Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1997-08-19
2002-07-16
Smith, Lynette R. F. (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, C424S192100, C424S237100, C530S300000, C530S350000, C536S023100, C536S023400, C536S023700, C435S069300, C435S320100
Reexamination Certificate
active
06419932
ABSTRACT:
FIELD OF INVENTION
The present invention relates broadly to the field of recombinant vaccines. The vaccines are directed to preventing Group A streptococcal infections, which may otherwise result in rheumatic fever.
BACKGROUND OF THE INVENTION
Acute rheumatic fever (ARF) is the major cause of heart disease in children around the world. The disease is rampant in developing countries where prevalence rates of rheumatic heart disease may be as high as 35-40 per thousand individuals. By one estimate, it affects nearly six millon school-age children in India. Although the incidence of ARF in the United States and other Western countries declined markedly during the later half of the twentieth century, there has been a remarkable resurgence of the disease in the United States.
Streptococci are a group of bacteria with the capacity to grow in chains. Many varieties are part of the normal bacterial flora in humans and are not especially harmful. However, a particular subgroup of streptococcal bacteria, called Group A and represented by
Streptococcus pyogenes.
is a human pathogen. Between 20 and 30 millon cases of Group A streptococcal infections occur every year in the United States alone. These cases include infections of the skin and throat, forms of pneumonia and a recently identified disease resembling toxic shock. The most common infection is acute streptococcal pharyngitis, or strep throat, which occurs predominantly in school-age children. Strep throat qualifies as a major worldwide health problem if judged only by time lost from school and work and by the amount spent on related doctor's fees.
Strep throat's toll is much greater, however. In as many as 4% of the pharyngitis cases that are untreated or treated ineffectively, the strep infection leads to ARF. Current attempts to prevent ARF rely on treatment of the pharyngitis with antibiotics. During a recent outbreak of ARF in Utah, only a fourth of the patients sought health care prior to the onset of symptoms, and only a third recalled a recent sore throat. The finding that ARF may follow a subclinical infection in such a high percentage of individuals and the fact that access to health care in developing countries is not widely available serve to underscore the need for a safe and effective vaccine against Group A streptococci.
The causal relationship between streptococcal pharyngitis and ARF was established over 50 years ago, yet the mechanism of the pathogenesis of the disease remains unclear. It is widely held that ARF is an autoimmune disease, and that in the susceptible host the infection triggers an immune response that leads to inflammatory and sometimes destructive changes in target tissues. Streptococci have been shown to contain antigens that are immunologically cross-reactive with host tissues (14, 20, 24, 26, 27, 35, 39 40, 41, 44, 55) and heart-crossreactive antibodies from patients with rheumatic fever have been shown to react with streptococci (15). However, it was also shown that sera from patients with uncomplicated pharyngitis also may contain heart-crossreactive antibodies (57), yet these patients do not develop clinical evidence of carditis. Until the significance of tissue-crossreactive antibodies in the pathogenesis of ARF is better understood, there remains a need to exclude potentially harmful epitopes from vaccine preparations.
The surface M protein of Group A streptococci is the major virulence factor and protective antigen of these organisms (45). Group A streptococci have developed a system for avoiding some of the antimicrobial defenses of a human host. Strains of streptococci that are rich in M protein evade phagocytosis by PMNs and multiply in non-immune blood (45). Yet, resistance to an infection by these bacteria is possible if the host's body can produce opsonic antibodies directed against the M protein. Such antibodies will neutralize the protective capacity of the M protein and allow the streptococcus to be engulfed and destroyed by phagocytes. The development of secretory or mucosal immunity is also now suspected of playing an important role in preventing streptococcal infections.
A major obstacle to effective vaccine development has been the tremendous number or M protein serotypes (now over 80) (33). Laboratory tests suggest that antibodies against one serotype do not offer protection against others. Immunity then appears to be type or sero-specific and optimal vaccines would require that most of the serotypes be represented. There is evidence that not all serotypes of Group A streptococci have the same potential to trigger acute rheumatic fever in susceptible individuals (12). The concept of “rheumatogenic” and “non-rheumatogenic” organisms is supported by multiple surveillance studies over many years and in diverse areas of the world. Thus, there are probably about 12-15 serotypes responsible for most cases of ARF. Some of these are types 1, 3, 5, 6, 14, 18, 19, 24, 27 and 29.
Previous studies have shown that in many cases the protective epitopes of M protein may be separated from the potentially harmful, autoimmune epitopes of the molecule (4, 5, 7, 23, 29). The NH
2
-terminal segments of M proteins have evoked antibodies with the greatest bactericidal activity (5, 23, 38).
Previous studies have also shown that synthetic peptides copying limited regions of types 5, 6 and 24M proteins evoked type-specific, opsonic antibodies that were not heart tissue cross-reactive (4, 5, 23). Because of their lack of immunogenicity (haptens), the synthetic peptides were chemically linked covalently to carrier proteins (4, 5, and 23). However, such fragments of M proteins linked to carrier proteins with chemical reagents do not result in hybrid proteins of defined structures. Thus, in general it has not been possible to obtain antigens which can elicit specific, desired antibodies or which decrease the risk of undesirable side reactions. Further, formation of hapten—carrier complexes using chemical cross-linking reagents is time-consuming and costly and results in undefined heterogenous mixtures of vaccine components.
It is evident from this description of the state of the art that there is an important need for a vaccine which is effective by raising sero-specific antibodies against the various serotypes of Group A streptococci, especially those serotypes capable of triggering acute rheumatic fever, which is known to follow a sore throat, without eliciting cross-reaction with human tissue. Particularly, there is an important need for a vaccine which has not only these properties, but which also is capable of raising protective antibodies to prevent sore throat, skin infections, deep tissue infections and streptococcal infections of the like that are not necessarily followed by rheumatic fever. The invention contributes to solving these important needs in human health.
SUMMARY OF THE INVENTION
The parent patent application is related to and was co-filed on the same day as patent application Ser. No. 07/945,954, entitled “RECOMBINANT MULTIVALENT M PROTEIN VACCINE” with named inventors James B. Dale and James W. Lederer.
The present invention provides recombinant M protein antigens. The antigens are constructed by recombinant DNA methods. They are comprised of amino acid fragments of serotypes of M protein, which fragments carry one or more epitopes that evoke opsonic antibodies against specific serotypes of Group A streptococcus and, if desired, when the fragments carry appropriate epitopes, also evoke protective antibodies. The fragments are either fused directly or linked in tandem by an amino acid linker to an appropriate carrier. The antigens are generally non-immunogenic (or not adequately immunogenic) because of their molecular size or for other reasons.
The invention thus provides a recombinant fusion antigen comprising a gene encoding the carrier protein and an NH
2
or COOH- terminal M protein fragment carrying one or more epitopes. The recombinant antigen does not elicit antibodies which cross react with human heart or other human tissue.
In accordance with the invention,
Baskar Padma
Seed Intellectual Property Law Group PLLC
Smith Lynette R. F.
University of Tennessee Research Corporation
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