GB2370770A - A Vaccine for Treatment of Degenerative Diseases - Google Patents

Abstract

The invention relates to a vaccine preparation and methods for the treatment of degenerative diseases of the young and old, such as rheumatic diseases, autoimmune conditions and malignant cell growths. The vaccine comprises live attenuated or dead Streptococcus, preferably Beta-Haemolytic Group A Streptococcus, optionally together with bacteriophage which are associated therewith.

Description

Treatment of Degenerative Diseases

This invention relates to new pharmaceutical preparations and methods for the treatment of degenerative diseases, particularly those such as rheumatoid arthritis which have traditionally been considered to be due to autoimmune factors.

Arthritis, rheumatism and associated conditions have generally been grouped together under the umbrella of rheumatic diseases. The Arthritis Research Campaign (ARC, England) recognises about two hundred different kinds of rheumatic diseases and puts them under four main headings: 1."Damage to the articulating surfaces of joints". This is associated with wear and tear of the articulating cartilages and underlying bone structure, e. g. osteoarthritis and degenerative joint disease.

2. "Inflammation of Joint Lining". This is due mainly to inflammation of the synovial membrane lining the freely movable joints and covering tendons in various positions, e. g. rheumatoid arthritis.

3. "Soft Tissue Rheumatism". This is a condition manifest by pain in the structures associated with joint movement, e. g. fibromyalgia.

4. "Back Pain"caused by inflammation or degeneration of any of the tissues of the vertebral column, e. g. ankylosing spondylitis.

The ARC states that approximately five million people in Great Britain are affected with osteoarthritis. It has also been estimated that 5% of women and 2% of men over the age of 55 are affected.

The diseased tissue in osteoarthritis is hyaline cartilage which covers the articulating surfaces of bones in synovial joints. The hyaline cartilage, which consists of cells in a ground substance, is subject to wear throughout life and therefore requires continuous maintenance of its structure, particularly when the joints are being used excessively.

The main symptoms of osteoarthritis are pain in the involved joint or joints with, in many cases, a reduced range of movement. The sufferer may also complain of creaking and cracking in the joint on movement. Swelling or enlargement of the joints can occur and is due to either increased fluid in the area or abnormal growth of bone or cartilage.

It is generally believed that osteoarthritis is a degenerative condition brought about by some unknown cause.

Rheumatoid arthritis is due to inflammation of the synovial membrane lining of the joint cavity and related structures that require lubrication to help movement.

There may be a sudden onset but generally this disease runs a slow insidious course with development of a symmetric polyarthritis of the small joints of the hands and feet. Sometimes one or more of the large joints may be involved. It can affect anyone but is more common in women of middle age. Autoimmune processes play a large part in the pathology of this disease.

Soft tissue rheumatism is more a rheumatic condition than an arthritic one although the joints can sometimes be affected. Many people tend to refer to the condition as fibrositis or muscular rheumatism. It is a disease of the structures associated with joint movement, mainly fibrous tissue, which is found all over the body in the connective tissues. Fibrous tissue also replaces all damaged tissue that cannot replace itself following injury or destruction by disease or other means.

Fibromyalgia, which is a soft tissue rheumatism, can affect fibrous tissue all over the body or it can occur in one or two situations. Mostly the condition is associated with skeletal muscles and their tendons. Sensory nerves are also involved and tender points can be found in certain areas associated with the nerve supply. Pressure on these tender points gives the person pain and an uncomfortable feeling.

Additional examples of"autoimmune"diseases include the following: Lupus erythematosis (thickening and reddening of mainly facial skin); Autoimmune haemolytic anaemia (self destruction of red blood cells) ; Thyrotoxicosis

(overactive thyroid gland) ; Myxoedema (degeneration of thyroid gland) ; and Multiple sclerosis (degeneration of nerve tissue).

It is generally considered that damage occurs in autoimmune diseases by autoimmune processes, i. e. when immune system attacks and destroys normal tissue cells. The trigger factor in many conditions is said to be various microorganisms or other foreign proteins, e. g. bacteria, viruses, protozoa or their products, whose antigens mimic those found in the body. The immune response generally manifests itself as an inflammation.

There is no curative treatment for rheumatic or autoimmune diseases but certain drugs and sometimes diet may help relieve some of the symptoms. Analgesics or pain relieving drugs sometimes help. These include paracetamol, codeine and various proprietary combinations.

Non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and ibruprofen are also often used. NSAIDS are useful for reducing inflammation and swelling, and also help in the relief of pain. More powerful non-steroidal drugs are generally given in severe rheumatic conditions. These include D-penicillamine, salazopyrine and many others. The use of the latter drugs has to be balanced against their side effects.

Corticosteroids and other immuno-suppressive drugs have powerful effects on the immune system and may be helpful in so-called autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosis. Examples of those that have been used in this regard are prednisolone, azathioprine and methotrexate.

Prophylactic penicillin has been used as a long term treatment for heart complications following rheumatic fever, particularly valvular heart disease.

Apart from the above, with a balanced diet, controlled exercise and physiotherapy, there is no other satisfactory treatment for rheumatic diseases.

Sufferers, in frustration, often seek help from complementary practitioners, many of whom are unqualified. These may in some cases provide some comfort, particularly in situations where a placebo effect or a special diet appears to aid orthodox treatment.

There remains therefore much need for further information on the primary causes of degenerative diseases such as rheumatoid arthritis and particularly on the causes of the secondary diseases which often follow the initial disease at some later point in time. Greater knowledge of the mechanisms involved in these processes will lead to more efficacious treatment regimes.

In contrast to established wisdom, it has now been found that a significant cause of the damage to the tissues of patients suffering from one of the abovementioned degenerative diseases, both in the initial and secondary diseases, is due to the production of enzymes and other extracellular products by an invading pathogen.

It has now been found that inflammation, degeneration and abnormal growth of body cells or tissues, where the origin is unknown, is fully or partly the result of infection by pathogenic organisms, in particular bacteria. Products associated with the pathogen lead directly or indirectly to tissue damage at the primary site of infection. The pathogen may then influence the behaviour of cells or tissues in remote secondary sites via its extracellular products or its phages. The pathogen may lie dormant at such secondary sites for an indeterminate length of time which may vary from weeks to years, particularly when a bacteriophage or free virus is involved with the primary infection. Following the dormant period, the pathogen may then be reactivated by a variety of trigger factors, and a further disease may be initiated.

The pathogens involved in this regard are particularly members of the Streptococcus family, although other bacteria (e. g. E. coli) may also be involved.

Accordingly, it has now been found that the treatment of a number of degenerative and so-called"autoimmune"diseases should be directed towards prevention of the spread and elimination of the causative pathogens from the body. Through the elimination of such pathogens, the agents that cause the damage to the body's cells and tissues will also be removed.

The invention therefore provides a method of preventing or treating a degenerative disease or an autoimmune disease which comprises the administration to a patient of an effective amount of an antibacterial or antibiotic agent or vaccine.

