WO2023067450A1 - Compositions and methods for improving the immune response to sars-cov2 - Google Patents

Compositions and methods for improving the immune response to sars-cov2 Download PDF

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WO2023067450A1
WO2023067450A1 PCT/IB2022/059870 IB2022059870W WO2023067450A1 WO 2023067450 A1 WO2023067450 A1 WO 2023067450A1 IB 2022059870 W IB2022059870 W IB 2022059870W WO 2023067450 A1 WO2023067450 A1 WO 2023067450A1
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seq
sars
cov2
composition
mcrag
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PCT/IB2022/059870
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French (fr)
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Rodrigo BACIGALUPE
Andrea DEL CORTONA
Nicolas Frederic DELAHAYE
Christophe Lambert
Benjamin Wizel
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Glaxosmithkline Biologicals Sa
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Publication of WO2023067450A1 publication Critical patent/WO2023067450A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747Lactobacilli, e.g. L. acidophilus or L. brevis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
    • A61K39/09Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/51Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/523Bacterial cells; Fungal cells; Protozoal cells expressing foreign proteins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/54Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541Mucosal route
    • A61K2039/542Mucosal route oral/gastrointestinal
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses

Definitions

  • Structural glycoproteins for the SAR-CoV2 virus include Spike/Surface (S), Envelop (E), Membrane (M) and Nucleocapsid (N).
  • S Spike/Surface
  • E Envelop
  • M Membrane
  • N Nucleocapsid
  • the S glycoprotein is reported to have a crucial role in the virus transmission as the receptor binding capability and entry to the host cell is regulated by the expression of S glycoprotein.
  • the E and M glycoproteins are responsible for viral assembly and N glycoprotein is necessary for RNA genome synthesis (see, Schoeman & Fielding, Virol. J. 16:69 (2019)).
  • the complex genetic makeup and high mutation rate of SARS-CoV-2 suggests the strategic development of a vaccine by targeting all the structural proteins.
  • microbiome-derived compositions and methods that can improve immune response to SARS-CoV2 and SARS-CoV2 vaccine antigens.
  • the provided improved methods include methods of prevention and treatment, as well as other uses of the microbiome- derived strains or microbiota, purified cells, compositions, and screening methods that will be apparent to those of skill in the art from the present teachings.
  • the present disclosure relates to a bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (mCRAg).
  • the bacterial cell is a recombinant bacterial cell that is engineered to express at least one SARS-CoV2 mCRAg.
  • the bacterial cell is derived from a bacterial strain, that is present in the human gut microbiome.
  • the present disclosure also relates to a composition comprising a bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (SARS-CoV2 mCRAg).
  • the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:1, SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6.
  • the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; and SEQ ID NO:21.
  • the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; and SEQ ID NO:30.
  • the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67; SEQ ID NO: 68; SEQ ID NO: 69; SEQ ID NO: 70; SEQ ID NO: 71; SEQ ID NO: 72; SEQ ID NO: 79; and SEQ ID NO: 80.
  • the at least one SARS-CoV2 mCRAg comprises a sequence selected from the group consisting of SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64; SEQ ID NO: 65; and SEQ ID NO: 78.
  • compositions comprising at least one bacterial strain selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG- 83(MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • Bacteroides dorei selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Oscillo
  • compositions comprising at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:76; and SEQ ID NO: 77.
  • the present disclosure also relates to compositions comprising at least two bacterial cells expressing at least one SARS-CoV2 mCRAg, such as comprising at least two of the bacterial strains disclosed herein.
  • a further embodiment is a composition that comprises the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • a further embodiment is a composition that comprises the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition is a pharmaceutical composition comprising a bacterial cell or SARS-CoV2 mCRAg as described herein, and a pharmaceutically acceptable excipient.
  • the embodiment comprising a pharmaceutical composition can further comprise a SARS-CoV2 vaccine.
  • kits comprising a composition as described herein, and a SARS-CoV2 vaccine.
  • a further embodiment of the present disclosure is a composition as described herein, formulated for delivery to the intestine.
  • An additional embodiment of the present disclosure relates to a nutraceutical composition, comprising a composition, bacterial cell, or SARS-CoV2 mCRAg as described herein, and optionally a nutrient.
  • An additional embodiment of the present disclosure is a vaccine comprising at least one SARS-CoV2 mCRAg.
  • the present disclosure also relates to a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject, the method comprising administering to the subject an immunologically effective amount of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition.
  • the present disclosure also relates to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of a composition as described herein.
  • the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises at least one SARS-CoV2 mCRAg selected from the group consisting of SEQ ID NOS: 1-30; 66-72, and 79-80.
  • the composition comprises at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 31- 35 and SEQ ID NOS: 73-77.
  • the at least one bacterial strain comprises a sequence selected from the group consisting of SEQ ID NOS: 58-65 and SEQ ID NO: 78.
  • the present disclosure also relates to a method of inducing an immune response to a SARS- CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition.
  • the present disclosure also relates to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of a composition as described herein.
  • the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises at least one SARS-CoV2 mCRAg selected from the group consisting of SEQ ID NOS: 1-30; 66-72, and 79-80.
  • the composition comprises at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 31-35 and SEQ ID NOS: 73-77.
  • the at least one bacterial strain comprises a sequence selected from the group consisting of SEQ ID NOS: 58-65 and 78.
  • the composition is administered in conjunction with a SARS-CoV2 vaccine, such as administered before, contemporaneous with, or after the administration of a SARS- CoV2 vaccine.
  • the present disclosure also relates to a method of identifying human gut microbiome species that express at least one SARS-CoV2 mCRAg, the method comprising the steps of identifying epitopes utilized by B-cells and T-cells to mount immune responses against SARS-CoV2; breaking the identified epitopes into peptide fragments ranging in length from about 9-mer to about 15-mer; comparing the peptide fragments to the protein sequences present in the Unified Human Gastrointestinal Genome (UHGG) collection, allowing one mismatch, thereby identifying overlapping epitopes; classifying the matches into types based on the number of overlapping epitopes present within the polypeptide and the pattern of the matching and mismatching peptides; using match types where the number of overlapping epitopes is three or greater to identify the sequence as a SARS-CoV2 epitope; using the match records to identify polypeptide sequences of interest comprising the SARS- CoV2 epitope as a SARS-CoV
  • the method can further comprise classifying the polypeptides identified as SARS-CoV2 mCRAgs as likely binding class I or class II HLA antigens.
  • the present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • a composition as disclosed herein such as a pharmaceutical or nutraceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine.
  • FIG.1 provides a flow chart summarizing the screening method of the present disclosure.
  • FIG.2A provides a schematic visualization of the different kinds of alignments obtained after 9-mers overlap and their corresponding metrics.
  • Type 7, Type 9, and Type 10 alignments contained hits with perfect matches between SARS-CoV29-mers and mCRAg polypeptides.
  • the example boxes show how mock consecutive 9-mers would be overlapped and extended into mock alignments, 9-mers with perfect matches are reported in bold.
  • # 9-mers number of SARS-CoV29-mers overlapped in the alignment
  • Leength final length of the alignment
  • Metations number of mismatches between the final alignment and the mCRAg polypeptide
  • Counter number of alignments of that Type generated.
  • FIG. 2B provides the classification of Type 1 alignments derived from SARS-CoV2 immunogenic epitopes/database protein matches (e.g., Universal Human Gut Proteome (UHGP-100, hereafter UHGP) (see, Almeida et al., Nature Biotech.
  • UHGP Universal Human Gut Proteome
  • FIG.3 graphically illustrates the number of distinct MHC alleles predicted to bind to SuperBugs mCRAgs.
  • Each of the 258 mCRAg polypeptides in the SuperBugs having matched with SARS-CoV2 epitopes are represented by a dot indicating the number of MHC alleles that they are predicted to bind to. Dots representing the same number of count overlap. Lines connect the predicted binding MHC-I and MHC-II alleles for the same mCRAg polypeptide.
  • FIG. 4 provides a graphic representation of the five bacterial strains, the SARS epitopes and mCRAg polypeptides expressed by the strains, and the MHC class I and class II binding for the utilized epitopes. These five strains represent an exemplary bacterial consortium for use in the improvement of the immune response against SARS-CoV2.
  • SEQ ID NO: 1 is the amino acid sequence encoded by the gufA gene, polypeptide accession GUT_GENOME093168_03303, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 2 is the amino acid sequence encoded by the uspA gene, polypeptide accession GUT_GENOME000481_00590, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 3 is the amino acid sequence encoded by the mscL gene, polypeptide accession GUT_GENOME025743_00100, uncharacterized Dakarella, and Mgnify accession MGYG-HGUT- 02447.
  • SEQ ID NO: 4 is the amino acid sequence encoded by the mnmE gene, polypeptide accession GUT_GENOME044080_00407, uncharacterized Faecalibacterium, and Mgnify accession MGYG- HGUT-00636.
  • SEQ ID NO: 5 is the amino acid sequence encoded by the pacL gene, polypeptide accession GUT_GENOME220297_01074, Sutterella wadsworthensis, and Mgnify accession MGYG-HGUT- 01410.
  • SEQ ID NO: 6 is the amino acid sequence encoded by the ybiR gene, polypeptide accession GUT_GENOME155999_02417, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 7 is the amino acid sequence encoded by the algI gene, polypeptide accession GUT_GENOME015529_01518, uncharacterized Lachnospira, and Mgnify accession MGYG- HGUT-02559.
  • SEQ ID NO: 8 is the amino acid sequence encoded by the brnQ gene, polypeptide accession GUT_GENOME000310_01026, Lactobacillus salivarius, and Mgnify accession MGYG-HGUT- 02324.
  • SEQ ID NO: 9 is the amino acid sequence encoded by the comEC gene, polypeptide accession GUT_GENOME205549_00776, Eubacterium sp003491505, and Mgnify accession MGYG-HGUT- 00209.
  • SEQ ID NO: 10 is the amino acid sequence encoded by the cydB gene, polypeptide accession GUT_GENOME000655_02696, Parabacteroides johnsonii, and Mgnify accession MGYG-HGUT- 00138.
  • SEQ ID NO: 11 is the amino acid sequence encoded by the cydC gene, polypeptide accession GUT_GENOME204275_00061, Mitsuokella jalaludinii, and Mgnify accession MGYG-HGUT- 00027.
  • SEQ ID NO: 12 is the amino acid sequence encoded by the gluP gene, polypeptide accession GUT_GENOME236875_01017, uncharacterized Parabacteroides, and Mgnify accession MGYG- HGUT-03521.
  • SEQ ID NO: 13 is the amino acid sequence encoded by the guaB gene, polypeptide accession GUT_GENOME027624_00533, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 14 is the amino acid sequence encoded by the Int gene, polypeptide accession GUT_GENOME029617_01714, Akkermansia muciniphila, and Mgnify accession MGYG-HGUT- 02454.
  • SEQ ID NO: 15 is the amino acid sequence encoded by the mltG gene, polypeptide accession GUT_GENOME008300_00218, uncharacterized Sutterella, and Mgnify accession MGYG-HGUT- 02101.
  • SEQ ID NO: 16 is the amino acid sequence encoded by the murJ gene, polypeptide accession GUT_GENOME027371_00296, Campylobacter hominis, and Mgnify accession MGYG-HGUT- 02479.
  • SEQ ID NO: 17 is the amino acid sequence encoded by the napF gene, polypeptide accession GUT_GENOME096975_01040, uncharacterized Bacteroides, and Mgnify accession MGYG-HGUT- 02622.
  • SEQ ID NO: 18 is the amino acid sequence encoded by the nqrF gene, polypeptide accession GUT_GENOME022949_00826, Caecibacter massiliensis, and Mgnify accession MGYG-HGUT- 01561.
  • SEQ ID NO: 19 is the amino acid sequence encoded by the spoVB gene, polypeptide accession GUT_GENOME130358_01140, UC5-1-2E3 sp001304875, and Mgnify accession MGYG-HGUT- 02136.
  • SEQ ID NO: 20 is the amino acid sequence encoded by the tcaB gene, polypeptide accession GUT_GENOME207411_00191, Gemella sp002871655, and Mgnify accession MGYG-HGUT-03121.
  • SEQ ID NO: 21 is the amino acid sequence encoded by the ydeD gene, polypeptide accession GUT_GENOME009027_01847, ER4 sp000765235, and Mgnify accession MGYG-HGUT-03686.
  • SEQ ID NO: 22 is the amino acid sequence encoded by the ypdA_4 gene, polypeptide accession GUT_GENOME096294_04674, Bacteroides oleiciplenus, and Mgnify accession MGYG-HGUT- 01422.
  • SEQ ID NO: 23 is the amino acid sequence encoded by the emrB gene, polypeptide accession GUT_GENOME003305_01683, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705.
  • SEQ ID NO: 24 is the amino acid sequence encoded by the acgS gene, polypeptide accession GUT_GENOME027892_01421, Acidaminococcus fermentans, and Mgnify accession MGYG-HGUT- 00901.
  • SEQ ID NO: 25 is the amino acid sequence encoded by the dcuD_1 gene, polypeptide accession GUT_GENOME096035_03870, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705.
  • SEQ ID NO: 26 is the amino acid sequence encoded by the gpsA gene, polypeptide accession GUT_GENOME095707_00513, uncharacterized Oscillospiraceae, and Mgnify accession MGYG- HGUT-01286.
  • SEQ ID NO: 27 is the amino acid sequence encoded by the IspA gene, polypeptide accession GUT_GENOME235066_01263, uncharacterized Duodenibacillus, and Mgnify accession MGYG- HGUT-00525.
  • SEQ ID NO: 28 is the amino acid sequence encoded by the menD gene, polypeptide accession GUT_GENOME006420_00274, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 29 is the amino acid sequence encoded by the nhaR gene, polypeptide accession GUT_GENOME000659_00630, CAG-56 sp900066615, and Mgnify accession MGYG-HGUT-00140.
  • SEQ ID NO: 30 is the amino acid sequence encoded by the ydbH gene, polypeptide accession GUT_GENOME096035_02490, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705.
  • SEQ ID NO: 31 is the 16S rRNA sequence of a strain of Bacteroides dorei, Mgnify accession MGYG-HGUT-02478.
  • SEQ ID NO: 32 is the 16S rRNA sequence of a strain of Pluralibacter gergoviae, Mgnify accession MGYG-HGUT-02520.
  • SEQ ID NO: 33 is the 16S rRNA sequence of a strain of Clostridium symbiosum, Mgnify accession MGYG-HGUT-01367.
  • SEQ ID NO: 34 is the 16S rRNA sequence of a strain of Eggerthella lenta, Mgnify accession MGYG-HGUT-02544.
  • SEQ ID NO: 35 is the 16S rRNA sequence of a strain of Oscillospiraceae strain Genus CAG- 83, Mgnify accession MGYG-HGUT-02617.
  • SEQ ID NO: 36 is the amino acid sequence of an identified epitope of the Nsp8 protein of the SARS-CoV2 virus (Nsp8(A)).
  • SEQ ID NO: 37 is the amino acid sequence of an identified epitope of the Nsp8 protein of the SARS-CoV2 virus (Nsp8(B)).
  • SEQ ID NO: 38 is the amino acid sequence of an identified epitope of the 3C-like protease of the SARS-CoV2 virus (3C-like protease (A)).
  • SEQ ID NO: 39 is the amino acid sequence of an identified epitope of the 3C-like protease of the SARS-CoV2 virus (3C-like protease (B)).
  • SEQ ID NO: 40 is the amino acid sequence of an identified epitope of the spike glycoprotein of the SARS-CoV2 virus (spike glycoprotein).
  • SEQ ID NO: 41 is the amino acid sequence of an identified epitope of the Envelop protein of the SARS-CoV2 virus (Envelop (A)).
  • SEQ ID NO:42 is the amino acid sequence of an identified epitope of the Envelop protein of the SARS-CoV2 virus (Envelop (B)).
  • SEQ ID NO: 43 is the amino acid sequence of an identified epitope of the Membrane protein of the SARS-CoV2 virus (Membrane).
  • SEQ ID NO: 44 is the amino acid sequence of an identified epitope of the Nucleocapsid protein of the SARS-CoV2 virus (Nucleocapsid (A)).
  • SEQ ID NO: 45 is the amino acid sequence of an identified epitope of the Nucleocapsid protein of the SARS-CoV2 virus (Nucleocapsid (B)).
  • SEQ ID NO: 46 is the amino acid sequence of an identified epitope of the Surface protein of the SARS-CoV2 virus (Surface (A)).
  • SEQ ID NO: 47 is the amino acid sequence of an identified epitope of the Surface protein of the SARS-CoV2 virus (Surface (B)).
  • SEQ ID NO: 48 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 1 overlap and extension process.
  • SEQ ID NO: 49 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 2 overlap and extension process.
  • SEQ ID NO: 50 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 3 overlap and extension process.
  • SEQ ID NO: 51 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 4 overlap and extension process.
  • SEQ ID NO: 52 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 5 overlap and extension process.
  • SEQ ID NO: 53 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 6 overlap and extension process.
  • SEQ ID NO: 54 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 7 overlap and extension process.
  • SEQ ID NO: 55 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 8 overlap and extension process.
  • SEQ ID NO: 56 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 9 overlap and extension process.
  • SEQ ID NO: 57 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 10 overlap and extension process.
  • SEQ ID NO: 58 is a Super Epitope of the SARS-CoV2 virus, Envelop_5, as defined herein.
  • SEQ ID NO: 59 is a Super Epitope of the SARS-CoV2 virus, Envelop_8, as defined herein.
  • SEQ ID NO: 60 is a Super Epitope of the SARS-CoV2 virus, Envelop_9, as defined herein.
  • SEQ ID NO: 61 is a Super Epitope of the SARS-CoV2 virus, Envelop_10, as defined herein.
  • SEQ ID NO: 62 is a Super Epitope of the SARS-CoV2 virus, Nucleocapsid_A_4, as defined herein.
  • SEQ ID NO: 63 is a Super Epitope of the SARS-CoV2 virus, Surface_B_2 as defined herein.
  • SEQ ID NO: 64 is a Super Epitope of the SARS-CoV2 virus, Surface_B_3 as defined herein.
  • SEQ ID NO: 65 is a Super Epitope of the SARS-CoV2 virus, Surface_B_4 as defined herein.
  • SEQ ID NO: 66 is an amino acid sequence encoded by the tig gene, polypeptide accession GUT_GENOME032335_01288, Oscillospiraceae strain ER4 sp000765235, and Mgnify accession MGYG-HGUT-03686.
  • SEQ ID NO: 67 is an amino acid sequence encoded by the oatA gene, polypeptide accession GUT_GENOME225847_00067, Lactobacillus gasseri_A, and Mgnify accession MGYG-HGUT- 02387.
  • SEQ ID NO: 68 is an amino acid sequence encoded by the rnc gene, polypeptide accession GUT_GENOME098263_02121, Pyramidobacter piscolens, and Mgnify accession MGYG-HGUT- 01589.
  • SEQ ID NO: 69 is an amino acid sequence encoded by the cdsA gene, polypeptide accession GUT_GENOME103719_00895, Butyricicoccus pullicaecorum, and Mgnify accession MGYG- HGUT-01434.
  • SEQ ID NO: 70 is an amino acid sequence encoded by the cadA gene, polypeptide accession GUT_GENOME142486_01853, Lactobacillus agilis, and Mgnify accession MGYG-HGUT-02390.
  • SEQ ID NO: 71 is an amino acid sequence encoded by the dltB gene, polypeptide accession GUT_GENOME000963_02927, Faecalicatena orotica, and Mgnify accession MGYG-HGUT-00176.
  • SEQ ID NO: 72 is an amino acid sequence encoded by the yaoK gene, polypeptide accession GUT_GENOME142485_00268, Lactobacillus sakei, and Mgnify accession MGYG-HGUT-02389.
  • SEQ ID NO: 73 is the 16S rRNA sequence of a strain of Butyricicoccus pullicaecorum, Mgnify accession MGYG-HGUT-01434.
  • SEQ ID NO: 74 is the 16S rRNA sequence of a strain of Lactobacillus agilis, Mgnify accession MGYG-HGUT-02390.
  • SEQ ID NO: 75 is the 16S rRNA sequence of a strain of Faecalicatena orotica, Mgnify accession MGYG-HGUT-00176.
  • SEQ ID NO: 76 is the 16S rRNA sequence of a strain of Lactobacillus sakei, Mgnify accession MGYG-HGUT-02389.
  • SEQ ID NO: 77 is the 16S rRNA sequence of a strain of Lactobacillus salivarius, Mgnify accession MGYG-HGUT-02324.
  • SEQ ID NO: 78 is a Super Epitope of the SARS-CoV2 virus, Nucleocapsid_A_2 as defined herein.
  • SEQ ID NO: 79 is an amino acid sequence encoded by a hypothetical gene (hypo), Loris_LMG9848_WP_003713042.1, Limosilactobacillus oris (strain ID LMG 9848).
  • SEQ ID NO: 80 is an amino acid sequence encoded by the htmp gene (heavy metal translocating P-type ATPase), Lfermentum_LMG6902_WP_003681665.1, Limosilactobacillus fermentum (strain ID LMG 6902).
  • a “microbiota-derived cross-reactive antigen” (“mCRAg”) is a polypeptide expressed by the human bacterial microbiome that raises an immune response against at least one pathogenic protein epitope.
  • a “SARS-CoV-2 mCRAg” is a polypeptide expressed by the human gut microbiome that raises an immune response against at least one SARS-CoV-2 protein epitope.
  • mCRAgs In order to raise cross- reactivity, mCRAgs must align to at least 9 amino acids of a pathogenic protein epitope (e.g., SARS- CoV-2), allowing for no more than two amino acid mismatches in the aligned region.
  • SARS-CoV- 2 mCRAgs can be identified according to methods described herein.
