US20240000921A1 - Coronavirus vaccine - Google Patents

Coronavirus vaccine Download PDF

Info

Publication number
US20240000921A1
US20240000921A1 US18/341,590 US202318341590A US2024000921A1 US 20240000921 A1 US20240000921 A1 US 20240000921A1 US 202318341590 A US202318341590 A US 202318341590A US 2024000921 A1 US2024000921 A1 US 2024000921A1
Authority
US
United States
Prior art keywords
cov
sars
protein
rna
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US18/341,590
Other versions
US11878055B1 (en
Inventor
Alexander Muik
Asaf PORAN
Kena Anne Swanson
Qi Yang
Hui Cai
Ugur Sahin
Kayvon Modjarrad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biontech SE
Original Assignee
Biontech SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2022/083740 external-priority patent/WO2023094713A2/en
Application filed by Biontech SE filed Critical Biontech SE
Priority to US18/341,590 priority Critical patent/US11878055B1/en
Assigned to BIONTECH US INC. reassignment BIONTECH US INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PORAN, Asaf
Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MODJARRAD, Kayvon, SWANSON, Kena Anne, CAI, HUI, YANG, QI
Assigned to BioNTech SE reassignment BioNTech SE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER INC.
Assigned to BioNTech SE reassignment BioNTech SE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIONTECH US INC.
Assigned to BioNTech SE reassignment BioNTech SE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAHIN, UGUR, Muik, Alexander
Publication of US20240000921A1 publication Critical patent/US20240000921A1/en
Publication of US11878055B1 publication Critical patent/US11878055B1/en
Application granted granted Critical
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20071—Demonstrated in vivo effect

Definitions

  • RNA to prevent or treat coronavirus infection.
  • 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. These methods and agents are, in particular, useful for the prevention or treatment of coronavirus infection.
  • Administration of RNA disclosed herein to a subject can protect the subject against coronavirus infection.
  • 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.
  • Administering to the subject RNA encoding vaccine antigen may provide (following expression of the RNA by appropriate target cells) vaccine antigen for inducing an immune response against vaccine antigen (and disease-associated antigen) in the subject.
  • the present invention is directed to a composition comprising an RNA molecule having:
  • the present invention is also directed to a composition of the invention for use in a method of inducing an immune response against coronavirus in a subject, said method comprising administering to a subject the composition.
  • the modified uridine can be N1-methyl-pseudouridine.
  • the 5′ cap can comprise m 2 7,3′-O Gppp(m 1 2′-O )ApG.
  • the RNA molecule can be encapsulated in a lipid nanoparticle (LNP), preferably wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
  • LNP lipid nanoparticle
  • the composition can comprise one or more additional RNA molecules, each having a nucleotide sequence encoding an S protein of a SARS-CoV-2 strain or variant that is not XBB.1.5, preferably wherein the one or more additional RNA molecules comprise a sequence that is at least 95% identical to that set forth in SEQ ID NO: 20, 72, or 103.
  • the RNA molecule comprises:
  • the composition can comprise about 10 mM Tris buffer and about 10% sucrose.
  • the composition can comprise at least one unit dose of LNP-encapsulated RNA molecules, optionally wherein the unit dose comprises the RNA molecule in an amount of about 30 ⁇ g, or wherein the unit dose comprises the RNA molecule in an amount of about 10 ⁇ g, or wherein the unit dose comprises the RNA molecule in an amount of about 3 ⁇ g.
  • the composition is formulated as a multi-dose formulation in a vial.
  • the subject can be 12 years or older, and the composition can comprise 30 ⁇ g of the RNA molecule, or the subject can be 5 years to less than 12 years old, and the composition can comprise 10 ⁇ g of the RNA molecule, or the subject can be 6 months to less than 5 years old, and the composition can comprise 3 ⁇ g of the RNA molecule.
  • the composition can be administered in a volume of about 200 ⁇ L to 300 ⁇ L.
  • the subject was previously administered one or more doses of a SARS-CoV-2 vaccine, preferably wherein the subject was previously administered a complete dosing regimen of a SARS-CoV-2 vaccine.
  • the subject was previously administered a first dose and a second dose of BNT162b2, wherein the first dose and the second dose were administered about 21 days apart, and/or wherein the subject was previously administered as a booster dose a bivalent vaccine that delivers (i) a SARS-CoV-2 S protein of an Omicron BA.4/5 variant and (ii) a SARS-CoV-2 S protein of a Wuhan strain.
  • said method can further comprise administering one or more vaccines against a non-SARS-CoV-2 disease, preferably wherein the one or more vaccines comprises an RSV vaccine, an influenza vaccine, or a combination thereof.
  • compositions disclosed herein can induce a strong immune response (e.g., high neutralization titers) against certain SARS-CoV-2 variants of concern (e.g., XBB variants of concern (including, e.g., an XBB.1.5 variant, an XBB.1.16 variant, an XBB.2.3 variant, and/or an XBB.2.3.2 variant)).
  • XBB variants of concern including, e.g., an XBB.1.5 variant, an XBB.1.16 variant, an XBB.2.3 variant, and/or an XBB.2.3.2 variant
  • such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant.
  • compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.16 variant. In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.2.3 variant. In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.2.3.2 variant. As demonstrated herein, in some embodiments, such compositions can induce surprisingly high neutralization titers against certain XBB variants of concern (including, e.g., XBB.1.5, XBB.1.16, and XBB.2.3 variants of concern).
  • compositions can induce neutralization titers that are higher against a given variant than a variant-matched vaccine (e.g., in some embodiments, RNA described herein comprising a nucleotide sequence that encodes an XBB.1.5 S protein, can induce neutralization titers against a XBB.1.16 variant of concern that are higher than those induced by an XBB.1.16-adapted vaccine).
  • the strong immune response can be observed in vaccine-na ⁇ ve subjects (e.g., young pediatric patients (e.g., patients 6 months to less than 5 years old).
  • the strong immune response can be observed in subjects without a previous or current coronavirus infection (e.g., a SARS-CoV-2 infection).
  • a strong immune response can be observed in subjects who previously received a SARS-CoV-2 vaccine (e.g., in some embodiments an RNA vaccine encoding a SARS-CoV-2 S protein, e.g., in some embodiments of a Wuhan strain) and/or who were previously infected with SARS-CoV-2.
  • a SARS-CoV-2 vaccine e.g., in some embodiments an RNA vaccine encoding a SARS-CoV-2 S protein, e.g., in some embodiments of a Wuhan strain
  • such broader cross-neutralization can be observed in young pediatric subjects (e.g., subjects aged 6 months to less than 2 years, and/or 2 years to less than 5 years).
  • FIG. 1 Experimental design for a study to characterize immune responses induced by variant-adapted vaccines in SARS-CoV-2 vaccine-experienced mice. Mice are split into 9 groups, each of which is administered a first dose of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2) and a second dose of a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-COV-2 S protein of an Omicron BA.4/5 variant (BNT162b2+BA.4/5).
  • BNT162b2+BA.4/5 Omicron BA.4/5 variant
  • mice are administered a composition comprising an RNA encoding a SARS-CoV-2 S protein of a strain or variant or combination of strains/variants, as indicated in the Figure.
  • the first and second doses are administered 21 days apart, and the third dose is administered about 70 days after the third dose. 119 days after administering the first dose, mice are sacrificed and the experiment concluded.
  • FIG. 2 Experimental design for a study to characterize variant-adapted vaccines in SARS-CoV-2 vaccine-experienced mice. Mice are split into 6 groups, each of which is administered a first and a second dose of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2), followed by a third dose of a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of a BA.4/5 Omicron variant (BNT162b2+BA.4/5).
  • mice are administered a composition comprising an RNA encoding an SARS-CoV-2 S protein of a variant or strain or combination of strains/variants, as indicated in the Figure.
  • the first and second doses are administered 21 days apart, the third dose is administered 70 days after the third dose, and the 4th dose is administered 21 days after the third dose. 126 days after administering the first dose, mice are sacrificed and the experiment concluded.
  • FIG. 3 Exemplary experimental protocol for testing variant-adapted vaccines as a primary series in mice.
  • Two doses of a monovalent or bivalent vaccine composition comprising mRNA(s) encoding the SARS-CoV-2 S protein(s) of the strains/variants indicated in the figure were administered to mice 21 days apart.
  • WT corresponds to RNA encoding a SARS-CoV-2 S protein from a Wuhan strain. Indicated in the figure is the mass of RNA ( ⁇ g) administered to mice.
  • FIG. 4 A monovalent XBB.1.5-adapted vaccine, as a primary series, elicits higher neutralization titers against XBB.1.5 than a bivalent Wuhan+BA.4/5 vaccine. Shown are results collected in performing the experiment summarized in FIG. 3 .
  • (A) shows pseudovirus neutralization titers of serum samples collected at Day 35 of the experiment summarized in FIG. 3 .
  • (B) Lists neutralization titer values for the bar graph shown in panel (A).
  • FIG. 5 Exemplary experimental protocol for testing variant-adapted vaccines as a fourth booster dose in mice.
  • “BNT162b2 Original WT” corresponds to a monovalent mRNA vaccine encoding a SARS-CoV-2 S protein of a Wuhan strain
  • “BNT162b2 Bivalent WT+BA.4/5” corresponds to a bivalent vaccine comprising an RNA encoding an S protein of a Wuhan strain and an RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant.
  • mice were administered a monovalent or bivalent vaccine encoding one of the strains, variants, or combinations indicated in the figure.
  • On days 134 and 160 blood samples were collected (represented by the test tube racks).
  • FIG. 6 An XBB.1.5-adapted booster vaccine elicits the highest neutralization titers against an XBB.1.5 and XBB.1.6 pseudovirus. Shown are results collected in performing the experiment summarized in FIG. 5 .
  • A shows neutralization titers collected for a panel of pseudoviruses (indicated in the figure legend). X-axis indicates vaccine administered. Titers collected at day 160.
  • B shows neutralization titer values for the bar graph shown in panel (A).
  • (C) Shows geometric mean ratios (GMR) of neutralization titers induced by the indicated vaccine relative to neutralization titers induced by a bivalent vaccine comprising an RNA encoding a SARS-CoV-2 S protein from a Wuhan strain (WT in the figure) and an RNA encoding a SARS-CoV-2 S protein from an Omicron BA.4/5 variant (GMR values calculated using neutralization titers at day 160).
  • D provides GMR values for the bar graph shown in panel (C).
  • (E) Shows GMR values comparing neutralization titers induced by the indicated vaccines relative to neutralization titers at day 135 (pre dose 4).
  • (F) shows GMR values for the graph shown in panel (E).
  • (G) shows neutralization titers against further SARS-CoV-2 variants (including XBB.2.3).
  • FIG. 7 Certain variant-adapted vaccines induce a neutralization response against Omicron XBB variants in vaccine-na ⁇ ve mice.
  • a summary of the experimental protocol is depicted at the top of the figure (syringes indicate days on which candidate vaccines were administered and the droplet indicates a day on which blood was collected).
  • Vaccine na ⁇ ve mice were administered two doses of the indicated candidate vaccines.
  • mice were bled and neutralization titers collected.
  • neutralization titers were induced against each of the variants tested, with a monovalent XBB.1.5-adapted vaccine inducing the highest neutralization titers against each of the XBB variants tested.
  • FIG. 8 Certain variant-adapted vaccines induce a neutralization response against Omicron XBB variants in vaccine-experienced mice.
  • a summary of the experimental protocol is depicted at the top of the figure (syringes indicate days on which candidate vaccines were administered and the droplet indicates a day on which blood was collected).
  • Mice were administered two doses of RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (WT), followed by a dose of a candidate vaccine.
  • WT Wuhan strain
  • mice Two weeks after receiving a dose of candidate vaccine, mice were bled and neutralization titers collected. As shown in the figure, neutralization titers were induced against each of the variants tested, with a monovalent XBB.1.5-adapted vaccine inducing the highest neutralization titers against each of the XBB variants tested.
  • RNA relates to a nucleic acid molecule which includes ribonucleotide residues. In preferred embodiments, the RNA contains all or a majority of ribonucleotide residues.
  • ribonucleotide refers to a nucleotide with a hydroxyl group at the 2′-position of a ⁇ -D-ribofuranosyl group.
  • RNA encompasses without limitation, double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations may refer to addition of non-nucleotide material to internal RNA nucleotides or to the end(s) of RNA. It is also contemplated herein that nucleotides in RNA may be non-standard nucleotides, such as chemically synthesized nucleotides or deoxynucleotides. For the present disclosure, these altered RNAs are considered analogs of naturally-occurring RNA.
  • the RNA is messenger RNA (mRNA) that relates to a RNA transcript which encodes a peptide or protein.
  • mRNA generally contains a 5′ untranslated region (5′-UTR), a peptide coding region and a 3′ untranslated region (3′-UTR).
  • the RNA is produced by in vitro transcription or chemical synthesis.
  • the mRNA is produced by in vitro transcription using a DNA template where DNA refers to a nucleic acid that contains deoxyribonucleotides.
  • RNA described herein may have modified nucleosides.
  • RNA comprises a modified nucleoside in place of at least one (e.g., every) uridine.
  • one or more uridine in the RNA described herein is replaced by a modified nucleoside.
  • RNA comprises a modified nucleoside in place of each uridine.
  • the modified nucleoside is a modified uridine.
  • One exemplary modified nucleoside is N1-methyl-pseudouridine (m1 ⁇ ), which has the structure:
  • RNA according to the present disclosure comprises a 5′-cap.
  • the term “5′-cap” refers to a structure found on the 5′-end of an mRNA molecule and generally consists of a guanosine nucleotide connected to the mRNA via a 5′- to 5′-triphosphate linkage. In one embodiment, this guanosine is methylated at the 7-position.
  • Providing an RNA with a 5′-cap or 5′-cap analog may be achieved by in vitro transcription, in which the 5′-cap is co-transcriptionally expressed into the RNA strand, or may be attached to RNA post-transcriptionally using capping enzymes.
  • the building block cap for RNA is m 2 7,3′-O Gppp(m 1 2′-O )ApG (also sometimes referred to as m 2 7,3′-O G(5′)ppp(5′)m 2′-O ApG), which has the following structure:
  • the 5′-UTR sequence is derived from the human alpha-globin mRNA and optionally has an optimized ‘Kozak sequence’ to increase translational efficiency.
  • RNA encoding an amino acid sequence comprising a SARS-CoV-2 S protein, an immunogenic variant thereof, or an immunogenic fragment of the SARS-CoV-2 S protein or the immunogenic variant thereof comprises a 5′ UTR comprising the nucleotide sequence of SEQ ID NO: 12, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 12.
  • a combination of two sequence elements derived from the “amino terminal enhancer of split” (AES) mRNA (called F) and the mitochondrial encoded 12S ribosomal RNA (called I) are placed between the coding sequence and the poly(A) sequence to assure higher maximum protein levels and prolonged persistence of the RNA (e.g., mRNA).
  • F amino terminal enhancer of split
  • I mitochondrial encoded 12S ribosomal RNA
  • two re-iterated 3′-UTRs derived from the human beta-globin mRNA are placed between the coding sequence and the poly(A) sequence to assure higher maximum protein levels and prolonged persistence of the RNA (e.g., mRNA).
  • RNA encoding an amino acid sequence comprising a SARS-CoV-2 S protein, an immunogenic variant thereof, or an immunogenic fragment of the SARS-CoV-2 S protein or the immunogenic variant thereof comprises a 3′ UTR comprising the nucleotide sequence of SEQ ID NO: 13, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 13.
  • a poly(A) sequence measuring 110 nucleotides in length, consisting of a stretch of 30 adenosine residues, followed by a linker sequence (e.g., 10 nucleotide linker sequence) and another 70 adenosine residues is used.
  • This poly(A) sequence was designed to enhance RNA stability and translational efficiency.
  • the poly-A sequence comprises at least 100 nucleotides.
  • the poly-A sequence comprises or consists of the nucleotide sequence of SEQ ID NO: 14.
  • RNA described herein encodes a SARS-CoV-2 S protein comprising one or more mutations characteristic of an Omicron XBB.1.5 variant.
  • the one or more mutations characteristic of an Omicron XBB.1.5 variant include F486P.
  • the one or more mutations characteristic of an Omicron XBB.1.5 variant include T19I, ⁇ 24-26, A27S, V83A, G142D, A144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, S486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K, or any combination thereof.
  • the one or more mutations characteristic of an Omicron XBB.1.5 variant include T19I, ⁇ 24-26, A27S, V83A, G142D, ⁇ 145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K, or any combination thereof.
  • RNA described herein encodes a SARS-CoV-2 S protein comprising one more mutations that stabilize a prefusion confirmation.
  • stabilization of a prefusion conformation of a SARS-CoV-2 S protein may be obtained by introducing two consecutive proline substitutions at residues 986 and 987 in the full length spike protein (positions shown relative to SEQ ID NO: 1; for variant adapted sequences, proline substitutions can be introduced at corresponding positions).
  • spike (S) protein stabilized protein variants can be obtained by exchanging the amino acid residue at position 986 to proline and the amino acid residue at position 987 to proline.
  • a SARS-CoV-2 S protein variant wherein the prototypical prefusion conformation is stabilized comprises the amino acid sequence shown in SEQ ID NO: 7.
  • the SARS-CoV-2 S protein can comprise the following mutations relative to SEQ ID NO: 7: T19I, ⁇ 24-26, A27S, V83A, G142D, ⁇ 145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and
  • an RNA composition described herein comprises an RNA encoding a polypeptide as set forth in SEQ ID NO: 158 or an immunogenic fragment thereof, or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 158).
  • an RNA composition comprises an RNA that includes the sequence of SEQ ID NO: 159 or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 159).
  • an RNA composition comprises an RNA that includes the sequence of SEQ ID NO: 161 or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 161).
  • an RNA composition comprises an RNA comprising (a) a nucleotide sequence of SEQ ID NO: 161 or a sequence that is at least 70% identical to SEQ ID NO: 161 (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to SEQ ID NO: 161), and/or (b) a nucleotide sequence that encodes a SARS-CoV-2 S protein having an amino acid sequence of SEQ ID NO: 158, or an amino acid sequence that is at least 70% identical to SEQ ID NO: 158 (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to SEQ ID NO: 158), and (c) wherein the SARS-CoV-2 S protein optionally comprises one or more mutations that stabilize a prefusion
  • such a composition comprises one or more additional RNAs, each encoding an S protein of a non-XBB.1.5 SARS-CoV strain or variant (e.g., a Wuhan strain, an Omicron BA.4/5 variant, and/or an Omicron BA.2.75.2 variant (e.g., such RNAs described herein)).
  • a non-XBB.1.5 SARS-CoV strain or variant e.g., a Wuhan strain, an Omicron BA.4/5 variant, and/or an Omicron BA.2.75.2 variant (e.g., such RNAs described herein)).
  • an RNA composition comprises an RNA comprising a nucleotide sequence that encodes a SARS-CoV-2 S protein comprising one or more mutations characteristic of an Omicron XBB.1.5 variant and wherein:
  • a composition comprising an RNA that comprises a nucleotide sequence encoding a SARS-CoV-2 S protein comprising one or more mutations characteristic of an XBB.1.5 variant further comprises one or more additional RNAs, each having a nucleotide sequence encoding a SARS-CoV-2 S protein of a non-XBB.1.5 SARS-CoV-2 strain or variant or strain.
  • non-XBB.1.5 strains or variants include a Wuhan strain, an Omicron BA.4/5 strain, and/or a BQ.1.1 variant.
  • the one or more additional RNA molecules comprise a sequence that is at least 70% identical (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to) SEQ ID NO: 20, 70, or 103, or wherein the one or more additional RNA molecules comprise a sequence SEQ ID NO: 20, 72, or 103.
  • LNPs Lipid Nanoparticles
  • nucleic acid such as RNA described herein is administered in the form of lipid nanoparticles (LNPs) (e.g., encapsulated within or associated with an LNP).
  • LNPs lipid nanoparticles
  • the LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated.
  • LNP comprise a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid; and RNA.
  • the cationic lipid is ALC-0315
  • the neutral lipid is DSPC
  • the steroid is cholesterol
  • the polymer conjugated lipid is ALC-0159.
  • the LNP comprises from 20 to 60 mol percent, 40 to 55 mol percent, from 40 to 50 mol percent, from 41 to 49 mol percent, from 41 to 48 mol percent, from 42 to 48 mol percent, from 43 to 48 mol percent, from 44 to 48 mol percent, from 45 to 48 mol percent, from 46 to 48 mol percent, from 47 to 48 mol percent, or from 47.2 to 47.8 mol percent of the cationic lipid.
  • the LNP comprises about 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9 or 48.0 mol percent of the cationic lipid.
  • the neutral lipid is present in a concentration ranging from 5 to 25 mol percent, 5 to 15 mol percent, from 7 to 13 mol percent, or from 9 to 11 mol percent. In one embodiment, the neutral lipid is present in a concentration of about 9.5, 10 or 10.5 mol percent.
  • the steroid is present in a concentration ranging from 25 to 55 mol percent, 30 to 50 mol percent, from 35 to 45 mol percent or from 38 to 43 mol percent. In one embodiment, the steroid is present in a concentration of about 40, 41, 42, 43, 44, 45 or 46 mol percent.
  • an LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
  • the preferred mode of administration is intramuscular administration, more preferably in aqueous cryoprotectant buffer for intramuscular administration.
  • Drug product is a preferably a preservative-free, sterile dispersion of RNA formulated in lipid nanoparticles (LNP) in aqueous cryoprotectant buffer for intramuscular administration.
  • LNP lipid nanoparticles
  • drug product comprises the components shown below, e.g., at the proportions or concentrations shown below:
  • particles disclosed herein are formulated in a solution comprising 10 mM Tris and 10% sucrose, and optionally having a pH of about 7.4. In some embodiments, particles disclosed herein are formulated in a solution comprising about 103 mg/ml sucrose, about 0.20 mg/ml tromethamine (Tris base), and about 1.32 mg/ml Tris.
  • a composition comprises:
  • the ratio of RNA (e.g., mRNA) to total lipid (N/P) is between 6.0 and 6.5 such as about 6.0 or about 6.3.
  • compositions provided herein are formulated as a multi-dose formulation, optionally in a vial.
  • methods that comprise administering a composition described herein.
  • methods described herein induce an immune response in a subject (e.g., an immune response against coronavirus).
  • an amount of the RNA described herein of at least 0.25 ⁇ g, at least 0.5 ⁇ g, at least 1 ⁇ g, at least 2 ⁇ g, at least 3 ⁇ g, at least 4 ⁇ g, at least 5 ⁇ g, at least 10 ⁇ g, at least 15 ⁇ g, at least 20 ⁇ g, at least 25 ⁇ g, at least 30 ⁇ g, at least 40 ⁇ g, at least 50 ⁇ g, or at least 60 ⁇ g may be administered per dose (e.g., in a given dose). In some embodiments, an amount of the RNA described herein of at least 3 ug may be administered in at least one of given doses.
  • an amount of the RNA described herein of at least 10 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 15 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 20 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 25 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 30 ug may be administered in at least one of given doses.
  • combinations of aforementioned amounts may be administered in a regimen comprising two or more doses (e.g., a prior dose and a subsequent dose can be of different amounts as described herein).
  • combinations of aforementioned amounts may be administered in a primary regimen and a booster regimen (e.g., different doses can be given in a primary regimen and a booster regimen).
  • a composition comprising an RNA described herein is administered as a first dose and/or as part of a priming vaccination regimen to a subject (e.g., a vaccine-na ⁇ ve subject is administered (i) two doses of such a composition, approximately 21 days apart, or (ii) three doses of such a composition, where the first and the second doses are administered approximately 21 days apart and the second and the third dose are administered about 28 days apart).
  • a subject e.g., a vaccine-na ⁇ ve subject is administered (i) two doses of such a composition, approximately 21 days apart, or (ii) three doses of such a composition, where the first and the second doses are administered approximately 21 days apart and the second and the third dose are administered about 28 days apart).
  • a composition that comprises an RNA described herein is administered to a subject who has previously been exposed to SARS-CoV-2 (e.g., a subject who has previously received at least one dose (e.g., a complete dosing regimen) of a SARS-CoV-2 vaccine and/or previously been infected one or more times with SARS-CoV-2).
  • a composition comprising an RNA described herein is administered as a booster dose.
  • a composition comprising an RNA described herein is administered as a booster dose to a subject who has previously received one or more doses (e.g., a complete primary dosing regimen and/or one or more booster doses) of a vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a composition comprising an RNA that comprises SEQ ID NO: 20, a commercially available vaccine (e.g., a commercially available vaccine described herein, (e.g., BNT162b2)) or any combination thereof).
  • a vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain
  • a commercially available vaccine e.g., a commercially available vaccine described herein, (e.g., BNT162b2)
  • SARS-CoV-2 vaccines include, e.g., an mRNA-1273 vaccine, an Ad26.CoV2.S vaccine, a ChAdxOx1 vaccine, an NVX-CoV2373 vaccine, a CvnCoV vaccine, a GAM-COVID0Vac vaccine, a CoronaVac vaccine, a BBIBP-CorV vaccine, an Ad5-nCoV vaccine, a zf2001 vaccine, a SCB-2019 vaccine, or other approved RNA (e.g., mRNA) or adenovector vaccines, etc.
  • RNA-1273 vaccine e.g., an Ad26.CoV2.S vaccine, a ChAdxOx1 vaccine, an NVX-CoV2373 vaccine, a CvnCoV vaccine, a GAM-COVID0Vac vaccine, a CoronaVac vaccine, a BBIBP-CorV vaccine, an Ad5-nCoV vaccine, a zf2001 vaccine, a SCB-2019 vaccine, or other
  • an RNA described herein is administered to a subject who has previously been administered at least two doses of BNT162b2 (e.g., two doses of BNT162b2 administered about 21 days apart).
  • an RNA described herein is administered to a subject who has previously been administered at least three doses of BNT162b2 embodiment, at least three doses are administered.
  • such third dose is administered a period of time after the second dose that is comparable to (e.g., the same as) the period of time between the first and second doses.
  • a third dose may be administered about 21 days following administration of the second dose.
  • a third dose is administered after a longer period of time relative to the second dose than the second dose was relative to the first dose.
  • a three-dose regimen is administered to an immunocompromised patient, e.g., a cancer patient, an HIV patient, a patient who has received and/or is receiving immunosuppressant therapy (e.g., an organ transplant patient).
  • the length of time between the second and third dose e.g., a second and third dose administered to an immunocompromised patient
  • an RNA described herein is administered to a subject who has previously been administered a vaccine that delivers an antigen of a SARS-CoV-2 variant (e.g., an Omicron BA.4/5 variant).
  • a vaccine that delivers an antigen of a SARS-CoV-2 variant
  • an RNA described herein is administered to a subject previously administered one or more doses of a SARS-CoV-2 vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., BNT162b2), and one or more booster doses of a variant adapted vaccine (e.g., one or more doses of a bivalent vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 strain).
  • a SARS-CoV-2 vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain
  • booster doses of a variant adapted vaccine e.g., one or more
  • BNT162b2 (which comprises an RNA comprising SEQ ID NO: 20) is an mRNA vaccine for prevention of COVID-19 and demonstrated an efficacy of 95% or more at preventing COVID-19.
  • the vaccine comprises a 5′capped mRNA encoding for the full-length SARS-CoV-2 spike glycoprotein (S) encapsulated in lipid nanoparticles (LNPs).
  • S SARS-CoV-2 spike glycoprotein
  • LNPs lipid nanoparticles
  • ingredients include: ALC-0315 (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and, in some embodiments, potassium chloride, potassium dihydrogen phosphate, sodium chloride, disodium phosphate dihydrate, sucrose and water for injection.
  • a composition comprising an RNA described herein is administered to a subject previously administered a priming dosing regimen of a composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a subject previously administered (i) two doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second doses were administered about 21 days apart, or (ii) three doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second dose were administered about 21 days apart and the third dose was administered about 28 days after the second dose).
  • a priming dosing regimen of a composition e.g., an RNA composition that delivers a SARS-CoV-2 S protein of a Wuhan strain
  • a subject previously administered i) two doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wu
  • a composition comprising an RNA described herein was administered as a further booster dose to a subject previously administered a priming dosing regimen and one or more booster doses of a composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a subject previously administered (i) three doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second doses were administered about 21 days apart, and the third dose was administered at least about 2 months after the second dose, (ii) four doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second dose were administered about 21 days apart, the third dose was administered about 28 days after the second dose, and the fourth dose was administered at least about three months after the second dose, or (iii) four doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain
  • a composition comprising an RNA described herein is administered to a subject previously administered one or more doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant.
  • a bivalent composition e.g., an RNA composition
  • a composition comprising an RNA described herein is administered as a booster dose to a subject previously administered a priming dosing regimen of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (e.g., a subject previously administered (i) two doses of a bivalent RNA vaccine, where the first and the second doses were administered about 21 days apart, or (ii) three doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart and the third dose was administered about 28 days after the second dose).
  • a bivalent composition e.g., an RNA composition
  • a subject previously administered i) two doses of a bivalent RNA vaccine, where the first and the second doses were administered about 21 days apart, or (ii) three doses of a bivalent RNA vaccine, where the first and the second dose were administered about
  • a composition comprising an RNA described herein is administered as a further booster dose to a subject previously administered a priming dosing regimen and one or more booster doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (e.g., a subject previously administered (i) three doses of a bivalent RNA vaccine, where the first and the second doses were administered about 21 days apart, and the third dose was administered at least about 2 months after the second dose, (ii) four doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart, the third dose was administered about 28 days after the second dose, and the fourth dose was administered at least about three months after the second dose, or (iii) four doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart, the third dose was administered at least about three months
  • a composition comprising an RNA described herein is administered to a subject previously administered (i) one or more doses of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain and (ii) one or more doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant.
  • a bivalent composition e.g., an RNA composition
  • composition comprising an RNA described herein is administered to a subject previously administered:
  • a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 30 ⁇ g of an RNA described herein. In some embodiments, a dose comprising about 30 ⁇ g of RNA described herein is administered to a subject who is 12 years or older.
  • a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 10 ⁇ g of an RNA described herein. In some embodiments, a dose comprising about 10 ⁇ g of RNA described herein is administered to a subject who is 5 years to less than 12 years old.
  • a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 3 ⁇ g of an RNA described herein. In some embodiments, a dose comprising about 3 ⁇ g of RNA described herein is administered to a subject who is 6 months to less than 5 years old.
  • a composition described herein is administered in a volume of between about 200 ⁇ l and about 300 ⁇ l (e.g., about 200 ⁇ l or about 300 ⁇ l).
  • RNA in a pharmaceutical RNA preparation is diluted prior to administration (e.g., diluted to a concentration of about 0.05 mg/ml). In some embodiments, administration volumes are between about 200 ⁇ l and about 300 ⁇ l. In some embodiments, RNA in a pharmaceutical RNA preparation is formulated in about 10 mM Tris buffer, and about 10% sucrose.
  • an RNA (e.g., mRNA) composition disclosed herein may be administered in conjunction with a vaccine targeting a different infectious agent.
  • the different infectious agent is one that increases the likelihood of a subject experiencing deleterious symptoms when coinfected with SARS-CoV-2 and the infectious agent.
  • the infectious agent is one that increases the infectivity of SARS-CoV-2 when a subject is coinfected with SARS-CoV-2 and the infectious agent.
  • at least one RNA (e.g., mRNA) composition described herein may be administered in combination with a vaccine that targets influenza.
  • At least two or more different drug products/formulations may comprise at least one RNA (e.g., mRNA) composition described herein and a vaccine targeting a different infectious agent (e.g., an influenza vaccine).
  • RNA e.g., mRNA
  • a vaccine targeting a different infectious agent e.g., an influenza vaccine
  • different drug products/formulations are separately administered.
  • such different drug product/formulations are separately administered at the same time (e.g., at the same vaccination session) at different sites of a subject (e.g., at different arms of the subject).
  • the vaccination regimen comprises a first vaccination using at least two doses of the RNA described herein, e.g., two doses of the RNA described herein (wherein the second dose may be administered about 21 days following administration of the first dose), and a second vaccination using a single dose or multiple doses, e.g., two doses, of the RNA described herein.
  • the second vaccination is administered at least about 2 months after a previous dose (e.g., 3 to 24 months, 6 to 18 months, 6 to 12 months, or 5 to 7 months after administration of a previous vaccine, e.g., after an initial two-dose regimen or a booster dose).
  • the amount of RNA used in each dose of the second vaccination may be equal or different to the amount of RNA used in each dose of the first vaccination. In one embodiment, the amount of RNA used in each dose of the second vaccination is equal to the amount of RNA used in each dose of the first vaccination. In one embodiment, the amount of RNA used in each dose of the second vaccination and the amount of RNA used in each dose of the first vaccination is about 30 ⁇ g per dose. In one embodiment, the same RNA as used for the first vaccination is used for the second vaccination.
  • an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-CoV-2 disease. In some embodiments, an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-COV-2 viral disease. In some embodiments, an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-CoV-2 respiratory disease. In some embodiments, the non-SARS-CoV-2 respiratory disease is a non-SARS-CoV-2 Coronavirus, an Influenza virus, a Pneumoviridae virus, or a Paramyxoviridae virus.
  • the Pneumoviridae virus is a Respiratory syncytial virus or a Metapneumovirus.
  • the Metapneumovirus is a human metapneumovirus (hMPV).
  • the Paramyxoviridae virus is a Parainfluenza virus or a Henipavirus.
  • the parainfluenzavirus is PIV3.
  • the non-SARS-CoV-2 coronavirus is a betacoronavirus (e.g., SARS-CoV-1).
  • the non-SARS-CoV-2 coronavirus is a Merbecovirus (e.g., a MERS-CoV virus).
  • an RNA composition described herein is co-administered with an RSV vaccine (e.g., an RSV A or RSV B vaccine).
  • the RSV vaccine comprises an RSV fusion protein (F), an RSV attachment protein (G), an RSV small hydrophobic protein (SH), an RSV matrix protein (M), an RSV nucleoprotein (N), an RSV M2-1 protein, an RSV Large polymerase (L), and/or an RSV phosphoprotein (P), or an immunogenic fragment of immunogenic variant thereof, or a nucleic acid (e.g., RNA), encoding any one of the same.
  • RSV vaccines are known in the art, any one of which can be co-administered with an RNA composition described herein. See, for example, the list of RSV vaccines provided on the website of PATH, a global health organization (see https:/www.path.org/resources/rsz-vaccine-and-mab-snapshot/), as well as in Mazur, Natalie I., et al, “The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates,” The Lancet Infectious Diseases 18.10 (2016): e295-e311, the contents of each of which is incorporated by reference herein.
  • an RNA composition described herein is co-administered with an RSV vaccine that has been previously published on (e.g., an RSV vaccine described on the PATH website page linked to above, or in Mazur et al.).
  • an RNA composition described herein is co-administered with a live-attenuated or chimeric vaccine (e.g., rBCG-N-hRSV (developed by Ponteificia Uinersidad Catolica de Chile), RSV D46 cp ⁇ M202 (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV LID ⁇ M2-2 1030s (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV ⁇ NS2 ⁇ 1313/11314L (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV D46 ⁇ NS2 N ⁇ M2-2 HindIII (developed by Sanofi Pasteur/LID/NIAD/NIH) or RSV D46 ⁇ NS2
  • a particle based vaccine e.g., RSV F nanoparticle (developed by Novavax) or SynGEM (developed by Mucosis), Icosavzx (developed by IVX-121), or V-306 (developed by Virometix)
  • a subunit vaccine e.g., GSK RSV F (developed by GSK), Arexvy (developed by GSK), DPX-RSV (developed by Dalousie Univeristy, Immunovaccine, and VIB), RSV F DS-Cavi (developed by NIH/NIAID/VRC), MEDI-7510 (developed by MedImmune), RSVpreF (developed by Pfizer), ADV110 (developed by Advaccine), VN-0200 (developed by Daiichi Sankyo, Inc.)), a vector vaccine (e.g., MVA-BN RSV (developed by Banarian Nordic), VXA-RSVf oral (developed by Vaxart), Ad26.RSV.pref (developed by Janssen), Ch
  • an RNA composition described herein is co-administered with an influenza vaccine.
  • influenza vaccine is an alpha-influenza virus, a beta-influenza virus, a gamma-influenza virus or a delta-influenza virus vaccine.
  • the vaccine is an Influenza A virus, an Influenza B virus, an Influenza C virus, or an Influenza D virus vaccine.
  • influenza A virus vaccine comprises a hemagglutinin selected from H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, or an immunogenic fragment or variant of the same, or a nucleic acid (e.g., RNA) encoding any one of the same.
  • a hemagglutinin selected from H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, or an immunogenic fragment or variant of the same, or a nucleic acid (e.g., RNA) encoding any one of the same.
  • influenza A vaccine comprises or encodes a neuraminidase (NA) selected from N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11, or an immunogenic fragment or variant of the same, or a nucleic acid (e.g., RNA) encoding any one of the same.
  • NA neuraminidase
  • the influenza vaccine comprises at least one Influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), non-structural protein 1 (NS1), non-structural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, and/or polymerase basic protein 2 (PB2), or an immunogenic fragment or variant thereof, or a nucleic acid (e.g., RNA) encoding any of one of the same.
  • Influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), non-structural protein 1 (NS1), non-structural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, and/or polymerase basic protein 2
  • an RNA composition described herein can be co-administered with a commercially approved influenza vaccine.
  • an RNA composition described herein can be co-administered with an inactivated influenza virus (e.g., Fluzone®, Fluzone high-dose Quadrivalent®, Fluzone Quadrivalent®, Fluzone intradermal Quardivalent®, Fluzone quadrivalent southern Hemisphere®, Fluad®, Fluad Quadrivalent®, Afluria Quardivalent®, Fluarix Quadrivalent®, FluLaval Quadrivalent®, or Flucelvax Quadrivalent®), a recombinant influenza vaccine (e.g., Flublok Quadrivalent®), a live attenuated influenza vaccine (e.g., FluMist Quadrivalent®), a non-adjuvanted influenza vaccine, an adjuvanted influenza vaccine, or a subunit or split vaccine.
  • an inactivated influenza virus e.g., Fluzone®, Fluzone high-dose Quadrivalent®, Flu
  • an RNA composition described herein is co-administered with an influenza vaccine and/or an RSV vaccine.
  • a composition or medical preparation is a pharmaceutical composition.
  • composition or medical preparation is a vaccine.
  • the present Example describes a study to characterize immune responses induced by certain variant-adapted vaccines in vaccine-experienced subjects (mice in the present Example).
  • the present Example describes an experiment to characterize immune responses induced in subjects previously administered (i) at least one dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain, and (ii) at least one dose of a bivalent composition comprising a first RNA that encodes a SARS-COV-2 S protein of a Wuhan strain and a second RNA that encodes a SARS-CoV-2 S protein of a BA.4/5 Omicron variant.
  • FIGS. 1 and 2 Two sets of experimental dosing regimens are summarized in FIGS. 1 and 2 .
  • mice are administered a first dose of an RNA vaccine encoding a SARS-CoV-2 S protein of a Wuhan variant (BNT162b2), and, 21 days later, a second dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding SARS-COV-2 S protein of a BA.4/5 Omicron variant.
  • mice are then administered one of the following compositions (comprising RNAs encoding SARS-CoV-2 S proteins from the listed strains/variants):
  • mice are sacrificed and final neutralization titers are collected.
  • neutralization titers are determined in mice administered two doses of a composition that delivers a Wuhan S protein, a third dose of a bivalent vaccine, and a fourth dose of one of the vaccines listed below (comprising RNAs encoding SARS-CoV-2 S proteins from the listed variants).
  • the design of this experiment is summarized in FIG. 2 .
  • the present Example provides data characterizing certain monovalent and bivalent variant-adapted vaccines in vaccine na ⁇ ve mice.
  • the particular vaccines tested are shown in FIG. 3 .
  • vaccines were administered vaccines on days 0 and 21 (the same vaccine composition and dose was administered on each day; dose amounts indicated in FIG. 3 ), and sera samples were collected on day 35 (14 days after the second dose of a vaccine).
  • Pseudovirus neutralization titers from sera samples collected on day 35 are shown in FIG. 4 .
  • each of the tested compositions can produce strong neutralization titers against the corresponding strain or variant.
  • a monovalent composition comprising an RNA encoding an S protein of an XBB.1.5 Omicron variant was shown to induce high neutralization titers against XBB.1.5 when administered as a primary series.
  • a bivalent composition comprising an RNA encoding an S protein of an XBB.1.5 Omicron variant and an RNA encoding an S protein of an Omicron BA.4/5 variant was also shown to induce high neutralization titers against XBB.1.5 when administered as a primary series, although titers were lower than those induced by an XBB.1.5 monovalent vaccine.
  • compositions comprising an RNA encoding an S protein of a SARS-CoV-2 variant (i.e., WT+BA.4/5, BA.4/5, XBB.1.5, and BA.4/5+XBB.1.5) was also found to induce broad cross-neutralization of other variants of concern.
  • the BA.4/5+XBB.1.5 bivalent vaccine was found to induce high neutralization titers both against the XBB.1.5 variant as well as other strains.
  • Neutralization titers against XBB.1.16 are expected to be similar to those induced against XBB.1.5, as neutralization data shows that the XBB.1.16 variant possesses no escape advantage relative to XBB.1.5 (see, e.g., FIG. 6 ).
  • neutralization titers for XBB.1.9.1/1.9.2 are expected to match those for XBB.1.5, as XBB.1.9.1/1.9.2 does not comprise any additional S protein mutations relative to XBB.1.5.
  • a similar experiment (summarized in the schematic at the top of FIG. 7 ) was also performed in which vaccine-na ⁇ ve mice were administered two doses of (i) a bivalent composition comprising RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, (ii) a monovalent composition comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant, or (iii) a bivalent composition comprising RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant and RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant.
  • RNA The two doses of RNA were administered 21 days apart, and neutralization titers were collected 4 weeks after administering the second dose.
  • an XBB.1.5-adapted monovalent vaccine e.g., as described herein
  • the present Example provides exemplary immune response data generated using certain monovalent and bivalent variant-adapted vaccines in vaccine-experienced mice.
  • vaccines e.g., monovalent or bivalent vaccines
  • RNA encoding an XBB.1.5 S protein can induce strong neutralization titers against an XBB.1.5 Omicron variant in previously vaccinated subjects (e.g., subjects previously administered RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, as in the present Example).
  • mice in all groups were administered the following vaccines (listed in order of administration): (1) a first dose of a vaccine comprising RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2 in the present example), (2) a second dose of a vaccine comprising an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (again, BNT162b2 in the present example; second dose administered about 21 days after the first dose), (3) a third dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (administered about 84 days after the second dose), and (4) a fourth dose of one of the monovalent or bivalent vaccines listed in the Figure (administered about 29 days after the third
  • Sera samples were collected 134 days after administration of the first dose of vaccine (immediately before administering the 4 th dose), and 160 days after administering the 1 st dose. Mice were administered 0.5 ⁇ g of each vaccine (for monovalent vaccines: 0.5 ⁇ g of an RNA, for bivalent vaccines: 0.25 ⁇ g of each RNA). On day 160, lymph nodes and spleen samples were also collected for T cell and B cell analysis.
  • Pseudovirus neutralization titers are shown in FIG. 6 .
  • vaccines comprising an RNA encoding an XBB.1.5 S protein were found to induce a strong neutralization response when administered as either a monovalent or bivalent (e.g., BA.4/5+XBB.1.5) vaccine.
  • the data demonstrates that such vaccines are especially effective when administered as a booster dose (e.g., to subjects previously administered one or more vaccines that deliver a SARS-CoV-2 S protein of a Wuhan strain and one or more bivalent vaccines (delivering a SARS-CoV-2 S protein of a Wuhan strain and an Omicron BA.4/5 variant), as tested in the present Example).
  • neutralization titers induced by an XBB.1.5 monovalent vaccine were found to be higher than those induced by a bivalent vaccine (BA.4/5+XBB.1.5).
  • neutralization titers for XBB.1.9.1/1.9.2 are expected to match those induced for XBB.1.5, as XBB.1.9.1/1.9.2 does not comprise any additional S protein mutations relative to XBB.1.5.
  • mice were divided into groups of 10, and administered two doses (21 days apart) of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2 in the present example), followed by a third dose (administered 14 days after the second dose) of a candidate vaccine encoding (i) a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, (ii) a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant, (iii) a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an X
  • a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant (e.g., an RNA described herein) induced the highest neutralization titers against each of the XBB.1.5, XBB.1.16, and XBB.2.3 variants.
  • an XBB.1.5 monovalent composition induced higher titers against an XBB.1.16 variant than a monovalent comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.16 variant.
  • SEQ ID NO Description 1 Amino acid sequence of a full length SARS-CoV-2 S protein of a Wuhan strain 2
  • Exemplary RNA sequence encoding an RBD of a Wuhan SARS-CoV-2 S protein 5
  • 1 Omicron variant 50 Exemplary RNA sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a BA.
  • 1 Omicron variant 51 Exemplary RNA sequence comprising a sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a BA.1 Omicron variant, along with 5′ UTR, 3′ UTR, and polyA sequences 52 Exemplary amino acid sequence of a prefusion-stabilized SARS-CoV-2 S protein of a BA.
  • RNA sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a BA.1 Omicron variant 54
  • Exemplary RNA sequence comprising a sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a BA.1 Omicron variant, along with 5′ UTR, 3′ UTR, and polyA sequences 55
  • Exemplary amino acid sequence of a prefusion-stabilized SARS-CoV-2 S protein of a beta variant 56
  • Exemplary RNA sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a beta variant 56
  • Exemplary RNA sequence comprising a sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a beta variant 57
  • Exemplary RNA sequence comprising a sequence encoding a prefusion-stabilized SARS-CoV-2 S protein of a beta variant, along with 5′ UTR, 3′ UTR, and polyA sequences 58

