Tetanus toxin functional fragment antigen and tetanus vaccine

Details Tetanus toxin functional fragment antigen and tetanus vaccine Tetanus toxin functional fragment antigen and tetanus vaccine

1997-09-24

2002-04-16

Swartz, Rodney P (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S184100, C424S185100, C424S190100, C424S234100, C424S239100, C424S247100

Reexamination Certificate

active

06372225

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a tetanus toxin functional fragment antigen and a tetanus vaccine comprising the same. More particularly, the present invention is concerned with a specific tetanus toxin functional fragment antigen which is extremely useful as an antigen for a tetanus vaccine since the functional fragment antigen is advantageous not only in that it is extremely excellent with respect to the diminution of side effects when used as an antigen, as compared to the current tetanus vaccine comprising as an antigen a whole tetanus toxin toxoid, but also in that it has an immunopotency which is substantially the same as that of the whole tetanus toxin toxoid. The present invention is also concerned with a very safe and effective tetanus vaccine (tetanus toxoid) comprising the tetanus toxin functional fragment antigen as an active component, a combined vaccine comprising the tetanus vaccine and at least one vaccine other than the tetanus vaccine, and methods for producing the fragment antigen and vaccines.
2. Prior Art
As is well known, tetanus is an infectious disease with extremely high mortality which produces serious symptoms, such as opisthotonos and dyspnea. Tetanus bacilli are widely distributed in the environments, and their spores are commonly found in soil, feces of animals, and the like. Therefore, every individual is exposed to the danger of tetanus infection from various types of traumas, such as punctured wounds and crushed wounds. Moreover, when an individual is infected with tetanus bacilli, conventional chemotherapies using antibiotics, muscle relaxants and the like cannot grossly change the mortality, whether tetanus patients are elderly or young. In developed countries, most deaths from tetanus have recently occurred among the elderly patients who escaped from vaccination against tetanus in their babyhood.
Further, even when an individual receives tetanus vaccination in baby- or child-hood for basal immunization and receives a booster, the immunity remaining in adulthood is not sufficient for preventing tetanus infection when the individual suffers unexpected injury in earthquakes, fires, traffic accidents or the like. Therefore, it is important for adults of the ages above ca. 40, especially elderly persons, to receive personally a booster injection in order to ensure protection against tetanus.
In developed countries, an increase in the number of intrahospital childbirths, and improvements in living environments and sanitation, an improvement in the quality of emergency medical care with respect to the provision of toxoids and antitoxins, and compulsory vaccinations for younger people, have reduced the number of tetanus patients to {fraction (1/30)} of that of half a century ago. Furthermore, tetanus is a non-epidemic disease and is not transmitted from person to person. Therefore, the importance of the prevention of this disease tends to be overlooked. However, even today, the number of tetanus deaths in the world is estimated to be about 1 million per year, including mostly neonatal tetanus deaths which are prevailing in developing countries. In addition, due to widespread drug abuse, the number of tetanus patients infected through contaminated injection needles is also increasing recently.
Under these circumstances, tetanus is now recognized as a disease to be prevented by vaccination, rather than to be treated, and preventive measures against tetanus are being actively undertaken. For example, in the Expanded Program of Immunization (EPI) of the World Health Organization (WHO), vaccination against tetanus is being adopted as one of the most important tasks, and the vaccination program is being promoted. The “International Conference on Tetanus”, one of whose goals is to eradicate the tetanus disease has been held about every three years in various countries since 1963.
As evident from the above, tetanus is a disease caused by a ubiquitous bacteria whose spores are impossible to eradicate from the earth, and it is not an exaggeration to say that vaccination against tetanus is the only way to reduce the death of human beings due to tetanus, irrespective of age and sex, to zero, and that the vaccination is essential for all human beings who are born on the earth not only at present, but also in the future.
For prevention of tetanus, tetanus toxoid has been used as a vaccine. Tetanus toxoid, which is used as an active component for tetanus vaccine, is tetanus toxin detoxified with formalin. Such a tetanus toxoid has been used in either a plain form without an adjuvant or in the form of a precipitated antigen preparation adsorbed on a small amount of an aluminum salt as an adjuvant or in the form of a combined antigen preparation prepared by mixing tetanus toxoid with other vaccines, such as diphtheria toxoid, pertussis vaccine and Haemophilus influenzae b vaccine. To infants, tetanus toxoid is generally administered in the form of the so-called DPT combined vaccine which is a mixture of vaccines of diphtheria (D), tetanus (T) and pertussis (P) in adsorbed forms. For a tetanus-prophylactic treatment of traumatic patients, a plain T toxoid vaccine or a DT combined toxoid vaccine is used. These toxoids are widely used over the world and the T toxoid preparations have been highly appreciated in the world as one of the most effective and important vaccines. However, the current tetanus toxoid preparations have various problems to be solved. For example, the tetanus toxoid has disadvantages in that there are various adverse side effects, that the product quality is uneven among different manufacturers, that the retention of immunity is limited to only approximately 5 to 10 years and, therefore, repeated vaccinations are necessary to keep the antitoxin level sufficient to prevent tetanus infection. Thus, the conventional tetanus toxoid has problems to be solved with respect to safety, control of quality, retention of immunity, and ease, labor saving and economy in administration. Therefore, for promoting the use of the tetanus vaccine, a large number of problems need to be solved mainly from a viewpoint of mass-production of high quality tetanus vaccine.
Hereinbelow, prior art is discussed in connection with the primary object of the present invention, which is to provide a tetanus toxin antigen, which is not only extremely excellent with respect to the diminution of adverse side effects when used as a vaccine, but also exhibits high immunopotency, thus solving the above-mentioned problems accompanying the prior art.
Various adverse side effects are known to accompany the use of conventional tetanus toxoid vaccines. Various adverse side effects, such as local reactions at injection sites (e.g., erythema, tenderness, swelling, edema and sterile abscess), systemic fever; and, although rare, allergy (e.g., local anaphylaxis, anaphylactic shock, serum sickness-like type III hypersensitivity and delayed hypersensitivity) and serious generalized reactions (e.g., peripheral neuropathy, lymphadenopathy, brachial plexus neuropathy, Guillain-Barret syndrome and acute transverse myelitis) have been reported (see “Vaccine”, 2nd edition, edited by S. A. Plotkin and E. A. Mortimer, pp. 75-77, W. B. Saunders Company, 1994; “Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases”, 4th edition, edited by G. L. Mandell et al., p. 2781, Churchill Livingstone & Son, Inc., 1995; Journal of the American Medical Association, 264(18), p. 2448, 1990 and 271(20), p. 1629, 1994; and Lancet, 339, pp. 1111-1112, May 2, 1992).
Various attempts to reduce or remove these adverse side effects of the tetanus toxoid vaccine have been made. For example, development of a method for obtaining highly purified toxoid, use of modified or new adjuvants, and individual use of the fragments A, B and C (which are subunits of the tetanus toxin and which are explained below) as an active component for a vaccine have been proposed. Of these attempts, with respect to the techniques of using a tetanus toxin fragment, as examples

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