Non-IgA Fc binding forms of the group B streptococcal &bgr;...

Details Non-IgA Fc binding forms of the group B streptococcal &bgr;... Non-IgA Fc binding forms of the group B streptococcal &bgr;...

1997-09-05

2001-08-28

Chin, Christopher L. (Department: 1641)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

C424S190100, C424S244100, C424S282100, C424S831000, C514S054000, C530S403000, C530S825000

Reexamination Certificate

active

06280738

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns the construction of a protein having a reduced or eliminated ability to bind human IgA, but that retains the immunological properties useful for formulating a conjugate vaccine against Group B streptococci.
2. Related Art
Streptococci are a large and varied set of gram-positive bacteria which have been ordered into several groups based on the antigenicity and structure of their cell wall polysaccharide (Lancefield, R. C.,
J. Exp. Med.
57:571-595 (1933); Lancefield, R. C.,
Proc. Soc. Exp. Biol. and Med.
38:473-478 (1938)). Two of these groups have been associated with serious human infections. Those that have been classified into Group A streptococci are the bacteria that people are most familiar and are the organisms which cause “strep throat.” Organisms of Group A streptococci also are associated with the more serious infections of rheumatic fever, streptococcal impetigo, and sepsis.
Group B streptococci were not known as a human pathogen in standard medical textbooks until the early 1970's. Since that time, studies have shown that Group B streptococci are an important perinatal pathogen in both the United States as well as the developing countries (Smith, A. L. and J. Haas,
Infections of the Central Nervous System,
Raven Press, Ltd., New York. (1991) p. 313-333). Systemic Group B streptococcal infections during the first two months of life affect approximately three out of every 1000 births (Dillon, H. C., Jr., et al.,
J Pediat.
110:31-36 (1987)), resulting in 11,000 cases annually in the United States. These infections cause symptoms of congenital pneumonia, sepsis, and meningitis. A substantial number of these infants die or have permanent neurological sequelae. Furthermore, these Group B streptococcal infections may be implicated in the high pregnancy-related morbidity which occurs in nearly 50,000 women annually. Others who are at risk from Group B streptococcal infections include those who either congenitally, chemotherapeutically, or by other means, have an altered immune response.
Group B streptococci can be further classified into several different types based on the bacteria's capsular polysaccharide. The most pathogenically important of these different types are streptococci having types Ia, Ib, II, or III capsular polysaccharides. Group B streptococci of these four types represent over 90% of all reported cases. The structure of each of these various polysaccharide types has been elucidated and characterized (Jennings, H. J., et al.,
Biochemistry
22:1258-1263 (1983); Jennings, H. J., et al.,
Can. J. Biochem.
58:112-120(1980); Jennings, H. J., et al.,
Proc. Nat. Acad. Sci. USA.
77:2931-2935 (1980); Jennings, H. J., et al.,
J. Biol. Chem.
258:1793-1798 (1983); Wessels, M. R., et al.,
J. Biol. Chem.
262:8262-8267 (1987)). As is found with many other human bacterial pathogens, it has been ascertained that the capsular polysaccharides of Group B streptococci, when used as vaccines, provide very effective, efficacious protection against infections with these bacteria. This was first noted by Lancefield (Lancefield, R. C., et al.,
J. Exp. Med.
142:165-179 (1975)) and more recently in the numerous studies of Kasper and coworkers (Baker, C. J., et al.,
N. Engl. J. Med.
319:1180-1185 (1988); Baltimore, R. S., et al.,
J. Infect. Dis.
140:81-86 (1979); Kasper, D. L., et al.,
J. Exp. Med.
149:327-339 (1979); Madoff, L. C., et al.,
J. Clin. Invest.
94:286-292 (1994); Marques, M. B., et al.,
Infect. Immun.
62:1593-1599 (1994); Wessels, M. R., et al.,
J. Clin. Invest.
86:1428-1433 (1990); Wessels, M. R., et al.,
Infect. Immun.
61:4760-4766 (1993); Wyle, S. A., et al.,
J. Infect. Dis.
126:514-522 (1972)). However, much like many other capsular polysaccharide vaccines (Anderson, P., et al.,
