WO2023060244A1

WO2023060244A1 - Methods and compositions including novel antibodies for diagnosing covid-19 variants

Info

Publication number: WO2023060244A1
Application number: PCT/US2022/077774
Authority: WO
Inventors: Rama Devudu PULIGEDDA; Fetweh H. AL-SALEEM; Scott K. Dessain
Original assignee: Lankenau Institute For Medical Research
Priority date: 2021-10-07
Filing date: 2022-10-07
Publication date: 2023-04-13

Abstract

Provided herein are antibodies and compositions as well as methods for utilizing the same. The methods include diagnosing a subject as being infected with a SARS-CoV-2 virus by contacting a sample obtained from the subject with an antibody that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan SI protein variant at N501, but does not bind a SARS-CoV-2 SI protein variant that has a spike protein mutation N501 Y, to form an antib ody/SARS -Co V-2 virus complex when the antigen is present in the sample. The subject is diagnosed as being infected with a SARS-CoV-2 virus variant having the residue N501 and not N501 Y when the antibody/SARS-CoV-2 virus complex is detected.

Description

METHODS AND COMPOSITIONS INCLUDING NOVEL ANTIBODIES FOR DIAGNOSING COVID-19 VARIANTS INCORPORATION-BY REFERENCE OF MATERIAL SUBMITTED IN ELECTRONIC FORM Applicant hereby incorporates by reference the Sequence Listing material filed in electronic form herewith. This .xml file is labeled “MLH-130.PCT”, was created on October 7, 2022, and is 38.0 KB (38,919 bytes) in size. BACKGROUND OF THE INVENTION Efforts to control SARS-CoV-2 have been challenged by the emergence of variant strains that have important implications for clinical and epidemiological decision making. These variants arise through error-prone genome replication and the outgrowth of strains with mutations that provide a selective advantage. The CDC has designated four of these strains Variants of Concern (VOCs): B.1.1.7 (alpha, United Kingdom), B.1.351 (beta, South Africa), P.1 (gamma, Brazil), and B.1.617.2 (delta, India). VOCs can evade antibody immunity, whether provided by vaccination or passive immunization with monoclonal antibodies (mAbs). VOCs are also more transmissible than earlier strains and therefore warrant enhanced mitigation practices. The VOCs pose a particular risk to health care facilities, congregate housing settings, public transportation hubs, and high-risk occupational environments. As multiple VOCs can circulate simultaneously within a population, variant- specific point-of-care testing (POC) is necessary to effectively diagnose and manage SARS- CoV-2 infections, as well as to monitor for changes in SARS-CoV-2 variant epidemiology. The VOCs can be distinguished by amino acid changes in the spike protein receptor binding domain (RBD), which mediates receptor binding and is one of the major targets of the SARS-CoV-2 neutralizing antibody response. Five RBD residues have undergone changes in the VOCs: K417, L452, T478, E484, and N501. One of the most common is the N501Y substitution, which occurs in the alpha, beta, and gamma VOCs. The N501 residue lies on the “right shoulder” of the RBD, where it directly contacts the ACE2 receptor through hydrophobic interactions. N501Y has arisen simultaneously in many lineages and confers a selective advantage over Wuhan-Hu-1 (L) by increasing the affinity of the RBD for the ACE2 receptor 3- to 16-fold. An RBD mutation screen for high affinity ACE2 binding repeatedly produced de novo N501Y mutants, consistent with the worldwide appearance of multiple independent N501Y-containing variants. N501Y collaborates with other RBD mutations to increase binding and infectivity (e.g. E484K), and structural and functional studies suggest that N501Y will continue to circulate among SARS-CoV-2 variants via co- selection with mutations that resist antibody neutralization. A recent example is the mu (B.1.621) Variant of Interest (VOI), which has spread worldwide spread since its identification in Colombia in January 2021 and is relatively resistant to vaccine immunity and some mAb therapeutics. Mu contains the RBD mutations R346K, E484K, and N501Y. N501Y has originated many times globally and is positively selected because it allows tyrosine side-chain interactions that increase infectivity through enhanced ACE2 binding. Mutagenesis and modeling experiments suggest that N501Y will be a feature of important variants likely to arise in the future, contributing to the spread of variants resistant to current anti-viral vaccines and therapeutics. Variant testing generally relies on Nucleic Acid Amplification Tests (NAATs) such as DNA sequencing, S-Gene Target Failure (SGTF), multiplex PCR, or CRISPR. However, these generally take too long for efficient POC use and require specialized laboratories. Immunoassays that detect viral antigens, e.g., Antigen-detection Rapid Diagnostic Tests (Ag- RDTs), are better suited to POC testing. Ag-RDTs are typically lateral flow assays (LFAs) that can be read within 15-30 minutes. They are less sensitive than NAATs, but they have high negative predictive values and are therefore ideal for POC testing, in which rapid turnaround time and high testing frequency are essential for pandemic control. At least twenty-five SARS-CoV-2 Ag-RDTs have been granted an Emergency Use Authorization by the FDA. However, variant-specific tests have not yet been implemented A continuing need in the art exists for new and effective tools and methods for identifying strain-specific infections and for treatment of the same. SUMMARY OF THE INVENTION Antibodies, compositions, and methods for diagnosing and treating COVID-19 variants are provided herein. In a first aspect, an antibody that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan S1 protein variant at N501, but does not bind a SARS-CoV-2 S1 protein variant that has a spike protein mutation N501Y is provided. In one embodiment, the antibody includes: (a) a heavy chain variable region (V_H) comprising (i) a complementarity- determining region 1 (CDR1) of SEQ ID NO: 15, (ii) a complementarity-determining region 2 (CDR2) of SEQ ID NO: 17, and (iii) a complementarity-determining region 3 (CDR3) of SEQ ID NO: 18; and/or (b) a light chain variable region (V_L) comprising, (i) a CDR1 of SEQ ID NO: 22, (ii) a CDR2 having the amino acid sequence Asp-Asp-Ser (DDS), and (iii) a CDR3 of SEQ ID NO: 23. In certain embodiments, the antibody includes a V_H having an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 14 and/or a V_L having an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 21. In one embodiment, the antibody includes a V_H comprising the amino acid sequence of SEQ ID NO: 14 and a V_L comprising the amino acid sequence of SEQ ID NO: 21. In certain embodiments, the antibody is formatted as a non-human antibody, wherein the V_H has CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 15, 17, and 18, respectively, and wherein the V_L has CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 22, amino acid sequence DDS and SEQ ID NO: 23, respectively. In another aspect, a method of diagnosing a subject as being infected with a SARS- CoV-2 virus or screening a subject for a SARS-CoV-2 infection