WO2023173032A2 - Recombinant newcastle disease viruses and immunogenic compositions for use in preventing covid-19 - Google Patents

Recombinant newcastle disease viruses and immunogenic compositions for use in preventing covid-19 Download PDF

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WO2023173032A2
WO2023173032A2 PCT/US2023/064063 US2023064063W WO2023173032A2 WO 2023173032 A2 WO2023173032 A2 WO 2023173032A2 US 2023064063 W US2023064063 W US 2023064063W WO 2023173032 A2 WO2023173032 A2 WO 2023173032A2
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amino acid
acid sequence
protein
seq
cov
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WO2023173032A3 (en
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Peter Palese
Adolfo Garcia-Sastre
Florian KRAMMER
Weina SUN
Irene GONZALEZ DOMINGUEZ
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Icahn School of Medicine at Mount Sinai
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Icahn School of Medicine at Mount Sinai
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Priority to KR1020247033613A priority patent/KR20240161963A/ko
Priority to CN202380026690.5A priority patent/CN119317446A/zh
Priority to AU2023231285A priority patent/AU2023231285A1/en
Priority to US18/845,323 priority patent/US20250186578A1/en
Priority to CA3245533A priority patent/CA3245533A1/en
Priority to EP23767708.3A priority patent/EP4489779A2/en
Priority to MX2024011049A priority patent/MX2024011049A/es
Publication of WO2023173032A2 publication Critical patent/WO2023173032A2/en
Publication of WO2023173032A3 publication Critical patent/WO2023173032A3/en
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    • 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
    • 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
    • A61K2039/525—Virus
    • A61K2039/5256—Virus expressing foreign proteins
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18111—Avulavirus, e.g. Newcastle disease virus
    • C12N2760/18141—Use of virus, viral particle or viral elements as a vector
    • C12N2760/18143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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

Definitions

  • recombinant NDV comprising a packaged genome, wherein the packaged genome comprises a transgene comprising a codon-optimized nucleic acid sequence encoding a protein comprising a spike protein of a SARS-CoV-2 or portion thereof (e.g., ectodomain or receptor binding domain of SARS-CoV-2 spike protein).
  • the packaged genome comprises a transgene encoding a chimeric F protein, wherein the chimeric F protein comprises a spike protein ectodomain of a SARS-CoV-2 and NDV F protein transmembrane and cytoplasmic domains.
  • the nucleotide sequence is an RNA sequence. In some embodiments, the nucleotide sequence is a DNA sequence (e.g., cDNA). In some embodiments, the nucleotide sequence is present in a vector (e.g., a plasmid or virus). In some embodiments, provided herein are immunogenic compositions comprising such a nucleotide sequence. In some embodiments, the immunogenic compositions comprise two or more nucleotide sequences described herein (e.g., the immunogenic compositions are bivalent or multivalent).
  • a derivative of a SARS-CoV-2 ectodomain comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 12, 13, 16, 17, 23, 24, 29, or 30.
  • the ectodomain of the SARS-CoV-2 spike protein or a derivative thereof is encoded by a codon-optimized nucleic acid sequence.
  • the NDV F protein transmembrane and cytoplasmic domains are of the LaSota strain or Hitchner strain.
  • the NDV F protein transmembrane and cytoplasmic domains comprise SEQ ID NO:42.
  • the derivative(s) of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain comprises the following amino acid substitutions at amino acid residues corresponding to amino acid residues of GenBank Accession No. MN908947.3: F817P, A892P, A899P, A942P, K986P, and V987P.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:29 or 30.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • a multivalent immunogenic composition comprising: (a) a first recombinant NDV comprising a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; (b) a second recombinant NDV comprising a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; and (c) a third recombinant NDV comprising a third chimeric F protein, and wherein the third chimeric F protein comprises a third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV
  • the derivative(s) of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain comprises the following amino acid substitutions at amino acid residues corresponding to amino acid residues of GenBank Accession No. MN908947.3: F817P, A892P, A899P, A942P, K986P, and V987P.
  • the fourth recombinant NDV comprises a fourth chimeric F protein
  • the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:23 or 24, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:23 or 24.
  • the nucleotide sequence encoding the chimeric F protein is codon optimized.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 85% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 90% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have 75% to 90% identity to each other.
  • the NDV F protein and cytoplasmic domains comprise the amino acid sequence of SEQ ID NO:42, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42.
  • an immunogenic composition comprising: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO:28 or 41, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least
  • an immunogenic composition comprising: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:22 or 39; and (b) a second recombinant ND V, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO:6 or 18, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least
  • an immunogenic composition comprising: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 11 or 40, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least
  • an immunogenic composition comprising: (a) a first recombinant NDV comprising a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:28 or 41, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:28 or 41; and (b) a second recombinant NDV comprising a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6, 18, 22, or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:6, 18, 22, or 39.
  • an immunogenic composition comprising: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO:28 or 41, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:28 or 41.
  • an immunogenic composition comprising: (a) a first recombinant NDV, wherein the first recombinant NDV a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 11 or 40, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11 or
  • a multivalent immunogenic composition comprising: (a) a first recombinant NDV comprising a first chimeric F protein, wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO:11 or 40, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV comprising a second chimeric F protein, wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 22 or 39, or an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid
  • substantially free of chemical precursors or other chemicals includes preparations in which the nucleic acid sequence, nucleotide sequence, or polynucleotide sequence is separated from chemical precursors or other chemicals which are involved in the synthesis of the nucleic acid sequence, nucleotide sequence, or polynucleotide sequence.
  • preparations of the nucleic acid sequence, nucleotide sequence, or polynucleotide sequence have less than about 50%, 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the nucleic acid sequence, nucleotide sequence, or polynucleotide sequence of interest.
  • the term “in combination” in the context of the administration of (a) therapy(ies) to a subject refers to the use of more than one therapy.
  • the use of the term “in combination” does not restrict the order in which therapies are administered to a subject.
  • a first therapy can be administered prior to, concomitantly with, or subsequent to the administration of a second therapy to a subject.
  • a typical spike protein comprises domains known to those of skill in the art including an SI domain, a receptor binding domain, an S2 domain, a transmembrane domain and a cytoplasmic domain. See, e.g., Wrapp et al., 2020, Science 367: 1260-1263 and Duan et al., 2020, Front. Immunol., Vol. 11, Article 576622 for a description of SARS-CoV-2 spike protein (in particular, the structure of such protein).
  • the spike protein may be characterized has having a signal peptide, a receptor binding domain, an ectodomain, an SI domain, an S2 domain, and a transmembrane and endodomain (or cytoplasmic).
  • the SARS-CoV-2 delta variant is of the AY.4, AY.25, AY.12, AY.3, AY.9, AY.3, AY.9, AY.5, AY.6, AY.20, AY.7.1, AY.23, AY.14, AY.10, AY.7, AY.13, AY.15, AY.16, AY.19, AY.2, AY.8, AY.11, AY. l, AY.21, AY.22, AY.7.2, AY.5.1, or AY.5.2 lineage.
  • the terms “SARS-CoV-2 mu variant spike protein” and “spike protein of SARS-CoV-2 mu variant” includes a SARS-CoV-2 mu variant spike protein known to those of skill in the art.
  • the SARS-CoV-2 mu variant spike protein may be a spike protein of the B.1.621, or B.1.621.1 lineage.
  • the terms “SARS-CoV-2 Omicron variant spike protein” and “spike protein of SARS-CoV-2 Omicron variant” includes a SARS-CoV-2 Omicron variant spike protein known to those of skill in the art.
  • the SARS-CoV-2 Omicron variant may be a spike protein of the B.1.1.529, BA.l, BA.1.1, BA.2, BA.3, BA.4 or BA.5 lineage.
  • FIGS. 4A-4D Trivalent and tetravalent NDV-HXP-S vaccination regimens induce protection against phylogenetically distant SARS-CoV-2 variants.
  • FIGS. 4A and 4B Design of the study and groups. Eight to ten-week old female BALB/c mice were used either vaccinated with 1 jug of total dose of inactivated NDV-HXP-S variant vaccines or WT NDV (negative control). Two immunizations were performed via the intramuscular route (IM) at DO and D21. At D44, mice were treated with Ad5-hACE2.
  • IM intramuscular route
  • mice were challenged with USA-WA1/2020, Delta (B.1.617.2) or Mu (B.1.621) strains and at day two after challenge, lungs were harvested and homogenized in 1 mL PBS and titers were measured by plaque assay.
  • Live trivalent NDV-HXP-S (SARS-CoV-2) vaccines induce broad antibody responses.
  • Mice were vaccinated intramuscularly with a trivalent NDV- HXP-S vaccine, a monovalent NDV-HXP-S (ancestral) vaccine, or wild type (WT) NDV as a negative control.
  • Mice were intramuscularly administered a prime dose of the trivalent vaccine, monovalent vaccine, or WT NDV and a boost dose twenty-one days later. Twenty- one days after the booster, mice were sacrificed to harvest blood and spleens to measure serum IgG levels as well as spike specific cl ass- switched memory B cells in the spleens.
  • Newcastle disease virus is a member of the Avulavirus genus in the Paramyxoviridae family, which has been shown to infect a number of avian species (Alexander, DJ (1988). Newcastle disease, Newcastle disease virus — an avian paramyxovirus. Kluwer Academic Publishers: Dordrecht, The Netherlands, pp 1-22). NDV possesses a single-stranded RNA genome in negative sense and does not undergo recombination with the host genome or with other viruses (Alexander, DJ (1988). Newcastle disease, Newcastle disease virus — an avian paramyxovirus. Kluwer Academic Publishers: Dordrecht, The Netherlands, pp 1-22).
  • any program that generates converts a nucleotide sequence to its reverse complement sequence may be utilized to convert a cDNA sequence encoding an NDV genome into the genomic RNA sequence (see, e.g., www.bioinformatics.org/sms/rev_comp.html, www.fr33.net/seqedit.php, and DNAStar). Accordingly, the nucleotide sequences provided in Tables 1-4, infra, may be readily converted to the negative-sense RNA sequence of the NDV genome by one of skill in the art.
  • the NDV that is engineered to comprise a transgene described herein is attenuated such that the NDV remains, at least partially, infectious and can replicate in vivo, but only generate low titers resulting in subclinical levels of infection that are non- pathogenic (see, e.g., Khattar et al., 2009, J. Virol. 83:7779-7782).
  • Such attenuated NDVs may be especially suited for embodiments wherein the virus is administered to a subject in order to act as an immunogen, e.g., a live vaccine.
  • the viruses may be attenuated by any method known in the art.
  • a polynucleotide sequence comprising: (1) a nucleotide sequence encoding NDV F, (2) a nucleotide sequence encoding NDV NP, (3) a nucleotide sequence encoding NDV P, (4) a nucleotide sequence encoding NDV M, (5) a nucleotide sequence encoding NDV HN, (6) a nucleotide sequence encoding NDV L, and (7) a transgene described herein.
  • a polynucleotide sequence comprising: (1) a nucleotide sequence encoding NDV F,
  • a recombinant NDV comprising a SARS- CoV-2 spike protein or a portion thereof (e.g., ectodomain or receptor binding domain of SARS-CoV-2 spike protein), or a derivative thereof.
  • recombinant ND V comprising a protein that comprises a SARS-CoV-2 spike protein ectodomain or a derivative thereof.
  • recombinant NDV comprising a protein that comprises a derivative of a SARS-CoV-2 spike protein ectodomain.
  • transgene comprising a nucleotide sequence encoding a protein comprising a SARS-CoV-2 Wuhan strain spike protein or portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain of the SARS-CoV-2 Wuhan spike protein).
  • a transgene comprising a nucleotide sequence encoding a protein comprising a SARS-CoV-2 beta variant spike protein or portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain of the SARS-CoV-2 beta variant spike protein) is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See, e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • a transgene comprising a nucleotide sequence encoding a protein comprising a SARS-CoV-2 Wuhan spike protein or portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain of the SARS-CoV-2 Wuhan spike protein) is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain).
  • sequence information to produce a transgene for incorporation into the genome of any NDV type or strain.
  • nucleic acid code there are a number of different polynucleotide sequences that may encode the same SARS-CoV-2 Wuhan strain spike protein or portion thereof (e.g., ectodomain, SI domain, S2 domain or receptor binding domain of the SARS-CoV-2 Wuhan strain spike protein).
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 gamma variant spike protein. In another specific embodiment, the SARS-CoV-2 spike protein is a SARS-CoV-2 Wuhan strain spike protein. In some embodiments, the SARS-CoV-2 is of the Bl.617.2 sublineage. In some embodiments, the SARS-CoV-2 is of the AY sublineage.
  • a fragment of the SARS-CoV-2 spike protein is at least 250, at least 500, at least 750, at least 1000, at least 1025, at least 1075, at least 1100, at least 1125, at least 1150, at least 1175, at least 1200, or at least 1215 amino acid residues in length.
  • Techniques known to one of skill in the art can be used to determine the percent identity between two amino acid sequences or between two nucleotide sequences.
  • Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389 3402.
  • PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.).
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the N-terminus substituted with another amino acid (e.g., a conservative amino acid substitution).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the N-terminus substituted with another amino acid (e.g., a conservative amino acid substitution).
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein receptor binding domain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the C-terminus of the receptor binding domain substituted with another amino acid (e.g., a conservative amino acid substitution).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein receptor binding domain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the C-terminus of the receptor binding domain substituted with another amino acid (e.g., a conservative amino acid substitution).
  • the N-terminus is the first 25 amino acid residues of the receptor binding domain of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein.
  • the C-terminus is the last 25 amino acid residues of the receptor binding domain of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein.
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 delta variant spike protein.
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 beta variant spike protein.
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 gamma variant spike protein. In another specific embodiment, the SARS-CoV-2 spike protein is a SARS-CoV-2 Wuhan strain spike protein.
  • conservative amino acid substitutions include, e.g., replacement of an amino acid of one class with another amino acid of the same class. In a particular embodiment, a conservative substitution does not alter the structure or function, or both, of a polypeptide.
  • MN908947.3 with amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 substituted with a single alanine, and amino acid residues corresponding to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of the following positions of GenBank Accession No. MN908947.3 substituted: 18, 19, 20, 26, 80, 138, 142, 156, 190, 215, 246, 417, 452, 478, 484, 501, 614, 655, 701, 950, and 1027.
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a derivative of the ectodomain of a SARS-CoV-2 spike protein, wherein the derivative comprises GenBank Accession No. NM908947.3 with (i) amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 substituted with a single alanine, (ii) amino acid substitutions corresponding to the following amino acid residues of GenBank Accession No.
  • the derivative of the SARS-CoV-2 spike protein ectodomain comprises the amino acid sequence of SEQ ID NO: 12 with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the following amino acid substitutions: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614N, H655Y, and T1027I.
