Coronavirus vaccine
Inventors
Muik, Alexander • Swanson, Kena Anne • Yang, Qi • Cai, Hui • Sahin, Ugur • Modjarrad, Kayvon
Assignees
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Publication Number
US-12208136-B2
Publication Date
2025-01-28
Expiration Date
Abstract
This disclosure relates to the field of RNA to prevent or treat coronavirus infection. In particular, the present disclosure relates to methods and agents for vaccination against coronavirus infection and inducing effective coronavirus antigen-specific immune responses such as antibody and/or T cell responses. Specifically, in one embodiment, the present disclosure relates to methods comprising administering to a subject RNA encoding a peptide or protein comprising an epitope of SARS-CoV-2 spike protein (S protein) for inducing an immune response against coronavirus S protein, in particular S protein of SARS-CoV-2, in the subject, i.e., vaccine RNA encoding vaccine antigen.
Core Innovation
The invention relates to compositions comprising an RNA molecule with a nucleotide sequence that is at least 99% identical to SEQ ID NO: 98 and comprises a 5′ cap. The RNA optionally comprises a modified uridine in place of one or more uridines, including N1-methyl-pseudouridine in place of each uridine in particular embodiments, and in further embodiments is encapsulated in a lipid nanoparticle (LNP). The 5′ cap comprises m2 7,3′-O Gppp(m1 2′-O)ApG.
In some embodiments, the RNA encodes a polypeptide having an amino acid sequence at least 95% identical to SEQ ID NO: 95, and the polypeptide comprises a proline substitution at one or both positions corresponding to residues 986 and 987 of SEQ ID NO: 1. The polypeptide further comprises at least 10 specified mutations as compared to SEQ ID NO: 1, including substitutions and deletions associated with SARS-CoV-2 spike variant changes.
The subject matter further includes mRNA vaccination regimens using nucleoside-modified messenger RNA encoding SARS-CoV-2 spike proteins from multiple Omicron lineages including BA.1, BA.2, BA.3, and BA.4/BA.5. It also describes multivalent vaccine dose formats in which variant RNAs are provided in a single composition or multiple boosters, including same-day mixing of variant RNAs, and booster timing relative to a primary Wuhan-strain dosing regimen.
Claims Coverage
The independent claims cover three composition-level scopes. Across the claims, the main inventive features are the SEQ ID NO: 98 RNA identity, the 5′ cap and uridine modification features, LNP encapsulation, and the encoded polypeptide mutation set.
Nucleotide sequence identity with capped, optionally modified uridine RNA
A composition comprising an RNA molecule having a nucleotide sequence that is at least 99% identical to SEQ ID NO: 98, wherein the RNA molecule comprises a 5′ cap, and wherein the RNA molecule optionally comprises a modified uridine in place of one or more uridines.
Defined cap structure with N1-methyl-pseudouridine and LNP encapsulation
A composition comprising an RNA molecule having a nucleotide sequence that is at least 99% identical to SEQ ID NO: 98, wherein the RNA molecule comprises N1-methyl-pseudouridine in place of each uridine, the RNA molecule comprises a 5′ cap that comprises m2 7,3′-O Gppp(m1 2′-O)ApG, and the RNA molecule is encapsulated in a lipid nanoparticle (LNP).
Unit-dose LNP population with proline-substituted, mutation-defined polypeptide-encoding RNA
A composition comprising at least one unit dose of a population of lipid nanoparticles (LNPs), wherein each LNP in the population encapsulates at least one RNA molecule, wherein the at least one RNA molecule comprises a nucleotide sequence that is at least 95% identical to SEQ ID NO: 98 and encodes a polypeptide having an amino acid sequence that is at least 95% identical to SEQ ID NO: 95, comprises a proline substitution at one or both positions corresponding to residues 986 and 987 of SEQ ID NO: 1, comprises at least 10 specified mutations as compared to SEQ ID NO: 1, comprises N1-methyl-pseudouridine in place of each uridine, and comprises a 5′ cap that comprises m2 7,3′-O Gppp(m1 2′-O)ApG.