is provided. The method includes contacting a sample obtained from the subject with at least one antibody or a panel of antibodies that bind selected S1 antigens in SARS-CoV-2 variants to form an antibody/SARS-CoV-2 virus complex when the antigen is present in the sample. One antibody in the panel of antibodies is an antibody as described herein that binds S1 antigens having only residue N501, not mutations at that site. The method further includes detecting the pattern of binding between said antibodies by the presence or absence of an antibody/SARS-CoV-2 virus complex, and diagnosing the subject as being infected with a specific SARS-CoV-2 virus variant based upon the pattern of binding between the panel of antibodies and the viral S1 protein. In one embodiment, the test is an Antigen Diagnostic Test immunoassay directed to detect at pattern of spike RBD polymorphisms at S1 amino acid residues K417, L452, E484, and N501, wherein the pattern detected by the selected antibodies or antigen binding fragments thereof distinguishes among SARS-CoV-2 variant infections. In another aspect, a method of diagnosing a subject as being infected with a SARS- CoV-2 virus or screening a subject for a SARS-CoV-2 infection includes contacting a sample obtained from the subject with at least one antibody or a panel of antibodies that bind selected S1 antigens in SARS-CoV-2 variants to form an antibody/SARS-CoV-2 virus complex when the antigen is present in the sample. In another embodiment, the method includes contacting a sample obtained from the subject with an antibody that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan S1 protein variant at N501, but does not bind a SARS-CoV-2 S1 protein variant that has a spike protein mutation N501Y, to form an antibody/SARS-CoV-2 virus complex when the antigen is present in the sample. The subject is diagnosed as being infected with a SARS-CoV-2 virus variant having the residue N501 and not N501Y, when the antibody/SARS-CoV-2 virus complex is detected. In one embodiment, the test further comprises a pan-SARS-CoV-2 specific antibody. In another aspect, a diagnostic composition is provided. The composition includes an antibody as described herein, conjugated to or associated with a detectable label. In yet another aspect, a transformed cell is provided, that expresses an antibody as described herein. In another aspect, a diagnostic kit for the diagnosis of a SARS-CoV-2 variant is provided. The diagnostic kit includes an antibody as described herein, conjugated to or associated with a detectable label. In certain embodiments, the kit includes a pan-SARS- CoV-2 specific antibody, conjugated to or associated with a detectable label. In another aspect, a pharmaceutical composition is provided. The composition includes an antibody as described herein, and a pharmaceutically acceptable carrier. In certain embodiments, the composition includes a second therapeutic agent. In yet another aspect, a method of preventing or treating a SARS-CoV-2 viral infection or COVID19 in a subject in need thereof is provided. The method includes administering to the subject a therapeutically effective amount of the composition that includes an antibody as described herein. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1A – FIG.1D show SARS-CoV-2 L strain (Wuhan-Hu-1) spike binding by the 2E8 human mAb. (FIG.1A) The 2E8 mAb binding in a direct ELISA to SARS-CoV-2 antigens: S1, S1 D614G, and nucleocapsid (Sino Biologicals); spike-pseudotyped VSV particles; and a recombinant S1 trimer. Samples were tested in triplicate. Error bars = S.E.M. (not visible due to minimal differences). (FIG.1B) S1 binding to 293T-hsACE2 cells in the presence of 2E8, 4G1 (isotype control IgG), CR3022, CB6, and an ACE2-Fc fusion protein was assessed by flow cytometry. S1 cell binding, x-axis; IgG binding, y-axis. (FIG.1C) Pseudovirus neutralization assay.293T-hsACE2 cells were transduced with SARS-CoV-2 luciferase (Wuhan-Hu-1 strain) reporter viral particles (RVPs) in the presence of the mAbs, 6A (isotype control IgG), CR3022, 2E8, and CB6, and a polyclonal IgG isolated from the 2E8 B cell donor (P24). Normalized percent infection is shown; samples were tested in triplicate. Error bars = S.E.M. (FIG.1D) SPR analysis of 2E8 binding to the spike S1 domain, performed on the Nicoya OpenSPR™; KD = 7.38 ± 0.58 nM. FIG.2A – FIG.2D show epitope binning for 2E8 on the SARS-CoV-2 S1 and RBD. We performed competition binding assays to test 2E8 binding in the presence of the CR3022, CB6, and the murine anti-S1 mAb. L-type spike (FIG.2A, FIG.2C) or RBD (FIG.2B, FIG. 2D) was captured on the plate and binding of biotinylated 2E8, or the anti-spike murine mAb was tested in the presence of non-biotinylated competitor mAbs. FIG.3A – FIG.3C show differential recognition of SARS-CoV-2 variant spike antigen by direct ELISA. The 2E8 (FIG.3A), CB6 (FIG.3B), and the mouse anti-S1 mAb (FIG.3C) were tested for binding to spike antigens adhered to an ELISA plate: L RBD (Wuhan-Hu-1), α S1 (B.1.1.7), β S1 (B.1.351), γ S1 (P.1), δ RBD (B.1.617.2), K417N RBD, κ RBD (B.1.617.1), ε S1 (B.1.429). Error bars = S.E.M. FIG.4A – FIG.4B show differential recognition of SARS-CoV-2 variant spike antigens using a sandwich ELISA with human mAbs. The mAbs were adhered to the ELISA plate and tested for capture of soluble spike antigen. Bound antigen was detected with the mouse anti-S1 mAb. (FIG.4A) Both 2E8 and CB6 are compared (left and right columns, respectively, for each variant). (FIG.4B) An anti-His tag capture antibody was used as a positive control. Antigens used (same as FIG.3A – FIG.3C): L RBD (Wuhan-Hu-1), α S1 (B.1.1.7), β S1 (B.1.351), γ S1 (P.1), δ RBD (B.1.617.2), K417N RBD, κ RBD (B.1.617.1), ε S1 (B.1.429). FIG.5 shows a full immobilization sequence of the SARS-CoV-2 S1 domain. The antigen was adhered via a His-tag onto an NTA Sensor in Active (Channel 2). A control His- Streptavidin was used Reference Channel 1.20 ug/ml for each protein resulted in matching levels of ligand density on the sensor surface at the end of immobilization. FIG.6 shows anti-spike antibody 2E8 binding to the immobilized S1 domain. The initial non-specific binding (NSB) test on the NTA sensor is performed with PBST supplemented with 0.1% BSA to reduce non-specific binding. Decreasing concentrations are displayed, starting with the highest concentration at the top. FIG.7A – FIG.7C show pseudotyped VSV-G:S1 and S1 trimer antigens. (FIG.7A) SDS:PAGE demonstrating proteins contained in the VSV-G:S1 pseudotyped particles. Detergent-solubilized G:Sa protein is shown for comparison. (FIG.7B) SDS:PAGE of the S1 trimer, analyzed as reduced and non-reduced (NR) samples. (FIG.7C) Map of the gene encoding the S1 trimer. FIG.8A and FIG.8B provide the heavy chain (FIG.8A; SEQ ID NO: 1) and light chain (FIG.8B; SEQ ID NO: 8) variable region sequences for the 2E8 mAb, including CDRs and framework regions. FIG.9A and FIG.9B provide an overview of a solid support diagnostic device having sequentially arranged reaction zones. DETAILED DESCRIPTION The present invention comprises antibodies, compositions, and methods useful for detection of specific SARS-CoV-2 