Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Combination of antigens from multiple bacterial species
Reexamination Certificate
1999-07-15
2002-05-21
Graser, Jennifer E. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Combination of antigens from multiple bacterial species
C424S256100, C424S251100, C424S234100, C424S193100, C424S203100, C424S197110, C530S350000
Reexamination Certificate
active
06391313
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the field of vaccinology and, in particular, to a multi-component vaccine comprising recombinant proteins from
Haemophilus influenzae
and
Moraxella catarrhalis.
BACKGROUND TO THE INVENTION
Haemophilus influenzae
is the cause of several serious human diseases, such as meningitis, epiglottitis, septicemia and otitis media. There are six serotypes of
H. influenzae
, designated a to f, that are identified by their capsular polysaccharide.
H. influenzae
type b (Hib) was a major cause of bacterial meningitis until the introduction of several Hib conjugate vaccines in the 1980's (ref. 1. Throughout the application, various references are referred to in parenthesis to more fully describe the state of the art to which this invention are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into the present disclosure). Vaccines based upon
H. influenzae
type b capsular polysaccharide conjugated to diphtheria toxoid (ref. 2), tetanus toxoid (ref. 3, and U.S. Pat. No. 4,496,538), or
Neisseria meningitidis
outer membrane protein (ref. 4) have been effective in reducing
H. influenzae
type b-induced meningitis. The other serotypes of
H. influenzae
are associated with invasive disease at low frequencies, although there appears to be an increase in the incidence in disease caused by these strains as the incidence of Hib disease declines (refs. 5, 6). Non-encapsulated or non-typeable
H. influenzae
(NTHi) are also responsible for a wide range of human diseases including otitis media, epiglottitis, pneumonia, and tracheobronchitis. The incidence of NTHi-induced disease has not been affected by the introduction of the Hib vaccines (ref. 7).
Otitis media is the most common illness of early childhood, with 60 to 70% of all children, of less than 2 years of age, experiencing between one and three ear infections (ref. 8). Chronic otitis media is responsible for hearing, speech and cognitive impairments in children.
H. influenzae
infections account for about 30% of the cases of acute otitis media and about 60% of chronic otitis media.
M. catarrhalis
infections account for an additional 15 to 20% of acute otitis media. In the United States alone, treatment of otitis media costs between 1 and 2 billion dollars per year for antibiotics and surgical procedures such as tonsillectomies, adenoidectomies and insertion of tympanostomy tubes. It is estimated that an additional $30 billion is spent per annum on adjunct therapies such as speech therapy and special education classes.
Moraxella
(
Branhamella
)
catarrhalis
is the third most common cause of otitis media and sinusitis in children, responsible for 15 to 20% of disease. It has also been associated with lower respiratory tract disease in children and adults, including pneumonia and chronic bronchitis and more rarely it can cause bacteremia and meningitis (refs. 9, 10, 11). There are no vaccines available to protect against
M. catarrhalis
disease. Furthermore, many of the causative organisms of otitis media are becoming resistant to antibiotic treatment. An effective prophylactic vaccine against otitis media is thus highly desirable.
During natural infection, surface-exposed outer membrane proteins that stimulate an antibody response are potentially important targets for bactericidal and/or protective antibodies and therefore potential vaccine candidates. Barenkamp and Bodor (ref. 12) demonstrated that convalescent sera from children suffering from otitis media due to NTHi, contained antibodies to high molecular weight (HMW) proteins. About 70 to 75% of NTHi strains express the HMW proteins and most of these strains contain two gene clusters termed hmw1ABC and hmw2ABC (ref s. 13, 14). The HMWA proteins have been demonstrated to be adhesins mediating attachment to human epithelial cells (ref. 15). Immunization with a mixture of native HMW1A and HMW2A proteins resulted in partial protection in the chinchilla intrabulla challenge model of otitis media (ref. 16).
U.S. Pat. No. 5,603,938 (Barenkamp), assigned to St. Louis University and Washington University and the disclosure of which is incorporated herein by reference, describes the cloning, expression and sequencing of the genes encoding the HMW1 and HMW2 proteins from strain 12 of non-typeable Haemophilus. The HMW proteins are a family of proteins from non-typeable Haemophilus of molecular weight of about 120 to 125 kDa which are found in non-typeable Haemophilus strains. The HMW proteins are absent from encapsulated strains of Haemophilus.
The production of native HMW proteins from
H. influenzae
strains is very low and a method for producing protective recombinant HMW (rHMW) proteins has been described in U.S. patent application Ser. No. 09/167,568 filed Oct. 7, 1998, assigned to the assignee hereof and the disclosure of which is incorporated herein by reference. A chinchilla nasopharyngeal colonization model has been developed specifically to demonstrate vaccine efficacy of adhesins (ref. 17) and the rHMW proteins are protective in this model as described in the aforementioned U.S. patent application No. 09/167,568. The rHMW1A and rHMW2A proteins were shown to afford equivalent protection to each other and the rHMW1A protein was chosen for further vaccine studies. In this application, rHMW refers to recombinant HMW1A from NTHi strain 12, although the corresponding recombinant HMW1A protein from other NTHi strains and corresponding rHMW2A protein from NTHi strains may be employed. The corresponding naturally-occurring proteins may be employed.
A second family of high molecular weight adhesion proteins has been identified in about 25% of NTHI and in encapsulated
H. influenzae
strains (refs. 18, 19, 20). U.S. Pat. No. 5,646,259 (St. Geme, III et al), assigned to St. Louis University and Washington University, and the disclosure of which is incorporated herein by reference, describes the cloning, expression and sequences of genes encoding what are termed therein the HA1 and HA2 proteins, which have limited homology to the HMW1 and HMW2 proteins of U.S. Pat. No. 5,603,938.
The NTHi member of this second family is termed
Haemophilus influenzae
adhesin or Hia (HA1) and the homologous protein found in encapsulated strains is termed
Haemophilus influenzae
surface fibril protein or Hsf (HA2). The hia gene was originally cloned from an expression library using convalescent sera from an otitis media patient, which indicates that it is an important immunogen during disease. The prototype Hia and Hsf proteins demonstrate about 82% sequence similarity, although the Hsf protein is considerably larger. The proteins are comprised of conserved amino and carboxy termini and several repeat motifs, with Hsf containing more repeat sequences than Hia.
U.S. patent application Ser. No. 09/268,347 filed Mar. 16, 1999 (1038-860), assigned to the assignee hereof and the disclosure of which is incorporated herein by reference, describes the production of full-length and N-terminally truncated versions of the Hia protein (rHia) in
E. coli
. These recombinant proteins have been demonstrated to protect against bacteremia caused by
H. influenzae
type a and type b organisms, and to confer partial protection against nasopharyngeal colonization by non-typeable
H. influenzae
. In this application, rHia refers to V38 rHia from NTHi strain 11, although other recombinant full-length and N-terminally truncated Hia proteins from other NTHi strains may be employed. Corresponding naturally-occurring proteins also may be employed.
A high molecular weight adhesin identified in
M. catarrhalis
, has been termed 200 kDa and is described in U.S. Pat. No. 5,808,024 (Sasaki et al), assigned to the assignee hereof and the disclosure of which is incorporated herein by reference, as well as copending U.S. application
Klein Michel H.
Loosmore Sheena M.
Sasaki Ken
Yang Yan-Ping
Aventis Pasteur Limited
Graser Jennifer E.
Sim & McBurney
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