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.

Description

  • This application claims the benefit of priority under 35 U.S.C. § 120 to each of the following applications, the disclosure of each of which is hereby incorporated by reference in its entirety: U.S. Application No. 63/355,648, filed Jun. 26, 2022; U.S. Application No. 63/357,628 filed Jun. 30, 2022; U.S. Application No. 63/358,522, filed Jul. 5, 2022; U.S. Application No. 63/394,571, filed Aug. 2, 2022; U.S. Application No. 63/402,444, filed Aug. 30, 2022; U.S. Application No. 63/417,680, filed: Oct. 19, 2022; U.S. Application No. 63/422,404, filed Nov. 3, 2022; U.S. Application No. 63/425,290, filed Nov. 14, 2022; U.S. Application No. 63/486,953 filed: Feb. 24, 2023; U.S. Application No. 63/452,148 filed: Mar. 14, 2023; U.S. Application No. 63/465,521, filed: May 10, 2023; and U.S. Application No. 63/469,472, filed May 29, 2023. This application also claims the benefit of priority under 35 U.S.C. § 119 to international application no. PCT/EP2022/083740, filed Nov. 29, 2022, the contents of which is incorporated by reference herein in its entirety.
  • The instant application contains a Sequence Listing which has been submitted electronically in .xml format and is hereby incorporated by reference in its entirety. Said .xml file, created on Jun. 26, 2023, is identified as 2013237-0687_SL.xml and is 540,905 bytes in size.
  • 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. These methods and agents are, in particular, useful for the prevention or treatment of coronavirus infection. Administration of RNA disclosed herein to a subject can protect the subject against coronavirus infection. 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. Administering to the subject RNA encoding vaccine antigen may provide (following expression of the RNA by appropriate target cells) vaccine antigen for inducing an immune response against vaccine antigen (and disease-associated antigen) in the subject.
  • SARS-CoV-2 infections and the resulting disease COVID-19 have spread globally, affecting a growing number of countries. On 11 Mar. 2020 the WHO characterized the COVID-19 outbreak as a pandemic. As of 1 Dec. 2020, there have been >63 million globally confirmed COVID-19 cases and >1.4 million deaths, with 191 countries/regions affected. The ongoing pandemic remains a significant challenge to public health and economic stability worldwide.
  • The present invention is directed to a composition comprising an RNA molecule having:
      • (a) a nucleotide sequence that is at least 99% identical to SEQ ID NO: 161;
      • (b) a nucleotide sequence that is at least 95% identical to SEQ ID NO: 161, and which encodes a SARS-CoV-2 S protein comprising the following mutations relative to SEQ ID NO: 1: T19I, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K, K986P, and V987P; or
      • (c) a nucleotide sequence as set forth in SEQ ID NO: 161; and
      • wherein the RNA molecule comprises:
      • (i) a 5′ cap; and
      • (ii) a modified uridine in place of each uridine.
  • The present invention is also directed to a composition of the invention for use in a method of inducing an immune response against coronavirus in a subject, said method comprising administering to a subject the composition.
  • In some embodiments, the modified uridine can be N1-methyl-pseudouridine.
  • In some embodiments, the 5′ cap can comprise m2 7,3′-OGppp(m1 2′-O)ApG.
  • In come embodiments, the RNA molecule can be encapsulated in a lipid nanoparticle (LNP), preferably wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
  • In some embodiments, the composition can comprise one or more additional RNA molecules, each having a nucleotide sequence encoding an S protein of a SARS-CoV-2 strain or variant that is not XBB.1.5, preferably wherein the one or more additional RNA molecules comprise a sequence that is at least 95% identical to that set forth in SEQ ID NO: 20, 72, or 103.
  • In some embodiments, the RNA molecule comprises:
      • (i) N1-methyl-pseudouridine in place of each uridine; and
      • (ii) a 5′ cap that comprises m2 7,3′-OGppp(m1 2′-O)ApG;
        wherein the RNA molecule is encapsulated in a lipid nanoparticle (LNP); and wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
  • In some embodiments, the composition can comprise about 10 mM Tris buffer and about 10% sucrose.
  • In some embodiments, the composition can comprise at least one unit dose of LNP-encapsulated RNA molecules, optionally wherein the unit dose comprises the RNA molecule in an amount of about 30 μg, or wherein the unit dose comprises the RNA molecule in an amount of about 10 μg, or wherein the unit dose comprises the RNA molecule in an amount of about 3 μg.
  • In some embodiments, the composition is formulated as a multi-dose formulation in a vial.
  • In some embodiments, the subject can be 12 years or older, and the composition can comprise 30 μg of the RNA molecule, or the subject can be 5 years to less than 12 years old, and the composition can comprise 10 μg of the RNA molecule, or the subject can be 6 months to less than 5 years old, and the composition can comprise 3 μg of the RNA molecule.
  • In some embodiments, the composition can be administered in a volume of about 200 μL to 300 μL.
  • In some embodiments, the subject was previously administered one or more doses of a SARS-CoV-2 vaccine, preferably wherein the subject was previously administered a complete dosing regimen of a SARS-CoV-2 vaccine.
  • In some embodiments, the subject was previously administered a first dose and a second dose of BNT162b2, wherein the first dose and the second dose were administered about 21 days apart, and/or wherein the subject was previously administered as a booster dose a bivalent vaccine that delivers (i) a SARS-CoV-2 S protein of an Omicron BA.4/5 variant and (ii) a SARS-CoV-2 S protein of a Wuhan strain.
  • In some embodiments, said method can further comprise administering one or more vaccines against a non-SARS-CoV-2 disease, preferably wherein the one or more vaccines comprises an RSV vaccine, an influenza vaccine, or a combination thereof.
  • In some embodiments, compositions disclosed herein (e.g., monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant) can induce a strong immune response (e.g., high neutralization titers) against certain SARS-CoV-2 variants of concern (e.g., XBB variants of concern (including, e.g., an XBB.1.5 variant, an XBB.1.16 variant, an XBB.2.3 variant, and/or an XBB.2.3.2 variant)). In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant. In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.16 variant. In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.2.3 variant. In some embodiments, such compositions are monovalent compositions comprising RNA encoding a SARS-CoV-2 S protein of an XBB.2.3.2 variant. As demonstrated herein, in some embodiments, such compositions can induce surprisingly high neutralization titers against certain XBB variants of concern (including, e.g., XBB.1.5, XBB.1.16, and XBB.2.3 variants of concern). Even more surprisingly, in some embodiments, such compositions can induce neutralization titers that are higher against a given variant than a variant-matched vaccine (e.g., in some embodiments, RNA described herein comprising a nucleotide sequence that encodes an XBB.1.5 S protein, can induce neutralization titers against a XBB.1.16 variant of concern that are higher than those induced by an XBB.1.16-adapted vaccine). In some embodiments, the strong immune response can be observed in vaccine-naïve subjects (e.g., young pediatric patients (e.g., patients 6 months to less than 5 years old). In some embodiments, the strong immune response can be observed in subjects without a previous or current coronavirus infection (e.g., a SARS-CoV-2 infection). In some embodiments, a strong immune response can be observed in subjects who previously received a SARS-CoV-2 vaccine (e.g., in some embodiments an RNA vaccine encoding a SARS-CoV-2 S protein, e.g., in some embodiments of a Wuhan strain) and/or who were previously infected with SARS-CoV-2. In some embodiments, such broader cross-neutralization can be observed in young pediatric subjects (e.g., subjects aged 6 months to less than 2 years, and/or 2 years to less than 5 years).
    • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 . Experimental design for a study to characterize immune responses induced by variant-adapted vaccines in SARS-CoV-2 vaccine-experienced mice. Mice are split into 9 groups, each of which is administered a first dose of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2) and a second dose of a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-COV-2 S protein of an Omicron BA.4/5 variant (BNT162b2+BA.4/5). Following the second dose, mice are administered a composition comprising an RNA encoding a SARS-CoV-2 S protein of a strain or variant or combination of strains/variants, as indicated in the Figure. The first and second doses are administered 21 days apart, and the third dose is administered about 70 days after the third dose. 119 days after administering the first dose, mice are sacrificed and the experiment concluded.
  • FIG. 2 . Experimental design for a study to characterize variant-adapted vaccines in SARS-CoV-2 vaccine-experienced mice. Mice are split into 6 groups, each of which is administered a first and a second dose of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2), followed by a third dose of a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of a BA.4/5 Omicron variant (BNT162b2+BA.4/5). Following the third dose, mice are administered a composition comprising an RNA encoding an SARS-CoV-2 S protein of a variant or strain or combination of strains/variants, as indicated in the Figure. The first and second doses are administered 21 days apart, the third dose is administered 70 days after the third dose, and the 4th dose is administered 21 days after the third dose. 126 days after administering the first dose, mice are sacrificed and the experiment concluded.
  • FIG. 3 . Exemplary experimental protocol for testing variant-adapted vaccines as a primary series in mice. Two doses of a monovalent or bivalent vaccine composition comprising mRNA(s) encoding the SARS-CoV-2 S protein(s) of the strains/variants indicated in the figure were administered to mice 21 days apart. “WT” corresponds to RNA encoding a SARS-CoV-2 S protein from a Wuhan strain. Indicated in the figure is the mass of RNA (μg) administered to mice.
  • FIG. 4 . A monovalent XBB.1.5-adapted vaccine, as a primary series, elicits higher neutralization titers against XBB.1.5 than a bivalent Wuhan+BA.4/5 vaccine. Shown are results collected in performing the experiment summarized in FIG. 3 . (A) shows pseudovirus neutralization titers of serum samples collected at Day 35 of the experiment summarized in FIG. 3 . (B) Lists neutralization titer values for the bar graph shown in panel (A).
  • FIG. 5 . Exemplary experimental protocol for testing variant-adapted vaccines as a fourth booster dose in mice. “BNT162b2 Original WT” corresponds to a monovalent mRNA vaccine encoding a SARS-CoV-2 S protein of a Wuhan strain, “BNT162b2 Bivalent WT+BA.4/5” corresponds to a bivalent vaccine comprising an RNA encoding an S protein of a Wuhan strain and an RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant. On day 134, mice were administered a monovalent or bivalent vaccine encoding one of the strains, variants, or combinations indicated in the figure. On days 134 and 160, blood samples were collected (represented by the test tube racks).
  • FIG. 6 . An XBB.1.5-adapted booster vaccine elicits the highest neutralization titers against an XBB.1.5 and XBB.1.6 pseudovirus. Shown are results collected in performing the experiment summarized in FIG. 5 . (A) shows neutralization titers collected for a panel of pseudoviruses (indicated in the figure legend). X-axis indicates vaccine administered. Titers collected at day 160. (B) shows neutralization titer values for the bar graph shown in panel (A). (C) Shows geometric mean ratios (GMR) of neutralization titers induced by the indicated vaccine relative to neutralization titers induced by a bivalent vaccine comprising an RNA encoding a SARS-CoV-2 S protein from a Wuhan strain (WT in the figure) and an RNA encoding a SARS-CoV-2 S protein from an Omicron BA.4/5 variant (GMR values calculated using neutralization titers at day 160). (D) provides GMR values for the bar graph shown in panel (C). (E) Shows GMR values comparing neutralization titers induced by the indicated vaccines relative to neutralization titers at day 135 (pre dose 4). (F) shows GMR values for the graph shown in panel (E). (G) shows neutralization titers against further SARS-CoV-2 variants (including XBB.2.3).
  • FIG. 7 . Certain variant-adapted vaccines induce a neutralization response against Omicron XBB variants in vaccine-naïve mice. A summary of the experimental protocol is depicted at the top of the figure (syringes indicate days on which candidate vaccines were administered and the droplet indicates a day on which blood was collected). Vaccine naïve mice were administered two doses of the indicated candidate vaccines. Four weeks after receiving a second dose of vaccine, mice were bled and neutralization titers collected. As shown in the figure, neutralization titers were induced against each of the variants tested, with a monovalent XBB.1.5-adapted vaccine inducing the highest neutralization titers against each of the XBB variants tested.
  • FIG. 8 . Certain variant-adapted vaccines induce a neutralization response against Omicron XBB variants in vaccine-experienced mice. A summary of the experimental protocol is depicted at the top of the figure (syringes indicate days on which candidate vaccines were administered and the droplet indicates a day on which blood was collected). Mice were administered two doses of RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (WT), followed by a dose of a candidate vaccine. Two weeks after receiving a dose of candidate vaccine, mice were bled and neutralization titers collected. As shown in the figure, neutralization titers were induced against each of the variants tested, with a monovalent XBB.1.5-adapted vaccine inducing the highest neutralization titers against each of the XBB variants tested.
    •  DEFINITIONS
  • The term “about” means approximately or nearly, and in the context of a numerical value or range set forth herein in one embodiment means±20%, ±10%, ±5%, or ±3% of the numerical value or range recited or claimed.
  • The terms “a” and “an” and “the” and similar reference used in the context of describing the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it was individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.
    • RNA
  • In the present disclosure, the term “RNA” relates to a nucleic acid molecule which includes ribonucleotide residues. In preferred embodiments, the RNA contains all or a majority of ribonucleotide residues. As used herein, “ribonucleotide” refers to a nucleotide with a hydroxyl group at the 2′-position of a β-D-ribofuranosyl group. RNA encompasses without limitation, double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations may refer to addition of non-nucleotide material to internal RNA nucleotides or to the end(s) of RNA. It is also contemplated herein that nucleotides in RNA may be non-standard nucleotides, such as chemically synthesized nucleotides or deoxynucleotides. For the present disclosure, these altered RNAs are considered analogs of naturally-occurring RNA.
  • In certain embodiments of the present disclosure, the RNA is messenger RNA (mRNA) that relates to a RNA transcript which encodes a peptide or protein. As established in the art, mRNA generally contains a 5′ untranslated region (5′-UTR), a peptide coding region and a 3′ untranslated region (3′-UTR). In some embodiments, the RNA is produced by in vitro transcription or chemical synthesis. In one embodiment, the mRNA is produced by in vitro transcription using a DNA template where DNA refers to a nucleic acid that contains deoxyribonucleotides.
  • In one embodiment, RNA described herein may have modified nucleosides. In some embodiments, RNA comprises a modified nucleoside in place of at least one (e.g., every) uridine. In some embodiments, one or more uridine in the RNA described herein is replaced by a modified nucleoside. In some embodiments, RNA comprises a modified nucleoside in place of each uridine. In some embodiments, the modified nucleoside is a modified uridine.
  • One exemplary modified nucleoside is N1-methyl-pseudouridine (m1Ψ), which has the structure:
  • Figure US20240000921A1-20240104-C00001
  • In some embodiments, RNA according to the present disclosure comprises a 5′-cap. The term “5′-cap” refers to a structure found on the 5′-end of an mRNA molecule and generally consists of a guanosine nucleotide connected to the mRNA via a 5′- to 5′-triphosphate linkage. In one embodiment, this guanosine is methylated at the 7-position. Providing an RNA with a 5′-cap or 5′-cap analog may be achieved by in vitro transcription, in which the 5′-cap is co-transcriptionally expressed into the RNA strand, or may be attached to RNA post-transcriptionally using capping enzymes.
  • In some embodiments, the building block cap for RNA is m2 7,3′-OGppp(m1 2′-O)ApG (also sometimes referred to as m2 7,3′-OG(5′)ppp(5′)m2′-OApG), which has the following structure:
  • Figure US20240000921A1-20240104-C00002
  • In one embodiment, the 5′-UTR sequence is derived from the human alpha-globin mRNA and optionally has an optimized ‘Kozak sequence’ to increase translational efficiency.
  • In one embodiment, RNA encoding an amino acid sequence comprising a SARS-CoV-2 S protein, an immunogenic variant thereof, or an immunogenic fragment of the SARS-CoV-2 S protein or the immunogenic variant thereof comprises a 5′ UTR comprising the nucleotide sequence of SEQ ID NO: 12, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 12.
  • In one embodiment, a combination of two sequence elements (FI element) derived from the “amino terminal enhancer of split” (AES) mRNA (called F) and the mitochondrial encoded 12S ribosomal RNA (called I) are placed between the coding sequence and the poly(A) sequence to assure higher maximum protein levels and prolonged persistence of the RNA (e.g., mRNA). In one embodiment, two re-iterated 3′-UTRs derived from the human beta-globin mRNA are placed between the coding sequence and the poly(A) sequence to assure higher maximum protein levels and prolonged persistence of the RNA (e.g., mRNA).
  • In one embodiment, RNA encoding an amino acid sequence comprising a SARS-CoV-2 S protein, an immunogenic variant thereof, or an immunogenic fragment of the SARS-CoV-2 S protein or the immunogenic variant thereof comprises a 3′ UTR comprising the nucleotide sequence of SEQ ID NO: 13, or a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to the nucleotide sequence of SEQ ID NO: 13.
  • In one embodiment, a poly(A) sequence measuring 110 nucleotides in length, consisting of a stretch of 30 adenosine residues, followed by a linker sequence (e.g., 10 nucleotide linker sequence) and another 70 adenosine residues is used. This poly(A) sequence was designed to enhance RNA stability and translational efficiency.
  • In one embodiment, the poly-A sequence comprises at least 100 nucleotides.
  • In one embodiment, the poly-A sequence comprises or consists of the nucleotide sequence of SEQ ID NO: 14.
    • RNA Encoding SARS-CoV-2 S Protein of an XBB.1.5 Variant
  • In some embodiments, RNA described herein encodes a SARS-CoV-2 S protein comprising one or more mutations characteristic of an Omicron XBB.1.5 variant. In some embodiments, the one or more mutations characteristic of an Omicron XBB.1.5 variant include F486P. In some embodiments, the one or more mutations characteristic of an Omicron XBB.1.5 variant include T19I, Δ24-26, A27S, V83A, G142D, A144, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, S486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K, or any combination thereof. In some embodiments, the one or more mutations characteristic of an Omicron XBB.1.5 variant include T19I, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K, or any combination thereof.
  • In some embodiments, RNA described herein encodes a SARS-CoV-2 S protein comprising one more mutations that stabilize a prefusion confirmation. In some embodiments, stabilization of a prefusion conformation of a SARS-CoV-2 S protein may be obtained by introducing two consecutive proline substitutions at residues 986 and 987 in the full length spike protein (positions shown relative to SEQ ID NO: 1; for variant adapted sequences, proline substitutions can be introduced at corresponding positions). Specifically, spike (S) protein stabilized protein variants can be obtained by exchanging the amino acid residue at position 986 to proline and the amino acid residue at position 987 to proline. In one embodiment, a SARS-CoV-2 S protein variant wherein the prototypical prefusion conformation is stabilized comprises the amino acid sequence shown in SEQ ID NO: 7. In one embodiment, the SARS-CoV-2 S protein can comprise the following mutations relative to SEQ ID NO: 7: T19I, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K.
  • In some embodiments, an RNA composition described herein comprises an RNA encoding a polypeptide as set forth in SEQ ID NO: 158 or an immunogenic fragment thereof, or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 158). In some embodiments, an RNA composition comprises an RNA that includes the sequence of SEQ ID NO: 159 or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 159). In some embodiments, an RNA composition comprises an RNA that includes the sequence of SEQ ID NO: 161 or a variant thereof (e.g., having at least 70% or more, including, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or higher, identity to SEQ ID NO: 161).
  • In some embodiments, an RNA composition comprises an RNA comprising (a) a nucleotide sequence of SEQ ID NO: 161 or a sequence that is at least 70% identical to SEQ ID NO: 161 (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to SEQ ID NO: 161), and/or (b) a nucleotide sequence that encodes a SARS-CoV-2 S protein having an amino acid sequence of SEQ ID NO: 158, or an amino acid sequence that is at least 70% identical to SEQ ID NO: 158 (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to SEQ ID NO: 158), and (c) wherein the SARS-CoV-2 S protein optionally comprises one or more mutations that stabilize a prefusion confirmation (e.g., proline mutations at positions 982 and 983 of SEQ ID NO: 158). In some embodiments, such a composition comprises one or more additional RNAs, each encoding an S protein of a non-XBB.1.5 SARS-CoV strain or variant (e.g., a Wuhan strain, an Omicron BA.4/5 variant, and/or an Omicron BA.2.75.2 variant (e.g., such RNAs described herein)).
  • In some embodiments, an RNA composition comprises an RNA comprising a nucleotide sequence that encodes a SARS-CoV-2 S protein comprising one or more mutations characteristic of an Omicron XBB.1.5 variant and wherein:
      • a) the SARS-CoV-2 S protein comprises an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO: 158, or an immunogenic fragment thereof, and/or
      • b) the RNA molecule encoding the SARS-CoV-2 S protein comprises a nucleotide sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO: 159; and/or at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO: 161, and wherein
      • c) the one or more mutations characteristic of an Omicron XBB.1.5 variant are optionally selected from: T19I, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, and N969K, or any combination thereof.
  • In some embodiments, a composition comprising an RNA that comprises a nucleotide sequence encoding a SARS-CoV-2 S protein comprising one or more mutations characteristic of an XBB.1.5 variant further comprises one or more additional RNAs, each having a nucleotide sequence encoding a SARS-CoV-2 S protein of a non-XBB.1.5 SARS-CoV-2 strain or variant or strain. In some embodiments, such non-XBB.1.5 strains or variants include a Wuhan strain, an Omicron BA.4/5 strain, and/or a BQ.1.1 variant. In some embodiments, the one or more additional RNA molecules comprise a sequence that is at least 70% identical (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or higher, identity to) SEQ ID NO: 20, 70, or 103, or wherein the one or more additional RNA molecules comprise a sequence SEQ ID NO: 20, 72, or 103.
  • TABLE 1
    Sequence of one embodiment of an exemplary Omicron XBB.1.5-specific RNA vaccine
    SEQ
    ID
    NO. Brief Description Sequence
    158 Amino acid MFVFLVLLPLVSSQCVNLITRTQSYTNSFTRGVYYPDKVFRSSVLHSTQDL
    sequence of FLPFFSNVTWFHAIHVSGTNGTKRFDNPALPFNDGVYFASTEKSNIIRGWIF
    RNA-encoded GTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLDVYQKNNKSWMESEF
    SARS-CoV-2 S RVYSSANNCTFEYVSQPFLMDLEGKEGNFKNLREFVFKNIDGYFKIYSKH
    protein from an TPINLERDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPVDSSSGWTA
    Omicron XBB.1.5 GAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEK
    variant (with GIYQTSNFRVQPTESIVRFPNITNLCPFHEVFNATTFASVYAWNRKRISNCV
    PRO mutations ADYSVIYNFAPFFAFKCYGVSPTKLNDLCFTNVYADSFVIRGNEVSQIAPG
    at positions QTGNIADYNYKLPDDFTGCVIAWNSNKLDSKPSGNYNYLYRLFRKSKLKP
    corresponding FERDISTEIYQAGNKPCNGVAGPNCYSPLQSYGFRPTYGVGHQPYRVVVL
    to K986P and SFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQ
    V987P of SEQ ID QFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQG
    NO: 1; i.e., VNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEYVNNSYECDI
    PRO mutations PIGAGICASYQTQTKSHRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPT
    at positions 982 NFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLKRALT
    and 983 of GIAVEQDKNTQEVFAQVKQIYKTPPIKYFGGFNFSQILPDPSKPSKRSFIEDL
    SEQ ID NO: 158) LFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQ
    YTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKL
    IANQFNSAIGKIQDSLSSTASALGKLQDVVNHNAQALNTLVKQLSSKFGAI
    SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLA
    ATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKN
    FTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGN
    CDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASV
    VNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIV
    MVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
    159 RNA sequence auguucguguuccuggugcugcugccucugguguccagccagugugugaaccugaucaccagaacacag
    encoding a ucauacaccaacagcuuuaccagaggcguguacuaccccgacaagguguucagauccagcgugcugcacuc
    SARS-CoV-2 S uacccaggaccuguuccugccuuucuucagcaacgugaccugguuccacgccauccacguguccggcacc
    protein from an aauggcaccaagagauucgacaaccccgcccugcccuucaacgacgggguguacuuugccagcaccgagaa
    Omicron XBB.1.5 guccaacaucaucagaggcuggaucuucggcaccacacuggacagcaagacccagagccugcugaucguga
    variant acaacgccaccaacguggucaucaaagugugcgaguuccaguucugcaacgaccccuuccuggacgucuac
    cagaagaacaacaagagcuggauggaaagcgaguuccggguguacagcagcgccaacaacugcaccuucga
    guacgugucccagccuuuccugauggaccuggaaggcaaggagggcaacuucaagaaccugcgcgaguuc
    guguuuaagaacaucgacggcuacuucaagaucuacagcaagcacaccccuaucaaccucgagcgggaucu
    gccucagggcuucucugcucuggaaccccugguggaucugcccaucggcaucaacaucacccgguuucag
    acacugcuggcccugcacagaagcuaccugacaccuguggauagcagcagcggauggacagcuggugccg
    ccgcuuacuaugugggcuaccugcagccuagaaccuuccugcugaaguacaacgagaacggcaccaucacc
    gacgccguggauugugcucuggauccucugagcgagacaaagugcacccugaaguccuucaccguggaaa
    agggcaucuaccagaccagcaacuuccgggugcagcccaccgaauccaucgugcgguuccccaauaucacc
    aaucugugccccuuccacgagguguucaaugccaccaccuucgccucuguguacgccuggaaccggaagc
    ggaucagcaauugcguggccgacuacuccgugaucuacaacuucgcccccuucuucgcauucaagugcua
    cggcguguccccuaccaagcugaacgaccugugcuucacaaacguguacgccgacagcuucgugauccgg
    ggaaacgaagugucacagauugccccuggacagacaggcaacaucgccgacuacaacuacaagcugcccga
    cgacuucaccggcugugugauugccuggaacagcaacaagcuggacuccaaacccagcggcaacuacaauu
    accuguaccggcuguuccggaaguccaagcugaagcccuucgaggggacaucuccaccgagaucuauca
    ggccggcaacaagccuuguaacggcguggcaggccccaacugcuacagcccacugcaguccuacggcuuu
    aggcccacauacggcgugggccaccagcccuacagagugguggugcugagcuucgaacugcugcaugccc
    cugccacagugugcggcccuaagaaaagcaccaaucucgugaagaacaaaugcgugaacuucaacuucaac
    ggccugaccggcaccggcgugcugacagagagcaacaagaaguuccugccauuccagcaguuuggccggg
    auaucgccgauaccacagacgccguuagagauccccagacacuggaaauccuggacaucaccccuugcagc
    uucggcggagugucugugaucaccccuggcaccaacaccagcaaucagguggcagugcuguaccagggcg
    ugaacuguaccgaagugcccguggccauucacgccgaucagcugacaccuacauggggguguacuccac
    cggcagcaauguguuucagaccagagccggcugucugaucggagccgaguacgugaacaauagcuacgag
    ugcgacauccccaucggcgcuggaaucugcgccagcuaccagacacagacaaagagccaccggagagccag
    aagcguggccagccagagcaucauugccuacacaaugucucuggggccgagaacagcguggccuacucc
    aacaacucuaucgcuauccccaccaacuucaccaucagcgugaccacagagauccugccuguguccaugac
    caagaccagcguggacugcaccauguacaucugcggcgauuccaccgagugcuccaaccugcugcugcag
    uacggcagcuucugcacccagcugaaaagagcccugacagggaucgccguggaacaggacaagaacaccca
    agagguguucgcccaagugaagcagaucuacaagaccccuccuaucaaguacuucggggcuucaauuuc
    agccagauucugcccgauccuagcaagcccagcaagcggagcuucaucgaggaccugcuguucaacaaagu
    gacacuggccgacgccggcuucaucaagcaguauggcgauugucugggcgacauugccgccagggaucug
    auuugcgcccagaaguuuaacggacugacagugcugccuccucugcugaccgaugagaugaucgcccagu
    acacaucugcccugcuggccggcacaaucacaagcggcuggacauuuggagcaggcgccgcucugcagau
    ccccuuugcuaugcagauggccuaccgguucaacggcaucggagugacccagaaugugcuguacgagaac
    cagaagcugaucgccaaccaguucaacagcgccaucggcaagauccaggacagccugagcagcacagcaag
    cgcccugggaaagcugcaggacguggucaaccacaaugcccaggcacugaacacccuggucaagcagcugu
    ccuccaaguucggcgccaucagcucugugcugaacgauauccugagcagacuggacccuccugaggccga
    ggugcagaucgacagacugaucacaggcagacugcagagccuccagacauacgugacccagcagcugauca
    gagccgccgagauuagagccucugccaaucuggccgccaccaagaugucugagugugugcugggccagag
    caagagaguggacuuuugcggcaagggcuaccaccugaugagcuucccucagucugccccucacggcgug
    guguuucugcacgugacauaugugcccgcucaagagaagaauuucaccaccgcuccagccaucugccacg
    acggcaaagcccacuuuccuagagaaggcguguucguguccaacggcacccauugguucgugacacagcg
    gaacuucuacgagccccagaucaucaccaccgacaacaccuucgugucuggcaacugcgacgucgugaucg
    gcauugugaacaauaccguguacgacccucugcagcccgagcuggacagcuucaaagaggaacuggacaa
    guacuuuaagaaccacacaagccccgacguggaccugggcgauaucagcggaaucaaugccagcgucgug
    aacauccagaaagagaucgaccggcugaacgagguggccaagaaucugaacgagagccugaucgaccugca
    agaacuggggaaguacgagcaguacaucaaguggcccugguacaucuggcugggcuuuaucgccggacug
    auugccaucgugauggucacaaucaugcuguguugcaugaccagcugcuguagcugccugaagggcugu
    uguagcuguggcagcugcugcaaguucgacgaggacgauucugagcccgugcugaagggcgugaaacug
    cacuacacaugauga
    160 DNA sequence atgttcgtgttcctggtgctgctgcctctggtgtccagccagtgtgtgaacctgatcaccagaacacagtcatacaccaa
    encoding a cagctttaccagaggcgtgtactaccccgacaaggtgttcagatccagcgtgctgcactctacccaggacctgttcctg
    SARS-CoV-2 S cctttcttcagcaacgtgacctggttccacgccatccacgtgtccggcaccaatggcaccaagagattcgacaacccc
    protein from an gccctgcccttcaacgacggggtgtactttgccagcaccgagaagtccaacatcatcagaggctggatcttcggcac
    Omicron XBB.1.5 cacactggacagcaagacccagagcctgctgatcgtgaacaacgccaccaacgtggtcatcaaagtgtgcgagttc
    variant cagttctgcaacgaccccttcctggacgtctaccagaagaacaacaagagctggatggaaagcgagttccgggtgta
    cagcagcgccaacaactgcaccttcgagtacgtgtcccagcctttcctgatggacctggaaggcaaggagggcaact
    tcaagaacctgcgcgagttcgtgtttaagaacatcgacggctacttcaagatctacagcaagcacacccctatcaacct
    cgagcgggatctgcctcagggcttctctgctctggaacccctggtggatctgcccatcggcatcaacatcacccggttt
    cagacactgctggccctgcacagaagctacctgacacctgtggatagcagcagcggatggacagctggtgccgcc
    gcttactatgtgggctacctgcagcctagaaccttcctgctgaagtacaacgagaacggcaccatcaccgacgccgtg
    gattgtgctctggatcctctgagcgagacaaagtgcaccctgaagtccttcaccgtggaaaagggcatctaccagacc
