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 6 months. 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 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.

A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity

“…For example, nucleotide-binding oligomerization domain (NOD)-like receptor-mediated IL-1β production is greater in human newborn cord than adult peripheral blood (43, 44) and slowly decreases to adult levels over the first years of life (45). A similar phenomenon for basal PGE 2 levels in WB has been observed (32). Therefore, further study of the IL-1β/PGE 2 axis as a predictive marker of vaccine reactogenicity may need to take ontogeny into account.…”

“…We have previously demonstrated that several of these licensed vaccines, such as the EasyFive (DTwP-HepB-Hib), induce distinct reactogenicity biomarker profiles in vitro (31, 32). When tested at equivalent v/v treatment concentrations, Δ lpxLI nOMV conversely induced a lower cytokine response for most innate cytokines (Figures 4A,B) and chemokines (Figure S7 in Supplementary Material) tested, grouping closer to pediatric vaccines such as PCV13 and HBV, than the more inflammatory (Alum + TLR agonist)-containing pediatric vaccines (i.e., PedvaxHIB and EasyFive).…”

Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus–Specific CD8+ T Cell Immunodominance Hierarchy in Neonates

“…This is consistent with published data evaluating DCs and other APC in cord blood and from other neonatal murine models suggesting that more robust responses can predominate if distinct or multiple TLR agonists are engaged (53, 54). Further research is necessary to understand the checkpoints that must be met through TLR activation to both recruit cDCs into peripheral tissues and further induce their expression of co-stimulatory molecules as our data and that of others suggests that these signaling pathways are not comparably activated between adults and neonates (55). …”

Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model

“…As such, TLR2 could serve as a target for therapeutic treatment of allergic asthma [13][14][15]. Moreover, the TLR2 agonist Pam 3 CSK 4 exhibits unique immunomodulatory properties, characterized by the capacity to induce robust cytokine production by naive CD4+ T lymphocytes (both IL-10 and IFN-γ) [16][17][18][19]. In a murine asthma model, Pam 3 CSK 4 treatment improved allergic hyper-responsiveness within the airways (AHR).…”