Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1997-10-28
2003-05-13
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...
C424S253100, C424S254100, C424S434000, C424S435000
Reexamination Certificate
active
06562352
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to vaccine compositions for delivery to mucosal surfaces, and to a method of inducing, in a mammal, an immune response to an antigen or a mixture of antigens by delivering the antigen or mixture of antigens to a mucosal surface of the mammal.
More particularly, the present invention relates to vaccine compositions for inoculating a mammal such as a human against tetanus and
B. pertussis
infections.
It has long been the practice of clinicians to immunise human infants against a variety of common diseases by means of mixed vaccines which are directed against a plurality of diseases. For example, multiple-component vaccine compositions directed against diphtheria, tetanus and whooping cough have been available for a considerable number of years. Such vaccines have hitherto been administered by injection. The advantages of multiple-component vaccines are readily apparent in that the patient (usually an infant) is subjected to a much smaller number of potentially distressing injections than would otherwise be the case.
The majority of infectious diseases are initiated by contact with a mucosal surface. The infecting agent may remain at or within the mucous membranes during the course of the infection or may penetrate into the body and localise at other sites. The importance of the mucous membranes in the first line of defence against infectious disease can be gleaned from the fact that 90% of the lymphocytes of the body underlie such surfaces. Priming mucosal surfaces by immunisation so that they respond vigorously and effectively control pathogenic organisms they encounter would be advantageous. Unfortunately traditional immunisation regimes are ineffective at eliciting mucosal responses. The systemic and local (mucosal) immune systems appear to be compartmentalised and in general do not impinge on one another; that is parenteral immunisation with non-living vaccines stimulates mucosal immune responses weakly if at all. Mucosal immunisation (oral or intranasal) can evoke serum antibodies but this is usually less effective than parenteral immunisation. The immunocytes of the different mucous membranes form a vast intercommunicating network, termed the common mucosal immune system, such that topical immunisation of one surface (e.g. the gastrointestinal tract) may lead to an immune response at that surface and also distance surfaces such as the respiratory tract.
Manclark and Shahin (U.S. patent application Sre. No. 07/532,327, now abandoned, filed May 6, 1990—available through the US Department of Commerce, National Technical Information Service, Springfield, Va. 22161, U.S.A.)—have described the intranasal and intraduodenal administration of filamentous hemagglutinin (FHA) obtained from
Bordetella pertussis
and have illustrated that FHA is an effective mucosal immuogen. Manclark and Shahin speculated in U.S. Ser. No. 07/532,327, now abandoned, that the 69-kD outer membrane protein (P69) of
B. pertussis
would also be an effective mucosal immunogen, but presented no experimental data to show that this was the case.
The fact that there are very few mucosal vaccines commercially available indicates that there are problems with developing such vaccines Many non-living soluble antigens, particularly those used traditionally by immunologists, such as ovalbumin (OVA) and Keyhole Limpet Haemocyanin (KLH), are poor mucosal immunogens. Large doses of such antigens are necessary to induce any responses but large doses can also cause tolerance in the individual to subsequent parenteral exposure to antigen, a condition known as oral tolerance. Some microbial components such as the cholera toxin (CT) or
E. coli
heat-labile toxin (LT) or the non-toxic binding portions of these toxins (CT-B and LT-B) have been found to be potent mucosal immunogens eliciting strong secretary and circulating antibodies, but the reason why such molecules are good mucosal immunogens has not yet been fully elucidated. One property that may be important is the ability of these molecules to bind to mucosal epithelial cells via certain surface receptors, although it has been found in studies by others that there is not necessarily a correlation between the ability of an antigen to bind to eucaryotic cells and its mucosal immunogenicity.
Thus, as far as we are aware, there is currently no way of predicting with any certainty whether a given antigen will possess good mucosal immunogenicity.
SUMMARY OF THE INVENTION
We have now found that certain molecules make excellent mucosal immunogens and such components can be utilised in the development of a mucosally (intranasally or orally) delivered vaccine against the diseases whooping cough and tetanus. In particular, we have found that the P69 outer membrane protein (P69—also known as pertactin) from
B. pertussis
and the non-toxic immunogenic 50 Kd portion of tetanus toxin (C-Fragment) from
C. tetanii
are highly immunogenic when given intranasally. C-Fragment and P.69 were generated by DNA recombinant technology. Recombinant C-Fragment and P.69 produced from
E. coli
and yeast have been demonstrated to be immunogenic and protective in mice, see M. Roberts et al, Recombinant P.69/pertactin: imminogenicity and protection of mice against
Bordetella pertussis
infection; Vaccine 10, 43 (1992); and see also N. F. Fairweather et al,
Infection and Immunity
, 55, 2541 (1987).
In a first aspect, the invention provides the use of a mucosally immunogenically active substance comprising the 50 kD C fragment of tetanus toxin, an immunogenic fragment thereof, or a derivative thereof formed by amino acid deletion, substitution or insertion, for the manufacture of a vaccine composition for immunising a patient against tetanus infection.
In one particular embodiment of the invention, there is provided the use of a mixture of antigens for the manufacture of a vaccine composition for administration to a mucosal surface to induce an immune response in the mucosal surface against each of the said antigens, the mixture of antigens comprising:
(a) a mucosally immunogenically active substance comprising the 50 kD C fragment of tetanus toxin, an immunogenic fragment thereof, or a derivative thereof formed by amino acid deletion, substitution or insertion; and
(b) a mucosally immunogenically active substance comprising the P.69 outer membrane protein of
B. pertussis
;
an immunogenic fragment thereof, or a derivative thereof formed by amino acid deletion, substitution or insertion.
In a preferred embodiment the invention provides the use of a mixture of antigens as hereinbefore defined but wherein said mixture comprises in addition to (a) and (b);
(c)a mucosally immunogenically active substance comprising
B. pertussis
filamentous haemaglutinin, an immunogenic fragment thereof, or a derivative thereof formed by amino acid deletion, substitution or insertion.
In a further aspect, the invention provides a vaccine composition for application to a mucosal surface, the composition comprising antigen (a) or a mixture of antigens as hereinbefore defined and a pharmaceutically acceptable carrier.
In another aspect the invention, provides a method of immunising a host such as a mammal, (e.g. human) against infection, which method comprises administering an effective amount of antigen (a), or a mixture of antigens as hereinbefore defined, directly to a mucosal surface in the host to induce in said mucosal surface an immune response to each said antigen.
The mucosal delivery compositions of the present invention can be formulated, for example, for delivery to one or more of the oral, gastro-intestinal, and respiratory (e.g. nasal and bronchial) mucosa.
Where the composition is intended for delivery to the respiratory (e.g. nasal or bronchial) mucosa, typically it is formulated as an aqueous solution for administration as an aerosol or nasal drops, or as a dry powder, e.g. for inhalation.
Compositions for administration as nasal drops may contain one or more excipients of the type usually included in such compositions, for example preservativ
Dougan Gordon
Roberts Mark
Medeva Holdings B.V.
Navarro Mark
Wolf Greenfield & Sacks P.C.
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