The invention particularly relates to the prevention or treatment of degenerative connective tissue diseases such as osteoarthritis, valvular heart disease and fibrositis.

The invention further relates to the prevention or treatment of immune complex diseases such as coronary heart disease and amyloid deposition and diseases of arterioles.

The invention further relates to the prevention or treatment of functional diseases of the thyroid.

The invention further relates to the prevention or treatment of benign or malignant diseases such as leukemias and anemias, and cancers of the skin, breast, lung and brain.

The invention further relates to the prevention or treatment of degenerative brain diseases, particularly diseases involving connective tissue, arterioles and nervous tissue.

The degenerative disease or autoimmune disease is preferably rheumatoid arthritis or osteoarthritis, fibromyalgia, ankylosing spondylitis, lupus erythematosis, autoimmune haemolytic anaemia, thyrotoxicosis, myxoedema or multiple sclerosis.

The invention further provides the use of an antibacterial or antibiotic agent, or vaccine as herein described, in the preparation of a medicament for the treatment of such diseases.

The amount of antibacterial or antibiotic agent is preferably one which leads to a prevention of the spread of or elimination of the pathogen from the patient, or which leads to a significant decrease in amount of bacterial enzymes, toxins, phages or breakdown products thereof.

Damage-causing bacterial enzymes of relevance in the current invention include, but are not limited to, streptokinase, streptodornase, hyaluronidase, haemolysins and erythrogenic toxins.

The administration of the agent may be in the form of continuous administration or periodic administration, i. e. over a period of hours, days, weeks, months or years.

The antibacterial or antibiotic agents (as well as the vaccines and other products of the invention) are preferably directed against Streptococci, particularly preferably against haemolytic Streptococci, most preferably against thehaemolytic Streptococci. The most preferred agents are directed Group A Streptococci. Group A Streptococci are also known as Streptococcus pyogenes.

Numerous antibiotic and antibacterial agents are known in the art which may be useable to treat the pathogenic infection. Examples of these include penicillin and its derivatives, sulphonamides and macrolides such as erythromycin. The skilled person will be well aware of numerous further examples which may be used in this regard.

With regard to the treatment of Streptococcal infections, in particular the treatment of Group A Streptococcal infections, the preferred agents include benzathine penicillin and phenoxymethyl penicillin.

Vaccines may be based, inter alia, on a live attenuated bacteria or dead bacteria.

Attenuation may be carried out by conventional methods, for example by passaging or exposure to a chemical agent. The vaccines generally comprise a pharmaceutically acceptable carrier or diluent, and optionally an adjuvant (e. g. aluminium hydroxide) and/or a lyophilisation stabiliser. The formulation of such vaccines will be known to the person skilled in the art.

In another aspect, therefore, the invention provides a vaccine comprising live attenuated bacteria or dead bacteria, preferably a Streptococcus, particularly preferably a haemolytic Streptococcus, most preferably p-haemolytic Streptococcus and even more preferably Group A Streptococcus, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents. Vaccines of the invention may also comprise more than one of the aforementioned bacteria, optionally together with non-Streptococcal bacteria.

The invention also provides a vaccine comprising one or more isolated bacterial antigens. In this context,"isolated"may be taken to mean either purified or substantially purified from the bacteria per se through means known in the art. It may also refer to the production of the antigen (s) through synthetic means, e. g. either chemical or recombinant means. The vaccine will preferably contain a combination of antigens, for example 2,3, 5,10 or more. Such combinations may comprise mixtures of antigens derived from the bacteria and by synthetic routes.

In particular, the vaccine may contain a combination of two or more (for example, 5, 10, 15 or more) different group-or type-specific antigens. The antigens in any one vaccine may be derived from the same bacteria, preferably a

Streptococcus, or from different bacteria.

Antigenic sites of interest on Group A Streptococci include the group-and typespecific antigens. These include the group-specific carbohydrates ; and the M, T and R type-specific protein antigens. The vaccine may also comprise lipoprotein where lipids are similar to mammalian protein.

DNA vaccines from which one or more relevant antigens may be expressed are also envisaged.

In some cases it will additionally be desirable to prevent the spread of bacteriophage which are associated with the pathogen. These bacteriophage may also be responsible, directly or indirectly, for damage caused to the tissues of the body.

The invention therefore also provides a vaccine comprising a live attenuated bacteria or dead bacteria, preferably a Streptococcus, particularly preferably a haemolytic Streptococcus, most preferably a p-haemolytic Streptococcus and even more preferably a Group A Streptococcus, together with a bacteriophage which is associated with one or more of the aforementioned bacteria, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents.

The vaccine may also comprise a combination of two or more of the aforementioned bacteria together with associated bacteriophage from at least one of those bacteria.

The bacteriophage should preferably be non-lethal and/or inactivated.

Vaccination should preferably be given before the first infection of a patient with a Streptococcus which is implicated in causing rheumatic fever or scarlet fever.

The invention therefore provides a method of prevention or treatment of a degenerative or autoimmune disease, preferably a degenerative or autoimmune disease as referred to herein, comprising the administration of a vaccine of the invention to a patient before the first infection of the patient with a Streptococcus which is capable of causing rheumatic fever or scarlet fever. Such vaccination will desirably occur before the patient is 3 months, 6 months or 1 year old, and may be of benefit in preventing the onset of or reducing the symptoms experienced in childhood rheumatic fever or scarlet fever.

In some cases, pathogenic degradation products, bacteriophage or particles released or derived therefrom may initiate autoimmune reactions leading to further tissue damage. Such phage or particles (notably ones which are associated with Streptococci) may particularly be ones which are released from a sequestered site, possibly in a glandular secretion. Treatment of such autoimmune diseases also falls within the scope of the invention.

Established treatments for benign or malignant growths are generally directed towards reversing or slowing down the growth of the cells concerned. The involvement of viruses in the initiation of such growths is well documented. It has now been found that bacteriophage also play a role in the transformation of cells to a benign or malignant form. This may be due to one or more of: genetic changes in cell growth brought about by bacteriophages from a dormant bacterium ; genetic changes in lymphatic cells brought about by release of phage from bacteria ; or genetic changes in stem cells or germ cells brought about by free phages released from a dormant bacterium that has become acceptable as self over a number of years. In all cases, treatment should be directed towards prevention of the primary infection, particularly with any haemolytic Streptococcus, by vaccination, use of prophylactic drugs, vaccination against particular bacteriophage, use of antibodies against bacteriophage and prevention of crossinfection through health education programmes.

The invention also provides a method for preventing damage to cells or tissues of a patient, where said damage is a direct or indirect result of a bacterial product (for example, a bacterial toxin, enzyme or hormone-like substance, preferably one referred to herein), comprising the administration to the patient of an effective amount of an antibacterial or antibiotic agent, preferably an anti-Streptococcal agent, or a vaccine as herein described.

In a further aspect, the invention provides the use of an antibacterial or antibiotic agent, preferably an anti-Streptococcal agent, or a vaccine as herein described, in the preparation of a medicament for preventing damage to cells or tissues of a patient, where said damage is a direct or indirect result of a bacterial product (for example, a bacterial toxin, enzyme or hormone-like substance, preferably one referred to herein).

