Streptococcus pneumoniae antigens and vaccines

Details Streptococcus pneumoniae antigens and vaccines Streptococcus pneumoniae antigens and vaccines

2000-03-28

2003-06-03

Navarro, Mark (Department: 1645)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C435S320100, C435S325000, C536S023700

Reexamination Certificate

active

06573082

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel
Streptococcus pneumoniae
antigens for the detection of Streptococcus and for the prevention or of disease caused by Streptococcus. The invention further relates to isolated nucleic acid molecules encoding antigenic polypeptides of
S. pneumoniae
. Antigenic polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention additionally relates to diagnostic methods for detecting Streptococcus gene expression.
BACKGROUND OF THE INVENTION
Streptococcus pneumoniae
has been one of the most extensively studied microorganisms since its first isolation in 1881. It was the object of many investigations that led to important scientific discoveries. In 1928, Griffith observed that when heat-killed encapsulated pneumococci and live strains constitutively lacking any capsule were concomitantly injected into mice, the nonencapsulated could be converted into encapsulated pneumococci with the same capsular type as the heat-killed strain. Years later, the nature of this “transforming principle,” or carrier of genetic information, was shown to be DNA. (Avery, O. T., et al.,
J. Exp. Med.,
79:137-157 (1944)).
In spite of the vast number of publications on
S. pneumoniae
many questions about its virulence are still unanswered, and this pathogen remains a major causative agent of serious human disease, especially community-acquired pneumonia. (Johnston, R. B., et al.,
Rev. Infect. Dis.
13(Suppl. 6):S509-517 (1991)). In addition, in developing countries, the pneumococcus is responsible for the death of a large number of children under the age of 5 years from pneumococcal pneumonia. The incidence of pneumococcal disease is highest in infants under 2 years of age and in people over 60 years of age. Pneumococci are the second most frequent cause (after
Haemophilus influenzae
type b) of bacterial meningitis and otitis media in children. With the recent introduction of conjugate vaccines for
H. influenzae
type b, pneumococcal meningitis is likely to become increasingly prominent.
S. pneumoniae
is the most important etiologic agent of community-acquired pneumonia in adults and is the second most common cause of bacterial meningitis behind
Neisseria meningitidis.
The antibiotic generally prescribed to treat
S. pneumoniae
is benzylpenicillin, although resistance to this and to other antibiotics is found occasionally. Pneumococcal resistance to penicillin results from mutations in its penicillin-binding proteins. In uncomplicated pneumococcal pneumonia caused by a sensitive strain, treatment with penicillin is usually successful unless started too late. Erythromycin or clindamycin can be used to treat pneumonia in patients hypersensitive to penicillin, but resistant strains to these drugs exist. Broad spectrum antibiotics (e.g., the tetracyclines) may also be effective, although tetracycline-resistant strains are not rare. In spite of the availability of antibiotics, the mortality of pneumococcal bacteremia in the last four decades has remained stable between 25 and 29%. (Gillespie, S. H., et al.,
J. Med. Microbiol.
28:237-248 (1989).
S. pneumoniae
is carried in the upper respiratory tract by many healthy individuals. It has been suggested that attachment of pneumococci is mediated by a disaccharide receptor on fibronectin, present on human pharyngeal epithelial cells. (Anderson, B. J., et al.,
J. Immunol.
142:2464-2468 (1989). The mechanisms by which pneumococci translocate from the nasopharynx to the lung, thereby causing pneumonia, or migrate to the blood, giving rise to bacteremia or septicemia, are poorly understood. (Johnston, R. B., et al.,
Rev. Inject. Dis.
13(Suppl. 6):S509-517 (1991).
Various proteins have been suggested to be involved in the pathogenicity of
S. pneumoniae
, however, only a few of them have actually been confirmed as virulence factors. Pneumococci produce an IgA1 protease that might interfere with host defense at mucosal surfaces. (Kornfield, S. J., et al.,
Rev. Inf. Dis.
3:521-534 (1981).
S. pneumoniae
also produces neuraminidase, an enzyme that may facilitate attachment to epithelial cells by cleaving sialic acid from the host glycolipids and gangliosides. Partially purified neuraminidase was observed to induce meningitis-like symptoms in mice; however, the reliability of this finding has been questioned because the neuraminidase preparations used were probably contaminated with cell wall products. Other pneumococcal proteins besides neuraminidase are involved in the adhesion of pneumococci to epithelial and endothelial cells. These pneumococcal proteins have as yet not been identified. Recently, Cundell et al., reported that peptide permeases can modulate pneumococcal adherence to epithelial and endothelial cells. It was, however, unclear whether these permeases function directly as adhesions or whether they enhance adherence by modulating the expression of pneumococcal adhesions. (De Velasco, E. A., et al.,
Micro. Rev.
59:591-603 (1995). A better understanding of the virulence factors determining its pathogenicity will need to be developed to cope with the devastating effects of pneumococcal disease in humans.
Ironically, despite the prominent role of
S. pneumoniae
in the discovery of DNA, little is known about the molecular genetics of the organism. The
S. pneumoniae
genome consists of one circular, covalently closed, double-stranded DNA and a collection of so-called variable accessory elements, such as prophages, plasmids, transposons and the like. Most physical characteristics and almost all of the genes of
S. pneumoniae
are unknown. Among the few that have been identified, most have not been physically mapped or characterized in detail. Only a few genes of this organism have been sequenced. (See, for instance current versions of GENBANK and other nucleic acid databases, and references that relate to the genome of
S. pneumoniae
such as those set out elsewhere herein.) Identification of in vivo-expressed, and broadly protective, antigens of
S. pneumoniae
has remained elusive.
SUMMARY OF THE INVENTION
The present invention provides isolated nucleic acid molecules comprising polynucleotides encoding the
S. pneumoniae
polypeptides described in Table 1 and having the amino acid sequences shown as SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and so on through SEQ ID NO:226. Thus, one aspect of the invention provides isolated nucleic acid molecules comprising polynucleotides having a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence encoding any of the amino acid sequences of the polypeptides shown in Table 1; and (b) a nucleotide sequence complementary to any of the nucleotide sequences in (a).
Further embodiments of the invention include isolated nucleic acid molecules that comprise a polynucleotide having a nucleotide sequence at least 90% identical, and more preferably at least 95%, 96%, 97%, 98% or 99% identical, to any of the nucleotide sequences in (a) or (b) above, or a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide in (a) or (b) above. This polynucleotide which hybridizes does not hybridize under stringent hybridization conditions to a polynucleotide having a nucleotide sequence consisting of only A residues or of only T residues. Additional nucleic acid embodiments of the invention relate to isolated nucleic acid molecules comprising polynucleotides which encode the amino acid sequences of epitope-bearing portions of an
S. pneumoniae
polypeptide having an amino acid sequence in (a) above.
The present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using these vectors for the production of
S. pneumoniae
polypeptides or peptides by recombinant techniques.
The invention further provides isolated
S. pneumoniae
polypeptides having an amino acid

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