J. Terry Ulrich

Monophosphoryl Lipid A as an Adjuvant

The increasing threat to the human population posed by new or resurgent infectious diseases, coupled with an alarming rise in the incidence of antibiotic-resistant microbes, has created a tremendous need for new vaccines. A critical element in the development of these new vaccines is the ability, via adjuvants, to potentiate and focus the immune response to the vaccine in beneficial ways so that optimal protection can be achieved. One promising candidate adjuvant in this regard is MPL® immunostimulant, a monophosphoryl lipid A preparation derived from the lipopolysaccharide (LPS) of Salmonella minnesota R595. MPL® is being considered as an adjuvant for a number of human vaccines, and experience to date has shown that it is safe, well tolerated, and able to provide a heightened immune response to coadministered antigens. In this chapter, various topics related to the preparation, formulation, and use of MPL® as an adjuvant will be discussed. In addition, our current knowledge of the mechanisms of action of MPL® will be reviewed.

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.

A Th1-inducing adjuvant, MPL, enhances antibody profiles in experimental animals suggesting it has the potential to improve the efficacy of allergy vaccines.

Background: Monophosphoryl lipid A (MPL®) is a detoxified derivative of the lipopolysaccharide (LPS) moiety of Salmonella minnesota R595, which has retained immunostimulatory activities. MPL® has been administered to many subjects in clinical trials as an adjuvant component of infectious disease vaccines and is currently a component of a licensed cancer vaccine, Melacine® (Corixa Inc., Schering Plough). MPL® has, in particular, been shown to promote Th1-type antigen specific responses. L-tyrosine is a depot adjuvant which is fully metabolisable and has been successfully employed in allergy vaccines for a number of years. Methods: Mice were immunised with MPL® adjuvant in conjunction with separate preparations of either ovalbumin or glutaraldehyde-modified ragweed pollen extract both coprecipitated with L-tyrosine. The specific antibody isotypes IgG1, IgG2a, IgG2b and also IgE were measured. Rats received booster injections of keyhole limpet haemocyanin (KLH) in conjunction with MPL® adjuvant following priming with KLH in alum alone. KLH-specific antibody responses were measured. Results: It was shown that a combination of L-tyrosine and MPL® were synergistic in enhancing murine antigen specific IgG antibody responses without enhancing antigen specific IgE responses. Furthermore, this adjuvant combination promoted strong IgG2 antigen specific responses indicative of a Th1 directed response. In KLH sensitised rats, treatment with MPL® was shown to prevent a secondary IgE antibody response when injected with booster injections of antigen. Conclusions: Immunisation of mice with two different antigens adsorbed to L-tyrosine induced a Th1-skewed primary response when in conjunction with MPL® adjuvant which also generally enhances a specific IgG response. Incorporation of MPL® adjuvant in the immunisation of rats prevented a secondary specific IgE response. These results suggest that the employment of this new adjuvant in clinical allergy vaccination formulations may result in an improved efficacy which could be utilised in various ways to improve compliance.

Synthesis and biological evaluation of a new class of vaccine adjuvants: aminoalkyl glucosaminide 4-phosphates (AGPs)

A novel series of acylated omega-aminoalkyl 2-amino-2-deoxy-4-phosphono-beta-D-glucopyranosides (aminoalkyl glucosaminide 4-phosphates) was synthesized and screened for immunostimulant activity. Several of these compounds enhance the production of tetanus toxoid-specific antibodies in mice and augment vaccine-induced cytotoxic T cells against EG.7-ova target cells.