Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1996-09-16
2002-12-31
Housel, James C. (Department: 1641)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C424S184100, C424S244100, C536S023700
Reexamination Certificate
active
06500613
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pneumococcal genes, portions thereof, expression products therefrom and uses of such genes, portions and products; especially to genes of
Streptococcus pneumoniae,
e.g., the gene encoding pneumococcal surface protein A (PspA) (said gene being “pspA”), pspA-like genes, pneumococcal surface protein C (PspC) (said gene being “pspC”), portions of such genes, expression products therefrom, and the uses of such genes, portions thereof and expression products therefrom. Such uses include uses of the genes and portions thereof for obtaining expression products by recombinant techniques, as well as for detecting the presence of Streptococcus pneumoniae or strains thereof by detecting DNA thereof by hybridization or amplification (e.g., PCR) and hybridization techniques (e.g., obtaining DNA-containing sample, contacting same with genes or fragment under PCR, amplification and/or hybridization conditions, and detecting presence of or isolating hybrid or amplified product). The expression product uses include use in preparing antigenic, immunological or vaccine compositions, for eliciting antibodies, an immunological response (other than or additional to antibodies) or a protective response (including antibody or other immunological response by administering composition to a suitable host); or, the expression product can be for use in detecting the presence of Streptococcus pneumoniae by detecting antibodies to Streptococcus pneumoniae protein(s) or antibodies to a portion thereof in a host, e.g., by obtaining an antibody-containing sample from a relevant host, contacting the sample with expression product and detecting binding (for instance by having the product labeled); and, the antibodies generated by the aforementioned compositions are useful in diagnostic or detection kits or assays. Thus, the invention relates to varied compositions of matter and methods for use thereof.
BACKGROUND OF THE INVENTION
Streptococcus pneumoniae
is an important cause of otitis media, meningitis, bacteremia and pneumonia. Despite the use of antibiotics and vaccines, the prevalence of pneumococcal infections has declined little over the last twenty-five years.
It is generally accepted that immunity to
Streptococcus pneumoniae
can be mediated by specific antibodies against the polysaccharide capsule of the pneumococcus. However, neonates and young children fail to make an immune response against polysaccharide antigens and can have repeated infections involving the same capsular serotype.
One approach to immunizing infants against a number of encapsulated bacteria is to conjugate the capsular polysaccharide antigens to protein to make them immunogenic. This approach has been successful, for example, with
Haemophilus influenzae
b (see U.S. Pat. No. 4,496,538 to Gordon and U.S. Pat. No. 4,673,574 to Anderson). However, there are over eighty known capsular serotypes of
S. pneumoniae
of which twenty-three account for most of the disease. For a pneumococcal polysaccharide-protein conjugate to be successful, the capsular types responsible for most pneumococcal infections would have to be made adequately immunogenic. This approach may be difficult, because the twenty-three polysaccharides included in the presently-available vaccine are not all adequately immunogenic, even in adults.
An alternative approach for protecting children, and also the elderly, from pneumococcal infection would be to identify protein antigens that could elicit protective immune responses. Such proteins may serve as a vaccine by themselves, may be used in conjunction with successful polysaccharide-protein conjugates, or as carriers for polysaccharides.
McDaniel et al. (I), J. Exp. Med. 160:386-397, 1984, relates to the production of hybridoma antibodies that recognize cell surface polypeptide(s) on
S. pneumoniae
and protection of mice from infection with certain strains of encapsulated pneumococci by such antibodies. This surface protein antigen has been termed “pneumococcal surface protein A” or PspA for short.
McDaniel et al. (II), Microbial Pathogenesis 1:519-531, 1986, relates to studies on the characterization of the PspA. Considerable diversity in the PspA molecule in different strains was found, as were differences in the epitopes recognized by different antibodies.
McDaniel et al. (III), J. Exp. Med. 165:381-394, 1987, relates to immunization of X-linked immunodeficient (XID) mice with non-encapsulated pneumococci expressing PspA, but not isogenic pneumococci lacking PspA, which protects mice from subsequent fatal infection with pneumococci.
McDaniel et al. (IV), Infect. Immun., 59:222-228, 1991, relates to immunization of mice with a recombinant full length fragment of PspA. that is able to elicit protection against pneumococcal strains of capsular types 6A and 3.
Crain et al, Infect.Immun., 56:3293-3299, 1990, relates to a rabbit antiserum that detects PspA in 100% (n=95) of clinical and laboratory isolates of strains of
S. pneumoniae.
When reacted with seven monoclonal antibodies to PspA, fifty-seven
S. pneumoniae
isolates exhibited thirty-one different patterns of reactivity.
The PspA protein type is independent of capsular type. it would seem that genetic mutation or exchange in the environment has allowed for the development of a large pool of strains which are highly diverse with respect to capsule, PspA, and possibly other molecules with variable structures. Variability of PspA's from different strains also is evident in their molecular weights, which range from 67 to 99 kD. The observed differences are stably inherited and are not the result of protein degradation.
Immunization with a partially purified PspA from a recombinant &lgr; gt11 clone, elicited protection against challenge with several
S. pneumoniae
strains representing different capsular and PspA types, as described in McDaniel et al. (IV), Infect. Immun. 59:222-228, 1991. Although clones expressing PspA were constructed according to that paper, the product was insoluble and isolation from cell fragments following lysis was not possible.
While the protein is variable in structure between different pneumococcal strains, numerous cross-reactions exist between all PspA's, suggesting that sufficient common epitopes may be present to allow a single PspA or at least a small number of PspA's to elicit protection against a large number of
S. pneumoniae
strains.
In addition to the published literature specifically referred to above, the inventors, in conjunction with co-workers, have published further details concerning PspA's, as follows:
1. Abstracts of 89th Annual Meeting of the American Society for Microbiology, p. 125, item D-257, May 1989;
2. Abstracts of 90th Annual Meeting of the American Society for Microbiology, p. 98, item D-106, May 1990;
3. Abstracts of 3rd International ASM Conference on Streptococcal Genetics, p. 11, item 12, June 1990;
4. Talkington et al, Infect. Immun. 59:1285-1289, 1991;
5. Yother et al (I), J. Bacteriol. 174:601-609, 1992; and
6. Yother et al (II), J. Bacteriol. 174:610-618, 1992.
7. McDaniel et al (V), Microbiol. Pathogenesis, 13:261-268.
It would be useful to provide PspA or fragments thereof in compositions, including PspA's or fragments from varying strains in such compositions, to provide antigenic, immunological or vaccine compositions; and, it is even further useful to show that the various strains can be grouped or typed, thereby providing a basis for cross-reactivities of PspA's or fragments thereof, and thus providing a means for determining which strains to represent in such compositions (as well as how to test for, detect or diagnose one strain from another).
Further, it would be advantageous to provide a pspA-like gene or a pspC gene in certain strains, as well as primers (oligonucleotides) for identification of such a gene, as well as of conserved regions in that gene and in pspA; for instance, for detecting, determining, isolating, or diagnosing strains of
S. pneumonia.
These uses and advantages, it is believed, hav
Briles David E.
Brooks-Walter Alexis
Crain Marilyn J.
Hollingshead Susan
McDaniel Larry S.
Frommer William S.
Frommer & Lawrence & Haug LLP
Housel James C.
Kowalski Thomas J.
Swartz Rodney P.
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