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the N-terminus of the ectodomain substituted with another amino acid (e.g., a conservative amino acid substitution) and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the C-terminus of the ectodomain substituted with another amino acid (e.g., a conservative amino acid substitution).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids at the N-terminus of the ectodomain substituted with another amino acid (e.g., a conservative amino acid substitution) and 1, 2, 3, 4, 5,
  • a protein comprises the ectodomain of a SARS-CoV-2 delta variant spike protein (e.g., a SARS-CoV-2 delta variant spike polypeptide/protein) comprises one or more trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • a SARS-CoV-2 delta variant spike protein e.g., a SARS-CoV-2 delta variant spike polypeptide/protein
  • trimerization domains known to one of skill in the art
  • a tag e.g., a His tag or Flag tag
  • a transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 13.
  • a transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) an amino acid sequence at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 13.
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 12.
  • a transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) an amino acid sequence at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 12.
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) the amino acid sequence of SEQ ID NO: 16.
  • the protein further comprises one or more polypeptide domains.
  • the one or more polypeptide domains may be at the C-terminus, N-terminus, or C-terminus and N-terminus. In a specific embodiment, the one or more polypeptide domains are at the C-terminus.
  • Useful polypeptide domains include domains that facilitate purification, folding and cleavage of portions of a polypeptide.
  • a protein comprises further comprises one or more trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • a protein comprises further comprises one or more trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acid substitutions and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids deleted.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a protein that comprises the ectodomain of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike polypeptide further comprises one or more trimerization domains known to one of skill in the art (e.g., a T4 foldon trimerization domain), and optionally a tag (e.g., a His tag or Flag tag).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • trimerization domains known to one of skill in the art
  • a tag e.g., a His tag or Flag tag
  • amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 are substituted with a single alanine.
  • amino acid substitutions corresponding to the following amino acid residues of GenBank Accession No. MN908947.3 are substituted: F817P, A892P, A899P, A942P, K986P, and V987P.
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 delta variant spike protein.
  • the SARS-CoV-2 spike protein is a SARS-CoV-2 beta variant spike protein.
  • transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mutations (e.g., amino acid substitutions, amino acid deletions, amino acid additions, or a combination thereof).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mutations (e.g., amino acid substitutions, amino acid deletions, amino acid additions, or a combination thereof).
  • the one or more polypeptide domains may be at the C-terminus, N-terminus, or C-terminus and N-terminus. In a specific embodiment, the one or more polypeptide domains are at the C- terminus.
  • Useful polypeptide domains include domains that facilitate purification, folding and cleavage of portions of a polypeptide.
  • a His tag His-His-His-His-His-His-His (SEQ ID NO:44)
  • FLAG epitope or other purification tag can facilitate purification of the protein provided herein.
  • the His tag has the sequence, (His)n, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or greater.
  • a transgene comprising a nucleotide sequence encoding a protein, wherein the protein comprises a spike protein ectodomain that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 12, 13, 23 or 29 without the signal sequence.
  • a transgene comprising a nucleotide sequence encoding a protein, wherein the protein comprises a spike protein ectodomain that is at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 12, 13, 23 or 29 without the signal sequence.
  • GenBank or websites such as VIPR virus pathogen website Bioinformatics domain website (www.cbs.dtu.dk/services/TMHMM/) or programs available to determine the transmembrane domain may be used to determine the ectodomain, transmembrane and cytoplasmic domains of the SARS-CoV-2 spike protein and NDV F protein. See, e.g., Table 2, infra, with the transmembrane and cytoplasmic domains of NDV F protein indicated.
  • the linker may comprise the sequence of (GGGGS)n, wherein n is 1, 2, 3, 4, 5 or more (SEQ ID NO:45).
  • the linker may comprise (G)n, wherein n is 3, 4, 5, 6, 7, 8 or more.
  • the linker comprises the sequence GGGGS (SEQ ID NO:7).
  • the NDV F protein transmembrane and cytoplasmic domains are fused directly to the SARS-CoV-2 spike protein ectodomain.
  • the transgene encoding the chimeric F protein is codon optimized. See, e.g., Section 5.1.4, infra, for a discussion regarding codon optimization.
  • the derivative comprises amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 are substituted with a single alanine. See, e.g., Table 2, infra, with the transmembrane and cytoplasmic domains of NDV F protein indicated.
  • the derivative comprises amino acid substitutions corresponding to the following amino acid residues of GenBank Accession No. MN908947.3: F817P, A892P, A899P, A942P, K986P, and V987P.
  • the derivative comprises amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No.
  • the linker may comprise the sequence of (GGGGS)n, wherein n is 1, 2, 3, 4, 5 or more (SEQ ID NO:45).
  • the linker may comprise (G)n, wherein n is 3, 4, 5, 6, 7, 8 or more.
  • the linker comprises the sequence GGGGS (SEQ ID NO:7).
  • the NDV F protein transmembrane and cytoplasmic domains are fused to directly to the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain.
  • the transgene encoding the chimeric F protein is codon optimized.
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from a different NDV strain than the transcription units of the NDV genome.
  • the NDV genome is of the LaSota strain.
  • the transgene encoding a chimeric F protein may be incorporated between any two NDV transcription units (e.g., between the NDV P and M transcription units, between the NDV NP and P transcription units, or between the NDV HN and L transcription units).
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from the same NDV strain as the transcription units of the NDV genome.
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric protein are from a different NDV strain than the transcription units of the NDV genome.
  • the NDV genome is of the LaSota strain.
  • Classes of amino acids may include hydrophobic (Met, Ala, Vai, Leu, He), neutral hydrophilic (Cys, Ser, Thr), acidic (Asp, Glu), basic (Asn, Gin, His, Lys, Arg), conformation disruptors (Gly, Pro) and aromatic (Trp, Tyr, Phe).
  • a transgene encoding a chimeric F protein is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See., e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • the SARS-CoV- 2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain is fused to the NDV F protein transmembrane and cytoplasmic domains via a linker (e.g., GGGGS (SEQ ID NO: 7)).
  • the linker may be any linker that does not interfere with folding of the ectodomain, function of the ectodomain or both.
  • the linker is an amino acid sequence (e.g., a peptide) that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids long.
  • transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) a derivative of a SARS- CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more mutations (e.g., amino acid substitutions, amino acid deletions, amino acid additions, or a combination thereof), and NDV F protein transmembrane and cytoplasmic domains.
  • SARS- CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein ectodomain e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more mutations (e.g., amino acid substitutions, amino acid deletions, amino acid additions, or a combination thereof), and NDV F protein transmembrane and cytoplasmic
  • the derivative of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain lacks the polybasic cleavage site (e.g., one, two or more residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 are substituted for other amino acid residues).
  • the lack of a polybasic cleavage means that the polybasic site is altered such that it cannot be cleaved by, e.g., furin.
  • the derivative comprises the following amino acid substitutions at amino acid residues corresponding to amino acid residues of GenBank Accession No. MN908947.3: F817P, A892P, A899P, A942P, K986P, and V987P.
  • the derivative comprises an amino acid substitution at amino acid residues corresponding to amino acid residues 682 to 685 (RRAR) of GenBank Accession No. MN908947.3 with a single alanine, and the following amino acid substitutions at amino acid residues corresponding to amino acid residues of GenBank Accession No.
  • the linker is an amino acid sequence (e.g., a peptide) that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids long.
  • the linker is a glycine (G) linker or glycine and serine (GS) linker.
  • the linker may comprise the sequence of (GGGGS)n, wherein n is 1, 2, 3, 4, 5 or more (SEQ ID NO:45).
  • the linker may comprise (G)n, wherein n is 3, 4, 5, 6, 7, 8 or more.
  • the linker comprises the sequence GGGGS (SEQ ID NO:7).
  • the transgene encoding a chimeric F protein may be incorporated between any two NDV transcription units (e.g., between the NDV P and M transcription units, between the NDV NP and P transcription units, or between the NDV HN and L transcription units).
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from the same NDV strain as the transcription units of the NDV genome.
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from a different NDV strain than the transcription units of the NDV genome.
  • the NDV genome is of the LaSota strain.
  • the linker is a glycine (G) linker or glycine and serine (GS) linker.
  • the linker may comprise the sequence of (GGGGS)n, wherein n is 1, 2, 3, 4, 5 or more (SEQ ID NO:45).
  • the linker may comprise (G)n, wherein n is 3, 4, 5, 6, 7, 8 or more.
  • the linker comprises the sequence GGGGS (SEQ ID NO:7).
  • the NDV F protein transmembrane and cytoplasmic domains are fused directly to the derivative of the SARS- CoV-2 spike protein ectodomain.
  • the transgene encoding the chimeric F protein is codon optimized.
  • a transgene encoding a chimeric F protein is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See., e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • the transgene encoding a chimeric F protein may be incorporated between any two NDV transcription units (e.g., between the NDV P and M transcription units, between NDV NP and P transcription units, or between the NDV HN and L transcription units).
  • transgene comprising a nucleotide sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 5.
  • a transgene comprising a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO:5 or 43.
  • transgene comprising a nucleotide sequence that is at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 5 or 43.
  • a transgene comprising a nucleotide sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 5 without the signal sequence.
  • transgene comprising the nucleotide sequence of SEQ ID NO:43. In another embodiment, provided herein is a transgene comprising the nucleotide sequence of SEQ ID NO:5 without the signal sequence. In another embodiment, provided herein is a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO:6 or 18.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 6 without the signal sequence.
  • a transgene comprising a nucleotide sequence encoding a protein comprising (or consisting of) an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 6 without the signal sequence.
  • transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) an amino acid sequence that is at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 6 without the signal sequence.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:6.
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from a different NDV strain than the transcription units of the NDV genome.
  • the NDV genome is of the LaSota strain.
  • a transgene encoding a chimeric F protein is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See., e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein, wherein the chimeric F protein comprises (or consists of) a SARS-CoV-2 spike protein ectodomain and NDV F protein transmembrane and cytoplasmic domains, and wherein the SARS-CoV-2 spike protein ectodomain comprises amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 13, or SEQ ID NO: 13 without the signal sequence.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein, wherein the chimeric F protein comprises (or consists of) a SARS-CoV-2 spike protein ectodomain and NDV F protein transmembrane and cytoplasmic domains, and wherein the SARS-CoV-2 spike protein ectodomain comprises amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 17.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein, wherein the chimeric F protein comprises (or consists of) a SARS-CoV-2 spike protein ectodomain and NDV F protein transmembrane and cytoplasmic domains, and wherein the SARS-CoV-2 spike protein ectodomain comprises amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 13 without the signal peptide.
  • transgene comprising a nucleotide sequence that is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 19 or 33.
  • a transgene comprising a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 19 or 33.
  • a transgene comprising a nucleotide sequence that is at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the nucleotide sequence of SEQ ID NO: 19 without the signal sequence.
  • a transgene comprising a nucleotide sequence that is at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the nucleotide sequence of SEQ ID NO: 19 without the signal sequence.
  • a transgene comprising the nucleotide sequence of SEQ ID NO: 19.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:22.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:39.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:22 without the signal sequence.
  • transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) an amino acid sequence that is at least 97%, at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence of SEQ ID NO: 11 without the signal sequence.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO: 11.
  • transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:40.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) of the amino acid sequence of SEQ ID NO:11 without the signal sequence.
  • Methods/techniques known in the art may be used to determine sequence identity (see, e.g., “Best Fit” or “Gap” program of the Sequence Analysis Software Package, version 10; Genetics Computer Group, Inc.).
  • the NDV F protein transmembrane and cytoplasmic domains of the chimeric F protein are from a different NDV strain than the transcription units of the NDV genome.
  • the NDV genome is of the LaSota strain.
  • the derivative of the SARS-CoV-2 delta variant spike protein ectodomain comprises the amino acid sequence of SEQ ID NO: 12 with one, two, three, four, five, six, or all of the following amino acid modifications: T19R, G142D, R158G, L452R, T478K, D614G, P681R, and D950N.
  • the derivative of the SARS-CoV-2 delta variant spike protein ectodomain does not comprise the amino acid substitution of P681R.
  • a conservative substitution does not alter the structure or function, or both, of a polypeptide.
  • Classes of amino acids may include hydrophobic (Met, Ala, Vai, Leu, He), neutral hydrophilic (Cys, Ser, Thr), acidic (Asp, Glu), basic (Asn, Gin, His, Lys, Arg), conformation disruptors (Gly, Pro) and aromatic (Trp, Tyr, Phe).
  • a transgene encoding a chimeric F protein is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See., e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • a transgene comprising a nucleotide sequence encoding a chimeric F protein comprising (or consisting of) a derivative of a SARS- CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein ectodomain and NDV F protein transmembrane and cytoplasmic domains, wherein the derivative comprises a SARS-CoV-2 spike protein ectodomain with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids deleted and lacks a polybasic cleavage site (e.g., as a result of one, two, or more amino acid substitutions in polybasic cleavage site), and wherein amino acid residues corresponding to amino acid residues 817, 892, 899, 942, 986, and 987 of the spike protein found at GenBank Accession No.
  • SARS- CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • the derivative comprises
  • a transgene comprising a nucleotide sequence that can hybridize under high, moderate or typical stringency hybridization conditions to the nucleic acid sequence set forth in SEQ ID NO:37 or 38.
  • a transgene comprising a nucleotide sequence that can hybridize under high, moderate to typical stringency hybridization conditions to a nucleic acid sequence encoding the protein set forth in SEQ ID NO: 11.
  • a transgene comprising a nucleotide sequence that can hybridize under high, moderate to typical stringency hybridization conditions to a nucleic acid sequence encoding the protein set forth in SEQ ID NO:40.
  • a transgene that comprises a nucleotide sequence encoding a chimeric F protein, wherein the chimeric F protein comprises a derivative of a SARS-CoV-2 spike protein ectodomain and an NDV F protein transmembrane and cytoplasmic domains, wherein the derivative comprises an amino acid sequence that is at least 96%, at least 97%, or at least 98%, at least 99%, or at least 99.5% identical to the amino acid sequence set forth in SEQ ID NO: 12, 13, 16, 17, 23, 24, 29, or 30. See, e.g., Table 2, infra, with the transmembrane and cytoplasmic domains of NDV F protein indicated.
  • a transgene encoding a chimeric F protein is incorporated into the genome of any NDV type or strain (e.g., NDV LaSota strain). See., e.g., Section 5.1.1, supra, for types and strains of NDV that may be used.
  • the transgene encoding a chimeric F protein may be incorporated between any two NDV transcription units (e.g., between the NDV P and M transcription units, between the NDV NP and P transcription units, or between the NDV HN and L transcription units).
  • the spike protein of a SARS-CoV-2 variant comprises the following mutations: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, and T1027I.
  • the spike protein of a SARS-CoV-2 variant comprises one, two or more, or all of the following mutations: D80A, D2I5G, D241/242/243, K417N, E484K, N5Q1Y, D614G, and A701V.
  • the spike protein of a SARS-CoV-2 variant comprises the following mutations: D80A, D215G, D241/242/243, K417N, E484K, N501Y, D614G, and A701V.
  • the spike protein of a SARS-CoV-2 variant comprises one or both of the following mutations: L452R and D614G.
