Streptococcal C5a peptidase vaccine

Details Streptococcal C5a peptidase vaccine Streptococcal C5a peptidase vaccine

1998-12-07

2001-08-07

Minnifield, Nita (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

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

C424S234100, C424S184100, C424S093200, C424S177100, C435S252300, C514S002600, C514S013800

Reexamination Certificate

active

06270775

ABSTRACT:

BACKGROUND OF THE INVENTION
There are several different &bgr;-hemolytic streptococcal species that have been identified.
Streptococcus pyogenes
, also called group A streptococci, is a common bacterial pathogen of humans. Primarily a disease of children, it causes a variety of infections including pharyngitis, impetigo and sepsis in humans. Subsequent to infection, autoimmune complications such as rheumatic fever and acute glomerulonephritis can occur in humans. This pathogen also causes severe acute diseases such as scarlet fever, necrotizing fasciitis and toxic shock.
Sore throat caused by group A streptococci, commonly called “strep throat,” accounts for at least 16% of all office calls in a general medical practice, depending on the season. Hope-Simpson, E., “
Streptococcus pyogenes
in the throat: A study in a small population, 1962-1975
,” J. Hyg. Camb
., 87:109-129 (1981). This species is also the cause of the recent resurgence in North America and four other continents of toxic shock associated with necrotizing fasciitis. Stevens, D. L., “Invasive group A streptococcus infections,”
Clin. Infect. Dis
., 14:2-13 (1992). Also implicated in causing strep throat and occasionally in causing toxic shock are groups C and G streptococci. Hope-Simpson, E., “Streptococcus pyogenes in the throat: A study in a small population, 1962-1975
,” J. Hyg. Camb
., 87:109-129 (1981).
Group B streptococci, also known as
Streptococcus agalactiae
, are responsible for neonatal sepsis and meningitis. T. R. Martin et al., “The effect of type-specific polysaccharide capsule on the clearance of group B streptococci from the lung of infant and adult rats”,
J. Infect Dis
., 165:306-314 (1992). Although frequently a member of vaginal mucosal flora of adult females, from 0.1 to {fraction (0.5/1000)} newborns develop serious disease following infection during delivery. In spite of the high mortality from group B streptococcal infections, mechanisms of the pathogenicity are poorly understood. Martin, T. R., et al., “The effect of type-specific polysaccharide capsule on the clearance of Group B streptococci from the lung of infant and adult rats,”
J. Infect. Dis
., 165:306-314 (1992).
Streptococcal infections are currently treated by antibiotic therapy. However, 25-30% of those treated have recurrent disease and/or shed the organism in mucosal secretions. At present no means is available to prevent streptococcal infections. Historically, streptococcal vaccine development has focused on the bacterium's cell surface M protein. Bessen, D., et al., “Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococci,”
Infect. Immun
., 56:2666-2672 (1988); Bronze, M. S., et al., “Protective immunity evoked by locally administered group A streptococcal vaccines in mice,”
Journal of Immunology
, 141:2767-2770 (1988).
Two major problems will limit the use, marketing, and possibly FDA approval, of a M protein vaccine. First, more than 80 different M serotypes of
S. pyogenes
exist and new serotypes continually arise. Fischetti, V. A., “Streptococcal M protein: molecular design and biological behavior,
Clin. Microbiol. Rev
., 2:285-314 (1989). Thus, inoculation with one serotype-specific M protein will not likely be effective in protecting against other M serotypes. The second problem relates to the safety of an M protein vaccine. Several regions of the M protein contain antigenic epitopes which are immunologically cross-reactive with human tissue, particularly heart tissue. The N-termini of M proteins are highly variable in sequence and antigenic specificity. Inclusion of more than 80 different peptides, representing this variable sequence, in a vaccine would be required to achieve broad protection against group A streptococcal infection. New variant M proteins would still continue to arise, requiring ongoing surveillance of streptococcal disease and changes in the vaccine composition. In contrast, the carboxyl-termini of M proteins are conserved in sequence. This region of the M protein, however, contains an amino acid sequence which is immunologically cross-reactive with human heart tissue. This property of M protein is thought to account for heart valve damage associated with rheumatic fever. P. Fenderson et al., “Tropomyosinsharies immunologic epitopes with group A streptococcal M proteins,