J. Clin. Invest.
51:39-44 (1972); Gold, R., et al.,
J. Clin. Invest.
56:1536-1547 (1975); Gold, R., et al.,
J. Infect. Dis.
136S:S31-S35 (1977); Gold, R. M., et al.,
J. Infect. Dis.
138:731-735 (1978); Mäkelä, P. R. H., et al.,
J. Infect. Dis.
136:S43-50 (1977); Peltola, A., et al.,
Pediatrics
60:730-737 (1977); Peltola, H., et al.
N. Engl. J. Med.
297:686-691 (1977)), vaccines formulated from pure type Ia, Ib, II, and III capsular carbohydrates are relatively poor immunogens and have very little efficacy in children under the age of 18 months (Baker, C. J. and D. L. Kasper.
Rev. Inf. Dis.
7:458-467 (1985); Baker, C. J., et al.,
N. Engl. J. Med.
319:1180-1185 (1988); Baker, C. J., et al.,
New Engl. J. Med.
322:1857-1860 (1990)). These pure polysaccharides are classified as T cell independent antigens because they induce a similar immunological response in animals devoid of T lymphocytes (Howard, J. G., et al.,
Cell. Immunol.
2:614-626 (1971)). It is thought that these polysaccharides do not evoke a secondary booster response because they do not interact with T cells, and therefore fail to provoke a subsequent “helper response” via the secretion of various cytokines. For this reason, each consecutive administration of the polysaccharide as a vaccine results in the release of a constant amount of antibodies, while a T cell dependent antigen would elicit an ever increasing concentration of antibodies each time it was administered.
Goebel and Avery found in 1931 that by covalently linking a pure polysaccharide to a protein that they could evoke an immune response to the polysaccharide which could not be accomplished using the polysaccharide alone (Avery, O. T. and W. F. Goebel,
J. Exp. Med.
54:437-447 (1931); Goebel, W. F. and O. T. Avery,
J. Exp. Med.
54:431-436 (1931)). These observations initiated and formed the basis of the current conjugate vaccine technology. Numerous studies have followed and show that when polysaccharides are coupled to proteins prior to their administration as vaccines, the immune response to the polysaccharides changes from a T independent response to a T dependent response (see Dick, W. E., Jr. and M. Beurret, Glycoconjugates of bacterial carbohydrate antigens In:
Contributions to Microbiology and Immunology.
Cruse et al., eds., (1989) p. 48-114; Jennings, H. J. and R. K. Sood,
Neoglycoconjugates: Preparation and Applications.
Y. C. Lee and R. T. Lee, eds., Academic Press, New York. (1994) p. 325-371; Robbins, J. B. and R. Schneerson,
J. Infect. Dis.
161:821-832 (1990)for reviews). Currently, most of these polysaccharide-protein conjugate vaccines are formulated with well known proteins such as tetanus toxoid and diphtheria toxoid or mutants thereof. These proteins were originally used because they were already licensed for human use and were well characterized. However, as more and more polysaccharides were coupled to these proteins and used as vaccines, interference between the various vaccines which used the same protein became apparent. For example, if several different polysaccharides were linked to tetanus toxoid and given sequentially, the immune response to the first administered polysaccharide conjugate would be much larger than the last. If, however, each of the polysaccharides were coupled to a different protein and administered sequentially, the immune response to each of the polysaccharides would be the same. Carrier suppression is the term used to describe this observed phenomenon. One approach to overcome this problem is to match the protein and polysaccharide so that they are derived from the same organism.
Among the various antigens used to classify and subgroup Group B streptococci, one was a protein known as the Ibc antigen. This protein antigen was first described by Wilkinson and Eagon in 1971 (Wilkinson, H. W. and R. G. Eagon,
Infect. Immun.
4:596-604 (1971)) and was known to be made up of two distinct proteins designated as alpha and beta. Later, the Ibc antigen was shown to be effective when used as a vaccine antigen in a mouse model of infection by Lancefield and co-workers (Lancefield, R. C., et al.,
J. Exp. Med.
142:165-179 (1975)). The isolation, purification and functional chara

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