Corona virus vaccine formulations
Inventors
Smith, Gale • MASSARE, Michael J. • Tian, Jing-Hui
Assignees
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Publication Number
US-11896664-B2
Publication Date
2024-02-13
Expiration Date
Abstract
Disclosed herein are coronavirus Spike (S) proteins and nanoparticles comprising the same, which are suitable for use in vaccines. The nanoparticles present antigens from pathogens surrounded to and associated with a detergent core resulting in enhanced stability and good immunogenicity. Dosages, formulations, and methods for preparing the vaccines and nanoparticles are also disclosed.
Core Innovation
The invention provides a non-naturally occurring SARS-CoV-2 spike (CoV S) glycoprotein that is distinct from a native S glycoprotein by two specified modifications. The first modification is an inactivated furin cleavage site having the amino acid sequence QQAQ (SEQ ID NO: 7), and the second modification is mutation of amino acids 973 and 974 to proline, with amino acids numbered according to SEQ ID NO: 2.
The invention further describes coronavirus spike polypeptide vaccine antigens formulated to stabilize prefusion spikes. It emphasizes non-naturally occurring modifications intended to maintain the prefusion conformation, including inactivated furin cleavage site variants and proline substitutions. These engineered spike antigens are presented in immunogenic compositions for eliciting antibody responses and T-cell responses.
For presentation of the spike antigens, the invention describes detergent-core nanoparticles assembled by detergent exchange to present multiple spike trimers. The nanoparticle approach uses a detergent core formed with non-ionic detergents and presents the CoV S glycoprotein on a nanoparticle structure to enhance stability and epitope presentation. The document also describes the inclusion of adjuvant components, including alum and saponin/Quillaja-derived ISCOM/Matrix-M™ fractions A and C.
The disclosed compositions and antigens are supported by data indicating antigen binding to hACE2 without off-target MERS receptor binding, improved thermal and chemical stability, and immunogenicity in multiple animal models and a Phase 1 human trial. The trial is reported to induce anti-CoV-S IgG, including neutralizing and hACE2-blocking activities, and to support dose sparing with Matrix-M™. The document also reports reduced viral replication, Th1-skewed polyfunctional T-cell responses, and acceptable safety and tolerability.
Claims Coverage
The partial content includes one independent claim covering an engineered non-naturally occurring SARS-CoV-2 spike glycoprotein with two modifications versus a native S glycoprotein. Other claims in the provided excerpt appear to be dependent refinements of immunogenic composition and formulation elements, but only one independent claim is explicitly provided.
Inactivated furin cleavage site sequence QQAQ with proline mutations at amino acids 973 and 974
A non-naturally occurring SARS-CoV-2 spike (CoV S) glycoprotein comprising an inactivated furin cleavage site having the amino acid sequence of QQAQ (SEQ ID NO: 7) and mutation of amino acids 973 and 974 to proline, wherein the amino acids are numbered according to SEQ ID NO: 2.
Across the provided claim material, the core inventive concept is the specific engineered SARS-CoV-2 CoV S glycoprotein defined by two non-naturally occurring modifications: an inactivated furin cleavage site (QQAQ, SEQ ID NO: 7) and proline substitutions at positions 973 and 974 (numbered according to SEQ ID NO: 2).
Stated Advantages
Antigen binding to hACE2 without off-target MERS receptor binding.
Improved thermal stability and chemical stability.
Improved epitope presentation through nanoparticle presentation of spike trimers.
Induction of antibody responses including neutralizing and hACE2-blocking antibody activities.
Dose sparing with Matrix-M™.
Reduced viral replication.
Th1-skewed polyfunctional T-cell responses.
Acceptable safety and tolerability.
Documented Applications
A Phase 1 human trial in human participants reporting anti-CoV-S IgG induction, including neutralizing and hACE2-blocking activities, along with dose sparing with Matrix-M™ and acceptable safety/tolerability.
Immunogenicity and efficacy studies in mice, including reports supporting antigen stability, immune responses, and reduced viral replication [procedural detail omitted for safety].
Immunogenicity and efficacy studies in olive baboons [procedural detail omitted for safety].
Immunogenicity and efficacy studies in cynomolgus macaques [procedural detail omitted for safety].
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