Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1996-11-15
2003-05-06
Navarro, Mark (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S249100, C424S250100
Reexamination Certificate
active
06558677
ABSTRACT:
INTRODUCTION
Group B meningococcal disease currently accounts for at least one half of all meningococcal disease in many countries including North and South America, and Europe. The emergence of a new virulent clone of group B
Neisseria meningitidis
, known as ET5, in Norway in the late 70's has since been responsible for prolonged epidemics in Norway, Cuba, Brazil, and Chile. These epidemics have created serious public health problems and led to intensive efforts to develop an effective group B vaccine in several of the affected countries. Recently, an outbreak of group B disease caused by the ET5 clone occured in the U.S. Northwest. This could indicate that the ET5 clone is gaining a foothold in the U.S. and that an increase in the incidence of group B disease in the U.S. may occur in the next few years. The absence of a U.S.-licensed group B vaccine along with the poor performance of the A and C capsular polysaccharide vaccines in children under 18 months have prevented serious consideration of routine childhood vaccination against meningococcal disease. Current efforts to develop conjugate group A and C polysaccharide vaccines by several companies will likely yield A and C vaccines with improved performance in young children and will make routine vaccination of children against meningococcal disease more attractive, particularly if an effective group B vaccine becomes available.
Neisseria, including
Neisseria meningitidis
and
Neisseria gonorrhoeae
have an outer membrane that is rather loosely associated with the rigid cell wall peptidoglycan layer and naturally blebs off during growth of the organism [Zollinger, W.D. et al. (1972)
Infect. Immun
. 6:835-851] (All documents cited herein supra and infra are hereby incorporated by reference thereto.). Vesicles of outer membrane can be obtained from a meningococcal culture supernatant or by extraction from the organism by mild procedures [Zollinger, W. D., ibid.]. These vesicles appear to be representative of intact outer membrane and can be easily obtained in high yield. Although an excellent antigen, the use of these vesicles directly as a vaccine against meningococcal disease has been considered impractical because of the high levels of lipopolysaccharide (a potent endotoxin) associated with them. Typically, the weight ratio of LPS to protein in the outer membrane is about 0.3 to 0.8. For many years, efforts have been made to utilize the outer membrane proteins as a vaccine for group B meningococcal disease by using detergents to remove most of the lipopolysaccharide from the outer membrane. These candidate vaccines have been partially successful (50 to 80% efficacy in field trials), but have failed to induce protective antibody responses in children under the age of four years. Protection induced by these vaccines also seems to be of limited duration. The young children have IgG antibody responses against the outer membrane proteins that equals or exceeds those of older children, but most of the antibodies are not bactericidal or protective.
Therefore, there is a need for a
Neisseria meningitidis
vaccine which produces a lasting, protective immunogenic response capable of protecting an individual against meningococcal disease.
SUMMARY
The present invention fulfills the need described above.
The present invention relates to a vaccine and methods of producing a vaccine or vaccines that can be used to immunize an individual against meningococcal disease, and in the extended application, against other Gram negative infections with bacteria such as Shigella, Brucella, Pseudomonas,
E. coli
, and Haemophilus.
The vaccine of the present invention introduce the outer membrane proteins (OMPs) in their natural phospholipid/lipopolysaccharide (LPS) environment as native outer membrane vesicles (NOMV), and results in an improved functional (bactericidal) antibody response to the outer membrane proteins (OMPs) in animals and should behave similarly in humans and children under the age of 4 years. We have shown that this type of vaccine, which is normally considered to be too toxic for use as a parenteral vaccine, can be safely administered via the intranasal route. Intranasal immunization is ideal for meningococcal vaccines since asymptomatic nasopharyngeal colonization by less pathogenic meningococci and closely related species results in natural immunization of most individuals. The human nasopharynx is the natural habitat of
N. meningitidis
and at any given time approximately 5 to 10% of healthy individuals carry it on their throats.
There are several advantages to using a native outer membrane vesicle as an intranasal vaccine for
N. meningitidis
or other Gram negative infection. NOMV can be prepared easily at relatively low cost so the technology and the product produced by it may be more accessible to under-developed countries.
The antigens presented as part of NOMV, including the OMPs and the LPS, are in a completely native configuration and environment as part of intact outer membrane that has not been exposed to detergent. This results in an antibody response that is directed primarily toward epitopes exposed on the surface of the intact bacterium. These antibodies are more likely to be functional than if directed against epitopes that are conformationally altered (by detergent extraction for example), or not fully exposed at the surface of the viable organism. In addition, giving the NOMV vaccine intranasally results in very little reactogenicity or toxicity in spite of relatively high endotoxin content.
The intranasal route of vaccination mimics the natural route of immunization for
N. meningitidis
and, as judged by the results of animal experiments, is expected to induce a mucosal immune response as well as a serum antibody response. Antibodies to antigens such as Opc and Opa proteins and pili may play a more important role in protection at the mucosal surface during the initial phases of pathogenesis than they do in the serum where the organism may have turned off their expression. The nasopharynx is the natural portal of infection for the meningococcus.
In the youngest children who have had little exposure to meningococci, it may be particularly important to prime the immune system with a very native antigen that can induce protective antibodies so that subsequent colonization with meningococci will be effective in boosting protective immunity. In contrast, isolated OMPs given as a vaccine tend to induce a preponderance of antibody that is non-functional in a bactericidal assay.
In particular, the present invention relates to the use of NOMV from a vaccine strain that has been genetically modified in order to produce maximum immunogenicity with least toxicity. More specifically, a vaccine strain of the present invention includes a modified strain which does not synthesize sialic acid (capsule and sialylated LPS) resulting in better interaction of the NOMV with the mucosal surface and producing higher immunogenicity.
Preferably, the vaccine strain is grown under iron limiting conditions to induce the expression of the iron uptake proteins including transferrin and lactoferrin binding proteins resulting in a vaccine that contains additional antigens with known protective potential both by inducing bactericidal antibodies and by inducing antibodies that can block the binding of iron by the organism.
Therefore, it is an object of the present invention to provide a Neisseria vaccine comprising purified native outer membrane vesicles of Neisseria in an amount effective to elicit protective antibodies in an animal to Neisseria; and a pharmaceutically acceptable diluent, carrier, or excipient.
It is another object of the present invention to provide a
Neisseria meningitidis
vaccine comprising purified native outer membrane vesicles of
Neisseria meningitidis
in an amount effective to elicit protective antibodies in an animal to
Neisseria meningitidis
; and a pharmaceutically acceptable diluent, carrier, or excipient
It is yet another object of the present invention to provide a
Neisseria
Brandt Brenda L.
Saunders Agnes G.
Shoemaker David R.
Zollinger Wendell D.
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