    agcaacttccgggtgcagcccaccgaatccatcgtgcggttccccaatatcaccaatctgtgccccttccacgaggtgt
    tcaatgccaccaccttcgcctctgtgtacgcctggaaccggaagcggatcagcaattgcgtggccgactactccgtga
    tctacaacttcgcccccttcttcgcattcaagtgctacggcgtgtcccctaccaagctgaacgacctgtgcttcacaaac
    gtgtacgccgacagcttcgtgatccggggaaacgaagtgtcacagattgcccctggacagacaggcaacatcgccg
    actacaactacaagctgcccgacgacttcaccggctgtgtgattgcctggaacagcaacaagctggactccaaaccc
    agcggcaactacaattacctgtaccggctgttccggaagtccaagctgaagcccttcgagcgggacatctccaccga
    gatctatcaggccggcaacaagccttgtaacggcgtggcaggccccaactgctacagcccactgcagtcctacggct
    ttaggcccacatacggcgtgggccaccagccctacagagtggtggtgctgagcttcgaactgctgcatgcccctgcc
    acagtgtgcggccctaagaaaagcaccaatctcgtgaagaacaaatgcgtgaacttcaacttcaacggcctgaccgg
    caccggcgtgctgacagagagcaacaagaagttcctgccattccagcagtttggccgggatatcgccgataccacag
    acgccgttagagatccccagacactggaaatcctggacatcaccccttgcagcttcggcggagtgtctgtgatcaccc
    ctggcaccaacaccagcaatcaggtggcagtgctgtaccagggcgtgaactgtaccgaagtgcccgtggccattca
    cgccgatcagctgacacctacatggcgggtgtactccaccggcagcaatgtgtttcagaccagagccggctgtctgat
    cggagccgagtacgtgaacaatagctacgagtgcgacatccccatcggcgctggaatctgcgccagctaccagaca
    cagacaaagagccaccggagagccagaagcgtggccagccagagcatcattgcctacacaatgtctctgggcgcc
    gagaacagcgtggcctactccaacaactctatcgctatccccaccaacttcaccatcagcgtgaccacagagatcctg
    cctgtgtccatgaccaagaccagcgtggactgcaccatgtacatctgcggcgattccaccgagtgctccaacctgctg
    ctgcagtacggcagcttctgcacccagctgaaaagagccctgacagggatcgccgtggaacaggacaagaacacc
    caagaggtgttcgcccaagtgaagcagatctacaagacccctcctatcaagtacttcggcggcttcaatttcagccaga
    ttctgcccgatcctagcaagcccagcaagcggagcttcatcgaggacctgctgttcaacaaagtgacactggccgac
    gccggcttcatcaagcagtatggcgattgtctgggcgacattgccgccagggatctgatttgcgcccagaagtttaac
    ggactgacagtgctgcctcctctgctgaccgatgagatgatcgcccagtacacatctgccctgctggccggcacaatc
    acaagcggctggacatttggagcaggcgccgctctgcagatcccctttgctatgcagatggcctaccggttcaacgg
    catcggagtgacccagaatgtgctgtacgagaaccagaagctgatcgccaaccagttcaacagcgccatcggcaag
    atccaggacagcctgagcagcacagcaagcgccctgggaaagctgcaggacgtggtcaaccacaatgcccaggc
    actgaacaccctggtcaagcagctgtcctccaagttcggcgccatcagctctgtgctgaacgatatcctgagcagact
    ggaccctcctgaggccgaggtgcagatcgacagactgatcacaggcagactgcagagcctccagacatacgtgac
    ccagcagctgatcagagccgccgagattagagcctctgccaatctggccgccaccaagatgtctgagtgtgtgctgg
    gccagagcaagagagtggacttttgcggcaagggctaccacctgatgagcttccctcagtctgcccctcacggcgtg
    gtgtttctgcacgtgacatatgtgcccgctcaagagaagaatttcaccaccgctccagccatctgccacgacggcaaa
    gcccactttcctagagaaggcgtgttcgtgtccaacggcacccattggttcgtgacacagcggaacttctacgagccc
    cagatcatcaccaccgacaacaccttcgtgtctggcaactgcgacgtcgtgatcggcattgtgaacaataccgtgtac
    gaccctctgcagcccgagctggacagcttcaaagaggaactggacaagtactttaagaaccacacaagccccgacg
    tggacctgggcgatatcagcggaatcaatgccagcgtcgtgaacatccagaaagagatcgaccggctgaacgaggt
    ggccaagaatctgaacgagagcctgatcgacctgcaagaactggggaagtacgagcagtacatcaagtggccctg
    gtacatctggctgggctttatcgccggactgattgccatcgtgatggtcacaatcatgctgtgttgcatgaccagctgct
    gtagctgcctgaagggctgttgtagctgtggcagctgctgcaagttcgacgaggacgattctgagcccgtgctgaag
    ggcgtgaaactgcactacacatgatga
    161 Full length RNA Agaauaaacuaguauucuucugguccccacagacucagagagaacccgccaccauguucguguuccuggu
    construct gcugcugccucugguguccagccagugugugaaccugaucaccagaacacagucauacaccaacagcuuu
    encoding a accagaggcguguacuaccccgacaagguguucagauccagcgugcugcacucuacccaggaccuguucc
    SARS-CoV-2 S ugccuuucuucagcaacgugaccugguuccacgccauccacguguccggcaccaauggcaccaagagauu
    protein from an cgacaaccccgcccugcccuucaacgacgggguguacuuugccagcaccgagaaguccaacaucaucagag
    Omicron XBB.1.5 gcuggaucuucggcaccacacuggacagcaagacccagagccugcugaucgugaacaacgccaccaacgug
    variant gucaucaaagugugcgaguuccaguucugcaacgaccccuuccuggacgucuaccagaagaacaacaagag
    cuggauggaaagcgaguuccggguguacagcagcgccaacaacugcaccuucgaguacgugucccagccu
    uuccugauggaccuggaaggcaaggagggcaacuucaagaaccugcgcgaguucguguuuaagaacaucg
    acggcuacuucaagaucuacagcaagcacaccccuaucaaccucgaggggaucugccucagggcuucucu
    gcucuggaaccccugguggaucugcccaucggcaucaacaucacccgguuucagacacugcuggcccugc
    acagaagcuaccugacaccuguggauagcagcagcggauggacagcuggugccgccgcuuacuauguggg
    cuaccugcagccuagaaccuuccugcugaaguacaacgagaacggcaccaucaccgacgccguggauugug
    cucuggauccucugagcgagacaaagugcacccugaaguccuucaccguggaaaagggcaucuaccagacc
    agcaacuuccgggugcagcccaccgaauccaucgugcgguuccccaauaucaccaaucugugccccuucca
    cgagguguucaaugccaccaccuucgccucuguguacgccuggaaccggaagcggaucagcaauugcgug
    gccgacuacuccgugaucuacaacuucgcccccuucuucgcauucaagugcuacggcguguccccuaccaa
    gcugaacgaccugugcuucacaaacguguacgccgacagcuucgugauccggggaaacgaagugucacag
    auugccccuggacagacaggcaacaucgccgacuacaacuacaagcugcccgacgacuucaccggcugugu
    gauugccuggaacagcaacaagcuggacuccaaacccagcggcaacuacaauuaccuguaccggcuguucc
    ggaaguccaagcugaagcccuucgagcgggacaucuccaccgagaucuaucaggccggcaacaagccuug
    uaacggcguggcaggccccaacugcuacagcccacugcaguccuacggcuuuaggcccacauacggcgug
    ggccaccagcccuacagagugguggugcugagcuucgaacugcugcaugccccugccacagugugcggcc
    cuaagaaaagcaccaaucucgugaagaacaaaugcgugaacuucaacuucaacggccugaccggcaccggc
    gugcugacagagagcaacaagaaguuccugccauuccagcaguuuggccgggauaucgccgauaccacag
    acgccguuagagauccccagacacuggaaauccuggacaucaccccuugcagcuucggcggagugucugu
    gaucaccccuggcaccaacaccagcaaucagguggcagugcuguaccagggcgugaacuguaccgaagug
    cccguggccauucacgccgaucagcugacaccuacauggggguguacuccaccggcagcaauguguuuc
    agaccagagccggcugucugaucggagccgaguacgugaacaauagcuacgagugcgacauccccaucgg
    cgcuggaaucugcgccagcuaccagacacagacaaagagccaccggagagccagaagcguggccagccaga
    gcaucauugccuacacaaugucucugggcgccgagaacagcguggccuacuccaacaacucuaucgcuauc
    cccaccaacuucaccaucagcgugaccacagagauccugccuguguccaugaccaagaccagcguggacug
    caccauguacaucugcggcgauuccaccgagugcuccaaccugcugcugcaguacggcagcuucugcacc
    cagcugaaaagagcccugacagggaucgccguggaacaggacaagaacacccaagagguguucgcccaagu
    gaagcagaucuacaagaccccuccuaucaaguacuucggcggcuucaauuucagccagauucugcccgauc
    cuagcaagcccagcaagcggagcuucaucgaggaccugcuguucaacaaagugacacuggccgacgccggc
    uucaucaagcaguauggcgauugucugggcgacauugccgccagggaucugauuugcgcccagaaguuu
    aacggacugacagugcugccuccucugcugaccgaugagaugaucgcccaguacacaucugcccugcugg
    ccggcacaaucacaagcggcuggacauuuggagcaggcgccgcucugcagauccccuuugcuaugcagau
    ggccuaccgguucaacggcaucggagugacccagaaugugcuguacgagaaccagaagcugaucgccaac
    caguucaacagcgccaucggcaagauccaggacagccugagcagcacagcaagcgcccugggaaagcugca
    ggacguggucaaccacaaugcccaggcacugaacacccuggucaagcagcuguccuccaaguucggogcca
    ucagcucugugcugaacgauauccugagcagacuggacccuccugaggccgaggugcagaucgacagacu
    gaucacaggcagacugcagagccuccagacauacgugacccagcagcugaucagagccgccgagauuagag
    ccucugccaaucuggccgccaccaagaugucugagugugugcugggccagagcaagagaguggacuuuug
    cggcaagggcuaccaccugaugagcuucccucagucugccccucacggcgugguguuucugcacgugaca
    uaugugcccgcucaagagaagaauuucaccaccgcuccagccaucugccacgacggcaaagcccacuuucc
    uagagaaggcguguucguguccaacggcacccauugguucgugacacagcggaacuucuacgagccccag
    aucaucaccaccgacaacaccuucgugucuggcaacugcgacgucgugaucggcauugugaacaauaccg
    uguacgacccucugcagcccgagcuggacagcuucaaagaggaacuggacaaguacuuuaagaaccacaca
    agccccgacguggaccugggcgauaucagcggaaucaaugccagcgucgugaacauccagaaagagaucg
    accggcugaacgagguggccaagaaucugaacgagagccugaucgaccugcaagaacuggggaaguacga
    gcaguacaucaaguggcccugguacaucuggcugggcuuuaucgccggacugauugccaucgugauggu
    cacaaucaugcuguguugcaugaccagcugcuguagcugccugaagggcuguuguagcuguggcagcug
    cugcaaguucgacgaggacgauucugagcccgugcugaagggcgugaaacugcacuacacaugaugacuc
    gagcugguacugcaugcacgcaaugcuagcugccccuuucccguccuggguaccccgagucucccccgac
    cucgggucccagguaugcucccaccuccaccugccccacucaccaccucugcuaguuccagacaccuccca
    agcacgcagcaaugcagcucaaaacgcuuagccuagccacacccccacgggaaacagcagugauuaaccuu
    uagcaauaaacgaaaguuuaacuaagcuauacuaaccccaggguuggucaauuucgugccagccacacccu
    ggagcuagcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagcauaugacuaaaaaaaaaaaaaaaaaaaaaaaa
    aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa
    162 Full length DNA Agaataaactagtattcttctggtccccacagactcagagagaacccgccaccatgttcgtgttcctggtgctgctgcc
    construct tctggtgtccagccagtgtgtgaacctgatcaccagaacacagtcatacaccaacagctttaccagaggcgtgtactac
    encoding a cccgacaaggtgttcagatccagcgtgctgcactctacccaggacctgttcctgcctttcttcagcaacgtgacctggtt
    SARS-CoV-2 S ccacgccatccacgtgtccggcaccaatggcaccaagagattcgacaaccccgccctgcccttcaacgacggggtg
    protein from an tactttgccagcaccgagaagtccaacatcatcagaggctggatcttcggcaccacactggacagcaagacccagag
    Omicron XBB.1.5 cctgctgatcgtgaacaacgccaccaacgtggtcatcaaagtgtgcgagttccagttctgcaacgaccccttcctgga
    variant cgtctaccagaagaacaacaagagctggatggaaagcgagttccgggtgtacagcagcgccaacaactgcaccttc
    gagtacgtgtcccagcctttcctgatggacctggaaggcaaggagggcaacttcaagaacctgcgcgagttcgtgttt
    aagaacatcgacggctacttcaagatctacagcaagcacacccctatcaacctcgagcgggatctgcctcagggcttc
    tctgctctggaacccctggtggatctgcccatcggcatcaacatcacccggtttcagacactgctggccctgcacaga
    agctacctgacacctgtggatagcagcagcggatggacagctggtgccgccgcttactatgtgggctacctgcagcc
    tagaaccttcctgctgaagtacaacgagaacggcaccatcaccgacgccgtggattgtgctctggatcctctgagcga
    gacaaagtgcaccctgaagtccttcaccgtggaaaagggcatctaccagaccagcaacttccgggtgcagcccacc
    gaatccatcgtgcggttccccaatatcaccaatctgtgccccttccacgaggtgttcaatgccaccaccttcgcctctgt
    gtacgcctggaaccggaagcggatcagcaattgcgtggccgactactccgtgatctacaacttcgcccccttcttcgc
    attcaagtgctacggcgtgtcccctaccaagctgaacgacctgtgcttcacaaacgtgtacgccgacagcttcgtgatc
    cggggaaacgaagtgtcacagattgcccctggacagacaggcaacatcgccgactacaactacaagctgcccgac
    gacttcaccggctgtgtgattgcctggaacagcaacaagctggactccaaacccagcggcaactacaattacctgtac
    cggctgttccggaagtccaagctgaagcccttcgagcgggacatctccaccgagatctatcaggccggcaacaagc
    cttgtaacggcgtggcaggccccaactgctacagcccactgcagtcctacggctttaggcccacatacggcgtgggc
    caccagccctacagagtggtggtgctgagcttcgaactgctgcatgcccctgccacagtgtgcggccctaagaaaag
    caccaatctcgtgaagaacaaatgcgtgaacttcaacttcaacggcctgaccggcaccggcgtgctgacagagagc
    aacaagaagttcctgccattccagcagtttggccgggatatcgccgataccacagacgccgttagagatccccagac
    actggaaatcctggacatcaccccttgcagcttcggcggagtgtctgtgatcacccctggcaccaacaccagcaatca
    ggtggcagtgctgtaccagggcgtgaactgtaccgaagtgcccgtggccattcacgccgatcagctgacacctacat
    ggcgggtgtactccaccggcagcaatgtgtttcagaccagagccggctgtctgatcggagccgagtacgtgaacaat
    agctacgagtgcgacatccccatcggcgctggaatctgcgccagctaccagacacagacaaagagccaccggaga
    gccagaagcgtggccagccagagcatcattgcctacacaatgtctctgggcgccgagaacagcgtggcctactcca
    acaactctatcgctatccccaccaacttcaccatcagcgtgaccacagagatcctgcctgtgtccatgaccaagacca
    gcgtggactgcaccatgtacatctgcggcgattccaccgagtgctccaacctgctgctgcagtacggcagcttctgca
    cccagctgaaaagagccctgacagggatcgccgtggaacaggacaagaacacccaagaggtgttcgcccaagtga
    agcagatctacaagacccctcctatcaagtacttcggcggcttcaatttcagccagattctgcccgatcctagcaagcc
    cagcaagcggagcttcatcgaggacctgctgttcaacaaagtgacactggccgacgccggcttcatcaagcagtatg
    gcgattgtctgggcgacattgccgccagggatctgatttgcgcccagaagtttaacggactgacagtgctgcctcctct
    gctgaccgatgagatgatcgcccagtacacatctgccctgctggccggcacaatcacaagcggctggacatttggag
    caggcgccgctctgcagatcccctttgctatgcagatggcctaccggttcaacggcatcggagtgacccagaatgtgc
    tgtacgagaaccagaagctgatcgccaaccagttcaacagcgccatcggcaagatccaggacagcctgagcagca
    cagcaagcgccctgggaaagctgcaggacgtggtcaaccacaatgcccaggcactgaacaccctggtcaagcagc
    tgtcctccaagttcggcgccatcagctctgtgctgaacgatatcctgagcagactggaccctcctgaggccgaggtgc
    agatcgacagactgatcacaggcagactgcagagcctccagacatacgtgacccagcagctgatcagagccgccg
    agattagagcctctgccaatctggccgccaccaagatgtctgagtgtgtgctgggccagagcaagagagtggactttt
    gcggcaagggctaccacctgatgagcttccctcagtctgcccctcacggcgtggtgtttctgcacgtgacatatgtgcc
    cgctcaagagaagaatttcaccaccgctccagccatctgccacgacggcaaagcccactttcctagagaaggcgtgt
    tcgtgtccaacggcacccattggttcgtgacacagcggaacttctacgagccccagatcatcaccaccgacaacacct
    tcgtgtctggcaactgcgacgtcgtgatcggcattgtgaacaataccgtgtacgaccctctgcagcccgagctggaca
    gcttcaaagaggaactggacaagtactttaagaaccacacaagccccgacgtggacctgggcgatatcagcggaat
    caatgccagcgtcgtgaacatccagaaagagatcgaccggctgaacgaggtggccaagaatctgaacgagagcct
    gatcgacctgcaagaactggggaagtacgagcagtacatcaagtggccctggtacatctggctgggctttatcgccg
    gactgattgccatcgtgatggtcacaatcatgctgtgttgcatgaccagctgctgtagctgcctgaagggctgttgtagc
    tgtggcagctgctgcaagttcgacgaggacgattctgagcccgtgctgaagggcgtgaaactgcactacacatgatg
    actcgagctggtactgcatgcacgcaatgctagctgcccctttcccgtcctgggtaccccgagtctcccccgacctcg
    ggtcccaggtatgctcccacctccacctgccccactcaccacctctgctagttccagacacctcccaagcacgcagca
    atgcagctcaaaacgcttagcctagccacacccccacgggaaacagcagtgattaacctttagcaataaacgaaagtt
    taactaagctatactaaccccagggttggtcaatttcgtgccagccacaccctggagctagcaaaaaaaaaaaaaaaa
    aaaaaaaaaaaaaagcatatgactaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa
    aaaaaaaaaaaaaaaaaa
    • Lipid Nanoparticles (LNPs)
  • In one embodiment, nucleic acid such as RNA described herein is administered in the form of lipid nanoparticles (LNPs) (e.g., encapsulated within or associated with an LNP). The LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated.
  • In one embodiment, LNP comprise a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid; and RNA. In one embodiment, the cationic lipid is ALC-0315, the neutral lipid is DSPC, the steroid is cholesterol, and the polymer conjugated lipid is ALC-0159.
  • In one embodiment, the LNP comprises from 20 to 60 mol percent, 40 to 55 mol percent, from 40 to 50 mol percent, from 41 to 49 mol percent, from 41 to 48 mol percent, from 42 to 48 mol percent, from 43 to 48 mol percent, from 44 to 48 mol percent, from 45 to 48 mol percent, from 46 to 48 mol percent, from 47 to 48 mol percent, or from 47.2 to 47.8 mol percent of the cationic lipid. In one embodiment, the LNP comprises about 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9 or 48.0 mol percent of the cationic lipid.
  • In one embodiment, the neutral lipid is present in a concentration ranging from 5 to 25 mol percent, 5 to 15 mol percent, from 7 to 13 mol percent, or from 9 to 11 mol percent. In one embodiment, the neutral lipid is present in a concentration of about 9.5, 10 or 10.5 mol percent.
  • In one embodiment, the steroid is present in a concentration ranging from 25 to 55 mol percent, 30 to 50 mol percent, from 35 to 45 mol percent or from 38 to 43 mol percent. In one embodiment, the steroid is present in a concentration of about 40, 41, 42, 43, 44, 45 or 46 mol percent.
  • In some embodiments, an LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
  • The preferred mode of administration is intramuscular administration, more preferably in aqueous cryoprotectant buffer for intramuscular administration. Drug product is a preferably a preservative-free, sterile dispersion of RNA formulated in lipid nanoparticles (LNP) in aqueous cryoprotectant buffer for intramuscular administration.
  • In different embodiments, drug product comprises the components shown below, e.g., at the proportions or concentrations shown below:
  •
    Component Function Proportion (mol %)
    ALC-0315 [1] Functional lipid 47.5
    ALC-0159 [2] Functional lipid 1.8
    DSPC [3] Structural lipid 10.0
    Cholesterol, Structural lipid 40.7
    synthetic
    Concentration
    Component Function (mg/mL)
    Drug Substance Active 0.5
    ALC-0315 [1] Functional lipid 7.17
    ALC-0159 [2] Functional lipid 0.89
    DSPC [3] Structural lipid 1.56
    Cholesterol, Structural lipid 3.1
    synthetic
    Sucrose Cryoprotectant 102.69
    NaCl Buffer 6.0
    KCl Buffer 0.15
    Na2HPO4 Buffer 1.08
    KH2PO4 Buffer 0.18
    Water for injection Solvent/Vehicle q.s.
    Concentration
    Component Function (mg/mL)
    Drug Substance Active 1.0
    ALC-0315 [1] Functional lipid 13.56
    ALC-0159 [2] Functional lipid 1.77
    DSPC [3] Structural lipid 3.11
    Cholesterol, Structural lipid 6.20
    synthetic
    Sucrose Cryoprotectant 102.69
    NaCl Buffer 6.0
    KCl Buffer 0.15
    Na2HPO4 Buffer 1.08
    KH2PO4 Buffer 0.15
    Water for injection Solvent/Vehicle q.s.
      • [1] ALC-0315=((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)/6-[N-6-(2-hexyldecanoyloxy)hexyl-N-(4-hydroxybutyl)amino]hexyl 2-hexyldecanoate
      • [2] ALC-0159=2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide/2-[2-(co-methoxy (polyethyleneglycol2000) ethoxy]-N,N-ditetradecylacetamide
      • [3] DSPC=1,2-Distearoyl-sn-glycero-3-phosphocholine q.s.=quantum satis (as much as may suffice)
  • In some embodiments, particles disclosed herein are formulated in a solution comprising 10 mM Tris and 10% sucrose, and optionally having a pH of about 7.4. In some embodiments, particles disclosed herein are formulated in a solution comprising about 103 mg/ml sucrose, about 0.20 mg/ml tromethamine (Tris base), and about 1.32 mg/ml Tris.
  • In some embodiments, a composition comprises:
      • (a) about 0.1 mg/mL RNA comprising an open reading frame encoding a polypeptide that comprises a SARS-CoV-2 protein or an immunogenic fragment or variant thereof,
      • (b) about 1.43 mg/ml ALC-0315,
      • (c) about 0.18 mg/ml ALC-0159,
      • (d) about 0.31 mg/ml DSPC,
      • (e) about 0.62 mg/ml cholesterol,
      • (f) about 103 mg/ml sucrose,
      • (g) about 0.20 mg/ml tromethamine (Tris base),
      • (h) about 1.32 mg/ml Tris (hydroxymethyl) aminomethane hydrochloride (Tris HCl), and
      • (i) q.s. water.
  • In one embodiment, the ratio of RNA (e.g., mRNA) to total lipid (N/P) is between 6.0 and 6.5 such as about 6.0 or about 6.3.
  • In some embodiments, compositions provided herein are formulated as a multi-dose formulation, optionally in a vial.
    • Methods of Administering
  • Also described in the present disclosure, among other things, are methods that comprise administering a composition described herein. In some embodiments, methods described herein induce an immune response in a subject (e.g., an immune response against coronavirus).
  • In some embodiments, an amount of the RNA described herein of at least 0.25 μg, at least 0.5 μg, at least 1 μg, at least 2 μg, at least 3 μg, at least 4 μg, at least 5 μg, at least 10 μg, at least 15 μg, at least 20 μg, at least 25 μg, at least 30 μg, at least 40 μg, at least 50 μg, or at least 60 μg may be administered per dose (e.g., in a given dose). In some embodiments, an amount of the RNA described herein of at least 3 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 10 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 15 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 20 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 25 ug may be administered in at least one of given doses. In some embodiments, an amount of the RNA described herein of at least 30 ug may be administered in at least one of given doses. In some embodiments, combinations of aforementioned amounts may be administered in a regimen comprising two or more doses (e.g., a prior dose and a subsequent dose can be of different amounts as described herein). In some embodiments, combinations of aforementioned amounts may be administered in a primary regimen and a booster regimen (e.g., different doses can be given in a primary regimen and a booster regimen).
  • In some embodiments, a composition comprising an RNA described herein is administered as a first dose and/or as part of a priming vaccination regimen to a subject (e.g., a vaccine-naïve subject is administered (i) two doses of such a composition, approximately 21 days apart, or (ii) three doses of such a composition, where the first and the second doses are administered approximately 21 days apart and the second and the third dose are administered about 28 days apart).
  • In some embodiments, a composition that comprises an RNA described herein is administered to a subject who has previously been exposed to SARS-CoV-2 (e.g., a subject who has previously received at least one dose (e.g., a complete dosing regimen) of a SARS-CoV-2 vaccine and/or previously been infected one or more times with SARS-CoV-2). In some embodiments, a composition comprising an RNA described herein is administered as a booster dose. In some embodiments, a composition comprising an RNA described herein is administered as a booster dose to a subject who has previously received one or more doses (e.g., a complete primary dosing regimen and/or one or more booster doses) of a vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a composition comprising an RNA that comprises SEQ ID NO: 20, a commercially available vaccine (e.g., a commercially available vaccine described herein, (e.g., BNT162b2)) or any combination thereof).
  • Commercially available SARS-CoV-2 vaccines are known in the art, and include, e.g., an mRNA-1273 vaccine, an Ad26.CoV2.S vaccine, a ChAdxOx1 vaccine, an NVX-CoV2373 vaccine, a CvnCoV vaccine, a GAM-COVID0Vac vaccine, a CoronaVac vaccine, a BBIBP-CorV vaccine, an Ad5-nCoV vaccine, a zf2001 vaccine, a SCB-2019 vaccine, or other approved RNA (e.g., mRNA) or adenovector vaccines, etc.
  • In some embodiments, an RNA described herein is administered to a subject who has previously been administered at least two doses of BNT162b2 (e.g., two doses of BNT162b2 administered about 21 days apart). In some embodiments, an RNA described herein is administered to a subject who has previously been administered at least three doses of BNT162b2 embodiment, at least three doses are administered. In some embodiments, such third dose is administered a period of time after the second dose that is comparable to (e.g., the same as) the period of time between the first and second doses. For example, in some embodiments, a third dose may be administered about 21 days following administration of the second dose. In some embodiments, a third dose is administered after a longer period of time relative to the second dose than the second dose was relative to the first dose. In some embodiments, a three-dose regimen is administered to an immunocompromised patient, e.g., a cancer patient, an HIV patient, a patient who has received and/or is receiving immunosuppressant therapy (e.g., an organ transplant patient). In some embodiments, the length of time between the second and third dose (e.g., a second and third dose administered to an immunocompromised patient) is at least about 21 days (e.g., at least about 28 days).
  • In some embodiments, an RNA described herein is administered to a subject who has previously been administered a vaccine that delivers an antigen of a SARS-CoV-2 variant (e.g., an Omicron BA.4/5 variant). For example, in some embodiments, an RNA described herein is administered to a subject previously administered one or more doses of a SARS-CoV-2 vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., BNT162b2), and one or more booster doses of a variant adapted vaccine (e.g., one or more doses of a bivalent vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 strain).
  • BNT162b2 (which comprises an RNA comprising SEQ ID NO: 20) is an mRNA vaccine for prevention of COVID-19 and demonstrated an efficacy of 95% or more at preventing COVID-19. The vaccine comprises a 5′capped mRNA encoding for the full-length SARS-CoV-2 spike glycoprotein (S) encapsulated in lipid nanoparticles (LNPs). The finished product is presented as a concentrate for dispersion for injection containing BNT162b2 as active substance. Other ingredients include: ALC-0315 (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and, in some embodiments, potassium chloride, potassium dihydrogen phosphate, sodium chloride, disodium phosphate dihydrate, sucrose and water for injection.
  • In some embodiments, a composition comprising an RNA described herein is administered to a subject previously administered a priming dosing regimen of a composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a subject previously administered (i) two doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second doses were administered about 21 days apart, or (ii) three doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second dose were administered about 21 days apart and the third dose was administered about 28 days after the second dose).
  • In some embodiments, a composition comprising an RNA described herein was administered as a further booster dose to a subject previously administered a priming dosing regimen and one or more booster doses of a composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain (e.g., a subject previously administered (i) three doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second doses were administered about 21 days apart, and the third dose was administered at least about 2 months after the second dose, (ii) four doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second dose were administered about 21 days apart, the third dose was administered about 28 days after the second dose, and the fourth dose was administered at least about three months after the second dose, or (iii) four doses of an RNA vaccine that encodes a SARS-CoV-2 S protein of a Wuhan strain, where the first and the second dose were administered about 21 days apart, the third dose was administered at least about 2 months after the second dose, and the fourth dose was administered at least about two months after the second dose).
  • In some embodiments, a composition comprising an RNA described herein is administered to a subject previously administered one or more doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant. In some embodiments, a composition comprising an RNA described herein is administered as a booster dose to a subject previously administered a priming dosing regimen of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (e.g., a subject previously administered (i) two doses of a bivalent RNA vaccine, where the first and the second doses were administered about 21 days apart, or (ii) three doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart and the third dose was administered about 28 days after the second dose). In some embodiments, a composition comprising an RNA described herein is administered as a further booster dose to a subject previously administered a priming dosing regimen and one or more booster doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (e.g., a subject previously administered (i) three doses of a bivalent RNA vaccine, where the first and the second doses were administered about 21 days apart, and the third dose was administered at least about 2 months after the second dose, (ii) four doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart, the third dose was administered about 28 days after the second dose, and the fourth dose was administered at least about three months after the second dose, or (iii) four doses of a bivalent RNA vaccine, where the first and the second dose were administered about 21 days apart, the third dose was administered at least about 2 months after the second dose, and the fourth dose was administered at least about two months after the second dose).
  • In some embodiments, a composition comprising an RNA described herein is administered to a subject previously administered (i) one or more doses of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain and (ii) one or more doses of a bivalent composition (e.g., an RNA composition) that delivers a SARS-CoV-2 S protein of a Wuhan strain and a SARS-CoV-2 S protein of an Omicron BA.4/5 variant.
  • In some embodiments, a composition comprising an RNA described herein is administered to a subject previously administered:
      • (ii) two doses (administered about 21 days apart) of an RNA vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain, and a dose of a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, where the bivalent composition was administered at least about two months after the most recent dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain;
      • (iii) three doses of an RNA vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (where the first and the second dose were administered about 21 days apart and the third dose was administered about 28 days after the second dose) and at least one dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, where the bivalent composition was administered at least about 2 months after the most recent dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain;
      • (iv) three doses of an RNA vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (where the first and the second dose were administered about 21 days apart and the third dose was administered at least about 2 months after the second dose) and at least one dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, where the bivalent composition was administered at least about 2 months after the most recent dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain.
      • (v) four doses of an RNA vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (where the first and the second dose were administered about 21 days apart, the third dose was administered about 28 days after the second dose, and the fourth dose was administered at least about 2 months after the third dose) and at least one dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, where the bivalent composition was administered at least about 2 months after the most recent dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain; or four doses of an RNA vaccine that delivers a SARS-CoV-2 S protein of a Wuhan strain (where the first and the second dose were administered about 21 days apart, the third dose was administered at least about 2 months after the second dose, and the fourth dose was administered at least about 4 months after the third dose) and at least one dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, where the bivalent composition was administered at least about 2 months after the most recent dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain.
  • In some embodiments, a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 30 μg of an RNA described herein. In some embodiments, a dose comprising about 30 μg of RNA described herein is administered to a subject who is 12 years or older.
  • In some embodiments, a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 10 μg of an RNA described herein. In some embodiments, a dose comprising about 10 μg of RNA described herein is administered to a subject who is 5 years to less than 12 years old.
  • In some embodiments, a dose (e.g., a dose administered as part of a primary dosing regimen or a booster regimen) comprises about 3 μg of an RNA described herein. In some embodiments, a dose comprising about 3 μg of RNA described herein is administered to a subject who is 6 months to less than 5 years old.
  • In some embodiments, a composition described herein is administered in a volume of between about 200 μl and about 300 μl (e.g., about 200 μl or about 300 μl).
  • In some embodiments, RNA in a pharmaceutical RNA preparation is diluted prior to administration (e.g., diluted to a concentration of about 0.05 mg/ml). In some embodiments, administration volumes are between about 200 μl and about 300 μl. In some embodiments, RNA in a pharmaceutical RNA preparation is formulated in about 10 mM Tris buffer, and about 10% sucrose.
  • In some embodiments, an RNA (e.g., mRNA) composition disclosed herein may be administered in conjunction with a vaccine targeting a different infectious agent. In some embodiments, the different infectious agent is one that increases the likelihood of a subject experiencing deleterious symptoms when coinfected with SARS-CoV-2 and the infectious agent. In some embodiments, the infectious agent is one that increases the infectivity of SARS-CoV-2 when a subject is coinfected with SARS-CoV-2 and the infectious agent. In some embodiments, at least one RNA (e.g., mRNA) composition described herein may be administered in combination with a vaccine that targets influenza. In some embodiments, at least two or more different drug products/formulations may comprise at least one RNA (e.g., mRNA) composition described herein and a vaccine targeting a different infectious agent (e.g., an influenza vaccine). In some embodiments, different drug products/formulations are separately administered. In some embodiments, such different drug product/formulations are separately administered at the same time (e.g., at the same vaccination session) at different sites of a subject (e.g., at different arms of the subject).