variants by detecting variant specific antigens. The described antibodies are useful as a component of antigen-detection rapid diagnostic tests (Ag-RDTs) that can be used in point-of-care and repeat testing situations to diagnose active COVID-19 cases in 15-30 minutes. Described herein, in one embodiment is a monoclonal antibody, designated as 2E8, that specifically binds to SARS-CoV-2 spike protein that contain an aspargine at position 501 (N501) and does not bind to SARS-CoV-2 spike proteins that contain a common mutation that occurs in many variants of concern (N501Y). The mAb 2E8 is useful in compositions, methods, and kits to immediately detect cases of variants that contain the N501Y mutation within the current background of delta (B.1.617.2) global predominance. Twenty-five Ag- RDTs have been granted an EUA by the FDA. None of these are antigen specific. The mAbs described in the present invention could be adapted by these companies to produce variant- specific Ag-RDTs. Technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and by reference to published texts, which provide one skilled in the art with a general guide to many of the terms used in the present application. The definitions contained in this specification are provided for clarity in describing the components and compositions herein and are not intended to limit the claimed invention. The terms “a” or “an” refers to one or more. For example, “an expression cassette” is understood to represent one or more such cassettes. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein. As used herein, the term “about” means a variability of plus or minus 10 % from the reference given, unless otherwise specified. The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively, i.e., to include other unspecified components or process steps. The words “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively, i.e., to exclude components or steps not specifically recited. An “antibody” or “antibody molecule” is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. In one embodiment, antibody or antibody molecule contemplates intact immunoglobulin molecules, immunologically active portions of an immunoglobulin molecule, and fusions of immunologically active portions of an immunoglobulin molecule. The antibodies described herein are capable of specifically complexing with, binding to, identifying or detecting an epitope of an antigen, e.g., SARS-CoV-2 spike variants with N501 but not N501Y. Unless otherwise indicated, the term “antibody” includes, in addition to antibodies comprising two full-length heavy chains (each chain comprising a variable region and a constant region) and two full-length light chains (each chain comprising a variable region and a constant region), modifications, antigen or epitope binding fragments, as well as “antibody mimics” or “antibody equivalents” or muteins thereof. In one embodiment, an “antibody” refers to an intact immunoglobulin, such as an IgA, IgD, IgE, IgG, and IgM, or to an antigen binding portion thereof that competes with the intact antibody for specific binding, unless otherwise specified. In one embodiment, an intact antibody is an IgG1, IgG2, IgG3 or IgG4. Heavy and light chain variable domain sequences and CDRs may be selected from those described herein, including in those provided in FIG.8A and FIG.8B and the in the Sequence Listing, e.g., SEQ ID NOs: 1-26. As used herein, an “antibody” or “antigen/epitope binding fragment” as described herein refers to an anti-SARS-CoV-2 spike protein antibody designated 2E8 or fragment thereof based upon the sequences defined herein. Such an antibody or fragment includes a monoclonal antibody, a synthetic antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, a multi-specific binding construct that can bind two or more epitopes, a dual specific antibody, a bi-specific antibody, a multi-specific antibody, an affinity matured antibody, a single antibody chain or an scFv fragment, a diabody, a single chain comprising complementary scFvs (tandem scFvs) or bispecific tandem scFvs, an Fv construct, a disulfide-linked Fv, a Fab construct, a Fab' construct, a F(ab')2 construct, an Fc construct, a monovalent or bivalent construct from which domains non-essential to monoclonal antibody function have been removed, a single-chain molecule containing one V_L (variable region of light chain), one V_H (variable region of heavy chain) antigen-binding domain, and one or two constant “effector” domains optionally connected by linker domains, a univalent antibody lacking a hinge region, a single domain antibody, a dual variable domain immunoglobulin (DVD-Ig) binding protein or a nanobody, or any recombinant versions thereof. Definitions and examples of these types of structures are found in the art and in, e.g., US Patent No.9,902,772, incorporated by reference herein. “Recombinant antibody” refers to an antibody that is expressed from a cell or cell line transfected with one or more expression vectors comprising a coding sequence of the antibody, where said coding sequence is not naturally associated with the cell or naturally occurred in the cell. Said cell may be termed as a host cell. In certain embodiments, the host cell may be a non-human cell or non-human cell line. In certain embodiments, the host cell may be a non-mammalian cell or cell line, for example, an insect cell or cell line, a yeast cell or cell line, or an E coli cell or cell line. In certain embodiments, the host cell may be a mammalian cell or cell line. In certain embodiments, the host cell may be a non-human mammalian cell or cell line. In certain embodiments, the host cell may be a human cell or cell line, for example a human embryonic kidney 293 cells or a hybridoma cell or cell line. In one embodiment, a recombinant antibody has a glycosylation pattern that is different than the glycosylation pattern of an antibody having the same sequence if it were to exist in nature. In one embodiment, a recombinant antibody is expressed in a mammalian host cell which is not a human host cell. Notably, individual mammalian host cells have unique glycosylation patterns. In certain embodiments, the antibody is produced using the on-cell mAb screening system described by Puligedda et al, MAbs, 2019 Apr;11(3):546-558. doi: 10.1080/19420862.2019.1574520. Epub 2019 Feb 22, which is incorporated herein by reference. Methods for producing such antibodies are well-known in the art. Indeed, commercial vectors for certain antibody and antibody fragment constructs are available. The antibody may also be a protein (e.g., a fusion protein) comprising at least one antibody or antibody fragment. In an embodiment, the antibody comprises an Fc region. In particular embodiments, these anti- antibodies and fragments thereof have a binding affinity (Ka) for an epitope of at least 10³M. In other embodiments, the antigen binding proteins exhibit a Ka of at least 10³ M, at least 10⁴ M, at least 10⁵ M, or at least 10⁶ M. As used herein, an “antibody mimic” or an “antibody equivalent” refers to a molecule (for example, an amino acid sequence, a protein, or a modified or conjugated version thereof). For