WO2023240148A2

WO2023240148A2 - Hybrid flu-coronavirus vaccine

Info

Publication number: WO2023240148A2
Application number: PCT/US2023/068080
Authority: WO
Inventors: Lbachir Benmohamed
Original assignee: The Regents Of The University Of California
Priority date: 2022-06-07
Filing date: 2023-06-07
Publication date: 2023-12-14
Also published as: WO2023240159A2; WO2023240148A3; WO2023240159A3

Abstract

A hybrid vaccine composition that prevents infection or reinfection by both influenza and coronaviruses, comprising at least a portion of a Coronavirus spike (S) protein and at least a portion of at least one influenza hemagglutinin (HA) protein. The portion of the coronavirus spike (S) protein is highly conserved among human and animal coronaviruses. The vaccine composition may comprise a Coronavirus protein comprising either: a structural protein, e.g., a Spike protein, a Nucleocapsid protein, or a combination thereof, or a non-structural protein, e.g., NSP2, NSP3, NSP14, or combination thereof; and at least a portion of at least one influenza hemagglutinin (HA) protein.

Description

HYBRID FLU-CORONAVIRUS VACCINE

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63/349,904 filed June 7, 2022, U.S Provisional Application No. 63/349,799 filed June 7, 2022, and U.S. Provisional Application No. 63/451 ,302 filed March 10, 2023, the specifications of which are incorporated herein in their entirety by reference.

[0002] This application also claims benefit of U.S. Application No. 18/046,862 filed October 14, 2022, U.S. Application No. 18/046,875 filed October 14, 2022, and U.S. Application No. 18/046,462 filed October 13, 2022, the specifications of which are incorporated herein in their entirety by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under Grant No. AI158060 awarded by National Institute of Health. The government has certain rights in the invention.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0004] The contents of the electronic sequence listing (name of the file UCI 22_11 PCT.xml; Size: 367,695 bytes; and Date of Creation: June 6, 2023) is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0005] The present invention relates to vaccines, for example, viral vaccines, such as those directed to coronaviruses and influenza, e.g., hybrid pan-coronavirus-flu vaccines.

BACKGROUND OF THE INVENTION

[0006] Influenza (flu) is a contagious respiratory illness caused by influenza viruses. There are two main types of influenza (flu) viruses: Types A and B. The influenza A and B viruses that routinely spread in people (human influenza viruses) are responsible for seasonal flu epidemics each year. The seasonal spread is due to a phenomenon known as antigenic drift (i.e., the viruses evolve just enough to evade human immune systems but not enough to develop into completely new versions of the virus). Thus, every year a new influenza vaccine is developed.

[0007] Over the last two decades, there have been three deadly human outbreaks of Coronaviruses (CoVs) caused by emerging zoonotic CoVs: SARS-CoV, MERS-CoV, and the latest highly transmissible and deadly SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats, the natural hosts, and were transmitted to humans via various intermediate animal reservoirs (e.g., pangolins, civet cats, and camels). Recently, COVID-19 is expected to become a seasonal illness like most respiratory viruses, e.g., the flu.

[0008] Therefore, it would be advantageous to develop a single hybrid influenza-coronavirus vaccine to combat these seasonal respiratory infections. Currently, seasonal flu vaccines are designed to protect against the influenza viruses that research indicates will be most common during the upcoming season. All flu vaccines in the United States are “quadrivalent” vaccines, which means they protect against four different flu viruses: an influenza A(H1 N1) virus, an influenza A(H3N2) virus, and two influenza B viruses. However, the present invention features a vaccine composition that utilizes the most conserved regions of various coronaviruses and influenza viruses to allow for broader protection from said viruses.

BRIEF SUMMARY OF THE INVENTION

[0009] It is an objective of the present invention to provide compositions and methods that allow for simultaneous prevention and/or treatment of a coronavirus infection and an influenza infection, as specified in the independent claims. Embodiments of the invention are given in the dependent claims. Embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.

[0010] One of the unique and inventive technical features of the present invention is the use of highly conserved regions of a coronavirus spike glycoprotein (S) and a highly conserved region of an influenza hemagglutinin (HA) protein. Without wishing to limit the invention to any theory or mechanism, it is believed that the technical feature of the present invention advantageously provides for broader protection from coronaviruses and influenza viruses.

[0011] The present invention features pan-coronavirus-influenza vaccine compositions. For example, the present invention features a pre-emptive pan-Coronavirus-influenza vaccine composition comprising: at least one of SEQ ID NO: 1 , 3, 5-11 ; and at least one of SEQ ID NO: 12, 14-16. The present invention also features a pre-emptive pan- Coronavirus-influenza vaccine composition comprising: at least one of SEQ ID NO: 1 , 3, 5-11 or at least one protein encoded by SEQ ID NO: 1 , 3, 5-11 ; and at least one of SEQ ID NO: 12, 14-16 or at least one protein encoded by SEQ ID NO: 12, 14-16. The present invention also features a pre-emptive pan-Coronavirus-influenza vaccine composition comprising at least a portion of at least one coronavirus protein selected from SEQ ID NO: 1 , 3, 5-11 , and at least a portion of at least one influenza hemagglutinin (HA) protein comprising a sequence according to SEQ ID NO: 12, 14-16. The present invention also features a pre-emptive pan- Coronavirus-influenza vaccine composition comprising at least a portion of one of SEQ ID NO: 1 , 3, 5-11 or at least one coronavirus protein encoded by SEQ ID NO: 1 , 3, 5-11 , and at least a portion of one of SEQ ID NO: 12, 14-16 or at least one influenza hemagglutinin (HA) protein encoded by SEQ ID NO: 12, 14-16. Said compositions may further comprise a generic promoter, wherein at least one of seq id no: 1-11 and at least one of seq id no: 12 are operatively linked to the generic promoter. Said compositions may further comprise or encode a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. Said compositions may further comprise or encode a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15.

[0012] The present invention also features a pre-emptive pan-Coronavirus-influenza vaccine composition, wherein the composition comprises, or comprises a sequence encoding, at least a portion of a Coronavirus spike (S) protein and at least a portion of at least one influenza hemagglutinin (HA) protein. The portion of the coronavirus spike (S) protein is highly conserved among human and animal coronaviruses. In some embodiments, the portion of the corona virus spike (S) protein is derived from one or more of: one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that has caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animals receptive to coronaviruses; or one or more coronaviruses that cause the common cold. The one or more SARS-CoV-2 human variants in current circulation include but are not limited to: variant B.1.177; variant B.1.160, variant B.1.1.7; variant B.1.351 ; variant P.1 ; variant B.1 .427/B.1 .429; variant B.1.258; variant B.1.221 ; variant B.1.367; variant B.1.1.277; variant B.1.1.302; variant B.1.525; variant B.1.526, variant S:677H; variant S:677P; B.1 ,617.2-Delta, variant B.1 .1 .529-Omicron (BA.1); sub-variant Omicron (BA.1); sub-variant Omicron (BA.2); sub-variant Omicron (BA.3); sub-variant Omicron (BA.4); and sub-variant Omicron (BA.5).

[0013] In some embodiments, the one or more coronaviruses that cause the common cold are selected from: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus. In some embodiments, the portion of the coronavirus spike (S) protein is derived from a full-length spike glycoprotein. In some embodiments, the portion of the coronavirus spike (S) protein is derived from a partial spike glycoprotein.

[0014] In some embodiments, the composition comprises at least one proline substitution. In some embodiments, the composition comprises at least two proline substitutions. In some embodiments, the composition comprises at least four proline substitutions. In some embodiments, the composition comprises at least six proline substitutions. In some embodiments, the portion of the coronavirus spike (S) protein comprises two consecutive proline substitutions at amino acid positions 986 and 987. In some embodiments, the proline substitutions are K986P and V987P mutations. In some embodiments, the portion of the coronavirus spike (S) protein is receptor-binding domain (RBD). In some embodiments, the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). In some embodiments, the portion of the coronavirus spike (S) protein comprises SEQ ID NO: 2 or 4. In some embodiments, the portion of the coronavirus spike protein is encoded by one of SEQ ID NOs: 1 , 3, 5-7.

[0015] In some embodiments, the portion of the influenza hemagglutinin (HA) protein is highly conserved among human influenza viruses. In some embodiments, the portion of an influenza hemagglutinin (HA) protein is derived from one or more of: H1 N1 virus strain, H3N2 virus strain, influenza B virus strains, or variants thereof. In some embodiments, the portion of the influenza hemagglutinin (HA) protein comprises SEQ ID NO: 13. In some embodiments, the portion of the influenza hemagglutinin (HA) protein is encoded by one of SEQ ID NOs: 12, 14-16.

[0016] The portion of a coronavirus spike (S) protein and the portion of the influenza hemagglutinin (HA) protein may be both/each operatively linked to a generic promoter. In some embodiments, the generic promoter is a CMV or a CAG promoter. In some embodiments, the portion of a coronavirus spike (S) protein and the portion of the influenza hemagglutinin (HA) protein are separated by a linker. The linker may be of an appropriate size, e.g., 2-10 amino acids, for example.