  • In one embodiment, the vaccination regimen comprises a first vaccination using at least two doses of the RNA described herein, e.g., two doses of the RNA described herein (wherein the second dose may be administered about 21 days following administration of the first dose), and a second vaccination using a single dose or multiple doses, e.g., two doses, of the RNA described herein. In various embodiments, the second vaccination is administered at least about 2 months after a previous dose (e.g., 3 to 24 months, 6 to 18 months, 6 to 12 months, or 5 to 7 months after administration of a previous vaccine, e.g., after an initial two-dose regimen or a booster dose). The amount of RNA used in each dose of the second vaccination may be equal or different to the amount of RNA used in each dose of the first vaccination. In one embodiment, the amount of RNA used in each dose of the second vaccination is equal to the amount of RNA used in each dose of the first vaccination. In one embodiment, the amount of RNA used in each dose of the second vaccination and the amount of RNA used in each dose of the first vaccination is about 30 μg per dose. In one embodiment, the same RNA as used for the first vaccination is used for the second vaccination.
  • In some embodiments, an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-CoV-2 disease. In some embodiments, an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-COV-2 viral disease. In some embodiments, an RNA composition described herein is co-administered with one or more vaccines against a non-SARS-CoV-2 respiratory disease. In some embodiments, the non-SARS-CoV-2 respiratory disease is a non-SARS-CoV-2 Coronavirus, an Influenza virus, a Pneumoviridae virus, or a Paramyxoviridae virus. In some embodiments, the Pneumoviridae virus is a Respiratory syncytial virus or a Metapneumovirus. In some embodiments, the Metapneumovirus is a human metapneumovirus (hMPV). In some embodiments, the Paramyxoviridae virus is a Parainfluenza virus or a Henipavirus. In some embodiments the parainfluenzavirus is PIV3. In some embodiments, the non-SARS-CoV-2 coronavirus is a betacoronavirus (e.g., SARS-CoV-1). In come embodiments the non-SARS-CoV-2 coronavirus is a Merbecovirus (e.g., a MERS-CoV virus).
  • In some embodiments, an RNA composition described herein is co-administered with an RSV vaccine (e.g., an RSV A or RSV B vaccine). In some embodiments, the RSV vaccine comprises an RSV fusion protein (F), an RSV attachment protein (G), an RSV small hydrophobic protein (SH), an RSV matrix protein (M), an RSV nucleoprotein (N), an RSV M2-1 protein, an RSV Large polymerase (L), and/or an RSV phosphoprotein (P), or an immunogenic fragment of immunogenic variant thereof, or a nucleic acid (e.g., RNA), encoding any one of the same.
  • Numerous RSV vaccines are known in the art, any one of which can be co-administered with an RNA composition described herein. See, for example, the list of RSV vaccines provided on the website of PATH, a global health organization (see https:/www.path.org/resources/rsz-vaccine-and-mab-snapshot/), as well as in Mazur, Natalie I., et al, “The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates,” The Lancet Infectious Diseases 18.10 (2018): e295-e311, the contents of each of which is incorporated by reference herein. In some embodiments, an RNA composition described herein is co-administered with an RSV vaccine that has been previously published on (e.g., an RSV vaccine described on the PATH website page linked to above, or in Mazur et al.). In some embodiments, an RNA composition described herein is co-administered with a live-attenuated or chimeric vaccine (e.g., rBCG-N-hRSV (developed by Ponteificia Uinersidad Catolica de Chile), RSV D46 cp ΔM202 (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV LID ΔM2-2 1030s (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV ΔNS2 Δ1313/11314L (developed by Sanofi Pasteur/LID/NIAD/NIH), RSV D46 ΔNS2 N ΔM2-2 HindIII (developed by Sanofi Pasteur/LID/NIAD/NIH) or RSV LID ΔM2-2 1030s (developed by Sanofi Pasteur/LID/NIAD/NIH), MV-012-968 (developed by Meissa Vaccines), SP0125 (developed by Sanofi), blb201 (developed by Blue lake), CodaVax™-RSV (developed by Cadagenix), RSVDeltaG (developed by Intravacc), or SeVRSV (developed by SIPL and St. Jude hospital), a particle based vaccine (e.g., RSV F nanoparticle (developed by Novavax) or SynGEM (developed by Mucosis), Icosavzx (developed by IVX-121), or V-306 (developed by Virometix)), a subunit vaccine (e.g., GSK RSV F (developed by GSK), Arexvy (developed by GSK), DPX-RSV (developed by Dalousie Univeristy, Immunovaccine, and VIB), RSV F DS-Cavi (developed by NIH/NIAID/VRC), MEDI-7510 (developed by MedImmune), RSVpreF (developed by Pfizer), ADV110 (developed by Advaccine), VN-0200 (developed by Daiichi Sankyo, Inc.)), a vector vaccine (e.g., MVA-BN RSV (developed by Banarian Nordic), VXA-RSVf oral (developed by Vaxart), Ad26.RSV.pref (developed by Janssen), ChAd155-RSV (developed by GSK) Immunovaccine, DPX-RSV (developed by VIB), or DS-Cav1 (developed by NIH/NIAID/VRC) or a nucleic acid vaccine (e.g., an mRNA vaccine being developed by CureVac (currently unnamed) or mRNA-1345 (developed by Moderna), or SP0274 (developed by Sanofi)).
  • In some embodiments, an RNA composition described herein is co-administered with an influenza vaccine. In some embodiments, the influenza vaccine is an alpha-influenza virus, a beta-influenza virus, a gamma-influenza virus or a delta-influenza virus vaccine. In some embodiments the vaccine is an Influenza A virus, an Influenza B virus, an Influenza C virus, or an Influenza D virus vaccine. In some embodiments, the influenza A virus vaccine comprises a hemagglutinin selected from H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, or an immunogenic fragment or variant of the same, or a nucleic acid (e.g., RNA) encoding any one of the same. In some embodiments the influenza A vaccine comprises or encodes a neuraminidase (NA) selected from N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, and N11, or an immunogenic fragment or variant of the same, or a nucleic acid (e.g., RNA) encoding any one of the same. In some embodiments, the influenza vaccine comprises at least one Influenza virus hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix protein 1 (M1), matrix protein 2 (M2), non-structural protein 1 (NS1), non-structural protein 2 (NS2), nuclear export protein (NEP), polymerase acidic protein (PA), polymerase basic protein PB1, PB1-F2, and/or polymerase basic protein 2 (PB2), or an immunogenic fragment or variant thereof, or a nucleic acid (e.g., RNA) encoding any of one of the same.
  • In some embodiments, an RNA composition described herein can be co-administered with a commercially approved influenza vaccine. In some embodiments, an RNA composition described herein can be co-administered with an inactivated influenza virus (e.g., Fluzone®, Fluzone high-dose Quadrivalent®, Fluzone Quadrivalent®, Fluzone intradermal Quardivalent®, Fluzone quadrivalent southern Hemisphere®, Fluad®, Fluad Quadrivalent®, Afluria Quardivalent®, Fluarix Quadrivalent®, FluLaval Quadrivalent®, or Flucelvax Quadrivalent®), a recombinant influenza vaccine (e.g., Flublok Quadrivalent®), a live attenuated influenza vaccine (e.g., FluMist Quadrivalent®), a non-adjuvanted influenza vaccine, an adjuvanted influenza vaccine, or a subunit or split vaccine.
  • In some embodiments, an RNA composition described herein is co-administered with an influenza vaccine and/or an RSV vaccine.
  • In one embodiment, a composition or medical preparation is a pharmaceutical composition.
  • In one embodiment, a composition or medical preparation is a vaccine.
    • EXAMPLES Example 1: Further Studies of Variant-Adapted Bi- and Trivalent Vaccines in Vaccine-Experienced Mice
  • The present Example describes a study to characterize immune responses induced by certain variant-adapted vaccines in vaccine-experienced subjects (mice in the present Example). In particular, the present Example describes an experiment to characterize immune responses induced in subjects previously administered (i) at least one dose of a composition that delivers a SARS-CoV-2 S protein of a Wuhan strain, and (ii) at least one dose of a bivalent composition comprising a first RNA that encodes a SARS-COV-2 S protein of a Wuhan strain and a second RNA that encodes a SARS-CoV-2 S protein of a BA.4/5 Omicron variant.
  • Two sets of experimental dosing regimens are summarized in FIGS. 1 and 2 .
  • In a first set of experiments (summarized in FIG. 1 ), BALB/C mice are administered a first dose of an RNA vaccine encoding a SARS-CoV-2 S protein of a Wuhan variant (BNT162b2), and, 21 days later, a second dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding SARS-COV-2 S protein of a BA.4/5 Omicron variant. About 10 weeks after administered the second dose, mice are then administered one of the following compositions (comprising RNAs encoding SARS-CoV-2 S proteins from the listed strains/variants):
      • Wuhan+BA.4/5
      • XBB.1.5
      • BA.2.75.2
      • BQ.1.1
      • Wuhan+BA. 4/5+XBB.1.5
      • Wuhan+BA.4/5+BA.2.75.2
      • BA.4/5+XBB.1.5
      • BA.4/5+BA.2.75.2
      • BA.4/5+BQ.1.1
  • About 28 days after the third dose, mice are sacrificed and final neutralization titers are collected.
  • In a related experiment, neutralization titers are determined in mice administered two doses of a composition that delivers a Wuhan S protein, a third dose of a bivalent vaccine, and a fourth dose of one of the vaccines listed below (comprising RNAs encoding SARS-CoV-2 S proteins from the listed variants). The design of this experiment is summarized in FIG. 2 .
      • XBB.1.5
      • BA.2.75.2
      • BQ.1.1
      • BA.4/5+XBB.1.5
      • BA.4/5+BA.2.75.2
      • BA.4/5+BQ.1.1
    Example 2: Further Studies Investigating Variant-Adapted Vaccines Administered to Vaccine-Naïve Mice
  • The present Example provides data characterizing certain monovalent and bivalent variant-adapted vaccines in vaccine naïve mice. The particular vaccines tested are shown in FIG. 3 . As shown in the Figure, vaccines were administered vaccines on days 0 and 21 (the same vaccine composition and dose was administered on each day; dose amounts indicated in FIG. 3 ), and sera samples were collected on day 35 (14 days after the second dose of a vaccine).
  • Pseudovirus neutralization titers from sera samples collected on day 35 are shown in FIG. 4 . As shown in the figure, each of the tested compositions can produce strong neutralization titers against the corresponding strain or variant. In particular, a monovalent composition comprising an RNA encoding an S protein of an XBB.1.5 Omicron variant was shown to induce high neutralization titers against XBB.1.5 when administered as a primary series. A bivalent composition comprising an RNA encoding an S protein of an XBB.1.5 Omicron variant and an RNA encoding an S protein of an Omicron BA.4/5 variant was also shown to induce high neutralization titers against XBB.1.5 when administered as a primary series, although titers were lower than those induced by an XBB.1.5 monovalent vaccine.
  • Each of the compositions comprising an RNA encoding an S protein of a SARS-CoV-2 variant (i.e., WT+BA.4/5, BA.4/5, XBB.1.5, and BA.4/5+XBB.1.5) was also found to induce broad cross-neutralization of other variants of concern. In particular, the BA.4/5+XBB.1.5 bivalent vaccine was found to induce high neutralization titers both against the XBB.1.5 variant as well as other strains. Neutralization titers against XBB.1.16 are expected to be similar to those induced against XBB.1.5, as neutralization data shows that the XBB.1.16 variant possesses no escape advantage relative to XBB.1.5 (see, e.g., FIG. 6 ). Similarly, neutralization titers for XBB.1.9.1/1.9.2 are expected to match those for XBB.1.5, as XBB.1.9.1/1.9.2 does not comprise any additional S protein mutations relative to XBB.1.5.
  • A similar experiment (summarized in the schematic at the top of FIG. 7 ) was also performed in which vaccine-naïve mice were administered two doses of (i) a bivalent composition comprising RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, (ii) a monovalent composition comprising RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant, or (iii) a bivalent composition comprising RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant and RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant. The two doses of RNA were administered 21 days apart, and neutralization titers were collected 4 weeks after administering the second dose. As shown in FIG. 7 , an XBB.1.5-adapted monovalent vaccine (e.g., as described herein) induced the highest neutralization titers against each of an XBB.1.5 variant, an XBB.1.16 variant, and an XBB.2.3 variant as compared to the other compositions tested.
    • Example 3: Further Studies Investigating Variant-Adapted Vaccines Administered to Vaccine-Experienced Mice
  • The present Example provides exemplary immune response data generated using certain monovalent and bivalent variant-adapted vaccines in vaccine-experienced mice. In particular, the present Example provides data demonstrating that vaccines (e.g., monovalent or bivalent vaccines) comprising an RNA encoding an XBB.1.5 S protein can induce strong neutralization titers against an XBB.1.5 Omicron variant in previously vaccinated subjects (e.g., subjects previously administered RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, as in the present Example).
  • The particular vaccines tested are shown in FIG. 5 . As shown in the Figure, mice in all groups were administered the following vaccines (listed in order of administration): (1) a first dose of a vaccine comprising RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2 in the present example), (2) a second dose of a vaccine comprising an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (again, BNT162b2 in the present example; second dose administered about 21 days after the first dose), (3) a third dose of a bivalent vaccine comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant (administered about 84 days after the second dose), and (4) a fourth dose of one of the monovalent or bivalent vaccines listed in the Figure (administered about 29 days after the third dose). Sera samples were collected 134 days after administration of the first dose of vaccine (immediately before administering the 4th dose), and 160 days after administering the 1st dose. Mice were administered 0.5 μg of each vaccine (for monovalent vaccines: 0.5 μg of an RNA, for bivalent vaccines: 0.25 μg of each RNA). On day 160, lymph nodes and spleen samples were also collected for T cell and B cell analysis.
  • Pseudovirus neutralization titers are shown in FIG. 6 . As shown in the figure, vaccines comprising an RNA encoding an XBB.1.5 S protein were found to induce a strong neutralization response when administered as either a monovalent or bivalent (e.g., BA.4/5+XBB.1.5) vaccine. In particular, the data demonstrates that such vaccines are especially effective when administered as a booster dose (e.g., to subjects previously administered one or more vaccines that deliver a SARS-CoV-2 S protein of a Wuhan strain and one or more bivalent vaccines (delivering a SARS-CoV-2 S protein of a Wuhan strain and an Omicron BA.4/5 variant), as tested in the present Example). In the present experiment, neutralization titers induced by an XBB.1.5 monovalent vaccine (in particular, neutralization titers against an XBB.1.5, XBB.1.16, and XBB.2.3-adapted pseudovirus) were found to be higher than those induced by a bivalent vaccine (BA.4/5+XBB.1.5). Other studies confirmed that monovalent or bivalent vaccine comprising an RNA encoding an XBB.1.5 S protein can induce a strong immune response against XBB variants (in particular, when administered as a booster), and further showed that, while a bivalent vaccine can induce higher neutralization titers at early time points, neutralization titers induced by a bivalent vaccine decreased faster than those induced by a monovalent vaccine, such that, 4 weeks after a booster dose, neutralization titers induced by a monovalent vaccine were higher than those induced by a bivalent vaccine (data not shown). As noted in previous Example 2, neutralization titers for XBB.1.9.1/1.9.2 are expected to match those induced for XBB.1.5, as XBB.1.9.1/1.9.2 does not comprise any additional S protein mutations relative to XBB.1.5.
  • A similar experiment was also performed to test the efficacy of an XBB.1.16-adapted vaccine (schematic summarizing the experimental protocol used is shown in FIG. 8 ). In short, mice were divided into groups of 10, and administered two doses (21 days apart) of an RNA encoding a SARS-CoV-2 S protein of a Wuhan strain (BNT162b2 in the present example), followed by a third dose (administered 14 days after the second dose) of a candidate vaccine encoding (i) a bivalent composition comprising a first RNA encoding a SARS-CoV-2 S protein of a Wuhan strain and a second RNA encoding a SARS-CoV-2 S protein of an Omicron BA.4/5 variant, (ii) a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant, (iii) a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.16 variant. 14 days after administering a third dose of vaccine, mice were bled and neutralization titers collected (e.g., using a pseudovirus neutralization assay described in one of the previous examples).
  • E01031 As shown in FIG. 8 , a monovalent composition comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.5 variant (e.g., an RNA described herein) induced the highest neutralization titers against each of the XBB.1.5, XBB.1.16, and XBB.2.3 variants. Surprisingly, an XBB.1.5 monovalent composition induced higher titers against an XBB.1.16 variant than a monovalent comprising an RNA encoding a SARS-CoV-2 S protein of an XBB.1.16 variant.
    • Example 4: Description of Sequences Provided in Sequence Listing
  • Table 2, below, provides a short description of sequences provided in the sequence listing submitted herewith.
  • SEQ ID
    NO Description
    1 Amino acid sequence of a full length SARS-CoV-2 S protein
    of a Wuhan strain
    2 Exemplary RNA sequence encoding a full length SARS-
    CoV-2 S protein of a Wuhan strain
    3 Exemplary amino acid sequence of a receptor binding
    domain (RBD) of a Wuhan SARS-CoV-2 S protein
    4 Exemplary RNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 S protein
    5 Exemplary amino acid sequence of an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin)
    6 Exemplary RNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 strain fused to a trimerization domain (fibritin)
    7 Exemplary amino acid sequence of a full length Wuhan
    SARS-CoV-2 S protein comprising prefusion stablizing
    mutations (proline substitutions at positions 986 and 987)
    8 Exemplary RNA sequence encoding a full length Wuhan
    SARS-CoV-2 S protein comprising prefusion stablizing
    mutations (proline substitutions at positions 986 and 987)
    9 Exemplary RNA sequence encoding a full length Wuhan
    SARS-CoV-2 S protein comprising prefusion stablizing
    mutations (proline substitutions at positions 986 and 987)
    10 Exemplary amino acid sequence of a “foldon” trimerization
    domain
    11 Exemplary RNA sequence encoding a “foldon” trimerization
    domain
    12 Exemplary 5′ UTR sequence
    13 Exemplary 3′ UTR sequence
    14 Exemplary polyA sequence
    15 Exemplary RNA sequence encoding a full length SARS-
    CoV-2 S protein of a Wuhan strain comprising prefusion
    stablizing mutations (proline substitutions at positions 986
    and 987)
    16 Exemplary RNA sequence encoding a full length SARS-
    CoV-2 S protein of a Wuhan strain comprising prefusion
    stablizing mutations (proline substitutions at positions 986
    and 987)
    17 Exemplary RNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin)
    18 Exemplary amino acid sequence of an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin)
    19 Exemplary RNA sequence comprising a sequence encoding a
    full length, prefusion stabilized SARS-CoV-2 S protein of a
    Wuhan strain, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    20 Exemplary RNA sequence comprising a sequence encoding a
    full length, prefusion stabilized SARS-CoV-2 S protein of a
    Wuhan strain, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    21 Exemplary RNA sequence comprising a sequence encoding
    an RBD of a Wuhan SARS-CoV-2 S protein fused to a
    trimerization domain (fibritin), along with 5′ UTR, 3′ UTR,
    and polyA sequences
    22 Exemplary amino acid sequence of alphavirus nsp1-4
    23 Exemplary amino acid sequence of an alphavirus non-
    structural protein
    24 Exemplary saRNA sequence encoding a full length SARS-
    CoV-2 S protein of a Wuhan strain comprising prefusion
    stablizing mutations (proline substitutions at positions 986
    and 987)
    25 Exemplary saRNA sequence encoding a full length SARS-
    CoV-2 S protein of a Wuhan strain comprising prefusion
    stablizing mutations (proline substitutions at positions 986
    and 987)
    26 Exemplary saRNA sequence encoding an RBD of a Wuhan
    strain fused to a trimerization domain (fibritin)
    27 Exemplary saRNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    28 Exemplary amino acid sequence of an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    29 Exemplary amino acid sequence of an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    30 Exemplary RNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    31 Exemplary amino acid sequence of an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    32 Exemplary RNA sequence encoding an RBD of a Wuhan
    SARS-CoV-2 S protein fused to a trimerization domain
    (fibritin) and a transmembrane domain
    33 Exemplary GS linker
    34 Exemplary GS linker
    35-42, Exemplary T cell epitopes recognized by vaccine-induced T
    142-145 cells (e.g., CD8+ T cell) and presented by an MHC class I
    allele present in at least 50% of subjects in a population
    43-48, Exemplary T cell epitope recognized by vaccine-induced T
    138-141, cells (e.g., CD8+ and/or CD4+ T cells) and presented by an
    146-151 MHC class I allele present in at least 50% of subjections in a
    population
    49 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of a BA. 1 Omicron variant
    50 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of a BA. 1 Omicron variant
    51 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a BA.1
    Omicron variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    52 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of a BA. 1 Omicron variant
    53 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of a BA.1 Omicron variant
    54 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a BA.1
    Omicron variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    55 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of a beta variant
    56 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of a beta variant
    57 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a beta variant,
    along with 5′ UTR, 3′ UTR, and polyA sequences
    58 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an alpha variant
    59 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an alpha variant
    60 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an alpha
    variant, along with 5′ UTR, 3′ UTR, and polyA sequences
    61 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of a delta variant
    62 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of a delta variant
    63 Exemplary dNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a delta
    variant, along with 5′ UTR, 3′ UTR, and polyA sequences
    64 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2 variant
    65 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2 variant
    66 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2 variant
    67 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    68 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    69 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    70 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    71 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    72 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.4/5 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    73 BA.4/5 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    74 Exemplary amino acid sequence of a SARS-CoV-2 S protein
    of a BA.4/5 variant, comprising prefusion-stabilizing
    mutations
    75 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    76 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    77 Exemplary amino acid sequence of a SARS-CoV-2 S protein
    of a BA.4/5 variant, comprising prefusion-stabilizing
    mutations
    78 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    79 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4/5 variant
    80 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75 variant
    81 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75 variant
    82 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75 variant
    83 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2.75 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    84 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2.75 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    85 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75.2 variant
    86 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75.2 variant
    87 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.2.75.2 variant
    88 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2.75.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    89 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.2.75.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    90 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4.6/BF.7 variant
    91 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4.6/BF.7 variant
    92 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BA.4.6/BF.7 variant
    93 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.4.6/BF.7 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    94 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BA.4.6/BF.7 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    95 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB variant
    96 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB variant
    97 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB variant
    98 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    99 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    100 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BQ.1.1 variant
    101 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BQ.1.1 variant
    102 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron BQ.1.1 variant
    103 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BQ.1.1 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    104 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    BQ.1.1 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    105 Exemplary HSV-1 gD signal peptide
    106 Exemplary HSV-2 gD signal peptide
    107 Exemplary HSV-2 signal peptide
    108 Exemplary SARS-CoV-2 Spike signal peptide
    109 Exemplary human Ig heavy chain signal peptide (huSec)
    110 Exemplary HuIgGk signal peptide
    111 Exemplary IgE heavy chain epsilon-1 signal peptide
    112 Exemplary Japanese encephalitis PRM signal sequence
    113 Exemplary VSVg protein signal sequence
    114-119 Exemplary signal peptides
    120 Exemplary nucleotide sequence encoding an HSV-1 gD
    signal peptide
    121 Exemplary nucleotide sequence encoding an HSV-1 gD
    signal peptide
    122 Exemplary nucleotide sequence encoding a SARS-CoV-2
    Spike signal peptide
    123 Exemplary nucleotide sequence encoding a human Ig heavy
    chain signal peptide (huSec)
    124 Exemplary epitope in a Wuhan SARS-CoV-2 S protein
    125 Exemplary epitope in a SARS-CoV-2 S protein of a delta
    variant comprising an L452R mutation
    126 Exemplary epitope in SARS-CoV-2 Wuhan strain RBD
    127 Exemplary epitope in an RBD of a delta variant of SARS-
    CoV-2
    128 Exemplary epitope in an RBD of Omicron BA.1 and BA.4/5
    variant of SARS-CoV-2
    129 Exemplary amino acid sequence of an RBD of a SARS-CoV-
    2 alpha variant
    130 Exemplary amino acid sequence of an RBD of a SARS-CoV-
    2 beta variant
    131 Exemplary amino acid sequence of an RBD of a SARS-CoV-
    2 delta variant
    132 Exemplary amino acid sequence of an RBD of a SARS-CoV-
    2 Omicron BA.1 variant
    133 Exemplary amino acid sequence of an RBD of a SARS-CoV-
    2 Omicron BA.4/5 variant
    134 Exemplary GS linker
    135 Exemplary GS linker
    136 Furin cleavage site in SARS-CoV-2 S protein
    137 Exemplary nucleotide sequence encodign a furin cleavage
    site in SARS-CoV-2 S protein
    152 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Beta variant
    153 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a Beta
    variant, along with 5′ UTR, 3′ UTR, and polyA sequences
    154 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Alpha variant
    155 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Alpha
    variant, along with 5′ UTR, 3′ UTR, and polyA sequences
    156 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of a Delta variant
    157 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of a Delta
    variant, along with 5′ UTR, 3′ UTR, and polyA sequences
    158 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.5 variant
    159 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.5 variant
    160 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.5 variant
    161 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.1.5 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    162 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.1.5 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    163 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.16 variant
    164 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.16 variant
    165 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.1.16 variant
    166 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.1.16 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    167 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.1.16 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    168 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3 variant
    169 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3 variant
    170 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3 variant
    171 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.2.3 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    172 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.2.3 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    173 Exemplary amino acid sequence of a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3.2 variant
    174 Exemplary RNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3.2 variant
    175 Exemplary DNA sequence encoding a prefusion-stabilized
    SARS-CoV-2 S protein of an Omicron XBB.2.3.2 variant
    176 Exemplary RNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.2.3.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences
    177 Exemplary DNA sequence comprising a sequence encoding a
    prefusion-stabilized SARS-CoV-2 S protein of an Omicron
    XBB.2.3.2 variant, along with 5′ UTR, 3′ UTR, and polyA
    sequences

