Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-03-03
2002-01-29
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...
C424S193100, C424S200100, C424S201100, C424S203100, C424S202100, C424S282100, C435S069100, C530S350000
Reexamination Certificate
active
06342232
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
which is useful in protecting against disease caused by
Haemophilus influenzae
including otitis media.
BACKGROUND OF 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 this application, various references 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 and 6). Non-encapsulated or nontypeable
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. 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. Furthermore, many of the causative organisms of otitis media are becoming resistant to antibiotic treatment. An effective prophylactic vaccine against otitis media is thus 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. 9) 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 (refs. 10, 11). The HMWA proteins have been demonstrated to be adhesins mediating attachment to human epithelial cells (ref. 12). Immunization with a mixture of native HMW1A and HMW2A proteins resulted in partial protection in the chinchilla intrabulla challenge model of otitis media (ref. 13)
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 influenzae
. The HMW proteins are a family of proteins from non-typeable
Haemophilus influenzae
of molecular weight of about 120 to 125 kDa which are absent from encapsulated strains of
Haemophilus influenzae.
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 copending 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. 14) and the rHMW proteins are protective in this model as described in the aforementioned copending U.S. patent application Ser. No. 09/167,568. The rHMW1A and rHMW2A proteins were shown to afford equivalent protection and the rHMW1A protein was chosen for further vaccine studies. In this application, rHMW refers to recombinant HMW1A from NTHi strain 12, although other corresponding recombinant HMW1A proteins from other NTHi strains and corresponding HMW2A proteins 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. 15, 16, 17). The NTHi member of this second family is termed
Haemophilus influenzae
adhesin or Hia and the homologous protein found in encapsulated strains is termed
Haemophilus influenzae
surface fibril protein or Hsf.
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 the Hia and Hsf proteins, which have limited homology to the HMW1 and HMW2 proteins of U.S. Pat. No. 5,603,938.
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.
United States patent application Ser. No. 09/268,347 filed Mar. 26, 1999, assigned to the assignee hereof and the disclosure of which is incorporated herein by reference, describes the production of full-length and N-terminal 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-terminal truncated Hia proteins from other NTHi strains may be employed. The corresponding naturally-occurring proteins may be employed. The corresponding naturally-occurring proteins may be employed.
When under environmental stress, such as high temperature, organisms overproduce stress response or heat shock proteins (hsps). Bacterial hsps have been shown to be important immunogens, stimulating both B cells and T cells (ref. 18). The bacterial HtrA or DegP heat shock proteins are expressed under conditions of stress and the
H. influenzae
HtrA or Hin47 protein has been shown to be a partially protective antigen in the intrabulla challenge model of otitis media (ref. 19). The HtrA proteins are serine proteases and their proteolytic activity makes them unstable. In addition, as components of a multicomponent vaccine, the wild-type HtrA protein will degrade mixed antigens. The site-directed mutagenesis of the
H. influenzae
htrA gene (termed hin47) and the properties of the mutants have been fully described in U.
Klein Michel H.
Loosmore Sheena M.
Yang Yan-Ping
Aventis Pasteur Limited
Graser Jennifer E.
Sim & McBurney
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