  • the spike protein of a SARS-CoV-2 variant comprises one, two or more, or all of the following mutations: SI 31, W152C, L452R, and D614G.
  • Table 5 SARS-CoV-2 Variants
  • Table 6 SARS-CoV-2 Variants (adapted from Sarkar et al., 2021, Arch Virol. 19: 1-12)
  • a transgene encoding a chimeric F protein is one described in the Example (Section 6), infra.
  • a transgene encodes a chimeric F protein described in FIG. 2A.
  • a transgene comprises a nucleotide sequence described in Table 3, infra.
  • a transgene encodes a protein comprising an amino acid sequence described in Table 3, infra.
  • a transgene encodes a chimeric F protein comprising an amino acid sequence described in Table 3, infra.
  • a protein e.g., a chimeric F protein
  • a transgene described herein e.g., a transgene described herein.
  • a chimeric F protein is one described in Section 6, infra (e.g., in FIG. 2A).
  • a chimeric F protein comprises an amino acid sequence described in Table 3, infra.
  • NDV F protein transmembrane and cytoplasmic domains of a chimeric F protein may be from any NDV strain known in the art or described herein.
  • NDV F protein transmembrane and cytoplasmic domains of a chimeric F protein may be from the NDV F protein of LaSota strain, Hitchner Bl strain, Fuller strain, Ulster strain, Roakin strain, or Komarov strain.
  • the NDV F protein transmembrane and cytoplasmic domains comprise the amino acid sequence of SEQ ID NO:42.
  • a transgene encoding a protein comprising (or consisting of) the ectodomain of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein comprises NDV regulatory signals (e.g., gene end, intergenic, and gene start sequences) and Kozak sequences.
  • a transgene encoding a protein comprising (or consisting of) a derivative of the ectodomain of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein comprises NDV regulatory signals (e.g., gene end, intergenic, and gene start sequences) and Kozak sequences.
  • a transgene encoding a chimeric F protein comprises NDV regulatory signals (e.g., gene end, intergenic, and gene start sequences) and Kozak sequences.
  • a transgene encoding a chimeric F protein comprises NDV regulatory signals (e.g., gene end, intergenic, and gene start sequences), Kozak sequences and restriction sites to facilitate cloning.
  • a transgene encoding a protein comprising (or consisting of) a SARS-CoV-2 spike protein or portion thereof e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein
  • NDV regulatory signals gene end, intergenic and gene start sequences
  • Kozak sequences restriction sites to facilitate cloning
  • additional nucleotides in the non-coding region to ensure compliance with the rule of six.
  • a transgene encoding a protein comprising (or consisting of) a derivative of a SARS-CoV-2 spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS- CoV-2 spike protein) comprises NDV regulatory signals (gene end, intergenic and gene start sequences), Kozak sequences, restriction sites to facilitate cloning, and additional nucleotides in the non-coding region to ensure compliance with the rule of six.
  • a transgene encoding a protein comprising (or consisting of) a derivative of the ectodomain of a SARS-CoV-2 spike protein comprises NDV regulatory signals (gene end, intergenic and gene start sequences), Kozak sequences, restriction sites to facilitate cloning, and additional nucleotides in the non-coding region to ensure compliance with the rule of six.
  • a transgene encoding a protein comprising (or consisting of) a chimeric F protein comprises NDV regulatory signals (gene end, intergenic and gene start sequences), Kozak sequences, restriction sites to facilitate cloning, and additional nucleotides in the non- coding region to ensure compliance with the rule of six.
  • the transgene complies with the rule of six.
  • provided herein is a protein encoded by a transgene describe herein. In some embodiments, provided herein is a chimeric F protein encoded by a transgene described herein. In some embodiments, provided herein is a protein comprising a SARS-CoV-2 spike protein ectodomain or derivative thereof (e.g., a SARS-CoV-2 spike protein ectodomain or derivative thereof described herein or known in the art). In some embodiments, provided herein is a protein comprising a derivative of a SARS-CoV-2 spike protein ectodomain (e.g., a derivative of a SARS-CoV-2 spike protein ectodomain described herein or known in the art).
  • the derivative of the SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12, 13, 16, 17, 23, 24, 29, or 30. In some embodiments, the derivative of the SARS-CoV-2 spike protein comprises an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 12, 13, 16, 17, 23, 24, 29, or 30. In some embodiments, provided herein is a chimeric F protein comprising the amino acid sequence of SEQ ID NO:6, 11, 18, 22, 28, 39, 40, or 41.
  • a chimeric F protein comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 6, 11, 18, 22, 28, 39, 40, or 41.
  • a derivative of a SARS-CoV-2 spike protein ectodomain includes (1) amino acid substitutions to prolines at amino acid positions 817, 892, 899, 942, 986, and 987 of the spike protein of the Wuhan strain, and (2) amino acids RRAR at positions corresponding to amino acid positions 682 to 685 of the spike protein of the Wuhan strain substituted for alanine.
  • NDV Newcastle disease virus
  • a recombinant NDV comprises a packaged genome, wherein the packaged genome comprises a transgene described herein.
  • a recombinant NDV comprises a packaged genome, wherein the packaged genome comprises a transgene encoding a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein).
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • transgenes encoding a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or portion thereof e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein
  • the transgene encoding a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or portion thereof e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein
  • transgenes encoding a SARS- CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein) which the packaged genome may comprise.
  • the transgene is one described in Section 5.1.2 or 6.
  • the SARS-CoV-2 spike protein or portion thereof e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein
  • a heterologous sequence encodes a protein that is not found associated with naturally-occurring NDV.
  • a recombinant NDV described herein comprises a packaged genome, wherein the genome comprises the genes found in NDV and a transgene encoding a SARS-CoV-2 spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein).
  • the recombinant NDV encodes for both NDV F protein and the SARS-CoV-2 spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein).
  • the genome of the recombinant NDV does not comprise a heterologous sequence encoding a heterologous protein other than a protein comprising (or consisting of) a SARS-CoV-2 variant spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein.
  • the genome of the recombinant NDV does not comprise a transgene other than a transgene encoding a protein comprising (or consisting of) a SARS-CoV-2 spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein).
  • a heterologous sequence encodes a protein that is not found associated with naturally-occurring NDV.
  • a recombinant NDV described herein comprises a packaged genome, wherein the genome comprises the genes found in NDV and a transgene encoding a protein comprising (or consisting of) a SARS-CoV-2 spike protein or portion thereof (e.g., the ectodomain, SI domain, S2 domain, or receptor binding domain of SARS-CoV-2 spike protein).
  • a recombinant NDV described herein comprises a packaged genome, wherein the genome comprises the genes found in NDV and a transgene encoding a protein comprising (or consisting of) a SARS-CoV-2 spike protein ectodomain or a derivative thereof, but does not include any other transgenes.
  • the packaged genome of recombinant NDV encodes a chimeric F protein described herein.
  • the genome of the recombinant NDV does not comprise a heterologous sequence encoding a heterologous protein other than the chimeric F protein.
  • a heterologous sequence encodes a protein that is not found associated with naturally-occurring NDV.
  • a NDV virion comprising a protein comprising (or consisting of) a derivative of a SARS-CoV-2 spike protein or a portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain thereof) described herein. See, e.g., Section 5.1.2 for examples of such a protein that may incorporated into the virion of a recombinant NDV.
  • the protein is one described in Section 5.1.2, supra.
  • the NDV virion is recombinantly produced.
  • a NDV virion comprising a chimeric F protein described herein (e.g., a chimeric F protein encoded by a transgene described herein). See, e.g., Section 5.1.2 and the Example (e.g., Section 6) for examples of a chimeric F protein that may incorporated into the virion of a recombinant NDV.
  • the chimeric F protein comprises an amino acid sequence that is at least 80%, at least 85%, or at least 90% identical to the amino acid sequence of SEQ ID NO: 6, 18, 22, 28, 39, 40, or 41.
  • the chimeric F protein comprises an amino acid sequence that is at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 6, 18, 22, 28, 39, 40, or 41. In a specific embodiment, the chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6, 18, 22, 28, 39, 40, or 41. In a specific embodiment, the chimeric F protein is one described in Section 5.1.2 or 6. In specific embodiments, the NDV virion is recombinantly produced.
  • a NDV virion comprising a chimeric F protein, wherein the chimeric F protein comprises a SARS-CoV-2 spike protein ectodomain or a derivative thereof and NDV F protein transmembrane and cytoplasmic domains.
  • a NDV virion comprising a chimeric F protein, wherein the chimeric F protein comprises a derivative of a SARS-CoV-2 spike protein ectodomain and NDV F protein transmembrane and cytoplasmic domains.
  • the derivative of the SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12, 13, 16, 17, 23, 24, 29, or 30.
  • a chimeric F protein described herein is in a pre-fusion conformation. In some embodiments, a chimeric F protein described herein is in a post- fusion conformation. 5.1.4 CODON OPTIMIZATION
  • Any codon optimization technique known to one of skill in the art may be used to codon optimize a nucleic acid sequence encoding a SARS-CoV-2 spike protein or a portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain thereof), a derivative of a SARS-CoV-2 spike protein or a portion thereof (e.g., ectodomain, SI domain, S2 domain, or receptor binding domain thereof), or a chimeric F protein.
  • Methods of codon optimization are known in the art, e.g., the OptimumGeneTM (GenScript®) protocol and Genewiz® protocol, which are incorporated by reference herein in its entirety. See also U.S. Patent No. 8,326,547 for methods for codon optimization, which is incorporated herein by reference in its entirety.
  • a nucleotide sequence encoding a heterologous amino acid sequence may be engineered into a NDV transcription unit so long as the insertion does not affect the ability of the virus to infect and replicate.
  • a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a SARS-CoV-2 spike protein or portion thereof (e.g., ectodomain or receptor binding domain of the SARS-CoV-2 spike protein) described herein comprises a LaSota strain backbone.
  • a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a SARS-CoV-2 spike protein ectodomain or derivative thereof described herein comprises a LaSota strain backbone.
  • a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a SARS- CoV-2 spike protein ectodomain or derivative thereof described herein comprises a Hitchner strain backbone.
  • a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a protein comprising a SARS-CoV-2 spike protein ectodomain or derivative thereof comprises a LaSota strain backbone.
  • a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a protein comprising a SARS-CoV-2 spike protein ectodomain or derivative thereof comprises a Hitchner strain backbone.
  • the genomic sequence of the LaSota strain backbone i.e., without the transgene
  • the recombinant NDVs described herein may be propagated in cell lines, e.g., cancer cell lines such as HeLa cells, MCF7 cells, THP-1 cells, U87 cells, DU145 cells, Lncap cells, and T47D cells.
  • the cells or cell lines e.g., cancer cells or cancer cell lines
  • the recombinant NDVs described herein are propagated in interferon deficient systems or interferon (IFN) deficient substrates, such as, e.g., IFN deficient cells (e.g., IFN deficient cell lines) or IFN deficient embryonated eggs.
  • IFN interferon
  • the recombinant NDVs described herein are propagated in chicken cells or embryonated chicken eggs.
  • Representative chicken cells include, but are not limited to, chicken embryo fibroblasts and chicken embryo kidney cells.
  • the recombinant NDVs described herein are propagated in Vero cells.
  • the recombinant NDVs described herein are propagated in chicken eggs or quail eggs.
  • a recombinant NDV virus described herein is first propagated in embryonated eggs and then propagated in cells (e.g., a cell line).
  • the recombinant ND Vs described herein are propagated as described in Section 6, infra.
  • the recombinant ND Vs described herein may be propagated in embryonated eggs (e.g., chicken embryonated eggs), e.g., from 6 to 14 days old, 6 to 12 days old, 6 to 10 days old, 6 to 9 days old, 6 to 8 days old, 8 to 10 days old, 9 to 11 days old, or 10 to 12 days old.
  • embryonated eggs e.g., chicken embryonated eggs
  • 10 day old embryonated chicken eggs are used to propagate the recombinant ND Vs described herein.
  • Young or immature embryonated eggs e.g., chicken embryonated eggs
  • Immature embryonated eggs encompass eggs which are less than ten day old eggs, e.g., eggs 6 to 9 days old or 6 to 8 days old that are IFN-deficient. Immature embryonated eggs also encompass eggs which artificially mimic immature eggs up to, but less than ten day old, as a result of alterations to the growth conditions, e.g., changes in incubation temperatures; treating with drugs; or any other alteration which results in an egg with a retarded development, such that the IFN system is not fully developed as compared with ten to twelve day old eggs.
  • the recombinant NDVs described herein can be propagated in different locations of the embryonated egg, e.g., the allantoic cavity (such as, e.g., the allantoic cavity of chicken embryonated eggs).
  • the allantoic cavity such as, e.g., the allantoic cavity of chicken embryonated eggs.
  • a virus is propagated as described in the Example below (e.g., Section 6).
  • the recombinant NDVs described herein can be removed from embryonated eggs or cell culture and separated from cellular components, typically by well- known clarification procedures, e.g., such as centrifugation, depth filtration, and microfiltration, and may be further purified as desired using procedures well known to those skilled in the art, e.g., tangential flow filtration (TFF), density gradient centrifugation, differential extraction, or chromatography.
  • a virus is isolated as described in the Example below (e.g., Section 6).
  • virus isolation from allantoic fluid of an infected egg begins with harvesting allantoic fluid, which is clarified using a filtration system to remove cells and other large debris.
  • a method for propagating a recombinant NDV described herein comprising (a) culturing a cell (e.g., a cell line) or embryonated egg infected with a recombinant NDV described herein; and (b) isolating the recombinant NDV from the cell or embryonated egg.
  • the cell or embryonated egg may be one described herein or known to one of skill in the art.
  • the cell or embryonated egg is IFN deficient.
  • a method for producing a pharmaceutical composition comprising a recombinant NDV described herein, the method comprising (a) propagating a recombinant NDV described herein a cell (e.g., a cell line) or embryonated egg; and (b) isolating the recombinant NDV from the cell or embryonated egg.
  • the method may further comprise adding the recombinant NDV to a container along with a pharmaceutically acceptable carrier.
  • compositions comprising a recombinant NDV described herein (e.g., Section 5.1, or 6).
  • the compositions are pharmaceutical compositions, such as immunogenic compositions (e.g., vaccine compositions).
  • immunogenic compositions comprising a recombinant NDV described herein (e.g., Section 5.1, or 6).
  • immunogenic compositions comprising a protein or chimeric F protein described herein (e.g., Section 5.1, or 6).
  • immunogenic compositions comprising a nucleotide sequence encoding a protein or chimeric F protein described herein (e.g., Section 5.1, or 6).
  • immunogenic compositions comprising a transgene described herein (e.g., Section 5.1, or 6).
