Universal influenza vaccine using nucleoside-modified mRNA

Inventors

Pardi, Norbert • Weissman, Drew • NACHBAGAUER, Raffael • Hensley, Scott • Palese, Peter • Krammer, Florian • Garcia-Sastre, Adolfo • Freyn, Alec W.

Assignees

Icahn School of Medicine at Mount Sinai • University of Pennsylvania

Abstract

The present invention relates to compositions and methods for inducing an immune response against influenza virus in a subject. In some embodiments, the present invention provides a composition comprising a nucleoside-modified nucleic acid molecule encoding at least one influenza virus antigen, such as a hemagglutinin antigen or a fragment thereof, neuraminidase antigen or a fragment thereof, nucleoprotein antigen or a fragment thereof, matrix protein 1 antigen or a fragment thereof, or matrix-2 ion channel antigen or a fragment thereof.

Core Innovation

The invention provides a composition for inducing an immune response against one or more influenza viruses in a subject. The composition comprises a combination of isolated nucleoside-modified RNA molecules encoding at least four influenza viral antigens selected from full length HA or a fragment comprising at least the HA-stalk domain or HA-head domain, full length NA or a fragment comprising at least the NA-stalk domain or NA-head domain, full length NP or a fragment thereof, full length M1 or a fragment thereof, and full length M2 ion channel antigen or a fragment comprising at least the M2 ion channel-extracellular domain or M2 ion channel-intracellular domain. All uridines in the nucleoside-modified RNA molecules are replaced with pseudouridine or 1-methyl pseudouridine.

The disclosed approach presents universal influenza vaccine compositions using nucleoside-modified RNA, including nucleoside-modified mRNA, that encode influenza antigens including HA, NA, NP, M1, and M2 ion channel. The compositions are formulated as vaccines, with optional adjuvants and delivery via lipid nanoparticle encapsulation, including nucleoside-modified RNA in purified, single-stranded forms. The document further includes SEQ ID NO-defined amino acid sequences and corresponding encoding nucleic acid sequences.

The disclosed antigen design emphasizes preserving antigen conformation for improved immune responses while improving safety. Preserving the full M2 transmembrane domain, including T-cell epitopes and proper conformational presentation, is described as enhancing immune responses, while ablation of ion-channel activity is described as increasing stimulated immunity by reducing surface toxicity. A soluble M2e construct is described as showing poor immunogenicity with an mRNA-LNP approach, and prime-boost regimens are described as increasing potency.

The content further describes mRNA-LNP antigen performance differences across influenza internal proteins, with NP outcompeting M1, higher CD8+ T-cell stimulation, stronger NP antibody responses, and little or no M1 response. The disclosed implementation also ties antigen selection and sequence identifiers to the composition, including specific antigen and domain options and optimized DNA coding sequences for influenza internal antigens, and indicates that the composition can include a lipid nanoparticle or that the nucleoside-modified RNA is encapsulated within an LNP.

Claims Coverage

The claim coverage centers on a nucleoside-modified RNA composition for inducing an immune response against influenza viruses using at least four specified influenza antigens, with all uridines replaced by pseudouridine or 1-methyl pseudouridine. The inventive features combine antigen selection, uridine substitution, optional LNP encapsulation, and influenza-associated treatment or prevention.

The claims are directed to a defined influenza antigen RNA composition that encodes at least four selected antigens, requires universal uridine replacement with pseudouridine or 1-methyl pseudouridine, and may include LNP encapsulation and use in treating or preventing influenza-associated conditions.

Stated Advantages

Documented Applications