[0017] In some embodiments, the composition is encoded by a sequence according to SEQ ID NO: [0018] The present invention also features a pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising a sequence according to SEQ ID NO: 21-53. The present invention also features a pre-emptive pan-coronavirus-influenza vaccine composition comprising a sequence according to one of SEQ ID NO: 21-53 or a protein encoded by one of SEQ ID NO: 21-53. The present invention also features a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding at least a portion of a coronavirus protein, the coronavirus protein being selected from: a structural protein, wherein the structural protein comprises a Spike protein, a Nucleocapsid protein, or a combination thereof; or a non-structural protein, wherein the non-structural protein comprises NSP2, NSP3, NSP14, or combination thereof; and at least a portion of at least one influenza hemagglutinin (HA) protein. In some embodiments, the Spike protein comprises SEQ ID NO: 2 or 4 or is encoded by one of SEQ ID NO: 1 , 3, 5-7. In some embodiments, the NSP2 sequence is encoded by SEQ ID NO: 8, the NSP sequence is encoded by SEQ ID NO: 9, and the NSP14 sequence is encoded by SEQ ID NO: 10. In some embodiments, the Nucleocapsid protein is encoded by SEQ ID NO: 11. In some embodiments, the HA protein comprises SEQ ID NO: 13 or is encoded by one of SEQ ID NO: 12, 14-16.

[0019] The present invention also features a pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising: at least one of SEQ ID NO: 1 , 3, 5-11 ; and at least one of SEQ ID NO: 12, 14-16. In some embodiments, the composition further comprises a generic promoter, wherein the at least one of SEQ ID NO: 1 , 3, 5-11 and the at least one of SEQ ID NO: 12, 14-16 are operatively linked to the generic promoter.

[0020] The present invention also features a pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding one or more large coronavirus sequences or proteins and one or more large influenza sequences or proteins. In some embodiments, the one or more large coronavirus sequences comprise or encode a structural protein, a non-structural protein, or a combination therein. In some embodiments, the structural proteins are selected from: a Spike Protein or a Nucleocapsid protein, and the non-structural proteins are selected from: NSP2, NSP3, and NSP14.

[0021] The large coronavirus sequences are highly conserved among human and animal coronaviruses. In some embodiments, the one or more large coronavirus sequences are derived from one or more of: one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that has caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animals receptive to coronaviruses; one or more coronaviruses that cause the common cold; or one or more coronaviruses that case past, current, and future outbreaks. In some embodiments, the one or more SARS-CoV-2 human variants in current circulation are selected from: variant B.1.177; variant B.1.160, variant B.1.1.7; variant B.1.351 ; variant P.1 ; variant B.1 .427/B.1 .429; variant B.1.258; variant B.1.221 ; variant B.1.367; variant B.1.1.277; variant B.1.1 .302; variant B.1.525; variant B.1.526, variant S:677H; variant S:677P; B.1 ,617.2-Delta, variant B.1 .1 .529-Omicron (BA.1); sub-variant Omicron (BA.1); sub-variant Omicron (BA.2); sub-variant Omicron (BA.3); sub-variant Omicron (BA.4); sub-variant Omicron (BA.5). In some embodiments, the one or more coronaviruses that cause the common cold are selected from: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus.

[0022] In some embodiments, the Spike (S) protein is derived from a full-length spike glycoprotein. In some embodiments, the Spike (S) protein is derived from a partial spike glycoprotein. In some embodiments, the Spike (S) protein further comprises at least one proline substitution. In some embodiments, the Spike (S) protein comprises a receptor-binding domain (RBD). In some embodiments, the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). In some embodiments, the one or more large coronavirus sequences comprises one of SEQ ID NOs: 1 , 3, 5-11. In some embodiments, the one or more large influenza sequences are highly conserved among human influenza viruses. In some embodiments, the one or more large influenza sequences are derived from one or more of: H1 N1 virus strain, H3N2 virus strain, or influenza B virus strains. In some embodiments, the one or more large influenza sequences comprises one of SEQ ID NOs: 12, 14-16. In some embodiments, the composition further comprises or encodes a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. In some embodiments, the composition further comprises or encodes a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15.

[0023] Referring to any of the embodiments herein, the H1 N1 virus strains or variants may be selected from: OK384178.1 , OM642156.1 , OM654386.1 , OL840606.1 , OK625377.1 , OM865246.1 , OM935941.1 , OM642158.1 , OM935953.1 , MW840068.1 , MW839847.1 , MW839825.1 , MW930730.1 , MT227010.1 , LC638096.1 , LC638077.1 , LC637999.1 , and LC645067.1.

[0024] Referring to any of the embodiments herein, the H3N2 virus strains or variants may be selected from: MZ005227.1 , MW849238.1 , MZ203409.1 , MZ198318.1 , MZ198312.1 , MZ198295.1 , MZ198289.1 , MZ198265.1 , MW789449.1 , MW798370.1 , MW790182.1 , MW789645.1 , MW789778.1 , MW789685.1 , MW789659.1 , and MW790001 .1 .

[0025] Referring to any of the embodiments herein, the influenza B virus strains or variants may be selected from: M10298.1 , MT738525.1 , MT808088.1 , MT056751 .1 , MT314641.1 , MT874090.1 , MT242979.1 , MT315665.1 , MT1055640.1 , MT057563.1 , MT056955.1 , MT243019.1 , MT306916.1 , MT057571.1 , MT314793.1 , MT343026.1 , MT874109.1 , MT243795.1 , MT315769.1 , and KX885875.1.

[0026] Referring to any of the embodiments herein, the vaccine composition may further comprise a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. In some embodiments, the vaccine composition further comprises a sequence encoding a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15.

[0027] In some embodiments, the vaccine composition induces strong and long-lasting protection mediated by antibodies (Abs), CD4+ T helper (Th1) cells, and/or CD8+ cytotoxic T-cells. In some embodiments, the composition protects against Sarbecoviruses, wherein sarbecoviruses comprise SARS-CoV1 or SARS-C0V2. [0028] The compositions herein elicit an immune response in subjects. The compositions herein are for preventing an infection or reinfection, e.g., by one or more coronavirus variants or subvariants and influenza, in a subject.

[0029] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least a portion of a conserved coronavirus Spike protein; and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-H1 N1 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-H3N2 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-Influenza B antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Spike protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. In some embodiments, the Spike protein comprises one or more proline substitutions.

[0030] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-H1 N1 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-H3N2 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-Influenza B antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen.

[0031] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-H1 N1 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-H3N2 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-Influenza B antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen.

[0032] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least a portion of a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP41 protein; and at least a portion of influenza HA-H1 N1 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP41 protein; and at least a portion of influenza HA-H3N2 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP14 protein; and at least a portion of influenza HA-Influenza B antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus NSP14 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen.

[0033] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least a portion of a conserved coronavirus Nucleoprotein (nucleocapsid); and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Nucleoprotein (nucleocapsid); and at least a portion of influenza HA-H1 N1 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Nucleoprotein (nucleocapsid); and at least a portion of influenza HA-H3N2 antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Nucleoprotein (nucleocapsid); and at least a portion of influenza HA-Influenza B antigen. In some embodiments, the composition comprises at least a portion of a conserved coronavirus Nucleoprotein (nucleocapsid); and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen.

[0034] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least two conserved coronavirus antigens selected from: (I) a conserved coronavirus Spike protein; (ii) a conserved coronavirus NSP2 protein; (iii) a conserved coronavirus NSP3 protein; (iv) a conserved coronavirus NSP14 protein; and (v) a conserved coronavirus Nucleoprotein (nucleocapsid); and at least a portion of one or more influenza HA antigens. The aforementioned proteins or antigens may refer to portions of a particular entire protein. Thus, the present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition comprising, or comprising a sequence encoding: at least two conserved coronavirus antigens selected from: (I) a conserved coronavirus Spike protein or a portion thereof; (ii) a conserved coronavirus NSP2 protein or a portion thereof; (iii) a conserved coronavirus NSP3 protein or a portion thereof; (iv) a conserved coronavirus NSP14 protein or a portion thereof; and (v) a conserved coronavirus Nucleoprotein (nucleocapsid) or a portion thereof; and at least a portion of one or more influenza HA antigens. In some embodiments, the influenza HA antigens are selected from: HA-H1 N1 , HA-H3N2, and HA-Influenza B.

[0035] In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); and a conserved coronavirus NSP2 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); and a conserved coronavirus NSP3 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus NSP3 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the Spike protein (or a portion thereof) comprises one or more proline substitutions. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus NSP3 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP14 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus NSP3 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the composition comprises a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens. In some embodiments, the Spike protein (or a portion thereof) comprises one or more proline substitutions. In some embodiments, the composition comprises a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); and a conserved coronavirus NSP14 protein (or a portion thereof); a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof); and at least a portion of one or more influenza HA antigens.

