Purified plasmodium and vaccine compositions
Inventors
Sim, B. Kim Lee • Li, Minglin • Stafford, Richard E. • Hoffman, Stephen L.
Assignees
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Publication Number
US-9241982-B2
Publication Date
2016-01-26
Expiration Date
Abstract
Disclosed are substantially purified Plasmodium sporozoites and preparations of Plasmodium sporozoites substantially separated from attendant non-sporozoite material, where the preparations of Plasmodium sporozoites have increasing levels of purity. Vaccines and pharmaceutical compositions comprising purified Plasmodium sporozoites are likewise provided. Methods of purifying preparations of Plasmodium sporozoites are also provided.
Core Innovation
The invention relates to conferring protective immunity in a human against malaria caused by a Plasmodium-species parasite by administering an aseptic, purified preparation of metabolically active Plasmodium sporozoites. The preparation is suitable for pharmaceutical use and is separated from attendant non-sporozoite material, including salivary gland material (SGM), to obtain a preparation containing less than 85 nanograms of attendant material per 25,000 sporozoites.
Aseptic purification methods and preparations are described for sporozoites, including substantially purified Plasmodium sporozoite preparations separated from attendant non-sporozoite material. Purification quantification is described using SGM-ELISA and a process that uses a series of size-exclusion filters and concentration/collection steps to achieve very low residual attendant material, with campaign results reported as routine low levels and very high reduction versus pre-purification levels.
The document also addresses sporozoite attenuation parameters and defines genetically attenuated sporozoites via introduction of heritable genetic alteration. Potency and safety assessment is described using PfLSA-1 expression in human hepatocyte cultures, with PfLSA-1 used as a measure after irradiation and with dose-dependent activity described.
Claims Coverage
The independent claim set covers a method of conferring protective immunity in a human by administering an aseptic, purified, metabolically active, genetically attenuated Plasmodium sporozoite preparation with tightly defined attendant-material content. The inventive features are focused on aseptic purified sporozoite preparations for pharmaceutical use, genetically attenuated sporozoites for immunogenic protective immunity, and quantitative thresholds and administration refinements.
Aseptic, purified metabolically active genetically attenuated sporozoite preparation for pharmaceutical use
Administering to a human host at least one dose of an aseptic, purified preparation of a metabolically active Plasmodium sporozoite that is genetically attenuated by introduction of at least one heritable genetic alteration, wherein the preparation is suitable for pharmaceutical use and confers protective immunity.
Low attendant material requirement per dose of sporozoites
The aseptic, purified preparation comprises less than 85 nanograms of attendant material per 25,000 sporozoites.
Tighter attendant-material threshold
The aseptic, purified preparation contains less than 15 nanograms of attendant material per 25,000 sporozoites.
Very high removal of attendant material from pre-purification preparation
Removing at least 99.97% of the attendant material present in a pre-purification preparation.
Parenteral inoculation route selection
Administering the preparation via a parenteral inoculation route selected from intravenous, intramuscular, intradermal, or subcutaneous inoculation.
Dose-level range of metabolically active genetically attenuated sporozoites
Each dose contains at least 5,000 but no more than 400,000 metabolically active, genetically attenuated sporozoites.
Full protection outcome against later pathogenic exposure
Protective immunity fully protects a human host from the clinical manifestations, pathology, or symptoms of malaria following later exposure to pathogenic Plasmodium parasites.
Across the claim set described, the core coverage centers on a method that administers an aseptic, purified, metabolically active, genetically attenuated Plasmodium sporozoite preparation suitable for pharmaceutical use, with explicit attendant-material thresholds. Dependent features further narrow to lower residual attendant material and/or higher removal percentages, specify allowable parenteral routes, define a quantitative sporozoite dose range, and define an outcome of full protection against clinical manifestations after later exposure.
Stated Advantages
Confer protective immunity in a human against malaria caused by a Plasmodium-species parasite.
Provide an aseptic, purified preparation suitable for pharmaceutical use.
Reduce attendant material to a quantified low level (less than 85 nanograms per 25,000 sporozoites) and, in refinements, to lower thresholds.
In certain refinements, fully protect against clinical manifestations, pathology, or symptoms of malaria after later exposure to pathogenic Plasmodium parasites.
Documented Applications
Vaccine/pharmaceutical compositions for conferring protective immunity in a human against malaria caused by a Plasmodium-species parasite.
Aseptic purified Plasmodium sporozoite preparations administered via parenteral inoculation routes (intravenous, intramuscular, intradermal, or subcutaneous) in the context of protective immunity.
Assessment of potency and safety using PfLSA-1 expression in human hepatocyte cultures as part of evaluating genetically attenuated sporozoites after irradiation.
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