Mosaic influenza virus hemagglutinin polypeptides and uses thereof
Inventors
Garcia-Sastre, Adolfo • Palese, Peter • Krammer, Florian • BRÖCKER, Felix • Sun, Weina
Assignees
Icahn School of Medicine at Mount Sinai
Publication Number
US-12364746-B2
Publication Date
2025-07-22
Expiration Date
2039-06-20
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
In one aspect, provided herein is a mosaic influenza virus hemagglutinin (HA) polypeptide comprising an influenza A virus HA ectodomain of an influenza A virus strain HA, wherein the HA ectodomain comprises an HA stem domain of the influenza A virus strain HA and an HA globular head domain of the influenza A virus strain HA, wherein the HA globular head domain of the influenza A virus strain HA has been engineered to comprise one or more amino acid substitutions in one, two, three, four or all of the antigenic sites. In another aspect, provided herein are immunogenic compositions comprising such a mosaic influenza virus HA polypeptide or an influenza A virus comprising such a mosaic influenza virus HA polypeptide. In yet another aspect, provided herein are methods for immunizing a subject against an influenza A virus in a subject comprising administering such an immunogenic composition to the subject.
Core Innovation
The invention provides mosaic influenza virus hemagglutinin (HA) polypeptides comprising the ectodomain of an influenza A virus HA, wherein the ectodomain includes an HA stem domain and an engineered HA globular head domain. The HA globular head domain has been modified with multiple amino acid substitutions within one or more antigenic sites, such as Sa, Sb, Ca1, Ca2, and Cb for group 1 viruses or A, B, C, D, and E for group 2 viruses. These substitutions can replace native amino acid residues with residues from corresponding antigenic sites of different influenza virus strains or subtypes or with random residues that do not alter the HA conformation.
The engineered mosaic HA polypeptides can optionally include transmembrane and cytoplasmic domains. Such mosaic HAs maintain a three-dimensional structure similar to wild-type HAs and retain functional properties such as fusogenic activity and receptor binding. The invention also encompasses nucleic acid sequences encoding the mosaic HA polypeptides, expression vectors, viral vectors (including influenza viruses), virus-like particles (VLPs), and immunogenic compositions—in particular vaccines—comprising these polypeptides or encoding nucleic acids.
The problem addressed is that influenza viruses, especially influenza A viruses, undergo frequent antigenic drift, with mutations occurring in the HA globular head domain's antigenic sites, leading to diminished vaccine effectiveness. Current vaccines require an accurate strain match, which is difficult due to rapid virus evolution and manufacturing lead times. There is also a need for vaccines that provide broad protection across multiple influenza A virus strains and subtypes, including pandemic strains, which are unpredictable.
By engineering mosaic HA polypeptides with modified antigenic sites, the invention aims to produce immunogens that elicit immune responses not only targeting conserved stem domains but also addressing immunodominant antigenic regions in the head domain while overcoming existing immunity biases. This approach can induce broad and cross-protective antibody responses against diverse influenza A virus strains and subtypes, potentially overcoming limitations of existing strain-specific vaccines.
Claims Coverage
The claims center around mosaic influenza virus hemagglutinin polypeptides comprising HA ectodomains from influenza A group 2 virus strains, engineered with amino acid substitutions within antigenic sites A to E of the HA globular head domain derived from a second group 2 influenza A virus strain, including specific embodiments involving H3 subtypes and particular strains like A/Hong Kong/4801/2014.
Mosaic influenza virus HA polypeptide with antigenic site substitutions
A polypeptide comprising an HA ectodomain of a first group 2 influenza A virus strain HA, where the HA globular head domain has amino acid substitutions in antigenic sites A to E. Each of these antigenic sites comprises multiple amino acid substitutions replaced with residues found in corresponding regions of an HA globular head domain of a second group 2 influenza A virus of a different subtype or strain.
Inclusion of transmembrane and cytoplasmic domains
The mosaic influenza virus HA polypeptide further comprises the transmembrane and cytoplasmic domains of the first group 2 influenza A virus HA strain.
Trimerization domain incorporation
The mosaic influenza virus HA polypeptide further comprises a trimerization domain.
Specific H3 subtype embodiment
The first group 2 influenza A virus strain is a strain of the H3 subtype, particularly influenza virus A/Hong Kong/4801/2014 (H3).
Correspondence to defined antigenic sites
Antigenic sites A to E of the first and second group 2 influenza A virus strains correspond to antigenic sites of influenza virus A/Hong Kong/4801/2014 HA (SEQ ID NO: 171).
Inclusion of substitutions outside antigenic sites
The mosaic HA polypeptide may include up to five amino acid substitutions outside antigenic sites A to E of the globular head domain.
The claims define mosaic influenza hemagglutinin polypeptides of group 2 influenza A viruses with engineered substitutions in multiple antigenic sites of the HA globular head domain, incorporating residues from different virus strains or subtypes to broaden antigenic coverage. Variations include specific strain embodiments, inclusion of transmembrane, cytoplasmic, and trimerization domains, and allowance for limited substitutions outside major antigenic sites, all aimed at producing broadly protective and structurally stable HA immunogens.
Stated Advantages
The mosaic influenza virus HA polypeptides elicit broad and cross-protective antibody responses targeting both conserved stem and modified head antigenic sites, potentially providing protection against different strains and subtypes of influenza A viruses, including pandemic strains.
The engineered HA polypeptides maintain proper folding and functionality, such as fusogenic activity, indicating they can function comparably to wild-type HA proteins in vaccines.
Immunogenic compositions comprising these mosaic HA polypeptides can boost immune responses to conserved antigenic sites and overcome limitations of current strain-specific vaccines, potentially improving vaccine effectiveness.
Documented Applications
Immunogenic compositions and vaccines comprising mosaic influenza virus HA polypeptides for immunizing subjects against influenza A virus infection or disease.
Methods for inducing an immune response against influenza A virus by administering vaccines containing mosaic HA polypeptides or nucleic acids encoding such polypeptides.
Methods for preventing and treating influenza virus disease or infection in subjects utilizing immunogenic compositions comprising mosaic HA polypeptides, viral vectors, inactivated or live attenuated viruses, split virus vaccines, subunit vaccines, virus-like particles, or virosomes.
Methods for assessing immune response changes in subjects by hemagglutination inhibition assays using a panel of influenza viruses expressing mosaic HA polypeptides.
Generation and isolation of antibodies using mosaic HA polypeptides for possible therapeutic use against influenza virus disease.
Interested in licensing this patent?