[0036] In some embodiments, the composition further comprises a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. In some embodiments, the composition further comprises a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15. In some embodiments, the conserved protein or antigen is conserved among human and animal coronaviruses. In some embodiments, the portion of the coronavirus spike (S) protein is derived from a full-length spike glycoprotein. In some embodiments, the portion of the coronavirus spike (S) protein is derived from a partial spike glycoprotein. In some embodiments, the portion of the coronavirus spike (S) protein is receptor-binding domain (RBD). In some embodiments, the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). In some embodiments, the coronavirus protein is encoded by one of SEQ ID NOs: 1 , 3, 5-11. In some embodiments, the HA antigen is highly conserved among human influenza viruses. In some embodiments, the influenza HA antigen is encoded by one of SEQ ID NOs: 12, 14-16.

[0037] The present invention also includes a pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding one or more large sequence coronavirus proteins and one or more influenza antigens, wherein the one or more large sequence coronavirus proteins comprises one or more of: a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); or a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof).

[0038] In some embodiments, the one or more large sequence coronavirus proteins comprises two or more of: a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); or a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof). In some embodiments, the one or more large sequence coronavirus proteins comprises three or more of: a conserved coronavirus Spike protein(or a portion thereof); a conserved coronavirus NSP2 protein(or a portion thereof); a conserved coronavirus NSP3 protein(or a portion thereof); a conserved coronavirus NSP14 protein(or a portion thereof); or a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof). In some embodiments, the one or more large sequence coronavirus proteins comprises four or more of: a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); or a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof). In some embodiments, the one or more large sequence coronavirus proteins comprises: a conserved coronavirus Spike protein (or a portion thereof); a conserved coronavirus NSP2 protein (or a portion thereof); a conserved coronavirus NSP3 protein (or a portion thereof); a conserved coronavirus NSP14 protein (or a portion thereof); and a conserved coronavirus Nucleoprotein (nucleocapsid) (or a portion thereof). In some embodiments, the composition comprises one or more influenza antigens selected from: HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen, or portions thereof. In some embodiments, the composition comprises two or more influenza antigens selected from: HA-H1N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. In some embodiments, the composition comprises HA-H1N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. In some embodiments, the large coronavirus sequences are highly conserved among human and animal coronaviruses. In some embodiments, the Spike (S) protein further comprises at least one proline substitution. In some embodiments, the Spike (S) protein comprises a receptor-binding domain (RBD). In some embodiments, the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). In some embodiments, the one or more large coronavirus sequences comprises one of SEQ ID NOs: 1 , 3, 5-11. In some embodiments, the one or more large influenza sequences are highly conserved among human influenza viruses. In some embodiments, the one or more large influenza sequences comprises one of SEQ ID NOs: 12, 14-16. In some embodiments, the composition further comprises a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. In some embodiments, the composition further comprises a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15.

[0039] The present invention also features a method of preventing infection or reinfection by one or more io coronavirus variants or subvariants and influenza in a subject, said method comprising administering a therapeutically effective amount of a composition according to the present invention.

[0040] The specification of U.S. Appiication No. 63/349,799 filed June 7, 2022 is hereby incorporated herein in its entirety by reference.

[0041] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skills in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0042] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

[0043] FIG. 1 shows the results of a sequence alignment of various influenza viruses and variants and the resulting conserved region.

[0044] FIG. 2 shows non-limiting examples of vaccine compositions described herein. For example, in some embodiments, the vaccine composition comprises a spike protein domain (optionally with a mutation such as stabilizing mutations and/or proline substitutions), e.g., a coronavirus spike protein or fragment thereof or derivative thereof, and an influenza HA domain or portion thereof or derivative thereof. In some embodiments, the vaccine compositions further comprise a promoter, e.g., CAG, CMV, etc. In some embodiments, the vaccine compositions comprise a signal peptide. In some embodiments, the spike protein domain and HA domain are separated by a linker. In some embodiments, the vaccine composition comprises a spike protein domain (optionally with a mutation such as stabilizing mutations and/or proline substitutions), e.g., a coronavirus spike protein or fragment thereof or derivative thereof, and two or more influenza HA domains or portion thereof or derivative thereof, e.g., HA-H1 N1 and/or HA-H3N2 and/or HA-Influenza B. In some embodiments, the two or more HA domains are selected from HA-H1 N1 , HA-H3N2, HA-Influenza B, and/or an HA conserved region. In some embodiments, the two or more HA domains are separated by a linker.

[0045] The terms S1 and S2 merely refer to subunits of the spike protein.

[0046] FIG. 3A shows non-limiting examples of influenza proteins and SARS-CoV2 proteins that may be used in the vaccine compositions as described herein; these proteins may be used in any combination to create said compositions. In FIG. 3A, “Nsp” may refer to Nsp1 , Nsp2, Nsp3, Nsp5, Nsp6, Nsp7, Nsp8, Nsp9, Nsp10, Nsp12, Nsp13, Nsp14, Nsp15, Nsp16, or a combination thereof.

[0047] FIG. 3B shows non-limiting examples of hybrid vaccine compositions described herein. The proteins may be covalently or non-covalently linked together for the administration of the vaccine composition. In FIG. 3B, “Nsp” may refer to Nsp1 , Nsp2, Nsp3, Nsp5, Nsp6, Nsp7, Nsp8, Nsp9, Nsp10, Nsp12, Nsp13, Nsp14, Nsp15, Nsp16, a portion thereof, or a combination thereof, “Spike protein” may refer to a portion of the spike protein, or a spike protein with one or more mutations (e.g., a spike protein with two or six proline substitutions); the spike protein or portion thereof is not limited to those comprising i i one or more mutations.

[0048] FIG. 3C shows non-limiting examples of hybrid vaccine compositions described herein. The proteins may be covalently or non-covalently linked together for the administration of the vaccine composition. In FIG. 3C, “HA” may refer to an influenza hemagglutinin (HA) protein may be derived from one or more of: the H1 N1 virus strain, the H3N2 virus strain, influenza B virus strains, or variants thereof, “Spike protein” may refer to a portion of the spike protein, or a spike protein with one or more mutations (e.g., a spike protein with two or six proline substitutions); the spike protein or portion thereof is not limited to those comprising one or more mutations.

TERMS

[0049] 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 a disclosed invention 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 ’’comprising" means that other elements can also be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation. Stated another way, the term "comprising" means "including principally, but not necessarily solely." Furthermore, variations of the word "comprising," such as "comprise" and "comprises," have correspondingly the same meanings. In one respect, the technology described herein is related to the herein described compositions, methods, and respective component(s) thereof, as essential to the invention, yet open to the inclusion of unspecified elements, essential or not ("comprising").

[0050] Suitable methods and materials for the practice and/or testing of embodiments of the disclosure are described below. Such methods and materials are illustrative only and are not intended to be limiting. Other methods and materials similar or equivalent to those described herein can be used. For example, conventional methods well known in the art to which the disclosure pertains are described in various general and more specific references, including, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, 1989; Sambrook et al., Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Press, 2001 ; Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates, 1992 (and Supplements to 2000); Ausubel et al., Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, 4th ed., Wiley & Sons, 1999; Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1990; and Harlow and Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.), “Guide to Protein Purification” in Methods in Enzymology (M. P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R. I. Freshney. 1987. Liss, Inc. New York, N.Y.), Gene Transfer and Expression Protocols, pp. 109-128, ed. E. J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, Tex.), the disclosures of which are incorporated in their entirety herein by reference. [0051] Although methods and materials similar or equivalent to those described herein can be used to practice or test the disclosed technology, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0052] As used herein, the term "immunological response" to a composition or vaccine refers to the development in the host of a cellular and/or antibody-mediated immune response to a composition or vaccine of interest. Usually, an "immunological response" includes but is not limited to one or more of the following effects: the production of antibodies, B cells, helper T cells, and/or cytotoxic T cells, directed specifically to an antigen or antigens included in the composition or vaccine of interest. The host may display either a therapeutic or protective immunological response, so resistance to new infection will be enhanced and/or the clinical severity of the disease reduced. Such protection will be demonstrated by either a reduction or lack of symptoms normally displayed by an infected host, a quicker recovery time and/or a lowered viral titer in the infected host.

[0053] As used herein, the term "variant" refers to a substantially similar sequence. For polynucleotides, a variant comprises a deletion and/or addition and/or change of one or more nucleotides at one or more sites within the native polynucleotide and/or a substitution of one or more nucleotides at one or more sites in the native polynucleotide. As used herein, a "native" polynucleotide or polypeptide comprises a naturally occurring nucleotide sequence or an amino acid sequence, respectively. Variants of a particular polynucleotide of the disclosure (e.g., the reference polynucleotide) can also be evaluated by comparison of the percent sequence identity between the polypeptide encoded by a variant polynucleotide and the polypeptide encoded by the reference polynucleotide. "Variant" protein is intended to mean a protein derived from the native protein by deletion or addition of one or more amino acids at one or more sites in the native protein and/or substitution of one or more amino acids at one or more sites in the native protein. Variant proteins encompassed by the present disclosure are biologically active; that is they have the ability to elicit an immune response.