J. Immunol
. 142:2475-2481 (1989). In an early trial, children who were vaccinated with M protein in 1979 had a ten fold higher incidence of rheumatic fever and associated heart valve damage. Massell, B. F., et al., “Rheumatic fever following streptococcal vaccination,
JAMA
, 207:1115-1119 (1969).
Other proteins under consideration for vaccine development are the erythrogenic toxins, streptococcal pyrogenic exotoxin A and streptococcal pyrogenic exotoxin B. Lee, P. K., et al., “Quantification and toxicity of group A streptococcal pyrogenic exotoxins in an animal model of toxic shock syndrome-like illness,”
J. Clin. Microb
., 27:1890-1892 (1989). Immunity to these proteins could prevent the deadly symptoms of toxic shock, but will not prevent colonization by streptococci, nor likely lower the incidence of strep throat. Estimates suggest that the incidence of toxic shock infections is 10 to 20 cases per 100,000 population; therefore, use of these proteins to immunize the general population against toxic shock is neither practical nor economically feasible.
Thus, there remains a continuing need for an effective means to prevent or ameliorate streptococcal infections. More specifically, a need exists to develop compositions useful in vaccines to prevent or ameliorate colonization of host tissues by streptococci, thereby reducing the incidence of strep throat and impetigo. Elimination of sequelae such as rheumatic fever, acute glomerulonephritis, sepsis, toxic shock and necrotizing fasciitis would be a direct consequence of reducing the incidence of acute infection and carriage of the organism. A need also exists to develop compositions useful in vaccines to prevent or ameliorate infections caused by all &bgr;-hemolytic streptococcal species, namely groups A, B, C and G.
SUMMARY OF THE INVENTION
The present invention provides a vaccine, and methods of vaccination, effective to prevent or reduce the incidence of &bgr;-hemolytic Streptococcus in susceptible mammals, including humans, and domestic animals such as dogs, cows, pigs and horses. The vaccine contains an immunogenic amount of streptococcal C5a peptidase (SCP), or one or more immunogenic fragments or mutants thereof in combination with a physiologically-acceptable, non-toxic vehicle. The vaccine may comprise a fragment or mutant SCP that lacks SCP enzymatic activity (dSCP). It may also contain an immunological adjuvant. The vaccine can be used to prevent colonization of group A Streptococcus, group B Streptococcus, group C Streptococcus or group G Streptococcus. The vaccine may comprise an immunogenic recombinant streptococcal C5a peptidase conjugated or linked to an immunogenic peptide or to an immunogenic polysaccharide.
The streptococcal C5a peptidase vaccine can be administered by subcutaneous or intramuscular injection. Alternatively, the vaccine can be administered by oral ingestion or intranasal inoculation.
As described in the working examples below, an SCP gene (scpA49) was cloned into an
E. coli
expression vector (pGex-4T-1). The transferase-SCP fusion from the
E. coli
clone was expressed and purified. The purified recombinant SCP (dSCP) was then used to immunize mice. The vaccinated mice and a control group of mice were then challenged with wild-type Streptococci. The mice receiving the recombinant SCP vaccine were free of streptococci soon after infection, whereas 30-50% of the control group were culture positive for many days. Therefore, the recombinant SCP was effective as a vaccine against &bgr;-hemolytic Streptococci.


REFERENCES:
patent: 4454121 (1984-06-01), Beachey
patent: 4695562 (1987-09-01), Beachey et al.
patent: 4772584 (1988-09-01), Cl

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