example, affibodies, i.e., a class of engineered affinity proteins, generally small (~6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given target, aptamers, polypeptide molecules that bind to a specific target, an affilin, an affitin, an affimer, an alphabody, an anticalin, an avimer, a DARPin (designed ankyrin repeat proteins), a Fynomer, a Kunitz domain peptide, a monobody, a peptabody and others known in the art. As used herein, a “modification” of an amino acid sequence (e.g., antibody or a fragment thereof) comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from, or substituted into the reference amino acid sequence, e.g., any of amino acid sequence encoding the variable light or heavy chains, and/or CDRs of antibody 2E8. One such modification is the replacement of one amino acid in such a sequence, e.g., any of SEQ ID NO: 1 to 26, with a conservative amino acid. Other modifications include, for example, fusion proteins formed by fusing the heavy chain of a selected antibody into an Ig backbone. Still another modification includes an antibody that has been modified via conjugation to another chemical moiety (such as, for example, polyethylene glycol or albumin, e.g., human serum albumin), or a post-translational modification, such as phosphorylation, glycosylation, acylation, acetylation, formylation, alkylation, amidation, arginylation, polyglutamylation, polyglycylation, butyrylation, gamma- carboxylation, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester or phosphoramidate, propionylation, pyroglutamate formation, S- glutathionylation, S-nitrosylation, S-sulfinylation, S-sulfonylation, succinylation addition of a succinyl group to lysine, and sulfation. In another embodiment, a modification of antibody 2E8 is a single chain human antibody, having a variable domain region from a heavy chain and a variable domain region from a light chain and a peptide linker connecting the heavy chain and light chain variable domain regions. As used herein, an antibody construct (e.g., an antibody, an antibody heavy chain, an antibody light chain, or any fragment or modification thereof) comprises three Complementarity-Determining Regions (CDRs, also known as HV, hypervariable regions, namely CDR1, CDR2, CDR3, from N-terminal to C-terminal, or 5’ to 3’ when corresponding nucleic acid sequence is referenced), and four framework regions (FRs, namely FR1, FR2, FR3 and FR4, from N-terminal to C-terminal, or 5’ to 3’ when corresponding nucleic acid sequence is referenced). See, e.g., Janeway, Charles A Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J (2001). Immunobiology: The Immune System in Health and Disease (5 ed.). New York: Garland Science. ISBN 0-8153-3642-X, which is incorporated herein by its entirety. It would be understood that in the antibody construct, CDRs are arranged non- consecutively, not immediately adjacent to each other, and may be separated by an FR. As part of the variable chain in an antibody construct and T cell receptors generated by B-cells and T-cells respectively, CDRs are where an antigen specifically binds. In certain embodiments, the antibody has one or more of the CDRs set forth in the table below. In some embodiments, the antibody has 1, 2, or all three of the CDRs from the heavy chain. In some embodiments, the antibody has 1, 2, or all three of the CDRs from the light chain. In some embodiments, the antibody has all 6 CDRs as described below. Table 1: 2E8 Antibody Variable Chain CDRs

It would be understood by one of skill in the art that the antibody constructs, fragments or modifications, and CDR described herein may be used in any embodiment, composition, reagent, or method, including those also described herein. It would also be understood that an antibody, antibody construct, fragment or modification provided herein may comprise an FR or a non-CDR J-region, other than those identified provided in the incorporated Sequence Listing. Such an antibody, antibody construct, fragment or modification may have a binding affinity and/or specificity to its SARS-CoV2 spike protein epitope or antigen at about 20%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 97%, about 99%, about 100%, more than about 100%, about 200%, about 300%, or about 500% of that of any antibody constructs described in this specification. Conventional methods, including enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), MSD assay, and antibody phage display library, may be used to determine such binding affinity and/or specificity. As used herein, the term “immunologically specific” refers to proteins or polypeptides, particularly antibodies, that bind to one or more epitopes of a protein or compound of interest, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic biological molecules. An “epitope” as used herein refers to the portion of a SARS-CoV2 spike protein or any naturally occurring or synthetic or recombinant amino acid sequence that is capable of specifically complexing with one or more of the antibodies or fragments or modified antibodies, as described herein. An epitope can comprise non-contiguous portions of the molecule (e.g., in a polypeptide, amino acid residues that are not contiguous in the polypeptide's primary sequence but that, in the context of the polypeptide's tertiary and quaternary structure, are near enough to each other to be bound by an antigen binding protein). In one embodiment, the epitope to which an anti-SARS-CoV2 spike protein antibody as described herein binds includes the residue N501 but not N501Y. See, Liu, H., Zhang, Q., Wei, P. et al. The basis of a more contagious 501Y.V1 variant of SARS-CoV-2. Cell Res 31, 720–722 (April 2021), which is incorporated herein by reference. The terms “percent (%) identity”, “sequence identity”, “percent sequence identity”, or “percent identical” in the context of amino acid sequences or nucleotide sequences refers to the residues in the two sequences which are the same when aligned for correspondence. Percent identity may be readily determined for amino acid sequences or nucleotide sequences over the full-length of a protein, polypeptide, or encoding region thereof, e.g., about 15 amino acids, about 150 amino acids, or a peptide fragment thereof or the corresponding nucleic acid sequence coding sequences. A suitable amino acid fragment may be at least about 4 amino acids in length and may be up to about 200 or up to about 700 amino acids or nucleotide fragments of from about 12 nucleotides to about 600 to 2100 nucleotides. Generally, when referring to “identity”, “homology”, or “similarity” between two different sequences, “identity”, “homology” or “similarity” is determined in reference to “aligned” sequences. “Aligned” sequences or “alignments” refer to multiple nucleic acid sequences or protein (amino acids) sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Alignments are performed using any of a variety of publicly or commercially available Multiple Sequence Alignment Programs. Sequence alignment programs are available for amino acid sequences, e.g., the “Clustal Omega”, “Clustal X”, “MAP”, “PIMA”, “MSA”, “BLOCKMAKER”, “MEME”, and “Match-Box” programs. Generally, any of