Claims (30)

We claim:
1. A composition comprising an RNA molecule having:
(a) a nucleotide sequence that is at least 99% identical to SEQ ID NO: 161; or
(b) a nucleotide sequence that is at least 95% identical to SEQ ID NO: 161, and which encodes a SARS-CoV-2 S protein comprising the following substitutions relative to SEQ ID NO: 1: T191, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K, K986P, and V987P; and
wherein the RNA molecule comprises:
(i) a 5′ cap; and
(ii) a modified uridine in place of each uridine.
2. The composition of claim 1, wherein the modified uridine is N1-methyl-pseudouridine.
3. The composition of claim 1, wherein the 5′ cap comprises m2 7,3′-OGppp(m1 2′-O)ApG.
4. The composition of claim 1, wherein the RNA molecule has a nucleotide sequence as set forth in SEQ ID NO: 161.
5. The composition of claim 1, wherein the RNA molecule is encapsulated in a lipid nanoparticle (LNP).
6. The composition of claim 5, wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
7. The composition of claim 1, wherein the composition comprises one or more additional RNA molecules, each having a nucleotide sequence encoding an S protein of a SARS-CoV-2 strain or variant that is not XBB.1.5.
8. The composition of claim 7, wherein the one or more additional RNA molecules comprise a sequence that has at least 95% identical to SEQ ID NO: 20, 72, or 103.
9. A composition comprising an RNA molecule having a nucleotide sequence as set forth in SEQ ID NO: 161, wherein the RNA molecule comprises:
(i) N1-methyl-pseudouridine in place of each uridine; and
(ii) a 5′ cap that comprises m2 7,3′-OGppp(m1 2′-O)ApG;
wherein the RNA molecule is encapsulated in a lipid nanoparticle (LNP); and
wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
10. The composition of claim 9, comprising about 10 mM Tris buffer and about 10% sucrose.
11. The composition of claim 9, wherein the composition is formulated as a multi-dose formulation in a vial.
12. A method of inducing an immune response against coronavirus in a subject, comprising administering to a subject the composition of claim 1.
13. The method of claim 12, wherein the RNA molecule comprises N1-methyl-pseudouridine in place of each uridine.
14. The method of claim 12, wherein the 5′ cap comprises m2 7,3′-OGppp(m1 2′-O)ApG.
15. The method of claim 12, wherein the RNA molecule is encapsulated in an LNP and wherein the LNP comprises molar ratios of 20-60% ionizable cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
16. The method of claim 15, wherein the subject is 12 years or older, and the composition comprises 30 μg of the RNA molecule.
17. The method of claim 15, wherein the subject is 5 years to less than 12 years old, and the composition comprises 10 μg of the RNA molecule.
18. The method of claim 15, wherein the subject is 6 months to less than 5 years old, and the composition comprises 3 μg of the RNA molecule.
19. The method of claim 15, wherein the composition is administered in a volume of about 200 μL to 300 μL.
20. The method of claim 15, wherein the subject was previously administered one or more doses of a SARS-CoV-2 vaccine.
21. The method of claim 20, wherein the subject was previously administered a complete dosing regimen of a SARS-CoV-2 vaccine.
22. The method of claim 15, wherein the subject was previously administered a first dose and a second dose of BNT162b2, wherein the first dose and the second dose were administered about 21 days apart.
23. The method of claim 22, wherein the subject was previously administered as a booster dose a bivalent vaccine that delivers (i) a SARS-CoV-2 S protein of an Omicron BA.4/5 variant and (ii) a SARS-CoV-2 S protein of a Wuhan strain.
24. The method of claim 15, further comprising co-administering one or more vaccines against a non-SARS-CoV-2 disease.
25. The method of claim 24, wherein the one or more vaccines comprise an RSV vaccine, an influenza vaccine, or a combination thereof.
26. A composition comprising at least one unit dose of LNP-encapsulated RNA molecules, wherein the composition comprises:
a population of LNPs encapsulating RNA molecules, wherein:
the LNPs comprise an ionizable cationic lipid, a neutral lipid, a sterol, and a PEG-modified lipid in molar ratios of 20-60%, 5-25%, 25-55%, and 0.5-15%, respectively; and
each LNP in the population encapsulates at least an RNA molecule, wherein the RNA molecule comprises
(a) a nucleotide sequence that is at least 99% identical to SEQ ID NO: 161; or
(b) a nucleotide sequence that is at least 95% identical to SEQ ID NO: 161, and which comprises a nucleotide sequence that encodes a SARS-CoV-2 protein comprising the following substitutions relative to SEQ ID NO: 1: T19I, Δ24-26, A27S, V83A, G142D, Δ145, H146Q, Q183E, V213E, G252V, G339H, R346T, L368I, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, V445P, G446S, N460K, S477N, T478K, E484A, F486P, F490S, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K, K986P, and V987P;
(b) N1-methyl-pseudouridine in place of each uridine; and
(c) a 5′ cap that comprises m2 7,3′-OGppp(m1 2′-O)ApG.
27. The composition of claim 26, comprising about 10 mM Tris buffer and about 10% sucrose.
28. The composition of claim 26, wherein the unit dose comprises the RNA molecule in an amount of about 30 μg.
29. The composition of claim 26, wherein the unit dose comprises the RNA molecule in an amount of about 10 μg.
30. The composition of claim 26, wherein the unit dose comprises the RNA molecule in an amount of about 3 μg.
US18/341,590 2022-06-26 2023-06-26 Coronavirus vaccine Active US11878055B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/341,590 US11878055B1 (en) 2022-06-26 2023-06-26 Coronavirus vaccine

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
US202263355648P 2022-06-26 2022-06-26
US202263357628P 2022-06-30 2022-06-30
US202263358522P 2022-07-05 2022-07-05
US202263394571P 2022-08-02 2022-08-02
US202263402444P 2022-08-30 2022-08-30
US202263417680P 2022-10-19 2022-10-19
US202263422404P 2022-11-03 2022-11-03
US202263425290P 2022-11-14 2022-11-14
WOPCT/EP22/83740 2022-11-29
PCT/EP2022/083740 WO2023094713A2 (en) 2021-11-29 2022-11-29 Coronavirus vaccine
WOPCT/EP2022/083740 2022-11-29
US202363486953P 2023-02-24 2023-02-24
US202363452148P 2023-03-14 2023-03-14
US202363465521P 2023-05-10 2023-05-10
US202363469472P 2023-05-29 2023-05-29
US18/341,590 US11878055B1 (en) 2022-06-26 2023-06-26 Coronavirus vaccine

Publications (2)

Publication Number Publication Date
US20240000921A1 true US20240000921A1 (en) 2024-01-04
US11878055B1 US11878055B1 (en) 2024-01-23

Family

ID=89383340

Family Applications (1)

Application Number Title Priority Date Filing Date
US18/341,590 Active US11878055B1 (en) 2022-06-26 2023-06-26 Coronavirus vaccine

Country Status (2)

Country Link
US (1) US11878055B1 (en)
WO (1) WO2024002985A1 (en)

