Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Combination of antigens from multiple viral species
Reexamination Certificate
2002-08-07
2003-12-02
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Combination of antigens from multiple viral species
C424S212100, C435S235100, C435S239000
Reexamination Certificate
active
06656476
ABSTRACT:
Mumps is essentially a disease of childhood, which normally presents itself with only minor symptoms. However, in certain cases the clinical consequences of mumps infection are serious. For example, mumps is the most common cause of meningoencephalitis in children under 15 years of age in the UK, and a cause of permanent sensorineural deafness in childhood. Although 30-40% of natural mumps infection are symptomless, the very fact that salivary gland involvement can be unpleasant and that in the adult population mumps can cause 1st trimester abortions and orchitis of men as well as the neurological complications noted above, has led, in many countries, to the adoption of mass vaccination programs.
Mumps virus belonging to Paramyxoviridae is constituted by a single strand genomic RNA of the minus sense and is about 15,3 kb with the gene order 3′ N-P-M-F-SH-HN-L5′ (N-nucleocapsid protein, P=phosphoprotein, M=matrix protein, F=fusion protein, SH=potentially expressed as small hydrophobic protein, HN-haemagglutinin neuraminidase, L=large protein). Among various mumps strains, Jeryl-Lynn (B-level) is a live attenuated variant which has been characterised by sequence analysis of the F,P,HN,M genes.
Until recently, two mumps virus strains have been approved for vaccination against Mumps. These are Urabe Am 9 and Jeryl-Lynn. However in September 1992 the Urabe strain was withdrawn following a reported incidence of unacceptable level of side effects [European Journal of Pediatrics (1993) 152:387].
The Jeryl-Lynn strain has been sold commercially by Merck Sharp and Dohme for many years under the trade name “Mumps Vax”. The Jeryl-Lynn strain was obtained from a clinical sample of a patient suffering from mumps, by amniotic inoculation into embryonated hen's eggs (Proc. Soc. Expt1. Biol. Med. 123 (3) (1966)).
Afzal et al. recently reported (J. of Gen. Virology 1993 74 917) that the Jeryl-Lynn strain used in mumps vaccines in the UK is in fact a mixture of two viruses, named JL-2 and JL-5.
Takeuchi et al. Virology (1991) 181 p364-366 report that among different mumps strains there can be substantial nucleotide sequence variation at the SH gene level.
Afzal et al have emphasised that the present commercially available vaccine “Mumps Vax” is made under carefully controlled conditions including a cell bank and passage limits and which are likely to preserve the proportion of the two variants from batch to batch. However with further passaging of the Jeryl-Lynn strain there is no guarantee that this balance between the two variants will be retained. Moreover it is difficult to assess the proportion of the two variants in any given batch of vaccine.
The present inventors have surprisingly identified a yet further isolate which differs from both JL-2 and JL-5 of Afzal et al. The difference was determined by nucleotide sequence analysis of the SH gene and regions surrounding it, more particularly the nontranslated intercistronic region 3′ to the SH coding sequence and 5′ to the HN gene. This isolate in clinical trials induces a higher zero conversion and have highest geometric mean titre of mumps antibody than the commercially available mumps vaccine.
Accordingly the present inventors provide an attenuated Jeryl-Lynn mumps strain containing the nucleotide sequence as set forth in FIG.
1
. This sequence encodes the SH gene and the N terminus of the HN gene. The strain is herein referred to as SBB JL-1.
In
FIG. 1
there is shown the c DNA sequence of the JL-1 mumps virus isolate over the SH gene coding and SH-HN intergenic regions.
The present invention also provides a mumps vaccine comprising a substantially homogenous immunogenic Jeryl-Lynn isolate.
By substantially homogenous it is meant that the isolate is not contaminated with more than 10%, and preferably less than 5% and most preferably less than 1% of another Jeryl-Lynn isolate as defined by the sequence of the region set forth above. In a preferred embodiment of the invention, the vaccine contains a pure homogenous Jeryl-Lynn isolate i.e. devoid of any contamination with other Jeryl-Lynn mumps isolates which differ within the region set forth in FIG.
1
.
In one embodiment of the invention there is provided a vaccine comprising homogenous SBB JL-1 devoid of contamination with JL-2.
The pure isolate does not suffer from the disadvantages of potential batch to batch variation between substrains and provides a product which is easier to ensure will meet consistent quality guidelines.
Homogenous Jeryl-Lynn according to the invention may be obtained by passaging commercially available Mumps Vax on Chick Embryo Fibroblast (CEF) cells, and selecting pure cultures by either limit dilution and examination of resulting isolates or by individual plaque isolation. Other suitable cell lines include Vero cells and MRC5 cells. This requires that methods are available for detection of minor proportions of a known variant virus within a population. Such examination methods include the Maprec assay proposed by Chumakov et al for attenuated polio virus (WO 92/07958 and PNAS 1991, 88; 199-203), and direct sequencing of viral plaques and differential hybridization of viral plaques.
The vaccine of the invention may advantageously contain other components, such as attenuated measles virus, and/or attenuated rubella virus, killed or subunits thereof for providing protection against measles and/or rubella infections. Trivalent mumps measles and rubella vaccines are well known in the art and the present mumps isolate would be formulated in a trivalent vaccine in an analogous manner to those vaccines already available. Additionally or alternatively the vaccine of the invention may contain a live Varicella Zoster attenuated virus for providing protection against varicella (chicken pox) or Zoster (shingles). In a preferred embodiment the Varicella Zoster virus will be the Oka strain as disclosed by Andre F E Postgraduate MED J. (1985) 61(Suppl. 4), 113-120 or Veskari T et al Acta paediatr. Scand. 80: 1051-1057, 1991. Preferably the vaccine of the invention will be quadrivalent and provide protection against mumps, rubella measles and varicella zoster viruses.
The invention also provides a process for preparing a whole virus vaccine, for example by freeze drying the virus in the presence of suitable stabilisers or admixing the strain according to the invention with a suitable carrier or adjuvant. It may also be advantageous to formulate the strain of the invention in liposomes or with carrier particles. Alternatively or in addition immunostimulants such as 3de-O-acyl monophosphoryl Lipid A (Ribi Immunochem) or the saponin derivative QS21 (Cambridge Biotech) may be included in the formulation.
In a further aspect, the invention provides a method of treating mumps infection in humans, which method comprises administering to a human subject in need thereof an immunologically effective dose of the vaccine according to the invention.
The mode of administration of the vaccine of the invention may be any suitable route which delivers an immunoprotective amount of the strain and other immunogenic component of the vaccine to the subject. However, the vaccine is preferably administered parenterally via the intramuscular or deep subcutaneous routes. Other modes of administration may also be employed, where desired, such as oral administration or via other parenteral routes, i.e., intradermally, intranasally, or intravenously.
The appropriate immunoprotective and non-toxic dose of such vaccine can be determined readily by those skilled in the art, i.e., the appropriate immunoprotective and non-toxic amount of the strain of this invention contained in the vaccine of this invention may be in the range of the effective amounts of antigen in conventional whole virus vaccines. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, general health, sex, and diet of the patient; the time of administration; the route of admini
Colau Brigitte Desiree Alberte
Didelez Jean
Harford Nigel Maurice
Majarian William R.
SmithKline Beecham Biologicals (S.A.)
Venetianer Stephen
Wortman Donna C.
LandOfFree
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