The invention also provides a method of preventing or treating a degenerative or autoimmune disease (in particular, one of the diseases referred to herein) in a patient previously infected with Streptococcal bacteria, comprising the administration to that patient of an effective amount of an antibacterial or antibiotic agent, preferably an anti-Streptococcal agent, or a vaccine as herein described.

In a further aspect, the invention provides the use of an antibacterial or antibiotic agent, preferably an anti-Streptococcal agent, or a vaccine as herein described, in the preparation of a medicament for preventing or treating a degenerative or autoimmune disease (in particular, one of the diseases referred to herein) in a patient previously infected with a Streptococcal bacteria.

The invention further provides a method of preventing or treating a degenerative or autoimmune disease (in particular, one of the diseases referred to herein) which is caused by the reactivation of a dormant bacteria, preferably Streptococcal bacteria, comprising the administration to that patient of an effective amount of an antibacterial or antibiotic agent, preferably an anti Streptococcal agent, or a vaccine as herein described.

In a further aspect, the invention provides the use of an antibacterial or antibiotic agent, preferably an anti-Streptococcal agent, or a vaccine as herein described, in the preparation of a medicament for preventing or treating a degenerative or autoimmune disease (in particular, one of the diseases referred to herein) which is

caused by the reactivation of a dormant bacteria, preferably a Streptococcal bacteria.

The invention also provides an in vitro method of determining the susceptibility of an individual to a degenerative or autoimmune disease comprising determining the presence of any antibodies against any Streptococcal bacteria or Streptococcal bacteriophage in a sample taken from the said individual, the sample preferably being a blood, tissue or serum sample.

The invention further provides a method of in vitro diagnosis of the cause of a degenerative or autoimmune disease or lymphatic leukemia comprising determining the presence of any antibodies against any Streptococcal bacteria or Streptococcal bacteriophage in a sample taken from the said individual, the sample preferably being a blood, tissue or serum sample.

Methods for the analysis of such samples are well known to the person skilled in the art, including ELISA, as are methods for the isolation of Streptococcal antigens.

The invention also provides a kit comprising antibodies against one or more Streptococcal antigens, preferably against one or more p-haemolytic Streptococcal antigens, together with antibodies against one or more Streptococcal bacteriophage antigens. Methods for the isolation of such antigens and the production of antibodies thereto are well known in the art.

The invention relates not only to the treatment of humans, but also to other animals, particularly domestic animals and preferably mammals ; and any references to a"patient"or"individual"should be construed accordingly.

The following comments are provided as a possible theoretical basis for the mechanisms though which the invention may work. The invention should not, however, be seen as being limited by these theories.

A brief description of the main diseases caused by Streptococcus is given below in order to illustrate the variety of actions that Streptococcus may have on the body.

This is followed by a consideration of the relationship between the known effects

of Streptococcus infection and the causes of degenerative and autoimmune diseases.

Diseases caused by Streptococcus include the following : Erysipelas. When the organism infects the skin or mucous membrane this condition occurs. Localised streptococcal infection of the surface layers of the skin is known as impetigo.

Sepsis. If the organism gains entry through broken skin, or mucous membrane surface, sepsis results.

Puerperal fever. When the lining of the uterus gets infected during the birth process, invariably septicaemia (blood poisoning) occurs.

Bacterial endocarditis. This condition may be either acute or subacute. The acute form occurs when the bacteria enter the bloodstream causing bacteraemia. The Streptococcus may attack a normal heart lining but it is more likely to attack damaged heart valves. Pneumococci and Staphylococci also cause the disease but these are also more likely to attack damaged valves or other damaged tissue. The subacute form involves damaged heart valves caused by repeated attacks of Streptococcal infections.

Enterococci infections. As mentioned above, the Enterococci are cocci normally found in the intestinal tract, one of which is the Streptococcus faecalis. This can cause urinary tract infections particularly in the female because of the proximity of the urethra to the anus. Other cocci may be found in the mouth and also the female genital tract where they can give rise to suppurative (pus-forming) lesions.

Streptococcal sore throat. In young children this condition usually presents as a subacute nasopharyngitis, with a runny nose, slight fever and enlargement of cervical lymph glands. It can extend to the middle ear, the mastoid bone and the meninges (covering of the brain). The condition is more acute in adults and usually shows a high temperature with other signs and symptoms more intense.

The nasopharynx and tonsils are inflamed and generally the condition is accompanied by enlarged painful cervical glands. The infection spreads to other lymphatic tissues throughout the body.

Haemolytic Streptococci are able to break down (haemolyse) red blood cells in blood culture medium. They are divided into groups alphabetically of which the main pathogenic one is group A. There are over fifty different types of group A haemolytic streptococcus which are identified by a distinct protein in each cell wall. Antibodies are produced only against the type causing the infection at the time. This accounts for repeated attacks of infection with this group, as antibodies against one type do not provide protection against any other type.

Diseases that can occur following an infection with Group A haemolytic Streptococci include the following: (a) Acute glomerulonephritis (inflammation of kidney tubules). This condition sometimes occurs two to three weeks after the initial Streptococcal infection and is known to be caused by one of the following group A types: 4,12, 49, or 57 (group A is divided into types based on their individual cell wall protein).

Approximately 23% of children with a skin infection caused by type 49 develop nephritis or haematuria. It is suggested by some authorities that an antigen-antibody complex is responsible as no organisms are found in the kidneys. This theory is still to be proven and as mentioned earlier, research is continuing in the area. Cells in the kidney tubules are replaced throughout life and it is possible that in their development or breakdown, antigens, similar to antigens of the streptococcus, present themselves to the circulating antibodies.

The condition is seldom fatal, most patients recover, but some develop a chronic nephritis later in life.

(b) Rheumatic fever. The condition follows an infection with Group A haemolytic Streptococcus which generally starts with a sore throat, inflammation of the tonsils and other lymphatic tissue. A number of weeks after the initial infection, rheumatic fever manifests itself in a number of different ways. It can affect the joints where it appears as acute rheumatism with a high temperature, tender swollen joints and pain flitting from one joint to another. The disease always attacks the heart to some extent and often attacks all three layers of the heart wall but the effect on the lining of the heart invariably leaves a chronic valvular condition with impaired function in later life. Sometimes the skin is affected and the condition presents itself as scarlet fever. Severe abdominal pain which occurs in young children with the disease, indicates a disturbance of some of the contents of the abdominal cavity, probably lymph nodes and Peyers patches as the lymphatic system is affected in all conditions where the immune

system comes into operation. The brain can be affected causing a condition known as St. Vitus's Dance or Sydenham's Chorea, the main signs of which are irregular uncontrollable movements, mainly noticeable in the facial muscles and muscles of the arms. No association has yet been made between St. Vitus's Dance and degenerative disease of the nervous system in later life but many possibilities exist. Unlike the other conditions which appear weeks after the initial sore throat or Streptococcal infection, chorea may take months or years for signs or symptoms of the disease to appear and may be missed altogether in some cases.