Family Cites Families (409)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898278A (en) 1986-12-05 1990-02-06 Nalge Company Storage container
FR2686899B1 (en) 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa NOVEL BIOLOGICALLY ACTIVE POLYPEPTIDES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
JPH10113117A (en) 1996-10-11 1998-05-06 Tomoji Tanaka Insulated box
DE69841002D1 (en) 1997-05-14 2009-09-03 Univ British Columbia Highly effective encapsulation of nucleic acids in lipid vesicles
EP2292771A3 (en) 1997-09-19 2011-07-27 Life Technologies Corporation Sense mRNA therapy
US20050287153A1 (en) 2002-06-28 2005-12-29 Genentech, Inc. Serum albumin binding peptides for tumor targeting
US6381981B1 (en) 2001-05-02 2002-05-07 Advanced Tissue Sciences, Inc. Container for shipping and storing frozen products
EP2305699B1 (en) 2001-06-05 2014-08-13 CureVac GmbH Stabilised mRNA with increased G/C content which is optimised for translation in its coded areas for the vaccination against sleeping sickness, leishmaniosis and toxoplasmosis
US7176278B2 (en) 2001-08-30 2007-02-13 Biorexis Technology, Inc. Modified transferrin fusion proteins
US20030082357A1 (en) 2001-09-05 2003-05-01 Cem Gokay Multi-layer core for vacuum insulation panel and insulated container including vacuum insulation panel
US7074596B2 (en) 2002-03-25 2006-07-11 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synthesis and use of anti-reverse mRNA cap analogues
AU2003245729A1 (en) 2002-06-27 2004-01-19 Dana-Farber Cancer Institute, Inc. Compositions and methods for modulating a cytotoxic t lymphocyte immune response
ATE485031T1 (en) 2002-06-28 2010-11-15 Protiva Biotherapeutics Inc METHOD AND DEVICE FOR PRODUCING LIPOSOMES
US7696320B2 (en) 2004-08-24 2010-04-13 Domantis Limited Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor
DE10229872A1 (en) 2002-07-03 2004-01-29 Curevac Gmbh Immune stimulation through chemically modified RNA
ES2655912T3 (en) 2002-11-08 2018-02-22 Ablynx N.V. Single domain antibodies directed against tumor necrosis factor-alpha and uses for them
CA2523875A1 (en) 2003-04-28 2004-11-11 Public Health Agency Of Canada Sars virus nucleotide and amino acid sequences and uses thereof
WO2005035556A2 (en) 2003-05-06 2005-04-21 Iguazu Biosciences Corp. Sars-coronavirus virus-like particles and methods of use
RU2325045C2 (en) 2003-06-10 2008-05-20 Нокиа Корпорейшн Method and device for off-line and target switch of mobile station transmission
CA2532196A1 (en) 2003-06-18 2005-01-20 Chinese National Human Genome Center At Shanghai Characterization of the earliest stages of the severe acute respiratory syndrome (sars) virus and uses thereof
WO2005012337A2 (en) 2003-07-15 2005-02-10 Crucell Holland B.V. Antigenic peptides of sars coronavirus and uses thereof
KR101206206B1 (en) 2003-07-22 2012-11-29 크루셀 홀란드 비.브이. Binding molecules against sars-coronavirus and uses thereof
WO2005013904A2 (en) 2003-08-04 2005-02-17 University Of Massachusetts Sars nucleic acids, proteins, vaccines, and uses thereof
WO2005027963A2 (en) 2003-09-15 2005-03-31 The United States Of America As Represented By Thesecretary Of Health And Human Services, Nih METHODS AND COMPOSITIONS FOR THE GENERATION OF A PROTECTIVE IMMUNE RESPONSE AGAINTS SARS-CoV
US7129042B2 (en) 2003-11-03 2006-10-31 Diagnostic Hybrids, Inc. Compositions and methods for detecting severe acute respiratory syndrome coronavirus
DE602004028506D1 (en) 2003-12-02 2010-09-16 Pasteur Institut NEW SARS CONNECTED CORONAVIRUS TRIBE AND ITS USES
MXPA06009072A (en) 2004-02-09 2007-03-29 Human Genome Sciences Inc Albumin fusion proteins.
US20050178142A1 (en) 2004-02-17 2005-08-18 Perry Ralph J. 96 hour duration insulated cryo-pack for maintaining -40 degree fahrenheit
US7870748B2 (en) 2005-02-25 2011-01-18 Byrne Kathleen H Method for controlled rate freezing and long term cryogenic storage
EP1882392A4 (en) 2005-05-10 2009-07-01 Monsanto Technology Llc Genes and uses for plant improvement
EP2476756A1 (en) 2005-06-15 2012-07-18 Massachusetts Institute of Technology Amine-containing lipids and uses thereof
DK2578685T3 (en) 2005-08-23 2019-06-03 Univ Pennsylvania RNA CONTAINING MODIFIED NUCLEOSIDES AND METHODS OF USE THEREOF
DE102005046490A1 (en) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz New nucleic acid molecule comprising promoter, a transcriptable nucleic acid sequence, a first and second nucleic acid sequence for producing modified RNA with transcriptional stability and translational efficiency
US20070269422A1 (en) 2006-05-17 2007-11-22 Ablynx N.V. Serum albumin binding proteins with long half-lives
EP2046826B1 (en) 2006-07-24 2011-09-14 Biorexis Pharmaceutical Corporation Exendin fusion proteins
CA2659301A1 (en) 2006-07-28 2008-02-07 Applera Corporation Dinucleotide mrna cap analogs
US8865398B2 (en) 2006-09-01 2014-10-21 Abbott Laboratories Combination hepatitis C virus antigen and antibody detection method
JP2010502208A (en) 2006-09-08 2010-01-28 アブリンクス エン．ヴェー． Serum albumin binding protein with long half-life
DE102006051516A1 (en) 2006-10-31 2008-05-08 Curevac Gmbh (Base) modified RNA to increase the expression of a protein
CN104072561B (en) 2007-06-19 2017-12-22 路易斯安那州州立大学及农业机械学院管理委员会 The synthesis of the anti-reverse phosphorothioate analogs of mRNA cap and purposes
WO2009030254A1 (en) 2007-09-04 2009-03-12 Curevac Gmbh Complexes of rna and cationic peptides for transfection and for immunostimulation
US20100322930A1 (en) 2007-12-27 2010-12-23 Frank Kolbinger Fibronectin-based binding molecules and their use
WO2009127060A1 (en) 2008-04-15 2009-10-22 Protiva Biotherapeutics, Inc. Novel lipid formulations for nucleic acid delivery
WO2009133208A1 (en) 2008-05-02 2009-11-05 Novartis Ag Improved fibronectin-based binding molecules and uses thereof
PL215513B1 (en) 2008-06-06 2013-12-31 Univ Warszawski New borane phosphate analogs of dinucleotides, their application, RNA particle, method of obtaining RNA and method of obtaining peptides or protein
AU2015210364B2 (en) 2008-10-09 2017-03-09 Arbutus Biopharma Corporation Improved amino lipids and methods for the delivery of nucleic acids
HUE051666T2 (en) 2008-12-09 2021-03-29 Novavax Inc Modified rsv f proteins and methods of their use
CA2751342C (en) 2009-01-29 2019-05-07 Alnylam Pharmaceuticals, Inc. Lipid formulations comprising cationic lipid and a targeting lipid comprising n-acetyl galactosamine for delivery of nucleic acid
EP2451475A2 (en) 2009-07-06 2012-05-16 Novartis AG Self replicating rna molecules and uses thereof
EP2281579A1 (en) 2009-08-05 2011-02-09 BioNTech AG Vaccine composition comprising 5'-Cap modified RNA
PT2506857T (en) 2009-12-01 2018-05-14 Translate Bio Inc Delivery of mrna for the augmentation of proteins and enzymes in human genetic diseases
US10233228B2 (en) 2010-04-09 2019-03-19 Albumedix Ltd Albumin derivatives and variants
DK2558491T3 (en) 2010-04-13 2018-10-15 Bristol Myers Squibb Co Fibronectin-based Scaffold domain proteins that bind PCSK9
PL2590626T3 (en) 2010-07-06 2016-04-29 Glaxosmithkline Biologicals Sa Liposomes with lipids having an advantageous pka-value for rna delivery
EP2600901B1 (en) 2010-08-06 2019-03-27 ModernaTX, Inc. A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof
AU2015210336B2 (en) 2010-08-17 2017-05-25 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hepatitis B virus (HBV) gene expression using short interfering nucleic acid (siNA)
LT3981427T (en) 2010-08-31 2022-08-10 Glaxosmithkline Biologicals S.A. Pegylated liposomes for delivery of immunogen-encoding rna
ES2737960T3 (en) 2010-10-01 2020-01-17 Modernatx Inc Nucleosides, nucleotides and modified nucleic acids and their uses
WO2012116715A1 (en) 2011-03-02 2012-09-07 Curevac Gmbh Vaccination in newborns and infants
WO2012116714A1 (en) 2011-03-02 2012-09-07 Curevac Gmbh Vaccination in elderly patients
AU2012236099A1 (en) 2011-03-31 2013-10-03 Moderna Therapeutics, Inc. Delivery and formulation of engineered nucleic acids
WO2012158736A1 (en) 2011-05-17 2012-11-22 modeRNA Therapeutics Engineered nucleic acids and methods of use thereof for non-human vertebrates
TR201910686T4 (en) 2011-06-08 2019-08-21 Translate Bio Inc Lipid nanoparticle compositions and methods for Mrna delivery.
EP3384938A1 (en) 2011-09-12 2018-10-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US20140220017A1 (en) 2011-09-23 2014-08-07 Universitat Stuttgart Serum half-life extension using igbd
EP3682905B1 (en) 2011-10-03 2021-12-01 ModernaTX, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
EP2780364A2 (en) 2011-11-18 2014-09-24 Eleven Biotherapeutics, Inc. Proteins with improved half-life and other properties
US20140308304A1 (en) 2011-12-07 2014-10-16 Alnylam Pharmaceuticals, Inc. Lipids for the delivery of active agents
WO2013130161A1 (en) 2011-12-14 2013-09-06 modeRNA Therapeutics Methods of responding to a biothreat
EP2791160B1 (en) 2011-12-16 2022-03-02 ModernaTX, Inc. Modified mrna compositions
RU2014129863A (en) 2011-12-21 2016-02-10 Модерна Терапьютикс, Инк. WAYS TO INCREASE VITALITY OR INCREASE THE LIFE OF A BODY OR EXPLANATE BODY
EP2809354B1 (en) 2012-01-31 2021-04-14 CureVac AG Negatively charged nucleic acid comprising complexes for immunostimulation
WO2013120499A1 (en) 2012-02-15 2013-08-22 Curevac Gmbh Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen
WO2013143555A1 (en) 2012-03-26 2013-10-03 Biontech Ag Rna formulation for immunotherapy
EP3260541B1 (en) 2012-03-27 2019-05-15 CureVac AG Artificial nucleic acid molecules for improved protein or peptide expression
ES2654205T3 (en) 2012-03-27 2018-02-12 Curevac Ag Artificial nucleic acid molecules for enhanced protein or peptide expression
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US10501513B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
AU2013243948A1 (en) 2012-04-02 2014-10-30 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with human disease
US9303079B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9512456B2 (en) 2012-08-14 2016-12-06 Modernatx, Inc. Enzymes and polymerases for the synthesis of RNA
EP4074834A1 (en) 2012-11-26 2022-10-19 ModernaTX, Inc. Terminally modified rna
AU2013355258A1 (en) 2012-12-07 2015-06-11 Alnylam Pharmaceuticals, Inc. Improved nucleic acid lipid particle formulations
WO2014093574A1 (en) 2012-12-13 2014-06-19 Moderna Therapeutics, Inc. Modified polynucleotides for altering cell phenotype
EP2931319B1 (en) 2012-12-13 2019-08-21 ModernaTX, Inc. Modified nucleic acid molecules and uses thereof
BR122021025267B1 (en) 2013-02-22 2023-12-05 Curevac Ag KIT PARTS AND PHARMACEUTICAL COMPOSITION COMPRISING A PD-1 PATHWAY INHIBITOR
BR112015018989B1 (en) 2013-02-22 2023-11-14 Curevac Ag COMBINATION VACCINE/PD-1 PATHWAY INHIBITOR, PD-1 PATHWAY INHIBITOR AND RNA VACCINE
US20160022840A1 (en) 2013-03-09 2016-01-28 Moderna Therapeutics, Inc. Heterologous untranslated regions for mrna
WO2014159813A1 (en) 2013-03-13 2014-10-02 Moderna Therapeutics, Inc. Long-lived polynucleotide molecules
CN105051213A (en) 2013-03-14 2015-11-11 夏尔人类遗传性治疗公司 Quantitative assessment for cap efficiency of messenger RNA
US10258698B2 (en) 2013-03-14 2019-04-16 Modernatx, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
EA201591229A1 (en) 2013-03-14 2016-01-29 Шир Хьюман Дженетик Терапис, Инк. METHODS OF CLEANING MATRIX RNA
EP2983804A4 (en) 2013-03-15 2017-03-01 Moderna Therapeutics, Inc. Ion exchange purification of mrna
CA2906732C (en) 2013-03-15 2023-08-08 The University Of British Columbia Lipid nanoparticles for transfection and related methods
WO2014144039A1 (en) 2013-03-15 2014-09-18 Moderna Therapeutics, Inc. Characterization of mrna molecules
WO2014152031A1 (en) 2013-03-15 2014-09-25 Moderna Therapeutics, Inc. Ribonucleic acid purification
WO2014144711A1 (en) 2013-03-15 2014-09-18 Moderna Therapeutics, Inc. Analysis of mrna heterogeneity and stability
US10077439B2 (en) 2013-03-15 2018-09-18 Modernatx, Inc. Removal of DNA fragments in mRNA production process
US10138507B2 (en) 2013-03-15 2018-11-27 Modernatx, Inc. Manufacturing methods for production of RNA transcripts
TW201534578A (en) 2013-07-08 2015-09-16 Daiichi Sankyo Co Ltd Novel lipid
WO2015024667A1 (en) 2013-08-21 2015-02-26 Curevac Gmbh Method for increasing expression of rna-encoded proteins
EP3036330B1 (en) 2013-08-21 2018-09-12 CureVac AG Method for increasing expression of rna-encoded proteins
WO2015051169A2 (en) 2013-10-02 2015-04-09 Moderna Therapeutics, Inc. Polynucleotide molecules and uses thereof
AU2014337156A1 (en) 2013-10-18 2016-05-12 Modernatx, Inc. Compositions and methods for tolerizing cellular systems
CA2925021A1 (en) 2013-11-01 2015-05-07 Curevac Ag Modified rna with decreased immunostimulatory properties
EP3062798B1 (en) 2013-11-01 2020-05-06 CureVac AG Modified rna with decreased immunostimulatory properties
SG10201805660WA (en) 2013-12-30 2018-08-30 Curevac Ag Methods for rna analysis
EP3090060B1 (en) 2013-12-30 2019-02-20 CureVac AG Methods for rna analysis
WO2015130584A2 (en) 2014-02-25 2015-09-03 Merck Sharp & Dohme Corp. Lipid nanoparticle vaccine adjuvants and antigen delivery systems
WO2015149944A2 (en) 2014-04-01 2015-10-08 Curevac Gmbh Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant
BR112016024644A2 (en) 2014-04-23 2017-10-10 Modernatx Inc nucleic acid vaccines
EA201691696A1 (en) 2014-04-25 2017-03-31 Шир Хьюман Дженетик Терапис, Инк. METHODS OF CLEANING MATRIX RNA
US10286086B2 (en) 2014-06-19 2019-05-14 Modernatx, Inc. Alternative nucleic acid molecules and uses thereof
US9738593B2 (en) 2014-06-25 2017-08-22 Acuitas Therapeutics Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
WO2016005004A1 (en) 2014-07-11 2016-01-14 Biontech Rna Pharmaceuticals Gmbh Stabilization of poly(a) sequence encoding dna sequences
EP4223285A3 (en) 2014-07-16 2023-11-22 Novartis AG Method of encapsulating a nucleic acid in a lipid nanoparticle host
CA2955250A1 (en) 2014-07-16 2016-01-21 Moderna Therapeutics, Inc. Chimeric polynucleotides
JP2017523777A (en) 2014-07-17 2017-08-24 モデルナティエックス インコーポレイテッドＭｏｄｅｒｎａＴＸ，Ｉｎｃ． Polynucleotide end modification
WO2016045732A1 (en) 2014-09-25 2016-03-31 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
US20170362627A1 (en) 2014-11-10 2017-12-21 Modernatx, Inc. Multiparametric nucleic acid optimization
ES2946969T3 (en) 2014-12-12 2023-07-28 CureVac SE Artificial nucleic acid molecules for enhanced protein expression
WO2016118724A1 (en) 2015-01-21 2016-07-28 Moderna Therapeutics, Inc. Lipid nanoparticle compositions
WO2016164762A1 (en) 2015-04-08 2016-10-13 Moderna Therapeutics, Inc. Polynucleotides encoding low density lipoprotein receptor egf-a and intracellular domain mutants and methods of using the same
SG11201707663SA (en) 2015-04-17 2017-11-29 Curevac Ag Lyophilization of rna
JP2018526321A (en) 2015-04-27 2018-09-13 ザ・トラステイーズ・オブ・ザ・ユニバーシテイ・オブ・ペンシルベニア Nucleoside-modified RNA for inducing an adaptive immune response
WO2016180430A1 (en) 2015-05-08 2016-11-17 Curevac Ag Method for producing rna
US10517827B2 (en) 2015-05-20 2019-12-31 Curevac Ag Dry powder composition comprising long-chain RNA
EP3928800A3 (en) 2015-05-20 2022-03-23 CureVac AG Dry powder composition comprising long-chain rna
WO2016193206A1 (en) 2015-05-29 2016-12-08 Curevac Ag A method for producing and purifying rna, comprising at least one step of tangential flow filtration
WO2016201377A1 (en) 2015-06-10 2016-12-15 Moderna Therapeutics, Inc. Targeted adaptive vaccines
EP3324979B1 (en) 2015-07-21 2022-10-12 ModernaTX, Inc. Infectious disease vaccines
WO2017015457A1 (en) 2015-07-21 2017-01-26 Modernatx, Inc. Ebola vaccine
US20190008938A1 (en) 2015-07-30 2019-01-10 Modernatx, Inc. Concatemeric peptide epitope rnas
WO2017019935A1 (en) 2015-07-30 2017-02-02 Modernatx, Inc. Multimeric mrna
CN116064623A (en) 2015-08-10 2023-05-05 库瑞瓦格制造业有限公司 Method for increasing replication of circular DNA molecules
WO2017031232A1 (en) 2015-08-17 2017-02-23 Modernatx, Inc. Methods for preparing particles and related compositions
US20180237849A1 (en) 2015-08-17 2018-08-23 Modernatx, Inc. Rna mapping/fingerprinting
AU2016315444B2 (en) 2015-08-28 2023-02-23 BioNTech SE Method for reducing immunogenicity of RNA
WO2017049286A1 (en) 2015-09-17 2017-03-23 Moderna Therapeutics, Inc. Polynucleotides containing a morpholino linker
PT3350157T (en) 2015-09-17 2022-03-18 Modernatx Inc Compounds and compositions for intracellular delivery of therapeutic agents
PL3350333T3 (en) 2015-09-17 2022-03-07 Modernatx, Inc. Polynucleotides containing a stabilizing tail region
SI3954225T1 (en) 2015-09-21 2024-03-29 Trilink Biotechnologies, Llc Initiating capped oligonucleotide primers for synthesizing 5'-capped rnas
US10849920B2 (en) 2015-10-05 2020-12-01 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
WO2017059902A1 (en) 2015-10-07 2017-04-13 Biontech Rna Pharmaceuticals Gmbh 3' utr sequences for stabilization of rna
WO2017066781A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Mrna cap analogs with modified phosphate linkage
WO2017066789A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Mrna cap analogs with modified sugar
WO2017066797A1 (en) 2015-10-16 2017-04-20 Modernatx, Inc. Trinucleotide mrna cap analogs
EP3362460A1 (en) 2015-10-16 2018-08-22 Modernatx, Inc. Mrna cap analogs and methods of mrna capping
US20180303929A1 (en) 2015-10-22 2018-10-25 Moderna TX, Inc. Herpes simplex virus vaccine
EP3364950A4 (en) 2015-10-22 2019-10-23 ModernaTX, Inc. Tropical disease vaccines
CA3002819A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Sexually transmitted disease vaccines
EP3365007A4 (en) 2015-10-22 2019-07-03 ModernaTX, Inc. Broad spectrum influenza virus vaccine
SG10201914006UA (en) 2015-10-22 2020-03-30 Modernatx Inc Respiratory syncytial virus vaccine
EP3364981A4 (en) 2015-10-22 2019-08-07 ModernaTX, Inc. Human cytomegalovirus vaccine
EP4011451A1 (en) 2015-10-22 2022-06-15 ModernaTX, Inc. Metapneumovirus mrna vaccines
CA3003090A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Cancer vaccines
CA3002912A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Nucleic acid vaccines for varicella zoster virus (vzv)
WO2018081480A1 (en) 2016-10-26 2018-05-03 Acuitas Therapeutics, Inc. Lipid nanoparticle formulations
PL3368507T3 (en) 2015-10-28 2023-03-27 Acuitas Therapeutics Inc. Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids
US20180312545A1 (en) 2015-11-09 2018-11-01 Curevac Ag Optimized nucleic acid molecules
US11389546B2 (en) 2015-12-09 2022-07-19 Modernatx, Inc. Heterologous UTR sequences for enhanced mRNA expression
EP3964200A1 (en) 2015-12-10 2022-03-09 ModernaTX, Inc. Compositions and methods for delivery of therapeutic agents
EP3390630A1 (en) 2015-12-17 2018-10-24 Modernatx, Inc. POLYNUCLEOTIDES ENCODING METHYLMALONYL-CoA MUTASE
AU2016377681B2 (en) 2015-12-22 2021-05-13 Modernatx, Inc. Compounds and compositions for intracellular delivery of agents
US10465190B1 (en) 2015-12-23 2019-11-05 Modernatx, Inc. In vitro transcription methods and constructs
GB2546257A (en) 2016-01-08 2017-07-19 The Wool Packaging Company Ltd Temperature controlled packaging and transportation method
US20210206818A1 (en) 2016-01-22 2021-07-08 Modernatx, Inc. Messenger ribonucleic acids for the production of intracellular binding polypeptides and methods of use thereof
WO2017180917A2 (en) 2016-04-13 2017-10-19 Modernatx, Inc. Lipid compositions and their uses for intratumoral polynucleotide delivery
WO2017191274A2 (en) 2016-05-04 2017-11-09 Curevac Ag Rna encoding a therapeutic protein
EP3458106A4 (en) 2016-05-18 2020-03-18 Modernatx, Inc. Polynucleotides encoding lipoprotein lipase for the treatment of hyperlipidemia
US20190298657A1 (en) 2016-05-18 2019-10-03 Modernatx, Inc. Polynucleotides Encoding Acyl-CoA Dehydrogenase, Very Long-Chain for the Treatment of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
KR102533456B1 (en) 2016-05-18 2023-05-17 모더나티엑스, 인크. Polynucleotides encoding relaxin
WO2017201317A1 (en) 2016-05-18 2017-11-23 Modernatx, Inc. Polyribonucleotides containing reduced uracil content and uses thereof
US10993918B2 (en) 2016-05-18 2021-05-04 Modernatx, Inc. Polynucleotides encoding citrin for the treatment of Citrullinemia type 2
WO2017201328A1 (en) 2016-05-18 2017-11-23 Modernatx, Inc. POLYNUCLEOTIDES ENCODING α-GALACTOSIDASE A FOR THE TREATMENT OF FABRY DISEASE
MA45052A (en) 2016-05-18 2019-03-27 Modernatx Inc POLYNUCLEOTIDES CODING FOR JAGGED1 FOR THE TREATMENT OF ALAGILLUS SYNDROME
CA3024509A1 (en) 2016-05-18 2017-11-23 Modernatx, Inc. Mrna combination therapy for the treatment of cancer
US20200085916A1 (en) 2016-05-18 2020-03-19 Modernatx, Inc. Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria
WO2017201347A1 (en) 2016-05-18 2017-11-23 Modernatx, Inc. Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis
MA45041A (en) 2016-05-18 2019-03-27 Modernatx Inc POLYNUCLEOTIDES CODING FOR GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE FOR THE TREATMENT OF TYPE 1 GALACTOSEMIA
WO2017218704A1 (en) 2016-06-14 2017-12-21 Modernatx, Inc. Stabilized formulations of lipid nanoparticles
CN116837052A (en) 2016-09-14 2023-10-03 摩登纳特斯有限公司 High-purity RNA composition and preparation method thereof
EP3529255A1 (en) 2016-10-19 2019-08-28 Arcturus Therapeutics, Inc. Trinucleotide mrna cap analogs
JP6980780B2 (en) 2016-10-21 2021-12-15 モデルナティーエックス， インコーポレイテッド Human cytomegalovirus vaccine
US10960070B2 (en) 2016-10-25 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Prefusion coronavirus spike proteins and their use
JP2019532657A (en) 2016-10-26 2019-11-14 モデルナティーエックス， インコーポレイテッド Messenger ribonucleic acid for enhancing immune response and method of use thereof
AU2017350488B2 (en) 2016-10-26 2022-06-23 Acuitas Therapeutics Inc. Lipid nanoparticle mRNA vaccines
EP3532613A4 (en) 2016-10-26 2020-05-06 ModernaTX, Inc. Methods and compositions for rna mapping
WO2018089540A1 (en) 2016-11-08 2018-05-17 Modernatx, Inc. Stabilized formulations of lipid nanoparticles
US10925958B2 (en) 2016-11-11 2021-02-23 Modernatx, Inc. Influenza vaccine
US11103578B2 (en) 2016-12-08 2021-08-31 Modernatx, Inc. Respiratory virus nucleic acid vaccines
US11384352B2 (en) 2016-12-13 2022-07-12 Modernatx, Inc. RNA affinity purification
US11141476B2 (en) 2016-12-23 2021-10-12 Curevac Ag MERS coronavirus vaccine
US20180243225A1 (en) 2017-01-25 2018-08-30 Modernatx, Inc. Ebola/marburg vaccines
WO2018144082A1 (en) 2017-02-01 2018-08-09 Modernatx, Inc. Rna cancer vaccines
CN117224710A (en) 2017-02-01 2023-12-15 莫得纳特斯公司 Immunomodulatory therapeutic MRNA compositions encoding mutant peptides that activate oncogenes
EP3577221A4 (en) 2017-02-01 2020-12-23 ModernaTX, Inc. Polynucleotide secondary structure
WO2018151816A1 (en) 2017-02-16 2018-08-23 Modernatx, Inc. High potency immunogenic compositions
US20200368162A1 (en) 2017-02-24 2020-11-26 Modernatx, Inc. Nucleic Acid-Based Therapy of Muscular Dystrophies
AU2018229278A1 (en) 2017-02-28 2019-10-17 Sanofi Therapeutic RNA
ES2911186T3 (en) 2017-03-15 2022-05-18 Modernatx Inc Crystalline forms of aminolipids
PL3596041T3 (en) 2017-03-15 2023-03-06 Modernatx, Inc. Compound and compositions for intracellular delivery of therapeutic agents
US11752206B2 (en) 2017-03-15 2023-09-12 Modernatx, Inc. Herpes simplex virus vaccine
EP3596118A4 (en) 2017-03-15 2021-04-07 Cue Biopharma, Inc. Methods for modulating an immune response
MA52262A (en) 2017-03-15 2020-02-19 Modernatx Inc BROAD SPECTRUM VACCINE AGAINST THE INFLUENZA VIRUS
US11045540B2 (en) 2017-03-15 2021-06-29 Modernatx, Inc. Varicella zoster virus (VZV) vaccine
MA47787A (en) 2017-03-15 2020-01-22 Modernatx Inc RESPIRATORY SYNCYTIAL VIRUS VACCINE
US11969506B2 (en) 2017-03-15 2024-04-30 Modernatx, Inc. Lipid nanoparticle formulation
MA47790A (en) 2017-03-17 2021-05-05 Modernatx Inc RNA-BASED VACCINES AGAINST ZOONOTIC DISEASES
WO2018175783A1 (en) 2017-03-22 2018-09-27 Modernatx, Inc. Rna bacterial vaccines
US11905525B2 (en) 2017-04-05 2024-02-20 Modernatx, Inc. Reduction of elimination of immune responses to non-intravenous, e.g., subcutaneously administered therapeutic proteins
US20200054737A1 (en) 2017-04-26 2020-02-20 Modema TX, Inc. Herpes simplex virus vaccine
ES2952779T3 (en) 2017-05-18 2023-11-06 Modernatx Inc Modified messenger RNA comprising functional RNA elements