these programs are used at default settings, although one of skill in the art can alter these settings as needed. Alternatively, one of skill in the art can utilize another algorithm or computer program which provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. See, e.g., (THOMPSON et al.1999). As used herein, the “conservative amino acid replacement” or “conservative amino acid substitutions” refers to a change, replacement or substitution of an amino acid to a different amino acid with similar biochemical properties (e.g., charge, hydrophobicity and size), which is known by practitioners of the art. Also see, e.g., FRENCH et al.1983, and YAMPOLSKY et al.2005. In certain embodiments, a CDR of the disclosed antibody or fragment thereof is free of conservative amino acid replacement. “Patient” or “subject” or “host” as used herein means a male or female mammalian animal, including a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research. In one embodiment, the subject of these methods and compositions is a human. The term “prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition resulting in a decrease in the probability that the subject will develop the condition. The term “treat” as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, or reduction in severity of the disease and its symptoms. As used herein, “disease”, “disorder” and “condition” are used interchangeably, to indicate an abnormal state in a subject. A “therapeutically effective amount” of a compound or a pharmaceutical composition refers to an amount effective to prevent, inhibit, treat, or lessen the symptoms of a particular disorder or disease. “Pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. A “carrier” refers to, for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described, for example, in “Remington's Pharmaceutical Sciences” by E.W. Martin. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. In general, the pharmaceutically acceptable carrier of the composition is selected from the group of diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. The compositions can include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). The compositions can also be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes or nanoparticles. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of the pharmaceutical composition described herein. As used herein, a “reaction zone” is defined as a region on the solid support of a diagnostic device containing predetermined concentrations of capture antibodies, attached to the solid support, each capture antibody capable of recognizing and binding a distinct epitope of a test protein or antigen (i.e., SARS-CoV-2 spike protein). As discussed herein, the reaction zone can be any designated region or portion of a membrane strip, or it can be in a container such as a test tube, or it can consist of a well in a microtiter plate. The reaction zone provides a specific location for detecting the presence and range of concentration of an antigen in a biological sample. As used herein, a “reagent zone” is defined as a region of a diagnostic device as described herein containing a mixture of incubation antibodies that are identical in type to the capture antibodies in the reaction zone, and a detection antibody. The reagent zone is preferably provided on the device as a designated region or portion of a membrane strip. Alternatively, the reagent zone is separate from the solid support containing the reaction zones for example, in a container such as a test tube or as a well in a microtiter plate. A test protein or antigen (i.e., SARS-CoV-2 spike protein in a sample is exposed to the reagent zone prior to being exposed to any reaction zone. The reagent zone is typically formed using an incubation solution containing incubation antibodies and other reagents, such as inert proteins and non-ionic detergent, to solubilize the test antigen and antibodies, and to reduce non- specific binding of the test antigen and antibodies. As used herein, a “capture antibody” is defined as an antibody, attached to the solid support of the device of the invention in a reaction zone. Each capture antibody is selected to recognize and bind a particular, distinct epitope of the test protein or antigen (i.e., SARS- CoV-2 spike protein at a predetermined concentration, and is identical in type to an incubation antibody in the reagent zone. As used herein, a “detection antibody” is defined as an antibody, that recognizes and binds the test protein or antigen (i.e., SARS-CoV-2 spike protein) at a binding site or epitope distinct from that of the incubation and capture antibodies. The detection antibody is coupled to a detectable label such as a chromophore, enzyme, radioisotope, or colored particle, such as colloidal gold or color latex. Examples of enzymes include, but are not limited to, alkaline phosphatase, beta galactosidase, or horseradish peroxidase which produce color when incubated with the appropriate substrate. The concentration of detection antibody to use in the device of the invention is predetermined by conducting experiments to determine amounts of detection antibodies that are needed to provide a detectable signal. It should be understood that while various embodiments in the specification are presented using “comprising” language, under various circumstances, a related embodiment is also described using “consisting of” or “consisting essentially of” language. “Comprising” is a term meaning inclusive of other components or method steps. When “comprising” is used, it is to be understood that related embodiments include descriptions using the “consisting of” terminology, which excludes other components or method steps, and “consisting essentially of” terminology, which excludes any components or method steps that substantially change the nature of the embodiment or invention. With regard to the description of these inventions, it is intended that each of the compositions herein described, is useful, in another embodiment, in the methods of the invention. In addition, it is also intended that each of the compositions herein described as useful in the methods, is, in another embodiment, itself an embodiment of the invention. It is to be noted that the term “a” or “an”, refers to one or more, for example, “an antibody”, is understood to represent one or more antibody/antibodies. As such, the terms “a” (or “an”), “one or more,” and “at least one” is used interchangeably herein. As used herein, the term “about” means a variability of plus or minus 10 % from the reference given, unless otherwise specified. Unless defined otherwise in this specification, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and by reference to published texts, which provide one skilled in the art with a general guide to many of the terms used in the present application. Antibody 2E8 Provided herein is a monoclonal antibody, designated 2E8, that distinguishes between SARS-CoV-2 spike variants with N501 and N501Y. As this is one of the most important mutations found in SARS-CoV-2 spike proteins expressed by medically important variants, this mAb has utility for diagnosis of present and future