  • the term “Simple mCRAg” is used to denote that a single SARS-CoV2 epitope aligns to a single polypeptide expressed by the human gut microbiome. This term describes a simple 1:1 relationship between a sequence section of the polypeptide and the SARS-CoV2 epitope, as illustrated in FIG.2B.
  • the term “Super mCRAg” is used to denote that at least two SARS-CoV2 epitopes align to a single polypeptide expressed by the human gut microbiome, as illustrated in FIG.2B.
  • a polypeptide is to be termed a Super mCRAg if there is at least one other distinct alignment to a SARS-CoV2 epitope found within the same polypeptide expressed by the same bacterial strain.
  • the further alignment can be a second alignment to the same SARS-CoV2 epitope in a different area of the polypeptide or an alignment with a different SARS-CoV2 epitope.
  • Super Bug is used to denote a bacterial strain found in the human gut microbiome that expresses two or more polypeptides that each comprise a sequence that aligns, as defined herein, with at least one SARS-CoV2 epitope, as illustrated in FIG.2B.
  • Super Epitope is used to denote a single SARS-CoV2 epitope that aligns, as defined herein, with sequences comprised within multiple mCRAg polypeptides expressed by different bacterial strains, as illustrated in FIG.2B.
  • hit protein is used to denote a bacterial polypeptide that comprises a sequence that aligns, as defined herein, with at least one SARS-CoV2 epitope.
  • substantially purified or “purified” as used herein refers to a bacterial cell, such as a bacterial strain, or a mixture of more than one bacterial cells or strains, that are substantially enriched in a sample.
  • the sample can be substantially purified or enriched for the bacterial strain or mixture of strains of interest such that the sample is at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99% or greater of the desired bacterial strain(s) or less than about 40%, 30%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the undesirable or other bacterial strains present. Purity and percentage of the various strains can be measured using standard laboratory procedures such as those provided in the Food and Drug Administration, Office of Regulatory Affairs, Pharmaceutical Microbiology Manual, Document Number ORA.007 (Rev. #2, August 25, 2020).
  • Human gut microbiome is the aggregate of all organisms of microbial scale that reside within the human gastrointestinal tract. Subset bacterial strains of the microbiome are denoted herein as “microbiota.”
  • Immuno response means the activation of a host's immune system, e.g., that of a subject, patient or mammal, in response to the introduction of an antigen.
  • the immune response can be in the form of a cellular, humoral, or mucosal immune response, or a mixture of these responses.
  • Protein protein
  • polypeptide are used interchangeably herein to denote a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modification.
  • a peptide can be natural, synthetic, or a modification or combination of natural and synthetic.
  • “Commensal” bacteria as used herein means symbiotic bacteria that inhabit a host and provide a benefit upon the host’s health.
  • the human gut microbiome and a subset of those bacterial strains, defined above as microbiota, are generally made up of commensal bacteria.
  • “Prebiotic” as used herein in its broadest sense can be anything added to a microbiota formulation that aids the growth of the bacteria. This can mean a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health.
  • “Probiotic” as used herein means live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.
  • “Postbiotic” as used herein are functional bioactive compounds that may confers a health benefit on the host.
  • Subject as used herein can mean a mammal that is in need of an increased immune response, through administration of the compositions provided herein, alone or in conjunction with a SARS- CoV2 vaccine or a SARS-CovV2 viral antigen.
  • the mammal can be, for example, a human, a chimpanzee, a dog, a cat, a horse, a cow, a mouse, or a rat.
  • immunologically effective amount or “immunologically effective dose” is a quantity of a composition (typically, an immunogenic composition) sufficient to elicit an immune response in a subject when administered alone or in conjunction with a SARS-CoV2 vaccine or a SARS-CoV2 viral antigen.
  • a composition typically, an immunogenic composition
  • the desired result is the production of an antigen-specific immune response that is capable of or contributes to protecting the subject against the pathogen, such as SARS-CoV2.
  • to obtain a protective immune response against a pathogen can require multiple administrations of the immunogenic composition.
  • the term immunologically effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining a protective immune response.
  • SARS-CoV2 severe Acute Respiratory Syndrome Coronavirus 2 refers to the virus that causes the respiratory disease called coronavirus disease 19 (COVID-19).
  • SARS-CoV2 encompasses a family of closely related variant viruses. See, e.g., Singh et al., Nature, 10: 16219 (2020); Ahmed et al., Viruses, 12(3):254 (2020); and Ahmad et al., Eur J Pharm Sci 151:105387 (Aug 1, 2020); Colson, et al., medRxiv 2021.09.10.21262922 (2021).
  • bitterraceutical and “nutraceutical composition” as used herein refer to an edible additive for food or beverage such that the substance provides a medicinal, health or immunological benefit to an animal, including a human, that ingests the nutraceutical.
  • antibiotic effect is used herein to describes the bacterial killing effect of antibiotic drugs. Within some methods of the present invention, antibiotic effect can be utilized to eliminate or reduce the levels of bacteria present in the subject so that dosing with compositions comprising bacterial cells of the present disclosure will result in a replacement of that bacterial population with bacterial cells of the present disclosure. All references cited herein are incorporated by reference in their entirety.
  • the present disclosure is based in part upon the discoveries that within polypeptides expressed by bacterial organisms, in particular those organisms that are components of the human gut microbiome, there are amino acid sequences expressed that align with those viral antigens that have been defined as the basis for T-cell or B-cell immunity to the SARS-CoV2 virus or a related virus.
  • the sequences within the polypeptides are SARS-CoV2 mCRAgs.
  • the present disclosure also is based in part upon the discovery and identification of specific SARS-CoV2 mCRAgs, the bacterial polypeptides that comprise those SARS-CoV2 mCRAgs, and the bacterial strains and purified cells that express the polypeptides that comprise the SARS-CoV2 mCRAgs and compositions thereof. Further, the present disclosure is based in part upon methods of increasing an immune response, pharmaceutical compositions and kits, nutraceuticals, and vaccines that comprise or utilize the SARS-CoV2 mCRAgs provided herein. mCRAg-Expressing Bacterial Cells The present disclosure describes bacterial cells that express mCRAg polypeptides that have been identified using the methods provided in this disclosure and its examples.
  • the methods provided in the examples provide support for the cross-reactivity between epitopes of SARS-CoV2 and the mCRAg polypeptide or polypeptides expressed by the bacterial cell.
  • the present disclosure therefore supports the use of such a bacterial cell for improving the immune response to SARS- CoV2.
  • the bacterial cell expresses at least one SARS-CoV2 mCRAg.
  • the bacterial cell of the present disclosure is a recombinant bacterial cell engineered to express at least one SARS-CoV2 mCRAg.
  • the bacterial cell of the present disclosure expresses at least one SARS-CoV2 mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NO: 58-65; or SEQ ID NO: 78.
  • the bacterial cell described in this disclosure expresses at least one mCRAg polypeptide with at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78.
  • the at least one bacterial cell is of a bacterial strain that is present in the human gut microbiome.
  • the present disclosure also provides derivatives of the bacterial cells which may be a daughter cell (progeny) or a cell cultured (subcloned) from the original.
  • a derivative of a bacterial cell of the present disclosure may be modified in any manner, for example at the genetic level, provided such modification does not ablate the immunological activity.
  • a derivative cell of the present disclosure is immunologically active.
  • a derivative cell will have comparable or improved positive immune modulatory activity to the immune response to SARS-CoV2 as the original.
  • the present disclosure provides a bacterial cell that is of at least one strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the bacterial cell can be of a bacterial strain selected from the group consisting of Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. These strains have been identified as natively expressing at least one mCRAg polypeptide of the present disclosure. In some embodiments, the bacteria are commensals. In other embodiments, the bacteria can be attenuated strains of pathogens.
  • Attenuated strains of pathogens will lack all or parts of virulence operons, may lack immune-stimulatory surface moieties (e.g., lipopolysaccharide for Gram-negative bacteria), or may contain one or more nutrient auxotrophies.
  • the bacteria are attenuated intracellular pathogens.
  • An alternative means of identifying the bacterial cells of the present disclosure is through the cell’s 16S rRNA sequence. See, e.g., Srinivasin et al., PLoS ONE; 10(2): e0117617 (Feb. 6, 2015).
  • the present disclosure also relates to a bacterial cell derived from a bacterial strain that has a 16S rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16S rRNA sequence of SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77.
  • the bacterial cell has the 16S rRNA sequence represented by SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77.
  • the bacterial cells can be partially or substantially purified.
  • the bacterial cells can comprise at least two bacterial strains.
  • a further means of identifying the expressed polypeptide or strains from which the bacterial cell is derived is through identification numbers assigned to the polypeptide or strain of interest through a database or other bacterial cell collection.
  • polypeptides can be identified through the polypeptide accession number GUT_GENOME or strains deposited in the EMBL-EBI microbiome collection can be identified by their Mgnify identification number (see, e.g. Mitchell et al., Nucl. Acids Res. Volume 48, Issue D1, 08 January 2020, Pages D570–D578).
  • polypeptides and strains can be identified by the respective identification numbers provided by the Belgian Coordinated Collection of Micro-organisms collection (BCCM/LMG) Sequence ID or Strain ID (see bccm(dot)belspo(dot)be/about-us/bccm-lmg). Another means of identifying the bacterial cell of the present disclosure is through the presence of a Super Epitope, as defined herein.
  • Particular embodiments of the bacterial cell of the present disclosure comprises at least one sequence selected from the group consisting of SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64; SEQ ID NO: 65; and SEQ ID NO: 78.
  • the bacterial cell described herein comprises at least one of the polypeptides of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 mCRAg polypeptides or Super Epitopes.
  • SEQ ID NOS: 1-30 such as 1, 2, 3, 4, 5, 6, 7, 8 or 9
  • SEQ ID NOS: 66-72 such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 mCRAg polypeptides or Super Epitopes.
  • genetically engineered bacteria can include bacteria harboring i) one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or on an endogenous plasmid, wherein the genetic change may result in the alteration, disruption, removal, or addition of one or more protein- coding genes, non-protein-coding genes, gene regulatory regions, or any combination thereof, and wherein such change maybe a fusion of two or more separate genomic regions or may be synthetically derived; ii) one or more foreign plasmids containing a mutant copy of an endogenous gene, such mutation being an insertion, deletion, or substitution, or any combination thereof, of one or more nucleotides; and iii) one or more foreign plasmids containing a mutant or non-mutant exogenous gene or a fusion of two or more endogenous, exogenous, or mixed genes.
  • the engineered bacteria may be produced using techniques including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, or any combination thereof.
  • mCRAg-Containing Compositions and Kits The present disclosure describes compositions that comprise bacterial cells that express mCRAg polypeptides or Super Epitopes that have been identified using the methods provided in this disclosure and its examples.
  • the composition of the present disclosure comprises at least one bacterial cell that expresses at least one SARS-CoV2 mCRAg.
  • the bacterial cell is a recombinant cell engineered to express the at least one SARS-CoV2 mCRAg.
  • the composition of the present disclosure comprises a bacterial cell that expresses a mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78.
  • the composition comprises a bacterial cell that expresses an mCRAg polypeptide or Super Epitope with least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78.
  • the composition comprises at least one bacterial cell is of a bacterial strain that is present in the human gut microbiome.
  • compositions comprising derivatives of the bacterial cells which may be a daughter cell (progeny) or a cell cultured (subcloned) from the original.
  • the derivative of the disclosed bacterial cell may be modified in any manner, for example at the genetic level, provided such modification does not ablate the immunological activity.
  • a derivative strain of the present disclosure is immunologically active.
  • a derivative strain will have comparable or improved positive immune modulatory activity to the immune response to SARS-CoV2 as the original.
  • the present disclosure provides compositions comprising a bacterial cell derived from particular bacterial strains.
  • the bacterial cell can be of a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG- HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei;Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. These strains have been identified as natively expressing at least one mCRAg polypeptide or Super Epitope of the present disclosure.
  • the composition will contain at least two bacterial strains. In certain embodiments, the at least two bacterial strains are selected from the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the present disclosure also relates to a composition
  • a composition comprising a bacterial cell derived from a bacterial strain that has a 16S rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16S rRNA sequence of SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77.
  • the composition comprises the bacterial cell that has the 16S rRNA sequence represented by SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77.
  • the bacterial cell or strain comprising the composition can be substantially purified.
  • the composition will comprise bacterial cell comprising at least one or more of the polypeptides of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 56-65; or SEQ ID NO: 78, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 mCRAg polypeptides or Super Epitopes.
  • the amount of the mCRAg comprising component for the compositions described can be suitably determined depending on purpose of use (prophylactic, health or therapeutic treatment).
  • compositions of the present disclosure can be made up of bacterial cells that not only express mCRAgs or Super Epitopes, as provided herein, but can also be a probiotic bacteria or non-pathogenic bacteria which, when the relative abundance altered, can confer a health benefit to the host.
  • the strains that express mCRAgs or Super Epitopes can also be optionally characterized as probiotic strains.
  • additional probiotic strains that do not express an mCRAg or a Super Epitope can be added to the present compositions for the health benefits provided. Probiotics are described in Hill et al., Nat Rev Gastroenterol Hepatol 2014 Aug;11(8):506-14.
  • Probiotic strains generally have the ability to survive the passage through the upper part of the digestive tract when administered orally. They are nonpathogenic, non-toxic and exercise their beneficial effect on health on the one hand, possibly via ecological interactions with the resident flora in the digestive tract, and on the other hand, possibly via their ability to influence the immune and metabolic systems in a positive manner via the "GALT" (gut-associated lymphoid tissue). These bacterial cells, when given in a sufficient number, have the ability to progress live through the intestine; however, they do not cross the intestinal barrier in large numbers and their primary effects are therefore induced in the lumen and/or the wall of the gastrointestinal tract. They then form part of the resident flora.
  • compositions may include bacterial cells or components that are viable (live), dormant, inactivated or dead, or any combination thereof.
  • the bacterial cells or components can include a mixture or combination of live bacterial strains. It is known to one of ordinary skill that the teachings of the present disclosure can apply to the other composition forms for antigens that can be used to increase the immune response to that antigen in a subject, and in turn, increase that subject’s response to an infection by a virus expressing that antigen.
  • any or all of the probiotic strains provided in the composition can be partially or substantially purified.
  • the above listed beneficial characteristics of particular probiotic strains can provide a selection step in the formulation of the compositions of the present disclosure.
  • many of the polypeptide and sequence results described in database records of the human gut microbiome, such as the UHGP are attributed to bacterial strains with no available isolates.
  • selection for a bacterial strain that is both (1) nonpathogenic and (2) a strain with known, available isolates is a further selection step that can be utilized to select the bacterial strain combination utilized in the compositions of the present methods.
  • the present disclosure also discloses bacterial strains that comprise SARS-CoV2 mCRAgs that are selected from a variety of antigen sources.
  • a mixture of bacterial strains comprising SARS-CoV2 mCRAgs including the epitopes Envelop_8 (VFLLVTLAI; SEQ ID NO: 59), Envelop_9 (FLLVTLAIL; SEQ ID NO: 60), Envelop_10 (LLVTLAILT; SEQ ID NO: 61), Surface_B_2 (VFLVLLPLV; SEQ ID NO: 63), and Surface_B_3 (FLVLLPLVS; SEQ ID NO: 64) could provide a wide variety of mCRAgs in the thus formed bacterial consortium.
  • concentration on a specific epitope could be advantageous, such as a mixture of bacterial strains comprising SARS-CoV2 mCRAgs including the epitopes Envelop_9 (FLLVTLAIL; SEQ ID NO: 60); Surface_B_2 (VFLVLLPLV; SEQ ID NO: 63) and Nucleocapsid_A_2 (DAALALLL; SEQ ID NO: 78).
  • Another aspect includes compositions including compounds or agents that alter the relative abundance of microbiota indirectly, such as through the administration of compound(s) or agent(s) that affect the growth, survival, persistence, transit or existence of at least one specific microbiota.
  • the additional compounds or agents can be “prebiotics.” These prebiotics are described in Gibson et al., Nat Rev Gastroenterol Hepatol 14, 491–502 (2017).
  • the term “prebiotics” can refer to a component which increases the number of probiotic bacteria in the intestine.
  • prebiotics as used herein may refer to any non-viable component that is specific to a bacteria thought to be of positive value.
  • the administration of at least one prebiotic compound may selectively enhance the relative abundance or general growth of at least one specific strain within the composition of the present disclosure in vivo resulting in the desired increase in immune response. Thus, such components are anticipated to be possible within the compositions of the present disclosure.
  • prebiotics can include bacterial cell wall components such as peptidoglycans, bacterial nucleic acids such as DNA and RNA, bacterial membrane components, and bacterial structural components such as proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins.
  • bacterial cell wall components such as peptidoglycans, bacterial nucleic acids such as DNA and RNA, bacterial membrane components, and bacterial structural components such as proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins.
  • Additional examples can also include organic acids, inorganic acids, bases, proteins and peptides, enzymes and co-enzymes, amino acids and nucleic acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, bioactive compounds, metabolites containing an inorganic component, small molecules, for example nitrous molecules or molecules containing a sulphurous acid, resistant starch, potato starch or high amylose starch, modified starches (including carboxylated starches, acetylated, propionated, and butyrated starches), non-digestible oligosaccharides such as fructooligosaccharides, glucooligosaccharides, xylooligosaccharides, galactooligosaccharides, arabinoxylans, arabinogalactans, galactomannans, polydextrose, oligofructose, inulin, derivatives of these, but not excluding other oligosaccharides able to
  • post-biotics are made up of inactivated micro-organisms that convey either a direct or indirect health benefit to the subject upon administration. These post-biotics have been described in Salimen et al., Nat Rev Gastroenterol Hepatol 18, 649–667 (2021). Other related terms have also been used for such preparations, including paraprobiotics, parapsychobiotics, ghost probiotics, metabiotics, tyndallized probiotics and bacterial lysates. The composition component described by any or all of these terms are encompassed in the possible addition of a post-biotic in the composition of the present disclosure.
  • the inactivated micro-organisms of a post-biotic are in a form that is stable and safe for consumption by a subject.
  • Some non-limiting examples of a post-biotic include inanimate strains belonging to established probiotic taxa within some genera of the family Lactobacillaceae (now comprising 31 genera) or the genus Bifidobacterium.
  • a microbial strain or consortium does not have to qualify as a probiotic (while living) for the inactivated version to be accepted as a postbiotic.
  • One microbiological composition includes one strain of Haemophilus influenzae, four strains of Streptococcus pneumoniae, two strains of Klebsiella pneumoniae subsp. pneumoniae, one strain of Klebsiella pneumoniae subsp.
  • spirulina formulations could qualify as postbiotics, but only if the processing and microorganism used (often species Arthrospira platensis) is well described (Zarezadeh, M. et al., Phytother Res.35, 577–586 (2021)). Any or all of these non-limiting examples can comprise a component of the compositions presently disclosed and any or all of these components can be substantially purified.
  • a further additional compound or agent that can be present in the composition of this disclosure are antibiotic treatments and/or antibacterial agents.
  • Antibiotics can also include naturally occurring antibacterial agents (e.g., magainins, defensins and others) or specialized nutrient mixtures that alter the relative composition of the microbiota.
  • compositions of the present disclosure which comprise at least one SARS-CoV2 mCRAg can be characterized as pharmaceutical compositions.
  • the composition according to the present disclosure may be characterized as including an appropriate carrier, excipient and diluent which are generally used in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition according to the present disclosure can be formulated for use in the form of oral formulations, external preparations, suppositories, and sterile injection solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols according to the well-known methods.
  • Suitable preparations known in the art are such as those disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton Pa.).
  • a particular formulation of the present disclosure is where the compositions are formulated for absorption by the intestines, which is achieved through the selection of the components of the composition to potentiate such administration.
  • Such formulations are known in the art, specifically for microbiome therapeutics, as described in Vass et al., AAPS PharmSciTech, 21, Article number 214 (2020); Mimee et al., Adv Drug Deliv Rev, 105(Pt A): 44-54 (2016).
  • Examples of the carrier, excipient and diluent, which may be included in the pharmaceutical composition comprising SARS-CoV2 mCRAgs according to the present disclosure, may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the preparations can be produced using generally used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations are produced by mixing the extract with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin or the like. In addition, apart from the simple excipient, lubricants such as magnesium stearate and talc may be used.
  • Liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups and the like.
  • diluents such as water and liquid paraffin as well as various excipients, for example, wetting agents, sweeteners, fragrances, preservatives and the like may be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lypophilized preparations and suppositories.
  • Useful non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like.
  • the base for suppositories includes Witepsol, Macrogol, Tween 61, cacao butter, laurin, glycerogelatin or the like.
  • the pharmaceutical composition of the present disclosure comprises a composition comprising at least one bacterial cell that expresses at least one SARS-CoV2 mCRAg and an excipient.
  • the bacterial cell is a recombinant cell engineered to express the at least one SARS-CoV2 mCRAg.
  • the pharmaceutical composition of the present disclosure comprises a composition comprising a bacterial cell that expresses a mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78.
  • the pharmaceutical composition of the present disclosure comprises a composition comprising a bacterial cell that expresses an mCRAg polypeptide or Super Epitope with least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78.
  • the pharmaceutical composition of the present disclosure comprises a composition which comprises at least one bacterial cell, wherein the bacterial strain is present in the human gut microbiome.
  • the bacterial cell can be of a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG- HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae
  • the pharmaceutical composition comprises a composition comprising the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the pharmaceutical composition comprises a composition which comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the pharmaceutical composition comprises a composition which comprises the following bacterial strains: Lactobacillus sakei;Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • a pharmaceutical composition comprising the composition as described herein.
  • a pharmaceutical composition comprising the composition as described herein and an excipient.
  • the composition is formulated for delivery to the intestine.
