Group B Streptococcus vaccine

Details Group B Streptococcus vaccine Group B Streptococcus vaccine

1998-03-18

2002-07-30

Graser, Jennifer E. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S184100, C424S193100, C424S197110, C424S203100, C530S350000, C536S123100

Reexamination Certificate

active

06426074

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the fields of microbiology and vaccine technology, and concerns the development of vaccines capable of conferring immunity to infection by group B Streptococcus.
BACKGROUND OF THE INVENTION
Streptococcus agalactiae
(GBS) is the leading cause of neonatal sepsis and early onset meningitis in infants in the United States, causing over 2,000 deaths each year. Thus GBS is an important disease pathogen. GBS is also responsible for more than 50,000 cases of maternal postpartum endometritis (Baker, C., In:
Infectious Diseases of the Fetus and Newborn Infant
. Remington J., et al. eds. Philadelphia: W. B. Saunders, (1990), pp. 742-811). Recently, GBS has increasingly been seen to cause serious infections in nonpregnant adults, primarily among the inmmunocompromised, elderly individuals and diabetics. Invasive infection has been diagnosed in 4.4 per 100,000 nonpregnant adults, with a mortality rate of 21% (Farley; M. M., et al.,
N. Engl. J Med
328(25):1807-1811 (1993)). This prospective surveillance study documented an annual incidence of invasive GBS disease to be 9.2 cases per 100,000 population. The incidence of invasive GBS infections in adults is higher than the incidence of infections caused by many other important pathogens, including the meningococci. Although GBS is sensitive to antibiotics, the rapid onset of the disease in neonates and infants also leads to high morbidity (50%) and mortality (20%) (Baker, C., In:
Infectious Diseases of the Fetus and Newborn Infant
. Remington J., et al. eds. Philadelphia: W. B. Saunders, (1990), pp. 742-811; Michel, J. L.,
Infectious Disease Practice
13:1-12 (1990)). Therefore, there is a need to develop vaccines capable of conferring immunity to infection by GBS.
The pathogenic streptococci express a number of surface-associated, opsonic, and protective polysaccharides and protein antigens (Kehoe, M. A.,
Vaccine
9:797-806 (1991); Lachenauer, C. S. & L. C. Madoff,
Infect. Immun
. 64:4255-4260 (1996)). The type-specific capsular polysaccharide by itself is not very immunogenic; however, antibodies to conjugates of the capsular polysaccharides and protein antigens elicit protection in animal models of GBS infections (Kasper, D., et al., in
Vaccines
94, E. Norrby (ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1994), pp. 113-117; Weis, J. H. in
Current Protocols in Molecular Biology
, Vol. 1, F. M., Ausubel, et al., (eds.), John Wiley & Sons, Inc., New York, (1994), pp. 6.2.1-6.2.3.; Paoletti, L. C., et al.,
Infect. Immun
. 62:3236-3243 (1994); Wessels, M. R., et al.,
Infect. Immun
. 61:4760-4766 (1993)).
GBS also expresses a family of protective and well-characterized protein antigens called C proteins (alpha and beta) and R protein (Rib), also known as R4 (Heden, L. et al.,
Eur. J. Immunol
. 21:1481-1490 (1991); Jerlstrom, P. G., et al.,
Mol. Microbiol
. 5:843-849 (1991); Larsson, C., et al.,
Infect. Immun
. 64:3518-3523 (1996); Michel, J. L., et al., in
Genetics and Molecular Biology of Streptococci, Lactococci, and Enterococci
, G. M. Dunny, et al., (eds.), American Society for Microbiology, Washington, D.C., (1991), pp. 214-218; Michel, J. L., et al.,
Infect. Immun
. 59:2023-2028 (1991); Michel, J. L., et al.,
Proc. Natl. Acad. Sci. USA
. 89:10060-10064 (1992); St{dot over (a)}lhammar-Carlemalm, M., et al.,
J. Exp. Med
. 177:1593-1603 (1993); Wästfelt, M., et al.,
J. Biol. Chem
. 271:18892-18897 (1996)). Recently an additional C-protein, the epsilon antigen was discovered (DuBois, N. B. Genetic and phenotypic properties of the surface proteins of group B Streptococcus and the identification of a new protein, Bachelor of Arts thesis in Biology, Harvard College, (1995)
