drugs, can be used in infants aged 2 weeks and older, concerns exist due to the potential for adverse effects, drug resistance, and limited effectiveness in young infants (2).Currently, there are three approved approaches for vaccination against influenza in the United States: intramuscular (i.m.) administration of inactivated influenza virus, intramuscular administration of recombinant hemagglutinin (HA) proteins, and intranasal administration of a live attenuated influenza virus (LAIV). The first is approved for use in individuals aged 6 months and older, the second for use in individuals aged 18 to 49 years, and the last for use in healthy individuals aged 2 to 49 years. Thus, none are approved for use in the vulnerable neonate population. While the lack of approval for the use of these vaccines in the very young may reflect some safety concerns, a principal factor is the poor immune responses elicited in human neonates (3,4).Previous studies, while limited, have shown that an initia...

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Nonhuman primate infants have an impaired respiratory but not systemic IgG antibody response following influenza virus infection

Cited by 20 publications

References 45 publications

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

Determinants of early life immune responses to RSV infection

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

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