Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2002-05-10
2003-09-02
Graser, Jennifer (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, C424S184100, C424S193100, C424S203100, C424S249100, C424S250100
Reexamination Certificate
active
06613336
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of vaccines useful for raising an immune response in an animal. In particular, the invention relates to
H. influenzae
polysaccharide-
N. meningitidis
outer membrane protein conjugates, pharmaceutical compositions and the use thereof.
2. Background Information
Haemophilus influenzae
are small, pleomorphic, Gram-negative coccobacilli. Isolates are classified into six antigenically distinct capsular types (a-f) and nonencapsulated, nontypable strains.
Haemophilus influenzae
can cause meningitis, otitis media, sinusitis, epiglottitis, septic arthritis, occult febrile bacteremia, cellulitis, pneumonia, and empyema; occasionally this organism causes neonatal meningitis and septicemia. Other
H. influenzae
infections include purulent pericarditis, endocarditis, conjunctivitis, osteomyelitis, peritonitis, epididymo-orchitis, glossitis, uvulitis, and septic thrombophlebitis. Most cases of invasive diseases in children before the introduction of
H. influenzae
type b (Hib) conjugate vaccination were caused by type b. Nonencapsulated organisms can cause invasive disease in newborns. Nonencapsulated strains cause upper respiratory tract infection, including otitis media, sinusitis, and bronchitis, and may cause pneumonia.
The source of the organism is the upper respiratory tract of humans. The mode of transmission is presumably person to person, by direct contact, or through inhalation of droplets of respiratory tract secretions containing the organism. Asymptomatic colonization by nonencapsulated strains is frequent; organisms are recovered from the throat of 60% to 90% of children. Colonization by type b organisms, however, is infrequent, ranging from 2% to 5% of children in the pre-vaccine era, and appears to be even less frequent with widespread Hib conjugate vaccination. The exact period of communicability is unknown but may be for as long as the organism is present in the upper respiratory tract.
Before the introduction of effective vaccines, Hib was the most common cause of bacterial meningitis in children in the United States and in many other countries. Meningitis and other invasive infections were most common in children 3 months to 3 years of age and approximately half of the cases occurred in infants younger than 12 months. The age-specific incidence of invasive type b disease in different populations in countries has varied; the proportion of disease in infants younger than 12 months tends to be greatest in populations with the highest total incidence, resulting in a lower median age of cases. In contrast to meningitis and most other invasive Hib diseases, epiglottitis is rare in infants younger than 12 months; its peak occurrence in the pre-vaccine era was 2 to 4 years of age. Epiglottitis also can occur in older, unvaccinated children and adults.
Invasive disease has been more frequent in boys, African-Americans, Alaskan Eskimos, Apache and Navajo Indians, child care center attendees, children living in overcrowded conditions and children who were not breast-fed. Unimmunized children, particularly those younger than 4 years who are in prolonged, close contact (such as in a household) with a child with invasive Hib disease, are at an increased risk for serious infection from this organism. Other factors predisposing to invasive disease include sickle cell disease, asplenia, HIV infection, certain immunodeficiency syndromes, and malignancies. Infants younger than 1 year with documented invasive infection are at an approximate 1% risk of recurrence, if not subsequently vaccinated.
Since 1988 when Hib conjugate vaccines were introduced, the incidence of invasive Hib disease has declined by 95% in infants and young children and the incidence of invasive infections caused by other encapsulated types is now similar to that caused by type b. As a result of this success, the U.S. Public Health Service has targeted Hib disease in children younger than 5 years for elimination in this country. Invasive Hib disease occurs now in this country primarily in under vaccinated children and among infants too young to have completed the primary series of vaccinations.
Four Hib conjugate vaccines have been licensed in the United States. These vaccines consist of the Hib capsular polysaccharide (ie, polyribosylribotol phosphate (PRP) or PRP oligomers) covalently linked to a carrier protein directly or via an intervening spacer molecule. Protective antibodies are directed against PRP. Conjugate vaccines differ in composition and immunogenicity and, as a result, recommendations for their use differ. For example, PRP-D is recommended only for children 12 months of age and older, whereas the other three vaccines, HbOC, PRP-T, and PRP-OMP, are recommended for infants beginning at 2 months of age.
Adjuvants are substances that augment the immune response to antigens and, therefore, have been used in many vaccines and vaccine candidates. The immune stimulatory effect of adjuvants is not antigen specific, as they boost immune responses towards many different types of antigens. The only adjuvants currently approved for human use by the FDA are aluminum salts, but many adjuvants used in animal vaccinations and in newer vaccine candidates are microbial in origin (61) e.g. Freund's adjuvant,
Corynebacterium parvum
, muramyl dipetide, tetanus toxoid, etc. The mechanisms for the immunopotentiating ability of microbial substances are unknown.
The major outer membrane proteins of the pathogenic Neisseria (
Neisseria gonorrhoeae
and
Neisseria meningitidis
) have been investigated for adjuvant potential (36, 37, 39, 40, 60) and for the mechanism behind their immunopotentiating ability. The proteins of interest are protein IA (PIA) and protein IB (PIB) from the gonococcus and class 1, 2 or 3 proteins from the meningococcus (C1, C2 and C3 respectively) (4). They all function as porins (41, 43, 62), have significant amino acid sequence homology amongst each other (6, 7, 21, 59) and are considered to be part of the gram negative porin superfamily (26).
Neisserial porins, when complexed non-covalently with malarial peptides, were shown to enhance the antibody response to these peptides as compared to when the peptides were used as an immunogen alone or covalently linked to other proteins (39, 40). In addition, peptides derived from Group A streptococcus (38), influenza virus hemagglutinin (38), or
Trypanosome bruceei
(40) were shown to be more immunogenic in mice when incorporated into complexes containing Neisserial porins as compared to when the mice were immunized with peptides alone. Meningococcal outer membrane vesicles (OMV), mainly consisting of the class 2 protein, were used as a carrier to boost the immune response towards the
H. influenzae
polysaccharide capsule in the recently licensed
H. influenzae
type b vaccine developed by Merck (10). Furthermore, Livingston has explored the use of purified Neisserial porins as adjuvants in anti-melanoma vaccines. Melanoma cells express much higher levels of the human gangliosides GM2 or GD3 on their surface as compared to normal melanocytes. To augment the immune response to GM2 and GD3, and possibly induce tumor immunity in melanoma patients, GM2 and GD3 were noncovalently associated with purified Neisserial porins and volunteers with malignant melanoma were immunized with these vaccine constructs. Anti-GM2 or anti-GD3 antibody responses were greatly enhanced in patients immunized with porin/GM2 or porin/GD3 complexes as compared to patients immunized with these gangliosides alone or complexed with BCG (36, 37). In addition, the tumor burden in patients immunized with porin/GM2 decreased significantly (personal communication, P. Livingston).
The mechanisms by which the Neisserial porins act as adjuvants are unknown. The group from Merck (10, 35, 56), who developed the Haemophilus polysaccharide capsule—meningococcal OMV conjugate vaccine, thought that it might be due to direct T cell stimulation by the class 2 protein. They initially demonstrated that the
Blake Milan S.
Fusco Peter C.
Heron Iver
Michon Francis
Baxter International Inc.
Faraci C. Joseph
Graser Jennifer
Heller Ehrman White & McAuliffe LLP
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