Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or... – Inactivation or attenuation; producing viral subunits
Patent
1996-07-19
1999-11-30
Scheiner, Laurie
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
Inactivation or attenuation; producing viral subunits
435237, 435238, 435239, 4242311, C12N 704
Patent
active
059941162
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage application of International Application No. PCT/GB95/00156, filed Jan. 25, 1995.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a form of herpesvirus particles suitable for use in vaccination, the preparation of such particles, and vaccines containing them.
2. Description of the Related Art
Herpes simplex virus type 1 (HSV-1) light particles (L-particles) are non-infectious virus-related particles, produced in approximately equal numbers with virions throughout the virus replication cycle in BHK cells (Szilagyi and Cunningham, 1991, J. Gen. Virol. 72, 661-668; Rixon et al., 1992, J. Gen. Virol. 73, 277-284). Similar L-particles have been isolated from pseudorabies virus (PRV); equine herpesvirus type 1 (EHV-1) (McLauchlan and Rixon, 1992, J. Gen. Virol. 73, 269-276); bovine herpes virus type 1 (BHV-1); varicella-zoster virus (VZV) (Dargan and Subak-Sharpe, unpublished) and HSV-2 (MacLean, unpublished). Because of the non-infectious nature of L-particles they have great potential as candidate vaccine materials (PCT Patent Application Publication No. 92/19748).
Comparative analysis of the protein composition of HSV-1, PRV and EHV-1 L-particles and virions show that most or all the virion tegument and envelope proteins are present in L-particles, but the nucleocapsid proteins are not present. Five phosphoproteins not detectable in HSV-1 virions are associated with HSV-1 L-particles (Szilagyi and Cunningham, 1991, J. Gen. Virol. 72, 661-668; McLauchlan and Rixon, 1992, J. Gen. Virol. 73, 269-276).
HSV-1 L-particles have been shown to be as efficient as virions in supplying functional tegument proteins to target cells. Thus, L-particles are biologically competent and have the potential to participate in the early stages of HSV-1 infections (McLauchlan et al., 1992, Virology, 190, 689-688).
Using an HSV-1 ts mutant (ts1201) (Preston et al., 1983, J. Virol. 45, 1056-1064) having a mutation in gene UL26, Rixon et al., 1992, J. Gen. Virol. 73, 277-284, demonstrated that L-particles were generated independently of virion maturation. Under non-permissive conditions ts1201 failed to make infectious virions but produced L-particles which were identical to typical wild-type virus L-particles in appearance and protein composition. Although viral DNA is synthesised normally in cells infected with ts1201 under their non-permissive conditions, viral DNA packaging into virions is blocked (Preston et al., 1983, J. Virol. 45, 1056-1064).
Although L-particles can be prepared to be substantially free of infectious virions, a typical preparation of HSV-1 L-particles containing a ratio of from 3.times.10.sup.3 :1 to 1.times.10.sup.4 :1 L-particles: infectious virions, there is a problem to improve on this ratio. Further, although the L-particles lack a capsid and the DNA within it, L-particle preparations still contain some viral DNA present in contaminating virions and/or possibly in the form of free nascent viral DNA. It would be advantageous to reduce the amount of such DNA present in the L-particle preparations, in order more easily to convince regulatory authorities of the safety of a vaccine containing them.
Additional prior art, the relevance of which becomes clear only in the context of the present invention, is referred to below after "Summary of the invention".
SUMMARY OF THE INVENTION
The inventors have now found a new type of herpesvirus particles, which are herein called pre-(viral DNA replication) enveloped particles (PREPS). Like L-particles, they are non-infectious. They can be prepared reliably to have a high ratio, typically for HSV-1 from 6.times.10.sup.5 :1 to 3.8.times.10.sup.8 :1 and frequently for HSV-1 of at least 10.sup.7 :1 PREPS:infectious virions. The underlying experimental finding is that HSV-1 PREPS can be produced under conditions where viral DNA replication is blocked either by use of drugs (e.g. Acyclovir [ACV]; Elion et al, 1977, Proceedings of the National Academy of Sciences, USA, 74, 5716); cytosine-.beta.-D-arabinofu
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Johnson
Dargan Derrick James
Patel Arvind Hirabhai
Subak-Sharpe John Herbert
Medical Research Council
Parkin Jeffrey S.
Scheiner Laurie
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