Influenza antigens and antibodies
Inventors
Stevens, James • DONIS, Ruben • Shore, David • WAN, Hongquan • Vassilev, Ventzislav Bojidarov
Assignees
GlaxoSmithKline Biologicals SA • US Department of Health and Human Services
Publication Number
US-9975925-B2
Publication Date
2018-05-22
Expiration Date
2034-08-26
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Abstract
Novel influenza antigens, novel immunogenic or vaccine compositions, as well as uses of and methods for producing said antigens and compositions, are described.
Core Innovation
The invention relates to novel influenza antigens, specifically modified forms of haemagglutinin (HA) that include additional Asn-linked glycosylation at specific surface patches. These modifications direct the immune response towards genetically conserved regions of HA rather than the more variable regions, potentially providing broader protection against diverse influenza strains. Furthermore, the invention includes immunogenic or vaccine compositions comprising these modified antigens, as well as antibodies that bind conserved regions of HA and methods for producing these antigens and compositions.
Influenza viruses cause significant morbidity, mortality, and economic burden worldwide, with antigenic variability challenging effective vaccination. Current seasonal vaccines primarily elicit responses against the highly variable HA regions, necessitating annual immunization. Previous approaches targeting conserved M2 and NP proteins yield weaker immune responses due to their low surface abundance. There is a recognized need for influenza vaccines that induce broad immunity, utilizing conserved epitopes including those within the HA head domain. The invention addresses this by designing modified HA antigens with additional glycosylation to mask hyper-variable epitopes, shifting immune focus to more conserved sites, thereby aiming to create broader protective immunity.
In addition to vaccines, the invention provides monoclonal anti-HA antibodies that are neutralizing and bind conserved HA regions across a broad range of influenza strains. These antibodies have potential utility for treatment and prevention of influenza infections regardless of strain identification. The combination of conserved epitope-targeting antibodies and modified HA antigens together offer improved strategies against influenza disease, overcoming limitations of strain-specific immunity.
Claims Coverage
The claims include one independent claim covering a modified influenza haemagglutinin antigen with specified glycosylation modifications and one independent claim for polynucleotides encoding such antigens, immunogenic compositions containing them, production methods, and methods of prevention. The inventive features encompass specific structural modifications of HA and related compositions and uses.
Modified influenza haemagglutinin antigen with additional Asn-linked glycosylation
A modified HA antigen comprising additional Asn-linked glycosylation introduced recombinantly on at least two surface patches selected from Sites A, B, C, D, and E, excluding natural glycosylation positions (11, 23, 154, 165, 286, 484). The glycosylation sites have the consensus sequence Asn-X-Ser/Thr, where X is not Pro.
Combinations of glycosylation at defined surface patches
Specific embodiments where additional glycosylation is attached to: (i) Site A and Site B; optionally Site D; (ii) Sites C, D, and E; optionally Site A; (iii) Sites A, B, and E; optionally Sites C and D; or any combination of Sites A-E.
Modified HA from various influenza strains
The modified HA antigen may be from any influenza subtype including H1, H2, H3, H5, H7, or H9, preferably H5. The antigen may be full-length or lacking all or part of the HA stalk.
Polynucleotide encoding the modified HA antigen
A nucleotide sequence encoding the modified HA antigen containing the introduced Asn-linked glycosylation sites corresponding to the modified sequences.
Immunogenic composition comprising the modified HA antigen
A composition containing the modified HA antigen and a pharmaceutically acceptable carrier, optionally including an adjuvant and optionally being multivalent.
Method for producing the modified HA antigen
Expression of the polynucleotide encoding the modified HA antigen in a eukaryotic cell, such as a mammalian or insect cell.
Method of prevention against influenza
Administration of the immunogenic composition comprising the modified HA antigen to a subject in need to prevent influenza, potentially with doses of less than 15 micrograms of HA and providing protection across different viral clades.
The claims cover modified HA antigens with novel additional Asn-linked glycosylation at specific antigenic sites to focus immune responses on conserved epitopes, nucleic acids encoding these antigens, vaccine compositions with optional adjuvants and multivalent forms, methods of manufacture in eukaryotic cells, and methods of using the compositions for influenza prevention.
Stated Advantages
The modified HA antigens direct immune responses to conserved regions of HA, potentially providing broad protection against various influenza strains rather than strain-specific immunity.
Antibodies described bind conserved HA regions and exhibit neutralizing activity across a broad spectrum of influenza strains, useful for treatment or prevention even without precise strain identification.
Masking variable epitopes with glycosylation minimizes immune focus on rapidly evolving regions, enhancing vaccine efficacy and durability of protection.
The compositions may use lower doses of HA antigen while meeting international efficacy criteria, enabling effective immunization with reduced antigen amounts.
Documented Applications
Use of modified HA antigens and compositions comprising them in vaccines for prevention of influenza disease in humans, including healthy adults, elderly, children, and immunocompromised individuals.
Therapeutic and prophylactic administration of identified broadly neutralizing anti-HA monoclonal antibodies for prevention or treatment of influenza infection.
Production of modified HA antigens by recombinant expression in eukaryotic cells for use in vaccine manufacture.
Use of additional glycosylation to mask variable antigen sites and direct immune responses towards conserved epitopes across multiple influenza subtypes.
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