Extracellular and intracellular products of a Streptococcal infection mainly come under the headings of toxins, enzymes and hormone-like substances. There are more than twenty recognised in total at the present time and some of the relevant ones are listed below: 1. Streptokinase. This is an enzyme which breaks down protein substances including fibrin, which is found in most connective tissues throughout the body.

2. Streptodornase. This is an enzyme that splits up DNA.

3. Hyaluronidase. This is an enzyme that splits a component of the ground substance of connective tissue, thereby helping in the breakdown of all connective tissues. It is also produced by many other microorganisms e. g. Pneumococci, Staphylococci, Enterococci and Clostridia.

4. Haemolysins. Haemolytic streptococci produce substances which dissolve red blood cells. Clostridia, Staphylococci and many Gram negative organisms (organisms that do not hold Gram's stain when washed with alcohol) also produce haemolysins.

5. Erythrogenic toxin. John Zabriskie at Rockefeller University showed (Freimer, H. F. and McCarty, M. (1965) Rheumatic Fever, Readings from Scientific American Reprint 1975; Immunology 24,225) that Group A haemolytic Streptococci, when they are carriers of a bacteriophage, possess the ability to produce the erythrogenic toxin responsible for the skin rash in scarlet fever. There are some minor differences between the erythrogenic toxins produced by different strains of the Streptococcus.

The concept of a process that could account for the missing links in the

development of such diverse conditions as the above, from a Streptococcal infection, would have to consider the following : 1. The kind of process that can produce localised lesions in various parts of the body i. e. joints, kidneys, heart, skin, brain, glands and blood cell producing organs, following a Streptococcal infection.

2. The cause of the time lapse with variations between the initial Streptococcal infection and the resulting localise condition in another part of the body.

3. The fact that only some people are susceptible to rheumatic fever.

4. Different manifestations of the disease appear unrelated to one another.

An infection with a beta-haemolytic Group A Streptococcus usually commences with a sore throat and tonsillitis. It may in some instances start with an infection of the skin or mucous membrane. From the primary focus it extends to all other lymphatic tissue throughout the body, i. e. the lymph nodes (glands), thymus, Peyers patches and isolated lymphoid cells throughout the body.

The immune system reacts and produces antibodies and other inflammatory substances to fight the infection. These antibodies and other substances are mainly directed against the antigens in the structure of the Streptococcus and its phages, and also against any of their products. The Streptococcal infection subsides in a couple of weeks sometimes with the aid of antibiotics.

During the incubation period and immune response certain extra cellular substances are produced by the Streptococcus and bacteriophages. The function of these substances is to prepare certain tissues for the spread and survival of the bacterium and its phages. There are over twenty known substances produced by Streptococcus and the relative ones have been mentioned above.

One known fact about Streptococcus is that it tends to stray throughout the body as opposed to other bacteria, e. g. the Staphylococcus, which stay in the area of infection. The explanation for this is that the Streptococcal infection and inflammation occur in the lymphatic tissue where the products of inflammation, broken down tissue cells and many of the lymphocytes, gain access to the lymphatic vessels through the lymphatic capillaries that have their origins in the

lymphatic tissue. The lymphatic fluid (lymph) gains direct entrance to the blood circulation through the right lymphatic duct and the thoracic duct.

When the extracellular substances enter the circulation some of them behave as antigens and some are non-antigenic. Streptolysin a which is a haemolysin and antigenic is readily oxidised and made inactive. Unfortunately it can be reactivated by reducing agents. Many of the enzymes or toxins go about their task in different ways but one end result is the sensitisation of particular tissues for the benefit and survival of the Streptococcus and its phages. The relationship between non-lethal bacteriophages and the bacterium appears to be symbiotic where a mutually beneficial partnership exists.

Some antigenic substances in the circulation are identified and fixed by antibodies to form soluble complex molecules. These in turn attract complement and form large molecules which become insoluble, precipitate and get trapped in small blood-vessels. When this occurs, the area is infiltrated with polymorphonuclear leucocytes, followed by the inflammatory process causing necrosis of vascular tissue. The complexes are broken down and the debris removed by neutrophils and eosinophils. The inflammation subsides leaving a damaged blood-vessel and fibrous tissue or a fatty plaque in its wake. Such an inflammation can occur in small blood-vessels anywhere in the body and may be responsible for Aschoff bodies which are the classic lesions of rheumatic fever, found in heart muscle and plain muscle in the endocardium.

The immune complex inflammation can be demonstrated experimentally by the "Arthus reaction". This is carried out by injecting a soluble antigen into an animal that has a high level of a particular antibody in its blood. Insoluble immune complexes are formed at the site of the injection and inflammatory activities are stimulated with the usual results of breakdown and necrosis of tissue, particularly of blood-vessel walls. When the small blood-vessels are affected the areas supplied by them are also affected.

The structures or tissues affected are those that can show a disturbance in rheumatic fever, i. e. the heart, the skin, the kidneys, the brain and the joints. The sensitising antigen may be an oxidised antigenic substance which identifies the specific cells or tissues and fixes to their membrane or covering. In the case of enzymes, streptokinase and hyaluronidase from the streptococcus are both antigenic and break down protein, particularly that of fibrous tissue and the

ground substance of connective tissue. All connective tissue and particularly white fibrous tissue can be affected. Any break down of tissue will lead to phagocytosis and the collection of mediators of inflammation and further break down.

Where tissue is broken down or weakened by sensitisation and upset of the circulation, any mechanical stress can cause further damage in the area and more break down of tissue. Where the heart is concerned arteritis occurs in small blood-vessels upsetting the blood supply. Fibrin is particularly vulnerable in the heart because thin strands of fibrin hold the heart valves in place to prevent blood returning to the atrium from the ventricle. These strands of fibrin are known as cordae tendinae and are found holding valve leaflets in position on both sides of the heart, but they are generally only damaged on the left side. When the heart pumps, stress is put on the softened sensitised cordae tendinae or their attachments causing some of them to stretch or break. Most damage occurs on the left side of the heart because greater energy is required to pump blood all over the body, as opposed to just the lungs which are supplied from the right side.

Further damage is done to chronic, partly repaired valves with each new Streptococcal or other infection. With each attack more antibodies are produced against the enzymes and against the specific protein of the new strain of streptococcus. Both enzymes and toxins of the new strain may vary slightly as does the erythrogenic toxin in further streptococcal attacks.

Most new Streptococcal infections are caused by a new strain of the bacterium with its new protein. It is generally accepted that the new strain arrives from outside the body. It is much more likely that the bacteriophage synthesises protein in the original streptococcus which, after the first infection, lies dormant probably in the lymphatic system or upper respiratory tract. These dormant inhabitants can only cause further infection when there is a change of protein in their structure and therefore a change of antigen. With the new protein, the organism can develop in times of mental stress, lowered resistance or where there are changes in mucous membrane that enhance bacterial development i. e. changes in pH, temperature or pressure.

