Plasmodium falciparum recombinanr xiexumapoeozoite protein compositions and method for vaccine delivery
Inventors
Dutta, Sheetij • BECK, Zoltan • Alving, Carl • Matyas, Gary
Assignees
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • United States Department of the Army
Publication Number
US-11583578-B2
Publication Date
2023-02-21
Expiration Date
2038-04-27
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Abstract
The invention relates to pharmaceutical compositions comprising at least one antigen and an adjuvant composition, where the adjuvant composition comprises a saponin and a liposome. The liposome of the composition comprises monophosphoryl lipid A (MPLA), cholesterol and a phospholipid that is in a liquid crystalline state at greater than or equal to 23° C., and the concentration of cholesterol to lipid in the liposome is greater than 50% (mol/mol). The antigen in the composition is a soluble Plasmodium falciparum recombinant circumsporozoite protein (rCSP) comprising the amino acid sequence of SEQ ID NO:1, or a P. falciparum rCSP peptide that is at least 95% identical to the amino acid sequence of SEQ ID NO:1.
Core Innovation
The invention relates to pharmaceutical compositions comprising at least one antigen and an adjuvant composition, wherein the adjuvant composition comprises a saponin and a liposome. The liposome of the composition comprises monophosphoryl lipid A (MPLA), cholesterol, and a phospholipid that is in a liquid crystalline state at greater than or equal to 23° C., where the concentration of cholesterol to lipid in the liposome is greater than 50% (mol/mol). The antigen in the composition is a soluble Plasmodium falciparum recombinant circumsporozoite protein (rCSP) comprising the amino acid sequence of SEQ ID NO:1, or a P. falciparum rCSP peptide at least 95% identical to SEQ ID NO:1.
Malaria caused by Plasmodium falciparum kills hundreds of thousands primarily in poor regions, and rapidly spreading multi-drug-resistant strains necessitate a safe and efficacious vaccine. Existing vaccines based on CSP, such as RTS,S containing the central repeat and C-terminal regions but lacking the N-terminal region, show limited efficacy and duration of protection against natural infection. Inclusion of B- and T-cell epitopes as well as protease cleavage sites in the N-terminal region of CSP may improve vaccine efficacy.
The invention provides pharmaceutical compositions with a nearly full-length recombinant CSP antigen containing both N- and C-terminal regions, formulated with a liposomal adjuvant containing saponin and MPLA, with optimized cholesterol content and lipid composition. These formulations, such as ALFQ, induce robust and sustained immunogenic responses, show protective efficacy in animal models against transgenic parasites, and demonstrate thermos-stability. The compositions induce a TH1-biased immune response with higher antibody titers and cellular immunity compared to prior adjuvants.
Claims Coverage
The claims include two independent claims covering a pharmaceutical composition and a method of immunizing against malaria. The main inventive features relate to the composition of the antigen and the specific adjuvant liposome composition.
Pharmaceutical composition comprising rCSP antigen with specific liposomal adjuvant
A pharmaceutical composition comprising at least one antigen and an adjuvant composition, where the adjuvant comprises a saponin and a liposome containing monophosphoryl lipid A (MPLA), cholesterol, and a phospholipid in a liquid crystalline state at ≥23° C. The cholesterol to lipid molar ratio in the liposome is greater than 50%. The antigen is a soluble Plasmodium falciparum recombinant circumsporozoite protein (rCSP) comprising SEQ ID NO:1 or a peptide at least 95% identical thereto.
Method of immunizing a subject against malaria using the specific composition
A method of immunizing a subject against malaria by administering the pharmaceutical composition including the specified rCSP antigen and the adjuvant comprising saponin and liposome with MPLA, cholesterol and phospholipid meeting the cholesterol to lipid molar ratio and liquid crystalline state criteria. Administration can be repeated multiple times with 2-6 weeks between doses.
The claims focus on the inventive use of a recombinant nearly full-length Plasmodium falciparum CSP antigen combined with a liposomal adjuvant composition characterized by a high cholesterol content lipid membrane, monophosphoryl lipid A, and saponin to enhance immune response and protection against malaria.
Stated Advantages
The composition induces a more robust immunogenic response compared to prior formulations.
It provides improved boosting of antibody titers after multiple vaccinations.
The vaccine formulation elicits a TH1-biased immune response correlated with protection.
The antigen formulation is thermos-stable at ambient and physiological temperatures.
Adjuvanted formulations confer higher protection against transgenic Plasmodium parasite challenge.
Documented Applications
Use as a malaria vaccine for immunization against Plasmodium falciparum infection in subjects.
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