The claims are directed to RNA compositions defined by sequence identity to SEQ ID NO: 98, a 5′ cap, and optional or required N1-methyl-pseudouridine substitution, with LNP encapsulation in more specific claims. One independent claim further adds unit-dose LNP population packaging and encoded polypeptide constraints, including proline substitutions at residues 986 and 987 and at least 10 specified mutations relative to SEQ ID NO: 1.
Stated Advantages
Neutralizing antibody responses assessed by GMT/GMC metrics and Th1-biased cellular immune responses with cytokines such as IL-2, TNFα, and IFNγ are described as immunogenic outcome targets.
Broader pan-Omicron neutralization following BA.2/BA.4/5 exposure or adaptation.
Improved breadth of neutralization in vaccinated and naïve hosts after BA.4/5-adapted and bivalent Omicron vaccination.
Extended neutralization against emerging Omicron sublines including BA.4.6/BF.7, BA.2.75, BA.2.75.2, BQ.1.1, and XBB.
Maintenance of cellular immunity despite antibody escape, supported by high conservation of T-cell epitopes and reduced conservation of B-cell neutralizing epitopes.
Serum from vaccinated subjects shows neutralizing activity against SARS-CoV-2 spike variants, including Omicron subvariants.
Protection is described as potentially reducing infection severity.
Non-immunogenic for the modified RNA (modRNA) in connection with nucleoside modifications and removal of dsRNA [procedural detail omitted for safety].
Enhanced cellular translation.
Markedly reduced innate immunogenicity.
Targeted RNA delivery to the lung.
Targeted RNA delivery to the lymphatic system, including the spleen, using net-negative charge principles for spleen targeting.
Delivery of RNA encoding vaccine antigens and/or immunostimulants for use with antigen presenting cells, including dendritic cells.
Use of extended-PK immunostimulant concepts (albumin or Fc fusions) intended to extend half-life of immunostimulants.
Documented Applications
Booster regimens using nucleoside-modified messenger RNA encoding SARS-CoV-2 spike proteins from multiple Omicron lineages including BA.1, BA.2, BA.3, and BA.4/BA.5, in multivalent dose formats including same-day mixing of variant RNAs.
Assessment of immunogenic outcomes including neutralizing antibody responses and Th1-biased cellular immune responses.
Vaccine and booster regimens with a primary Wuhan-strain dosing regimen followed by boosters at timing options described relative to the primary regimen.
Immune-serology and vaccine performance evaluation across Omicron sublineages, including neutralization outcomes after BA.1, BA.2, and BA.4/5 breakthrough infections.
Vaccine booster immune-response assessment using BA.4/5-bivalent boosters in a clinical trial context.
Mouse and vaccine-boost studies evaluating BA.4/5-adapted and bivalent Omicron vaccine immune breadth.
In silico analysis of T-cell epitope conservedness versus B-cell neutralizing epitope conservedness across Omicron variants.
Assessment of immune response and vaccine efficacy against SARS-CoV-2 spike variants defined by specific spike mutation sets, including Omicron subvariants.
Vaccine antigen expression in antigen presenting cells using RNA compositions, including RNA vaccine platform embodiments for SARS-CoV-2 S antigen and RBD.
RNA vaccine platform architectures and antigen targets, including SARS-CoV-2 S protein (full-length or fragments such as receptor binding domain (RBD)) and variant-specific mutations, implemented using uRNA, modRNA, and self-amplifying RNA (saRNA) formats.
Vaccine use cases involving RNA encoding vaccine antigens.
Immunostimulant use cases involving RNA encoding cytokines such as IL2, IL7, IL12, IL15, IFN-α, IFN-γ, and related immunostimulants.
Targeted RNA delivery to the lung.
Targeted RNA delivery to the lymphatic system, including the spleen.
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