  • the immunogenic composition is bivalent or multivalent (e.g., trivalent or tetravalent). The compositions may be used in methods of inducing an immune response to SARS-CoV-2 spike protein.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein and second derivative of the ectodomain of the SARS-CoV-2 spike protein are selected from: (i) a derivative of the ectodomain of a SARS- CoV-2 Wuhan strain spike protein; (2) a derivative of the ectodomain of a SARS-CoV-2 delta variant spike protein; (3) a derivative of the ectodomain of a SARS-CoV-2 beta variant spike protein; and (4) a derivative of the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the first and second chimeric F proteins are selected from those described herein (e.g., in Section 5.1 or 6).
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 12 or 16.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13, 17, 23, 24, 29 or 30, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13, 17, 23, 24, 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 23 or 24, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 23 or 24.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13, 17, 29 or 30, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13, 17, 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 29 or 30.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16, and the second derivative of the ectodomain comprises the amino acid sequence of SEQ ID NO:29 or 30. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, and the second derivative of the ectodomain comprises the amino acid sequence of SEQ ID NO: 23 or 24.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, and the second derivative of the ectodomain comprises the amino acid sequence of SEQ ID NO: 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 23 or 24, and the second derivative of the ectodomain comprises the amino acid sequence of SEQ ID NO: 29 or 30.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV- 2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; and (c) a third recombinant NDV, wherein the third recombinant NDV, where
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein, the second derivative of the ectodomain of the SARS-CoV-2 spike protein, and the third derivative of the ectodomain of the SARS-CoV- 2 spike protein are selected from: (i) a derivative of the ectodomain of a SARS-CoV-2 Wuhan strain spike protein; (2) a derivative of the ectodomain of a SARS-CoV-2 delta variant spike protein; (3) a derivative of the ectodomain of a SARS-CoV-2 beta variant spike protein; and (4) a derivative of the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the third derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:23 or 24, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 23 or 24.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the second derivative of the ectodomain of a SARS- CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 12 or 16.
  • the third derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 90%(or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 29 or 30. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the multivalent immunogenic composition further comprises a fourth recombinant ND V, wherein the fourth recombinant NDV comprises a fourth transgene comprising a nucleotide sequence encoding a fourth chimeric F protein, and wherein the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:23 or 24, or an amino acid sequence at least 90% (or at least 95%, at least 96%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 23 or 24.
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein, wherein the first derivative of the ectodomain comprises the amino acid sequence of SEQ ID NO: 12 or 16; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 11 or 40, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11 or 40; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6 or 18, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 11 or 40, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11 or 40; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 22 or 39, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 11 or 40, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11 or 40; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 28 or 41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 22 or 39, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6 or 18, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 22 or 39, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 28 or 41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 28 or 41, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28 or 41; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6 or 18, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:
  • an immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first transgene comprising a nucleotide sequence encoding a first chimeric F protein, and wherein the first chimeric F protein comprises the amino acid sequence of SEQ ID NO: 22 or 39, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 22 or 39; and (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second transgene comprising a nucleotide sequence encoding a second chimeric F protein, and wherein the second chimeric F protein comprises the amino acid sequence of SEQ ID NO: 6 or 18, or an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO:
  • an immunogenic composition comprises: (a) a first recombinant NDV comprising a first chimeric F protein, and wherein the first chimeric F protein comprises a first ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; and (b) a second recombinant NDV comprising a second chimeric F protein, and wherein the second chimeric F protein comprises a second ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; in an admixture with a pharmaceutically acceptable carrier, wherein the first and second chimeric F proteins are different from each other.
  • the first ectodomain of the SARS- CoV-2 spike protein is the ectodomain of a SARS-CoV-2 delta variant spike protein. In another specific embodiment, the first ectodomain of the SARS-CoV-2 spike protein is the ectodomain of a SARS-CoV-2 beta variant spike protein. In another specific embodiment, the first ectodomain of the SARS-CoV-2 spike protein is the ectodomain of a SARS-CoV-2 gamma variant spike protein. In another specific embodiment, the first ectodomain of the SARS-CoV-2 spike protein is the ectodomain of a SARS-CoV-2 Wuhan strain spike protein.
  • the first ectodomain of the SARS-CoV-2 spike protein and second SARS-CoV-2 spike protein are selected from: (i) the ectodomain of a SARS-CoV-2 Wuhan strain spike protein; (2) the ectodomain of a SARS-CoV-2 delta variant spike protein; (3) the ectodomain of a SARS-CoV-2 beta variant spike protein; and (4) the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the immunogenic composition further comprises a third recombinant NDV comprising a third chimeric F protein, and wherein the third chimeric F protein comprises a third ectodomain of a SARS- CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein, and wherein the third chimeric F protein is different than the first and second chimeric F proteins.
  • the immunogenic composition further comprises: (c) a third recombinant NDV comprising a third chimeric F protein, and wherein the third chimeric F protein comprises a third ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; and (d) a fourth recombinant NDV comprising a fourth chimeric F protein, and wherein the fourth chimeric F protein comprises a fourth ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein, and wherein the third and fourth chimeric F proteins are different from each other and different from the first and second chimeric F proteins.
  • the fragment of the ectodomain comprises (or consists of) at least 500, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 amino acid residues of the ectodomain.
  • the differences between the chimeric F proteins are the sequences of the ectodomain or fragment thereof.
  • an immunogenic composition comprises: (a) a first recombinant NDV comprising a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; and (b) a second recombinant NDV comprising a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV- 2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; in an admixture with a pharmaceutically acceptable carrier, wherein the first and second chimeric F proteins are different from each other.
  • the first derivative ectodomain of the SARS-CoV-2 spike protein is a derivative the ectodomain of a SARS-CoV-2 Wuhan strain spike protein.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein and second derivative of the SARS-CoV-2 spike protein are selected from: (i) a derivative of the ectodomain of a SARS-CoV-2 Wuhan strain spike protein; (2) a derivative of the ectodomain of a SARS- CoV-2 delta variant spike protein; (3) a derivative of the ectodomain of a SARS-CoV-2 beta variant spike protein; and (4) a derivative of the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the immunogenic composition further comprises a third recombinant NDV comprising a third chimeric F protein, and wherein the third chimeric F protein comprises a third derivative of the ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein, and wherein the third chimeric F protein is different than the first and second chimeric F proteins.
  • the immunogenic composition further comprises: (c) a third recombinant NDV comprising a third chimeric F protein, and wherein the third chimeric F protein comprises a third derivative of the ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein; and (d) a fourth recombinant NDV comprising a fourth chimeric F protein, and wherein the fourth chimeric F protein comprises a fourth derivative of the ectodomain of a SARS-CoV-2 spike protein or a fragment thereof, and the transmembrane and cytoplasmic domains of NDV F protein, and wherein the third and fourth chimeric F proteins are different from each other and different from the first and second chimeric F proteins.
  • the fragment of the ectodomain comprises (or consists of) at least 500, at least 750, at least 800, at least 850, at least 900, at least 950, or at least 1000 amino acid residues of the ectodomain.
  • the differences between the chimeric F proteins are the sequences of the ectodomain or fragment thereof.
  • an immunogenic composition comprises: (a) a first recombinant NDV comprising a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; and (b) a second recombinant NDV comprising a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; in an admixture with a pharmaceutically acceptable carrier, wherein the first derivative and second derivative are different from each other.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein is a derivative of the ectodomain of the SARS-CoV-2 delta variant spike protein.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein is a derivative of the ectodomain of the SARS-CoV-2 beta variant spike protein.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein is a derivative of the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the first derivative ectodomain of the SARS-CoV-2 spike protein is a derivative the ectodomain of a SARS-CoV-2 Wuhan strain spike protein.
  • the first derivative of the ectodomain of the SARS-CoV-2 spike protein and second derivative of the SARS-CoV-2 spike protein are selected from: (i) a derivative of the ectodomain of a SARS-CoV-2 Wuhan strain spike protein; (2) a derivative of the ectodomain of a SARS-CoV-2 delta variant spike protein; (3) a derivative of the ectodomain of a SARS-CoV-2 beta variant spike protein; and (4) a derivative of the ectodomain of a SARS-CoV-2 gamma variant spike protein.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 12 or 16.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13, 17, 23, 24, 29, or 30, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13, 17, 23, 24, 29, or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO:29 or 30.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16 and the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16 and the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 23 or 24.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16 and the second derivative of the ectodomain of a SARS- CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, and the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 23 or 24.
  • the first derivative of the ectodomain of a SARS-CoV- 2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, and the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:23 or 24, and the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein, and wherein the first chimeric F protein comprises a first derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; (b) a second recombinant ND V, wherein the second recombinant NDV comprises a second chimeric F protein, and wherein the second chimeric F protein comprises a second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a third chimeric F protein, and wherein the third chimeric F protein comprises a third derivative of the ectodomain
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the third derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO:29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 23 or 24, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO:23 or 24.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 12 or 16, or an amino acid at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 12 or 16.
  • the third derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO:29 or 30, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO:29 or 30.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 29 or 30, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO:29 or 30. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the second derivative of the ectodomain of a SARS-CoV-2 spike protein comprises the amino acid sequence of SEQ ID NO: 13 or 17, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to the amino acid sequence of SEQ ID NO: 13 or 17.
  • the multivalent immunogenic further comprises a fourth recombinant NDV, wherein the fourth recombinant NDV comprises a fourth transgene comprising a nucleotide sequence encoding a fourth chimeric F protein, and wherein the fourth chimeric F protein comprises a fourth derivative of the ectodomain of a SARS-CoV-2 spike protein, and the transmembrane and cytoplasmic domains of NDV F protein, and wherein the fourth derivative is different from the first derivative, the second derivative, and the third derivative.
  • the fourth chimeric F protein are selected from the chimeric F proteins described herein (e.g., in Section 5.1.2 or 6).
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein described herein; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein described herein; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a third chimeric F protein described herein; in an admixture with a pharmaceutically acceptable carrier, wherein the first chimeric F protein, the second first chimeric F protein, and the third chimeric F protein are different from each other.
  • the first chimeric F protein, the second first chimeric F protein, and the third first chimeric F protein comprise the ectodomain of different SARS-CoV-2 spike proteins or a derivative of the ectodomains of different SARS-CoV-2 spike proteins.
  • the NDV F protein transmembrane and cytoplasmic domains of the first chimeric F protein, the second first chimeric F protein, and the third first chimeric F protein are the same.
  • the first chimeric F protein, the second chimeric F protein, and the third chimeric F protein are selected from the chimeric F proteins described herein (e.g., in Section 5.1.2 or 6).
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein comprising the amino acid sequence of SEQ ID NO:11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:22 or 39.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein comprising the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:28 or 41.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein comprising the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein comprising the amino acid sequence of SEQ ID NO:22 or 39; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:28 or 41.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein described herein; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein described herein; (c) a third recombinant NDV, wherein the third recombinant ND V comprises a third chimeric F protein described herein; and (d) a fourth recombinant NDV, wherein the fourth recombinant NDV comprises a third chimeric F protein described herein; in an admixture with a pharmaceutically acceptable carrier, wherein the first chimeric F protein, the second first chimeric F protein, the third chimeric F protein, and the fourth chimeric F protein are different from each other.
  • the first chimeric F protein, the second first chimeric F protein, and the third first chimeric F protein comprise the ectodomain of different SARS-CoV-2 spike proteins or a derivative of the ectodomains of different SARS-CoV-2 spike proteins.
  • the NDV F protein transmembrane and cytoplasmic domains of the first chimeric F protein, the second first chimeric F protein, and the third first chimeric F protein are the same.
  • the first chimeric F protein, the second chimeric F protein, and the third chimeric F protein are selected from the chimeric F proteins described herein (e.g., in Section 5.1.2 or 6).
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a packaged genome comprising a transgene encoding a first chimeric F protein comprising the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a packaged genome comprising a transgene encoding second chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a packaged genome comprising a transgene encoding a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:28 or 41.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a packaged genome comprising a transgene encoding a first chimeric F protein comprising the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a packaged genome comprising a transgene encoding second chimeric F protein comprising the amino acid sequence of SEQ ID NO:22 or 39; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a packaged genome comprising a transgene encoding a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:28 or 41.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a packaged genome comprising a transgene encoding a first chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a packaged genome comprising a transgene encoding second chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; and (c) a third recombinant NDV, wherein the third recombinant NDV comprises a packaged genome comprising a transgene encoding a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:22 or 39.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a packaged genome comprising a transgene encoding a first chimeric F protein described herein; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a packaged genome comprising a transgene encoding a second chimeric F protein described herein; (c) a third recombinant NDV, wherein the third recombinant NDV comprises a packaged genome comprising a transgene encoding a third chimeric F protein described herein; and (d) a fourth recombinant NDV, wherein the fourth recombinant NDV comprises a packaged genome comprising a transgene encoding a fourth chimeric F protein described herein; in an admixture with a pharmaceutically acceptable carrier, wherein the first chimeric F protein, the second first chimeric F protein, the second first
  • the first chimeric F protein, the second first chimeric F protein, the first chimeric F protein, and the fourth chimeric F protein comprise the ectodomain of different SARS-CoV-2 spike proteins or a derivative of the ectodomains of different SARS-CoV-2 spike proteins.
  • the NDV F protein transmembrane and cytoplasmic domains of the first chimeric F protein, the second first chimeric F protein, the first chimeric F protein, and the fourth chimeric F protein are the same.
  • the first chimeric F protein, the second first chimeric F protein, the first chimeric F protein, and the fourth chimeric F protein are selected from the chimeric F proteins described herein (e.g., in Section 5.1.2 or 6).
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a packaged genome comprising a transgene encoding a first chimeric F protein comprising the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a packaged genome comprising a transgene encoding second chimeric F protein comprising the amino acid sequence of SEQ ID NO:6 or 18; (c) a third recombinant NDV, wherein the third recombinant NDV comprises a packaged genome comprising a transgene encoding a third chimeric F protein comprising the amino acid sequence of SEQ ID NO:22 or 39; and (d) a fourth recombinant NDV, wherein the fourth recombinant NDV comprises a packaged genome comprising a transgene encoding a fourth chimeric
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises a first chimeric F protein described herein; (b) a second recombinant NDV, wherein the second recombinant NDV comprises a second chimeric F protein described herein; (c) a third recombinant NDV, wherein the third recombinant ND V comprises a third chimeric F protein described herein; and (d) a fourth recombinant NDV, wherein the fourth recombinant NDV comprises a fourth chimeric F protein described herein; in an admixture with a pharmaceutically acceptable carrier, wherein the first chimeric F protein, the second first chimeric F protein, the third chimeric F protein, and the fourth chimeric F protein are different from each other.
  • a multivalent immunogenic composition comprises: (a) a first recombinant NDV, wherein the first recombinant NDV comprises the amino acid sequence of SEQ ID NO: 11 or 40; (b) a second recombinant NDV, wherein the second recombinant NDV comprises the amino acid sequence of SEQ ID NO:6 or 18; (c) a third recombinant NDV, wherein the third recombinant NDV comprises the amino acid sequence of SEQ ID NO:22 or 39; and (d) a fourth recombinant NDV, wherein the fourth recombinant NDV comprises the amino acid sequence of SEQ ID NO:28 or 41.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 85% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 90% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 95% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 98% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 99% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein and the second derivative of the ectodomain of a SARS-CoV-2 spike protein have 75% to 90% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 85% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 90% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 95% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 98% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 99% identity to each other. In some embodiments, the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, and the third derivative of the ectodomain of a SARS-CoV-2 spike protein have 75% to 90% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 85% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 95% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 98% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have less than 99% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have 75% to 90% identity to each other.