[0054] As used herein, the terms "treat" or "treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow the development of the disease, such as slow down the development of a disorder, or reducing at least one adverse effect or symptom of a condition, disease or disorder, e.g., any disorder characterized by insufficient or undesired organ or tissue function. Treatment is generally "effective" if one or more symptoms or clinical markers are reduced as that term is defined herein. Alternatively, a treatment is "effective" if the progression of a disease is reduced or halted. That is, "treatment" includes not just the improvement of symptoms or decrease of markers of the disease, but also a cessation or slowing of progress or worsening of a symptom that would be expected in absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (e.g., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treatment” also includes ameliorating a disease, lessening the severity of its complications, preventing it from manifesting, preventing it from recurring, merely preventing it from worsening, mitigating an inflammatory response included therein, or a therapeutic effort to affect any of the aforementioned, even if such therapeutic effort is ultimately unsuccessful.

[0055] As used herein, the term “carrier,” or “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable vehicle” refers to any appropriate or useful carrier or vehicle for introducing a composition to a subject. Pharmaceutically acceptable carriers or vehicles may be conventional but are not limited to conventional vehicles. For example, E. W. Martin, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 15th Edition (1975) and D. B. Troy, ed. Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore MD and Philadelphia, PA, 21^st Edition (2006) describe compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds or molecules. Carriers (e.g., pharmaceutical carriers, pharmaceutical vehicles, pharmaceutical compositions, pharmaceutical molecules, etc.) are materials generally known to deliver molecules, proteins, cells and/or drugs and/or other appropriate material into the body. In general, the nature of the carrier will depend on the nature of the composition being delivered as well as the particular mode of administration being employed. In addition to biologically-neutral carriers, pharmaceutical compositions administered may contain minor amounts of non- toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like. Patents that describe pharmaceutical carriers include, but are not limited to: U.S. Patent No. 6,667,371 ; U.S. Patent No. 6,613,355; U.S. Patent No. 6,596,296; U.S. Patent No. 6,413,536; U.S. Patent No. 5,968,543; U.S. Patent No. 4,079, 038; U.S. Patent No. 4,093,709; U.S. Patent No. 4,131 ,648; U.S. Patent No. 4,138,344; U.S. Patent No. 4,180,646; U.S. Patent No. 4,304,767; U.S. Patent No. 4,946,931 , the disclosures of which are incorporated in their entirety by reference herein. The carrier may, for example, be solid, liquid (e.g., a solution), foam, a gel, the like, or a combination thereof. In some embodiments, the carrier comprises a biological matrix (e.g., biological fibers, etc.). In some embodiments, the carrier comprises a synthetic matrix (e.g., synthetic fibers, etc.). In certain embodiments, a portion of the carrier may comprise a biological matrix and a portion may comprise synthetic matrix.

[0056] As used herein, “coronavirus” may refer to a group of related viruses such as but not limited to severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). All the coronaviruses cause respiratory tract infection that range from mild to lethal in mammals. Several non-limiting examples of Coronavirus strains are described herein.

[0057] As used herein, the term “conserved” refers to a large sequence that is among the most highly conserved large sequences identified in a sequence alignment and analysis. For example, the conserved large sequences may be the 2 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 3 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 4 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 5 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 6 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 7 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 8 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 9 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 10 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 15 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 20 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 25 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 30 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 40 most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 50 most highly conserved sequences identified. In some embodiments, the conserved sequences may be the 50% most highly conserved large sequences identified. In some embodiments, the conserved large sequences may be the 60% most highly conserved sequences identified. In some embodiments, the large conserved sequences may be the 70% most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 80% most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 90% most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 95% most highly conserved sequences identified. In some embodiments, the conserved large sequences may be the 99% most highly conserved sequences identified. The present invention is not limited to the aforementioned thresholds.

[0058] A “subject” is an individual and includes, but is not limited to, a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent), a fish, a bird, a reptile, or an amphibian. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included. A “patient” is a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects

[0059] The terms “administering,” and “administration” refer to methods of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, administering the compositions orally, parenterally (e.g., intravenously, and subcutaneously), by intramuscular injection, by intraperitoneal injection, intrathecally, transdermally, extracorporeally, topically or the like.

DETAILED DESCRIPTION OF THE INVENTION

[0060] Before the present compounds, compositions, and/or methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods or to specific compositions, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Embodiments ofthe present invention can be freely combined with each other if they are not mutually exclusive.

[0061] The vaccine compositions, e.g., the antigens herein, feature multiple large sequences, which may comprise multiple conserved epitopes, that help provide multiple opportunities for the body to develop an immune response for preventing infection. Further, the vaccines herein may be designed to be effective against past, current, and future coronavirus and/or influenza outbreaks.

[0062] The vaccine composition comprises multiple large sequences. In certain embodiments, the large sequences are conserved large sequences, e.g., sequences that are highly conserved among human coronaviruses and/or animal coronaviruses (e.g., coronaviruses isolated from animals susceptible to coronavirus infections).

[0063] The large sequences may comprise a T-cell epitope restricted to a large number of human class 1 and class 2 HLA haplotypes and not restricted to HLA-0201 for class 1 or HLA-DR for class 2. The conserved large sequences may be restricted to human HLA class 1 and 2 haplotypes. In some embodiments, the conserved epitopes are restricted to cat and dog MHC class 1 and 2 haplotypes.

[0064] The antigen may comprise large sequences, such as conserved large sequences that are highly conserved among human and animal coronaviruses. As used herein, the term large sequence refers to a sequence having at least 25 amino acids or at least 75 nucleotides. The large sequences comprise epitopes, such as the conserved epitopes described herein.

[0065] Referring now to FIG. 1 , FIG. 2, FIG. 3A, FIG. 3B and FIG. 3C, the present invention features a pan-coronavirus-influenza vaccine composition. The composition comprises at least a portion of a coronavirus spike (S) protein and at least a portion of an influenza hemagglutinin (HA) protein.

Large Coronavirus Sequences:

[0066] Coronaviruses used for determining conserved large sequences may include human SARS-CoVs as well as animal CoVs (e.g., bats, pangolins, civet cats, minks, camels, etc.) as described herein. As an example, an evolutionary comparison of genome sequences among beta-coronavirus strains isolated from humans and animals.

[0067] Additionally, other coronaviruses may be used for determining conserved large sequences (including human SARS-CoVs as well as animal CoVs (e.g., bats, pangolins, civet cats, minks, camels, etc.)) that meet the criteria to be classified as “variants of concern” or “variants of interest.” Coronavirus variants that appear to meet one or more of the undermentioned criteria may be labeled "variants of interest" or "variants under investigation" pending verification and validation of these properties. In some embodiments, the criteria may include increased transmissibility, increased morbidity, increased mortality, increased risk of “long COVID,” ability to evade detection by diagnostic tests, decreased susceptibility to antiviral drugs (if and when such drugs are available), decreased susceptibility to neutralizing antibodies, either therapeutic (e.g., convalescent plasma or monoclonal antibodies) or in laboratory experiments, ability to evade natural immunity (e.g., causing reinfections), ability to infect vaccinated individuals, increased risk of particular conditions such as multisystem inflammatory syndrome or long-haul COVID or Increased affinity for particular demographic or clinical groups, such as children or immunocompromised individuals. Once validated, variants of interest are renamed “variants of concern” by monitoring organizations, such as the CDC. [0068] In order to identify the conserved large sequences, sequence alignments and analysis were performed as described herein as well as below.

[0069] Sequence homology analysis was performed, and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) isolate Wuhan-Hu-1 was compared to complete genome with sequences of SARS-CoV-2 variants, common cold coronavirus strains (HKU1 genotype B, CoV-OC43, CoV-NL63, and CoV-229E), SARS-CoV-Urbani, MERS and coronavirus strains from bats (Rhinolophus affinis and R. malayanus), pangolin (Manis javanica), civet cats (Paguma larvata), and camel (Camelus dromedarius and C.bactrianus).

[0070] The human SARS-CoV-2 variant genome sequences were retrieved from the GISAID database, representing major Variants of Concern which are known for their high degree of transmissibility and pathogenicity. The sequences used in this study are 20A.EU1 from Spain

(EPI_ISL_691726-hCoV-19-VOC-20A.EU1), 20A.EU2 from Australia

(EP l_l SL_418799-hCoV-19-VOC-20A.EU2), B.1.1.7 from England

(EPI_ISL_581117-hCoV-19-VOC-B.1 .1 .7), B.1 .351 from South Africa

(EPI_ISL_660615-hCoV-19-VOC-B.1 .351), P.1 from Brazil (EPI_ISL_581117-hCoV-19-VOC-P.1),

CAL.20C from California (EPI_ISL_730092-hCoV-19-VOC-B.1 .427/B.1 .429), B.1.258 from Scotland (EPI_ISL_858559-hCoV-19-VOC-B.1 .258), B.1.221 from Belgium/Netherlands

(EPI_ISL_734790-hCoV-19-VOC-B.1 .221), B.1.367 from Norway/France

(EPI_ISL_541518-hCoV-19-VOC-B.1 .367), B.1.1.277 from Netherlands/Denmark/UK

(EPI_ISL_500783-hCoV-19-VOC-B.1 .1.277), B.1.1.302 from Sweden

(EPI_ISL_717929-hCoV-19-VOC-B.1.1.302). Similarly, HKU1 genotype B (AY884001), CoV-OC43 (KF923903), CoV-NL63 (NC_005831), and CoV-229E (KY983587), SARS-CoV-Urbani (AY278741.1),

MERS (NC_019843).

