Pharmaceutical compositions comprising attenuated Plasmodium sporozoites and glycolipid adjuvants
Inventors
CHAKRAVARTY, Sumana • Hoffman, Stephen L. • Tsuji, Moriya
Assignees
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Publication Number
US-9278125-B2
Publication Date
2016-03-08
Expiration Date
Abstract
Disclosed herein are pharmaceutical compositions comprising Plasmodium sporozoite-stage parasites and compatible glycolipid adjuvants useful in vaccines for preventing or reducing the risk of malaria. In particular, human host range Plasmodium and analogues of α-galactosylceramide (α-GalCer), a ligand for natural killer T (NKT) cells, are combined in pharmaceutical compositions, which are useful as vaccines against malaria. Methods of use are also provided.
Core Innovation
The invention relates to malaria-preventive pharmaceutical compositions and malaria vaccines that combine live attenuated Plasmodium sporozoite-stage parasites with a glycolipid adjuvant. The glycolipid adjuvant is represented by the structure of formula 1, where R is (CH2)10Ph(p-F), and the live attenuated parasites include one or more Plasmodium species, including human host-range species such as P. falciparum.
The disclosure addresses malaria prevention using sporozoite-stage vaccination, where dose numbers and dose amounts for parenteral sporozoite vaccination are reduced. It describes glycolipid adjuvants related to α-GalCer and NKT-cell activation to achieve dose-sparing in sporozoite vaccination and to improve protection, with administration by concurrent or sequential co-administration with or without an antimalarial drug.
The disclosure also defines representative glycolipid analogue structures and R-group variants, including a specific example identified as 7DW8-5 with fluorinated aromatic ring substituents. Mouse data are reported showing that an intraperitoneal regimen with 7DW8-5 combined with suboptimal IV irradiated P. yoelii sporozoites increases protection, and that protection can be maintained upon rechallenge.
Claims Coverage
The partial content provides two independent claims: one directed to a pharmaceutical composition and one directed to a malaria vaccine. Both independent claims cover the same core inventive structure: live attenuated Plasmodium sporozoite-stage parasites together with a glycolipid adjuvant defined by formula 1 with R=(CH2)10Ph(p-F).
Pharmaceutical composition with formula 1 glycolipid adjuvant and R=(CH2)10Ph(p-F)
A pharmaceutical composition comprising one or more species of live attenuated Plasmodium sporozoite-stage parasites, an excipient, and a glycolipid adjuvant represented by the structure of formula 1, wherein R is (CH2)10Ph(p-F).
Malaria vaccine with formula 1 glycolipid adjuvant and R=(CH2)10Ph(p-F)
A malaria vaccine comprising one or more species of live attenuated Plasmodium sporozoite-stage parasites, an excipient, and a glycolipid adjuvant represented by the structure of formula 1, wherein R is (CH2)10Ph(p-F).
Across both independent claims, the inventive coverage centers on pairing live attenuated Plasmodium sporozoite-stage parasites with a defined glycolipid adjuvant (formula 1 with R=(CH2)10Ph(p-F)), with dependent claims further limiting the Plasmodium species set to include specific species such as P. falciparum.
Stated Advantages
Dose-sparing for parenteral (IV and non-IV) sporozoite vaccination, reducing dose numbers and dose amounts.
Improved protection, including increased protection after combination regimens and maintained protection upon rechallenge.
Documented Applications
Malaria vaccine and malaria-preventive use cases based on live attenuated Plasmodium sporozoite-stage parasites formulated with a glycolipid adjuvant.
Prevention of malaria in mouse models using irradiated P. yoelii sporozoites combined with the disclosed glycolipid adjuvant example 7DW8-5, with protection evaluated after challenge and rechallenge.
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