  • the first derivative of the ectodomain of a SARS-CoV-2 spike protein, the second derivative of the ectodomain of a SARS-CoV-2 spike protein, the third derivative of the ectodomain of a SARS-CoV-2 spike protein, and the fourth derivative of the ectodomain of a SARS-CoV-2 spike protein have 85% to 90% identity to each other.
  • the first recombinant NDV, the second recombinant NDV, and the third recombinant NDV in an immunogenic composition described herein are of the same strain. In some embodiments, the first recombinant NDV, the second recombinant NDV, and third recombinant NDV in an immunogenic composition described herein are of the different strains.
  • an immunogenic composition is one described in Section 6, infra (e.g., a monovalent, bivalent, trivalent, or tetravalent composition described in FIG. 4B).
  • a bivalent immunogenic composition is one described in Section 6, infra.
  • a multivalent immunogenic composition is one described in Section 6, infra (e.g., a trivalent or tetravalent composition described in FIG. 4B).
  • a recombinant NDV virion comprising NDV F and HN proteins in addition to a chimeric F protein described herein might cause steric hindrance with the S2 domain of the ectodomain of a SARS-CoV-2 spike protein or a derivative thereof and focus the immune response on the more immunogenic and less conserved S 1 domain of the ectodomain or a derivative thereof.
  • administration of an immunogenic composition to a subject generates an immune response in the subject that reduces the likelihood of developing COVID-19 by at least 25%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative a subject of the same species not administered the immunogenic composition.
  • the recombinant NDV included in an immunogenic composition described herein is a live virus.
  • the recombinant NDV included in a pharmaceutical composition described herein is an attenuated live virus.
  • the recombinant NDV included in an immunogenic composition described herein is inactivated. Any technique known to one of skill in the art may be used to inactivate a recombinant NDV described herein. For example, formalin or beta- propiolactone may be used to inactivate a recombinant NDV described herein.
  • the recombinant NDV included in a composition described herein is inactivated using 0.05% to 2% (e.g., 0.05%, 0.1%, 0.5%, 1%, or 2%) beta-Propiolactone, or another technique known to one of skill in the art.
  • DSP disodium phosphate
  • BPL beta-Propiolactone
  • the inactivated allantoic fluid may be clarified by centrifugation at 4,000 rpm for 20-40 minutes (e.g., about 30 minutes).
  • the clarified allantoic fluids may be laid on top of a 20% sucrose cushion in PBS and ultracentrifuged at 25,000 rpm for about 2 hours at 4°C using, e.g., a Beckman L7-65 ultracentrifuge with a Beckman SW28 rotor, to pellet the virus through the sucrose cushion to remove soluble egg protein.
  • the virus may then be resuspended in PBS at, e.g., about pH 7 to about 7.6 (such as, e.g., pH 7.4).
  • the total protein is determined using the bicinchoninic acid (BCA) assay, or another assay known to one of skill in the art.
  • BCA bicinchoninic acid
  • the recombinant NDV is inactivated as described in Section 6, infra.
  • a chimeric F protein is stable in an inactivated recombinant NDV described herein for a period of time (e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer), as assessed by the ability of the inactivated recombinant NDV to induce anti-SARS-CoV-2 spike protein antibodies.
  • an immunogenic composition described herein or a recombinant NDV described herein does not require frozen storage, which makes it difficult to transport and store in low-income countries.
  • an immunogenic composition described herein or a recombinant NDV described herein may be stored at about 2°C to about 8°C (e.g., 4°C).
  • the immunogenic compositions are formulated to be suitable for the intended route of administration to a subject.
  • an immunogenic composition may be formulated to be suitable for parenteral, intravenous, intraarterial, intrapleural, inhalation, intranasal, intraperitoneal, oral, intradermal, colorectal, intraperitoneal, and intracranial administration.
  • an immunogenic composition may be formulated for intravenous, intraarterial, oral, intraperitoneal, intranasal, intratracheal, intrapleural, intracranial, subcutaneous, intramuscular, topical, or pulmonary administration.
  • an immunogenic composition may be formulated for intranasal administration.
  • the term "adjuvant" refers to a compound that when administered in conjunction with or as part of a composition described herein augments, enhances and/or boosts the immune response to a recombinant NDV, but when the compound is administered alone does not generate an immune response to the virus.
  • the adjuvant generates an immune response to a recombinant NDV and does not produce an allergy or other adverse reaction.
  • Adjuvants can enhance an immune response by several mechanisms including, e.g., lymphocyte recruitment, stimulation of B and/or T cells, and stimulation of macrophages.
  • the adjuvant can be used with or without other specific immunostimulating agents such as MPL or 3-DMP, QS21, polymeric or monomeric amino acids such as poly glutamic acid or polylysine.
  • the adjuvant is a liposomal suspension adjuvant (R-enantiomer of the cationic lipid DOTAP, R-DOTAP) or an MF-59 like oil-in-water emulsion adjuvant (AddaVax).
  • the adjuvant may be a toll-like receptor (TLR) agonist (e.g., a TLR7 agonist, TLR8 agonist, TLR7/8 agonist, or TLR9 agonist).
  • the adjuvant is a toll-like receptor 9 (TLR9) agonist adjuvant. In certain embodiments, the adjuvant is CpG 1018® adjuvant. In some embodiments, a composition described herein (e.g., a live recombinant NDV composition) does not contain an adjuvant.
  • an immunogenic composition described herein comprises 1 to 15 micrograms of a SARS-CoV-2 spike protein or a portion thereof (e.g., an ectodomain), a derivative of a SARS-CoV-2 spike protein or a portion thereof (e.g., an ectodomain), or a chimeric F protein expressed by a recombinant NDV described herein.
  • composition e.g., an immunogenic composition
  • pharmaceutical composition comprises 1 to 15 micrograms per ml of a SARS-CoV-2 spike protein or a portion thereof (e.g., an ectodomain), a derivative of a SARS-CoV-2 spike protein or a portion thereof (e.g., an ectodomain), or a chimeric F protein expressed by a recombinant NDV described herein.
  • an immunogenic composition described herein comprises 0.2 x 10 6 to 0.5 x 10 6 EID50 of each recombinant NDV.
  • an immunogenic composition described herein comprises 0.33 x 10 6 of each recombinant NDV.
  • an immunogenic composition described herein may be stored at 2 0 to 8° C (e.g., 4°C).
  • an immunogenic composition described herein is stable for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months or at least 1 year at 2 0 to 8° C.
  • an immunogenic composition described herein is stable for 3-6 months, 3-9 months, 6-12 months, or 9-12 months at 2 0 to 8° C (e.g., 4°C).
  • the stability is assessed by protein denaturation assays, immunoassays or a combination thereof.
  • the recombinant NDV(s) described herein or an immunogenic composition described herein may be used to immunize a subject against SARS-CoV-2, induce an immune response to SARS-CoV-2 spike protein, or prevent COVID-19.
  • the recombinant NDV(s) described herein may be used to immunize a subject against a SARS-CoV-2 delta variant, induce an immune response to a SARS-CoV-2 delta variant spike protein, or prevent COVID-19 caused by or associated with a SARS-CoV-2 delta variant.
  • presented herein are methods for inducing an immune response in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition comprising a recombinant NDV described herein.
  • a method for inducing an immune response to a SARS-CoV-2 spike protein in a subject comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein, such as described in Section 5.4.
  • presented herein is a method for inducing an immune response to a SARS-CoV-2 spike protein in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • a subject e.g., a human subject
  • an effective amount of a recombinant NDV described herein or an immunogenic composition described herein See, e.g., Section 5.1 and 6 for recombinant NDV and Section 5.4 or 6 for immunogenic compositions.
  • the recombinant NDV is one described in Section 5.1 or 6
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for inducing an immune response to a SARS-CoV-2 delta variant spike protein in a subject (e.g, a human subject), comprising administering the subject (e.g, a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for inducing an immune response to a SARS-CoV-2 delta variant spike protein in a subject comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for inducing an immune response to a SARS-CoV-2 beta variant spike protein in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for inducing an immune response to a SARS-CoV-2 beta variant spike protein in a subject comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for inducing an immune response to a SARS-CoV-2 gamma variant spike protein in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for inducing an immune response to a SARS-CoV-2 gamma variant spike protein in a subject e.g., a human subject
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for inducing an immune response to a SARS-CoV-2 Wuhan strain spike protein in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for inducing an immune response to a SARS-CoV-2 Wuhan strain spike protein in a subject comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • a subject e.g., a human subject
  • SARS-CoV-2 e.g., a SARS-CoV-2 delta variant
  • administering e.g., a human subject
  • a recombinant ND V described herein or an immunogenic composition comprising a recombinant NDV described herein.
  • a method for immunizing a subject e.g., a human subject
  • SARS-CoV-2 e.g., a human subject
  • a method for immunizing a subject e.g., a human subject
  • SARS-CoV-2 e.g., a human subject
  • a method for immunizing a subject e.g., a human subject
  • SARS-CoV-2 comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • a recombinant NDV described herein or an immunogenic composition described herein.
  • the recombinant NDV is one described in Section 5.1 or 6
  • the immunogenic composition is one described in Section 5.4 or 6.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for immunizing a subject (e.g, a human subject) against SARS-CoV-2 beta variant, comprising administering the subject (e.g, a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • presented herein is a method for immunizing a subject (e.g., a human subject) against SARS-CoV-2 beta variant, comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein. See, e.g., Section 5.1 and 6 for recombinant NDV and Section 5.4 and 6 for compositions.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for immunizing a subject (e.g., a human subject) against SARS-CoV-2 gamma variant, comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for immunizing a subject (e.g., a human subject) against SARS-CoV-2 gamma variant comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • presented herein is a method for immunizing a subject (e.g., a human subject) against SARS-CoV-2 Wuhan strain, comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • presented herein is a method for immunizing a subject (e.g., a human subject) against SARS-CoV-2 Wuhan strain, comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • a subject e.g., a human subject
  • an effective amount of a recombinant NDV described herein or an immunogenic composition described herein See, e.g., Section 5.1 and 6 for recombinant NDV and Section 5.4 and 6 for compositions.
  • the recombinant NDV is one described in Section 5.1 or 6.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • a method for immunizing a subject against two or more SARS-CoV-2 comprising administering a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for immunizing a subject against two or more SARS-CoV-2 comprising administering an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the recombinant NDV is one described in Section 5.1 or 6.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • the two or more SARS-CoV-2 are different variants (e.g., Mu variant (e.g., B.1.621, B.1.621.1), beta variant (e.g., B.1.351), a gamma variant (e.g., P.1), or a delta variant (e.g., B.617.2)).
  • Mu variant e.g., B.1.621, B.1.621.1
  • beta variant e.g., B.1.351
  • a gamma variant e.g., P.1
  • a delta variant e.g., B.617.2
  • a method for immunizing a subject against two or more SARS-CoV-2 comprising administering two, three or four recombinant NDVs described herein or a bivalent or multivalent (e.g., trivalent or tetravalent) immunogenic composition described herein.
  • a method for immunizing a subject against two or more SARS-CoV-2 comprising administering an effective amount of two, three or four recombinant NDVs described herein or a bivalent or multivalent (e.g., trivalent or tetravalent) immunogenic composition described herein.
  • a method for immunizing a subject against one or more SARS-CoV-2 (e.g., 2, 3, 4, or more), wherein the one or more SARS- CoV-2 are heterologous to the SARS-CoV-2 from which the ectodomains of the chimeric F protein included in an immunogenic composition described herein are derived, the method comprising administering the immunogenic composition described herein to the subject.
  • a method for immunizing a subject against one or more SARS-CoV-2 (e.g., 2, 3, 4, or more), wherein the one or more SARS-CoV-2 are heterologous to the SARS-CoV-2 from which the ectodomains of the chimeric F proteins included in an immunogenic composition described herein are derived, the method comprising administering an effective amount of the immunogenic composition described herein to the subject.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • the one or more SARS-CoV-2 are different variants (e.g., Mu variant (e.g., B.1.621, B.1.621.1), beta variant (e.g., B.1.351), a gamma variant (e.g., P. l), or a delta variant (e.g., B.617.2)).
  • Mu variant e.g., B.1.621, B.1.621.1
  • beta variant e.g., B.1.351
  • a gamma variant e.g., P. l
  • a delta variant e.g., B.617.2
  • two or more doses of the immunogenic composition are administered to the subject.
  • a method for inducing antibodies that neutralize one or more SARS-CoV-2 e.g., 2, 3, 4, or more
  • the one or more SARS-CoV-2 are heterologous to the SARS-CoV-2 from which the ectodomains of the chimeric F protein included in an immunogenic composition described herein are derived, the method comprising administering the immunogenic composition described herein to the subject.
  • provided herein is a method for inducing antibodies that neutralize one or more SARS-CoV-2 (e.g., 2, 3, 4, or more) in a subject, wherein the one or more SARS-CoV-2 are heterologous to the SARS-CoV-2 from which the ectodomains of the chimeric F protein included in an immunogenic composition described herein are derived, the method comprising administering an effective amount of the immunogenic composition described herein to the subject.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • the one or more SARS-CoV-2 are different variants (e.g., Mu variant (e.g., B.1.621, B.1.621.1), beta variant (e.g., B.1.351), a gamma variant (e.g., P.l), or a delta variant (e.g., B.617.2)).
  • Mu variant e.g., B.1.621, B.1.621.1
  • beta variant e.g., B.1.351
  • a gamma variant e.g., P.l
  • a delta variant e.g., B.617.2
  • two or more doses of the immunogenic composition are administered to the subject.
  • a method for inducing antibodies that cross-react with one or more SARS-CoV-2 spike proteins in a subject wherein the one or more SARS-CoV-2 spike proteins are heterologous to the SARS-CoV-2 spike proteins from which the ectodomains included in an immunogenic composition described herein are derived, the method comprising administering the immunogenic composition described herein to the subject.
  • provided herein is a method for inducing antibodies that cross-react with one or more SARS-CoV-2 spike proteins in a subject, wherein the one or more SARS-CoV-2 spike proteins are heterologous to the SARS-CoV-2 spike proteins from which the ectodomains included in an immunogenic composition described herein are derived, the method comprising administering an effective amount of the immunogenic composition described herein to the subject.
  • the immunogenic composition is one described in Section 5.4 or 6.
  • the one or more SARS-CoV-2 are different variants (e.g., Mu variant (e.g., B.1.621, B.1.621.1), beta variant (e.g., B.1.351), a gamma variant (e.g., P.l), or a delta variant (e.g., B.617.2)).
