Neisseria meningitidis compositions and methods thereof
Inventors
Zlotnick, Gary Warren • Hoiseth, Susan Kay • Jansen, Kathrin Ute • Moran, Justin Keith • Ruppen, Mark E. • Anderson, Annaliesa Sybil • Farley, John Erwin • Bernfield, Liesel A.
Assignees
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Publication Number
US-9561269-B2
Publication Date
2017-02-07
Expiration Date
Abstract
In one aspect, the invention relates to an isolated polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 71. In another aspect, the invention relates to an immunogenic composition including an isolated non-lipidated, non-pyruvylated ORF2086 polypeptide from Neisseria meningitidis serogroup B, and at least one conjugated capsular saccharide from a meningococcal serogroup.
Core Innovation
The invention concerns isolated ORF2086 polypeptides, also referred to as fHBP/P2086, defined by amino acid sequences set forth in SEQ ID NO: 71, 76, and 77, including lipidated and non-lipidated forms. The disclosed polypeptides are immunogenic and include non-lipidated, non-pyruvylated variants characterized by deletion or substitution of the N-terminal cysteine at position 1 and by evaluation of pyruvylation status using mass spectrometry to assess the presence or absence of a +70 Da mass shift.
The disclosed work emphasizes expression and structural optimization of non-lipidated ORF2086 variants, including modifications involving an N-terminal cysteine deletion and an extension or optimization of the Gly/Ser stalk. The content further describes specific example variant combinations and compares breadth of bactericidal activity among non-lipidated and lipidated forms, while preserving expression and immunogenicity.
The invention also encompasses immunogenic compositions containing the sequence-defined polypeptides and an adjuvant, with parenteral administration and formulation options described as aqueous versus lyophilized. The compositions can include selected ORF2086 subfamily A and/or subfamily B polypeptides and meningococcal capsular saccharide conjugates from serogroups A, C, W135, and Y, including conjugates with CRM197, and are associated with bactericidal antibodies and serum bactericidal assay responses.
Claims Coverage
The independent claims in the provided content cover three isolated sequence-defined ORF2086 polypeptides, centered on SEQ ID NO: 76, with one feature directed to deletion of the cysteine at position 1 and an associated mass-spectrometry constraint. Additional claim coverage in the combined items characterizes lipidated or non-lipidated, immunogenic forms and immunogenic compositions including an adjuvant or conjugated saccharides.
Sequence-defined isolated polypeptide
An isolated polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 76.
Cysteine at position 1 deletion
An isolated polypeptide comprising the sequence set forth in SEQ ID NO: 76, wherein the cysteine at position 1 is deleted.
Isolated polypeptide consisting of SEQ ID NO: 76
An isolated polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 76.
Across the independent claims, coverage centers on isolated ORF2086 (fHBP/P2086) polypeptides defined by SEQ ID NO: 76, including a form where the cysteine at position 1 is deleted and a form consisting of the SEQ ID NO: 76 sequence. The combined items also describe dependent characterization by lipidation status, immunogenicity, pyruvylation-related mass spectrometry behavior, and immunogenic compositions including an adjuvant or conjugated saccharides.
Stated Advantages
Generates broad cross-reactive bactericidal responses across homologous and heterologous fHBP/ORF2086 variants.
Adjuvant choice can improve SBA titers and responder rates.
Elicits bactericidal antibodies and serum bactericidal assay (SBA) responses.
Avoids pyruvylation while retaining expression and immunogenicity.
Provides synergistic effects when combining multiple ORF2086 polypeptides.
Provides synergistic effects when combining ORF2086 polypeptides with conjugated saccharides.
Documented Applications
Immunogenic compositions for parenteral administration including the disclosed sequence-defined polypeptides and an adjuvant, with formulation formats described as aqueous and lyophilized.
Immunogenic compositions comprising ORF2086 (fHBP/P2086) isolated polypeptides combined with meningococcal capsular saccharide conjugates from serogroups A, C, W135, and Y for generating functional bactericidal and SBA responses.
Evaluation of bactericidal activity and cross-reactivity using serum bactericidal assay, including measurement of SBA titers and responder rates.
Vaccination studies using monovalent and multivalent combinations of non-lipidated variants and related forms, including assessment of protection breadth across homologous and heterologous variants.
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