CN107033250B (en) 2017-05-23 2020-01-21 山东省农业科学院奶牛研究中心 Bovine coronavirus recombinant multi-epitope antigen and application thereof
US11786607B2 (en) 2017-06-15 2023-10-17 Modernatx, Inc. RNA formulations
WO2018232355A1 (en) 2017-06-15 2018-12-20 Modernatx, Inc. Rna antibodies
CN111328287A (en) 2017-07-04 2020-06-23 库瑞瓦格股份公司 Novel nucleic acid molecules
WO2019035998A1 (en) 2017-08-17 2019-02-21 Modernatx, Inc. Systems with fluid path control and regulation
EP3668977A4 (en) 2017-08-18 2021-04-21 Modernatx, Inc. Analytical hplc methods
EP3668522A4 (en) 2017-08-18 2021-04-21 Modernatx, Inc. Efficacious mrna vaccines
EP3668979A4 (en) 2017-08-18 2021-06-02 Modernatx, Inc. Methods for hplc analysis
WO2019036682A1 (en) 2017-08-18 2019-02-21 Modernatx, Inc. Rna polymerase variants
US10653767B2 (en) 2017-09-14 2020-05-19 Modernatx, Inc. Zika virus MRNA vaccines
US20190192646A1 (en) 2017-11-03 2019-06-27 Modernatx, Inc. Salmonella vaccines
WO2019092002A1 (en) 2017-11-07 2019-05-16 Valneva Se Pharmaceutical compositions for treatment or prevention of viral infections
GB201718660D0 (en) 2017-11-10 2017-12-27 Ucl Business Plc Improved liposome for mRNA delivery to cells
JP2021504445A (en) 2017-11-21 2021-02-15 モデルナティーエックス， インコーポレイテッド Epstein-Barr virus vaccine
MA54676A (en) 2018-01-29 2021-11-17 Modernatx Inc RSV RNA VACCINES
CA3089117A1 (en) 2018-01-30 2019-08-08 Modernatx, Inc. Compositions and methods for delivery of agents to immune cells
CA3106812A1 (en) 2018-04-27 2019-10-31 Seattle Children's Hospital (dba Seattle Children's Research Institute) Homology-directed repair template design and delivery to edit hemoglobin-related mutations
EP3801627A1 (en) 2018-05-30 2021-04-14 Translate Bio, Inc. Phosphoester cationic lipids
CN113365639A (en) 2018-06-27 2021-09-07 摩登纳特斯有限公司 Personalized cancer vaccine epitope selection
TW202019955A (en) 2018-07-31 2020-06-01 德商英麥提克生物技術股份有限公司 Immunotherapy with b*07 restricted peptides and combination of peptides against cancers and related methods
CA3111836A1 (en) 2018-09-13 2020-03-19 Modernatx, Inc. Modified mrna for the treatment of progressive familial intrahepatic cholestasis disorders
JP7410135B2 (en) 2018-09-19 2024-01-09 モデルナティエックス インコーポレイテッド Compounds and compositions for intracellular delivery of therapeutic agents
EP3852732A1 (en) 2018-09-19 2021-07-28 ModernaTX, Inc. Peg lipids and uses thereof
CA3113353A1 (en) 2018-09-19 2020-03-26 Modernatx, Inc. High-purity peg lipids and uses thereof
CA3113651A1 (en) 2018-09-20 2020-03-26 Modernatx, Inc. Preparation of lipid nanoparticles and methods of administration thereof
CN113039174B (en) 2018-10-02 2023-11-17 英特利亚治疗股份有限公司 Ionizable amine lipids
EP3876947A4 (en) 2018-11-07 2022-08-31 ModernaTX, Inc. Rna cancer vaccines
CN111200358B (en) 2018-11-19 2021-09-03 广东美的白色家电技术创新中心有限公司 System for restraining electromagnetic interference of refrigerant radiator and household appliance
AU2020208193A1 (en) 2019-01-14 2021-07-29 BioNTech SE Methods of treating cancer with a PD-1 axis binding antagonist and an RNA vaccine
BR112021014845A2 (en) 2019-01-31 2021-11-03 Modernatx Inc Lipid Nanoparticle Preparation Methods
MA55037A (en) 2019-02-20 2021-12-29 Modernatx Inc RNA POLYMERASE VARIANTS FOR CO-TRANSCRIPTIONAL STYLING
MX2021011031A (en) 2019-03-11 2021-12-10 Modernatx Inc Fed-batch in vitro transcription process.
US20220241399A1 (en) 2019-03-15 2022-08-04 Moderna TX, Inc. Hiv rna vaccines
US20220162618A1 (en) 2019-03-25 2022-05-26 Ohio State Innovation Foundation Engineered mrna sequences and uses thereof
EP3976057A4 (en) 2019-05-31 2023-08-30 ModernaTX, Inc. Expanded t cell assay
EP3986480A1 (en) 2019-06-24 2022-04-27 ModernaTX, Inc. Messenger rna comprising functional rna elements and uses thereof
CN110378000B (en) 2019-07-11 2020-11-24 上海理工大学 Structural static strength design method based on strength field
CA3149498A1 (en) 2019-08-14 2021-02-18 Modernatx, Inc. Processes for purifying downstream products of in vitro transcription
CA3150458A1 (en) 2019-08-14 2021-02-18 Acuitas Therapeutics, Inc. Improved lipid nanoparticles for delivery of nucleic acids
WO2021050864A1 (en) 2019-09-11 2021-03-18 Modernatx, Inc. Human cytomegalovirus vaccine
JP2022548957A (en) 2019-09-19 2022-11-22 モデルナティエックス インコーポレイテッド CAP GUIDE AND ITS USE FOR RNA MAPPING
GB201915905D0 (en) 2019-11-01 2019-12-18 Spybiotech Ltd Viruses with modified capsid proteins
US20230007597A1 (en) 2019-12-02 2023-01-05 Beijing Xiaomi Mobile Software Co., Ltd. Safety control method and apparatus
MX2022007680A (en) 2019-12-20 2022-09-26 Curevac Ag Lipid nanoparticles for delivery of nucleic acids.
EP4085130A4 (en) 2019-12-31 2024-04-10 Elixirgen Therapeutics Inc Temperature-based transient delivery of nucleic acids and proteins to cells and tissues
EP4088281A4 (en) 2020-01-10 2024-02-21 Modernatx Inc Variational autoencoder for biological sequence generation
WO2021147025A1 (en) 2020-01-22 2021-07-29 The University Of Hong Kong-Shenzhen Hospital Anti 2019-ncov vaccine
US10953089B1 (en) 2020-01-27 2021-03-23 Novavax, Inc. Coronavirus vaccine formulations
MX2022009167A (en) 2020-01-27 2022-08-17 Novavax Inc Coronavirus vaccine formulations.
US20210228707A1 (en) 2020-01-28 2021-07-29 Modernatx, Inc. Coronavirus rna vaccines
KR20220133224A (en) 2020-01-28 2022-10-04 모더나티엑스, 인크. coronavirus RNA vaccine
KR20220133911A (en) 2020-01-30 2022-10-05 모더나티엑스, 인크. Respiratory Virus Immunization Composition
KR20220134622A (en) 2020-01-31 2022-10-05 베쓰 이스라엘 디코니스 메디칼 센터 인크 Compositions and methods for preventing and treating coronavirus infection - SARS-COV-2 vaccine
WO2021155760A1 (en) 2020-02-03 2021-08-12 康希诺生物股份公司 Mrna vaccine for 2019-ncov coronavirus, preparation method and application thereof
US11576966B2 (en) 2020-02-04 2023-02-14 CureVac SE Coronavirus vaccine
EP3886897A1 (en) 2020-02-04 2021-10-06 CureVac AG Coronavirus vaccine
US11241493B2 (en) 2020-02-04 2022-02-08 Curevac Ag Coronavirus vaccine
WO2021155733A1 (en) 2020-02-05 2021-08-12 复旦大学 Polypeptide, and preparation method therefor and use thereof
EP4100066A4 (en) * 2020-02-07 2024-05-01 Rnaimmune Inc Composition and method of mrna vaccines against novel coronavirus infection
AU2021215938A1 (en) 2020-02-07 2022-09-01 Modernatx, Inc. Sars-cov-2 mrna domain vaccines
CN111592602B (en) 2020-02-10 2021-03-02 中国科学院微生物研究所 Beta coronavirus antigen, preparation method and application thereof
JP2023513693A (en) 2020-02-11 2023-04-03 ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ SARS-CoV-2 vaccine
US20230293630A1 (en) 2020-02-12 2023-09-21 La Jolla Institute For Immunology Coronavirus T Cell Epitopes and Uses Thereof
CN113186203B (en) 2020-02-13 2022-12-30 斯微(上海)生物科技股份有限公司 Vaccine agent for treating or preventing coronavirus diseases
CA3167611A1 (en) * 2020-02-13 2021-08-19 Etienne Simon-Loriere Nucleic acid vaccine against the sars-cov-2 coronavirus
CN116472279A (en) 2020-02-13 2023-07-21 巴斯德研究院 Measles carrier covd-19 immunogenic compositions and vaccines
WO2021163456A1 (en) 2020-02-14 2021-08-19 Epivax, Inc. T cell epitopes and related compositions useful in the prevention, diagnosis, and treatment of covid-19
GB2594683A (en) 2020-02-17 2021-11-10 Vaxbio Ltd Vaccine
CN111303254A (en) 2020-02-20 2020-06-19 北京新创生物工程有限公司 Novel coronavirus (SARS-CoV-2) antigen detection kit
WO2021000969A2 (en) 2020-02-23 2021-01-07 广州恩宝生物医药科技有限公司 Nucleic acid sequence expressing sars-cov-2 virus antigen peptide and use thereof
CN110974950B (en) 2020-03-05 2020-08-07 广州恩宝生物医药科技有限公司 Adenovirus vector vaccine for preventing SARS-CoV-2 infection
CN110951756B (en) 2020-02-23 2020-08-04 广州恩宝生物医药科技有限公司 Nucleic acid sequence for expressing SARS-CoV-2 virus antigen peptide and its application
CN112300251B (en) 2020-02-24 2022-04-05 成都威斯克生物医药有限公司 Protein and vaccine for anti SARS-CoV-2 infection
CN111218458B (en) 2020-02-27 2020-11-20 珠海丽凡达生物技术有限公司 mRNAs encoding SARS-CoV-2 virus antigen and vaccine and preparation method of vaccine
US20230110516A1 (en) 2020-03-01 2023-04-13 Dynavax Technologies Corporation Coronavirus vaccines comprising a tlr9 agonist
US11213482B1 (en) 2020-03-05 2022-01-04 University of Pittsburgh—Of the Commonwealth System of Higher Educat SARS-CoV-2 subunit vaccine and microneedle array delivery system
US20210332085A1 (en) 2020-03-05 2021-10-28 Swey-Shen Chen CoV-2 (CoV-n) antibody neutralizing and CTL vaccines using protein scaffolds and molecular evolution
WO2021178637A1 (en) 2020-03-05 2021-09-10 Iowa State University Research Foundation, Inc. IMMUNOGENIC AND VACCINE COMPOSITIONS AGAINST SARS-CoV-2
JP2023519173A (en) 2020-03-09 2023-05-10 アークトゥラス・セラピューティクス・インコーポレイテッド Compositions and methods for inducing an immune response
US20220016234A1 (en) 2020-03-11 2022-01-20 Immunitybio, Inc. Anti covid-19 therapies using nucleocapsid and spike proteins
CA3171939A1 (en) 2020-03-13 2021-09-16 Oxford University Innovation Limited Compositions and methods for inducing an immune response
CN111218459B (en) 2020-03-18 2020-09-11 中国人民解放军军事科学院军事医学研究院 Recombinant novel coronavirus vaccine taking human replication-defective adenovirus as vector
US20230136960A1 (en) 2020-03-19 2023-05-04 Nature's Toolbox, Inc. Novel MRNA-Based COVID-19 Multi-Valent Vaccine and Methods of Scaled Production of the Same
CN111088283B (en) 2020-03-20 2020-06-23 苏州奥特铭医药科技有限公司 mVSV viral vector, viral vector vaccine thereof and mVSV-mediated novel coronary pneumonia vaccine
CN111560074B (en) 2020-03-20 2021-07-09 中山大学 Novel coronavirus S protein single-region subunit nano vaccine based on helicobacter pylori ferritin
KR20230004508A (en) 2020-03-20 2023-01-06 비온테크 에스이 Coronavirus vaccine and how to use it
WO2021189056A2 (en) 2020-03-20 2021-09-23 Kansas State University Research Foundation Sars-coronavirus 2 (sars-cov-2) subunit vaccine candidates
WO2021194826A2 (en) 2020-03-24 2021-09-30 Icahn School Of Medicine At Mount Sinai Recombinant sars-cov-2 spike protein and uses thereof
GB202004493D0 (en) 2020-03-27 2020-05-13 Imp College Innovations Ltd Coronavirus vaccine
JPWO2021200800A1 (en) 2020-03-30 2021-10-07
US11559577B2 (en) 2020-03-31 2023-01-24 Engimata, Inc. Immunogenic composition forming a vaccine, and a method for its manufacture
WO2021201612A1 (en) 2020-03-31 2021-10-07 주식회사 에스엘백시젠 Novel vaccine composition for prevention and treatment of coronavirus
US11278617B2 (en) 2020-03-31 2022-03-22 Engimata, Inc Immunogenic composition forming a SARS-CoV-2 vaccine, and a method for its manufacture
US20230226169A1 (en) 2020-04-01 2023-07-20 University Of Florida Research Foundation Incorporated Multilamellar rna nanoparticle vaccine against sars-cov-2
CA3179038A1 (en) 2020-04-01 2021-10-07 Diosynvax Ltd Coronavirus vaccines
WO2021202599A2 (en) 2020-04-01 2021-10-07 Valiant Biosciences, Llc Adeno-associated virus based compositions and related methods for inducing humoral immunity
TW202202169A (en) 2020-04-02 2022-01-16 中央研究院 Biodegradable nanocomplex vaccines, methods for prevention of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection
CN111748557B (en) 2020-04-03 2022-03-11 苏州吉玛基因股份有限公司 Small interfering nucleic acid for inhibiting novel coronavirus, composition and application
WO2021203044A2 (en) 2020-04-03 2021-10-07 Icahn School Of Medicine At Mount Sinai High-throughput assay for circulating antibodies against severe acute respiratory syndrome coronavirus 2
CA3174505A1 (en) 2020-04-03 2021-10-07 Zsolt CSISZOVSZKI Coronavirus vaccine
GB202004974D0 (en) 2020-04-03 2020-05-20 Treos Bio Ltd Coronavirus vaccine
RU2747762C1 (en) 2020-04-05 2021-05-13 Илья Владимирович Духовлинов Vaccine for the prevention or treatment of coronavirus infection based on a genetic construct
CN112023035A (en) 2020-04-07 2020-12-04 中国医学科学院医学生物学研究所 Nano vaccine taking S protein RBD region of SARS-CoV-2 virus as antigen and preparation thereof
US20230321218A1 (en) 2020-04-07 2023-10-12 Ramot At Tel-Aviv University Ltd. Sars-cov2 coronavirus reconstituted rbm and uses thereof
TW202204622A (en) 2020-04-09 2022-02-01 大陸商蘇州艾博生物科技有限公司 Nucleic acid vaccines for coronavirus
US20230310582A1 (en) 2020-04-14 2023-10-05 Duke University Sars-2 spike protein designs, compositions and methods for their use
EP4135765A4 (en) 2020-04-14 2024-05-08 Univ California Pan-coronavirus vaccine compositions
US20230146256A1 (en) 2020-04-17 2023-05-11 Regents Of The University Of Minnesota SARS-CoV-2 SPIKE RECEPTOR BINDING DOMAIN AND COMPOSITIONS AND METHODS THEREOF
WO2021209824A1 (en) 2020-04-17 2021-10-21 Institut Pasteur Methods and products for serological analysis of sars-cov-2 infection
WO2021210686A1 (en) 2020-04-17 2021-10-21 Vlp Therapeutics, Inc. Coronavirus vaccine
WO2021214081A2 (en) 2020-04-20 2021-10-28 Nec Oncoimmunity As Sars-cov-2 vaccines
WO2021216738A2 (en) 2020-04-21 2021-10-28 Intima Bioscience, Inc. Compositions and methods of generating an immune response
EP4138893A1 (en) 2020-04-21 2023-03-01 Intima Bioscience, Inc. Cellular vaccine platform and methods of use
US20230143228A1 (en) 2020-04-21 2023-05-11 Emory University Coronavirus vaccines, compositions, and methods related thereto
WO2021212568A1 (en) 2020-04-21 2021-10-28 苏州方科生物科技有限公司 Novel coronavirus specific antigen peptide and use thereof
GB2594365B (en) 2020-04-22 2023-07-05 BioNTech SE Coronavirus vaccine
CN115843330A (en) 2020-04-22 2023-03-24 辉瑞公司 Coronavirus vaccine
US20220048954A1 (en) 2020-04-24 2022-02-17 Salk Institute For Biological Studies Sars-cov2 vaccine vector methods and compositions
WO2021222304A1 (en) 2020-04-27 2021-11-04 Modernatx, Inc. Sars-cov-2 rna vaccines
KR102482994B1 (en) 2020-04-29 2022-12-29 에스케이바이오사이언스(주) Vaccine composition for preventing or treating infection of SARS-CoV-2
IT202000009625A1 (en) 2020-04-30 2021-10-30 Takis S R L SARS-COV-2 ANTIGEN CODING POLYNUCLEOTIDES AND RELATED USE IN THE MEDICAL FIELD AS VACCINES.
WO2021223647A1 (en) 2020-05-06 2021-11-11 The University Of Hong Kong Compositions and methods for making and using vaccines against covid-19
WO2021224946A1 (en) 2020-05-07 2021-11-11 Bharat Biotech International Limited Coronavirus vaccine through nasal immunization
EP4146265A1 (en) * 2020-05-07 2023-03-15 Translate Bio, Inc. Optimized nucleotide sequences encoding sars-cov-2 antigens
EP4105228A4 (en) 2020-05-11 2023-10-11 Hengda Biomedical Technology Co., Ltd. Sars-cov-2 antigen polypeptide, recombinant adeno-associated virus thereof, and application in preparation of vaccine
CN111518175B (en) 2020-05-11 2021-02-26 广东珩达生物医药科技有限公司 SARS-COV-2 antigen polypeptide and its recombinant adeno-associated virus and application in preparing vaccine
EP4149540A1 (en) 2020-05-12 2023-03-22 Greffex, Inc. Engineering coronavirus spike proteins as vaccine antigens, their design and uses
US20230142529A1 (en) 2020-05-15 2023-05-11 Modernatx, Inc. Rna formulations for high volume distribution
WO2021159130A2 (en) 2020-05-15 2021-08-12 Modernatx, Inc. Coronavirus rna vaccines and methods of use
US20210355170A1 (en) 2020-05-18 2021-11-18 The Regents Of The University Of Colorado, A Body Corporate Stabilizing Mutants of Prefusion Sars-Cov-2 (Covid-19) Spike Protein And Improved Yeast Surface Display Engineering Platform For The Same
EP4153139A1 (en) 2020-05-21 2023-03-29 Vaxess Technologies, Inc. Compositions and devices for vaccine release and uses thereof
CN111363858B (en) 2020-05-26 2020-09-29 南京黎明生物制品有限公司 2019-nCoV S gene detection nucleic acid composition, kit and production method
BR112022023591A2 (en) 2020-05-29 2022-12-27 Univ Texas MODIFIED CORONAVIRUS SPIKE(S) PROTEIN AND METHODS OF USE THEREOF
EP3993828A1 (en) 2020-05-29 2022-05-11 CureVac AG Nucleic acid based combination vaccines
WO2021253172A1 (en) 2020-06-15 2021-12-23 上海市公共卫生临床中心 Method for inducing anti-novel coronavirus neutralizing antibody using receptor recognition domain
US10906944B2 (en) 2020-06-29 2021-02-02 The Scripps Research Institute Stabilized coronavirus spike (S) protein immunogens and related vaccines
WO2022003119A1 (en) 2020-07-01 2022-01-06 CEBINA GmbH Cross-reactive coronavirus vaccine
GB2596820A (en) 2020-07-07 2022-01-12 Spicona Inc Combination vaccine
US20230248818A1 (en) 2020-07-08 2023-08-10 The Trustees Of The University Of Pennsylvania Nucleoside-modified RNA for Inducing an Immune Response Against SARS-CoV-2
CN111978377B (en) 2020-07-09 2022-05-31 苏州和锐生物科技有限公司 COVID-19 antigen, preparation method and application
EP4178545A2 (en) 2020-07-10 2023-05-17 Engimata, Inc Immunogenic composition forming a vaccine, and a method for its manufacture
CN112043825B (en) 2020-07-13 2023-12-05 中国医学科学院医学生物学研究所 Subunit vaccine for preventing novel coronavirus infection based on novel coronavirus spike protein S1 region
CN111848753B (en) 2020-07-20 2022-03-15 中国科学院过程工程研究所 Novel coronavirus epitope and application thereof
RU2733834C1 (en) 2020-07-28 2020-10-07 Федеральное бюджетное учреждение науки Государственный научный центр вирусологии и биотехнологии "Вектор" Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека (ФБУН ГНЦ ВБ "Вектор" Роспотребнадзора) Artificial ectos_sc2 gene encoding an ectodomain of the sars-cov-2 coronavirus s glycoprotein with a c-terminal trimerization domain, a recombinant plasmid pstem-rvsv-ectos_sc2, which provides expression of the artificial gene, and a recombinant strain of vesicular stomatitis virus rvsv-ectos_sc2, used to create a vaccine against sars-cov-2 coronavirus
CN112028976A (en) 2020-08-05 2020-12-04 上海裕隆生物科技有限公司 2019 novel coronavirus spike protein receptor binding domain protein and application
CN111939250B (en) 2020-08-17 2022-07-29 郑州大学 Vaccine for preventing COVID-19 and preparation method thereof
RU2731356C9 (en) 2020-08-22 2021-10-05 федеральное государственное бюджетное учреждение "Национальный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи" Министерства здравоохранения Российской Федерации Expression vector for creating immunobiological agent for inducing specific immunity to virus of severe acute respiratory syndrome sars-cov-2 (embodiments)
RU2731342C9 (en) 2020-08-22 2021-10-05 федеральное государственное бюджетное учреждение "Национальный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи" Министерства здравоохранения Российской Федерации Pharmaceutical agent and method for use thereof for inducing specific immunity to virus of severe acute respiratory syndrome sars-cov-2 (embodiments)
EP4157344A2 (en) 2020-08-31 2023-04-05 CureVac SE Multivalent nucleic acid based coronavirus vaccines
CN112048005B (en) 2020-09-04 2022-09-09 江苏省中国科学院植物研究所 Novel coronavirus S protein fragment polyploid, preparation method thereof, detection kit, vaccine and medicament
IL301503A (en) 2020-09-23 2023-05-01 Yeda res & development co ltd Methods and compositions for treating coronaviral infections
CN112094327A (en) 2020-09-25 2020-12-18 军事科学院军事医学研究院军事兽医研究所 Truncation body based on novel coronavirus RBD-SD1 protein and application thereof
CN112266411B (en) 2020-09-25 2022-06-24 北京诺思兰德生物技术股份有限公司 Novel coronavirus vaccine and application thereof
CA3128660A1 (en) 2020-10-09 2022-04-09 Eric G. Marcusson Compositions and methods for the prevention and/or treatment of covid-19
CN112226445B (en) 2020-10-20 2021-05-11 成都欧林生物科技股份有限公司 Nucleic acid for coding spike protein of SARS-CoV-2 virus and its application
CN112358533B (en) 2020-10-30 2023-07-14 上海泽润生物科技有限公司 Recombinant spike protein and preparation method and application thereof
CN112220920B (en) 2020-10-30 2023-06-13 上海泽润生物科技有限公司 Recombinant novel coronavirus vaccine composition
US20240041785A1 (en) 2020-11-16 2024-02-08 BioNTech SE Compositions and methods for stabilization of lipid nanoparticle mrna vaccines
EP4034548A4 (en) 2020-11-30 2023-06-28 Guangzhou Argorna Biopharmaceuticals Co., Ltd. Coronavirus vaccines and uses thereof
CN112480217B (en) 2020-11-30 2022-04-08 广州阿格纳生物医药制造有限公司 Vaccines and compositions based on S antigen protein of SARS-CoV-2
CN112626089B (en) 2020-12-08 2022-03-11 杭州百凌生物科技有限公司 SARS-CoV-2 virus S protein receptor binding region coding gene, antibody and application
WO2022131832A1 (en) 2020-12-16 2022-06-23 주식회사 에스엘백시젠 Novel vaccine composition for prevention and treatment of coronavirus
WO2022137133A1 (en) 2020-12-22 2022-06-30 Curevac Ag Rna vaccine against sars-cov-2 variants
KR20230164648A (en) 2020-12-22 2023-12-04 큐어백 에스이 RNA vaccines against SARS-CoV-2 variants
CN112794884B (en) 2020-12-28 2022-02-18 中国科学院微生物研究所 Novel coronavirus protein, preparation method and neutralizing antibody detection kit
CN112321688B (en) 2021-01-06 2021-03-26 广东华南疫苗股份有限公司 Stable coronavirus recombinant protein dimer and expression vector thereof
AU2022207495A1 (en) 2021-01-15 2023-08-03 Modernatx, Inc. Variant strain-based coronavirus vaccines
BR112023017984A2 (en) 2021-03-08 2023-11-14 Eyegene Inc VACCINE COMPOSITION FOR PREVENTION OF SARS-COV-2
WO2022192594A2 (en) 2021-03-11 2022-09-15 Sorrento Therapeutics, Inc. Nucleic acid molecules and vaccines comprising same for the prevention and treatment of coronavirus infections and disease
WO2022197720A2 (en) 2021-03-15 2022-09-22 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for treating coronavirus infection
MX2021003199A (en) 2021-03-18 2022-09-19 Centro De Investig Y De Estudios Avanzados Del I P N Vaccines to prevent covid-19 based on non-glycosylated sites of the receptor binding domain (rbd) of the s protein of the sars-cov-2 virus.
WO2022212659A1 (en) 2021-03-31 2022-10-06 The Trustees Of The University Of Pennsylvania Multi-genic mrna vaccine compositions and methods of use
CA3197160A1 (en) 2021-04-12 2022-10-20 Academia Sinica Messenger rna vaccines against wide spectrum of coronavirus variants
AU2022258335A1 (en) 2021-04-13 2023-11-23 Modernatx, Inc. Respiratory virus combination vaccines
JP2024513999A (en) 2021-04-14 2024-03-27 モデルナティエックス インコーポレイテッド Influenza-coronavirus combination vaccine
BR112023021654A2 (en) 2021-04-20 2023-12-26 BioNTech SE VIRUS VACCINE
JP2024517780A (en) 2021-05-03 2024-04-23 ファイザー・インク Vaccination against bacterial and betacoronavirus infections
CA3226213A1 (en) 2021-07-13 2023-01-19 Gennova Biopharmaceuticals Ltd. Rna adsorbed onto lipid nano-emulsion particles and its formulations.
WO2023004415A2 (en) 2021-07-22 2023-01-26 University Of Miami Sars-cov-2 vaccine using bacterial spores expressing antigenic fragments
WO2023044346A2 (en) 2021-09-14 2023-03-23 Ausper Biopharma Co., Ltd. Vaccines for coronavirus prevention and treatment
TW202330020A (en) 2021-09-22 2023-08-01 美商百歐恩泰美國公司 Coronavirus vaccines and methods of use
CN116940685A (en) 2021-10-08 2023-10-24 苏州艾博生物科技有限公司 Coronavirus multivalent nucleic acid vaccine based on sequences derived from SARS-CoV-2Beta and Delta strains
TW202334198A (en) 2021-10-12 2023-09-01 聯亞生技開發股份有限公司 Vaccine compositions against sars-cov-2 omicron ba.4/ba.5 to prevent infection and treat long-haul covid
WO2023064907A1 (en) 2021-10-15 2023-04-20 Yale University Compositions and methods for vaccination against pathogenic coronavirus species and variants
WO2023073190A1 (en) * 2021-10-28 2023-05-04 BioNTech SE Rna constructs and uses thereof
EP4183409A1 (en) 2021-11-17 2023-05-24 Charité - Universitätsmedizin Berlin Vaccine with improved immunogenicity against mutant coronaviruses
TW202333780A (en) 2021-11-29 2023-09-01 德商拜恩技術股份公司 Coronavirus vaccine
WO2023102448A2 (en) 2021-11-30 2023-06-08 Novavax, Inc. Coronavirus vaccine formulations
CN117580587A (en) 2021-12-03 2024-02-20 苏州艾博生物科技有限公司 Coronavirus nucleic acid vaccine based on sequences derived from SARS-CoV-2 Omikovia strain
WO2023111725A1 (en) 2021-12-14 2023-06-22 Janssen Pharmaceuticals, Inc. Sars-cov-2 vaccines
WO2023137550A1 (en) 2022-01-21 2023-07-27 Providence Therapeutics Holdings Inc. Compositions and methods for the prevention and/or treatment of covid-19
CN116549625A (en) 2022-01-27 2023-08-08 四川三叶草生物制药有限公司 Coronavirus vaccine compositions, methods and uses thereof
CN114150004B (en) 2022-02-09 2022-04-22 广州恩宝生物医药科技有限公司 Nucleic acid sequence for expressing SARS-CoV-2 Ormcken mutant strain virus antigen peptide and its application
CN114150005B (en) 2022-02-09 2022-04-22 广州恩宝生物医药科技有限公司 Adenovirus vector vaccine for prevention of SARS-CoV-2 Oncuronjorn strain
WO2023150838A1 (en) 2022-02-11 2023-08-17 The University Of Melbourne Coronavirus vaccination regimen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NONE CITED. *