[0071] Bat CoV strains used in this analysis include strains RaTG13 (MN996532.2), Rs672/2006 (FJ588686.1), YNLF_31 C (KP886808.1), WIV1 (KF367457.1), WIV16 (KT444582.1), ZXC21 (MG772934.1), RmYN02 (EPI_ISL_412977), bat-RmYN01 (EPI_ISL_412976), MERS-Bat-CoV/P.khulii/ltaly/206645-63/2011 (MG596803.1). More-so, five genome sequences representing Pangolin (MT040333.1-PCoV_GX-P4L, MT040334.1-PCoV_GX-P1 E,

MT040335.1-PCoV_GX-P5L, MT040336.1-PCoV_GX-P5E, MT072864.1-PCoV_GX-P2V,

MT121216.1-PCoV-MP789), three Civet cat specific genome sequences (AY572034.1 , AY686864.1 , AY686863.1), and four CoV sequences from camels (NC_028752.1 , KF917527.1 , MN514967.1 , KT368891.1) were included in this sequence homology analysis aimed at evaluating the most conserved regions in different structural and non-structural proteins in CoV genome. These sequences were obtained either from National Center for Biotechnology Information (NCBI) or Global initiative on sharing all influenza data (GISAID). For phylogenetic analyses, SARS-CoV-2 full-genome sequences were aligned with CLUSTAL W using MEGAX. All the SARS-CoV-2 sequences were compared to existing genomes using online NCBI BLAST.

[0072] In some embodiments, the large sequences are each highly conserved among one or a combination of: SARS-CoV-2 human strains, SL-CoVs isolated from bats, SL-CoVs isolated from pangolin, SL-CoVs isolated from civet cats, and MERS strains isolated from camels. For example, in certain embodiments, the large sequences are each highly conserved among one or a combination of: at least 50,000 SARS-CoV-2 human strains, five SL-CoVs isolated from bats, five SL-CoVs isolated from pangolin, three SL-CoVs isolated from civet cats, and four MERS strains isolated from camels. In certain embodiments, the large sequences are each highly conserved among one or a combination of: at least 80,000 SARS-CoV-2 human strains, five SL-CoVs isolated from bats, five SL-CoVs isolated from pangolin, three SL-CoVs isolated from civet cats, and four MERS strains isolated from camels. In certain embodiments, the large sequences are each highly conserved among one or a combination of: at least 50,000 SARS-CoV-2 human strains in circulation during the COVI-19 pandemic, at least one CoV that caused a previous human outbreak, five SL-CoVs isolated from bats, five SL-CoVs isolated from pangolin, three SL-CoVs isolated from civet cats, and four MERS strains isolated from camels. In certain embodiments, the large sequences are each highly conserved among at least 1 SARS-CoV-2 human strain in current circulation, at least one CoV that has caused a previous human outbreak, at least one SL-CoV isolated from bats, at least one SL-CoV isolated from pangolin, at least one SL-CoV isolated from civet cats, and at least one MERS strain isolated from camels. In certain embodiments, the large sequences are each highly conserved among at least 1 ,000 SARS-CoV-2 human strains in current circulation, at least two CoVs that has caused a previous human outbreak, at least two SL-CoVs isolated from bats, at least two SL-CoVs isolated from pangolin, at least two SL-CoVs isolated from civet cats, and at least two MERS strains isolated from camels. In certain embodiments, the large sequences are each highly conserved among one or a combination of: at least one SARS-CoV-2 human strain in current circulation, at least one CoV that has caused a previous human outbreak, at least one SL-CoV isolated from bats, at least one SL-CoV isolated from pangolin, at least one SL-CoV isolated from civet cats, and at least one MERS strain isolated from camels. The present invention is not limited to the aforementioned coronavirus strains that may be used to identify conserved large sequences.

[0073] In certain embodiments, one or more of the conserved large sequences are derived from one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that has caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animal receptive to coronaviruses; and/or one or more coronaviruses tthat cause the common cold; or one or more coronaviruses that case past, current, and future outbreaks. SARS-CoV-2 human strains and variants in current circulation may include the original SARS-CoV-2 strain (SARS-CoV-2 isolate Wuhan-Hu-1), and several variants of SARS-CoV-2 including but not limited to variant B.1.177 (Spain); variant B.1.160 (Australia), variant B.1 .1 .7 (UK), variant P.1 (Japan/Brazil), variant B.1 .351 (South Africa), variant B.1 .427 (California), variant B.1.429 (California), variant B.1.258 (Scotland); variant B.1 .221 (Belgium/Netherlands); variant B.1 .367 (Norway/France); variant B.1.1.277 (UK); variant B.1.1.302 (Sweden); variant B.1.525 (North America, Europe, Asia, Africa, and Australia); variant B.1 .526 (New York), variant S:677H; variant S:677P; B.1.617.2-Delta, variant B.1 .1 .529-Omicron (BA.1); sub-variant Omicron (BA.1); sub-variant Omicron (BA.2); sub-variant Omicron (BA.3); sub-variant Omicron (BA.4); sub-variant Omicron (BA.5). The present invention is not limited to the aforementioned variants of SARS-CoV-2 and encompasses variants identified in the future. The one or more coronaviruses that cause the common cold may include but are not limited to strains 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), HKU1 (beta coronavirus).

[0074] The large sequence(s) may be derived from structural proteins, non-structural proteins, or a combination thereof. The large sequence(s) may be selected from ORFIab protein, Spike glycoprotein (e.g., the RBD), ORF3a protein, Envelope protein, Membrane glycoprotein, ORF6 protein, ORF7a protein, ORF7b protein, ORFS protein, Nucleocapsid protein, and/or an ORF10 protein. Note the ORFIab protein comprises nonstructural protein (Nsp) 1 , Nsp2, Nsp3, Nsp4, Nsp5, Nsp6, Nsp7, NspS, Nsp9, Nsp10, Nsp11 , Nsp12, Nsp13, Nsp14, Nsp15 and Nsp16.

[0075] In some embodiments, the portion of the coronavirus spike (S) protein is highly conserved among human and animal coronaviruses. The portion of the coronavirus spike (S) protein may be derived from one or more of: one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that have caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animals receptive to coronaviruses; or one or more coronaviruses that cause the common cold; or one or more coronaviruses that case past, current, and future outbreaks.

[0076] In some embodiments, the conserved large sequences are identified by: performing a sequence alignment and analysis of a particular number of coronavirus or influenza sequences to determine sequence similarity or identity amongst the group of analyzed sequences. The conserved large sequences are those that are among the most highly conserved sequences identified in the analysis.

[0077] In some embodiments, the one or more SARS-CoV-2 human strains or variants in current circulation are selected from: variant B.1 .177; variant B.1 .160, variant B.1.1 .7; variant B.1 .351 ; variant P.1 ; variant B.1 .427/B.1 .429; variant B.1.258; variant B.1 .221 ; variant B.1.367; variant B.1.1.277; variant B.1.1.302; variant B.1.525; variant B.1.526, variant S:677H; variant S:677P; variant B.1 .1.529-Omicron (BA.1); variant B.1 .1 ,529-Omicron (BA.2); and variant B.1 ,617.2-Delta). In some embodiments, the one or more coronaviruses that cause the common cold are selected from: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus.

[0078] In some embodiments, the portion of the coronavirus spike (S) protein is derived from a full-length spike glycoprotein. In other embodiments, the portion of the coronavirus spike (S) protein is derived from a partial spike glycoprotein. In some embodiments, the portion of the coronavirus spike (S) protein comprises at least one proline substitution, or at least two proline substitution, or at least, four proline substitutions, or at least six proline substitutions. The portion of the coronavirus spike (S) protein may comprise two consecutive proline substitutions at amino acid positions 986 and 987. The proline substitutions may comprise K986P and V987P mutations. In further embodiments, the portion of the coronavirus spike (S) protein is the receptor-binding domain (RBD). In some embodiments, the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD).

[0079] In some embodiments, the transmembrane anchor of the spike protein has an intact S1-S2 cleavage site. In some embodiments, the spike protein is in its stabilized conformation. In some embodiments, the spike protein is stabilized with proline substitutions at amino acid positions 986 and 987 at the top of the central helix in the S2 subunit. In some embodiments, the composition comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). In some embodiments, the trimerized SARS-CoV-2 receptor-binding domain (RBD) sequence is modified by the addition of a T4 fibritin-derived foldon trimerization domain. In some embodiments, the addition of a T4 fibritin-derived foldon trimerization domain increases immunogenicity by multivalent display

[0080] Table 1 : Shows non-limiting examples of a portion of a coronavirus spike (S) protein that may be used in accordance with the present invention.

[0081] Table 2 shows non-limiting examples of proteins that may be used to create a vaccine composition described herein. In some embodiments, the proteins listed below may be arranged in a plurality of combinations. In some embodiments, the proteins may be directly linked together. In other embodiments, the proteins are linked together via a linker.

