Pneumococcal protein homologs and fragments for vaccines

Details Pneumococcal protein homologs and fragments for vaccines Pneumococcal protein homologs and fragments for vaccines

2000-08-25

2004-12-21

Wax, Robert A. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C530S350000, C424S184100, C424S130100, C424S243100, C424S244100, C536S023100

Reexamination Certificate

active

06833356

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to the field of bacterial antigens and their use, for example, as immunogenic agents in humans and animals to stimulate an immune response. More specifically, it relates to the vaccination of mammalian species, especially humans, with one or more polypeptides derived from gram positive bacteria and which show sequence homology with an immunogenic polypeptide obtained from
Streptococcus pneumoniae.
BACKGROUND OF THE INVENTION
Polypeptides derived from gram positive bacteria are useful for stimulating production of antibodies that protect the vaccine recipient against infection by a wide range of serotypes of pathogenic gram positive bacteria, including
S. pneumoniae
. Further, the invention relates to antibodies against such polypeptides useful in diagnosis and passive immune therapy with respect to diagnosing and treating such pneumococcal infections.
The genus Streptococcus contains a variety of species responsible for causing disease in mammals, including humans, while also encompassing species that constitute normal flora in humans and other mammals. Among the bacterial species implicated in the etiology of diseases in humans are
S. pyogenes
(part of the group A streptococcal bacteria, herein designated “GAS” for “group A streptococci”),
S. pneumoniae
(referred to as “pneumococcus”) and
S. agalactiae
(the group B streptococci or “GBS”). The group A streptococci cause serious diseases such as necrotizing fasciitis, scarlet fever and sepsis, as well as less virulent diseases such as impetigo and pharyngitis. The pneumococci are the most common cause of community-acquired pneumonia and are also responsible for more than half of all cases of otitis media in children. The pneumococci are also the second most common pathogen associated with bacterial meningitis. The group B streptococci are the most prevalent pathogen associated with illness and death among newborns in the United States.
Currently, there are no vaccines available for the prevention of diseases caused by the group A and group B streptococci and presently available pneumococcal vaccines are not effective in children under 2 years of age or in the elderly due to the poor immunogenicity of the capsular carbohydrates that compose the current vaccine. It would therefore be highly advantageous to produce a vaccine that would prevent infection by these classes of pathogen, especially in the age groups mentioned.
In addition to the pathogens just described, some bacteria of the genus Staphylococcus are also of clinical importance. In fact, two of these are among the leading causes of nosocomial infections (infections acquired while in the hospital). Both
Staphylococcus aureus
and
Staphylococcus epidermidis
readily colonize the skin of healthy individuals and can cause acute disease in patients following immunosuppression or traumatic injury. Infections caused by these species include bacteremia, endocarditis, osteomyelitis, wound infections and infections associated with indwelling catheters.
Streptococcus pneumoniae
is a gram positive bacterium that is a major causative agent in invasive infections in animals and humans, such as the aforementioned sepsis, meningitis, and otitis media, as well as lobar pneumonia (Tuomanen, et al.
New England J. of Medicine
322:1280-1284 (1995)). As part of the infection process, pneumococci readily bind to non-inflamed human epithelial cells of the upper and lower respiratory tract by binding to eukaryotic carbohydrates in a lectin-like manner (Cundell et al.,
Micro. Path
. 17:361-374 (1994)). Conversion to invasive pneumococcal infections for bound bacteria may involve the local generation of inflammatory factors which may activate the epithelial cells to change the number and type of receptors on their surface (Cundell, et al.,
Nature
, 377:435-438 (1995)). Apparently, one such receptor, platelet activating factor (PAF) is engaged by the pneumococcal bacteria and within a very short period of time (minutes) from the appearance of PAF, pneumococci exhibit strongly enhanced adherence and invasion of tissue. Certain soluble receptor analogs have been shown to prevent the progression of pneumococcal infections (Idanpaan-Heikkila et al.,
J. Inf. Dis
., 176:704-712 (1997)). A number of other proteins have been suggested as being involved in the pathogenicity of
S. pneumoniae.
Streptococcus pneumoniae
itself has been shown to contain a gene which encodes a protein designated herein as Sp36. This protein has a predicted molecular mass of 91,538 Da and contains 5 histidine triad motifs (proposed to be involved in metal binding). The gene encoding this protein appears to be present the 23 serotypes comprising the current commercially available pneumococcal-capsular vaccine. Immunization of mice with this protein, in the presence of Freund's adjuvant, stimulates an immune response which protects these mice from an intraperitoneal challenge with a dose of virulent pneumococci that would normally kill the mice.
For the reasons already stated above, there not only remains a need for identifying polypeptides having epitopes in common from various strains of
S. pneumoniae
but also from a broader spectrum of gram positive bacteria in order to utilize such polypeptides as vaccines to provide protection against a wide variety of infectious organisms.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided vaccines that include polypeptides obtained from gram positive bacteria other than
S. pneumoniae
, as well as variants of said polypeptides and active fragments of such polypeptides.
The present invention is also directed to novel genes, and the polypeptides encoded thereby, derived from gram positive bacteria other than
S. pneumoniae
, and which bear sequence homology to the Sp36 gene already described. Such gram positive bacteria include the group A and B streptococci, as described herein, as well as species of the genus Staphylococcus, especially
S. aureus.
In a particular embodiment, the present invention is directed to specific gene sequences, and proteins encoded thereby, derived from the group A and group B streptococci, and to the use of such expressed polypeptides and proteins as the basis for pharmaceutical compositions useful as vaccines and as a means for enabling isolation of antibodies with therapeutic and/or prophylactic activity (such as would be useful in preparing products like CytoGam).
In a further embodiment, the present invention also relates to the preparation and use of fragments of the novel polypeptides disclosed herein, such fragments being immunogenic in nature and being useful in the preparation of vaccines against diseases caused by the pathogens from which such polypeptides, and fragments thereof, are derived.


REFERENCES:
patent: 4694073 (1987-09-01), Bentle et al.
patent: 2003/0031682 (2003-02-01), Brodeur et al.
patent: WO 98/18930 (1998-05-01), None
patent: WO 99/42588 (1999-08-01), None
patent: WO 00/06736 (2000-02-01), None
Spellerberg et al., Lmb, a protein with similarities to the Lral adhesin family, mediates attachment of streptococcus agalactiae to human laminin. Infection and Immunity Feb. 1999, vol. 67 871-878.

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