MPL Adjuvant Contains Competitive Antagonists of Human TLR4

Abstract

Monophosphoryl lipid A (MPL ®) is the first non-alum vaccine adjuvant to achieve widespread clinical and market acceptance, a remarkable achievement given that it is manufactured from a Salmonella enterica endotoxin. To understand how MPL ® successfully balanced the dual mandate of vaccine design-low reactogenicity with high efficacy-clinical-and research-grade MPL was evaluated in human and mouse cell systems. Stimulatory dose response curves revealed that most preparations of MPL are much more active in mouse than in human cell systems, and that the limited efficacy observed in human cells correlated with TLR4 inhibitory activity that resulted in a partial agonist profile. Further analysis of the major components of MPL ® adjuvant prepared synthetically identified two structural variants that functioned as competitive antagonists of human TLR4. A partial agonist profile could be recapitulated and manipulated by spiking synthetic agonists with synthetic antagonists to achieve a broad dose range over which TLR4 stimulation could be constrained below a desired threshold. This report thus identifies mixed agonist-antagonist activity as an additional mechanism by which MPL ® adjuvant is detoxified, relative to its parental LPS, to render it safe for use in prophylactic vaccines.

Distinct single-component adjuvants steer human DC-mediated T-cell polarization via Toll-like receptor signaling toward a potent antiviral immune response

“…This might be attributed to the significantly higher cytokine levels of IL-23, IL-12p70, and TNFα when stimulating with MPL-s or LPS compared to MPL-SM. Along this line, Wang et al recently demonstrated that various research-grade Salmonella enterica –derived MPLA preparations purchased from different companies showed varying efficacy on TLR4 stimulation and TNFα secretion in human THP-1 cells, whereas mouse RAW264.7 cells responded similarly to these compounds ( 44 ). The phenomenon of TLR-induced, antigen-independent lymphocyte expansion has been described before but has gained little interest in vaccine development so far.…”

Monophosphoryl Lipid A and Poly I:C Combination Adjuvant Promoted Ovalbumin-Specific Cell Mediated Immunity in Mice Model

“…MPL, a TLR4 agonist, is a detoxified lipopolysaccharide (LPS), which has been proved to be an effective adjuvant in several studies [ 19 ]. Poly I:C is a synthetic double-stranded (ds) RNA, a mimic of viral dsRNA.…”

Bacterial Outer Membrane Vesicles as Antibiotic Delivery Vehicles

“…Lipid A is usually diphosphorylated (82). Edgar Ribi observed that monophosphorylated lipid A is significantly less immunogenic (83), and since then, monophosphoryl lipid A (MPL) has been FDA-approved as an adjuvant (84). A promising strategy to create OMVs consisting of monophosphorylated lipid A is to express the Helicobacter pylori Hp0021 gene in the OMVproducing organism.…”