Monophosphoryl lipid A enhances mucosal and systemic immunity to vaccine antigens following intranasal administration.

The induction of protective immunity stemming from vaccines delivered by mucosal routes is dependent on the development of safe and effective mucosal adjuvants. The immunostimulant monophosphoryl lipid A (MPL(R)) was evaluated for its ability to enhance both systemic and mucosal immunity to three distinct antigens. Vaccines formulated with MPL(R) and hepatitis B surface antigen, tetanus toxoid or influenza antigens were administered by intranasal delivery to mice. In each case the vaccines formulated with MPL(R) resulted in enhanced IgA titers from mucosal samples. Enhanced IgA concentrations were detected in samples from both local and distal mucosal sites. In addition, the MPL(R) formulated vaccines induced systemic immunity characteristic of a Th1-type of response. Serum IgG2a antibody titers were elevated and cytotoxic T cell activity was enhanced.

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities.

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.