Influenza virus hemagglutinin proteins and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • ERMLER, Megan • Krammer, Florian
Assignees
Icahn School of Medicine at Mount Sinai
Publication Number
US-12233123-B2
Publication Date
2025-02-25
Expiration Date
2037-06-14
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Abstract
Provided herein are chimeric hemagglutinin (HA) polypeptides and uses thereof for inducing an immune response (e.g., an antibody response) against influenza virus. Also provided herein are methods of generating antibodies to the chimeric HA polypeptides in a subject.
Core Innovation
Provided herein are chimeric hemagglutinin (HA) polypeptides derived from influenza B viruses that comprise multiple amino acid substitutions within one or more antigenic loops of the globular head domain (120 loop, 150 loop, 160 loop, and/or 190 helix). These substitutions replace amino acid residues in influenza B virus HA with corresponding residues from influenza A virus HA sequences. The chimeric HA polypeptides may also include portions such as signal peptide, transmembrane domain, and cytoplasmic tail domain from influenza A or B viruses, and nucleic acids encoding these chimeric HAs are provided.
The invention addresses the problem that influenza viruses undergo frequent antigenic changes, requiring annual vaccine updates which are often inaccurate and insufficient. There is a need for vaccines that cross-protect against different influenza virus strains and subtypes, including the unpredictable strains that may cause pandemics. Current vaccines are limited because they depend on strain-specific matches that may not be timely or accurate, particularly for pandemic preparedness.
Claims Coverage
The patent includes one independent claim directed to a method of inducing an immune response against influenza B virus in a subject by administering an immunogenic composition comprising a chimeric HA polypeptide or nucleic acid encoding the polypeptide. The main inventive features relate to specific amino acid substitutions at key antigenic loops of influenza B virus HA with sequences from influenza A virus HA to create the chimeric HA.
Chimeric hemagglutinin polypeptide with antigenic loop substitutions from influenza A virus
A chimeric hemagglutinin (HA) polypeptide comprising an ectodomain from influenza B virus B/Yamagata/16/88, wherein amino acid residues in the 120 loop, 150 loop, 160 loop, and/or 190 helix of the globular head domain are substituted with amino acid residues from corresponding regions of influenza A virus HA. Specific substitutions include sequences such as FIP and KIQLSTKNVINAEHAPGGPYRL for the 120 loop, PYQGKSS for the 150 loop, KKNSTY for the 160 loop, and NDAAMQT for the 190 helix.
Administration of immunogenic composition with chimeric HA comprising specific loop substitutions
A method of inducing an immune response against influenza B virus in a subject through administration of an immunogenic composition containing a chimeric HA or nucleic acid encoding it, where the chimeric HA includes defined substitutions in the 120 loop, 150 loop, 160 loop, and/or 190 helix as specified with sequences from influenza A virus incorporated into the influenza B/Yamagata/16/88 ectodomain.
The claims cover methods of immunizing a subject against influenza B virus using immunogenic compositions comprising chimeric HA polypeptides containing substituted loop regions derived from influenza A virus HA sequences. The methods specify particular substitutions in the 120, 150, 160 loops and 190 helix of influenza B/Yamagata/16/88 HA ectodomain with precise amino acid sequences from influenza A virus HAs.
Stated Advantages
The chimeric HA constructs can be incorporated into viruses that grow efficiently in eggs and replicate robustly in vitro and in vivo, while preserving conserved epitopes in both the stalk and the head domain.
Chimeric HAs display drastically reduced strain-specific hemagglutination inhibition activity, indicating effective modification or removal of immunodominant epitopes.
The invention provides a universal vaccination strategy against influenza B viruses by replacing dominant antigenic sites in influenza B HA with sequences from exotic influenza A virus strains, potentially enhancing cross-protection against diverse influenza B strains.
Documented Applications
Inducing an immune response against influenza virus, specifically influenza B virus, in a subject by administering immunogenic compositions comprising chimeric hemagglutinin polypeptides or nucleic acids encoding them.
Methods for immunizing subjects, including humans, against influenza B virus disease or infection using vaccines comprising chimeric HA proteins with altered antigenic loops.
Vaccination regimens comprising sequential administration of different chimeric HA immunogenic compositions to elicit broader immune responses.
Use in preventing and/or treating influenza virus infections and diseases, particularly those caused by influenza B virus, potentially across different virus lineages and strains.
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