The kidneys are also affected by Streptococcal infection. In some cases the cement substance joining the cells of the basal membrane of Bowman's capsule are sensitised or damaged. Antigen-antibody complexes have been identified in the glomeruli by a number of researchers, where they cause damage to

blood-vessels forming the glomeruli. More damage is done with each new infection.

When urine is produced normally in the kidneys, one part of the process is filtration under pressure through the glomeruli. Filtration under pressure through weakened membrane, particularly with high blood pressure and high temperature as occurs in rheumatic fever, causes break down of some of the membrane allowing blood to pass through and be excreted in the urine (haematuria). With one or two attacks, the condition is seldom fatal and usually clears up without treatment. However, continuous attacks by affinative strains of Streptococci can, over time, cause destruction of kidney tissue leading to chronic nephritis.

In some cases of rheumatic fever, acute rheumatism occurs where mostly large joints are affected. Sometimes one joint only appears involved but generally all joints are swollen with pain, flitting from one joint to another. The disease is triggered by the Streptococcal infection with release of enzymes, toxins, bacteriophages and hormone like substances acting in the circulation some weeks later.

The enzymes and toxins sometimes act as antibodies and identify the specific tissue with similar protein to the Streptococcus, in the case of arthritis some or all of the joint tissues. Identification and sensitisation by attachment to tissues attracts antibodies to form complexes. Rheumatic fever does not always manifest itself in the same way but any damage to tissue, either from upset of the blood supply or release of the hidden or protected antigens by mechanical stress, leaves the way open for further destruction or degeneration of that tissue. The tissues that may be sensitised in joints are the fibrous ligaments, pads of fibrocartilage, hyaline cartilage and synovial membrane. Any of these tissues may suffer injury due to sensitisation, interference with blood supply and damage due to mechanical stress particularly if the tissue has been previously traumatised.

The rheumatic fever condition that is set apart from all the others is chorea which involves the nervous system and therefore nervous tissue. It appears to involve the central nervous system but could easily originate in any of the peripheral sensory nerves. The fact that it occurs in many cases months after the primary infection has disappeared, indicates a viral connection. A viral association with a Streptococcus points to a bacteriophage.

A non-lethal bacteriophage associated with the beta-haemolytic Group A Streptococcus has enormous possibilities for upsetting homeostasis in the human body. In one situation, it works with the bacterium using the organism's enzymes and antigens and, at the same time, producing its own enzymes and toxins to enhance the spread of the bacterium and hence its own survival. Viruses are capable of altering the DNA structure of cells and therefore the future behaviour of a particular cell i. e. stem cells. In the case of the Streptococcus, it can switch the behaviour of the RNA to produce a new specific protein for a future generation of bacteria. Much of the nervous tissue is sequestered (hidden) from the normal activities of hormones, enzymes and toxins generally active throughout the body, and any interference with the system is most likely to be delayed. This delay may be the cause of the lengthened time factor in chorea.

To find other connections with the nervous system it is necessary to consider some of the effects on muscle tissue that have been researched. The two situations already mentioned are the binding of cardiac muscle and plain muscle in the blood-vessels and heart lining with antigen-antibody complexes. Melvin Kaplin (1962), showed immunological cross-reaction between cardiac muscle and group A streptococcus. This was confirmed by Freimer & McCarty (1965), and extended to show a similar cross reaction with plain muscle in small arteries. The only common factor between these two muscles and the nervous system which does not affect other muscles, is the post-ganglionic neuro-transmitter substance of the sympathetic system which is noradrenalin. The neuro-transmitter substance of the pre-ganglionic and post-ganglionic fibres of the parasympathic and somatic nervous systems is acetylcholine.

Apart from noradrenalin which is the precursor to adrenalin, one other substance which is involved with the nervous system should be mentioned here. That substance is dopamine which is the precursor to noradrenalin and is also regarded as a transmitter substance. It is suggested by some authorities that noradrenalin and dopamine have important functions in the regulation of sensorimotor behaviour. Dopamine is thought to be a transmitter substance for an important sensorimotor system that has its main centre in the basal ganglia at the base of the brain. Injury or disease of this system results in Parkinson's disease, in which patients suffer from uncontrollable movements. No complexes or sensitisation have yet been identified in chorea but if sensitisation of nervous tissue is involved, there is the possibility that phages or any part of a phage can become part of nervous tissue cells. In this situation, phages or particles of viruses cannot be

identified unless genes are damaged or absent, or a new protein can be identified.

Changes in gene structure and absence of particular genes have been reported recently in leukaemia patients. Upset of the sensory motor system anywhere in the body can create a temporary upset of movement control.

On the basis of the above, the following is postulated as the occurrence of events that take place following an invasion of the body with the Group A beta-haemolytic Streptococcus: A disease can occur anywhere in the body if a functioning tissue is put under mechanical stress when sensitised or weakened by products of bacteria. Most likely it is a preparation for the spread of the organism and therefore the particular tissue would relate to the enzymes or toxins produced by the invading organism, i. e. the Streptococcus and its bacteriophage in this case. Further attacks of Streptococcal infections with a new protein or antigen would produce some slightly changed enzymes, toxins or other extracellular substances.

Previously formed antibodies will destroy most of the old antigenic substances but the ones that are slightly changed, as occurs with the erythrogenic toxin in scarlet fever, are not destroyed. Some will be destroyed by complexes being formed and creating peripheral change with their destruction. Identification and sensitisation by over fifty different hidden antigenic proteins can account for many more lesions than the ones that occur in the rheumatic conditions. This accounts also for what appears to be unrelated manifestations of the disease.

The nervous system can be affected in the same way as any other tissue particularly where there are nervous connective tissue cells (neuroglia) proliferating. On the other hand, viruses have already been identified in the form of bacteriophages and these can be easily associated with any nervous condition if they, or any part of them, move from their original habitat. If the presence of a bacteriophage is necessary for the disease to occur, then only those infected with a Streptococcus harbouring that particular bacteriophage can suffer from the disease. It is possible therefore that a particular Streptococcus could be harboured within a family or family habitat and account for the hereditary factor in rheumatic diseases.

The cause and variation in time lapse between the primary infection and the subsequent manifestation of secondary diseases, is due partly to mechanical damage which can occur at any time following the sensitisation by extracellular

substances and phages. The time lapse between the initial Streptococcal infection and the onset of rheumatic diseases is the time it takes to incubate a response to most antigens, except of course in the case of a virus i. e. chorea. In the case of chorea it is most likely due to the upset of the transmitter substance at the neuro-muscular junction of the sympathetic system i. e. noradrenalin and therefore dopamine, a precursor of noradrenalin, may also be involved, causing upset at neuro-muscular junctions in the brain. Viral immune complexes may also be involved when they cause disease of small arteries. Upset of reflex action in the autonomic nervous system is also likely to occur.

