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Safety evaluation of monophosphoryl lipid A (MPL): an immunostimulatory adjuvant
Paul Baldrick1, Derek Richardson, Gary Elliott
1Covance Laboratories Ltd. Otley Road, Harrogate, North Yorkshire, HG3 1PY, England, United Kingdom.
Abstract:
Animal models have shown the potential use of monophosphoryl lipid A (MPL), a detoxified bacterial lipopolysaccharide, as a vaccine adjuvant. Immunostimulatory activity with diverse effects on the cellular elements of the immune system has been demonstrated and a range of vaccines incorporating MPL, including allergy vaccines, are currently under clinical evaluation. A series of preclinical safety investigations was performed to support clinical use of MPL as used in allergy vaccines and comprised cardiovascular/respiratory assessment in dog (up to 100 microg/kg/day); repeat-dose toxicity in rat, rabbit, and dog (up to 2500 and 1200 microg/kg/day in the rat and dog, respectively); reproduction toxicity in rat and rabbit (up to 100 microg/kg/day); and genotoxicity studies. Overall, repeat-dose toxicity studies in the rat and dog showed expected immunostimulatory effects and/or signs of toxicity associated with overstimulation of the immune system (notably increased spleen weight and white blood cell values). Studies in the rabbit with weekly doses of MPL produced no effects. MPL was shown to have no adverse effects on cardiovascular/respiratory function, reproduction, and genotoxicity.
Insights
Monophosphoryl lipid A (MPL) shows potential as a vaccine adjuvant, with preclinical safety studies supporting its use in allergy vaccines. MPL demonstrated no adverse effects on cardiovascular, respiratory, reproductive, or genetic systems.
Area of Science:
- Immunology
- Pharmacology
- Toxicology
Background:
- Monophosphoryl lipid A (MPL), a detoxified lipopolysaccharide, is recognized for its vaccine adjuvant properties.
- MPL exhibits immunostimulatory activity, influencing various immune system components.
- Allergy vaccines incorporating MPL are currently in clinical evaluation.
Purpose of the Study:
- To assess the preclinical safety of MPL for its use in allergy vaccines.
- To support the clinical application of MPL through comprehensive safety investigations.
Main Methods:
- Cardiovascular/respiratory assessment in dogs.
- Repeat-dose toxicity studies in rats, rabbits, and dogs.
- Reproduction toxicity studies in rats and rabbits.
- Genotoxicity assessments.
Main Results:
- Repeat-dose studies in rats and dogs indicated expected immunostimulatory effects and potential toxicity from immune overstimulation (e.g., increased spleen weight, elevated white blood cell counts).
- Rabbits receiving weekly MPL doses showed no adverse effects.
- MPL did not negatively impact cardiovascular/respiratory function, reproduction, or genetic material.
Conclusions:
- MPL is generally safe for use in allergy vaccines, with observed effects in repeat-dose studies being consistent with immune system stimulation.
- Preclinical safety data support the further clinical development of MPL-containing vaccines.