Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1998-12-07
2002-03-12
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S197110, C424S200100, C424S237100, C424S244100, C424S823000, C424S825000, C424S828000, C424S829000, C435S007340, C435S024000, C435S036000, C435S093000, C435S165000, C435S216000, C435S219000, C435S253400, C435S340000, C530S388400
Reexamination Certificate
active
06355255
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. Maitin 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 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 an 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-teimini 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 may not prevent colonization by streptococci.
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 immunize a susceptible mammal against &bgr;-hemolytic Streptococcus. The susceptible mammal could be a human or a domestic animal such as a dog, a cow, a pig or a horse. Such immunization could prevent, ameliorate or reduce the incidence of &bgr;-hemolytic Streptococcus colonization in the mammal. The vaccine contains an immunogenic amount of streptococcal C5a peptidase (SCP), wherein the SCP is a variant of wild-type SCP in combination with a physiologically-acceptable, non-toxic vehicle.
A “variant” of SCP is a polypeptide or oligopeptide SCP that is not completely identical to native SCP. Such a variant SCP can be obtained by altering the amino acid sequence by insertion, deletion or substitution of one or more amino acid. The amino acid sequence of the protein is modified, for example by substitution, to create a polypeptide having substantially the same or improved qualities as compared to the native polypeptide. The substitution may be a conserved substitution. A “conserved substitution” is a substitution of an amino acid with another amino acid having a similar side chain. A conserved substitution would be a substitution with an amino acid that makes the smallest change possible in the charge of the amino acid or size of the side chain of the amino acid (alternatively, in the size, charge or kind of chemical group within the side chain) such that the overall peptide retains its spacial conformation but has altered biological activity. For example, common conserved changes might be Asp to Glu, Asn or Gln; His to Lys, Arg or Phe; Asn to Gin, Asp or Gli and Ser to Cys, Thr or Gly. Alanine is commonly used to substitute for other amino acids. The 20 essential amino acids can be grouped as follows: alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan and methionine having nonpolar side chains; glycine, serine, threonine, cystine, tyrosine, asparaginc and glutamine having uncharged polar side chains; aspartate and glutamate having acidic side chains; and lysine, arginine, and histidine having basic side chains. L. Stryer,
Cleary Paul Patrick
Stafslien Deborah K.
Hines Jana A.
Regents of the University of Minnesota
Schwegman Lundberg Woessner & Kluth P.A.
Smith Lynette R. F.
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