Certain degenerative diseases can originate with other infectious agents and in some cases, organisms attack tissues that have been sensitised, traumatised or diseased previously e. g. when the Staphylococcus or Pneumococcus causes bacterial endocarditis, the disease usually occurs where there are previously damaged or sensitised heart linings or valves.

As stated previously, the body's immune system reacts to the presence of foreign substances that have gained entry into the internal environment, with the resultant inflammation. Most drugs are directed towards the destruction of the bacterium concerned and usually this is sufficient when the infection and inflammation is confined to a particular area. Destruction of the bacterium generally implies destruction of its phages also. When there is an invasion of the lymphatic system with the Streptococcus, there is a completely different situation.

The initial infection and inflammation of the lymphatic tissue produces the signs and symptoms of the primary disease but, because of direct access to the lymphatic vessels and then the blood system, the products of breakdown and extracellular products of the bacteria are concentrated and poured into the circulation. Following the release of products into the circulation, a further incubation period of about one to three weeks occurs before the rheumatic complication arises. Where the bacteriophages are involved, secondary disease may occur months or even years later, particularly where the bacterium lies dormant and releases antigens and bacteriophages during activity or break down.

Following the first upper respiratory tract infection with the beta-haemolytic Streptococcus, the organism, in some form, remains in the body and lies dormant in the upper respiratory tract, alimentary tract or in lymphoid tissue throughout the body. Further infections are described as being due to a Streptococcus with a different antigenic structure which has to be destroyed by the immune system. If

this is so, then the organism must originate or evolve somewhere in living cells. It is known that the Streptococcus infects a number of mammals and it may be that one of these mammals acts as a host during the change of protein or production of new protein. If the mutation can occur in other mammals then it can also occur in humans. While the organism lies dormant the genes can be changed by a bacteriophage when the right environment exists. This right environment may be produced by a change in acidity or alkalinity of body fluids and when the mutation occurs, the organism is free of the immune system to cause a further infection. The Streptococcus could also accept viruses as phages when they enter the respiratory tract. Chemical products or other substances that gain entry to the internal environment and then into a bacterial cell may also interfere with the genetic structure of the bacterium or it may enhance the change in bacteria or body cells by viruses. In most cases adjuvants or helper substances are required before organisms can gain entry to cells either bacterial or human.

Phages or viruses when they are separated from their bacterial host can enter any of the cells prepared for them during the infection. The prepared cell will be the one with similar tissue component to the Streptococcus and phages or the one for which the Streptococcus has an affinity. If the phages or viruses can alter the genes of a bacterial host, then they can equally switch or destroy part of the DNA structure to produce a mutation in particular germ or stem cells in the human body.

Red blood cells receive much attention from the Streptococcus because of its haemolytic properties. Its products not only break down red cells but also white cells and possibly sensitised body cells. If the Streptococcus attacks all blood cells it must also have an affinity for the haemopoietic stem cell. Invasion of the stem cell by bacteriophages, viruses or viral particles can be the origin of most anaemias or leukaemias, where the DNA is interfered with. Chemical particles may in some cases use the sensitising products to gain entry to germ cells and cause mutations. They may in some cases behave as adjuvants and allow bacteria, viruses and phages to enter body cells.

The series of events that take place following a Group A beta-haemolytic Streptococcal infection is as follows: 1. Inflammation of lymphoid tissue.

2. Release of enzymes, toxins, etc., into bloodstream.

3. Sensitisation of particular tissues mainly fibrous tissue, matrix or ground substance of all connective tissue, epithelial cells and their cement substances bone marrow cells and some nerve cells.

4. Production of a variety of antigens which form Ag-Ab complexes with sensitised tissue or soluble Ag-Ab complexes in blood. The soluble complexes are either broken down by the cells of the immune system or become lodged in small blood-vessels anywhere in the body or filtered out by the kidney where the complexes can create destruction of kidney tissue.

5. Sensitisation of glandular cell tissue where the secretion contains antigen, either phage particles or DNA particles e. g. synovial fluid from synovial membrane ; neurotransmitters of sympathetic nerves, intestinal secretion from gastric and duodenal glands ; pancreatic secretions; thyroid secretions or secretions of any other endocrine glands.

6. Sensitisation of particular cells, e. g. stem cells or germ cells, for entry of phages or phage particles, where mutations or abnormal growth of cells can be stimulated.

7. Sensitisation of skin and mucous membrane where substances from the external environment react to cause hypersensitive states. Sensitisation of mucous membrane linings may create a pathway for entry of many microorganisms into the internal environment.

On the basis of the above, I believe that the rheumatic process can be explained as follows: Streptococci are widely distributed throughout the world. Some of them are part of the normal flora of human skin and mucous membrane. Most human beings have their first infection with the beta-haemolytic Group A Streptococci early in life and the organism generally remains dormant somewhere in the body for the remainder of the individual's life.

The first infection may be so mild that it is not even noticeable, nevertheless it can produce a number of antigens that get into the blood circulation and sensitise

particular cells or tissues and interfere with glandular secretions where DNA or other antigens are released from sequestered positions.

If the initial infection does not harbour particular bacteriophages then with each subsequent infection the body's immune system destroys the bacterium and therefore the bacteriophages. Unfortunately, the initial Streptococcal infection with relevant bacteriophages may produce new types of Streptococci within the body that have the ability to release new antigens and enzyme-like substances at some later date. It would be advisable therefore to vaccinate, before the initial infection, with a Streptococcus not harbouring a bacteriophage.

With regard to osteoarthritis, it is generally accepted that osteoarthritis is a degenerative condition brought about by some unknown cause. It is postulated herein that it is the result of a Streptococcal infection. The infection spreads throughout the lymphatic system with the production of enzymes, toxins and phage particles as extracellular substances. These extracellular substances enter the lymphatic vessels and then the blood stream by way of the lymphatic ducts i. e. the right lymphatic duct and the thoracic duct. Circulating throughout the body these substances identify and attach themselves to tissues similar to any one of the antigens of the streptococcus or their coverings. The function of these extracellular substances is to prepare particular tissues for the spread and survival of the organism. Antibodies against the particular enzyme, toxin or other antigen, are produced when the immune system reacts. These may form antigen-antibody complexes in the area of the identified tissue. It has been mentioned earlier in relation to rheumatic fever, that complexes have been identified in the kidney tubules, in heart muscle and in small blood-vessels.

The tissue that becomes sensitised in the joints in osteoarthritis is hyaline cartilage or fibrous tissue and in previously injured joints, the fibrous tissue used in the repair. The known enzymes in this case are streptokinase for fibrous tissue and hyaluronidase for the cartilage. Extra stress on sensitised tissues causes breakdown and wasting of the cartilages and fibrous tissue. The process is very slow where cartilage is concerned and may take years in many cases to show wear.

Degeneration and wear and tear of hyaline cartilage can occur if there is nutritional imbalance, injury or disease of local blood-vessels or their nerve supply. Upset of any of the sensory nerves of pain, temperature or pressure, which are responsible for the feedback mechanism, can also cause degeneration. Many

of the upsets can be caused by any infectious agents in the diseased area but these can generally be recognised.

