Immunogenic peptide against group a Streptococcus
Inventors
Good, Michael F. • Pandey, Manisha • Batzloff, Michael Raymond
Assignees
Publication Number
US-11732033-B2
Publication Date
2023-08-22
Expiration Date
2038-08-22
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Abstract
A modified p145 peptide having enhanced mucosal immunogenicity for use in eliciting a mucosal immune response to group A Streptococcal bacteria in a mammal such as a human. Intramuscular administration of the modified p145 5 peptide may be particularly efficacious. An S2 peptide or variant may be co-administered with the modified p145 peptide to enhance the immune response.
Core Innovation
This invention relates to a modified p145 peptide with enhanced mucosal immunogenicity for eliciting a mucosal immune response to group A streptococcal bacteria in mammals, including humans. The core innovation includes the discovery that targeted amino acid substitutions in the p145 peptide sequence substantially increase immunogenicity, enabling protection against group A streptococcal infections, even from hypervirulent strains, with a single immunization. Notably, the modified p145 peptide elicits a mucosal immune response characterized by predominant IgG production and relatively reduced or absent IgA production upon administration, including via intramuscular injection.
The problem addressed is the lack of effective peptide-based vaccines against group A Streptococcus (GAS), which causes debilitating diseases such as rheumatic fever, invasive infections, and post-streptococcal glomerulonephritis, particularly in developing countries. Prior vaccine candidates, such as the J8 peptide derived from the p145 sequence, require multiple doses for protection and have limited immunogenicity. Moreover, peptide epitopes generally have limited ability to stimulate broad immune repertoires and induce protective immunity. The invention solves this by demonstrating that specific modifications to the p145 peptide improve immune response potency and breadth, including mucosal immunity, overcoming previous limitations.
Claims Coverage
The patent discloses multiple independent claims focusing on methods of eliciting mucosal immune responses, inducing mucosal immunity, treating or preventing group A streptococcal infections, and ameliorating various forms of GAS infections using modified peptides. The claims also cover compositions comprising peptides, conjugates, and combinations with immunogenic fragments of SpyCEP proteins or variants.
Use of modified p145 peptides to elicit mucosal immunity
Methods involving intramuscular administration of isolated proteins containing the amino acid sequences of SEQ ID NO:1 or SEQ ID NO:21, or their conjugates to carrier proteins, to elicit a mucosal immune response or mucosal immunity to group A streptococcal bacteria in mammals.
Combination with immunogenic SpyCEP fragments
Co-administration of isolated immunogenic fragments comprising SEQ ID NO:23, variants having at least 90% identity, lysine-extended variants, SEQ ID NO:24, or their conjugates to carrier proteins, to enhance immune responses.
Single immunization protection efficacy
A single immunization with the specified modified p145 peptides (or conjugates) suffices to protect mammals against group A streptococcal skin disease.
Use of specific carrier proteins for conjugation
Employing carrier proteins such as thyroglobulin, albumin, toxins (including diphtheria, tetanus, pertussis, Pseudomonas, E. coli, Staphylococcus, Streptococcus toxins), or toxoids to conjugate with the peptides to enhance immunogenicity.
Method of ameliorating multiple GAS infections by parenteral administration
Parenteral administration of modified p145 peptides or conjugates to treat or ameliorate group A streptococcal skin, intranasal, or invasive infections in mammals.
The independent claims collectively protect methods of intramuscular administration of specific modified p145 peptides or their conjugates to elicit mucosal immunity against GAS, optionally combined with immunogenic SpyCEP fragments, providing single-dose protection and treatment of GAS infections with defined carrier proteins to enhance immunogenicity.
Stated Advantages
The modified p145 peptide induces a mucosal immune response characterized predominantly by IgG with substantially reduced or absent IgA, which is unexpected for mucosal responses.
The enhanced immunogenicity allows protection against group A streptococcal infection with a single immunization dose, including against hypervirulent strains.
Intramuscular administration of the modified peptide effectively elicits mucosal immunity, which is surprising as mucosal immunity is often best induced by mucosal routes.
The modified peptide is more immunogenic and induces higher affinity antibodies recognizing both the peptide and the bacterial M protein compared to the unmodified p145 peptide.
Combination with SpyCEP protein fragments further enhances the immune response and protection.
Documented Applications
Eliciting a mucosal immune response to group A streptococcal bacteria in a mammal via intramuscular vaccination.
Inducing mucosal immunity against group A streptococcal bacterial infections in mammals.
Treating or preventing group A streptococcal bacterial infections including skin infections, intranasal infections, and invasive infections in mammals using immunogenic peptides and their variants.
Use of the modified p145 peptide in compositions and vaccines for immunization against GAS-associated diseases.
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