Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 6 to 7 amino acid residues in defined sequence
Patent
1984-06-08
1987-09-15
Phillips, Delbert R.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
6 to 7 amino acid residues in defined sequence
530326, 530403, 424 88, C07K 706, C07K 708, A61K 3902
Patent
active
046940715
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to polypeptides having biological activity, particularly for use in vaccines for diseases caused by enteroviruses in particular polioviruses.
BACKGROUND ART
In the past, vaccines for diseases caused by enteroviruses have relied either on inactivated virus or on live attenuated virus. This can be illustrated by reference to the history or vaccines against poliomyelitis which began in the 1950's with the Salk vaccine, prepared by growing poliovirus in tissue culture, inactivating it with formaldehyde. The resulting inactivated or dead virus is administered by injection and appears to stimulate circulating antibodies which can neutralise the virus. A so-called trivalent vaccine is generally injected containing inactivated polio-viruses of types 1, 2 and 3 in order to immunise against all of these. Apart from the expense of preparing this vaccine, it also has the disadvantage that it is typically made using a potentially virulent virus and there is a delicate margin between rendering the virus non-infectious while at the same time retaining its immunogenicity. In fortunately rare cases, the vaccine virus can actually cause polio.
An alternative vaccine was subsequently developed, the Sabin vaccine, which was prepared by passage of the virus in cell cultures until it lost its ability to cause the disease, i.e. it became attenuated. This live attenuated virus is administered orally and replicates in the gut to induce a protective antibody response. This vaccine also has the disadvantage of being expensive since each batch of the vaccine has to be extensively tested in animals. In addition, there are three major disadvantages stemming from the use of a live virus in the vaccine. Firstly, the vaccine viruses can, very occasionally, revert to virulence causing paralysis in the patient and his contacts. Type 3 polioviruses are most troublesome in this respect being the least stable of the three types. Secondly, although the Sabin vaccine is widely used in developed countries, it does not apparently work in tropical countries, either because the virus does not replicate under those climatic conditions producing no immune response, or because the virus actually administered is no longer live. Finally, while live viruses are being used in vaccines in this way, it will never be possible to eradicate the poliovirus entirely.
There has therefore been a requirement for a vaccine which is simply and inexpensively produced, does not employ whole viruses and, while inducing an appropriate immune response, does not risk producing the corresponding disease.
Although the live-attenuated poliovirus vaccines developed by Sabin have been in use for more than twenty years, the molecular basis of their reduced neuropatho genicity remains unclear. Numerous studies, comparing the vaccine strains with their neurovirulent progenitors, have been made. Recently, Nomoto et al determined the RNA sequence of the attenuated poliovirus type 1 Sabin strain (Proc. Natn. Acad. Sci USA 79 5793-5797 (1982)) and compared their sequence with that obtained by Kitamura et al for the poliovirus type 1 Mahoney strain (see Nature (1981) 291 547-553). They were able to identify base substitutions particularly in the region coding for the VP1 capsid protein and suggested that base substitutions in this coding region might contribute to the attenuation of the virus i.e. that changes in this region would render the virus nonvirulent but still capable of producing an equivalent immune response. This supposition is not supported by any experimental results.
The role of VP1 in poliovirus antigenicity has also been discussed by Minor et al in Nature (1982) 299 109-110 where it was reported that the isolated whole polypeptides VP1, VP2 and VP3 were only capable of inducing low levels of neutralizing antibody in animals. Experimental results indicated that the antigenic determinants were likely to be complex, being specified by the tertiary configuration of polypeptide(s) rather than a simple amino acid sequence.
DISCLOSU
REFERENCES:
patent: 4554101 (1985-11-01), Hopp
"Poliomyelitis-Epidemiology, Molecular Biology and Immunology", P. D. Minor et al., Nature, vol. 299, Sep. 9, 1982, pp. 109-110.
"Primary Structure, Gene Organization and Polypeptide Expression of Poliovirus RNA", Kitamura et al., Nature, vol. 291, Jun. 18, 1981, pp. 547-553.
"Complete Nucleotide Sequence of the Attenuated Poliovirus Sabin I Strain Genome", A. Nomoto et al, Proc. Natl. Acad. Sci., USA, vol. 79, Oct. 1982, pp. 5793-5797.
"Location and Primary Structure of a Major Antigenic Site for Poliovirus Neutralisation", P. D. Minor et al, Nature, vol. 301, Feb. 24, 1983, pp. 674-679.
"Poliovirus Type 3-Molecular Cloning of the Genome and Nucleotide Sequence of the Region Encoding the Protease and Polymerase Proteins", A. J. Cann et al, Nuc. Acid Res., vol. 11, No. 5, 1983, pp. 1267-1281.
"Functional Basis of Poliovirus Neutralization Determined with Monospecific Neutralising Antibodies", E. A. Emini et al., J. Virology, vol. 46, No. 2, May 1983, pp. 466-475.
"Critical Role of an Eight-Amino Acid Sequence of VP1 in Neutralisation of Poliovirus Type 3", D. M. A. Evans et al., Nature, vol. 304, Aug. 4, 1983, pp. 459-462.
"Priming for and Induction of Antipoliovirus Neutralising Antibodies by Synthetic Peptides", E. A. Emini et al, Nature, vol. 304, Aug. 25, 1983, pp. 699-703.
"Will Peptides Make Vaccines", P. Newmask, Nature, vol. 304, Sep. 1, 1983.
"Neutralizing Site of Poliovirus" F. Brown, Nature, vol. 304, Aug. 4, 1983, pp. 395-396.
Almond Jeffrey W.
Evans David M. A.
Minor Phillip D.
Schild Geoffrey C.
National Research Development Corporation
Phillips Delbert R.
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