  • a pharmaceutical composition comprising the composition as described herein and a SARS-CoV2 vaccine.
  • the composition is formulated for delivery to the intestine.
  • the preferred dose of the pharmaceutical composition according to the present disclosure comprising SARS-CoV2 mCRAgs can be suitably selected by those skilled in the art according to patient's conditions and body weight, severity of disease, dosage form, and administration route and period.
  • the composition of the present disclosure can be administrated daily at a dose of about 0.001 mg/kg to about 1000 mg/kg.
  • the composition can be administered in a single dose per day or in multiple doses per day.
  • the dose should not be construed as limiting the scope of the present disclosure in any context.
  • the pharmaceutical compositions of the present disclosure can include a SARS-CoV2 vaccine. Any vaccine that has been developed to induce an immunological reaction against the SARS-CoV2 virus can be utilized in the pharmaceutical compositions.
  • Such vaccines include those presently utilized (see, Creech et al., JAMA, JAMA.2021;325(13):1318-1320) and those currently in the approval phase (see, Kyriakidis et al., npj Vaccines 6: 28 (2021)).
  • mRNA-1273 (Moderna); BNT162b2 (Pfizer-BioNTech); Ad26.CoV2.5 (Janssen/Johnson & Johnson); ChAdOx1 (AstraZeneca/Oxford); NVX-CoV2373 (Novavax); CVnCoV (CureVac/GSK); Gam-COVID-Vac (Sputnik V; Gamaleya National Research Center for Epidemiology and Microbiology); CoronaVac (Sinovac Biotech) and BBIBP-CorV (Sinopharm 1/2).
  • a vaccine comprising at least one SARS-CoV2 mCRAg as described herein.
  • the vaccine may further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be functional molecules such as vehicles, carriers, or diluents.
  • the pharmaceutically acceptable excipient can be a transfection facilitating agent, which can include surface active agents, such as immune-stimulating complexes (ISCOMS), Freunds incomplete adjuvant, LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene and squalene, hyaluronic acid, lipids, liposomes, calcium ions, viral proteins, polyanions, polycations, or nanoparticles, or other known transfection facilitating agents.
  • ISCOMS immune-stimulating complexes
  • LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene and squalene, hyaluronic acid, lipids, lip
  • the pharmaceutically acceptable excipient can be an adjuvant.
  • the adjuvant can be other genes that are expressed in an alternative plasmid or are delivered as proteins in combination with the plasmid above in the mCRAg comprising vaccine.
  • the adjuvant may be selected from the group consisting of: ⁇ -interferon(IFN- ⁇ ), ⁇ -interferon (IFN- ⁇ ), ⁇ -interferon, platelet derived growth factor (PDGF), tumor necrosis factor alpha (TNF- ⁇ ) tumor necrosis factor beta (TNF- ⁇ ), granulocyte- macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), cutaneous T cell- attracting chemokine (CTACK), epithelial thymus-expressed chemokine (TECK), mucosae- associated epithelial chemokine (MEC), IL-12, IL-15, MHC, CD80, CD86 including IL-15 having the signal sequence deleted and optionally including the signal
  • the adjuvant can be IL-12, IL-15, IL-28, CTACK, TECK, platelet derived growth factor (PDGF), TNF- ⁇ , TNF- ⁇ , GM-CSF, epidermal growth factor (EGF), IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, or a combination thereof.
  • genes that can be useful as adjuvants include those encoding: MCP-1, MIP-1a, MIP- 1p, IL-8, RANTES, L-selectin, P-selectin, E-selectin, CD34, GlyCAM-1, MadCAM-1, LFA-1, VLA-1, Mac-1, p150.95, PECAM, ICAM-1, ICAM-2, ICAM-3, CD2, LFA-3, M-CSF, G-CSF, IL- 4, mutant forms of IL-18, CD40, CD4OL, vascular growth factor, fibroblast growth factor, IL-7, nerve growth factor, vascular endothelial growth factor, Fas, TNF receptor, Flt, Apo-1, p55, WSL- 1, DR3, TRAMP, Apo-3, AIR, LARD, NGRF, DR4, DRS, KILLER, TRAIL-R2, TRICK2, DR6, Caspase ICE, Fos, c-jun, Sp-1, Ap-1, Ap-2
  • the composition disclosed herein is used in a method of increasing an immune response to a SARS CoV2 vaccine in a subject comprising: administering an antibiotic to a subject before the administration of the vaccine; administering to the subject an immunologically effective amount of the composition after the clearance of the antibiotic effect; and administering the vaccine.
  • the administration of the antibiotic occurs fourteen to twenty-one days prior to the administration of the vaccine.
  • the present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical composition for use in a method of increasing an immune response to a SARS- CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • the present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • a composition as disclosed herein, such as a pharmaceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine.
  • the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine.
  • the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine.
  • kits for example a kit which comprises one or more pharmaceutical compositions of the present disclosure and a vaccine, wherein the vaccine is for inducing an immunological response to the same virus expressing the viral epitopes that were used to screen for the SARS-CoV2 mCRAgs present in the pharmaceutical compositions
  • the present disclosure therefore also encompasses kits comprising one or more compositions of the present disclosure.
  • the kit can comprise one or more components in immunologically effective amounts for each component of the kit to be administered to a subject.
  • the components can be pharmaceutical compositions of the present disclosure, nutraceutical compositions of the present disclosure, or a vaccine or a combination thereof. Some components of the kit can be for later administration, for example after administration of the vaccine.
  • kits can further comprise instructions for using the kit.
  • a kit comprising the composition as described herein and a SARS-CoV2 vaccine.
  • the kit of the present disclosure is formulated for delivery to the intestine.
  • Nutraceutical Compositions the present disclosure provides a nutraceutical for increasing the immune response to the SARS-CoV2 mCRAg comprised in the composition containing, as an active ingredient, the SARS-CoV2 mCRAg.
  • nutraceutical originally was coined as a combination of the words “nutrition” and “pharmaceutical.”
  • a nutraceutical may be a food/beverage or food/beverage component, such as a dietary supplement or a food additive.
  • food is intended to encompass any edible substance, which substance may be in solid, liquid, paste, tablet or other orally ingestible form.
  • a nutraceutical may also supplement the diet, and includes traditional dietary supplements such as vitamins, minerals, herbs, oils and substances such as glucosamine, amino acids and other dietary supplements.
  • a nutraceutical is intended for oral ingestion and provides a health, medicinal or immunological benefit that may aid in disease prevention, disease treatment, and immunologic response.
  • a nutraceutical may be a pharmaceutical-grade nutrient with standardized properties.
  • a nutraceutical may also be a combination of substances including any combination of dietary supplements, food additives, vitamins, minerals, probiotics, prebiotics, spirulina, cereals and other substances that confer a health benefit to the animal, including a human, that ingests the nutraceutical.
  • a nutraceutical may also be considered a functional food or functional food ingredient that provides a health, medicinal or immunological benefit in addition to the basic nutritional value of the food or food ingredient.
  • a nutraceutical may be any functional or medicinal food that plays a role in maintaining well-being, enhancing health, modulating immunity and thereby aiding in preventing as well as treating specific diseases.
  • composition according to the present disclosure When the composition according to the present disclosure is used as a nutraceutical, it may be added alone or it may be used in combination with other foods or food ingredients and may be suitably used according to the conventional methods.
  • the compounds or agents can be provided in a food, drink, dietary supplement, and/or food additive or can be used to modify a food, drink, dietary supplement, and/or food additive.
  • the composition according to the present disclosure is used for the preparation of a food or beverage, it is generally added in an amount of about 15 wt % or less, or about 10 wt % or less, based on the total weight of the food or beverage.
  • Nutraceutical compositions as described herein can comprise from about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% to about 10%, 9%, 8%, 7%, 6%, or 5% or less of the total weight of the food or beverage.
  • the amount of the active ingredient may be smaller than the lower limit of the range defined above.
  • the active ingredient may be used in an amount higher than the upper limit of the above range and it only limited from the point of view of safety. Any safe and effective nutraceutical formulation can be utilized to administer the mCRAgs of the present disclosure.
  • the SARS-CoV2 mCRAg comprising composition according to the present disclosure may include a variety of nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickening agents, pH adjusting agents, stabilizers, antiseptics, glycerine, alcohol and carbonating agents for carbonated drinks.
  • the composition according to the present disclosure may include fruit or vegetables for producing natural fruit juices, fruit juice drinks and vegetable drinks. This ingredient may be used alone or in combination. The proportion of this additive is not significantly important but is generally determined within the range of about 0.01 to about 0.1 parts by weight with respect to about 100 parts by weight of the composition according to the present disclosure.
  • Purified antigens such as mCRAgs can be combined with the adjuvant as described above.
  • the immune response induced by the mCRAg can be boosted or increased when combined with the adjuvant.
  • Such an immune response can be a humoral immune response, a cellular immune response, or a mucosal immune response or a mixture thereof.
  • the combination of the adjuvant and the mCRAg can boost or increase a cellular immune response in the subject.
  • the combination of the adjuvant and the mCRAg can boost or increase a humoral immune response in the subject.
  • the combination of the adjuvant and the mCRAg can boost or increase a mucosal immune response in the subject.
  • the mCRAg can be in the form of a nucleic acid sequence, an amino acid sequence, or a combination thereof.
  • the nucleic acid sequence can be DNA, RNA, cDNA, a variant thereof, a fragment thereof, or a combination thereof.
  • the nucleic acid sequence can also include additional sequences that encode linker or tag sequences that are linked to the mCRAg by a peptide bond.
  • the amino acid sequence can be a protein, a peptide, a variant thereof, a fragment thereof, or a combination thereof.
  • a nutraceutical composition comprising the bacterial cell as described herein.
  • provided herein is a nutraceutical composition comprising the composition as described herein.
  • the nutraceutical composition additionally comprises a nutrient.
  • Methods of Use The present disclosure is also directed to methods of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject by administration of an immunologically effective amount of the composition of the present disclosure.
  • the present disclosure is further directed to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of the composition of the present disclosure.
  • Increasing or inducing the immune response can be used to treat and/or prevent disease in a subject.
  • the present disclosure is also directed to methods of increasing an immune response in a subject by administration of a vaccine comprising the mCRAgs of the present disclosure.
  • These methods can therefore include either administering the composition, administering the vaccine to the subject, or administering a combination of the compositions and a vaccine to the subject.
  • the subject administered the composition, vaccine, or combination can have an increased or boosted immune response as compared to a subject administered the composition or the vaccine on its own.
  • the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination can be increased by about 15% to about 650%, about 10% to about 100%, or about 20% to about 200%.
  • the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination may be increased by about 50% to about 250%.
  • the immune response to the SARS- CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination may be increased by about 100% to about 150%.
  • the administered composition, vaccine, or combination can increase or boost the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject by at least about 1.2 fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10-fold.
  • the composition or vaccine dose can be between about 1 ⁇ g to about 10 mg active component/kg body weight/time and can be about 20 ⁇ g to about 10 mg component/kg body weight/time.
  • composition or vaccine can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • the number of composition or vaccine doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • administration means providing the predetermined composition according to the present disclosure to a subject by any suitable method.
  • the pharmaceutical composition can be administered in vivo or in vitro via a route such as intravenous, intraperitoneal, intramuscular, subcutaneous, intradermal, nasal, mucosal, inhalation or oral route as long as the administration results in an increase in an immune response of the subject.
  • the preferred dose of the pharmaceutical composition according to the present disclosure comprising SARS-CoV2 mCRAgs can be suitably selected by those skilled in the art according to patient's conditions and body weight, severity of disease, dosage form, and administration route and period.
  • the composition of the present disclosure can be administrated daily at a dose of about 0.001 mg/kg to about 1000 mg/kg.
  • the composition can be administered in a single dose per day or in multiple doses per day.
  • the dose should not be construed as limiting the scope of the present disclosure in any context.
  • the composition of the present disclosure can also be administered in the same composition with compounds or agents such as vaccines or can be administered individually with the compounds or agents administered before, concurrent with, and/or after the present compositions.
  • the present composition can be administered at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more prior to the administration of compounds or agents.
  • the present composition can also be administered at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more after the administration of compounds or agents.
  • the present composition can be administered concurrently with the administration of compounds or agents. It is possible to utilize an antibiotic to “reset” the microbiome prior to the administration of the composition of the present disclosure. In such case, the administration of the antibiotic occurs between 14, 15, 16, 17, 18, 19, 20, or 21 days prior to the administration of the composition and vaccine.
  • the composition used in the method comprises at least one bacterial strain selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83(MGYG-HGUT- 02229); Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • Bacteroides dorei selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Os
  • the method uses the composition comprising the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum.
  • the method uses at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
  • the bacterial cell or strain of the composition can be partially or substantially purified.
  • the composition can comprise at least two bacterial strains. An alternative way of identifying the bacterial strains for utilization in the presently disclosed methods is through the strain’s 16S rRNA sequence as discussed above.
  • the at least one bacterial strain of the methods of use compositions can comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS:31-35 and SEQ ID NOS:73-77.
  • the at least one bacterial strain comprises a Super Epitope and a subset of such Super Epitopes are at least one sequence selected from the group consisting of SEQ ID NOS: 58-65 and SEQ ID NO: 78.
  • the present disclosure also relates to the use of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • a composition as disclosed herein such as a pharmaceutical or nutraceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition.
  • the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine.
  • the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine. In some embodiments the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine.
  • the methods of use of the present disclosure use of the composition disclosed herein in a method of increasing an immune response to a SARS CoV2 vaccine in a subject comprising: administering an antibiotic to a subject before the administration of the vaccine; administering to the subject an immunologically effective amount of the composition after the clearance of the antibiotic effect; and administering the vaccine. In some embodiments the administration of the antibiotic occurs fourteen to twenty-one days prior to the administration of the vaccine.
  • SARS-CoV2 mCRAgs have been identified using a method that is taught herein and summarized by the flow chart of FIG.1.
  • An exemplary source of potential epitopes to be used for the identification of SARS-CoV2 mCRAgs can be published epitope sequences for this virus or closely related viruses, including SARS-CoV, such as those provided by Singh et al., Nature, 10: 16219 (2020); Ahmed et al., Viruses, 12(3):254 (2020); and Ahmad et al., Eur J Pharm Sci 151:105387 (Aug 1, 2020); Colson, et al., medRxiv 2021.09.10.21262922 (2021).
  • sequences are aligned with a reference sequence, also obtained from an appropriate database, such as GenBank, accessed at www(dot)ncbi(dot)nlm(dot)nih(dot)gov/genbank/.
  • GenBank a database that maps amino acid residues to amino acid residues.
  • sequences are then translated into amino acid residues according to the coding sequence positions provided along the reference sequence for SARS-CoV-2 proteins (orf1a, orf1b, S, ORF3a, E, M, ORF6, ORF7a, ORF7b, ORF8, N, and ORF10).
  • sequences can be aligned separately for each protein using a multiple sequence alignment program such as MAFFT (available at mafft(dot)cbrc(dot)jp/alignment/software/).
  • MAFFT available at mafft(dot)cbrc(dot)jp/alignment/software/).
  • Reference protein sequences can also be obtained at GenBank or some other appropriate database source.
  • One source of possible epitope sequences is SARS-CoV2 virus or closely related viruses. It is desirable to obtain an increased immunological response against said viruses through the use of SARS-CoV2 mCRAgs.
  • the evolutionary relationship of viruses is such that sequences associated with other viral genomes can also be overlapping potential epitopes and thus useful in the methods of the present disclosure as a starting point for mCRAg identification.
  • such viruses include, but are not limited to SARS-CoV, but can also comprise the genomes of related subgroups of corona viruses, including alphacoronaviruses and betacoronaviruses.
  • the genome sequence of these related viruses can be very close, for example, SARS-CoV shares a 79.5% genome sequence identity with SARS-CoV, a 96.2% identity with Bat-CoV RaTG13, and multiple SARS-CoV2- related coronaviruses with 85.5 to 92.3% sequence identity with pangolin-infecting coronaviruses such as Pangolin-CoV-2020 and GD Pangolin CoV (see, Li et al., J.
  • viruses even those which are not infectious to humans, can also be utilized in the screening methods of the present disclosure although use of human specific viruses, and the SARS-CoV2 mCRAgs isolated therefrom, are particular embodiments of the present disclosure.
  • one method of finding experimentally-derived sequences for B cell and T cell epitopes of SARS-CoV2 or related viruses, such as SARS-CoV is from the NIAID Virus Pathogen Database and Analysis Resource (ViPR) (accessible at www(dot)viprbrc(dot)org/) through queries on the virus name and “human” hosts.
  • ViPR NIAID Virus Pathogen Database and Analysis Resource
  • selected epitopes should be supported by positive assays such as (i) Positive B cell assays (e.g. enzyme-linked immunosorbent assay (ELISA)-based qualitative binding for B cell epitopes, and (ii) either positive T cell assays (such as enzyme-linked immune absorbent spot (ELISPOT) or intracellular cytokine staining (ICS) IFN- ⁇ release) or positive major histocompatibility complex (MHC) binding assays for T cell epitopes.
  • positive B cell assays e.g. enzyme-linked immunosorbent assay (ELISA)-based qualitative binding for B cell epitopes
  • positive T cell assays such as enzyme-linked immune absorbent spot (ELISPOT) or intracellular cytokine staining (ICS) IFN- ⁇ release
  • MHC major histocompatibility complex
  • This set of B cell and T cell epitopes can be utilized to screen for SARS-CoV2 mCRAgs as will be described.
  • the immunogenic epitopes are identified, they are used to generate a list of all possible epitopes of a selected size. These possible epitopes will be used to sequence align with expressed polypeptides in order to identify potential mCRAgs.
  • the size of epitopes to be used for selection can range from about 9-mer to about 15-mer in length in length with the use of all possible 10-mer, 11-mer, 12-mer, 13-mer, and 14-mer epitopes all being possible embodiments of the present methods.
  • the epitopes are utilized to produce a list of all possible epitopes of the selected size. It is this list of all possible epitopes that are used to screen a database of polypeptide sequences for alignments, thus identifying those polypeptides that comprise an epitope of SARS-CoV2.
  • a preliminary alignment is a one to one match, with a small number of amino acid mismatches. Again, the number of mismatches involved needs to be selected to expand the number of hits beyond those that are just exact matches, but not give so much leeway as to result in unmanageable numbers of positive results.
  • the present method utilizes up to one mismatch per 9-mer as described in the Examples below, however this number can be adjusted upwards to two, three, or more or downward to no mismatches, depending on how long the epitope peptide sequences are, how many hits are obtained initially, what polypeptide database is being utilized, what screening processes are utilized in later method steps to focus the match results, and other analysis-specific factors. Many methods of obtaining sequence alignments are known to one of ordinary skill.
  • the goal of this process is the match of a particular, relatively short amino acid coding pattern within much larger sequences, while accommodating mismatches at selected places in the epitope peptide.
  • These criteria limit the particular alignment programs that would function well for this task.
  • the present method can be practiced using the fuzzpro protein pattern matcher from the EMBOSS suite v.6.6.0.0 (Rice et al., Trends in Genetics, 16: 276-77 (2000)).
  • Program fuzzpro is set up to do a protein pattern search of typically short length sequence within a larger sequence. It can be used to find an exact match or can allow various ambiguities, matches to variable length sequences and repeated subsections of sequence. The program selects the optimum searching algorithm to use depending on the complexity of search pattern specified.
  • This database is a collection of protein sequences, at least partially annotated, of those proteins likely produced by bacteria that comprise the human gut microbiome.
  • the present disclosure involved the development of custom python scripts to include mCRAg polypeptide annotations and taxonomy according to the information present in the UHGP database.
  • other suitable protein databases can be utilized depending on the ultimate goal of the analysis.
  • this screening method describes the use of amino acid peptides, such peptides could be converted into DNA or RNA sequences for screening nucleic acid sequence databases, although there is the acknowledged extra area of uncertainty given the wobble present in the third member of nucleic acid codons which could be overcome using all possible encodings.
  • the amount of hits that could result from such an approach may prove impractical, making the use of epitope peptide to protein sequence matching a particular embodiment of the present mCRAg screening process.
  • the listed epitopes can be overlapped and extended to provide the longest possible alignment between the SARS-CoV2 immunogenic epitopes and the proteins of the UHGP or another similar database.
  • This overlap and extension process also taking into account the number of mismatches, can be performed in many different ways, while an exemplary approach is documented in FIG.2A that provides for ten approaches for overlapping and extending the two, three, or four epitopes to provide further means of matching the identified sequences to the database polypeptides. These ten Types are described in detail in Example 1.
  • the results can be sorted into the following four categories: Simple mCRAgs, Super mCRAgs, Super Bugs, and Super Epitopes. These categories are defined above and discussed further in the Examples.
  • the majority of the match results are anticipated to be Simple mCRAgs.
  • Simple mCRAgs are anticipated to function effectively as components of embodiments of the present disclosure, utilized either on their own or in combinations, to increase immune response.
  • T cell receptor T cell receptor
  • APC antigen-presenting cells
  • MHC major histocompatibility complex
  • T cell epitopes are presented by class I and II MHC molecules that are recognized by two distinct subsets of T cells, CD8 and CD4 T cells, respectively.
  • T cell epitope prediction aims to identify the shortest peptides within an antigen that are able to stimulate either CD4 or CD8 T cells.
  • MHC I molecules can bind short peptides ranging from about 9 to about 11 amino acids, whose N- and C-terminal ends remain pinned to conserved residues of the MHC I molecule through a network of hydrogen bonds.
  • the peptide-binding groove of MHC II molecules is open, allowing the N- and C-terminal ends of a peptide to extend beyond the binding groove.
  • MHC II-bound peptides vary widely in length (9-22 residues).