Large Influenza Sequences:

[0082] In some embodiments, the portion of an influenza hemagglutinin (HA) protein is highly conserved among human influenza viruses. The portion of an influenza hemagglutinin (HA) protein may be derived from one or more of: the H1N1 virus strain, the H3N2 virus strain, influenza B virus strains, or variants thereof.

[0083] In some embodiments, the H1N1 virus strains or variants are selected from 28566 available complete genome sequences in NCBI for the hemagglutinin (HA) gene. Some of the prominent strains are: OK384178.1, OM642156.1, OM654386.1, OL840606.1, OK625377.1, OM865246.1, OM935941.1, OM642158.1, OM935953.1, MW840068.1, MW839847.1, MW839825.1, MW930730.1 , MT227010.1, LC638096.1 , LC638077.1 , LC637999.1 , and LC645067.1. In some embodiments, the H3N2 virus strains or variants are selected from 33620 available complete genome sequences in NCBI for the hemagglutinin (HA) gene. Some of the prominent strains are: MZ005227.1, MW849238.1 , MZ203409.1, MZ198318.1, MZ198312.1, MZ198295.1, MZ198289.1, MZ198265.1, MW789449.1, MW798370.1, MW790182.1, MW789645.1, MW789778.1, MW789685.1, MW789659.1, and MW790001.1. In some embodiments, the influenza B virus strains or variants are selected from 16596 available complete genome sequences in NCBI for the hemagglutinin (HA) gene. Some of the prominent strains are: M10298.1, MT738525.1, MT808088.1, MT056751.1 , MT314641.1, MT874090.1, MT242979.1, MT315665.1 , MT1055640.1, MT057563.1, MT056955.1 , MT243019.1, MT306916.1 , MT057571.1 , MT314793.1 , MT343026.1 , MT874109.1, MT243795.1, MT315769.1 , and KX885875.1

[0084] Table 3: Shows non-limiting examples of a portion of an influenza hemagglutinin (HA) protein that may be used in accordance with the present invention.

Antigen Delivery System-.

[0085] The present invention also features vaccine compositions in the form of an antigen delivery system. Any appropriate antigen delivery system may be considered for delivery of the antigens described herein. The present invention is not limited to the antigen delivery systems described herein.

[0086] In certain embodiments, the antigen delivery system is for targeted delivery of the vaccine composition, e.g., for targeting to the tissues of the body where the virus replicates.

[0087] In certain embodiments, the antigen delivery system comprises adenoviruses such as but not limited to Ad5, Ad26, Ad35, etc., as well as carriers such as lipid nanoparticles, polymers, peptides, etc. In other embodiments, the antigen delivery system comprises a vesicular stomatitis virus (VSV) vector.

[0088] The present invention is not limited to adenovirus vector-based antigen delivery systems. In certain embodiments, the antigen delivery system comprises an adeno-associated virus vector-based antigen delivery system, such as but not limited to the adeno-associated virus vector type 9 (AAV9 serotype), AAV type 8 (AAV8 serotype), etc. In certain embodiments, the adeno-associated virus vectors used are tropic, e.g., tropic to lungs, brain, heart and kidney, e.g., the tissues of the body that express ACE2 receptors. For example, AAV9 is known to be neurotropic, which would help the vaccine composition to be expressed in the brain.

[0089] In the antigen delivery system, the one or more large sequences are operatively linked to a promoter. In certain embodiments, the one or more large sequences are operatively linked to a generic promoter. For example, in certain embodiments, the one or more large sequences are operatively linked to a CMV promoter. In certain embodiments, the one or more large sequences are operatively linked to a CAG, EFIA, EFS, CBh, SFFV, MSCV, mPGK, hPGK, SV40, UBC, or another appropriate promoter.

[0090] In some embodiments, the one or more large sequences are operatively linked to a tissue-specific promoter (e.g., a lung-specific promoter). For example, the antigen may be operatively linked to a SpB promoter or a CD144 promoter.

[0091] As discussed, in certain embodiments, the vaccine composition comprises a molecular adjuvant. In certain embodiments, the molecular adjuvant is operatively linked to a generic promoter, e.g., as described above. In certain embodiments, the molecular adjuvant is operatively linked to a tissue-specific promoter, e.g., a lung-specific promoter, e.g., SpB or CD144.

[0092] As discussed, in certain embodiments, the vaccine composition comprises a T cell attracting chemokine. In certain embodiments, the T cell attracting chemokine is operatively linked to a generic promoter, e.g., as described above. In certain embodiments, the T cell attracting chemokine is operatively linked to a tissue-specific promoter, e.g., a lung-specific promoter, e.g., SpB or CD144.

[0093] As discussed, in certain embodiments, the vaccine composition comprises a composition for promoting T cell proliferation. In certain embodiments, the composition for promoting T cell proliferation is operatively linked to a generic promoter, e.g., as described above. In certain embodiments, the composition for promoting T cell proliferation is operatively linked to a tissue-specific promoter, e.g., a lung-specific promoter, e.g., SpB or CD144.

[0094] In some embodiments, the portion of a coronavirus spike (S) protein and the portion of an influenza hemagglutinin (HA) protein are operatively linked to a generic promoter. The generic promoter may be a CMV or a CAG promoter. [0095] Table 4 shows non-limiting examples of a portion of a promoter that may be used in accordance with the present invention.

[0096] In some embodiments, the portion of a coronavirus spike (S) protein and the portion of an influenza hemagglutinin (HA) protein are separated by a linker. The linker may be 2 to 10 amino acids in length.

[0097] The large sequences may be each separated by a linker. In certain embodiments, the linker allows for an enzyme to cleave between the large sequences. The present invention is not limited to particular linkers or particular lengths of linkers. As an example, in certain embodiments, one or more large sequences may be separated by a linker 2 amino acids in length or a linker 3 amino acids in length, or a linker 4 amino acids in length, or a linker 5 amino acids in length, or a linker 6 amino acids in length, or a linker 7 amino acids in length, or a linker 8 amino acids in length, or a linker 9 amino acids in length, or a linker 10 amino acids in length. In certain embodiments, one or more large sequences may be separated by a linker from 2 to 10 amino acids in length.

[0098] Linkers are well known to one of ordinary skill in the art. Non-limiting examples of linkers include AAY, KK, and GPGPG.

Vaccine Composition:

[0099] In some embodiments, the compositions described herein may be used to prevent a coronavirus and/or influenza infection prophylactically in a subject. In some embodiments, the compositions described herein may elicit an immune response in a subject.

[00100] Table 5, FIG. 2, and FIG. 3B show additional examples of vaccine compositions described herein (FIG. 3A shows non-limiting examples of coronavirus and influenza virus proteins that may be considered, or may be the proteins from which partial proteins are derived, for vaccine candidates). The present invention is not limited to the examples in Table 4:

[00101] In some embodiments, the delivery system is an adenovirus system. In some embodiments, the adenovirus delivery system is Ad26, Ad5, Ad35, or a combination thereof. In some embodiments, one or more of the large sequences are operatively linked to a generic promoter. In some embodiments, the generic promoter is a CMV or a CAG promoter. In some embodiments, the one or more large sequences are operatively linked to a lung-specific promoter. In some embodiments, the lung-specific promoter is SpB or CD144. In some embodiments, the composition further comprises a T cell attracting chemokine. In some embodiments, the delivery system is a lipid nanoparticle encapsulated mRNA system. In some embodiments, the vaccine composition is in the form of DNA, RNA, modified RNA, protein (or peptide), or a combination thereof.

[00102] In some embodiments, the vaccine compositions described herein are used to prevent a coronavirus and/or influenza disease in a subject. In other embodiments, the vaccine compositions described herein are used to prevent a coronavirus and/or influenza infection prophylactically in a subject. In further embodiments, the vaccine compositions described herein elicits an immune response in a subject.

[00103] The present invention also features oligonucleotide compositions. For example, the present invention includes oligonucleotides disclosed in the sequence listings. The present invention also includes oligonucleotides in the form of antigen delivery systems. The present invention also includes oligonucleotides encoding the conserved large sequences disclosed herein. The present invention also includes oligonucleotide compositions comprising one or more oligonucleotides encoding any of the vaccine compositions according to the present invention. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises modified DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises modified RNA. In some embodiments, the oligonucleotide comprises mRNA. In some embodiments, the oligonucleotide comprises modified mRNA

[00104] Additional sequences and details about methods to select sequences can be found in U.S. Application No. PCT/US21/27355, U.S. Application No. PCT/US21/27340, U.S. Application No. PCT/US21/27341 the specifications of which are hereby incorporated in their entirety by reference.

[00105] As used herein, the term “about” refers to plus or minus 10% of the referenced number.

[00106] Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of’ or “consisting of,” and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of’ or “consisting of’ is met.

Claims

WHAT IS CLAIMED IS:

1 . A pre-emptive pan- Coronavirus-influenza vaccine composition, the composition comprising: a. at least one of SEQ ID NO: 1 , 3, 5-11 ; and b. at least one of SEQ ID NO: 12, 14-16.