  • Mu variant e.g., B.1.621, B.1.621.1
  • beta variant e.g., B.1.351
  • a gamma variant e.g., P.l
  • a delta variant e.g., B.617.2
  • two or more doses of the immunogenic composition are administered to the subject.
  • presented herein are methods for preventing COVID-19 in a subject (e.g., a human subject), comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition comprising a recombinant NDV described herein.
  • a method for preventing COVID-19 in a subject comprising administering the subject (e.g., a human subject) a recombinant NDV described herein or an immunogenic composition described herein.
  • a method for preventing COVID-19 in a subject comprising administering the subject (e.g., a human subject) an effective amount of a recombinant NDV described herein or an immunogenic composition described herein.
  • the recombinant NDV is one described in Section 5.1 or 6, and the immunogenic composition is one described in Section 5.4 or 6.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 delta variant.
  • the COVID-19 may be caused or associated with SARS-CoV-2 that is not a delta variant.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 gamma variant.
  • a subject e.g., a human subject
  • administering the subject e.g., a human subject
  • a bivalent or multivalent immunogenic composition comprising a recombinant NDV described herein.
  • presented herein is a method for preventing COVID-19 in a subject (e.g., a human subject), comprising administering the subject (e.g, a human subject) two, three, or four recombinant NDVs described herein or a bivalent or multivalent (e.g., trivalent or tetravalent) immunogenic composition described herein.
  • a method for preventing COVID-19 in a subject comprising administering the subject (e.g., a human subject) an effective amount two, three, or four recombinant NDVs described herein, or a bivalent or multivalent (e.g., trivalent or tetravalent) immunogenic composition described herein.
  • the recombinant NDVs are ones described in Section 5.1 or 6, and the bivalent or multivalent immunogenic composition is one described in Section 5.4 or 6.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 delta variant.
  • the COVID-19 may be caused or associated with SARS-CoV-2 that is not a delta variant.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 gamma variant.
  • the COVID-19 may be caused or associated with SARS-CoV-2 that is not a gamma variant.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 beta variant.
  • the COVID-19 may be caused or associated with SARS-CoV-2 that is not a beta variant.
  • the COVID-19 may be caused by or associated with a SARS-CoV-2 Wuhan strain.
  • the recombinant NDV and one or more additional therapies may be administered concurrently or sequentially to the subject. In certain embodiments, the recombinant NDV and one or more additional therapies are administered in the same composition. In other embodiments, the recombinant NDV and one or more additional therapies are administered in different compositions. The recombinant NDV and one or more other therapies may be administered by the same or different routes of administration to the subject. Any route known to one of skill in the art or described herein may be used to administer the recombinant NDV and one or more other therapies. In a specific embodiment, the recombinant ND V is administered intranasally or intramuscularly and the one or more other therapies are administered by the same or a different route. In a specific embodiment, the recombinant NDV is administered intranasally and the one or more other therapies is administered intravenously.
  • a recombinant NDV described herein or an immunogenic composition described herein is administered to a subject previously vaccinated with a COVID-19 vaccine.
  • a recombinant NDV described herein or an immunogenic composition described herein is administered to a subject previously vaccinated with a COVID-19 vaccine other than a NDV-based COVID-19 vaccine.
  • the COVID-19 vaccine may be Pfizer’s COVID-19 vaccine, Modema’s COVID-19 vaccine, AstraZeneca’s COVID-19 vaccine, Johnson & Johnson’s COVID-19, or another COVID-19 vaccine.
  • a recombinant NDV described herein or an immunogenic composition described herein is administered to a subject previously experiencing symptoms of COVID-19.
  • a recombinant ND V described herein or an immunogenic composition described herein is administered to a subject previously diagnosed with COVID-19.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated with a SARS-CoV-2 delta variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein binds to a SARS-CoV-2 spike protein delta variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein may neutralize a SARS-CoV-2 delta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated a SARS-CoV-2 delta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 that is not caused by or associated a SARS- CoV-2 delta variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 spike protein that is not a SARS-CoV-2 spike protein delta variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein neutralizes a SARS-CoV-2 that is not a SARS-CoV-2 delta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated with a SARS-CoV-2 beta variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein binds to a SARS-CoV-2 spike protein beta variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein may neutralize a SARS-CoV-2 beta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated a SARS-CoV-2 beta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 that is not caused by or associated a SARS- CoV-2 beta variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 spike protein that is not a SARS-CoV-2 spike protein beta variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein neutralizes a SARS-CoV-2 that is not a SARS-CoV-2 beta variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated with a SARS-CoV-2 gamma variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein binds to a SARS- CoV-2 spike protein gamma variant.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein may neutralize a SARS-CoV-2 gamma variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated a SARS-CoV-2 gamma variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 that is not caused by or associated a SARS- CoV-2 gamma variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 spike protein that is not a SARS-CoV-2 spike protein gamma variant, as assessed by an assay described herein or known to one of skill in the art.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein neutralizes a SARS-CoV-2 that is not a SARS-CoV-2 gamma variant, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated with a SARS-CoV-2 Wuhan strain.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein binds to a SARS-CoV-2 spike protein Wuhan strain.
  • an antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein may neutralize a SARS-CoV-2 Wuhan strain, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 caused by or associated a SARS-CoV-2 Wuhan strain, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of a recombinant NDV described herein, or an immunogenic composition described herein provides some protection against COVID-19 that is not caused by or associated a SARS- CoV-2 Wuhan strain, as assessed by an assay described herein or known to one of skill in the art.
  • the immune response resulting from administration of an immunogenic composition described herein induces antibodies that are cross-reactive with SARS-CoV-2 spike proteins which are not found or from which the ectodomain or a fragment thereof is not derived.
  • the antibodies that are cross-reactive include neutralizing antibodies.
  • the immune response resulting from administration of an immunogenic composition described herein provides some protection (e.g., partial protection) against a SARS-CoV-2 variant, wherein the SARS-CoV-2 variant is different than the SARS- CoV-2 from which the spike protein ectodomain or a fragment thereof is derived and included in the immunogenic composition.
  • a recombinant NDV described herein or an immunogenic composition described herein, or a combination therapy described herein is administered to a patient to prevent the onset of one, two or more symptoms of COVID-19.
  • the administration of a recombinant NDV described herein or an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the onset or development of one, two or more symptoms of COVID-19, or reduces the severity of one, two or more symptoms of COVID-19.
  • the administration of a recombinant NDV described herein or an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the onset or development of one, two or more symptoms of COVID-19 and reduces the severity of one, two or more symptoms of COVID-19.
  • Symptoms of COVID-19 include congested or runny nose, cough, fever, sore throat, fatigue, headache, wheezing, rapid or shallow breathing or difficulty breathing, bluish color the skin due to lack of oxygen, chills, muscle pain, loss of taste and/or smell, nausea, vomiting, and diarrhea.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the spread of SARS-CoV-2 infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the spread of SARS-CoV-2 delta variant virus infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the spread of SARS-CoV-2 gamma variant virus infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the spread of SARS-CoV-2 beta variant virus infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents the spread of SARS-CoV-2 Wuhan strain infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents hospitalization.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents recurring SARS-CoV-2 beta variant virus infections.
  • the administration of a recombinant ND V described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents recurring SARS-CoV-2 Wuhan strain infection.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject prevents asymptomatic SARS-CoV-2 infection.
  • the administration of a recombinant ND V described herein, or an immunogenic composition described herein induces antibodies to SARS-CoV-2 spike protein.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces antibodies specific to SARS-CoV-2 spike protein.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 delta variant spike protein if it binds to the SARS-CoV-2 delta variant spike protein with a higher affinity than a spike protein that is not a SARS-CoV-2 delta spike protein, or other unrelated protein.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 delta variant spike protein if it binds to the SARS-CoV-2 delta virus spike protein with a higher affinity than a SARS-CoV-2 spike protein that is not a SARS-CoV-2 delta variant spike protein.
  • an antibody(ies) specific for SARS-CoV-2 delta variant spike protein may bind to a SARS-CoV-2 delta virus spike protein with a 10 fold higher for affinity than the antibody(ies) binds to a SARS-CoV-2 spike protein that is not a SARS-CoV-2 delta variant.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 gamma variant spike protein if it binds to the SARS-CoV-2 gamma variant spike protein with a higher affinity than a spike protein that is not a SARS-CoV-2 gamma spike protein, or other unrelated protein.
  • an antibody(ies) specific for SARS-CoV-2 gamma variant spike protein may bind to a SARS-CoV-2 gamma variant spike protein with a 10 fold higher for affinity than the antibody(ies) binds to a spike protein that is not a SARS-CoV-2 gamma variant spike protein, or other unrelated protein.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces antibodies specific to SARS-CoV-2 gamma variant spike protein.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 gamma variant spike protein if it binds to the SARS- CoV-2 gamma variant spike protein with a higher affinity than a SARS-CoV-2 spike protein that is not a SARS-CoV-2 gamma variant spike protein.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 beta variant spike protein if it binds to the SARS-CoV-2 beta variant spike protein with a higher affinity than a spike protein that is not a SARS-CoV-2 beta variant spike protein, or other unrelated protein.
  • an antibody(ies) specific for SARS-CoV-2 beta virus spike protein may bind to a SARS-CoV-2 beta variant spike protein with a 10 fold higher for affinity than the antibody(ies) binds to a spike protein that is not a SARS-CoV-2 beta variant spike protein, or other unrelated protein.
  • an antibody(ies) specific for SARS-CoV-2 beta virus spike protein may bind to a SARS-CoV-2 beta variant spike protein with a 10 fold higher for affinity than the antibody(ies) binds to a SARS-CoV-2 spike protein that is not a SARS-CoV-2 beta variant.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces antibodies specific to SARS-CoV-2 Wuhan strain virus spike protein.
  • An antibody(ies) may specifically bind to a SARS-CoV-2 Wuhan strain spike protein if it binds to the SARS-CoV-2 Wuhan strain spike protein with a higher affinity than a SARS-CoV-2 spike protein that is not a SARS-CoV-2 Wuhan strain spike protein.
  • an antibody(ies) specific for SARS-CoV-2 beta virus spike protein may bind to a SARS-CoV-2 Wuhan strain spike protein with a 10 fold higher for affinity than the antibody(ies) binds to a SARS-CoV-2 spike protein that is not a SARS-CoV-2 Wuhan strain.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces an antibody(ies) that binds to the SI domain of a SARS-CoV-2 spike protein.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces a higher concentration of antibodies that bind to the SI domain of a SARS-CoV-2 spike protein than the concentration of antibodies that bind to the S2 domain of the SARS- CoV-2.
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces both mucosal and systemic antibodies to SARS-CoV-2 gamma variant spike protein (e.g., neutralizing antibodies).
  • the administration of a recombinant NDV described herein, or an immunogenic composition described herein induces both mucosal and systemic antibodies to SARS-CoV-2 Wuhan strain spike protein (e.g., neutralizing antibodies).
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 delta variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 beta variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 gamma variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 Wuhan strain spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 alpha spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 gamma variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 beta variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing IgG antibody to SARS-CoV-2 Wuhan strain spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces IgG antibody to SARS-CoV-2 spike protein at a level that is considerate moderate to high in an ELISA approved by the FDA for measuring antibody in a patient specimen.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces IgG antibody to SARS-CoV-2 delta variant spike protein at a level that is considerate moderate to high in an ELISA approved by the FDA for measuring antibody in a patient specimen.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces IgG antibody to SARS-CoV-2 gamma variant spike protein at a level that is considerate moderate to high in an ELISA approved by the FDA for measuring antibody in a patient specimen.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces IgG antibody to SARS-CoV-2 beta variant spike protein at a level that is considerate moderate to high in an ELISA approved by the FDA for measuring antibody in a patient specimen.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces IgG antibody to SARS-CoV-2 Wuhan strain spike protein at a level that is considerate moderate to high in an ELISA approved by the FDA for measuring antibody in a patient specimen.
  • the administration of a recombinant ND V described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing antibody to SARS-CoV-2 spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing antibody to SARS-CoV-2 delta variant spike protein.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces neutralizing antibody to SARS-CoV-2 gamma variant spike protein.
  • antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with one, two, three, four, or more, or all of the following: a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 alpha spike protein, a SARS-CoV-2 beta variant spike protein, a SARS-CoV-2 Mu variant spike protein, a SARS-CoV-2 Omicron variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, a SARS-CoV-2 beta variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, a SARS-CoV-2 beta variant spike protein, a SARS-CoV-2 Mu variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • neutralizing antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with one, two, three, four, or more, or all of the following: a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 alpha spike protein, a SARS-CoV- 2 beta variant spike protein, a SARS-CoV-2 Mu variant spike protein, a SARS-CoV-2 Omicron variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • neutralizing antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross-reacts with a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, a SARS-CoV-2 beta variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • neutralizing antibody induced by a recombinant NDV described herein, or an immunogenic composition described herein cross- reacts with a SARS-CoV-2 delta variant spike protein, a SARS-CoV-2 gamma variant spike protein, a SARS-CoV-2 beta variant spike protein, a SARS-CoV-2 Mu variant spike protein, and a SARS-CoV-2 Wuhan strain spike protein, as assessed by an assay described herein or known to one of skill in the art.
  • the administration of a recombinant ND V described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces robust, long-lived (e.g., 6 months, 1 year, 2 years, 3 years or more), antigen-specific humoral immunity.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject induces T cell immunity.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein (e.g., by intranasal administration) to a subject induces mucosal immunity.
  • the administration of a recombinant ND V described herein, an immunogenic composition described herein, or a combination therapy described herein (e.g., by intranasal administration) to a subject induces mucosal immunity which can lead to sterilizing immunity blocking infection and transmission.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein induces sterilizing immunity and complete prevention of onward transmission of SARS-CoV-2, as assessed by a method known to one of skill in the art.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein e.g., by intranasal administration
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein induces sterilizing immunity and reduces onward transmission of SARS-CoV-2 by at least 25%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, as assessed by a method known to one of skill in the art.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein induces sterilizing immunity and reduces onward transmission of SARS-CoV-2 delta virus by at least 25%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, as assessed by a method known to one of skill in the art.
  • an immunogenic composition described herein induces antibodies against one, two, three, four, or more, or all of the following: SARS-CoV-2 delta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 Omicron variant spike protein, SARS-CoV-2 Mu variant spike protein, SARS-CoV-2 alpha spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • the administration of an immunogenic composition described herein induces antibodies against SARS-CoV- 2 delta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • the administration of an immunogenic composition described herein induces antibodies against SARS-CoV-2 delta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 Mu variant spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • an immunogenic composition described herein induces neutralizing antibodies against one, two, three, four, or more, or all of the following: SARS- CoV-2 delta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 Omicron variant spike protein, SARS-CoV-2 Mu variant spike protein, SARS-CoV-2 alpha spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • the administration of an immunogenic composition described herein induces neutralizing antibodies against SARS-CoV-2 delta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • the administration of an immunogenic composition described herein e.g., by intranasal administration to a subject induces neutralizing antibodies against SARS-CoV-2 delta variant spike protein, SARS-CoV- 2 gamma variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 Mu variant spike protein, and SARS-CoV-2 Wuhan strain spike protein.