  • peptide sequences are generally available in specialized epitope databases such as IEDB (http://tools.iedb.org/main/tcell/), EPIMHC (Reche et al. Bioinformatics, 21(9):2140-2141), and AntiJen (http://www.ddg- pharmfac.net/antijen/AntiJen/antijenhomepage.htm).
  • Structure-based approaches generally rely on modeling the peptide-MHC structure followed by evaluation of the interaction through methods such as molecular dynamics simulations. Structure-based methods have a great advantage without needing experimental data. However, they are seldom used as they are computationally intensive and exhibit lower predictive performance than data-driven methods.
  • the epitopes selected for utilization included Nsp8(A) (SEQ ID NO: 36); Nsp8(B) (SEQ ID NO: 37); 3C-like protease (A) (SEQ ID NO: 38); 3C-like protease (B) (SEQ ID NO: 39); spike glycoprotein (SEQ ID NO: 40); Envelop (A) (SEQ ID NO: 41); Envelop (B) (SEQ ID NO:42); Membrane (SEQ ID NO: 43); Nucleocapsid (A) (SEQ ID NO: 44); Nucleocapsid (B) (SEQ ID NO: 45); Surface (A) (SEQ ID NO: 46); and Surface (B) (SEQ ID NO: 47) (see Table 1).
  • the immunogenic epitopes are named for the viral proteins they are derived from. In Table 1, the published epitope sequence is reported in bold, with the corresponding 9-mers below it. Envelop (A) and Envelop (B) epitopes were overlapped and merged since they were overlapping and consecutive, to avoid redundant 9-mers. The generated 9-mers were aligned against the Universal Human Gut Proteome (UHGP-100, hereafter UHGP) (Almeida et al., Nature Biotech. 39:105-14 (2021)) using the fuzzpro protein pattern matcher from the EMBOSS suite v.6.6.0.0 (Rice et al., Trends in Genetics, 16: 276-77 (2000)).
  • UHGP-100 Universal Human Gut Proteome
  • the matcher was set to allow up to one mismatch between the 9-mers and the target protein.
  • the output table with 9-mers/mCRAg polypeptide matches was processed using custom python scripts to mCRAg polypeptide annotations and taxonomy according to the information included in UHGP metadata tables. Splitting the 12 SARS-CoV2 proteins epitopes into 9-mers resulted in 53 non-redundant SARS-CoV29-mers.
  • the 9-mers were aligned against 170.6 million proteins in the UHGP database resulting in 32,169 hits to 26,578 unique proteins (0.01% of total UHGP proteins) in 25,346 species.
  • Table 2 a + ndcates addtona ts to protens rom taxa w ere t e taxonomc assgnment at t e speces eve was not possbe Table 3
  • groups of 9-mers were overlapped and extended based on the amino acids found in the further sequence on either side of the base 9-mer to identify other immunogenic sequences to be used for comparison, thus obtaining additional “mock” alignments between these epitopes and UHGP protein sequences. This overlap and extension process provides a systematic way of looking for other possible mCRAgs using the mined sequence data.
  • Type 1 involves a single 9-mer with one mismatch (mutation) and the provided example is FAPSA*AFF (SEQ ID NO: 48) where * represents the mismatch.
  • Type 2 involves a single 9-mer with no mismatches (mutations) where the provided example is ALALLLLDR (SEQ ID NO: 49), although this Type is purely theoretical and cannot be observed since it would be automatically extended.
  • Type 3 involves the single extended overlap of two 9-mers, thus having a total length of ten peptides and allows a single, shared mismatch (mutation) with the provided example LFLAF*VFLL (SEQ ID NO: 50).
  • Type 4 involves the overlap of two 9-mers, with two possible mismatches, thus having a total length of eleven peptides and the provided example of L*LAFVVFL*V (SEQ ID NO:51).
  • Type 5 involves the match of a single 9-mer in two non- consecutive and non-overlapping regions on the same polypeptide from the UHGP protein database, thus resulting the use of two 9-mers without overlap, thus resulting in two distinct 9-mers each with one mismatch and each of length of nine peptides and the provided example of FA*SASAFF (SEQ ID NO: 121) and FAPSAS*FF (SEQ ID NO: 122) (collectively FA*SAS*FF, SEQ ID NO: 52).
  • Type 6 involves the overlap of three 9-mer sequences with a single extension on either end of the 9-mer, thus having a total length of eleven peptides and allows a single, shared mismatch (mutation) with the provided example LALL*LDRLNQ (SEQ ID NO: 53).
  • Type 7 involves the overlap of three 9-mer sequences with a single extension on either end of the 9-mer and allows two possible mismatches, thus having a total length of eleven peptides with a provided example of *FLAFVVFLL* (SEQ ID NO:54).
  • Type 8 involves the match of a single 9-mer in three non- consecutive and non-overlapping regions on the same polypeptide from the UHGP protein database, thus resulting in three distinct 9-mers each with one mismatch and each of length of nine peptides and the provided example of FA*SASAFF (SEQ ID NO: 121), FAPSAS*FF (SEQ ID NO: 122), FAP*ASAFF (SEQ ID NO: 123) (or collectively FA**AS*FF; SEQ ID NO:55).
  • Type 9 involves the overlap of four 9-mers, made up of two different exact match 9-mers, with an extension of two on one end and one on the other, resulting in a length of 12 peptides and having two mismatches, with the provided example of *ALALLLLDRL* (SEQ ID NO: 56).
  • Type 10 involves overlap of four 9-mers, made up of only a single 9-mer, with an extension of two on one end and one on the other, resulting in a length of 12 peptides and having two mismatches, with the provided example of L*LAFVVFLLV* (SEQ ID NO: 57).
  • Type 7 (58 alignments): o 6 / 58 alignments obtained with SARS-CoV2 Envelop 9-mers ⁇ 3 alignments hit hypothetical proteins (GUT_GENOME096132_01117, GUT_GENOME245595_01465, GUT_GENOME094310_00658), 2 mscL (see Type 10), 1 oatA. o 51 / 58 alignments obtained with SARS-CoV2 Nucleocapsid 9-mers ⁇ 3 alignments hit hypothetical protein (GUT_GENOME115628_01722, GUT_GENOME186246_00249, GUT_GENOME008160_01084).
  • ⁇ 5 alignments hit a tRNA modification GTPase MnmE from 4 strains of Firmicutes, one Faecalibacterium and an uncharacterized bacterial strain from the Genus Duodenobacillus.
  • ⁇ 5 alignments hit ribonuclease 3 rnc (5 strains of Pyramidobacter from Asia and North-America).
  • o 1 / 58 alignments obtained with SARS-CoV2 Surface 9-mers
  • the alignment hit a hypothetical protein (GUT_GENOME234933_01511).
  • Type 9 o 3 / 3 alignments obtained with SARS-CoV2 Nucleocapsid (A) 9-mers ⁇ All alignments hit lspA (Lipoprotein signal peptidase): - Protein involved in the release of signal peptides from bacterial membrane pro-lipoproteins. It is an integral component of the inner plasma membrane. - The hit is outside the predicted transmembrane alpha-helices (7-24, 60-79, 86-108, 123-145), at the beginning (22-33) of the target protein. - 3D structure available (SwissProt: Q8D2R1).
  • the alignment hit Tig (trigger factor): - The protein is a cytosolic protein bounded to inner plasma membrane involved in protein export. - The hit is on the ribosomal binding domain located in the first part of the target protein (97-108). - Multiple 3D structures available. - None of the SARS-CoV2 9-mers in the alignment were from the cytotox T epitope.
  • this Example identifies SARS-CoV2 mCRAgs in the human gut microbiome, using immunogenic epitopes from 7 SARS-CoV2 proteins that were divided into 9-mers and used to scan the most comprehensive human gut proteome to date (UHGP) in a sequence similarity search. Only hits with up to one mismatch between SARS-CoV29-mers and mCRAg polypeptides were retained. Adjacent hits from adjacent 9-mers were aligned an overlapped to obtain the longest alignment possible between SARS-CoV2 epitopes and UHGP mCRAg polypeptides.
  • Example 2 –mCRAg Classification and Related Strains and Epitopes
  • the match collection of 21,657 hits between 9-mers and UHGP proteins (Type 1 of FIG.2A) were further classified into four categories (Simple mCRAg, Super mCRAg, Super Bug, and Super Epitope) according to their relationship using a custom python script (see FIG.2B).
  • Simple mCRAgs were identified by looking for simple 1-to-1 relationships between SARS-CoV2 epitope alignments and the mCRAg polypeptides in a single bacterial strain.
  • Super mCRAgs were identified by looking at multiple distinct SARS-CoV2 alignments targeting the same mCRAg polypeptide from the same bacterial strain.
  • mCRAg polypeptides with highest frequency of hits largely overlapped with mCRAg polypeptides of Type 7, Type 9, and Type 10 alignments, Super Bugs and Super Epitopes (see below).
  • gufA 1,756 simple mCRAGs Hits
  • uspA 1,620 simple mCRAGs Hits
  • mscL 916 simple mCRAGs Hits
  • mnmE 270 simple mCRAGs Hits
  • pacL 135 simple mCRAGs Hits
  • ybiR 60 simple mCRAGs Hits.
  • pacL and ybiR (bolded in the list above) were present as well in the list of mCRAg polypeptides from potential Super Bugs, as will be described further below.
  • 116 distinct bacterial species were identified as Super Bugs, coding for 2 or more mCRAg polypeptides to SARS-CoV2 alignments, for a total of 126 distinct proteins (Table 4).
  • mnmE and mscL were re-identified as well as a number of the proteins that were found as Type 7 and Type 10 alignments with perfect matches.
  • the top eight species of Super Bugs are provided in Table 5.
  • All twelve immunogenic B and T cells epitopes identified from the seven SARS-CoV2 proteins can be classified as Super Epitopes based on the given definition. Among them, five 9-mers belonging to three epitopes were identified as having a higher chance to raise protection against SARS-CoV2 based on perfect matches between SARS-CoV2 epitopes and UHGP mCRAg polypeptides, predicted binding to MHC-I and MHC-II alleles (see Example 3 below), the number of matches retrieved for each mCRAg polypeptide across the whole analysis and whether the mCRAg polypeptide was identified as expressed by Super Bugs (Table 6).
  • Envelop 9-mer envelop_5 (SEQ ID NO: 58) matched with tig and mscL, while envelop_10 (SEQ ID NO: 61) targeted uspA ⁇
  • Nucleocapsid 9-mer Nucleocapsid_A_4 (SEQ ID NO: 62) matched with IspA, mnmE and ybiR ⁇
  • Example 2 documents that the matches were further classified into four categories according to the relationship between SARS-CoV2 alignments and mCRAg polypeptides: Simple mCRAgs, Super mCRAgs, Super Bug and Super Epitope. While most of the hits were classified as Simple mCRAgs and none of the hits aligned to the definition of Super mCRAgs, 116 Super Bug were identified. The top Super Bug bacterial species, having the highest number of proteins matching with SARS-CoV2 envelop, surface and nucleocapsid epitopes, was Bacteroides dorei.
  • SARS- CoV2 epitopes used in this study could be classified as Super Epitopes based on the given definition, at least five specific 9-mers derived from SARS-CoV2 envelop, nucleocapsid and surface epitopes were identified as potential best Super Epitopes.
  • Super Bugs mCRAg polypeptides which included the mCRAg polypeptides (PP) of the best 5 Super Epitopes, were further characterized to predict their binding affinity to the most common human MHC-I and MHC-II alleles. At least 70% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-I allele.
  • Table 4 Table 5
  • Example 3 – mCRAg Binding Affinity to MHC-I and MHC-II The binding affinity to MHC-I and MHC-II alleles was restricted to the 258 mCRAg polypeptides matched to SARS-CoV2 alignments identified in the 116 SuperBugs. For each mCRAg polypeptide, the binding affinity to the most common MHC-I and MHC-II alleles was predicted, covering about 90% of human population MHC alleles.
  • At least 70% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-I allele and more than 90% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-II alleles.
  • the results of these Examples point toward the presence of multiple human gut bacterial species (Super Bugs) expressing several proteins with peptides matching SARS-CoV2 immunogenic epitopes (Super Epitopes). Those Super Bugs proteins are predicted to have high binding affinity for the most common human MHC-I and MHC-II alleles, suggesting their immunogenicity and use for raising immunological protection against SARS-CoV2.
  • Example 4 Bacterial Consortium Selection A final selection of an exemplary bacterial or probiotic strain consortium of five strains was performed based on the results discussed above. The further selection criteria included non- pathogenicity, availability of isolates, and the ability of the selected mCRAgs to bind both MHC I and MHC II, if possible. Based on these criteria, the five bacterial strains disclosed in Table 7 were selected as an exemplary bacterial consortium. Another exemplary consortium is illustrated in FIG. 4.

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Abstract

The present disclosure provides compositions comprising at least one bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (SARS-CoV2 mCRAg). The present disclosure provides specific SARS-CoV2 mCRAgs, and the bacterial cells that express the polypeptides that comprise the SARS-CoV2 mCRAgs and compositions thereof. The present specification provides methods for screening for SARS-CoV2 mCRAgs. Further, the present disclosure also comprises prevention methods, treatment methods, pharmaceutical and nutraceutical compositions and kits, and vaccines that comprise or utilize the SARS-CoV2 mCRAgs provided herein.

Description

COMPOSITIONS AND METHODS FOR IMPROVING THE IMMUNE RESPONSE TO SARS-COV2 SEQUENCE LISTING This application is accompanied by a sequence listing entitled VU67131- WO_SEQ_LISTING_ST26.xml, created September 14, 2022, which is approximately 158 kilobytes in size. This sequence listing is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION In 2008, global immunization programs were credited with preventing an approximate 2- 3 million deaths per year and markedly reducing disease morbidity (Andre et al., Bull. World Health Organ. 86: 140-146). With the recent pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and its associated coronavirus disease (COVID-19), and the effectiveness of developed vaccines against this viral disease, such immunization efforts have become even more urgent for the preservation of public health. Recent clinical studies and animal models have suggested that the composition and function of the gut microbiota may be a crucial component to determining individual responses to vaccination. In a recent review, Lynn et al. has summarized the data supporting this conclusion and supporting the use of microbiota-based strategies to positively impact vaccine response (Nature Reviews, Immunol. (2021) doi(dot)org/10.1038/s41577-021-00554-7). There is an urgent need to maximize the immune response against SARS-CoV2 and SARS- CoV2 vaccine antigens. Structural glycoproteins for the SAR-CoV2 virus include Spike/Surface (S), Envelop (E), Membrane (M) and Nucleocapsid (N). The S glycoprotein is reported to have a crucial role in the virus transmission as the receptor binding capability and entry to the host cell is regulated by the expression of S glycoprotein. The E and M glycoproteins are responsible for viral assembly and N glycoprotein is necessary for RNA genome synthesis (see, Schoeman & Fielding, Virol. J. 16:69 (2019)). The complex genetic makeup and high mutation rate of SARS-CoV-2 suggests the strategic development of a vaccine by targeting all the structural proteins. Therefore, improving immune response for a vaccine that triggers a response against epitopes included in any or all of these glycoproteins is a goal. General teachings of the possibility of probiotic consortiums to reduce the symptoms of SARS-CoV2 are known in the art. For example, Lehtinen et al. (bioRxiv 2021.07.23.453521 (2021)) reported that two probiotic consortia (OL-1 and OL-2) improved antiviral immune responses when administered to ferrets, and enhanced expression of genes and cytokines thought to be important to SARS-CoV2 immunity in primary human cells. There remains a need in the art for microbiome-derived compositions and methods that can improve immune response to SARS-CoV2 and SARS-CoV2 vaccine antigens. The provided improved methods include methods of prevention and treatment, as well as other uses of the microbiome- derived strains or microbiota, purified cells, compositions, and screening methods that will be apparent to those of skill in the art from the present teachings. SUMMARY OF THE INVENTION This summary is provided to introduce a selection of concepts that are further described below in the detailed description. This summary is not intended to identify key or essential features of the disclosed subject matter, nor should it be construed as limiting the scope of the disclosed subject matter. The present disclosure relates to a bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (mCRAg). In one embodiment, the bacterial cell is a recombinant bacterial cell that is engineered to express at least one SARS-CoV2 mCRAg. In one embodiment the bacterial cell is derived from a bacterial strain, that is present in the human gut microbiome. The present disclosure also relates to a composition comprising a bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (SARS-CoV2 mCRAg). In one embodiment the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:1, SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6. In another embodiment the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; and SEQ ID NO:21. In another embodiment the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; and SEQ ID NO:30. In another embodiment, the at least one SARS-CoV2 mCRAg expressed by the bacterial cell is selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67; SEQ ID NO: 68; SEQ ID NO: 69; SEQ ID NO: 70; SEQ ID NO: 71; SEQ ID NO: 72; SEQ ID NO: 79; and SEQ ID NO: 80. In another embodiment, the at least one SARS-CoV2 mCRAg comprises a sequence selected from the group consisting of SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64; SEQ ID NO: 65; and SEQ ID NO: 78. The present disclosure also relates to compositions comprising at least one bacterial strain selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG- 83(MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment is a composition comprising at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:76; and SEQ ID NO: 77. The present disclosure also relates to compositions comprising at least two bacterial cells expressing at least one SARS-CoV2 mCRAg, such as comprising at least two of the bacterial strains disclosed herein. A further embodiment is a composition that comprises the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. A further embodiment is a composition that comprises the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In one embodiment the composition is a pharmaceutical composition comprising a bacterial cell or SARS-CoV2 mCRAg as described herein, and a pharmaceutically acceptable excipient. The embodiment comprising a pharmaceutical composition can further comprise a SARS-CoV2 vaccine. Also provided is a kit comprising a composition as described herein, and a SARS-CoV2 vaccine. A further embodiment of the present disclosure is a composition as described herein, formulated for delivery to the intestine. An additional embodiment of the present disclosure relates to a nutraceutical composition, comprising a composition, bacterial cell, or SARS-CoV2 mCRAg as described herein, and optionally a nutrient. An additional embodiment of the present disclosure is a vaccine comprising at least one SARS-CoV2 mCRAg. The present disclosure also relates to a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject, the method comprising administering to the subject an immunologically effective amount of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition. The present disclosure also relates to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of a composition as described herein. In one embodiment the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In one embodiment the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In a further embodiment the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In another embodiment, the composition comprises at least one SARS-CoV2 mCRAg selected from the group consisting of SEQ ID NOS: 1-30; 66-72, and 79-80. In a further embodiment the composition comprises at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 31- 35 and SEQ ID NOS: 73-77. In another embodiment, the at least one bacterial strain comprises a sequence selected from the group consisting of SEQ ID NOS: 58-65 and SEQ ID NO: 78. The present disclosure also relates to a method of inducing an immune response to a SARS- CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition. The present disclosure also relates to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of a composition as described herein. In one embodiment the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In one embodiment the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In a further embodiment the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In another embodiment, the composition comprises at least one SARS-CoV2 mCRAg selected from the group consisting of SEQ ID NOS: 1-30; 66-72, and 79-80. In a further embodiment the composition comprises at least one bacterial strain that comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 31-35 and SEQ ID NOS: 73-77. In another embodiment, the at least one bacterial strain comprises a sequence selected from the group consisting of SEQ ID NOS: 58-65 and 78. In some embodiments the composition is administered in conjunction with a SARS-CoV2 vaccine, such as administered before, contemporaneous with, or after the administration of a SARS- CoV2 vaccine. The present disclosure also relates to a method of identifying human gut microbiome species that express at least one SARS-CoV2 mCRAg, the method comprising the steps of identifying epitopes utilized by B-cells and T-cells to mount immune responses against SARS-CoV2; breaking the identified epitopes into peptide fragments ranging in length from about 9-mer to about 15-mer; comparing the peptide fragments to the protein sequences present in the Unified Human Gastrointestinal Genome (UHGG) collection, allowing one mismatch, thereby identifying overlapping epitopes; classifying the matches into types based on the number of overlapping epitopes present within the polypeptide and the pattern of the matching and mismatching peptides; using match types where the number of overlapping epitopes is three or greater to identify the sequence as a SARS-CoV2 epitope; using the match records to identify polypeptide sequences of interest comprising the SARS- CoV2 epitope as a SARS-CoV2 mCRAg; and identifying the species that express the polypeptides of interest thereby identifying human gut microbiome species comprising a SARS-CoV2 mCRAg. The method can further comprise classifying the polypeptides identified as SARS-CoV2 mCRAgs as likely binding class I or class II HLA antigens. The present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition. The present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition. In some embodiment the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine. BRIEF DESCRIPTION OF THE FIGURES Representative embodiments of Compositions and Methods for Improving the Immune Response To SARS-COV2 are described with reference to the following figures. FIG.1 provides a flow chart summarizing the screening method of the present disclosure. FIG.2A provides a schematic visualization of the different kinds of alignments obtained after 9-mers overlap and their corresponding metrics. Type 7, Type 9, and Type 10 alignments contained hits with perfect matches between SARS-CoV29-mers and mCRAg polypeptides. The example boxes show how mock consecutive 9-mers would be overlapped and extended into mock alignments, 9-mers with perfect matches are reported in bold. “# 9-mers”: number of SARS-CoV29-mers overlapped in the alignment; “Length”: final length of the alignment; “Mutations”: number of mismatches between the final alignment and the mCRAg polypeptide; “Count”: number of alignments of that Type generated. Figure discloses SEQ ID NOS 48-49, 124, 126, 121, 125, 127, 122, 128, 131, 121, 133, 126, 129, 88, 49, 135, 130, 132, 122, 101, 89, 123, 134, and 136, respectively, in order of appearance. FIG. 2B provides the classification of Type 1 alignments derived from SARS-CoV2 immunogenic epitopes/database protein matches (e.g., Universal Human Gut Proteome (UHGP-100, hereafter UHGP) (see, Almeida et al., Nature Biotech. 