title: In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant.
abstract: Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1β, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than in infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines.
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Precision Vaccines Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Simon D
authors.initials: SD
authors.lastname: van Haren
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Ganapathi
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Children's Hospital Primary Care Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Banks
authors.affiliation: Precision Vaccines Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Children's Hospital Primary Care Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Samuels
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue, Suite 400, Seattle, WA 98102, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Vaccine Platform Group, MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marshall
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Precision Vaccines Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: ofer.levy@childrens.harvard.edu.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000375:Aging / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors
keywords: Adjuvant; Immune ontogeny; Infant; Neonate; Newborn; Toll-like receptor (TLR)