  • the administration of an immunogenic composition described herein induces a (partially or completely) protective immune response against a homologous SARS-CoV-2, such as, e.g., provided in Section 6, infra.
  • a homologous SARS-CoV-2 such as, e.g., provided in Section 6, infra.
  • the protective immune response is complete.
  • the protective immune response is partial.
  • an immunogenic composition described herein induces a (partially or completely) protective immune response against one, two, three, four, or more, or all of the following: SARS-CoV-2 delta variant, SARS-CoV-2 gamma variant, SARS- CoV-2 beta variant, SARS-CoV-2 alpha spike protein, SARS-CoV-2 Mu variant, SARS- CoV-2 Omicron variant, and SARS-CoV-2 Wuhan strain.
  • the administration of an immunogenic composition described herein (e.g., by intranasal administration) to a subject induces a (partially or completely) protective immune response against SARS-CoV-2 delta variant, SARS-CoV-2 gamma variant, SARS-CoV-2 beta variant, and SARS-CoV-2 Wuhan strain.
  • the administration of an immunogenic composition described herein (e.g., by intranasal administration) to a subject induces a (partially or completely) protective immune response against SARS-CoV-2 delta variant, SARS-CoV-2 gamma variant, SARS-CoV-2 beta variant, SARS-CoV-2 Mu variant, and SARS-CoV-2 Wuhan strain.
  • the protective immune response is complete. In some embodiments, the protective immune response is partial.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein exhibits very good immunogenicity.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein is safe and exhibits very low reactogenicity, as assessed by a method described herein or known in the art.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject may not result in injection site pain and/or transient influenza-like symptoms in the subject.
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein to a subject may result in less injection site pain and/or fewer transient influenza-like symptoms than one, two, or more authorized COVID-19 vaccines (e.g., Pfizer’s COVID-19 vaccine (BNT162b2), Moderna’s COVID-19 vaccine (mRNA-1273), Johnson & Johnson’s COVID-19 vaccine (Ad26.COV2.S), AstraZeneca’s COVID-19 vaccine, SinoVac’s COVID-19 vaccine, SinoPharm’s COVID-19 vaccine, Bharat’s COVID-19 vaccine, or Cansino’s COVID-19 vaccine).
  • COVID-19 vaccines e.g., Pfizer’s COVID-19 vaccine (BNT162b2), Moderna’s COVID-19 vaccine (mRNA-1273), Johnson & Johnson’s COVID-19 vaccine (Ad26.COV2.S
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein induces protective immunity in a subject (e.g., a human subject or non-human subject).
  • a subject e.g., a human subject or non-human subject
  • the administration of a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein induces immunity in a subject (e.g., a human subject or non-human subject) that protects (partially or completely) the subject from disease (e.g., COVID-19) due to subsequent infection by SARS-CoV-2 (e.g., SARS-CoV-2 delta virus infection).
  • SARS-CoV-2 e.g., SARS-CoV-2 delta virus infection
  • a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein is administered a subject (e.g., a human subject) with a condition that increases susceptibility to SARS-CoV-2 complications or for which SARS-CoV-2 increases complications associated with the condition.
  • conditions that increase susceptibility to SARS-CoV-2 complications or for which SARS-CoV-2 increases complications associated with the condition include conditions that affect the lung, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), emphysema, asthma, or bacterial infections (e.g., infections caused by Haemophilus influenzae, Streptococcus pneumoniae, Legionella pneumophila, and Chlamydia trachomatusy, cardiovascular disease (e.g., congenital heart disease, congestive heart failure, and coronary artery disease); and endocrine disorders (e.g., diabetes).
  • COPD chronic obstructive pulmonary disease
  • bacterial infections e.g., infections caused by Haemophilus influenzae, Streptococcus pneumoniae, Legionella pneumophila, and Chlamydia trachomatusy
  • cardiovascular disease e.g., congenital heart disease, congestive heart failure, and coronary artery disease
  • a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein is administered a subject (e.g., a human subject) that is a health care worker (e.g., a doctor or nurse).
  • a recombinant NDV described herein, an immunogenic composition described herein, or a combination therapy described herein is administered a subject (e.g., a human subject) that is a smoker.
  • a recombinant NDV or an immunogenic composition described herein which will be effective in the prevention of COVID-19, or immunization against SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) will depend on the route of administration, the general health of the subject, etc.
  • Suitable dosage ranges of a recombinant NDV for administration are generally about 10 4 to about 10 12 EID50, and can be administered to a subject once, twice, three, four or more times with intervals as often as needed.
  • a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 10 4 to about 10 12 EID50. In some embodiments, a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 10 5 to about 10 8 EID50. In some embodiments, a dose of about 10 4 to about 10 12 EID50 of a composition comprising live recombinant NDV is administered to a subject (e.g., human). In a specific embodiment, a live recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 10 7 to 10 9 EID50.
  • a dose of 10 7 to 10 9 EID50 of a composition comprising a live recombinant NDV described herein is administered to a subject (e.g., a human).
  • a live recombinant NDV described herein is administered to a subject (e.g., human) at a dose of about 10 8 to about 10 9 EID50.
  • a live recombinant NDV described herein is administered to a subject (e.g., human) at a dose of about 10 7 to about 10 8 EID50.
  • a dose of about 0.2 x 10 6 to about 0.5 x 10 6 EID50 of each recombinant NDV described herein is administered to a subject (e.g., human). In some embodiments, a dose of about 0.5 x 10 6 to about 10 6 EID50 of each recombinant NDV described herein is administered to a subject (e.g., human). In some embodiments, a dose of about 0.33 x 10 6 EID50 of each recombinant NDV described herein is administered to a subject (e.g., human). In some embodiments, a dose of recombinant NDV administered to a subject is a dose described in Section 6.
  • a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 1 to 15 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a derivative of SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or a portion thereof e.g.,
  • a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 1 to 10 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a derivative of a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or a portion thereof e
  • a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 1 microgram, 3 micrograms, or 10 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a recombinant NDV described herein is administered to a subject (e.g., human) at a dose of 4 micrograms, 5 micrograms, 6 micrograms, 7 micrograms, 8 micrograms or 9 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or
  • a composition described herein is administered to a subject (e.g., human) at a dose of 1 to 15 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a derivative of SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or a portion thereof e.g., a derivative of the
  • an immunogenic composition described herein is administered to a subject (e.g., human) at a dose of 1 to 10 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a derivative of SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or a portion thereof e.g., a derivative of the
  • an immunogenic composition NDV described herein is administered to a subject (e.g., human) at a dose of 1 microgram, 3 micrograms, or 10 micrograms of SARS- CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS- CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS- CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • an immunogenic composition described herein is administered to a subject (e.g., human) at a dose of 4 micrograms, 5 micrograms, 6 micrograms, 7 micrograms, 8 micrograms or 9 micrograms of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., the ectodomain of a SARS-CoV-2 spike protein), a derivative of SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or a portion thereof (e.g., a derivative of the ectodomain of a SARS-CoV-2 spike protein), or a chimeric F protein.
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • an immunogenic composition described herein is administered to a subject (e.g., human) at a dose of 10 to 100 micrograms of inactivated recombinant NDV described herein. In some embodiments, an immunogenic composition described herein is administered to a subject (e.g., human) at a dose of 10 to 100 micrograms of inactivated recombinant NDV described herein. In specific embodiments, an immunogenic composition described herein is administered to a subject (e.g., human) at a dose of 10 micrograms, 30 micrograms, or 100 micrograms of inactivated recombinant NDV described herein.
  • dosages of a recombinant NDV described herein, or a composition described herein similar to those currently being used in clinical trials for NDV are administered to a subject.
  • a dose(s) of a recombinant NDV used in Section 6 is administered to a subject.
  • a recombinant NDV or an immunogenic composition described herein is administered to a subject as a single dose followed by a second dose 1 to 6 weeks, 1 to 5 weeks, 1 to 4 weeks, 1 to 3 weeks, 1 to 2 weeks, 6 to 12 weeks, 3 to 6 months, 6 to 9 months, 6 to 12 months, or 6 to 9 months later.
  • a recombinant NDV or an immunogenic composition described herein is administered to a subject as a single dose followed by a second dose about 3 to about 6 months, about 6 to about 9 months, about 6 to about 12 months, or about 12 months later.
  • a recombinant NDV or an immunogenic composition described herein is administered to a subject as a single dose followed by a second dose about 6 months later.
  • booster inoculations may be administered to the subject at 3 to 6 month or 6 to 12 month intervals following the second inoculation.
  • booster inoculations may be administered to the subject at about 6 months following the second inoculation.
  • a subject is administered one or more boosters.
  • the recombinant NDV used for each booster may be the same or different.
  • the two, three, four, or more recombinant ND Vs described herein, or immunogenic compositions described herein administered to the subject may administered by the same or different routes.
  • administration of the same recombinant NDV or immunogenic composition may be repeated and the administrations may be separated by at least 7 days, 10 days, 14 days, 15 days, 21 days, 28 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • administration of the same recombinant NDV or immunogenic composition may be repeated and the administrations may be separated by 1 to 14 days, 1 to 7 days, 7 to 14 days, 1 to 30 days, 15 to 30 days, 15 to 45 days, 15 to 75 days, 15 to 90 days, 1 to 3 months, 3 to 6 months, 3 to 12 months, or 6 to 12 months.
  • the first recombinant NDV may comprise a packaged genome comprising a transgene that comprises a nucleotide sequence encoding a SARS-CoV-2 spike protein or portion thereof (e.g., ectodomain or receptor binding domain of the SARS-CoV-2 spike protein), and the second recombinant NDV may comprise a package genome comprising a transgene that comprises a nucleotide sequence encoding a chimeric F protein, wherein the chimeric F protein comprises a SARS-CoV-2 delta variant spike protein ectodomain or a derivative thereof and NDV F protein transmembrane and cytoplasmic domains.
  • the derivative of the SARS-CoV-2 spike protein ectodomain lacks the polybasic cleavage site (e.g., amino acid residues of the polybasic cleavage site (RRAR) are substituted with a single alanine), and amino acid residues corresponding to amino acid residues 817, 892, 899, 942, 986, and 987 of the spike protein found at GenBank Accession No. MN908947 are substituted with prolines.
  • the SARS-CoV-2 delta variant spike protein ectodomain or derivative thereof is fused to the NDV F protein transmembrane and cytoplasmic domains via a linker (e.g., GGGGS (SEQ ID NO:7)).
  • the linker comprises the sequence GGGGS (SEQ ID NO:7).
  • the NDV F protein transmembrane and cytoplasmic domains are fused directly to the SARS-CoV-2 spike protein ectodomain or derivative thereof. See, e.g., Sections 5.1 and 6 for examples of recombinant ND Vs.
  • the recombinant NDVs are ones described in Section 5.1 or 6.
  • the first and second recombinant NDVs, or first and second immunogenic compositions may be separated by at least 7 days, 10 days, 14 days, 15 days, 21 days, 28 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • the first and second recombinant NDVs, or immunogenic compositions may be separated by 1 to 14 days, 1 to 7 days, 7 to 14 days, 1 to 30 days, 15 to 30 days, 15 to 45 days, 15 to 75 days, 15 to 90 days, 1 to 3 months, 3 to 6 months, 3 to 12 months, 6 to 12 months, or about 12 months.
  • a first dose of a recombinant NDV described herein or an immunogenic composition described herein may be administered to a subject (e.g., a human) and a second dose of the recombinant NDV or immunogenic composition may be administered to the subject 3 to 6 weeks later.
  • a first dose of a recombinant NDV described herein or an immunogenic composition described herein may be administered to a subject (e.g., a human) and a second dose of the recombinant NDV or immunogenic composition may be administered to the subject about 21 days later.
  • a first dose of a recombinant NDV described herein or immunogenic composition may be administered to a subject (e.g., a human) and a second dose of the recombinant NDV or an immunogenic composition described herein may be administered to the subject about 3-6 months later.
  • a first dose of a recombinant NDV described herein or an immunogenic composition described herein may be administered to a subject (e.g., a human) and a second dose of the recombinant NDV or immunogenic composition may be administered to the subject about 6-12 months later.
  • a first dose of a recombinant NDV described herein or an immunogenic composition described herein may be administered to a subject (e.g., a human) and a second dose of the recombinant NDV or immunogenic composition may be administered to the subject about 12 months later.
  • the subject is administered two or more boosters of the recombinant NDV or the immunogenic composition.
  • a recombinant NDV described herein or an immunogenic composition described is administered as a booster to a subject previously vaccinated with a COVID-19 vaccine.
  • a recombinant NDV described herein or an immunogenic composition is administered as a booster to a subject that previously tested positive for SARS-CoV-2 e.g., by PCR or an antigen test).
  • the COVID-19 vaccine may be Pfizer’s COVID-19 vaccine (BNT162b2), Modema’s COVID-19 vaccine (mRNA-1273), AstraZeneca’s COVID-19 vaccine, Johnson & Johnson’s COVID-19 (Ad26.COV2.S), SinoVac’s COVID-19 vaccine, SinoPharm’s COVID-19 vaccine, Bharat’s COVID-19 vaccine, Cansino’s COVID-19 vaccine, or another COVID-19 vaccine.
  • the subject was previously vaccinated with a COVID-19 other than an immunogenic composition described herein.
  • the subject was previously vaccinated with a CO VID-19 other than a recombinant NDV-based COVID-19 vaccine.
  • a recombinant NDV described herein or an immunogenic composition described herein is administered as a booster to a subject previously infected with SARS-CoV-2.
  • a recombinant NDV described herein or an immunogenic composition described herein is administered as a booster to a subject previously diagnosed with a SARS-CoV-2 infection (e.g., a SARS-CoV-2 delta variant infection, a SARS-CoV-2 beta variant infection, a SARS-CoV-2 gamma variant infection, a SARS-CoV-2 Wuhan strain infection or another SARS-CoV-2 infection).
  • a SARS-CoV-2 infection e.g., a SARS-CoV-2 delta variant infection, a SARS-CoV-2 beta variant infection, a SARS-CoV-2 gamma variant infection, a SARS-CoV-2 Wuhan strain infection or another SARS-CoV-2 infection.
  • a recombinant NDV or an immunogenic composition described herein is administered to a subject in combination with one or more additional therapies, such as a therapy described in Section 5.5.3, infra.
  • the dosage of the other one or more additional therapies will depend upon various factors including, e.g., the therapy, the route of administration, the general health of the subject, etc. and should be decided according to the judgment of a medical practitioner.
  • the dose of the other therapy is the dose and/or frequency of administration of the therapy recommended for the therapy for use as a single agent is used in accordance with the methods disclosed herein. Recommended doses for approved therapies can be found in the Physician’s Desk Reference.