39:105-14 (2021)) into four further relationships: Simple mCRAg, Super mCRAg, Super Bug, and Super Epitope. FIG.3 graphically illustrates the number of distinct MHC alleles predicted to bind to SuperBugs mCRAgs. Each of the 258 mCRAg polypeptides in the SuperBugs having matched with SARS-CoV2 epitopes are represented by a dot indicating the number of MHC alleles that they are predicted to bind to. Dots representing the same number of count overlap. Lines connect the predicted binding MHC-I and MHC-II alleles for the same mCRAg polypeptide. The two violin graphs indicate the distribution of the dots, with quartiles and median value as indicated by the horizontal black lines. FIG. 4 provides a graphic representation of the five bacterial strains, the SARS epitopes and mCRAg polypeptides expressed by the strains, and the MHC class I and class II binding for the utilized epitopes. These five strains represent an exemplary bacterial consortium for use in the improvement of the immune response against SARS-CoV2. BRIEF DESCRIPTION OF THE SEQUENCES IN THE SEQUENCE LISTING SEQ ID NO: 1 is the amino acid sequence encoded by the gufA gene, polypeptide accession GUT_GENOME093168_03303, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 2 is the amino acid sequence encoded by the uspA gene, polypeptide accession GUT_GENOME000481_00590, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 3 is the amino acid sequence encoded by the mscL gene, polypeptide accession GUT_GENOME025743_00100, uncharacterized Dakarella, and Mgnify accession MGYG-HGUT- 02447. SEQ ID NO: 4 is the amino acid sequence encoded by the mnmE gene, polypeptide accession GUT_GENOME044080_00407, uncharacterized Faecalibacterium, and Mgnify accession MGYG- HGUT-00636. SEQ ID NO: 5 is the amino acid sequence encoded by the pacL gene, polypeptide accession GUT_GENOME220297_01074, Sutterella wadsworthensis, and Mgnify accession MGYG-HGUT- 01410. SEQ ID NO: 6 is the amino acid sequence encoded by the ybiR gene, polypeptide accession GUT_GENOME155999_02417, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 7 is the amino acid sequence encoded by the algI gene, polypeptide accession GUT_GENOME015529_01518, uncharacterized Lachnospira, and Mgnify accession MGYG- HGUT-02559. SEQ ID NO: 8 is the amino acid sequence encoded by the brnQ gene, polypeptide accession GUT_GENOME000310_01026, Lactobacillus salivarius, and Mgnify accession MGYG-HGUT- 02324. SEQ ID NO: 9 is the amino acid sequence encoded by the comEC gene, polypeptide accession GUT_GENOME205549_00776, Eubacterium sp003491505, and Mgnify accession MGYG-HGUT- 00209. SEQ ID NO: 10 is the amino acid sequence encoded by the cydB gene, polypeptide accession GUT_GENOME000655_02696, Parabacteroides johnsonii, and Mgnify accession MGYG-HGUT- 00138. SEQ ID NO: 11 is the amino acid sequence encoded by the cydC gene, polypeptide accession GUT_GENOME204275_00061, Mitsuokella jalaludinii, and Mgnify accession MGYG-HGUT- 00027. SEQ ID NO: 12 is the amino acid sequence encoded by the gluP gene, polypeptide accession GUT_GENOME236875_01017, uncharacterized Parabacteroides, and Mgnify accession MGYG- HGUT-03521. SEQ ID NO: 13 is the amino acid sequence encoded by the guaB gene, polypeptide accession GUT_GENOME027624_00533, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 14 is the amino acid sequence encoded by the Int gene, polypeptide accession GUT_GENOME029617_01714, Akkermansia muciniphila, and Mgnify accession MGYG-HGUT- 02454. SEQ ID NO: 15 is the amino acid sequence encoded by the mltG gene, polypeptide accession GUT_GENOME008300_00218, uncharacterized Sutterella, and Mgnify accession MGYG-HGUT- 02101. SEQ ID NO: 16 is the amino acid sequence encoded by the murJ gene, polypeptide accession GUT_GENOME027371_00296, Campylobacter hominis, and Mgnify accession MGYG-HGUT- 02479. SEQ ID NO: 17 is the amino acid sequence encoded by the napF gene, polypeptide accession GUT_GENOME096975_01040, uncharacterized Bacteroides, and Mgnify accession MGYG-HGUT- 02622. SEQ ID NO: 18 is the amino acid sequence encoded by the nqrF gene, polypeptide accession GUT_GENOME022949_00826, Caecibacter massiliensis, and Mgnify accession MGYG-HGUT- 01561. SEQ ID NO: 19 is the amino acid sequence encoded by the spoVB gene, polypeptide accession GUT_GENOME130358_01140, UC5-1-2E3 sp001304875, and Mgnify accession MGYG-HGUT- 02136. SEQ ID NO: 20 is the amino acid sequence encoded by the tcaB gene, polypeptide accession GUT_GENOME207411_00191, Gemella sp002871655, and Mgnify accession MGYG-HGUT-03121. SEQ ID NO: 21 is the amino acid sequence encoded by the ydeD gene, polypeptide accession GUT_GENOME009027_01847, ER4 sp000765235, and Mgnify accession MGYG-HGUT-03686. SEQ ID NO: 22 is the amino acid sequence encoded by the ypdA_4 gene, polypeptide accession GUT_GENOME096294_04674, Bacteroides oleiciplenus, and Mgnify accession MGYG-HGUT- 01422. SEQ ID NO: 23 is the amino acid sequence encoded by the emrB gene, polypeptide accession GUT_GENOME003305_01683, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705. SEQ ID NO: 24 is the amino acid sequence encoded by the acgS gene, polypeptide accession GUT_GENOME027892_01421, Acidaminococcus fermentans, and Mgnify accession MGYG-HGUT- 00901. SEQ ID NO: 25 is the amino acid sequence encoded by the dcuD_1 gene, polypeptide accession GUT_GENOME096035_03870, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705. SEQ ID NO: 26 is the amino acid sequence encoded by the gpsA gene, polypeptide accession GUT_GENOME095707_00513, uncharacterized Oscillospiraceae, and Mgnify accession MGYG- HGUT-01286. SEQ ID NO: 27 is the amino acid sequence encoded by the IspA gene, polypeptide accession GUT_GENOME235066_01263, uncharacterized Duodenibacillus, and Mgnify accession MGYG- HGUT-00525. SEQ ID NO: 28 is the amino acid sequence encoded by the menD gene, polypeptide accession GUT_GENOME006420_00274, Bacteroides dorei, and Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 29 is the amino acid sequence encoded by the nhaR gene, polypeptide accession GUT_GENOME000659_00630, CAG-56 sp900066615, and Mgnify accession MGYG-HGUT-00140. SEQ ID NO: 30 is the amino acid sequence encoded by the ydbH gene, polypeptide accession GUT_GENOME096035_02490, Citrobacter portucalensis, and Mgnify accession MGYG-HGUT- 01705. SEQ ID NO: 31 is the 16S rRNA sequence of a strain of Bacteroides dorei, Mgnify accession MGYG-HGUT-02478. SEQ ID NO: 32 is the 16S rRNA sequence of a strain of Pluralibacter gergoviae, Mgnify accession MGYG-HGUT-02520. SEQ ID NO: 33 is the 16S rRNA sequence of a strain of Clostridium symbiosum, Mgnify accession MGYG-HGUT-01367. SEQ ID NO: 34 is the 16S rRNA sequence of a strain of Eggerthella lenta, Mgnify accession MGYG-HGUT-02544. SEQ ID NO: 35 is the 16S rRNA sequence of a strain of Oscillospiraceae strain Genus CAG- 83, Mgnify accession MGYG-HGUT-02617. SEQ ID NO: 36 is the amino acid sequence of an identified epitope of the Nsp8 protein of the SARS-CoV2 virus (Nsp8(A)). SEQ ID NO: 37 is the amino acid sequence of an identified epitope of the Nsp8 protein of the SARS-CoV2 virus (Nsp8(B)). SEQ ID NO: 38 is the amino acid sequence of an identified epitope of the 3C-like protease of the SARS-CoV2 virus (3C-like protease (A)). SEQ ID NO: 39 is the amino acid sequence of an identified epitope of the 3C-like protease of the SARS-CoV2 virus (3C-like protease (B)). SEQ ID NO: 40 is the amino acid sequence of an identified epitope of the spike glycoprotein of the SARS-CoV2 virus (spike glycoprotein). SEQ ID NO: 41 is the amino acid sequence of an identified epitope of the Envelop protein of the SARS-CoV2 virus (Envelop (A)). SEQ ID NO:42 is the amino acid sequence of an identified epitope of the Envelop protein of the SARS-CoV2 virus (Envelop (B)). SEQ ID NO: 43 is the amino acid sequence of an identified epitope of the Membrane protein of the SARS-CoV2 virus (Membrane). SEQ ID NO: 44 is the amino acid sequence of an identified epitope of the Nucleocapsid protein of the SARS-CoV2 virus (Nucleocapsid (A)). SEQ ID NO: 45 is the amino acid sequence of an identified epitope of the Nucleocapsid protein of the SARS-CoV2 virus (Nucleocapsid (B)). SEQ ID NO: 46 is the amino acid sequence of an identified epitope of the Surface protein of the SARS-CoV2 virus (Surface (A)). SEQ ID NO: 47 is the amino acid sequence of an identified epitope of the Surface protein of the SARS-CoV2 virus (Surface (B)). SEQ ID NO: 48 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 1 overlap and extension process. SEQ ID NO: 49 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 2 overlap and extension process. SEQ ID NO: 50 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 3 overlap and extension process. SEQ ID NO: 51 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 4 overlap and extension process. SEQ ID NO: 52 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 5 overlap and extension process. SEQ ID NO: 53 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 6 overlap and extension process. SEQ ID NO: 54 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 7 overlap and extension process. SEQ ID NO: 55 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 8 overlap and extension process. SEQ ID NO: 56 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 9 overlap and extension process. SEQ ID NO: 57 is an epitope of the SARS-CoV2 virus that is the result of an exemplary Type 10 overlap and extension process. SEQ ID NO: 58 is a Super Epitope of the SARS-CoV2 virus, Envelop_5, as defined herein. SEQ ID NO: 59 is a Super Epitope of the SARS-CoV2 virus, Envelop_8, as defined herein. SEQ ID NO: 60 is a Super Epitope of the SARS-CoV2 virus, Envelop_9, as defined herein. SEQ ID NO: 61 is a Super Epitope of the SARS-CoV2 virus, Envelop_10, as defined herein. SEQ ID NO: 62 is a Super Epitope of the SARS-CoV2 virus, Nucleocapsid_A_4, as defined herein. SEQ ID NO: 63 is a Super Epitope of the SARS-CoV2 virus, Surface_B_2 as defined herein. SEQ ID NO: 64 is a Super Epitope of the SARS-CoV2 virus, Surface_B_3 as defined herein. SEQ ID NO: 65 is a Super Epitope of the SARS-CoV2 virus, Surface_B_4 as defined herein. SEQ ID NO: 66 is an amino acid sequence encoded by the tig gene, polypeptide accession GUT_GENOME032335_01288, Oscillospiraceae strain ER4 sp000765235, and Mgnify accession MGYG-HGUT-03686. SEQ ID NO: 67 is an amino acid sequence encoded by the oatA gene, polypeptide accession GUT_GENOME225847_00067, Lactobacillus gasseri_A, and Mgnify accession MGYG-HGUT- 02387. SEQ ID NO: 68 is an amino acid sequence encoded by the rnc gene, polypeptide accession GUT_GENOME098263_02121, Pyramidobacter piscolens, and Mgnify accession MGYG-HGUT- 01589. SEQ ID NO: 69 is an amino acid sequence encoded by the cdsA gene, polypeptide accession GUT_GENOME103719_00895, Butyricicoccus pullicaecorum, and Mgnify accession MGYG- HGUT-01434. SEQ ID NO: 70 is an amino acid sequence encoded by the cadA gene, polypeptide accession GUT_GENOME142486_01853, Lactobacillus agilis, and Mgnify accession MGYG-HGUT-02390. SEQ ID NO: 71 is an amino acid sequence encoded by the dltB gene, polypeptide accession GUT_GENOME000963_02927, Faecalicatena orotica, and Mgnify accession MGYG-HGUT-00176. SEQ ID NO: 72 is an amino acid sequence encoded by the yaoK gene, polypeptide accession GUT_GENOME142485_00268, Lactobacillus sakei, and Mgnify accession MGYG-HGUT-02389. SEQ ID NO: 73 is the 16S rRNA sequence of a strain of Butyricicoccus pullicaecorum, Mgnify accession MGYG-HGUT-01434. SEQ ID NO: 74 is the 16S rRNA sequence of a strain of Lactobacillus agilis, Mgnify accession MGYG-HGUT-02390. SEQ ID NO: 75 is the 16S rRNA sequence of a strain of Faecalicatena orotica, Mgnify accession MGYG-HGUT-00176. SEQ ID NO: 76 is the 16S rRNA sequence of a strain of Lactobacillus sakei, Mgnify accession MGYG-HGUT-02389. SEQ ID NO: 77 is the 16S rRNA sequence of a strain of Lactobacillus salivarius, Mgnify accession MGYG-HGUT-02324. SEQ ID NO: 78 is a Super Epitope of the SARS-CoV2 virus, Nucleocapsid_A_2 as defined herein. SEQ ID NO: 79 is an amino acid sequence encoded by a hypothetical gene (hypo), Loris_LMG9848_WP_003713042.1, Limosilactobacillus oris (strain ID LMG 9848). SEQ ID NO: 80 is an amino acid sequence encoded by the htmp gene (heavy metal translocating P-type ATPase), Lfermentum_LMG6902_WP_003681665.1, Limosilactobacillus fermentum (strain ID LMG 6902). DETAILED DESCRIPTION OF THE INVENTION In the summary and this detailed description, each numerical value should be read once as modified by the term "about" (unless already expressly so modified), and then read again as not so modified unless otherwise indicated in context. Also, in the summary and this detailed description, it should be understood that a physical range listed or described as being useful, suitable, or the like, is intended that any and every value within the range, including the end points, is to be considered as having been stated. For example, "a range of from 1 to 10" is to be read as indicating each and every possible number along the continuum between about 1 and about 10. Thus, even if specific data points within the range, or even no data points within the range, are explicitly identified or refer to only a few specific data points, it is to be understood that inventors appreciate and understand that any and all data points within the range are to be considered to have been specified, and that inventors possessed knowledge of the entire range and all points within the range. Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "plurality" refers to two or more. The term “at least one” refers to one or more. A “microbiota-derived cross-reactive antigen” (“mCRAg”) is a polypeptide expressed by the human bacterial microbiome that raises an immune response against at least one pathogenic protein epitope. A “SARS-CoV-2 mCRAg” is a polypeptide expressed by the human gut microbiome that raises an immune response against at least one SARS-CoV-2 protein epitope. In order to raise cross- reactivity, mCRAgs must align to at least 9 amino acids of a pathogenic protein epitope (e.g., SARS- CoV-2), allowing for no more than two amino acid mismatches in the aligned region. SARS-CoV- 2 mCRAgs can be identified according to methods described herein. The term “Simple mCRAg” is used to denote that a single SARS-CoV2 epitope aligns to a single polypeptide expressed by the human gut microbiome. This term describes a simple 1:1 relationship between a sequence section of the polypeptide and the SARS-CoV2 epitope, as illustrated in FIG.2B. The term “Super mCRAg” is used to denote that at least two SARS-CoV2 epitopes align to a single polypeptide expressed by the human gut microbiome, as illustrated in FIG.2B. For clarity, it is to be understood that a polypeptide is to be termed a Super mCRAg if there is at least one other distinct alignment to a SARS-CoV2 epitope found within the same polypeptide expressed by the same bacterial strain. The further alignment can be a second alignment to the same SARS-CoV2 epitope in a different area of the polypeptide or an alignment with a different SARS-CoV2 epitope. The term “Super Bug” is used to denote a bacterial strain found in the human gut microbiome that expresses two or more polypeptides that each comprise a sequence that aligns, as defined herein, with at least one SARS-CoV2 epitope, as illustrated in FIG.2B. The term “Super Epitope” is used to denote a single SARS-CoV2 epitope that aligns, as defined herein, with sequences comprised within multiple mCRAg polypeptides expressed by different bacterial strains, as illustrated in FIG.2B. The term “hit protein” is used to denote a bacterial polypeptide that comprises a sequence that aligns, as defined herein, with at least one SARS-CoV2 epitope. The term “substantially purified” or “purified” as used herein refers to a bacterial cell, such as a bacterial strain, or a mixture of more than one bacterial cells or strains, that are substantially enriched in a sample. The sample can be substantially purified or enriched for the bacterial strain or mixture of strains of interest such that the sample is at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99% or greater of the desired bacterial strain(s) or less than about 40%, 30%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the undesirable or other bacterial strains present. Purity and percentage of the various strains can be measured using standard laboratory procedures such as those provided in the Food and Drug Administration, Office of Regulatory Affairs, Pharmaceutical Microbiology Manual, Document Number ORA.007 (Rev. #2, August 25, 2020). “Human gut microbiome” is the aggregate of all organisms of microbial scale that reside within the human gastrointestinal tract. Subset bacterial strains of the microbiome are denoted herein as “microbiota.” "Immune response" as used herein means the activation of a host's immune system, e.g., that of a subject, patient or mammal, in response to the introduction of an antigen. The immune response can be in the form of a cellular, humoral, or mucosal immune response, or a mixture of these responses. "Peptide," "protein," or "polypeptide" are used interchangeably herein to denote a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modification. As used herein a peptide can be natural, synthetic, or a modification or combination of natural and synthetic. “Commensal” bacteria as used herein means symbiotic bacteria that inhabit a host and provide a benefit upon the host’s health. The human gut microbiome and a subset of those bacterial strains, defined above as microbiota, are generally made up of commensal bacteria. “Prebiotic” as used herein in its broadest sense can be anything added to a microbiota formulation that aids the growth of the bacteria. This can mean a selectively fermented ingredient that results in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health. “Probiotic” as used herein means live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. “Postbiotic” as used herein are functional bioactive compounds that may confers a health benefit on the host. "Subject" as used herein can mean a mammal that is in need of an increased immune response, through administration of the compositions provided herein, alone or in conjunction with a SARS- CoV2 vaccine or a SARS-CovV2 viral antigen. The mammal can be, for example, a human, a chimpanzee, a dog, a cat, a horse, a cow, a mouse, or a rat. The term ‘‘immunologically effective amount” or “immunologically effective dose” is a quantity of a composition (typically, an immunogenic composition) sufficient to elicit an immune response in a subject when administered alone or in conjunction with a SARS-CoV2 vaccine or a SARS-CoV2 viral antigen. Commonly, the desired result is the production of an antigen-specific immune response that is capable of or contributes to protecting the subject against the pathogen, such as SARS-CoV2. However, to obtain a protective immune response against a pathogen can require multiple administrations of the immunogenic composition. Thus, in the context of this disclosure, the term immunologically effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining a protective immune response. The term “SARS-CoV2” (Severe Acute Respiratory Syndrome Coronavirus 2) refers to the virus that causes the respiratory disease called coronavirus disease 19 (COVID-19). As used herein, SARS-CoV2 encompasses a family of closely related variant viruses. See, e.g., Singh et al., Nature, 10: 16219 (2020); Ahmed et al., Viruses, 12(3):254 (2020); and Ahmad et al., Eur J Pharm Sci 151:105387 (Aug 1, 2020); Colson, et al., medRxiv 2021.09.10.21262922 (2021). The terms “nutraceutical” and “nutraceutical composition” as used herein refer to an edible additive for food or beverage such that the substance provides a medicinal, health or immunological benefit to an animal, including a human, that ingests the nutraceutical. The term “antibiotic effect” is used herein to describes the bacterial killing effect of antibiotic drugs. Within some methods of the present invention, antibiotic effect can be utilized to eliminate or reduce the levels of bacteria present in the subject so that dosing with compositions comprising bacterial cells of the present disclosure will result in a replacement of that bacterial population with bacterial cells of the present disclosure. All references cited herein are incorporated by reference in their entirety. The present disclosure is based in part upon the discoveries that within polypeptides expressed by bacterial organisms, in particular those organisms that are components of the human gut microbiome, there are amino acid sequences expressed that align with those viral antigens that have been defined as the basis for T-cell or B-cell immunity to the SARS-CoV2 virus or a related virus. The sequences within the polypeptides are SARS-CoV2 mCRAgs. The present disclosure also is based in part upon the discovery and identification of specific SARS-CoV2 mCRAgs, the bacterial polypeptides that comprise those SARS-CoV2 mCRAgs, and the bacterial strains and purified cells that express the polypeptides that comprise the SARS-CoV2 mCRAgs and compositions thereof. Further, the present disclosure is based in part upon methods of increasing an immune response, pharmaceutical compositions and kits, nutraceuticals, and vaccines that comprise or utilize the SARS-CoV2 mCRAgs provided herein. mCRAg-Expressing Bacterial Cells The present disclosure describes bacterial cells that express mCRAg polypeptides that have been identified using the methods provided in this disclosure and its examples. The methods provided in the examples provide support for the cross-reactivity between epitopes of SARS-CoV2 and the mCRAg polypeptide or polypeptides expressed by the bacterial cell. The present disclosure therefore supports the use of such a bacterial cell for improving the immune response to SARS- CoV2. In certain embodiments, the bacterial cell expresses at least one SARS-CoV2 mCRAg. In some embodiments, the bacterial cell of the present disclosure is a recombinant bacterial cell engineered to express at least one SARS-CoV2 mCRAg. In certain embodiments, the bacterial cell of the present disclosure expresses at least one SARS-CoV2 mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NO: 58-65; or SEQ ID NO: 78. In other embodiments, the bacterial cell described in this disclosure expresses at least one mCRAg polypeptide with at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78. In some embodiments, the at least one bacterial cell is of a bacterial strain that is present in the human gut microbiome. The present disclosure also provides derivatives of the bacterial cells which may be a daughter cell (progeny) or a cell cultured (subcloned) from the original. A derivative of a bacterial cell of the present disclosure may be modified in any manner, for example at the genetic level, provided such modification does not ablate the immunological activity. A derivative cell of the present disclosure is immunologically active. A derivative cell will have comparable or improved positive immune modulatory activity to the immune response to SARS-CoV2 as the original. The present disclosure provides a bacterial cell that is of at least one strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment of the present disclosure the bacterial cell can be of a bacterial strain selected from the group consisting of Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. These strains have been identified as natively expressing at least one mCRAg polypeptide of the present disclosure. In some embodiments, the bacteria are commensals. In other embodiments, the bacteria can be attenuated strains of pathogens. Attenuated strains of pathogens will lack all or parts of virulence operons, may lack immune-stimulatory surface moieties (e.g., lipopolysaccharide for Gram-negative bacteria), or may contain one or more nutrient auxotrophies. In further embodiments, the bacteria are attenuated intracellular pathogens. An alternative means of identifying the bacterial cells of the present disclosure is through the cell’s 16S rRNA sequence. See, e.g., Srinivasin et al., PLoS ONE; 10(2): e0117617 (Feb. 6, 2015). The present disclosure also relates to a bacterial cell derived from a bacterial strain that has a 16S rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16S rRNA sequence of SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77. In some embodiments, the bacterial cell has the 16S rRNA sequence represented by SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77. In all embodiments described herein, the bacterial cells can be partially or substantially purified. In all embodiments described herein, the bacterial cells can comprise at least two bacterial strains. A further means of identifying the expressed polypeptide or strains from which the bacterial cell is derived is through identification numbers assigned to the polypeptide or strain of interest through a database or other bacterial cell collection. For example, polypeptides can be identified through the polypeptide accession number GUT_GENOME or strains deposited in the EMBL-EBI microbiome collection can be identified by their Mgnify identification number (see, e.g. Mitchell et al., Nucl. Acids Res. Volume 48, Issue D1, 08 January 2020, Pages D570–D578). In another example, polypeptides and strains can be identified by the respective identification numbers provided by the Belgian Coordinated Collection of Micro-organisms collection (BCCM/LMG) Sequence ID or Strain ID (see bccm(dot)belspo(dot)be/about-us/bccm-lmg). Another means of identifying the bacterial cell of the present disclosure is through the presence of a Super