2. A pre-emptive pan-Coronavirus-influenza vaccine composition, the composition comprising: a. at least one of SEQ ID NO: 1 , 3, 5-11 or at least one protein encoded by SEQ ID NO: 1 , 3, 5-11 ; and b. at least one of SEQ ID NO: 12, 14-16 or at least one protein encoded by SEQ ID NO: 12, 14-16.

3. A pre-emptive pan-Coronavirus-influenza vaccine composition, the composition comprising at least a portion of at least one coronavirus protein selected from SEQ ID NO: 1 , 3, 5-11 , and at least a portion of at least one influenza hemagglutinin (HA) protein comprising a sequence according to SEQ ID NO: 12, 14-16.

4. A pre-emptive pan-Coronavirus-influenza vaccine composition, the composition comprising at least a portion of one of SEQ ID NO: 1 , 3, 5-11 or at least one coronavirus protein encoded by SEQ ID NO: 1 , 3, 5-11 , and at least a portion of one of SEQ ID NO: 12, 14-16 or at least one influenza hemagglutinin (HA) protein encoded by SEQ ID NO: 12, 14-16.

5. The composition of any one of claims 1-4, wherein the composition further comprises a generic promoter, wherein at least one of seq id no: 1-11 and at least one of seq id no: 12 are operatively linked to the generic promoter.

6. The composition of any of claims 1-5 further comprising or encoding a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof.

7. The composition of any of claims 1-6 further comprising or encoding a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15.

8. A pre-emptive pan-Coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding, at least a portion of a Coronavirus spike (S) protein and at least a portion of at least one influenza hemagglutinin (HA) protein.

9. The composition of claim 8, wherein the portion of the coronavirus spike (S) protein is highly conserved among human and animal coronaviruses.

10. The composition of claim 9, wherein the portion of the coronavirus spike (S) protein is derived from one or more of: one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that has caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animals receptive to coronaviruses; or one or more coronaviruses that cause the common cold; or one or more coronaviruses that case past, current, and future outbreaks.

11. The composition of claim 10, wherein the one or more SARS-CoV-2 human variants in current circulation are selected from: variant B.1.177; variant B.1.160, variant B.1.1.7; variant B.1.351 ; variant P.1 ; variant B.1 .427/B.1 .429; variant B.1.258; variant B.1.221 ; variant B.1.367; variant B.1 .1.277; variant B.1.1.302; variant B.1.525; variant B.1 .526, variant S:677H; variant S:677P; B.1 .617.2-Delta, variant B.1 .1.529-Omicron (BA.1); sub-variant Omicron (BA.1); sub-variant Omicron (BA.2); sub-variant Omicron (BA.3); sub-variant Omicron (BA.4); sub-variant Omicron (BA.5) and the one or more coronaviruses that cause the common cold are selected from: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus. The composition of claim 8, wherein the portion of the coronavirus spike (S) protein is derived from a full-length spike glycoprotein. The composition of claim 8, wherein the portion of the coronavirus spike (S) protein is derived from a partial spike glycoprotein. The composition of any of claims 8-13, wherein the Coronavirus spike (S) protein further comprises at least one proline substitution. The composition of claim 8, wherein the portion of the coronavirus spike (S) protein is receptor-binding domain (RBD). The composition of claim 15, wherein the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). The composition of claim 8, wherein the portion of a coronavirus spike (S) protein is encoded by one of SEQ ID NOs: 1 , 3, 5-7. The composition of claim 8, wherein the portion of the influenza hemagglutinin (HA) protein is highly conserved among human influenza viruses. The composition of claim 18, wherein the portion of the influenza hemagglutinin (HA) protein is derived from one or more of: H1 N1 virus strain, H3N2 virus strain, or influenza B virus strains, wherein the H1 N1 virus strains or variants are selected from: OK384178.1 , OM642156.1 , OM654386.1 , OL840606.1 , OK625377.1 , OM865246.1 , OM935941 .1 , OM642158.1 ,

OM935953.1 , MW840068.1 , MW839847.1 , MW839825.1 , MW930730.1 , MT227010.1 ,

LC638096.1 , LC638077.1 , LC637999.1 , and LC645067.1 ; wherein the H3N2 virus strains or variants are selected from: MZ005227.1 , MW849238.1 , MZ203409.1 , MZ198318.1 , MZ198312.1 , MZ198295.1 , MZ198289.1 , MZ198265.1 , MW789449.1 , MW798370.1 , MW790182.1 ,

MW789645.1 , MW789778.1 , MW789685.1 , MW789659.1 , and MW790001.1 and wherein the influenza B virus strains or variants are selected from: M10298.1 , MT738525.1 , MT808088.1 , MT056751.1 , MT314641.1 , MT874090.1 , MT242979.1 , MT315665.1 , MT1055640.1 ,

MT057563.1 , MT056955.1 , MT243019.1 , MT306916.1 , MT057571.1 , MT314793.1 , MT343026.1 , MT874109.1 , MT243795.1 , MT315769.1 , and KX885875.1. The composition of claim 8 or 17, wherein the portion of the influenza hemagglutinin (HA) protein is encoded by one of SEQ ID NOs: 12, 14-16. The composition of claim 8, wherein the composition is encoded by one of SEQ ID NO: 21-53. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising a sequence according to SEQ ID NO: 21-53. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising a sequence according to one of SEQ ID NO: 21-53 or a protein encoded by one of SEQ ID NO: 21-53. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a coronavirus protein, the coronavirus protein being selected from: a structural protein, wherein the structural protein comprises a Spike protein, a Nucleocapsid protein, or a combination thereof; or a non-structural protein, wherein the non-structural protein comprises NSP2, NSP3, NSP14, or combination thereof; and b. at least a portion of at least one influenza hemagglutinin (HA) protein. The composition of claim 24, wherein the Spike protein comprises SEQ ID NO: 2 or 4 or is encoded by one of SEQ ID NO: 1 , 3, 5-7. The composition of claim 24, wherein the NSP2 sequence is encoded by SEQ ID NO: 8, the NSP sequence is encoded by SEQ ID NO: 9, and the NSP14 sequence is encoded by SEQ ID NO: 10. The composition of claim 24, wherein the Nucleocapsid protein is encoded by SEQ ID NO: 11 . The composition of any one of claims 24-27, wherein the HA protein comprises SEQ ID NO: 13 or is encoded by one of SEQ ID NO: 12, 14-16. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising: a. at least one of SEQ ID NO: 1 , 3, 5-11 ; and b. at least one of SEQ ID NO: 12, 14-16. The composition of claim 29 further comprising a generic promoter, wherein the at least one of SEQ ID NO: 1 , 3, 5-11 and the at least one of SEQ ID NO: 12, 14-16 are operatively linked to the generic promoter. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding, one or more large coronavirus sequences or proteins and one or more large influenza sequences or proteins. The composition of claim 31 , wherein the one or more large coronavirus sequences comprise or encode a structural protein, a non-structural protein, or a combination therein. The composition of claim 31 , wherein the structural proteins are selected from: a Spike Protein or a Nucleocapsid protein, and wherein the non-structural proteins are selected from: NSP2, NSP3, and NSP14. The composition of any one of claims 31-33, wherein the large coronavirus sequences are highly conserved among human and animal coronaviruses. The composition of any one of claims 31-34, wherein the one or more large coronavirus sequences are derived from one or more of: one or more SARS-CoV-2 human strains or variants in current circulation; one or more coronaviruses that has caused a previous human outbreak; one or more coronaviruses isolated from animals selected from a group consisting of bats, pangolins, civet cats, minks, camels, and other animals receptive to coronaviruses; one or more coronaviruses that cause the common cold; or one or more coronaviruses that case past, current, and future outbreaks. The composition of claim 35, wherein the one or more SARS-CoV-2 human variants in current circulation are selected from: variant B.1.177; variant B.1.160, variant B.1.1.7; variant B.1.351 ; variant R1 ; variant B.1 .427/B.1 .429; variant B.1.258; variant B.1.221 ; variant B.1.367; variant B.1 .1.277; variant B.1.1.302; variant B.1.525; variant B.1 .526, variant S:677H; variant S:677P; B.1 .617.2-Delta, variant B.1 .1.529-Omicron (BA.1); sub-variant Omicron (BA.1); sub-variant Omicron (BA.2); sub-variant Omicron (BA.3); sub-variant Omicron (BA.4); sub-variant Omicron (BA.5); and the one or more coronaviruses that cause the common cold are selected from: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, and HKU1 beta coronavirus. The composition of claim 31 , wherein the Spike (S) protein is derived from a full-length spike glycoprotein. The composition of claim 31 , wherein the Spike (S) protein is derived from a partial spike glycoprotein. The composition of claim 31 , wherein the Spike (S) protein further comprises at least one proline substitution. The composition of claim 31 , wherein the Spike (S) protein comprises a receptor-binding domain (RBD). The composition of claim 40, wherein the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). The composition of claim 31 , wherein the one or more large coronavirus sequences comprises one of SEQ ID NOs: 1 , 3, 5-11. The composition of claim 31 , wherein the one or more large influenza sequences are highly conserved among human influenza viruses. The composition of claim 43, wherein the one or more large influenza sequences are derived from one or more of: H1 N1 virus strain, H3N2 virus strain, or influenza B virus strains, wherein the H1 N1 virus strains or variants are selected from: OK384178.1 , OM642156.1 , OM654386.1 , OL840606.1 , OK625377.1 , OM865246.1 , OM935941.1 , OM642158.1 , OM935953.1 ,

