Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in non-human primates Authors

Toll-like receptor ligands (TLR-L) represent novel vaccine adjuvants, but their immunological effects in humans in-vivo remain poorly defined. Here we analyzed the innate responses stimulated by different TLR-L in rhesus macaques, a relevant preclinical model for vaccine testing. MPL (TLR4-L), R-848 (TLR7/8-L) or CpG-ODN (TLR9-L) induced rapid (3hr) and robust (>92% of WBC) expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-L induced rapid (3-8hr) expansion of CD14 + monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14 + CD16 + and CD14 dim CD16 ++ monocytes; and only TLR7/8-L and 9-L induced activation of myeloid (mDC) and plasmacytoid DC (pDC), production of IP-10 and type-I IFN and expression of type-I IFN-related and chemokine genes in the blood. In the draining LN, consistent with the effects in blood, all TLR-L induced expansion of CD14 + monocytes but only TLR7/8-L and TLR9-L expanded the activated CD14 + CD16 + cells. TLR4-L and TLR9-L differentially induced expansion of mDCs and pDCs (1-3d), but no DC activation. In contrast, TLR7/8-L induced no DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced expression of genes related to chemokines and type-I IFNs in LN. Thus different TLR-L mediate distinct signatures of early innate responses, locally and systemically.