Epitope, as defined herein. Particular embodiments of the bacterial cell of the present disclosure comprises at least one sequence selected from the group consisting of SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64; SEQ ID NO: 65; and SEQ ID NO: 78. In certain embodiments, the bacterial cell described herein comprises at least one of the polypeptides of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 mCRAg polypeptides or Super Epitopes. To accomplish the expression of multiple mCRAg polypeptides or Super Epitopes, it is possible to utilize genetic engineering techniques, although such techniques can also be utilized to provide expression of a single mCRAg polypeptide or Super Epitope. For example, genetically engineered bacteria can include bacteria harboring i) one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or on an endogenous plasmid, wherein the genetic change may result in the alteration, disruption, removal, or addition of one or more protein- coding genes, non-protein-coding genes, gene regulatory regions, or any combination thereof, and wherein such change maybe a fusion of two or more separate genomic regions or may be synthetically derived; ii) one or more foreign plasmids containing a mutant copy of an endogenous gene, such mutation being an insertion, deletion, or substitution, or any combination thereof, of one or more nucleotides; and iii) one or more foreign plasmids containing a mutant or non-mutant exogenous gene or a fusion of two or more endogenous, exogenous, or mixed genes. The engineered bacteria may be produced using techniques including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, or any combination thereof. mCRAg-Containing Compositions and Kits The present disclosure describes compositions that comprise bacterial cells that express mCRAg polypeptides or Super Epitopes that have been identified using the methods provided in this disclosure and its examples. In certain embodiments, the composition of the present disclosure comprises at least one bacterial cell that expresses at least one SARS-CoV2 mCRAg. In certain embodiments, the bacterial cell is a recombinant cell engineered to express the at least one SARS-CoV2 mCRAg. In certain embodiments, the composition of the present disclosure comprises a bacterial cell that expresses a mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78. In other embodiments, the composition comprises a bacterial cell that expresses an mCRAg polypeptide or Super Epitope with least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78. In some embodiments, the composition comprises at least one bacterial cell is of a bacterial strain that is present in the human gut microbiome. The present disclosure also provides compositions comprising derivatives of the bacterial cells which may be a daughter cell (progeny) or a cell cultured (subcloned) from the original. For inclusion in the composition, the derivative of the disclosed bacterial cell may be modified in any manner, for example at the genetic level, provided such modification does not ablate the immunological activity. A derivative strain of the present disclosure is immunologically active. A derivative strain will have comparable or improved positive immune modulatory activity to the immune response to SARS-CoV2 as the original. The present disclosure provides compositions comprising a bacterial cell derived from particular bacterial strains. Specifically, the bacterial cell can be of a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG- HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum. In one embodiment the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In a further embodiment the composition comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment the composition comprises the following bacterial strains: Lactobacillus sakei;Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. These strains have been identified as natively expressing at least one mCRAg polypeptide or Super Epitope of the present disclosure. In some embodiments of the composition, the composition will contain at least two bacterial strains. In certain embodiments, the at least two bacterial strains are selected from the following strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. The present disclosure also relates to a composition comprising a bacterial cell derived from a bacterial strain that has a 16S rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16S rRNA sequence of SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77. In some embodiments, the composition comprises the bacterial cell that has the 16S rRNA sequence represented by SEQ ID NOS: 31-35 or SEQ ID NOS: 73-77. In all compositions described herein, the bacterial cell or strain comprising the composition can be substantially purified. In certain embodiments, the composition will comprise bacterial cell comprising at least one or more of the polypeptides of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 56-65; or SEQ ID NO: 78, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 mCRAg polypeptides or Super Epitopes. The amount of the mCRAg comprising component for the compositions described can be suitably determined depending on purpose of use (prophylactic, health or therapeutic treatment). It is anticipated that the compositions of the present disclosure can be made up of bacterial cells that not only express mCRAgs or Super Epitopes, as provided herein, but can also be a probiotic bacteria or non-pathogenic bacteria which, when the relative abundance altered, can confer a health benefit to the host. Thus, the strains that express mCRAgs or Super Epitopes can also be optionally characterized as probiotic strains. Further, additional probiotic strains that do not express an mCRAg or a Super Epitope can be added to the present compositions for the health benefits provided. Probiotics are described in Hill et al., Nat Rev Gastroenterol Hepatol 2014 Aug;11(8):506-14. Probiotic strains generally have the ability to survive the passage through the upper part of the digestive tract when administered orally. They are nonpathogenic, non-toxic and exercise their beneficial effect on health on the one hand, possibly via ecological interactions with the resident flora in the digestive tract, and on the other hand, possibly via their ability to influence the immune and metabolic systems in a positive manner via the "GALT" (gut-associated lymphoid tissue). These bacterial cells, when given in a sufficient number, have the ability to progress live through the intestine; however, they do not cross the intestinal barrier in large numbers and their primary effects are therefore induced in the lumen and/or the wall of the gastrointestinal tract. They then form part of the resident flora. This colonization (or transient colonization) allows the probiotic bacterial cells to exercise a beneficial effect, such as the repression of other micro-organisms present in the flora and interactions with the immune system of the intestine. The presently disclosed compositions may include bacterial cells or components that are viable (live), dormant, inactivated or dead, or any combination thereof. In some embodiments, the bacterial cells or components can include a mixture or combination of live bacterial strains. It is known to one of ordinary skill that the teachings of the present disclosure can apply to the other composition forms for antigens that can be used to increase the immune response to that antigen in a subject, and in turn, increase that subject’s response to an infection by a virus expressing that antigen. Any or all of the probiotic strains provided in the composition can be partially or substantially purified. The above listed beneficial characteristics of particular probiotic strains can provide a selection step in the formulation of the compositions of the present disclosure. Further, many of the polypeptide and sequence results described in database records of the human gut microbiome, such as the UHGP are attributed to bacterial strains with no available isolates. Thus, selection for a bacterial strain that is both (1) nonpathogenic and (2) a strain with known, available isolates is a further selection step that can be utilized to select the bacterial strain combination utilized in the compositions of the present methods. The present disclosure also discloses bacterial strains that comprise SARS-CoV2 mCRAgs that are selected from a variety of antigen sources. For example, a mixture of bacterial strains comprising SARS-CoV2 mCRAgs including the epitopes Envelop_8 (VFLLVTLAI; SEQ ID NO: 59), Envelop_9 (FLLVTLAIL; SEQ ID NO: 60), Envelop_10 (LLVTLAILT; SEQ ID NO: 61), Surface_B_2 (VFLVLLPLV; SEQ ID NO: 63), and Surface_B_3 (FLVLLPLVS; SEQ ID NO: 64) could provide a wide variety of mCRAgs in the thus formed bacterial consortium. In a further example, concentration on a specific epitope could be advantageous, such as a mixture of bacterial strains comprising SARS-CoV2 mCRAgs including the epitopes Envelop_9 (FLLVTLAIL; SEQ ID NO: 60); Surface_B_2 (VFLVLLPLV; SEQ ID NO: 63) and Nucleocapsid_A_2 (DAALALLL; SEQ ID NO: 78). Another aspect includes compositions including compounds or agents that alter the relative abundance of microbiota indirectly, such as through the administration of compound(s) or agent(s) that affect the growth, survival, persistence, transit or existence of at least one specific microbiota. The additional compounds or agents can be “prebiotics.” These prebiotics are described in Gibson et al., Nat Rev Gastroenterol Hepatol 14, 491–502 (2017). The term “prebiotics” can refer to a component which increases the number of probiotic bacteria in the intestine. Thus, prebiotics as used herein may refer to any non-viable component that is specific to a bacteria thought to be of positive value. The administration of at least one prebiotic compound may selectively enhance the relative abundance or general growth of at least one specific strain within the composition of the present disclosure in vivo resulting in the desired increase in immune response. Thus, such components are anticipated to be possible within the compositions of the present disclosure. Some non-limiting examples of prebiotics can include bacterial cell wall components such as peptidoglycans, bacterial nucleic acids such as DNA and RNA, bacterial membrane components, and bacterial structural components such as proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins. Additional examples can also include organic acids, inorganic acids, bases, proteins and peptides, enzymes and co-enzymes, amino acids and nucleic acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, bioactive compounds, metabolites containing an inorganic component, small molecules, for example nitrous molecules or molecules containing a sulphurous acid, resistant starch, potato starch or high amylose starch, modified starches (including carboxylated starches, acetylated, propionated, and butyrated starches), non-digestible oligosaccharides such as fructooligosaccharides, glucooligosaccharides, xylooligosaccharides, galactooligosaccharides, arabinoxylans, arabinogalactans, galactomannans, polydextrose, oligofructose, inulin, derivatives of these, but not excluding other oligosaccharides able to exert prebiotic effects, other soluble fibers, and combinations thereof. An additional possible component of the presently described compositions is a “post-biotic.” Such post-biotics are made up of inactivated micro-organisms that convey either a direct or indirect health benefit to the subject upon administration. These post-biotics have been described in Salimen et al., Nat Rev Gastroenterol Hepatol 18, 649–667 (2021). Other related terms have also been used for such preparations, including paraprobiotics, parapsychobiotics, ghost probiotics, metabiotics, tyndallized probiotics and bacterial lysates. The composition component described by any or all of these terms are encompassed in the possible addition of a post-biotic in the composition of the present disclosure. In general, the inactivated micro-organisms of a post-biotic are in a form that is stable and safe for consumption by a subject. Some non-limiting examples of a post-biotic include inanimate strains belonging to established probiotic taxa within some genera of the family Lactobacillaceae (now comprising 31 genera) or the genus Bifidobacterium. However, a microbial strain or consortium does not have to qualify as a probiotic (while living) for the inactivated version to be accepted as a postbiotic. Specific strains of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides xylanisolvens, Bacteroides uniformis, Eubacterium hallii, Clostridium cluster IV and XIVa, Apilactobacillus kunkeei and the fungus Saccharomyces boulardii have all been investigated for potential beneficial effects in an inanimate form (Aguilar-Toala, J. E. et al. Probiotics Antimicrob. Proteins12, 608–622 (2019); Martin, R. et al. Front. Microbiol. 8, 1226 (2017); Brodmann, T. et al. Front. Microbiol.8, 1725 (2017); Breyner, N. M. et al. Front. Microbiol.8, 114 (2017); Cani, P. D. & de Vos, W. M. Front. Microbiol.8, 1765 (2017)). Many bacterial lysates have been used for medical purposes (European Medicines Agency. Assessment report. Referral under Article 31 of Directive 2001/83/EC). One microbiological composition includes one strain of Haemophilus influenzae, four strains of Streptococcus pneumoniae, two strains of Klebsiella pneumoniae subsp. pneumoniae, one strain of Klebsiella pneumoniae subsp. ozaenae, two strains of Staphylococcus aureus, one strain of Streptococcus pyogenes, three strains of Streptococcus sanguinis and three strains of Moraxella catarrhalis (Huber, M. et al., Eur. J. Med. Res.10, 209–217 (2005)). Bacterial lysates have further been shown to exert anti-infection effects and, indeed, efficacy in reducing the frequency of acute respiratory infections among those prone to recurrent respiratory infections has been demonstrated in clinical trials (Braido, F. et al., Int. J. Chron. Obstruct Pulmon Dis.2, 335–345 (2007)). Also, some spirulina formulations could qualify as postbiotics, but only if the processing and microorganism used (often species Arthrospira platensis) is well described (Zarezadeh, M. et al., Phytother Res.35, 577–586 (2021)). Any or all of these non-limiting examples can comprise a component of the compositions presently disclosed and any or all of these components can be substantially purified. A further additional compound or agent that can be present in the composition of this disclosure are antibiotic treatments and/or antibacterial agents. Antibiotics can also include naturally occurring antibacterial agents (e.g., magainins, defensins and others) or specialized nutrient mixtures that alter the relative composition of the microbiota. In some embodiments, provided herein is a composition comprising the bacterial cell as described herein. Pharmaceutical Compositions In another embodiment, the compositions of the present disclosure which comprise at least one SARS-CoV2 mCRAg can be characterized as pharmaceutical compositions. The composition according to the present disclosure may be characterized as including an appropriate carrier, excipient and diluent which are generally used in the preparation of pharmaceutical compositions. The pharmaceutical composition according to the present disclosure can be formulated for use in the form of oral formulations, external preparations, suppositories, and sterile injection solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols according to the well-known methods. Suitable preparations known in the art are such as those disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton Pa.). A particular formulation of the present disclosure is where the compositions are formulated for absorption by the intestines, which is achieved through the selection of the components of the composition to potentiate such administration. Such formulations are known in the art, specifically for microbiome therapeutics, as described in Vass et al., AAPS PharmSciTech, 21, Article number 214 (2020); Mimee et al., Adv Drug Deliv Rev, 105(Pt A): 44-54 (2016). Examples of the carrier, excipient and diluent, which may be included in the pharmaceutical composition comprising SARS-CoV2 mCRAgs according to the present disclosure, may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The preparations can be produced using generally used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like. These solid preparations are produced by mixing the extract with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin or the like. In addition, apart from the simple excipient, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups and the like. Generally used diluents such as water and liquid paraffin as well as various excipients, for example, wetting agents, sweeteners, fragrances, preservatives and the like may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lypophilized preparations and suppositories. Useful non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like. The base for suppositories includes Witepsol, Macrogol, Tween 61, cacao butter, laurin, glycerogelatin or the like. In some embodiments, the pharmaceutical composition of the present disclosure comprises a composition comprising at least one bacterial cell that expresses at least one SARS-CoV2 mCRAg and an excipient. In certain embodiments, the bacterial cell is a recombinant cell engineered to express the at least one SARS-CoV2 mCRAg. In some embodiments, the pharmaceutical composition of the present disclosure comprises a composition comprising a bacterial cell that expresses a mCRAg polypeptide with sequence identity to at least one of SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78. In other embodiments, the pharmaceutical composition of the present disclosure comprises a composition comprising a bacterial cell that expresses an mCRAg polypeptide or Super Epitope with least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NOS: 1-30; or SEQ ID NOS: 66-72; or SEQ ID NOS: 79-80; or SEQ ID NOS: 58-65; or SEQ ID NO: 78. In some embodiments, the pharmaceutical composition of the present disclosure comprises a composition which comprises at least one bacterial cell, wherein the bacterial strain is present in the human gut microbiome. In certain embodiments the bacterial cell can be of a bacterial strain selected from the group of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83 (MGYG-HGUT-02229); Oscillospiraceae strain Genus CAG-83 (MGYG- HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum. In one embodiment the pharmaceutical composition comprises a composition comprising the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In a further embodiment the pharmaceutical composition comprises a composition which comprises at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment the pharmaceutical composition comprises a composition which comprises the following bacterial strains: Lactobacillus sakei;Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In some embodiments, provided herein is a pharmaceutical composition comprising the composition as described herein. In some embodiments, provided herein is a pharmaceutical composition comprising the composition as described herein and an excipient. In certain embodiments, the composition is formulated for delivery to the intestine. In certain embodiments, provided herein is a pharmaceutical composition comprising the composition as described herein and a SARS-CoV2 vaccine. In certain embodiments, the composition is formulated for delivery to the intestine. The preferred dose of the pharmaceutical composition according to the present disclosure comprising SARS-CoV2 mCRAgs can be suitably selected by those skilled in the art according to patient's conditions and body weight, severity of disease, dosage form, and administration route and period. In order to achieve desired effects, the composition of the present disclosure can be administrated daily at a dose of about 0.001 mg/kg to about 1000 mg/kg. The composition can be administered in a single dose per day or in multiple doses per day. The dose should not be construed as limiting the scope of the present disclosure in any context. The pharmaceutical compositions of the present disclosure can include a SARS-CoV2 vaccine. Any vaccine that has been developed to induce an immunological reaction against the SARS-CoV2 virus can be utilized in the pharmaceutical compositions. Such vaccines include those presently utilized (see, Creech et al., JAMA, JAMA.2021;325(13):1318-1320) and those currently in the approval phase (see, Kyriakidis et al., npj Vaccines 6: 28 (2021)). Some specific non-limiting examples include mRNA-1273 (Moderna); BNT162b2 (Pfizer-BioNTech); Ad26.CoV2.5 (Janssen/Johnson & Johnson); ChAdOx1 (AstraZeneca/Oxford); NVX-CoV2373 (Novavax); CVnCoV (CureVac/GSK); Gam-COVID-Vac (Sputnik V; Gamaleya National Research Center for Epidemiology and Microbiology); CoronaVac (Sinovac Biotech) and BBIBP-CorV (Sinopharm 1/2). In certain embodiments, provided herein is a vaccine comprising at least one SARS-CoV2 mCRAg as described herein. In certain embodiments, the vaccine may further comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be functional molecules such as vehicles, carriers, or diluents. The pharmaceutically acceptable excipient can be a transfection facilitating agent, which can include surface active agents, such as immune-stimulating complexes (ISCOMS), Freunds incomplete adjuvant, LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene and squalene, hyaluronic acid, lipids, liposomes, calcium ions, viral proteins, polyanions, polycations, or nanoparticles, or other known transfection facilitating agents. The pharmaceutically acceptable excipient can be an adjuvant. The adjuvant can be other genes that are expressed in an alternative plasmid or are delivered as proteins in combination with the plasmid above in the mCRAg comprising vaccine. The adjuvant may be selected from the group consisting of:α-interferon(IFN-α), β-interferon (IFN-β), γ-interferon, platelet derived growth factor (PDGF), tumor necrosis factor alpha (TNF-α) tumor necrosis factor beta (TNF-β), granulocyte- macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), cutaneous T cell- attracting chemokine (CTACK), epithelial thymus-expressed chemokine (TECK), mucosae- associated epithelial chemokine (MEC), IL-12, IL-15, MHC, CD80, CD86 including IL-15 having the signal sequence deleted and optionally including the signal peptide from IgE. The adjuvant can be IL-12, IL-15, IL-28, CTACK, TECK, platelet derived growth factor (PDGF), TNF-α, TNF-β, GM-CSF, epidermal growth factor (EGF), IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, or a combination thereof. Other genes that can be useful as adjuvants include those encoding: MCP-1, MIP-1a, MIP- 1p, IL-8, RANTES, L-selectin, P-selectin, E-selectin, CD34, GlyCAM-1, MadCAM-1, LFA-1, VLA-1, Mac-1, p150.95, PECAM, ICAM-1, ICAM-2, ICAM-3, CD2, LFA-3, M-CSF, G-CSF, IL- 4, mutant forms of IL-18, CD40, CD4OL, vascular growth factor, fibroblast growth factor, IL-7, nerve growth factor, vascular endothelial growth factor, Fas, TNF receptor, Flt, Apo-1, p55, WSL- 1, DR3, TRAMP, Apo-3, AIR, LARD, NGRF, DR4, DRS, KILLER, TRAIL-R2, TRICK2, DR6, Caspase ICE, Fos, c-jun, Sp-1, Ap-1, Ap-2, p38, p65Rel, MyD88, IRAK, TRAF6, IkB, Inactive NIK, SAP K, SAP-1, JNK, interferon response genes, NFkB, Bax, TRAIL, TRAILrec, TRAILrecDRC5, TRAIL-R3, TRAIL-R4, RANK, RANK LIGAND, Ox40, Ox40 LIGAND, NKG2D, MICA, MICB, NKG2A, NKG2B, NKG2C, NKG2E, NKG2F, TAP1, TAP2 and functional fragments thereof. In some embodiments the composition disclosed herein is used in a method of increasing an immune response to a SARS CoV2 vaccine in a subject comprising: administering an antibiotic to a subject before the administration of the vaccine; administering to the subject an immunologically effective amount of the composition after the clearance of the antibiotic effect; and administering the vaccine. In some embodiments the administration of the antibiotic occurs fourteen to twenty-one days prior to the administration of the vaccine. The present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical composition for use in a method of increasing an immune response to a SARS- CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition. The present disclosure also relates to a composition as disclosed herein, such as a pharmaceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition. In some embodiment the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine. In some embodiment the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine. Further utilizations of the pharmaceutical compositions are in the form of kits, for example a kit which comprises one or more pharmaceutical compositions of the present disclosure and a vaccine, wherein the vaccine is for inducing an immunological response to the same virus expressing the viral epitopes that were used to screen for the SARS-CoV2 mCRAgs present in the pharmaceutical compositions