Modified Zika virus NS1 protein with reduced cross-reactive immunogenicity
Inventors
Bremel, Robert D. • Homan, Jane • Imboden, Michael
Assignees
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Publication Number
US-11434259-B2
Publication Date
2022-09-06
Expiration Date
Abstract
The present invention relates to vaccine compositions and therapeutic interventions for treating and preventing infections and diseases caused by flaviviruses, including Zika, dengue, and Usutu virus. It also relates to compositions and methods for diagnosis and differential diagnosis of flaviviruses and co-endemic pathogens.
Core Innovation
The invention relates to an isolated, non-naturally occurring Zika virus NS1 polypeptide in which the B-cell epitope STTAS (SEQ ID NO:702) is modified through deletion or mutation so that it is no longer capable of inducing a cross-reactive immune response with the human spindle-like microcephaly associated protein (ASPM). The modification focuses on altering the capability of the NS1 sequence to trigger cross-reactive immune response involving ASPM.
The described concept preserves the NS1 polypeptide as an isolated, non-naturally occurring construct while changing a B-cell epitope recognized by B-cell activity. The goal is to produce an NS1-based construct that avoids inducing cross-reactivity with ASPM, which is characterized as the relevant human target for the cross-reactive immune response.
The dependent variations further refine the NS1 constructs by specifying particular NS1 amino acid regions from defined SEQ ID references, and by incorporating the synthetic polypeptide into fusion proteins. Additional exogenous peptide elements can be in operable association with the synthetic polypeptide, and the constructs can be provided as immunogenic compositions formulated with a pharmaceutically acceptable carrier, optionally further including an adjuvant.
Claims Coverage
The independent claim covers one inventive feature directed to an isolated, non-naturally occurring Zika virus NS1 polypeptide with a modified B-cell epitope STTAS (SEQ ID NO:702), altered by deletion or mutation so it no longer induces a cross-reactive immune response with human ASPM. The dependent claims refine this core by specifying NS1 amino-acid ranges, fusion protein formats, exogenous operable peptide elements, and immunogenic composition formulations with optional adjuvant.
Modified Zika virus NS1 polypeptide lacks STTAS cross-reactivity to human ASPM
An isolated, non-naturally occurring Zika virus NS1 polypeptide having an amino acid sequence wherein the B-cell epitope STTAS (SEQ ID NO:702) is modified through deletion or mutation and is no longer capable of inducing a cross-reactive immune response with the human spindle-like microcephaly associated protein (ASPM).
Specific NS1 amino-acid region from defined SEQ ID references
A synthetic NS1 polypeptide that includes an amino-acid sequence chosen from amino acids 21-384 of SEQ ID NO:441 or amino acids 21-213 of SEQ ID NO:445.
Fusion protein including the synthetic NS1 polypeptide sequences
A fusion protein made by including the synthetic polypeptide sequences from claim 1.
Fusion protein with exogenous operable peptide elements
A fusion protein in which selected peptide elements comprising a signal sequence, a linker sequence, a purification tag sequence, and an immunoglobulin sequence are in operable association with the synthetic polypeptide and are exogenous to the synthetic polypeptide sequence.
Immunogenic composition formulated with a pharmaceutically acceptable carrier
An immunogenic composition containing a synthetic polypeptide formulated with a pharmaceutically acceptable carrier.
Immunogenic composition including an adjuvant
The immunogenic composition further includes an adjuvant.
Overall claim coverage centers on altering the B-cell epitope STTAS (SEQ ID NO:702) in an isolated, non-naturally occurring Zika virus NS1 polypeptide via deletion or mutation to remove the ability to induce cross-reactive immune responses with ASPM. Dependent claims further constrain the NS1 sequence to specific amino-acid ranges, incorporate the synthetic NS1 sequences into fusion proteins with exogenous peptide components, and formulate the resulting construct as an immunogenic composition with an optional adjuvant.
Stated Advantages
No longer capable of inducing a cross-reactive immune response with the human spindle-like microcephaly associated protein (ASPM).
Supports immunogenic composition formulation as an immunogenic composition with a pharmaceutically acceptable carrier.
Optionally includes an adjuvant in the immunogenic composition.
Documented Applications
In silico identification and reporting of B-cell linear epitope pentamer motifs and epitope mimics for flavivirus NS1 proteins, including Zika virus NS1 and related dengue and Usutu findings.
Vaccine designs removing mimic epitopes by modifying the Zika virus NS1 B-cell epitope STTAS (SEQ ID NO:702).
Differential serodiagnostic arrays for flaviviruses, including use of diagnostic peptide arrays to assess reduced cross-reactivity against other flaviviruses and selected co-endemic pathogens.
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