Although specific research has not been done on the suggested"trigger factor", it is known that in osteoarthritis there is a wasting of the articular cartilage in the joint or joints affected. This wasting, which is regarded as degeneration, should not normally occur but can occur in certain conditions or diseases such as hormone imbalance or injury. Injury to a large joint can sometimes lead to an osteoarthritic joint. Progression in one joint with any abnormal shortening) resulting in bad posture tends to cause the companion joint to behave in a similar way, particularly in the knees and hips where the greatest stress occurs.

Possible causes of degeneration of articular cartilage: 1. Sensitisation of connective tissue within the joint due to bacterial enzymes or other extracellular products of bacteria.

2. Softening of cartilage by hormonal or nutritional disturbance.

3. Upset of blood supply either by disturbance of the composition of blood, (e. g. bacterial haemolysis of red blood cells or nutritional imbalance) or interference with the flow of blood by injury or disease of the blood vessels concerned with the supply of blood to the part affected.

4. The presence of auto-antibodies unless it can be proved that autoimmunity is caused by an infective agent.

All the above should be considered in self treatment by a person with osteoarthritis. Emphasis is placed on prevention initially and then on prevention of further extension of the disease with a good health education programme including prevention of further attacks of streptococcal infection. This may in some cases halt or slow down the destruction of cartilage particularly where unsatisfactory exercise, bad posture, overweight or incorrect diet are contributing factors.

With regard to back pain, a haemolytic Streptococcal infection can disturb the structure of the synovial joints between the vertebrae. Fibrous tissue may be sensitised, weakened and suffer breakages either small or large in any area of the.

spine. This not only involves the joints between the vertebrae but also any fibrous tissue connecting voluntary muscle to any of the processes of the vertebrae.

Upset of blood supply due to antigen-antibody complexes, sensitisation of plain muscle and probably the lining of small blood-vessels and capillary cement substance can all cause degeneration and have a lasting effect on the activities of the spinal column and on nerves entering and leaving the spinal cord.

Finally, viruses and free phages can enter sensitised nerve cells in the region of the cord or in the cord itself and cause a disturbance in any area of the body even after being dormant for a number of years.

EXAMPLES Example 1-Test for the origin of the Streptococcus that causes recurring infection Four, six week old bottle-fed animals, reared in a sterile environment, are vaccinated as described below: Animal (1) Vaccinated with dead Group A type 1 beta-haemolytic Streptococcus.

Animal (2) Vaccinated with live attenuated Group A type 1 beta-haemolytic Streptococcus.

Animal (3) Vaccinated with attenuated rheumatic type Streptococcus.

Animal (4) Untreated.

In four weeks after vaccination all four animals are tested for antibodies (Abs) against four stated beta-haemolytic Streptococcal types W. X. Y. Z. as shown below.

W-Group A type 1 used in vaccination of (1) and (2).

X-Kidney affinity type.

Y-Scarlet fever type.

Z-Rheumatic fever type.

Antibodies from animals 14 following above vaccination procedure.

(1) (2) (3) (4) Streptococcal Type W W (l) W (2) W (3) W (4) X X (1) X (2) X (3) X (4) Y Y (1) Y (2) Y (3) Y (4) z Z (1) Z (2) Z (3) Z (4)

Abs from Animals (1) and (2) behave in the same way and should show protection against antigens (Ags) from Type W. For further discussion Abs from Animal (2) will indicate reaction of (1) and (2).

Abs from Animal (3) should provide protection against Type Z. There should be no reaction between serum from Animal (4) and Types W. X. Y. Z.

If no reaction is shown between Abs (2) and X. Y. Z. it must be assumed that a further secondary infection with haemolytic Streptococci are reinfections from the external environment, with a different type, or reactivation of a dormant organism from a primary infection with or without a changed antigenic structure.

Similarly reaction between Abs (3) and Z only, indicates reinfection from external environment with a different type or reactivation of a dormant organism from a primary infection with or without a changed antigenic structure.

If there is a reaction between Abs (2) and (3) and Types X. Y. Z. then protection is provided against secondary infections from external environment.

If protection is provided against secondary infections from external environment and further infections do occur they may be due to: (i) reactivation of primary infecting Streptococcus in times of stress or lowered resistance similar to behaviour of Mycobacterium tuberculosis; or (ii) reactivation of primary infecting Streptococcus with a changed antigenic structure which is not acceptable as self to the host organism.

This could occur also with Mycobacterium tuberculosis.

If reactivation of the organism causing the primary infection is responsible for future infections then one of the above vaccinations (whichever is most satisfactory on test) should provide lifelong immunity against the Streptococcus and therefore protection against many of the diseases of old age. The vaccination needs to be given before the primary infection and following the loss of maternal antibodies or any passive immunity.

If (1) and (2) antibodies provides protection against (W) only and (3) antibodies provides protection against (Z) only then individual vaccination would have to be given against individual types and these may already have been tried.

It is possible but highly unlikely that dormant organisms can be eliminated from the body following a primary infection therefore further destruction of tissue following the primary infection can only be prevented by prophylactic antibiotics chemotherapy, herbal concoctions and anti-enzymes, antitoxins or hormonal treatments. Penicillin has already been used successfully to reduce the incidence of heart disease in rheumatic fever patients. The Streptococcus does not become resistance to penicillin G and therefore it can be given indefinitely without ill effects, unless the patient is sensitive to the drug.

Example 2-Vaccine formulations A number of Streptococcus-based vaccines are known in the art, both monovalent and polyvalent vaccines. The formulation of such vaccines is therefore well within the scope of the person skilled in the art.

Example 3-Eradication of Streptococcal infection Benzathine penicillin 916mg (1.2 million Units) is given to the patient on diagnosis, once a week for three weeks, and then monthly for the first year.

Subsequent prophylaxis may be with oral phenoxymethyl penicillin 500mg continued for at least 5 years after the last attack. If compliance with an oral regimen is in doubt, the i. m. administration may be employed. A sulphonamide or erythromycin may be used if the patient is allergic to penicillin.

Claims (23)

1. A vaccine comprising a live attenuated or dead bacteria, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteria is a member of the Streptococcus family.

2. A vaccine as claimed in claim 1 wherein the bacteria is a haemolytic Streptococcus.

3. A vaccine as claimed in claim 1 or claim 2 wherein the bacteria is a p- haemolytic Streptococcus.

4. A vaccine as claimed in any one of the previous claims wherein the bacteria is a Group A Streptococcus.

5. A vaccine as claimed in any one of the previous claims wherein the vaccine comprises two or more different bacteria.

6. A vaccine comprising one or more isolated bacterial antigens, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteria is one of the bacteria mentioned in any one of claims 1 to 4.

7. A vaccine comprising one or more bacteriophage, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteriophage is one which is associated with one or more of the bacteria mentioned in any one of claims 1 to 4.

8. A vaccine as claimed in any one of claims 1 to 5 wherein the vaccine additionally comprises one or more bacteriophage which is one which is associated with one or more of the bacteria mentioned in any one of claims 1 to 5.