SARS-CoV-2 strains. The antibody described (2E8) has anti-viral activity and is useful in the treatment of disease caused by N501 containing SARS-CoV-2. As used herein the term “2E8 antibody” may refer to the monoclonal antibody described herein derived from the hybridoma or antibodies that contain fragments derived from that sequence. As a non-limiting example, an ScFv having the variable heavy chain of the 2E8 monoclonal antibody and the variable light chain of the 2E8 monoclonal antibody may be referred to herein as the 2E8 antibody. Recombinant, synthetic, monoclonal or other antibodies or fragments that bind to one or more SARS-CoV2 spike protein epitopes that include the residue N501 include, in one embodiment a heavy chain variable domain SEQ ID NO: 14 and/or light chain variable domain sequence SEQ ID NO: 21 (antibody 2E8), or sequences at least 80% (for example, about 85%, about 86%, about 87% about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100%) identical thereto. In certain embodiments, antibodies or fragments that bind to one or more SARS-CoV2 spike protein epitopes that include the residue N501 include any one or two or all three CDRs of the heavy chain of antibody 2E8. In certain embodiments, antibodies or fragments that bind to one or more epitopes that include the residue N501 include any one or two or all three CDRs of the light chain of antibody 2E8. In certain embodiments, antibodies or fragments that bind to one or more epitopes that include the residue N501 include any one or two or three or four or five or all six CDRs of antibody 2E8. In certain embodiments, the nucleic acid sequence is suitable for expression of the antibodies or fragments thereof in a host cell. Fragments of antibody 2E8 heavy chain nucleotide sequence SEQ ID NO: 1 and amino acid sequence SEQ ID NO: 14 include those sequences identified in the table below. Table 2: Heavy Chain Variable Sequence of mAb 2E8

Fragments of antibody 2E8 light chain nucleotide sequence SEQ ID NO: 8 and amino acid sequence SEQ ID NO: 21 include those sequences identified in the table below. Table 3: Light Chain Variable Sequence of mAb 2E8

The antibodies and antibody constructs may be further modified from those exemplified. In a particular embodiment, the domains of the antibody or antibody fragment have at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology or identity with the domains present in the anti- monoclonal antibody 2E8, and illustrated in the sequences identified in herein, in the Sequence Listing, and the tables above. The domains in the tables may be longer or shorter than the domains identified in the tables by about 1, 2, 3, 4, or 5, amino acids, particularly 1 or 2 amino acids, at the N terminus and/or C-terminus of the domain. The domains may be encoded by nucleotide sequences longer or shorter than those in the Sequence listings by 3, 6, 9, 12, or 15 nucleotides, particularly 3 or 6 nucleotides, at the 5’ terminus and/or 3’ terminus of the sequence encoding a domain. In certain embodiments, the CDR of an antibody can be determined by one of skill in the art, for example, via various databases, software, or algorithms. See, www.imgt.org. In certain embodiments, the CDRs are illustrated in FIG.8A and FIG.8B as well as provided in Table 2 and Table 3. In certain embodiments, the CDRs comprises one or two or three or four or five or six more or less amino acids at the N-terminal side and/or C-terminal side of the CDRs as illustrated herein. In certain embodiments, the CDRs are shifted toward the N- terminal side or the C-terminal side by one or two or three or four or five or six or seven or eight or nine or ten amino acid(s) compared to the ones as illustrated in FIG.8A and FIG.8B and provided in Table 2 and Table 3. In one embodiment of a modification, the antibodies may be converted into a non- human immunoglobulin format. In a particular embodiment, the selected sequences of the heavy or light chains of any of the antibodies disclosed herein (or a portion thereof) are inserted into the backbone of a non-human antibody or antibody fragment construct. For example, the variable light domain and/or variable heavy domain of the antibodies described herein may be inserted into another antibody construct. Still another embodiment comprises a fully human Fab antibody fragment having a heavy chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 14; or having a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 21 or combinations thereof. Still other modifications of the antibodies are single chain antibodies having a heavy chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 14, and a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 21, and combinations thereof, with a peptide linker connecting the heavy and light chains. These same combinations can be generated by use of the corresponding chain encoding nucleotide sequences or sequences having at least 80, 85, 90, 95 or 99% identity thereto. The production of antibodies or fragments that specifically bind to a SARS-CoV2 spike protein epitope that include the residue N501, can utilize any of the amino acid sequences of the heavy chain and light chain variable regions, or the nucleotide sequences encoding same, i.e., SEQ ID NOs: 1 to 21, or the other fragments of the antibodies identified herein, including epitope binding fragments, or modifications thereof as described. In one embodiment, polyclonal antibody compositions are typically produced by immunizing a selected mammal, e.g., a primate, rodent, or human, with a peptide/ polypeptide composition containing a specific epitope. The selection of high titer, high affinity polyclonal antibodies can be monitored by standard techniques, such as with an enzyme-linked immunosorbent assay and surface plasma resonance. If desired, the polyclonal antibody molecules can be isolated from the mammal, e.g., from the whole blood, plasma or serum, and further purified from the plasma or serum of the immunized mammal by conventional techniques. Conventional harvesting techniques can include plasmapheresis, protein A and G chromatography, among others. Such polyclonal antibody compositions may themselves be employed as pharmaceutical compositions as described herein. In another embodiment, monoclonal antibodies are made by now conventional techniques, using antibody producing cells obtained from the immunized mammals and fused to non-IgG-producing myeloma cells to form hybridomas or from selection from activated immune B cells with extraction by known molecular biological techniques. These monoclonal antibodies can be further used to prepare other forms of antibodies, e.g., chimeric antibodies, humanized antibodies, human antibodies. Other antibody fragments or ligands can be produced by screening phage display libraries, antibody fragments and mixtures thereof. Techniques for generating these types of antibodies and ligands are well-known in the art and the ligands themselves may be generated using the disclosed amino acid sequences of the above-identified epitopes. Chimeric antibodies may similarly be developed using known techniques. Chimeric antibodies are molecules in which