Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 11 to 14 amino acid residues in defined sequence
Reexamination Certificate
1998-12-30
2002-09-03
Ponnaluri, Padmashri (Department: 1618)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
11 to 14 amino acid residues in defined sequence
C435S072000, C435S235100, C435S243000, C435S173300, C435S091500, C435S091500
Reexamination Certificate
active
06444787
ABSTRACT:
II. FIELD OF THE INVENTION
This invention relates to new vaccines against microorganisms based on antigenically mimetic peptides. The invention also relates to methods of discovering such mimetic peptides by screening peptide-display phage libraries with antibodies against the microbial carbohydrates(s) of interest to locate antigenically mimetic peptides. Vaccines against Group B Streptococcus, or
Streptococcus Agalactiae,
can be produced using this method. Vaccines against other microbial pathogens may also be produced using this method.
III. BACKGROUND OF THE INVENTION
Vaccines protect against disease by harnessing the body's innate ability to protect itself against foreign invading agents. During vaccination, the patient is injected with antigens, or DNA encoding antigens, which generate protective antibodies but which typically cannot cause severe disease themselves. For example, vaccination for bacterial diseases such as typhoid fever consists of injecting a patient with the bacterial agents of these diseases, after they have been disabled in some fashion to prevent them from causing disease. The patient's body recognizes these bacteria nonetheless and generates an antibody response against them.
It is not always possible, however, to stimulate antibody formation merely by injecting the foreign agent which causes the disease. The foreign agent must be immunogenic, that is, it must be able to induce an immune response. Certain agents such as tetanus toxoid are innately immunogenic, and may be administered in vaccines. Other clinically important agents are not immunogenic, however, and must be converted into immunogenic molecules before they can induce an immune response. Successfully accomplishing this conversion for a variety of antigens is a major goal of a great deal of immunologic research.
However, researchers have yet to successfully convert a variety of poorly immunogenic antigens into optimally immunogenic molecules. Of particular importance to the present invention is the failure of immunologic researchers to successfully convert carbohydrates into optimally immunogenic molecules.
Carbohydrates are poorly immunogenic largely because of the way in which they interact with the body's immune system. Carbohydrates frequently function as T-independent antigens, which cannot be properly processed by the antigen presenting cells that begin the typical mammalian immune response. By contrast, T-dependent antigens are initially processed by antigen presenting cells and then rely on T-cells to stimulate B cells to manufacture large quantities of antibodies against the antigen. As a result of these molecular biological differences, T-dependent antigens are immunologically superior to T-independent antigens, including carbohydrates, in three ways:
(1) T-dependent antigens are remembered by the immune system while T-independent antigens are not. Thus, after vaccination, an infection with a T-dependent antigen will be met with an extremely swift and concentrated antibody attack compared to the response to the initial vaccination. Infections with T-independent antigens, by contrast, generally receive the same level of antibody response, even after vaccination;
(2) T-dependent antigens are met with specific antibodies of increasing affinity against them over time, while T-independent antigens are met with antibodies of constant affinity; and
(3) T-dependent antigens stimulate a neonatal or immature immune system more effectively than T-independent antigens.
One approach which researchers have taken to enhance the immune response to T-independent antigens is to inject subjects with polysaccharide or oligosaccharide antigens that have been conjugated to a single T-dependent antigen such as tetanus or diphtheria toxoid. (Kasper, D., et al., J. Clin. Invest., Vol. 98, No. 10 2308-2314, 1996) (Schneerson, R. et al., Inf. Immun. 52:519, 1986) (Anderson, P W, et al., J. Immunol. 142:2464, 1989). These conjugate vaccines improve on vaccines based on carbohydrates alone because they “trick” the T-cells into directing the immune response, giving this response something of the character of a T-dependent response, even though it is directed against a T-dependent/T-independent conjugate. However, this “trick” is imperfect—although T-cells do assist, their assistance against conjugates is not as effective as it is against true T-dependent antigens. As a result, generally only low levels of antibody titres are elicited, and only some subjects respond to initial immunizations. Thus, several immunizations are frequently required. This poses a serious obstacle because patients are not always willing, or able, to complete this entire process; this is often true, for example, of patients who live a great distance from medical facilities, as is frequently the case for patients in lesser developed nations. And even when patients do complete the process, there is no guarantee of success—infants less than two months of age may mount little or no antibody response even after repeated immunization. Furthermore, the process itself sometimes takes so long that patients contract the disease in a virulent form before they have been properly vaccinated.
In another attempt to gain the advantages of T-dependent response with T-independent antigens, including carbohydrates, researchers have attempted to discover T-dependent antigens which are structurally related to the T-independent antigen of interest. In theory, these structural mimics might elicit a superior immune response, compared to a vaccine based on either the original T-independent antigen alone or as part of a conjugate. Under this approach, at least, no part of the antigen in the vaccine is incompatible with T-cell assistance.
Yet locating T-dependent antigens which are sufficiently structurally related to T-independent antigens to be true immunological mimics has proven difficult. Researchers have taken three different approaches to this problem, each of which has serious limitations.
First, some researchers have succeeded in designing synthetic peptides which are immunologically mimetic by using computer simulations and protein databases to construct a protein structure which closely resembles the structure of the T-independent antigen of interest, as ascertained through x-ray crystallography. (Westeruik et al., Proc. Nat. Acad. Sci. USA Vol. 92, 4021-4025, 1995). However, this approach is only as good as the researcher's knowledge of the various structures involved, which is frequently far from complete. Furthermore, because even a single amino acid error can have a profound effect on the immunogenicity of the synthetic peptide, as Westernik notes, a very high level of precision is required—higher than may be possible for molecular systems whose structure is not well understood.
Second, some researchers have generated immunologic mimics by isolating anti-idiotypic antibodies which can elicit an immune response to carbohydrate antigens of
S. pneumonia
(McNamara et al., Science 226:1325, 1984),
P. aeruginosa
(Schreiber et al, J. Inf. Dis. 164:507, 1991),
E. coli
(Kacack, M. B. et al., Infec. Immun. 61:2289, 1991) and Group A Streptococci (Manafo, W. J. et al., J. Immunol. 139:2702, 1987). Anti-idiotypic antibodies are known to be structurally similar to the antigens of interest because of their design: they are generated against the idiotypes of antibodies which are known to specifically bind the carbohydrate of interest. As a result, the anti-idiotypic antibody and the carbohydrate bind specifically to the same idiotype structure (an antigenic determining structure in the antigen-binding portion of the carbohydrate binding antibody). Thus, much as two keys which fit the same lock have a high level of structural similarity, anti-idiotypic antibodies are thought to be structurally similar to the antibody-binding structures on carbohydrates. However, the similarity is not complete: these are still antibodies, isolated from the cells of mice, not complete carbohydrate structural mimics. As a result, there has been some conc
Morgan & Lewis & Bockius, LLP
Ponnaluri Padmashri
Research & Development Institute, Inc.
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