Group A streptococcus vaccine
Inventors
Pandey, Manisha • Batzloff, Michael • Good, Michael
Assignees
Publication Number
US-10513544-B2
Publication Date
2019-12-24
Expiration Date
2035-04-15
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Abstract
The invention relates to methods of eliciting an immune response to group A streptococcal bacteria in a mammal, the method including the step of administering to the mammal an effective amount of a composition comprising an isolated p145 peptide of SEQ ID NO: 56 and/or a p145 peptide variant having an amino acid sequence at least 90% identical to SEQ ID NO: 56, and an isolated SpyCEP peptide of SEQ ID NO: 18 and/or a SpyCEP peptide variant having an amino acid sequence at least 90% identical to SEQ ID NO: 18.
Core Innovation
The invention relates to methods of eliciting an immune response to group A streptococcal bacteria in a mammal by administering to the mammal an effective amount of a composition comprising an isolated p145 peptide of SEQ ID NO: 56 or a variant thereof, and an isolated SpyCEP peptide of SEQ ID NO: 18 or a variant thereof. It involves administering an M protein fragment, variant or derivative and an agent that facilitates restoring or enhancing neutrophil activity to thereby elicit an immune response to group A streptococcal bacteria in the mammal.
The problem being solved is that vaccines against Group A Streptococcus (GAS) have limitations, especially against virulent strains with CovR/S mutations that express SpyCEP, a protease that degrades the neutrophil chemotactic agent interleukin 8, thereby inhibiting neutrophil response and reducing vaccine efficacy. This neutrophil inhibition reduces the protective efficacy of existing M protein fragment-based vaccines such as J8 peptide vaccines, particularly against invasive GAS disease and antibiotic-resistant strains causing serious infections including necrotizing fasciitis.
The inventors discovered that neutrophil activity is important for successful immunization against GAS, and that targeting the SpyCEP protease restores or enhances neutrophil activity by neutralizing its IL-8 degrading activity. By including SpyCEP or its immunogenic fragment alongside M protein fragments such as p145 or J8 peptides, the composition synergistically enhances immune protection. They identified a dominant, immunogenic epitope on SpyCEP (SEQ ID NO: 18) capable of generating functional antibodies that block IL-8 degradation. Variants of Streptococcal peptides that induce high antibody titers against streptococcal sequences alone were also developed, further improving vaccine efficacy.
Claims Coverage
There is one independent claim which broadly covers the method of eliciting an immune response to group A streptococcal bacteria in a mammal involving administration of specific peptides.
Use of isolated p145 peptide or variant thereof
Administering to the mammal an effective amount of an isolated p145 peptide of SEQ ID NO: 56 or a variant thereof that is at least 90% identical to SEQ ID NO: 56.
Use of isolated SpyCEP peptide or variant thereof
Administering to the mammal an effective amount of an isolated SpyCEP peptide of SEQ ID NO: 18 or a variant thereof that is at least 90% identical to SEQ ID NO: 18.
The claims cover a composition and method for eliciting an immune response to GAS by administering the combination of a p145 peptide or variant and a SpyCEP peptide or variant, which facilitates restoring or enhancing neutrophil activity to improve immune protection against GAS.
Stated Advantages
Neutrophil activity is a key factor in the efficacy of vaccination with J8 peptide against Group A Streptococcus.
Immunization with the combination of J8 peptide and recombinant SpyCEP provides synergistically enhanced protection against virulent GAS strains expressing SpyCEP compared to either antigen alone.
Anti-SpyCEP antibodies can effectively neutralize the IL-8 degrading activity of SpyCEP, providing a therapeutic intervention for existing GAS infections.
Identification of a dominant epitope on SpyCEP (SEQ ID NO: 18) enables the development of safer vaccines by avoiding the use of whole SpyCEP protein while still eliciting functional antibodies.
Variant J8 peptides exclusively derived from streptococcal sequences induce higher antibody titers specifically targeting streptococcal antigens, potentially improving vaccine specificity and efficacy.
Documented Applications
Prevention and treatment of infections caused by Group A Streptococcus in mammals, including humans.
Vaccination against Group A streptococcal diseases such as rheumatic fever, rheumatic heart disease, invasive GAS disease, post-streptococcal glomerulonephritis, pharyngitis, impetigo, and severe infections caused by antibiotic-resistant and virulent GAS strains including necrotizing fasciitis.
Therapeutic administration of anti-SpyCEP antibodies to sites of GAS infection to neutralize SpyCEP activity and enhance neutrophil response.
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