The C proteins (alpha and beta, and epsilon) are surface-associated proteins on GBS carrying immunogenic epitopes that elicit protective antibodies. Antibodies raised against partially purified C proteins in rabbits were originally shown by Lancefield et al. to provide passive protection in mice against challenge with C protein-positive strains; C protein antibodies did not protect against C protein-negative strains (Lancefield, R. C., et al.,
J. Exp. Med
. 142(1):165-179 (1975)). Strains bearing C proteins resist phagocytosis and inhibit intracellular killing (Payne, N. R, et al.,
J. Infec. Dis
. 151:672-681 (1985)).
The C proteins have been divided into two species (Russel-Jones et al.,
J. Exp. Med
. 160:1476-1484, 1984) that are independently expressed and antigenically distinct, and have been defined biochemically and immunologically. The alpha antigen is trypsin-resistant and has been shown to increase resistance to opsonophagocytic killing (Madoff et al.,
Infect. Immun
. 59:2638-2644, 1991)), whereas the beta antigen is trypsin-sensitive, and binds preferentially to human serum IgA (Russel-Jones, G. J.,
J. Exp. Med
. 160:1467-1475 (1984)) by a non-immune mechanism. Additionally, there is the epsilon antigen which is believed to be a member of the alpha antigen family. The specific biological roles of these proteins in virulence are not known.
The sequence of the alpha C-protein gene (bca) of GBS reveals four distinct domains: a signal sequence, an N-terminal region, a tandem repeat region, and a C-terminal anchor region (Michel, J. L., et al.,
Proc. Natl. Acad. Sci. USA
. 89:10060-10064 (1992)). Presumably, the epsilon antigen gene (bce) has similar, though not necessarily identical domains. Identification and characterization of protective epitopes within the domains of the alpha, beta and epsilon C proteins will help determine the: immunological properties of these regions. These protective epitopes could be used to develop a C-protein-capsular polysaccharide conjugate vaccines to protect against a broad range of GBS strains.
The alpha antigen gene, bca, was previously cloned from the prototype Ia/C(&agr;/&bgr;) strain A909. The antibodies raised to the cloned gene product were protective in an animal model (Michel, J. L. et al.,
Inf. Immun
. 59:2023-2028 (1991)). In addition, the nucleotide sequence was determined and the derived animo acid sequence analyzed (Michel, J. L., et al.,
Proc. Natl. Acad. Sci. USA
. 89:10060-10064 (1992)). The nucleotide sequence of alpha antigen revealed an open reading frame of 3,060 nucleotides encoding a precursor protein of 108.7 kilodaltons (kDa). The gene is composed of four distinct regions. Cleavage of a putative signal sequence of 56 amino acid yields a mature protein of 104.1 kDa. The 20.4 kDa N-terminal region shows no homology to previously described protein sequences and is followed by a series of nine tandem repeating units that make up 74% of the mature protein. The repeating units are identical, and each consists of 82 amino acids with a molecular mass of 8.7 kDa, which is encoded by 246 nucleotides. The C-terminal region of the alpha antigen contains a membrane anchor domain motif that is shared by a number of gram-positive surface-associated proteins (Michel, J. L., et al.,
Proc. Natl. Acad. Sci. USA
89(21):10060-10065 (1992)) including the group A streptococcal M proteins and the IgG-binding proteins of Staphylococcus (Fischetti, V., et al.,
Mol. Microbiol
. 4:1603-1605, (1990); Wren, B. W., Mol Microbiol 5(4):797-803 (1991)). Immunoblot analysis of the native alpha antigen probed with either antisera to the cloned alpha antigen or an alpha antigen specific monoclonal antibody, 4G8, which binds to the repeat region, yields a regularly spaced ladder pattern of heterogeneous peptides. The bands are spaced at 8-kDa intervals, corresponding to the coding region defined by a single repeating subunit in the gene (Michel, J. L., et al.,
Proc. Natl. Acad. Sci. USA
89(21):10060-10065 (1992)). This correlation suggests that the repeat region is responsible for the laddered peptide heterogeneity of the alpha antigen.
It was reported that the size of the largest alpha antigen expressed by a given strain varies widely, from 54 to >200 kDa Opsonophagocytic killing in the presence of 4G8 antibodies correlated directly with incr

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