different portions are derived from different animal species. Single chain antibodies may also be prepared by conventional methods, such as described in US Patent Nos.4,946,778 and 4,704,692 using the variable portions of the polyclonal or monoclonal antibodies produced according to this invention. The production of bi-specific antibodies or ligands that specifically bind to two or more selected epitopes, can employ conventional techniques. See, e.g., Hornig N, Färber- Schwarz A., “Production of bispecific antibodies: diabodies and tandem scFv.”, 2012, Methods Mol Biol., 907:713-27; Speiss, C. et al, Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies, Jul 7, 2013, Nature Biotechnology, 31:753-758; and Jonathan S Martin and Zhenping Zhu, “Recombinant approaches to IgG-like bispecific antibodies”, 2005 Acta Pharmacologica Sinica, 26: 649– 658. The availability of nucleic acid molecules encoding the heavy and light chains of a SARS-CoV2 spike protein antibody also enables production of a recombinant antibody, fragment or modification using in vitro expression methods and cell-free expression systems known in the art. In vitro transcription and translation systems are commercially available, e.g., from Promega Biotech (Madison, WI) or Gibco-BRL (Gaithersburg, MD). The antibodies, epitope-binding fragments or modifications thereof may also be produced by expression in a suitable prokaryotic or eukaryotic system. Similarly modifications may be inserted by use of a variety of CRISPR techniques and other related, e.g., zinc finger, methodologies for modifying amino acid and nucleotide sequences. Antibody recombinant engineering techniques are well-taught in the art including in publications, texts and reviews, such as Edwards, W. B., Xu, B., Akers, W., Cheney, P. P., Liang, K., Rogers, B. E., et al. (2008). Agonist-antagonist dilemma in molecular imaging: evaluation of a monomolecular multimodal imaging agent for the somatostatin receptor. Bioconjug. Chem.19, 192–200; Roque, A. C., Lowe, C. R., and Taipa, M. A. (2004). Antibodies and genetically engineered related molecules: production and purification. Biotechnol. Prog.20, 639–654; Smith, G. P. (1985). Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317; Saeed, AFUH et al, Antibody Engineering for Pursuing a Healthier Future, Front. Microbiol., 28 March 2017; 8:495; Green, MR and Sambrook, J., 2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, all incorporated herein by reference. The antibodies of the instant invention may also be conjugated/linked to other components. For example, the antibodies may be operably linked (e.g., covalently linked, optionally, through a linker) to at least one detectable agent, imaging agent, contrast agent, or therapeutic compound (e.g., see above). The antibodies of the instant invention may also comprise at least one purification tag (e.g., a His-tag). The antibody molecules of the invention may be prepared using a variety of methods known in the art. Polyclonal and monoclonal antibodies may be prepared as described in Current Protocols in Molecular Biology, Ausubel et al. eds. Antibodies may be prepared by chemical cross-linking, hybrid hybridoma techniques and by expression of recombinant antibody fragments expressed in host cells, such as bacteria or yeast cells. In one embodiment of the invention, the antibody molecules are produced by expression of recombinant antibody or antibody fragments in host cells. The nucleic acid molecules encoding the antibody may be inserted into expression vectors and introduced into host cells. The resulting antibody molecules are then isolated and purified from the expression system. The antibodies optionally comprise a purification tag by which the antibody can be purified. The purity of the antibody molecules of the invention may be assessed using standard methods known to those of skill in the art, including, but not limited to, ELISA, immunohistochemistry, ion-exchange chromatography, affinity chromatography, immobilized metal affinity chromatography (IMAC), size exclusion chromatography, polyacrylamide gel electrophoresis (PAGE), western blotting, surface plasmon resonance and mass spectroscopy. Still other antibody modifications employing the SEQ ID Nos disclosed herein, e.g., as taught by the techniques referenced in above-cited US Patent Publication No. US2019/0062452, incorporated by reference herein. Diagnostic Methods In another aspect, the anti-SARS-CoV-2 antibodies described herein are useful in diagnosing COVID-19 infection. Herein is described 2E8, a human antibody that binds the Wuhan-Hu-1 spike having N501 with high affinity, but does not bind variants containing the N501Y mutation. This mutation is shared among the Variants Being Monitored (VBMs) alpha, B.1.1.7, beta, B.1.351, gamma, P.1., and mu B.1.621. Given the global predominance of delta (B.1.167), which is bound by the 2E8, identifying of a SARS-CoV-2 strain that does not bind 2E8 will reveal an infection with a non-delta strain. The use of the 2E8 in an antigen diagnostic test (ADT) has immediate utility for monitoring the ingress of SARS-CoV-2 variants that do not contain this mutation. The residue recognized by the 2E8 antibody, N501, lies on the “right shoulder” of the RBD and is involved in hydrophobic interactions with ACE2 during receptor binding [Vazquez-Lombardi R., et al. Nat. Protoc.2018;13:99–117; Tursi S.A., et al., et al. Nat. Commun.2020;11:1007]. The N501Y mutation does not appear to globally alter the structure of the spike, rather, it allows tyrosine side-chain interactions that enhance ACE2 binding affinity that likely mediate the increased infectivity of N501Y-containing viruses [Vazquez- Lombardi R., et al. Nat. Protoc.2018;13:99–117; Tursi S.A., et al., et al. Nat. Commun.2020;11:1007]. Without wishing to be bound by theory, this may explain why the 2E8 is sensitive to a single residue change and not affected by the other RBD mutations. The 2E8 binds the same epitope on the spike, but with interactions that make it useful for variant detection. The 2E8 binding site overlaps the CB6 site, yet its binding is not affected by changes at K417, and CB6 binding is largely insensitive to the N501Y change [Zahradnik J., et al. Nat. Microbiol.2021;6:1188–1198]. This highlights the structural independence of these two epitopes in the variant RBDs. In one embodiment, a method of detecting, or screening for, a SARS-CoV-2 infection in a subject. The method includes contacting a sample from the subject with a 2E8 antibody, as described herein, wherein, in the presence of a SARS-CoV-2 spike protein having the N501 residue, binds the same, and detecting the bound complex. As used herein, the term “sample” includes any product produced by a subject, or a product derived therefrom. A sample may be taken from any tissue or bodily fluid, e.g., a blood sample (including blood- derived samples), serum sample, lymph sample, saliva sample, synovial fluid sample, phlegm, nasal swab, etc. A blood-derived sample may be a selected fraction of a patient's blood, e.g., a selected cell-containing fraction, or a plasma or serum fraction. In certain embodiments, the sample is a