The present disclosure therefore also encompasses kits comprising one or more compositions of the present disclosure. For example, the kit can comprise one or more components in immunologically effective amounts for each component of the kit to be administered to a subject. The components can be pharmaceutical compositions of the present disclosure, nutraceutical compositions of the present disclosure, or a vaccine or a combination thereof. Some components of the kit can be for later administration, for example after administration of the vaccine. The components can be packaged in a suitable container and with a device for administration. The kit can further comprise instructions for using the kit. In some embodiments, provided herein is a kit comprising the composition as described herein and a SARS-CoV2 vaccine. In certain embodiments, the kit of the present disclosure is formulated for delivery to the intestine. Nutraceutical Compositions In addition, the present disclosure provides a nutraceutical for increasing the immune response to the SARS-CoV2 mCRAg comprised in the composition containing, as an active ingredient, the SARS-CoV2 mCRAg. The term nutraceutical originally was coined as a combination of the words “nutrition” and “pharmaceutical.” A nutraceutical may be a food/beverage or food/beverage component, such as a dietary supplement or a food additive. As used herein, the term food is intended to encompass any edible substance, which substance may be in solid, liquid, paste, tablet or other orally ingestible form. A nutraceutical may also supplement the diet, and includes traditional dietary supplements such as vitamins, minerals, herbs, oils and substances such as glucosamine, amino acids and other dietary supplements. As used herein, a nutraceutical is intended for oral ingestion and provides a health, medicinal or immunological benefit that may aid in disease prevention, disease treatment, and immunologic response. A nutraceutical may be a pharmaceutical-grade nutrient with standardized properties. A nutraceutical may also be a combination of substances including any combination of dietary supplements, food additives, vitamins, minerals, probiotics, prebiotics, spirulina, cereals and other substances that confer a health benefit to the animal, including a human, that ingests the nutraceutical. A nutraceutical may also be considered a functional food or functional food ingredient that provides a health, medicinal or immunological benefit in addition to the basic nutritional value of the food or food ingredient. A nutraceutical may be any functional or medicinal food that plays a role in maintaining well-being, enhancing health, modulating immunity and thereby aiding in preventing as well as treating specific diseases. When the composition according to the present disclosure is used as a nutraceutical, it may be added alone or it may be used in combination with other foods or food ingredients and may be suitably used according to the conventional methods. The compounds or agents can be provided in a food, drink, dietary supplement, and/or food additive or can be used to modify a food, drink, dietary supplement, and/or food additive. When the composition according to the present disclosure is used for the preparation of a food or beverage, it is generally added in an amount of about 15 wt % or less, or about 10 wt % or less, based on the total weight of the food or beverage. Nutraceutical compositions as described herein can comprise from about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% to about 10%, 9%, 8%, 7%, 6%, or 5% or less of the total weight of the food or beverage. However, when prolonged intake is intended for the purpose of health, hygiene or health control, the amount of the active ingredient may be smaller than the lower limit of the range defined above. In addition, the active ingredient may be used in an amount higher than the upper limit of the above range and it only limited from the point of view of safety. Any safe and effective nutraceutical formulation can be utilized to administer the mCRAgs of the present disclosure. In addition to the ingredients and formulations described above, the SARS-CoV2 mCRAg comprising composition according to the present disclosure may include a variety of nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickening agents, pH adjusting agents, stabilizers, antiseptics, glycerine, alcohol and carbonating agents for carbonated drinks. Further, the composition according to the present disclosure may include fruit or vegetables for producing natural fruit juices, fruit juice drinks and vegetable drinks. This ingredient may be used alone or in combination. The proportion of this additive is not significantly important but is generally determined within the range of about 0.01 to about 0.1 parts by weight with respect to about 100 parts by weight of the composition according to the present disclosure. Purified antigens, such as mCRAgs can be combined with the adjuvant as described above. The immune response induced by the mCRAg can be boosted or increased when combined with the adjuvant. Such an immune response can be a humoral immune response, a cellular immune response, or a mucosal immune response or a mixture thereof. In some embodiments, the combination of the adjuvant and the mCRAg can boost or increase a cellular immune response in the subject. In other embodiments, the combination of the adjuvant and the mCRAg can boost or increase a humoral immune response in the subject. In other embodiments, the combination of the adjuvant and the mCRAg can boost or increase a mucosal immune response in the subject. The mCRAg can be in the form of a nucleic acid sequence, an amino acid sequence, or a combination thereof. The nucleic acid sequence can be DNA, RNA, cDNA, a variant thereof, a fragment thereof, or a combination thereof. The nucleic acid sequence can also include additional sequences that encode linker or tag sequences that are linked to the mCRAg by a peptide bond. The amino acid sequence can be a protein, a peptide, a variant thereof, a fragment thereof, or a combination thereof. In some embodiments, provided herein is a nutraceutical composition comprising the bacterial cell as described herein. In some embodiments, provided herein is a nutraceutical composition comprising the composition as described herein. In some embodiments, the nutraceutical composition additionally comprises a nutrient. Methods of Use The present disclosure is also directed to methods of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject by administration of an immunologically effective amount of the composition of the present disclosure. The present disclosure is further directed to methods of inducing an immune response to a SARS-CoV2 mCRAg, the method comprising administering to a subject in need thereof, an immunologically effective amount of the composition of the present disclosure. Increasing or inducing the immune response can be used to treat and/or prevent disease in a subject. The present disclosure is also directed to methods of increasing an immune response in a subject by administration of a vaccine comprising the mCRAgs of the present disclosure. These methods can therefore include either administering the composition, administering the vaccine to the subject, or administering a combination of the compositions and a vaccine to the subject. The subject administered the composition, vaccine, or combination can have an increased or boosted immune response as compared to a subject administered the composition or the vaccine on its own. In some embodiments, the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination can be increased by about 15% to about 650%, about 10% to about 100%, or about 20% to about 200%. Alternatively, the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination may be increased by about 50% to about 250%. In still other alternative embodiments, the immune response to the SARS- CoV2 vaccine or to the mCRAg in the subject administered the composition, vaccine, or combination may be increased by about 100% to about 150%. In other embodiments, the administered composition, vaccine, or combination can increase or boost the immune response to the SARS-CoV2 vaccine or to the mCRAg in the subject by at least about 1.2 fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, or at least about 10-fold. The composition or vaccine dose can be between about 1 µg to about 10 mg active component/kg body weight/time and can be about 20 µg to about 10 mg component/kg body weight/time. The composition or vaccine can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. The number of composition or vaccine doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The term "administration" as used herein means providing the predetermined composition according to the present disclosure to a subject by any suitable method. The pharmaceutical composition can be administered in vivo or in vitro via a route such as intravenous, intraperitoneal, intramuscular, subcutaneous, intradermal, nasal, mucosal, inhalation or oral route as long as the administration results in an increase in an immune response of the subject. The preferred dose of the pharmaceutical composition according to the present disclosure comprising SARS-CoV2 mCRAgs can be suitably selected by those skilled in the art according to patient's conditions and body weight, severity of disease, dosage form, and administration route and period. In order to achieve desired effects, the composition of the present disclosure can be administrated daily at a dose of about 0.001 mg/kg to about 1000 mg/kg. The composition can be administered in a single dose per day or in multiple doses per day. The dose should not be construed as limiting the scope of the present disclosure in any context. The composition of the present disclosure can also be administered in the same composition with compounds or agents such as vaccines or can be administered individually with the compounds or agents administered before, concurrent with, and/or after the present compositions. The present composition can be administered at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more prior to the administration of compounds or agents. The present composition can also be administered at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more after the administration of compounds or agents. The present composition can be administered concurrently with the administration of compounds or agents. It is possible to utilize an antibiotic to “reset” the microbiome prior to the administration of the composition of the present disclosure. In such case, the administration of the antibiotic occurs between 14, 15, 16, 17, 18, 19, 20, or 21 days prior to the administration of the composition and vaccine. In one embodiment of the disclosed methods of use, the composition used in the method comprises at least one bacterial strain selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis; Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum; Eggerthella lenta; Oscillospiraceae strain Genus CAG-83(MGYG-HGUT- 02229); Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum. In one embodiment the method uses the composition comprising the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; and Butyricicoccus pullicaecorum. In a further embodiment the method uses at least one bacterial strain selected from the group consisting of: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In a further embodiment of the presently disclosed methods of use, the composition comprises the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum. In all methods of use embodiments described herein, the bacterial cell or strain of the composition can be partially or substantially purified. In all methods of use embodiments described herein, the composition can comprise at least two bacterial strains. An alternative way of identifying the bacterial strains for utilization in the presently disclosed methods is through the strain’s 16S rRNA sequence as discussed above. Therefore the at least one bacterial strain of the methods of use compositions can comprises a 16S rRNA sequence having at least 97% sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NOS:31-35 and SEQ ID NOS:73-77. In another method of the present disclosure the at least one bacterial strain comprises a Super Epitope and a subset of such Super Epitopes are at least one sequence selected from the group consisting of SEQ ID NOS: 58-65 and SEQ ID NO: 78. The present disclosure also relates to the use of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of increasing an immune response to a SARS-CoV2 vaccine or SARS-CoV2 viral antigen in a subject comprising administering to the subject an immunologically effective amount of the composition. The present disclosure also relates to the use of a composition as disclosed herein, such as a pharmaceutical or nutraceutical composition for use in a method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition. In some embodiments the administration of the immunologically effective amount of the composition occurs before the administration of the vaccine. In some embodiments the administration of the immunologically effective amount of the composition occurs at the time of the administration of the vaccine. In some embodiments the administration of the immunologically effective amount of the composition occurs after the administration of the vaccine. In some embodiments, the methods of use of the present disclosure use of the composition disclosed herein in a method of increasing an immune response to a SARS CoV2 vaccine in a subject comprising: administering an antibiotic to a subject before the administration of the vaccine; administering to the subject an immunologically effective amount of the composition after the clearance of the antibiotic effect; and administering the vaccine. In some embodiments the administration of the antibiotic occurs fourteen to twenty-one days prior to the administration of the vaccine. Methods of Identifying SARS-CoV2 mCRAgs The SARS-CoV2 mCRAgs of the present disclosure have been identified using a method that is taught herein and summarized by the flow chart of FIG.1. An exemplary source of potential epitopes to be used for the identification of SARS-CoV2 mCRAgs can be published epitope sequences for this virus or closely related viruses, including SARS-CoV, such as those provided by Singh et al., Nature, 10: 16219 (2020); Ahmed et al., Viruses, 12(3):254 (2020); and Ahmad et al., Eur J Pharm Sci 151:105387 (Aug 1, 2020); Colson, et al., medRxiv 2021.09.10.21262922 (2021). However, such publications are themselves based on bioinformatics efforts, and thus, comparable results can be obtained using approaches known to a skilled person through the comparative analysis of experimentally- determined SARS-CoV2 or related viruses data of B cell epitopes (preferably linear, but possibly discontinuous) and T-cell epitopes sequence information to viral genomic sequences. Briefly, genome sequences of the virus or related viruses are obtained from an appropriate database, such as GISAID, maintained by Freunde von GISAID e.V., accessed at gisaid(dot)org. After screening for sequencing errors, the sequences are aligned with a reference sequence, also obtained from an appropriate database, such as GenBank, accessed at www(dot)ncbi(dot)nlm(dot)nih(dot)gov/genbank/. The sequences are then translated into amino acid residues according to the coding sequence positions provided along the reference sequence for SARS-CoV-2 proteins (orf1a, orf1b, S, ORF3a, E, M, ORF6, ORF7a, ORF7b, ORF8, N, and ORF10). These sequences can be aligned separately for each protein using a multiple sequence alignment program such as MAFFT (available at mafft(dot)cbrc(dot)jp/alignment/software/). Reference protein sequences can also be obtained at GenBank or some other appropriate database source. One source of possible epitope sequences is SARS-CoV2 virus or closely related viruses. It is desirable to obtain an increased immunological response against said viruses through the use of SARS-CoV2 mCRAgs. The evolutionary relationship of viruses is such that sequences associated with other viral genomes can also be overlapping potential epitopes and thus useful in the methods of the present disclosure as a starting point for mCRAg identification. For SARS-CoV2, such viruses include, but are not limited to SARS-CoV, but can also comprise the genomes of related subgroups of corona viruses, including alphacoronaviruses and betacoronaviruses. The genome sequence of these related viruses can be very close, for example, SARS-CoV shares a 79.5% genome sequence identity with SARS-CoV, a 96.2% identity with Bat-CoV RaTG13, and multiple SARS-CoV2- related coronaviruses with 85.5 to 92.3% sequence identity with pangolin-infecting coronaviruses such as Pangolin-CoV-2020 and GD Pangolin CoV (see, Li et al., J. of Virol., 94 (22): https://doi.org/10.1128/JVI.01283-20). Accordingly, related viruses, even those which are not infectious to humans, can also be utilized in the screening methods of the present disclosure although use of human specific viruses, and the SARS-CoV2 mCRAgs isolated therefrom, are particular embodiments of the present disclosure. Thus, one method of finding experimentally-derived sequences for B cell and T cell epitopes of SARS-CoV2 or related viruses, such as SARS-CoV, is from the NIAID Virus Pathogen Database and Analysis Resource (ViPR) (accessible at www(dot)viprbrc(dot)org/) through queries on the virus name and “human” hosts. Ideally, selected epitopes should be supported by positive assays such as (i) Positive B cell assays (e.g. enzyme-linked immunosorbent assay (ELISA)-based qualitative binding for B cell epitopes, and (ii) either positive T cell assays (such as enzyme-linked immune absorbent spot (ELISPOT) or intracellular cytokine staining (ICS) IFN-γ release) or positive major histocompatibility complex (MHC) binding assays for T cell epitopes. Technically, this last set are antigens which are candidate epitopes, but these can be utilized as epitopes for the processes described here. Population coverage sets of the T cell epitopes can be computed as described in Ahmed et al. to expand the T cell epitope set, if needed. This set of B cell and T cell epitopes can be utilized to screen for SARS-CoV2 mCRAgs as will be described. Once the immunogenic epitopes are identified, they are used to generate a list of all possible epitopes of a selected size. These possible epitopes will be used to sequence align with expressed polypeptides in order to identify potential mCRAgs. In particular, it is anticipated that the size of epitopes to be used for selection can range from about 9-mer to about 15-mer in length in length with the use of all possible 10-mer, 11-mer, 12-mer, 13-mer, and 14-mer epitopes all being possible embodiments of the present methods. Selection of the particular length of the epitopes used for comparison will depend on many factors, however it is this range of length that anticipated to be sufficiently short to find unique sequences within the polypeptides being screened but sufficiently long to be anticipated to function as an antigen. Thus, it is also anticipated that other epitope lengths may be useful in the methods of the present disclosure depending on how unique the sequence of the epitope is within the polypeptides to be screened. The epitopes are utilized to produce a list of all possible epitopes of the selected size. It is this list of all possible epitopes that are used to screen a database of polypeptide sequences for alignments, thus identifying those polypeptides that comprise an epitope of SARS-CoV2. A preliminary alignment is a one to one match, with a small number of amino acid mismatches. Again, the number of mismatches involved needs to be selected to expand the number of hits beyond those that are just exact matches, but not give so much leeway as to result in unmanageable numbers of positive results. The present method utilizes up to one mismatch per 9-mer as described in the Examples below, however this number can be adjusted upwards to two, three, or more or downward to no mismatches, depending on how long the epitope peptide sequences are, how many hits are obtained initially, what polypeptide database is being utilized, what screening processes are utilized in later method steps to focus the match results, and other analysis-specific factors. Many methods of obtaining sequence alignments are known to one of ordinary skill. the goal of this process is the match of a particular, relatively short amino acid coding pattern within much larger sequences, while accommodating mismatches at selected places in the epitope peptide. These criteria limit the particular alignment programs that would function well for this task. As an example, the present method can be practiced using the fuzzpro protein pattern matcher from the EMBOSS suite v.6.6.0.0 (Rice et al., Trends in Genetics, 16: 276-77 (2000)). Program fuzzpro is set up to do a protein pattern search of typically short length sequence within a larger sequence. It can be used to find an exact match or can allow various ambiguities, matches to variable length sequences and repeated subsections of sequence. The program selects the optimum searching algorithm to use depending on the complexity of search pattern specified. This program is publicly available and functions well for the needed comparisons, however other equivalent programs, such as ScanProsite (prosite(dot)expasy(dot)org/scanprosite/) are also available. Essentially, any reference database that contains SARS-CoV2 epitopes could be utilized, given a possible means of scanning for patterns. This can be accomplished through software specially developed for the particular database or any modern programming language through the use of regular expression or pattern matching functions. Because of the desire to find SARS-CoV2 mCRAgs within the human gut microbiome in the present methods, a suitable database for screening includes the Universal Human Gut Proteome (UHGP-100, hereafter UHGP) (see, Almeida et al., Nature Biotech. 