Also Published As

Publication number Publication date
WO2024002985A1 (en) 2024-01-04
US11878055B1 (en) 2024-01-23

Similar Documents

Publication Publication Date Title
DE112021000012B4 (en) Coronavirus Vaccine
US11771652B2 (en) Lipid nanoparticles for delivering mRNA vaccines
ES2806412T3 (en) Signal for packaging of influenza virus vectors
US11155583B2 (en) Stabilized soluble pre-fusion RSV F proteins
KR101280094B1 (en) Novel vaccine containing adjuvant capable of inducing mucosal immunity
EP4226938A2 (en) Coronavirus vaccine
WO2022110099A1 (en) Coronavirus vaccines and uses thereof
WO2023147092A9 (en) Coronavirus vaccine
WO2023015332A1 (en) Vaccine antigen
JP2024020214A (en) chimera vector
US11878055B1 (en) Coronavirus vaccine
US20230105376A1 (en) Piv5-based coronavirus vaccines and methods of use thereof
EP4295862A2 (en) Coronavirus vaccine
GB2620028A (en) Coronavirus vaccine
CN117899208A (en) Coronavirus vaccine
WO2024083178A1 (en) Gene of interest rna formulations
US20230338512A1 (en) Coronavirus vaccine
WO2024086575A1 (en) Combination vaccines against coronavirus infection, influenza infection, and/or rsv infection
CN118043451A (en) Vaccine antigens
WO2024102923A1 (en) Low dose vaccine compositions

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

AS Assignment

Owner name: BIONTECH SE, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PFIZER INC.;REEL/FRAME:065740/0115

Effective date: 20231006

Owner name: BIONTECH SE, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIONTECH US INC.;REEL/FRAME:065740/0109

Effective date: 20230811

Owner name: BIONTECH US INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PORAN, ASAF;REEL/FRAME:065740/0095

Effective date: 20230727

Owner name: PFIZER INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SWANSON, KENA ANNE;YANG, QI;CAI, HUI;AND OTHERS;SIGNING DATES FROM 20220712 TO 20230622;REEL/FRAME:065775/0977

Owner name: BIONTECH SE, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MUIK, ALEXANDER;SAHIN, UGUR;SIGNING DATES FROM 20231030 TO 20231115;REEL/FRAME:065740/0040

STCF Information on status: patent grant

Free format text: PATENTED CASE