MW840068.1 , MW839847.1 , MW839825.1 , MW930730.1 , MT227010.1 , LC638096.1 ,

LC638077.1 , LC637999.1 , and LC645067.1 ; wherein the H3N2 virus strains or variants are selected from: MZ005227.1 , MW849238.1 , MZ203409.1 , MZ198318.1 , MZ198312.1 ,

MZ198295.1 , MZ198289.1 , MZ198265.1 , MW789449.1 , MW798370.1 , MW790182.1 ,

MW789645.1 , MW789778.1 , MW789685.1, MW789659.1 , and MW790001.1 and wherein the influenza B virus strains or variants are selected from: M10298.1 , MT738525.1 , MT808088.1 , MT056751.1 , MT314641.1 , MT874090.1 , MT242979.1 , MT315665.1 , MT1055640.1 ,

MT057563.1 , MT056955.1 , MT243019.1 , MT306916.1 , MT057571 .1 , MT314793.1 , MT343026.1 , MT874109.1 , MT243795.1 , MT315769.1 , and KX885875.1. The composition of claim 32 wherein the one or more large influenza sequences comprises one of SEQ ID NOs: 12, 14-16. The composition of any of claims 31-45 further comprising or encoding a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. The composition of any of claims 31-46 further comprising or encoding a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a conserved coronavirus Spike protein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 48, wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 48, wherein the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-H1 N1 antigen. The composition of claim 48, wherein the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-H3N2 antigen. The composition of claim 48, wherein the composition comprises at least a portion of a conserved coronavirus Spike protein; and at least a portion of influenza HA-Influenza B antigen. The composition of claim 48, wherein the composition comprises at least a portion of a conserved coronavirus Spike protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. The composition of any one of claims 48-53, wherein the Spike protein comprises one or more proline substitutions. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a conserved coronavirus NSP2 protein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 55, wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 55, wherein the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-H1 N1 antigen. The composition of claim 55, wherein the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-H3N2 antigen. The composition of claim 55, wherein the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and at least a portion of influenza HA-Influenza B antigen. The composition of claim 55, wherein the composition comprises at least a portion of a conserved coronavirus NSP2 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a conserved coronavirus NSP3 protein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 61 , wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 61 , wherein the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-H1 N1 antigen. The composition of claim 61 , wherein the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-H3N2 antigen. The composition of claim 61 , wherein the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and at least a portion of influenza HA-Influenza B antigen. The composition of claim 61 , wherein the composition comprises at least a portion of a conserved coronavirus NSP3 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a conserved coronavirus NSP14 protein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 67, wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 67, wherein the composition comprises at least a portion of a conserved coronavirus NSP41 protein; and at least a portion of influenza HA-H1 N1 antigen. The composition of claim 67, wherein the composition comprises at least a portion of a conserved coronavirus NSP41 protein; and at least a portion of influenza HA-H3N2 antigen. The composition of claim 67, wherein the composition comprises at least a portion of a conserved coronavirus NSP14 protein; and at least a portion of influenza HA-Influenza B antigen. The composition of claim 67, wherein the composition comprises at least a portion of a conserved coronavirus NSP14 protein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least a portion of a conserved coronavirus Nucleoprotein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 73, wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 73, wherein the composition comprises at least a portion of a conserved coronavirus Nucleoprotein; and at least a portion of influenza HA-H1 N1 antigen. The composition of claim 73 wherein the composition comprises at least a portion of a conserved coronavirus Nucleoprotein; and at least a portion of influenza HA-H3N2 antigen. The composition of claim 73, wherein the composition comprises at least a portion of a conserved coronavirus Nucleoprotein; and at least a portion of influenza HA-Influenza B antigen. The composition of claim 73, wherein the composition comprises at least a portion of a conserved coronavirus Nucleoprotein; and two or more of HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding: a. at least two conserved coronavirus antigens selected from: (I) a conserved coronavirus Spike protein; (ii) a conserved coronavirus NSP2 protein; (ill) a conserved coronavirus NSP3 protein; (iv) a conserved coronavirus NSP14 protein; and (v) a conserved coronavirus Nucleoprotein; and b. at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the influenza HA antigens are selected from: HA-H1N1 , HA-H3N2, and HA-Influenza B. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; and a conserved coronavirus NSP2 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; and a conserved coronavirus NSP3 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; and a conserved coronavirus NSP3 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP14 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of any one of claims 79-90, wherein the Spike protein comprises one or more proline substitutions. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; and a conserved coronavirus NSP3 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP3 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP14 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; a conserved coronavirus NSP14 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; and at least a portion of one or more influenza HA antigens. . The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of claim 79, wherein the composition comprises a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of any one of claims 102-104 wherein the Spike protein comprises one or more proline substitutions. . The composition of claim 79, wherein the composition comprises a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; and a conserved coronavirus NSP14 protein; a conserved coronavirus Nucleoprotein; and at least a portion of one or more influenza HA antigens. . The composition of any one of claims 48-106, wherein the composition further comprises a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. . The composition of any of claims 48-107, wherein the composition further comprises a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15. . The composition of any of claims 48-108, wherein the conserved protein or antigen is conserved among human and animal coronaviruses. The composition of any of claims 48-108, wherein the portion of the coronavirus spike (S) protein is derived from a full-length spike glycoprotein. The composition of any of claims 48-108, wherein the portion of the coronavirus spike (S) protein is derived from a partial spike glycoprotein. The composition of any of claims 48-108, wherein the portion of the coronavirus spike (S) protein is receptor-binding domain (RBD). The composition of claim 112, wherein the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). The composition of any one of claims 48-108, wherein the coronavirus protein is encoded by one of SEQ ID NOs: 1 , 3, 5-11. The composition of any one of claims 48-114, wherein the HA antigen is highly conserved among human influenza viruses. The composition of any one of claims 48-115, wherein the influenza HA antigen is encoded by one of SEQ ID NOs: 12, 14-16. A pre-emptive pan-coronavirus-influenza vaccine composition, the composition comprising, or comprising a sequence encoding, one or more large sequence coronavirus proteins and one or more influenza antigens, wherein the one or more large sequence coronavirus proteins comprises one or more of: a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; or a conserved coronavirus Nucleoprotein. . The composition of claim 117, wherein the one or more large sequence coronavirus proteins comprises two or more of: a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; or a conserved coronavirus Nucleoprotein. . The composition of claim 117, wherein the one or more large sequence coronavirus proteins comprises three or more of: a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; or a conserved coronavirus Nucleoprotein. . The composition of claim 117, wherein the one or more large sequence coronavirus proteins comprises four or more of: a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; or a conserved coronavirus Nucleoprotein. . The composition of claim 117, wherein the one or more large sequence coronavirus proteins comprises: a conserved coronavirus Spike protein; a conserved coronavirus NSP2 protein; a conserved coronavirus NSP3 protein; a conserved coronavirus NSP14 protein; and a conserved coronavirus Nucleoprotein. . The composition of any one of claims 117-121 , wherein the composition comprises one or more influenza antigens selected from: HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. . The composition of any one of claims 117-121 , wherein the composition comprises two or more influenza antigens selected from: HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. . The composition of any one of claims 117-121 , wherein the composition comprises HA-H1 N1 antigen, HA-H3N2 antigen, and HA-Influenza B antigen. . The composition of any one of claims 117-124, wherein the large coronavirus sequences are highly conserved among human and animal coronaviruses. . The composition of any one of claims 117-125, wherein the Spike (S) protein further comprises at least one proline substitution. . The composition of any one of claims 117-126, wherein the Spike (S) protein comprises a receptor-binding domain (RBD). . The composition of any one of claims 117-126, wherein the RBD comprises a trimerized SARS-CoV-2 receptor-binding domain (RBD). . The composition of any one of claims 117-128, wherein the one or more large coronavirus sequences comprises one of SEQ ID NOs: 1 , 3, 5-11. . The composition of any one of claims 117-129, wherein the one or more large influenza sequences are highly conserved among human influenza viruses. . The composition of any one of claims 117-130 wherein the one or more large influenza sequences comprises one of SEQ ID NOs: 12, 14-16. . The composition of any of claims 117-131 further comprising a T cell attracting chemokine, wherein the T cell attracting chemokine is CCL5, CXCL9, CXCL10, CXCL11 , or a combination thereof. . The composition of any of claims 117-132 further comprising a composition that promotes T cell proliferation and T-cell memory, wherein the composition that promotes T cell proliferation and memory is IL-7, IL-2, or IL-15. . A method of preventing infection or reinfection by one or more coronavirus variants or subvariants and influenza in a subject, said method comprising administering a therapeutically effective amount of a composition according to one of claims 1-133.