Multivalent meningococcal conjugates and methods for preparing conjugates
Inventors
Lee, Che-Hung Robert • Pinto, Valerian B.
Assignees
US Department of Health and Human Services • United States Department of the Army • US Army Medical Research and Development Command
Publication Number
US-9427476-B2
Publication Date
2016-08-30
Expiration Date
2033-05-23
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Abstract
Disclosed herein are meningococcal immunogenic conjugates which can elicit immune responses against meningococcal polysaccharides (PS) from groups A, C, W-135, and Y and group B factor H binding protein (fHbp). The disclosed conjugates also exhibit bactericidal activity against meningococcal A, C, W-135, Y, B, and X serogroups. Also disclosed are improved methods for preparing conjugates, such as immunogenic conjugates, including activation of a polysaccharide with a cyanylation agent at about 4° C.
Core Innovation
Disclosed herein are meningococcal immunogenic conjugates capable of eliciting immune responses against meningococcal polysaccharides from groups A, C, W-135, and Y, as well as group B factor H binding protein (fHbp) or Neisseria surface protein A (NspA). The conjugates also exhibit bactericidal activity against meningococcal serogroups A, C, W-135, Y, B, and X. The disclosure further provides improved methods for preparing such conjugates, including activation of polysaccharides with a cyanylation agent at approximately 4° C., enhancing yield and control compared to conventional room temperature methods.
The problem addressed is that although there are vaccines approved for meningococcal serogroups A, C, W-135, and Y, group B capsular polysaccharide is poorly immunogenic due to its structural similarity to human tissues and may pose a risk of autoimmune response if used in vaccines. Additionally, a need exists to develop vaccines targeting group B and group X meningococcal serogroups. Conventional polysaccharide activation methods using cyanylation agents have limited controllability and yield, necessitating improved conjugation procedures.
The disclosed innovation encompasses multivalent immunogenic conjugates wherein one or more immunogenic-distinct polysaccharides are conjugated to meningococcal fHbp or NspA proteins, including fusion proteins combining variants of fHbp. These conjugates induce strong antibody responses and bactericidal activities when administered. The improved conjugation methods use longer activation times at lower temperatures (about 4° C.) with cyanylation agents to activate polysaccharides, resulting in higher conjugation yield and better process control, which is particularly advantageous for large-scale vaccine production.
Claims Coverage
The independent claims cover pharmaceutical compositions comprising immunogenic conjugates of meningococcal polysaccharides conjugated to an fHbp fusion protein, and methods of eliciting an immune response using said compositions, comprising four main inventive features.
Pharmaceutical composition including multiple meningococcal polysaccharide-fHbp fusion protein conjugates
A pharmaceutical composition comprising immunogenic conjugates of meningococcal group A, C, W, and Y polysaccharides each conjugated to an fHbp fusion protein comprising the amino acid sequence SEQ.ID.NO:8.
Inclusion of pharmaceutically acceptable carriers and adjuvants
Pharmaceutical compositions further comprising a pharmaceutically acceptable carrier and optionally an adjuvant.
Method of eliciting an immune response by administering composition
Methods of eliciting an immune response to Neisseria meningitidis in a subject comprising administering an effective amount of the pharmaceutical compositions containing the immunogenic conjugates to the subject.
The claims collectively define compositions incorporating meningococcal polysaccharide conjugates linked to a specific fHbp fusion protein, formulations with acceptable carriers and adjuvants, and methods of immunization to induce immune responses against Neisseria meningitidis.
Stated Advantages
Improved control and convenience in conjugate production due to polysaccharide activation at lower temperature for longer duration.
Increased yield of polysaccharide-protein conjugates compared to conventional room temperature activation methods.
Enhanced immunogenicity of meningococcal polysaccharides, including poorly immunogenic group B polysaccharides, by conjugation to fHbp or NspA proteins.
The multivalent conjugates induce bactericidal activity against multiple meningococcal serogroups, including groups A, B, C, W-135, X, and Y.
Suitability of improved methods for large-scale conjugate vaccine production.
Documented Applications
Vaccines for prevention or treatment of meningococcal disease caused by Neisseria meningitidis serogroups A, B, C, W-135, X, and Y.
Immunogenic compositions administered to subjects to elicit protective immune responses against meningococcal infection.
Use of multivalent conjugates including various meningococcal polysaccharides conjugated to fHbp or NspA to induce broad immune protection.
Production of immunogenic conjugates for use in pharmaceutical compositions, optionally including adjuvants, for parenteral, mucosal, pulmonary, topical, or other administration routes.
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