Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,...
Reexamination Certificate
2000-03-13
2001-06-12
Salimi, Ali R. (Department: 1648)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
C430S018000, C424S204100, C530S300000, C530S350000
Reexamination Certificate
active
06245568
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to a human papillomavirus (HPV) vaccine which contains virus-like particles (VLPs) which have been disassembled into capsomeres and then reassembled into VLPs. This invention also relates to processes of making this vaccine resulting in more homogeneous HPV VLPs and greatly improved storage stability.
BACKGROUND OF THE INVENTION
Human Papillomavirus (HPV) infects the genital tract and has been associated with various dysplasias, cancers, and other diseases. These diseases are currently targets for vaccine development and vaccines containing virus-like particles (VLPs) which contain L1 or the combination of L1+L2 proteins are currently in clinical trials.
It has been found, however, that recombinant L1 protein HPV VLPs purified from yeast are not stable during long-term storage, either in solution or when adsorbed onto aluminum adjuvant particles.
In the past, various researchers have investigated the conditions of HPV VLP assembly and disassembly. For example, McCarthy et al, 1998 “Quantitative Disassembly and Reassembly of Human Papillomavirus Type 11 Viruslike Particles in Vitro”
J. Virology
72(1):32-41, describes the disassembly and reassembly of recombinant L1 HPV 11 VLPs purified from insect cells in order to obtain a homogeneous preparation of VLPs. A prolonged incubation (about 16 hours at 4° C.) with a relatively high concentration of reducing agent at physiological ionic strength was used to disassemble the VLPs, and removal of the reducing agent at a higher ionic strength was used to reassemble the VLPs. This method is quite time-consuming, however.
In order to develop a commercially useful vaccine, a storage stable formulation is needed. It would be desirable to have a relatively simple, quick and quantitative treatment procedure for making a storage stable HPV VLP formulation.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a process for making stable human papillomavirus (HPV) virus-like particles (VLPs), the process comprising the steps of:
(a) incubating VLPs in a dissociation mixture comprising a relatively low concentration of a reducing agent, a salt present in a range from physiological ionic strength up to 1.25M, a non-ionic surfactant, a metal chelating agent and a buffer until disassembled VLPs are produced;
(b) removing the reducing agent from the dissociation mixture; and
(c) reassembling the disassembled VLPs into VLPs.
In some embodiments, the reassembled VLPs are adsorbed onto an aluminum adjuvant.
This invention also relates to VLPs made by a process comprising the steps of:
(a) incubating purified VLPs in a high salt dissociation mixture comprising a relatively low concentration of a reducing agent, a salt present in a range of 0.5 M to 1.25M salt, a non-ionic surfactant, a metal chelating agent, and a buffer until disassembled VLPs are produced;
(b) removing the reducing agent from the dissociation mixture; and
(c) reassembling the disassembled VLPs; and
(d) optionally adsorbing the reassembled HPV VLPs to aluminum adjuvant.
Another embodiment of this invention relates to VLPs made by a process comprising the steps of:
(a) incubating purified VLPs in a low salt dissociation mixture comprising a relatively low concentration of a reducing agent, a salt present at approximately physiological ionic strength, a non-ionic surfactant, a metal chelating agent, and a buffer until disassembled VLPs are produced;
(b) removing the reducing agent from the dissociation mixture; and
(c) reassembling the disassembled VLPs; and
(d) optionally adsorbing the reassembled HPV VLPs to aluminum adjuvant.
Another aspect of this invention relates to vaccines made from the VLPs produced by any of the above processes.
This invention also relates to vaccine formulations comprising VLPs made by the above processes, and which are stored in a formulation buffer. The formulation buffer comprises a salt, a histidine buffer, and a nonionic surfactant.
REFERENCES:
patent: WO 98/44944 (1998-10-01), None
patent: WO 99/01557 (1999-01-01), None
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Search Report for PCT counterpart of this application.
Mach Henryk
Shi Li
Volkin David B.
Giesser Joanne M.
Merck & Co. , Inc.
Salimi Ali R.
Tribble Jack L.
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