9. A vaccine comprising a live attenuated or dead Group A Streptococcus together with a bacteriophage which is capable of infecting a Group A Streptococcus, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents.

10. A vaccine as claimed in any one of the previous claims for treating a

degenerative or autoimmune disease.

11. Use of a live attenuated or dead bacteria, wherein the bacteria is a member of the Streptococcus family, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

12. Use as claimed in claim 11, wherein the bacteria is a haemolytic Streptococcus.

13. Use as claimed in claim 12, wherein the bacteria is a p-haemolytic Streptococcus.

14. Use as claimed in claim 13, wherein the bacteria is a Group A Streptococcus.

15. Use as claimed in any one of claims 11 to 14, wherein two or more different bacteria are used.

16. Use of one or more isolated bacterial antigens, wherein the bacteria is one of the bacteria mentioned in any one of claims 11 to 14, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

17. Use of one or more bacteriophage, wherein the bacteriophage is one which is associated with one or more of the bacteria mentioned in any one of claims 11 to 14, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

18. Use as claimed in any one of claims 11 to 15 wherein the medicament additionally comprises one or more bacteriophage which is one which is associated with one or more of the bacteria mentioned in any one of claims 11 to 14, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

19. Use of a live attenuated or dead Group A Streptococcus together with a bacteriophage which is capable of infecting a Group A Streptococcus, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

20. Use of an antibacterial or antibiotic agent in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

21. A use as claimed in claim 20, wherein the antibacterial or antibiotic agent is an anti-Streptococcal agent.

22. A use as claimed in claim 21, wherein the antibacterial or antibiotic agent is benzathine penicillin or phenoxymethyl penicillin.

23. Use of haemolytic Streptococcus in the manufacture of a medicament for the prevention of cell transformation of a benign or malignant form.

23. A use as claimed in any one of claims 11 to 22 wherein medicament is administered to the patient prior to the patient being infected with a Streptococcal infection, preferably prior to the patent being infected with a p- haemolytic Streptococcus.

24. A use as claimed in claim 23, wherein the medicament is administered to the patient at the age of 3 months, 6 months or 1 year of age.

25. A method of preventing or treating a degenerative disease or an autoimmune disease comprising the administration to a patient of an effective amount of a vaccine as claimed in any one of claims 1 to 10.

26. A method of preventing or treating a degenerative disease or an autoimmune disease comprising the administration to a patient of an effective amount of an antibacterial or antibiotic agent.

27. A method as claimed in claim 26 wherein the antibacterial or antibiotic agent is an anti-Streptococcal agent.

28. A method as claimed in claim 27 wherein the antibacterial or antibiotic agent is benzathine penicillin or phenoxymethyl penicillin.

29. A use as claimed in any one of claims 11 to 24 or a method as claimed in any one of claims 25 to 28 wherein the disease is a degenerative connective tissue disease, preferably osteoarthritis, valvular heart disease or fibrositis.

30. A use as claimed in any one of claims 11 to 24 or a method as claimed in any one of claims 25 to 28 wherein the disease is an immune complex disease,

preferably coronary heart disease, amyloid deposition or a disease of arterioles. 31. A use as claimed in any one of claims 11 to 24 or a method as claimed in any one of claims 25 to 28 wherein the disease is rheumatoid arthritis or osteoarthritis, fibromyalgia, ankylosing spondylitis, lupus erythematosis, autoimmune haemolytic anaemia, thyrotoxicosis, myxoedema or multiple sclerosis.

32. A use as claimed in any one of claims 11 to 24 or a method as claimed in any one of claims 25 to 28 wherein the disease is a degenerative brain disease, preferably involving connecting tissue, arterioles or nervous tissue.

Amendments to the claims have been filed as follows

1. A vaccine comprising a live attenuated or dead bacteria, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteria is a p-haemolytic Group A Streptococcus.

2. A vaccine as claimed in claim 1 wherein the vaccine comprises two or more different bacteria.

3. A vaccine comprising one or more isolated bacterial antigens, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteria is one of the bacteria mentioned in claim 1.

4. A vaccine comprising one or more bacteriophage, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents, wherein the bacteriophage is one which is associated with one or more of the bacteria mentioned in claim 1.

5. A vaccine as claimed in any one of claims 1 to 2 wherein the vaccine additionally comprises one or more bacteriophage which is one which is associated with one or more of the bacteria mentioned in any one of claims 1 to 2.

6. A vaccine comprising a live attenuated or dead Group A Streptococcus together with a bacteriophage which is capable of infecting a Group A Streptococcus, optionally together with one or more pharmaceutically acceptable adjuvants, carriers or diluents.

7. A vaccine as claimed in any one of the previous claims for treating a degenerative or autoimmune disease.

8. Use of a live attenuated or dead bacteria, wherein the bacteria is a P- haemolytic Group A Streptococcus, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

9. Use as claimed in claim 8, wherein two or more different bacteria are used.

10. Use of one or more isolated bacterial antigens, wherein the bacteria is one of the bacteria mentioned in claim 8, In the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

11. Use of one or more bacteriophage, wherein the bacteriophage is one which is associated with one or more of the bacteria mentioned in claim 8, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

12. Use as claimed in any one of claims 8 or 9 wherein the medicament additionally comprises one or more bacteriophage which is one which is associated with one or more of the bacteria mentioned in claim 8, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

13. Use of a live attenuated or dead Group A Streptococcus together with a bacteriophage which is capable of infecting a Group A Streptococcus, in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

14. Use of an antibacterial or antibiotic agent in the manufacture of a medicament for the prevention or treatment of a degenerative disease or an autoimmune disease.

15. A use as claimed in claim 14, wherein the antibacterial or antibiotic agent is an anti-Streptococcal agent.

16. A use as claimed in claim 15, wherein the antibacterial or antibiotic agent is benzathine penicillin or phenoxymethyl penicillin.

17. A use as claimed in any one of claims 8 to 16 wherein the medicament is administered to the patient prior to the patient being infected with a Streptococcal infection, preferably prior to the patient being infected with a -haemolytic Streptococcus.

18. A use as claimed in claim 17, wherein the medicament is administered to the patient at the age of 3 months, 6 months or 1 year.

19. A use as claimed in any one of claims 8 to 18 wherein the disease is a degenerative connective tissue disease, preferably osteoarthritis, valvular heart disease or fibrositis.

20. A use as claimed in any one of claims 8 to 18 wherein the disease is an immune complex disease, preferably coronary heart disease, amyloid deposition or a disease of arterioles.

21. A use as claimed in any one of claims 8 to 18 wherein the disease is rheumatoid arthritis or osteoarthritis, fibromyalgia, ankylosing spondylitis, lupus erythematosis, autoimmune haemolytic anaemia, thyrotoxicosis, myxoedema or multiple sclerosis.

22. A use as claimed in any one of claims 8 to 18 wherein the disease is a degenerative brain disease, preferably involving connecting tissue, arterioles or nervous tissue.