Bacterial polysaccharide-conjugated carrier proteins and use thereof
Inventors
Price, Gregory A. • Lee, Che-Hung Robert • Bash, Margaret C.
Assignees
US Department of Health and Human Services
Publication Number
US-11116830-B2
Publication Date
2021-09-14
Expiration Date
2038-12-18
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Abstract
Immunogenic compositions that include a bacterial capsular polysaccharide conjugated to a carrier protein are described. In some embodiments, the bacterial capsular polysaccharide is a Neisseria meningitidis capsular polysaccharide. The carrier protein includes an N. meningitidis factor H binding protein (fHbp) linked to cholera toxin subunit B (CTB). Administration of the immunogenic compositions elicits an immune response that includes production of meningococcal polysaccharide-specific and fHbp-specific antibodies. Use of the immunogenic compositions as meningococcal vaccines is also described.
Core Innovation
The invention describes immunogenic compositions comprising a bacterial capsular polysaccharide conjugated to a carrier protein that includes a Neisseria meningitidis factor H binding protein (fHbp) fused to a linking domain and cholera toxin subunit B (CTB), with the fHbp-linking domain fused covalently or non-covalently to CTB. These compositions elicit immune responses producing meningococcal polysaccharide-specific and fHbp-specific antibodies, useful as meningococcal vaccines.
The problem addressed is rooted in the limitations of existing fHbp-based vaccines, where the interaction of human factor H with fHbp can reduce immunogenicity. Moreover, prior conjugate vaccines using fHbp as a carrier protein yielded low titer antibacterial responses. There exists a need for improved fHbp systems that enhance immunogenicity and broaden protection, especially by overcoming the negative effects of fHbp-factor H binding and improving bactericidal antibody responses.
Claims Coverage
The patent includes one independent claim focused on a novel immunogenic composition comprising a bacterial polysaccharide conjugated to a protein component.
Composition with bacterial polysaccharide conjugated to a carrier protein
The immunogenic composition includes a bacterial capsular polysaccharide conjugated to a carrier protein comprising a N. meningitidis factor H binding protein (fHbp) fused to a linking domain and a cholera toxin subunit B (CTB), where the fHbp is covalently or non-covalently linked to CTB, and the polysaccharide includes N. meningitidis serogroups A, B, C, D, X, Y, Z, 29E, or W.
Specific polysaccharide and protein sequence features
The capsular polysaccharide can specifically be N. meningitidis serogroup A. The fHbp amino acid sequence is at least 95% identical to SEQ ID NO: 1, and may consist of SEQ ID NO: 1. The linking domain comprises cholera toxin subunit A2 domain with at least 95% identity to SEQ ID NO: 2, and CTB has at least 95% identity to SEQ ID NO: 3.
Inclusion of pharmaceutically acceptable components
The immunogenic composition may further include a pharmaceutically acceptable carrier and can optionally contain an adjuvant to enhance the immune response.
Method of inducing immune response by administration
A method for inducing an immune response in a subject by administering an effective amount of the immunogenic composition, wherein the immune response targets N. meningitidis, is protective or therapeutic, and applicable to human subjects.
The claims focus on immunogenic compositions combining meningococcal capsular polysaccharides conjugated to a fusion protein carrier of fHbp linked to CTB, specific sequence identities for components, optional inclusion of carriers and adjuvants, and the use of such compositions to induce immune responses against Neisseria meningitidis.
Stated Advantages
The immunogenic compositions elicit high bactericidal antibody responses against meningococcal strains compared to prior fHbp carrier systems.
Non-covalent assembly of fHbp to CTB enhances immunogenicity compared to mixing antigens, likely due to native-like protein folding and adjuvanticity of CTB.
Use of an fHbp-CTB chimera preserves functional epitopes and enables better immune responses without the need for lipidation or external adjuvants.
Conjugation of meningococcal polysaccharide to the holotoxin-like fHbp-CTB chimera serves as an effective carrier, enhancing antibody responses to both polysaccharide and fHbp antigens, enabling multivalent vaccine development.
Documented Applications
Prevention and treatment of bacterial infections, particularly meningococcal infection caused by Neisseria meningitidis.
Immunization of humans and veterinary subjects to induce protective or therapeutic immune responses against N. meningitidis serogroups A, B, C, D, X, Y, Z, 29E, or W.
Use of the immunogenic composition as meningococcal vaccines to elicit bactericidal antibody production targeting both capsular polysaccharides and fHbp protein domains.
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