39:105-14 (2021)). This database is a collection of protein sequences, at least partially annotated, of those proteins likely produced by bacteria that comprise the human gut microbiome. The present disclosure involved the development of custom python scripts to include mCRAg polypeptide annotations and taxonomy according to the information present in the UHGP database. However, other suitable protein databases can be utilized depending on the ultimate goal of the analysis. Although this screening method describes the use of amino acid peptides, such peptides could be converted into DNA or RNA sequences for screening nucleic acid sequence databases, although there is the acknowledged extra area of uncertainty given the wobble present in the third member of nucleic acid codons which could be overcome using all possible encodings. However, the amount of hits that could result from such an approach may prove impractical, making the use of epitope peptide to protein sequence matching a particular embodiment of the present mCRAg screening process. Beyond the one to one matches, the listed epitopes can be overlapped and extended to provide the longest possible alignment between the SARS-CoV2 immunogenic epitopes and the proteins of the UHGP or another similar database. This overlap and extension process, also taking into account the number of mismatches, can be performed in many different ways, while an exemplary approach is documented in FIG.2A that provides for ten approaches for overlapping and extending the two, three, or four epitopes to provide further means of matching the identified sequences to the database polypeptides. These ten Types are described in detail in Example 1. As would be clear to one of ordinary skill, these approaches represent only one set of many ways the SARS-CoV2 epitopes could be combined and extended in order to provide for longer length sequence matches with the polypeptides provided in the expression database. Because these resulting peptide sequences are longer, there are generally expected to be less matches than what is obtained through the initial peptide list match (e.g., the 9-mer list of the Examples). Thus, the results of comparing these peptides sequences to the protein database can be reviewed manually. It is anticipated that not all overlap and extension Types result in useful matches so only those that look promising need to be examined. An exemplary set of results for such a manual review of Types 7, 9, and 10 is provided in Example 1. Given the relatively large number of results of the one to one matches, it is desirable to have an automated method of screening the results and through rankings select those mCRAg sequences that have the greatest chance of achieving increased immune response when utilized as provided herein. Thus, the results can be sorted into the following four categories: Simple mCRAgs, Super mCRAgs, Super Bugs, and Super Epitopes. These categories are defined above and discussed further in the Examples. The majority of the match results are anticipated to be Simple mCRAgs. Simple mCRAgs are anticipated to function effectively as components of embodiments of the present disclosure, utilized either on their own or in combinations, to increase immune response. The experiments provided in the present specification did not identify any Super mCRAgs as all the identified Super mCRAg sequences turned out to target orthologous proteins of different strains of the same bacterial species or different bacterial species. Super Bugs were identified through the coding of 2 or more mCRAg polypeptides within the same bacterial strain. It is anticipated that such Super Bugs will be useful as components in some embodiments of the present disclosure utilized to increase immune response. All epitopes identified through the experiments reported in the Examples can be considered a Super Epitope, but particular ones are called out in the Example discussion. It is anticipated that such Super Epitopes will be useful as components in some embodiments of the present disclosure utilized to increase immune response. It is also possible to categorize the selected mCRAgs into those that are predicted to bind MHC class I and class II alleles and those that would not be predicted to bind. On the surface of T cells, there exists a specific receptor known as T cell receptor (TCR) that enables the recognition of antigens when they are displayed on the surface of antigen-presenting cells (APCs) bound to major histocompatibility complex (MHC) molecules. T cell epitopes are presented by class I and II MHC molecules that are recognized by two distinct subsets of T cells, CD8 and CD4 T cells, respectively. T cell epitope prediction aims to identify the shortest peptides within an antigen that are able to stimulate either CD4 or CD8 T cells. MHC I molecules can bind short peptides ranging from about 9 to about 11 amino acids, whose N- and C-terminal ends remain pinned to conserved residues of the MHC I molecule through a network of hydrogen bonds. The peptide-binding groove of MHC II molecules is open, allowing the N- and C-terminal ends of a peptide to extend beyond the binding groove. As a result, MHC II-bound peptides vary widely in length (9-22 residues). Methods to predict peptide-MHC binding can be divided into two main categories: data- driven and structure-based methods. Data-driven methods for peptide-MHC binding predictions are based on peptide sequences that are known to bind to MHC molecules. These peptide sequences are generally available in specialized epitope databases such as IEDB (http://tools.iedb.org/main/tcell/), EPIMHC (Reche et al. Bioinformatics, 21(9):2140-2141), and AntiJen (http://www.ddg- pharmfac.net/antijen/AntiJen/antijenhomepage.htm). Structure-based approaches generally rely on modeling the peptide-MHC structure followed by evaluation of the interaction through methods such as molecular dynamics simulations. Structure-based methods have a great advantage without needing experimental data. However, they are seldom used as they are computationally intensive and exhibit lower predictive performance than data-driven methods. Such prediction can be useful for the selection of mCRAgs as such MHC binding is necessary but not sufficient for recognition by T cells. Thus, those mCRAgs that would be predicted to bind would have a greater possibility of functioning as an antigen for T cells and therefore would have a greater chance of increasing the immune response to SARS-CoV2 by its presence. The disclosure is further illustrated by the following non-limiting examples. EXAMPLES Many modifications and variations of the present disclosure are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, a skilled person in the art would recognize that the invention may be practiced otherwise than as specifically described. The illustrative embodiments and examples should not be construed as limiting the invention. Example 1 –mCRAgs Screening/Identification Twelve immunogenic B and T cells epitopes identified from 7 SARS-CoV2 proteins (Singh et al., Nature, 10: 16219 (2020); (Amed et al., Viruses, 12(3):254 (2020)); and (Ahmad et al., Eur J Pharm Sci 151:105387 (Aug 1, 2020)) were used for the identification of mCRAgs across the human gut proteome. First, for each immunogenic epitope a list of all the possible 9-mers were generated. The epitopes selected for utilization included Nsp8(A) (SEQ ID NO: 36); Nsp8(B) (SEQ ID NO: 37); 3C-like protease (A) (SEQ ID NO: 38); 3C-like protease (B) (SEQ ID NO: 39); spike glycoprotein (SEQ ID NO: 40); Envelop (A) (SEQ ID NO: 41); Envelop (B) (SEQ ID NO:42); Membrane (SEQ ID NO: 43); Nucleocapsid (A) (SEQ ID NO: 44); Nucleocapsid (B) (SEQ ID NO: 45); Surface (A) (SEQ ID NO: 46); and Surface (B) (SEQ ID NO: 47) (see Table 1). The immunogenic epitopes are named for the viral proteins they are derived from. In Table 1, the published epitope sequence is reported in bold, with the corresponding 9-mers below it. Envelop (A) and Envelop (B) epitopes were overlapped and merged since they were overlapping and consecutive, to avoid redundant 9-mers. The generated 9-mers were aligned against the Universal Human Gut Proteome (UHGP-100, hereafter UHGP) (Almeida et al., Nature Biotech. 39:105-14 (2021)) using the fuzzpro protein pattern matcher from the EMBOSS suite v.6.6.0.0 (Rice et al., Trends in Genetics, 16: 276-77 (2000)). The matcher was set to allow up to one mismatch between the 9-mers and the target protein. The output table with 9-mers/mCRAg polypeptide matches was processed using custom python scripts to mCRAg polypeptide annotations and taxonomy according to the information included in UHGP metadata tables. Splitting the 12 SARS-CoV2 proteins epitopes into 9-mers resulted in 53 non-redundant SARS-CoV29-mers. The 9-mers were aligned against 170.6 million proteins in the UHGP database resulting in 32,169 hits to 26,578 unique proteins (0.01% of total UHGP proteins) in 25,346 species. 114 hits were perfect matches (i.e.: no mismatch between the 9-mer and the mCRAg polypeptide, see Table 2), while in 32,053 hits there was a single mismatch between the 9-mer and the mCRAg polypeptide (see Table 3). Table 1
Figure imgf000038_0001
Figure imgf000039_0001
Table 2
Figure imgf000039_0002
: a + ndcates addtona ts to protens rom taxa w ere t e taxonomc assgnment at t e speces eve was not possbe Table 3
Figure imgf000040_0001
Beyond seeking matches of the listed 9-mers, groups of 9-mers were overlapped and extended based on the amino acids found in the further sequence on either side of the base 9-mer to identify other immunogenic sequences to be used for comparison, thus obtaining additional “mock” alignments between these epitopes and UHGP protein sequences. This overlap and extension process provides a systematic way of looking for other possible mCRAgs using the mined sequence data. The 32,169 identified hits resulted in 26,583 alignments, where the sequences used for comparison had compositions that ranged between a single 9-mer (no overlap possible) to four 9-mers included into the alignment. The overlap and extension process results are one of 10 Types, that are described and exemplified in FIG. 2A. As would be understood by one of ordinary skill, these Types are provided as exemplary approaches for analysis and are not exclusive, that is, it is possible that one epitope sequence could be correctly classified as more than one Type. In particular, Type 1 involves a single 9-mer with one mismatch (mutation) and the provided example is FAPSA*AFF (SEQ ID NO: 48) where * represents the mismatch. Type 2 involves a single 9-mer with no mismatches (mutations) where the provided example is ALALLLLDR (SEQ ID NO: 49), although this Type is purely theoretical and cannot be observed since it would be automatically extended. Type 3 involves the single extended overlap of two 9-mers, thus having a total length of ten peptides and allows a single, shared mismatch (mutation) with the provided example LFLAF*VFLL (SEQ ID NO: 50). Type 4 involves the overlap of two 9-mers, with two possible mismatches, thus having a total length of eleven peptides and the provided example of L*LAFVVFL*V (SEQ ID NO:51). Type 5 involves the match of a single 9-mer in two non- consecutive and non-overlapping regions on the same polypeptide from the UHGP protein database, thus resulting the use of two 9-mers without overlap, thus resulting in two distinct 9-mers each with one mismatch and each of length of nine peptides and the provided example of FA*SASAFF (SEQ ID NO: 121) and FAPSAS*FF (SEQ ID NO: 122) (collectively FA*SAS*FF, SEQ ID NO: 52). Type 6 involves the overlap of three 9-mer sequences with a single extension on either end of the 9-mer, thus having a total length of eleven peptides and allows a single, shared mismatch (mutation) with the provided example LALL*LDRLNQ (SEQ ID NO: 53). Type 7 involves the overlap of three 9-mer sequences with a single extension on either end of the 9-mer and allows two possible mismatches, thus having a total length of eleven peptides with a provided example of *FLAFVVFLL* (SEQ ID NO:54). Type 8 involves the match of a single 9-mer in three non- consecutive and non-overlapping regions on the same polypeptide from the UHGP protein database, thus resulting in three distinct 9-mers each with one mismatch and each of length of nine peptides and the provided example of FA*SASAFF (SEQ ID NO: 121), FAPSAS*FF (SEQ ID NO: 122), FAP*ASAFF (SEQ ID NO: 123) (or collectively FA**AS*FF; SEQ ID NO:55). Type 9 involves the overlap of four 9-mers, made up of two different exact match 9-mers, with an extension of two on one end and one on the other, resulting in a length of 12 peptides and having two mismatches, with the provided example of *ALALLLLDRL* (SEQ ID NO: 56). Type 10 involves overlap of four 9-mers, made up of only a single 9-mer, with an extension of two on one end and one on the other, resulting in a length of 12 peptides and having two mismatches, with the provided example of L*LAFVVFLLV* (SEQ ID NO: 57). Of the 26,583 alignments obtained during this process, 103 contained hits with perfect matches between the SARS-CoV29-mer-based sequence and the mCRAg polypeptide. Type 7, Type 9, and Type 10 alignments were further manually analyzed, since they were the longest alignments obtained and contained hits with perfect matches between SARS-CoV29-mers and mCRAg polypeptides. A summary of these results is provided below. · Type 7 (58 alignments): o 6 / 58 alignments obtained with SARS-CoV2 Envelop 9-mers · 3 alignments hit hypothetical proteins (GUT_GENOME096132_01117, GUT_GENOME245595_01465, GUT_GENOME094310_00658), 2 mscL (see Type 10), 1 oatA. o 51 / 58 alignments obtained with SARS-CoV2 Nucleocapsid 9-mers · 3 alignments hit hypothetical protein (GUT_GENOME115628_01722, GUT_GENOME186246_00249, GUT_GENOME008160_01084). ■ 5 alignments hit a tRNA modification GTPase MnmE from 4 strains of Firmicutes, one Faecalibacterium and an uncharacterized bacterial strain from the Genus Duodenobacillus. ■ 5 alignments hit ribonuclease 3 rnc (5 strains of Pyramidobacter from Asia and North-America). o 1 / 58 alignments obtained with SARS-CoV2 Surface 9-mers ■ The alignment hit a hypothetical protein (GUT_GENOME234933_01511). · Type 9 (3 alignments): o 3 / 3 alignments obtained with SARS-CoV2 Nucleocapsid (A) 9-mers ■ All alignments hit lspA (Lipoprotein signal peptidase): - Protein involved in the release of signal peptides from bacterial membrane pro-lipoproteins. It is an integral component of the inner plasma membrane. - The hit is outside the predicted transmembrane alpha-helices (7-24, 60-79, 86-108, 123-145), at the beginning (22-33) of the target protein. - 3D structure available (SwissProt: Q8D2R1). - None of the SARS-CoV2 9-mers in the alignment were from the cytotox T epitope. - 3 distinct bacterial strains from the Genus Duodenobacillus, isolated in Oceania. · Type 10 (42 alignments): o 41 / 42 alignments obtained with SARS-CoV2 Envelop 9-mers ■ All alignments hit mscL (Large-conductance mechanosensitive channel): - The protein is an integral component of the plasma membrane. - The hit is in the centre (97-108) of the target protein, outside the predicted transmembrane alpha-helices (7-24, 60-79, 86-108, 123- 145), in the non-cytoplasmatic domain. - None of the SARS-CoV2 9-mers in the alignment were from the cytotox T epitope. - At least 2 distinct bacteria from the Genus Dakarella, isolated in Asia, Europe, and North-America. o 1 / 42 alignments obtained with SARS-CoV2 Envelop 9-mers ■ The alignment hit Tig (trigger factor): - The protein is a cytosolic protein bounded to inner plasma membrane involved in protein export. - The hit is on the ribosomal binding domain located in the first part of the target protein (97-108). - Multiple 3D structures available. - None of the SARS-CoV2 9-mers in the alignment were from the cytotox T epitope. - 1 bacteria (Escherichia coli K-12) isolated from Asia In conclusion, this Example identifies SARS-CoV2 mCRAgs in the human gut microbiome, using immunogenic epitopes from 7 SARS-CoV2 proteins that were divided into 9-mers and used to scan the most comprehensive human gut proteome to date (UHGP) in a sequence similarity search. Only hits with up to one mismatch between SARS-CoV29-mers and mCRAg polypeptides were retained. Adjacent hits from adjacent 9-mers were aligned an overlapped to obtain the longest alignment possible between SARS-CoV2 epitopes and UHGP mCRAg polypeptides. This resulted in 26,583 alignments, and only 103 of them (0.4%) containing perfect matches between SARS- CoV2-derived 9-mers and mCRAg polypeptides. Despite some of the SARS-CoV2 epitopes being of low complexity (e.g.: Nucleocapsid_A 9-mers), they were not overrepresented in the 170.6M proteins of UHGP. In fact, only 0.01% of total UHGP proteins had a positive match with SARS- CoV29-mers. Example 2 –mCRAg Classification and Related Strains and Epitopes The match collection of 21,657 hits between 9-mers and UHGP proteins (Type 1 of FIG.2A) were further classified into four categories (Simple mCRAg, Super mCRAg, Super Bug, and Super Epitope) according to their relationship using a custom python script (see FIG.2B). In brief, Simple mCRAgs were identified by looking for simple 1-to-1 relationships between SARS-CoV2 epitope alignments and the mCRAg polypeptides in a single bacterial strain. Super mCRAgs were identified by looking at multiple distinct SARS-CoV2 alignments targeting the same mCRAg polypeptide from the same bacterial strain. For the identification of Super Bugs, hits already characterized as Simple mCRAgs and uncharacterized proteins were eliminated from consideration before the classification to retain only the most informative hits. In case of presence of multiple orthologs of the same protein from distinct strains referring to the same UHGP reference genome, only one was retained as representative for that protein-bacterial species group. Super Epitopes were identified by looking at single SARS-CoV2 epitopes targeting multiple mCRAg polypeptides from different bacterial strains. Most of the identified hits (21,658 / 26,583) can be classified as simple mCRAgs and correspond to 305 characterized proteins in more than 371 bacterial Genera. The characterized mCRAg polypeptides with highest frequency of hits largely overlapped with mCRAg polypeptides of Type 7, Type 9, and Type 10 alignments, Super Bugs and Super Epitopes (see below). Among them, were identified: gufA: 1,756 simple mCRAGs Hits; uspA: 1,620 simple mCRAGs Hits; mscL: 916 simple mCRAGs Hits; mnmE: 270 simple mCRAGs Hits; pacL: 135 simple mCRAGs Hits; and ybiR: 60 simple mCRAGs Hits. None of the identified alignments strictly fit into the definition of Super mCRAg (i.e.: multiple distinct SARS-CoV2 epitopes alignments target the same mCRAg polypeptide from the same bacterial strain). There were 17 mCRAg polypeptides (algI, brnQ, comEC, cydB, cydC, gluP, guaB, Int, mltG, murJ, napF, nqrF, pacL, spoVB, tcaB, ybiR, ydeD), however, the different SARS-CoV2 epitopes targeted orthologous proteins of different strains of the same bacterial species or different bacterial species. Among these 17 proteins, pacL and ybiR (bolded in the list above) were present as well in the list of mCRAg polypeptides from potential Super Bugs, as will be described further below. 116 distinct bacterial species were identified as Super Bugs, coding for 2 or more mCRAg polypeptides to SARS-CoV2 alignments, for a total of 126 distinct proteins (Table 4). Among these proteins, mnmE and mscL were re-identified as well as a number of the proteins that were found as Type 7 and Type 10 alignments with perfect matches. The top eight species of Super Bugs are provided in Table 5. All twelve immunogenic B and T cells epitopes identified from the seven SARS-CoV2 proteins can be classified as Super Epitopes based on the given definition. Among them, five 9-mers belonging to three epitopes were identified as having a higher chance to raise protection against SARS-CoV2 based on perfect matches between SARS-CoV2 epitopes and UHGP mCRAg polypeptides, predicted binding to MHC-I and MHC-II alleles (see Example 3 below), the number of matches retrieved for each mCRAg polypeptide across the whole analysis and whether the mCRAg polypeptide was identified as expressed by Super Bugs (Table 6). · Envelop: 9-mer envelop_5 (SEQ ID NO: 58) matched with tig and mscL, while envelop_10 (SEQ ID NO: 61) targeted uspA · Nucleocapsid: 9-mer Nucleocapsid_A_4 (SEQ ID NO: 62) matched with IspA, mnmE and ybiR · Surface: 9-mer Surface_B_2 (SEQ ID NO: 63) matched with pacL while Surface_B_4 (SEQ ID NO: 64) matched with ybiR. Example 2 documents that the matches were further classified into four categories according to the relationship between SARS-CoV2 alignments and mCRAg polypeptides: Simple mCRAgs, Super mCRAgs, Super Bug and Super Epitope. While most of the hits were classified as Simple mCRAgs and none of the hits aligned to the definition of Super mCRAgs, 116 Super Bug were identified. The top Super Bug bacterial species, having the highest number of proteins matching with SARS-CoV2 envelop, surface and nucleocapsid epitopes, was Bacteroides dorei. While all SARS- CoV2 epitopes used in this study could be classified as Super Epitopes based on the given definition, at least five specific 9-mers derived from SARS-CoV2 envelop, nucleocapsid and surface epitopes were identified as potential best Super Epitopes. Super Bugs mCRAg polypeptides, which included the mCRAg polypeptides (PP) of the best 5 Super Epitopes, were further characterized to predict their binding affinity to the most common human MHC-I and MHC-II alleles. At least 70% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-I allele. More than 90% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-II allele. Table 4
Figure imgf000045_0001
Table 5
Figure imgf000046_0002
Table 6
Figure imgf000046_0001
Example 3 – mCRAg Binding Affinity to MHC-I and MHC-II The binding affinity to MHC-I and MHC-II alleles was restricted to the 258 mCRAg polypeptides matched to SARS-CoV2 alignments identified in the 116 SuperBugs. For each mCRAg polypeptide, the binding affinity to the most common MHC-I and MHC-II alleles was predicted, covering about 90% of human population MHC alleles. This calculation was done using the T Cell Tools provided by the National Institute of Allergy and Infectious Diseases; tools(dot)iedb(dot)org/main/tcell/ although other methods of predicting binding are known and widely available. On average, more MHC-II alleles (average 26.7) were predicted to bind to the mCRAg polypeptides than MHC-I alleles (average 5.3). Moreover, 79 mCRAg polypeptides (30.6%) were predicted to have no binding affinity to MHC-I alleles in the collection, while only 23 of them (8.9%) had no binding affinity for MHC-II alleles (FIG.3). In sum, at least 70% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-I allele and more than 90% of the analyzed mCRAg polypeptides had high binding affinity for at least one MHC-II alleles. Taken all together, the results of these Examples point toward the presence of multiple human gut bacterial species (Super Bugs) expressing several proteins with peptides matching SARS-CoV2 immunogenic epitopes (Super Epitopes). Those Super Bugs proteins are predicted to have high binding affinity for the most common human MHC-I and MHC-II alleles, suggesting their immunogenicity and use for raising immunological protection against SARS-CoV2. Example 4 – Bacterial Consortium Selection A final selection of an exemplary bacterial or probiotic strain consortium of five strains was performed based on the results discussed above. The further selection criteria included non- pathogenicity, availability of isolates, and the ability of the selected mCRAgs to bind both MHC I and MHC II, if possible. Based on these criteria, the five bacterial strains disclosed in Table 7 were selected as an exemplary bacterial consortium. Another exemplary consortium is illustrated in FIG. 4.
Table 7
Figure imgf000048_0001
  

Claims

CLAIMS What is claimed is: 1. A bacterial cell that expresses at least one SARS-CoV2 microbiota-derived cross-reactive antigen (mCRAg).
2. The bacterial cell of claim 1, wherein the bacterial cell is a recombinant cell engineered to express the at least one SARS-CoV2 mCRAg.
3. The bacterial cell of claim 1 or claim 2, wherein the bacterial cell is a bacterial strain present in the human gut microbiome.
4. The bacterial cell of any one of claims 1-3, wherein the at least one SARS-CoV2 mCRAg is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:1, SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6.
5. The bacterial cell of any one of claims 1-3, wherein the at least one SARS-CoV2 mCRAg is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; and SEQ ID NO:21.
6. The bacterial cell of any one of claims 1-3, wherein the at least one SARS-CoV2 mCRAg is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; and SEQ ID NO:30.
7. The bacterial cell of any one of claims 1-3, wherein the at least one SARS-CoV2 mCRAg is selected from the group consisting of a polypeptide sequence having at least 90% sequence identity to SEQ ID NO: 66; SEQ ID NO: 67; SEQ ID NO: 68; SEQ ID NO: 69; SEQ ID NO: 70; SEQ ID NO: 71; SEQ ID NO: 72; SEQ ID NO: 79; and SEQ ID NO: 80.
8. The bacterial cell of any one of claims 1-3, wherein at least one SARS-CoV2 mCRAg comprises a sequence selected from the group consisting of SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63; SEQ ID NO: 64 SEQ ID NO: 65; and SEQ ID NO:78.
9. The bacterial cell of any one of claims 1-8, wherein the bacterial cell is of at least one strain selected from the group consisting of Bacteroides dorei; Citrobacter portucalensis, Oscillospiraceae strain ER4 sp000765235; Pluralibacter gergoviae; Clostridium symbiosum, Eggerthella lenta; Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02229) and Oscillospiraceae strain Genus CAG-83(MGYG-HGUT-02617); Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Faecalicatena orotica; Butyricicoccus pullicaecorum; Limosilactobacillus oris; and Limosilactobacillus fermentum.
10. A composition comprising the bacterial cell of any one of claims 1-9.
11. A composition comprising at least one bacterial cell which comprises 16S rRNA sequences having at least 97% sequence identity with nucleic acid sequences selected from the group consisting of SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:76; and SEQ ID NO: 77.
12. The composition of claim 10 or claim 11 comprising at least two bacterial strains.
13. The composition of claim 12 comprising the following bacterial strains: Lactobacillus sakei; Lactobacillus agilis; Lactobacillus salivarius; Limosilactobacillus oris; and Limosilactobacillus fermentum.
14. A composition comprising at least one SARS-CoV2 mCRAg.
15. A pharmaceutical composition comprising the composition of any one of claims 10-14 and an excipient.
16. A pharmaceutical composition comprising the composition of claim 15 and a SARS-CoV2 vaccine.
17. A kit comprising the composition of any one of claims 10-15 and a SARS-CoV2 vaccine.
18. The composition of any one of claims 10-16 or the kit of claim 17, wherein the composition is formulated for delivery to the intestine.
19. A nutraceutical composition comprising the composition of any one of claims 10-14 and optionally a nutrient.
20. A vaccine comprising at least one SARS-CoV2 mCRAg.
21. A method of increasing the immune response to a SARS CoV2 vaccine in a subject comprising administering to the subject an immunologically effective amount of the composition of any one of claims 10-16.
22. A method of inducing an immune response to a SARS-CoV2 mCRAg in a subject comprising administering to the subject an immunologically effective amount of the composition of any one of claims 10-16.
23. The method of claim 21 or claim 22, wherein the administration of the immunologically effective amount of the composition occurs before, concurrently, or after the administration of a SARS-CoV2 vaccine.
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