  • a recombinant NDV or an immunogenic composition described herein is administered to a subject concurrently with the administration of one or more additional therapies.
  • an immunogenic composition comprising recombinant NDV and a pharmaceutical composition comprising one or more additional therapies may be administered concurrently, or before or after each other.
  • the immunogenic composition and pharmaceutical composition are administered concurrently to the subject, or within 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours of each other.
  • Additional therapies that can be used in a combination with a recombinant NDV described herein or a composition thereof include, but are not limited to, acetaminophen, ibuprofen, throat lozenges, cough suppressants, inhalers, antibiotics, monoclonal antibodies, and oxygen.
  • the additional therapy is a second recombinant NDV described herein.
  • the additional therapy is a monoclonal antibody, such as sotrovimab.
  • the additional therapy(ies) may include remdesivir, sotrovimab, bamlanivimab plus etesevimab (Alla), casirivimab plus imdevimab (Alla), dexamethasone, tocilizumab, oxygen, or a combination thereof.
  • a recombinant NDV described herein, or an immunogenic composition described herein is administered to a non-human subject (e.g., a mouse, rat, etc.) and the antibodies generated in response to the polypeptide are isolated.
  • a non-human subject e.g., a mouse, rat, etc.
  • the antibodies may also be optimized.
  • the antibodies produced are humanized or chimerized.
  • the non-human subject produces human antibodies.
  • the antibodies produced using a recombinant NDV described herein, or an immunogenic composition described herein may be optimized, using techniques known to one of skill in the art.
  • antibodies generated using a recombinant NDV described herein, or an immunogenic composition described herein may be used to prevent, treat or prevent and treat COVID-19.
  • the antibodies generated using a recombinant NDV described herein, or an immunogenic composition described herein may be used in an immunoassay to detect SARS-CoV-2.
  • a recombinant NDV described herein is used in an immunoassay (e.g., an ELISA assay) known to one of skill in the art or described herein to detect antibody specific for SARS-CoV-2 spike protein (e.g., SARS-CoV-2 delta variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 gamma variant spike protein, SARS-CoV-2 Wuhan strain spike protein, or SARS-CoV-2 Mu variant spike protein).
  • an immunoassay e.g., an ELISA assay
  • a method for detecting the presence of antibody specific to SARS-CoV-2 spike protein comprising contacting a specimen with a recombinant NDV described herein in an immunoassay (e.g., an ELISA).
  • the specimen is a biological specimen.
  • the biological specimen is blood, plasma or sera from a subject (e.g., a human subject).
  • the specimen is an antibody or antisera.
  • one, two or more of the assays described in Section 6 may be used to characterize a recombinant NDV described herein, a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., the ectodomain or receptor binding domain of the SARS-CoV-2 spike protein), a derivative of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., the ectodomain or receptor binding domain of the SARS-CoV-2 spike protein), or a chimeric F protein.
  • a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • a derivative of a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or portion thereof e.g., the
  • one, two or more of the assays described in Section 6 may be used to characterize immunoglobulin samples from a subject (e.g., a human subject) administered a recombinant NDV described herein or a composition described herein, such as, e.g., described in the Example, infra (e.g., Section 6).
  • a subject e.g., a human subject
  • a composition described herein such as, e.g., described in the Example, infra (e.g., Section 6).
  • the IgG titer and microneutralization of IgG may be assessed as described herein or known to one of skill in the art.
  • a subject administered a recombinant ND V described herein or a composition described herein is assessed for anti-NDV antibodies as well as anti-SARS-CoV-2 spike protein antibodies (e.g., anti-SARS-CoV-2 Wuhan strain spike protein antibodies, anti- SARS-CoV-2 delta variant spike protein antibodies, anti-SARS-CoV-2 beta variant spike protein antibodies, or anti-SARS-CoV-2 gamma variant antibodies).
  • anti-SARS-CoV-2 spike protein antibodies e.g., anti-SARS-CoV-2 Wuhan strain spike protein antibodies, anti- SARS-CoV-2 delta variant spike protein antibodies, anti-SARS-CoV-2 beta variant spike protein antibodies, or anti-SARS-CoV-2 gamma variant antibodies.
  • Viral assays include those that indirectly measure viral replication (as determined, e.g., by plaque formation) or the production of viral proteins (as determined, e.g., by western blot analysis) or viral RNAs (as determined, e.g., by RT-PCR or northern blot analysis) in cultured cells in vitro using methods which are well known in the art.
  • Growth of the recombinant ND Vs described herein can be assessed by any method known in the art or described herein (e.g., in cell culture (e.g., cultures of BSTT7 or embryonated chicken cells) (see, e.g., Section 6).
  • Viral titer may be determined by inoculating serial dilutions of a recombinant ND V described herein into cell cultures (e.g., BSTT7 or embryonated chicken cells), chick embryos (e.g., 9 to 11 day old embryonated eggs), or live non-human animals. After incubation of the virus for a specified time, the virus is isolated using standard methods. Physical quantitation of the virus titer can be performed using PCR applied to viral supernatants (Quinn & Trevor, 1997; Morgan et al., 1990), hemagglutination assays, tissue culture infectious doses (TCID50) or egg infectious doses (EID50).
  • Immunofluorescence-based approaches may also be used to detect virus and assess viral growth. Such approaches are well known to those of skill in the art, e.g., fluorescence microscopy and flow cytometry. Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2 nd ed:, Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ).
  • FACS fluorescence activated cell sorting
  • Fluorescent reagents suitable for modifying nucleic acids including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).
  • Interferon (IFN) induction and release by a recombinant NDV described herein may be determined using techniques known to one of skill in the art.
  • the amount of IFN induced in cells following infection with a recombinant NDV described herein may be determined using an immunoassay (e.g., an ELISA or Western blot assay) to measure IFN expression or to measure the expression of a protein whose expression is induced by IFN.
  • the amount of IFN induced may be measured at the RNA level by assays, such as Northern blots and quantitative RT-PCR, known to one of skill in the art.
  • the amount of IFN released may be measured using an ELISPOT assay.
  • the IFN may be alpha, beta, or gamma. Further, the induction and release of cytokines and/or interferon-stimulated genes may be determined by, e.g., an immunoassay or ELISPOT assay at the protein level and/or quantitative RT-PCR or northern blots at the RNA level.
  • the levels of such protein and mRNA and activity can be determined by any method well known in the art.
  • protein can be quantitated by known immunodiagnostic methods such as ELISA, Western blotting or immunoprecipitation using antibodies, including commercially available antibodies.
  • mRNA can be quantitated using methods that are well known and routine in the art, for example, using northern analysis, RNase protection, or polymerase chain reaction in connection with reverse transcription.
  • Cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art.
  • the level of cellular ATP is measured to determined cell viability.
  • a recombinant NDV described herein or composition thereof does not kill healthy (z.e., non- cancerous) cells.
  • cell viability may be measured in three-day and seven- day periods using an assay standard in the art, such as the CellTiter-Glo Assay Kit (Promega) which measures levels of intracellular ATP. A reduction in cellular ATP is indicative of a cytotoxic effect.
  • cell viability can be measured in the neutral red uptake assay.
  • visual observation for morphological changes may include enlargement, granularity, cells with ragged edges, a filmy appearance, rounding, detachment from the surface of the well, or other changes.
  • the recombinant ND Vs described herein or compositions described herein, or combination therapies can be tested for in vivo toxicity in animal models.
  • animals are administered a range of pfu of a recombinant NDV described herein, and subsequently, the animals are monitored over time for various parameters, such as one, two or more of the following: lethality, weight loss or failure to gain weight, and levels of serum markers that may be indicative of tissue damage (e.g., creatine phosphokinase level as an indicator of general tissue damage, level of glutamic oxalic acid transaminase or pyruvic acid transaminase as indicators for possible liver damage).
  • tissue damage e.g., creatine phosphokinase level as an indicator of general tissue damage, level of glutamic oxalic acid transaminase or pyruvic acid transaminase as indicators for possible liver damage.
  • These in vivo assays may also be adapted to test the
  • the toxicity, efficacy or both of a recombinant NDV described herein or a composition thereof, or a combination therapy described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Therapies that exhibit large therapeutic indices are preferred.
  • the recombinant ND Vs described herein or compositions described herein, or combination therapies described herein can be tested for biological activity using animal models for inhibiting COVID-19, antibody response to the recombinant ND Vs, etc. (see, e.g., Section 6).
  • animal model systems include, but are not limited to, rats, mice, hamsters, cotton rats, chicken, cows, monkeys (e.g., African green monkey), pigs, dogs, rabbits, etc.
  • the recombinant ND Vs described herein, compositions described herein, or combination therapies described herein may be tested using animal models for the ability to induce a certain geometric mean titer of antibody(ies) that binds to the SARS-CoV-2 spike protein.
  • An immunoassay such as an ELISA, or known to one of skill in the art may be used to measure antibody titer.
  • the recombinant ND Vs described herein, compositions described herein, or combination therapies described herein may be tested using animal models for the ability to induce antibodies that have neutralizing activity against SARS-CoV-2 spike protein (e.g., SARS- CoV-2 delta virus spike protein) in a microneutralization assay.
  • the recombinant ND Vs described herein, compositions described herein, or combination therapies described herein may be tested using animal models for the ability to induce antibodies that neutralize SARS-CoV-2 (e.g., SARS-CoV-2 delta virus) in a microneutralization assay.
  • the recombinant NDVs described herein, compositions described herein, or combination therapies described herein may be tested using animal models for the ability to induce a certain geometric mean titer of antibody(ies) that binds to the SARS-CoV-2 spike protein (e.g., SARS-CoV-2 delta variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 gamma variant spike protein, or SARS-CoV-2 Wuhan strain spike protein) and neutralizes SARS-CoV-2 (e.g., SARS-CoV-2 delta variant, SARS-CoV-2 beta variant, SARS-CoV-2 gamma variant, or SARS-CoV-2 Wuhan strain) in a microneutralization assay.
  • SARS-CoV-2 spike protein e.g., SARS-CoV-2 delta variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 gamma variant spike protein, or SARS-CoV-2 Wuhan strain spike protein
  • the recombinant NDVs described herein or compositions thereof, or combination therapies described herein may be tested using animal models for the ability to induce a certain geometric mean titer of antibody(ies) that binds to the SARS-CoV-2 spike protein (e.g., SARS-CoV-2 delta variant spike protein, SARS-CoV-2 beta variant spike protein, SARS-CoV-2 gamma variant spike protein, or SARS-CoV-2 Wuhan strain spike protein) and neutralizes SARS-CoV-2 (e.g., SARS-CoV-2 delta variant, SARS-CoV-2 beta variant, SARS-CoV-2 gamma variant, or SARS-CoV-2 Wuhan strain) in a microneutralization assay such as described herein.
  • the recombinant ND Vs described herein, or compositions described herein, or combination therapies described herein may be tested using animal models for the ability to induce a protective immune response.
  • a recombinant NDV described herein, a composition described herein, or a combination therapy described herein is administered (e.g., intramuscularly or intravenously) to a subject(s) (e.g., a mouse or mice), a certain number of days later the subject(s) is transduced or otherwise administered a non-replicating human angiotensin converting enzyme-2, and then subsequently infected with SARS-CoV-2. See, e.g., Section 6 for a description of such a model.
  • the protection from infection with the SARS-CoV-2, the antibody response induced by the recombinant NDV, composition, or combination therapy, and/or the cellular immune response induced by the recombinant NDV, composition, or combination therapy may be assessed using techniques known to one of skill in the art or described herein.
  • a recombinant NDV described herein, a composition described herein, or a combination therapy described herein may be tested in a clinical trial study.
  • a recombinant ND V described herein, a composition described herein, or a combination therapy described herein is administered to a human subject.
  • a human subject administered a recombinant NDV described herein, a composition described herein, or a combination therapy described herein may be assessed for one, two or more, or all of the following may be assessed following administration of a recombinant NDV described herein, or a composition described herein, or a combination therapy described herein: GMT, anti-SARS-CoV-2 spike protein Ig (e.g., IgG, IgA, IgM, etc.), T cell response, NT50 seropositive response, NT80 seropositive response, T cell response, anti-NDV HN antibody, and anti-NDV F antibody.
  • GMT anti-SARS-CoV-2 spike protein Ig
  • IgG anti-SARS-CoV-2 spike protein
  • T cell response e.g., IgG, IgA, IgM, etc.
  • NT50 seropositive response NT80 seropositive response
  • T cell response anti-NDV HN antibody
  • anti-NDV F antibody anti-NDV
  • SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or portion thereof e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain
  • a derivative of a SARS-CoV-2 e.g., Wuhan strain, delta variant, beta variant, or gamma variant
  • spike protein or portion thereof e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain
  • a chimeric F protein in cells infected with a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS- CoV-2 spike protein ectodomain or receptor binding domain), a derivative of a SARS-CoV-2 (e.g., Wuhan strain,
  • ELISA is utilized to detect expression of a SARS-CoV-2 2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 delta variant spike protein ectodomain or receptor binding domain), a derivative of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain), or a chimeric F protein in cells infected with a recombinant NDV comprising a packaged genome comprising a transgene that comprises a nucleotide sequence encoding of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain).
  • a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain), a derivative of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS- CoV-2 spike protein ectodomain or receptor binding domain), or a chimeric F protein encoded by a packaged genome of a recombinant NDV described herein is assayed for proper folding by testing its ability to bind specifically to an anti -SARS-CoV-2 spike protein (e.g., anti -SARS-CoV-2 delta variant spike protein antibody, anti-SARS-CoV-2 beta variant spike protein antibody, anti-SARS-CoV-2 gamma variant spike protein antibody, or anti-SARS- CoV-2 Wuhan strain spike protein
  • a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain), a derivative of a SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain), or a chimeric F protein encoded by a packaged genome of a recombinant NDV described herein is assayed for proper folding by determination of the structure or conformation of the SARS-CoV-2 (e.g., Wuhan strain, delta variant, beta variant, or gamma variant) spike protein or portion thereof (e.g., SARS-CoV-2 spike protein ectodomain or receptor binding domain), a derivative of a SARS- CoV-2 (e.g., Wuhan strain, delta

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KR1020247033613A KR20240161963A (ko) 2022-03-10 2023-03-09 Covid-19을 예방하는 데 사용하기 위한 재조합 뉴캐슬병 바이러스 및 면역원성 조성물
CN202380026690.5A CN119317446A (zh) 2022-03-10 2023-03-09 用于预防covid-19的重组新城疫病毒和免疫原性组合物
AU2023231285A AU2023231285A1 (en) 2022-03-10 2023-03-09 Recombinant newcastle disease viruses and immunogenic compositions for use in preventing covid-19
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JP2024553586A JP2025509352A (ja) 2022-03-10 2023-03-09 Ｃｏｖｉｄ－１９の予防に使用するための組み換え型ニューカッスル病ウイルスおよび免疫原性組成物
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