nasal swab. In certain embodiments, the antibodies are useful in an assay, such as an immunoassay, for detecting or typing a SARS-CoV-2 infection in a subject. In one embodiment, the immunoassay is an ELISA, or “sandwich assay”. Methods of performing sandwich assays are known in the art. For example, one antibody is coupled to a solid support, and a second antibody is coupled to a detectable label. A test antigen having separate binding sites (epitopes) for the first and second antibodies is exposed to the antibody coupled to the solid support such that the antigen binds to that antibody. Subsequently, the labeled second antibody is added to the support to permit the binding of the labeled second antibody to the test antigen. Thus, the amount of the antigen present in a sample is a function of the amount of detected label bound to the second antibody bound to the antigen. Examples of such detectable labels include chromophores, radioisotopes, or enzymes which can be converted into a product that can be measured photometrically. The 2E8 antibodies may be used alone, or in conjunction with other antibodies, in sandwich and other types of assays, to provide a specific diagnosis of the SARS-CoV-2 variant in a clinical sample. For example, referring to Table 5 below, the 2E8 antibody binds the SARS-CoV-2 delta strain, but not alpha, beta, or gamma. The 2E8 antibody may be used in conjunction with a second antibody that can be used as a positive control for the presence of SARS-CoV-2, in which the second antibody binds SARS-CoV-2 spike protein regardless of the amino acid at position 501. An example here is the anti 6XHIS tag antibody, which binds a polypeptide tag appended to the N terminus of the recombinant spike proteins tested. In a clinical test for detection of SARS-CoV-2 virions (which do not express a 6XHIS tag) any of a number of pan-SARS-CoV-2 specific antibodies could be used that are known to be state of the art. For additional differentiation among SARS-CoV-2 variants, VOCs, VBMs, etc. an additional mAb could be used. An example shown in the instant invention is CB6, which binds alpha and gamma strains, but not beta, and therefore differentiates among the N501Y mutated strains by providing specific binding to B.1.1.7 and P.1, but no binding to B.1.351. Many other mAbs known to the state of the art could be combined in a 2E8-based testing strategy to create rapid antigen diagnostic tests for diagnosis of SARS-CoV-2 variants in point-of-care testing and epidemiological surveillance. Various ADTs have been granted Emergency Use Authorization in the US. These include those in Table 4 below. The 2E8 antibody is useful with the ADTs shown in the table. Table 4: ADTs granted Emergency Use Authorization

In one embodiment, the antibody is useful in an ADT. The ADT, in certain embodiments, includes a diagnostic device that includes a solid support, such as a membrane strip, having a plurality of sequentially arranged reaction zones, and preferably, at least one reagent zone (FIG.9A, FIG.9B, well A). The membrane strip may be made of synthetic or natural materials, such as polystyrene, nylon, nitrocellulose membrane, or filter paper. The reaction zones contain capture antibodies that bind epitopes of a SARS-CoV-2 spike protein. In one embodiment, the strip contains one reaction zone, that contains the 2E8 antibody as the capture antibody. In another embodiment, the strip contains at least one additional reaction zone, wherein one of the additional reaction zones includes a capture antibody that binds alpha and gamma strains, but not beta or delta. In another embodiment, the strip contains at least one additional reaction zone, wherein one of the additional reaction zones includes a capture antibody that presumptively binds all strains of SARS-CoV-2. The solid support permits a solution containing the sample being assayed to be transferred to each of the reaction zones by diffusion, or by physical means, such as pipetting (FIG.9A and FIG.9B). Other suitable solid supports include, but are not limited to, microtiter plates, chromatographic membranes, or other immunoassay devices such as silica chips (Affmatrix, Palo Alto, Calif.). In certain embodiments, such as those shown in FIG.9A and FIG.9B, the 2E8 capture antibody is attached at the first reaction zone (well B), the C6B capture antibody is attached at the second reaction zone (well C), and a capture antibody that presumptively binds all COVID-19 strains is attached at the third reaction zone. The capture antibodies are attached to the membrane strip, for example, by physical attachment as a result of the “stickiness” of the antibodies, or by chemical reaction coupling, so that they will not become soluble and detach when the membrane strip becomes wet. In other words, the capture antibodies can be understood to generally form a solid phase in the reaction zones. In some embodiments, the solid support is provided without a reagent zone, and the sample is administered directly into the first reaction zone, and optionally additional reaction zones. In some embodiments, the ADT includes a detection antibody. The detection antibody may be an antibody that binds to a different antigen on the SARS-CoV-2 spike protein. In other embodiments, the 2E8 antibody is biotinylated, and the antibody-antigen binding is detected with, e.g., a streptavidin-HRP conjugate. The reactions are then developed with OPD substrate. Other enzyme substrates are known in the art and useful herein and include, without limitation, TMB (3,3',5,5'-tetramethylbenzidine), ABTS (2,2'-Azinobis [3- ethylbenzothiazoline-6-sulfonic acid]-diammonium salt, OPD (o-phenylenediamine dihydrochloride), PNPP (p-Nitrophenyl Phosphate), ONPG (o-nitrophenyl-β-D- galactopyranoside). Useful enzymes include, without limitation, horseradish peroxidase and alkaline phosphatase. The incubation solution used to form the reagent zone also contains inert proteins, such as bovine serum albumin (BSA); and a non-ionic detergent, such as Tween-20®. In addition, the incubation solution can include other components, such as casein, gelatin, nonfat dry milk, ovalbumin, polyvinyl pyrrolidone, polyvinyl alcohol, or animal serum components including bovine IgG, murine IgG, and goat IgG, to improve the usability and performance of the device of the invention. The particular components, in addition to the incubation and detection antibodies, used in the incubation solution and their concentrations vary depending on the antigen being tested and the experimental conditions of the assay. The components are preferably chosen based on results of empirical test experiments. The components are selected to optimize the results obtained with the device of the invention, for example, components are preferably chosen to increase the intensity and contrast of antigen specific staining, and minimize background staining, thereby optimizing the signal to noise ratio of the device of the invention. The incubation solution is prepared by mixing the foregoing components in a buffer solution, such as phosphate buffered saline (PBS). In certain embodiments, the reagent zone is generated by placing a volume (e.g., 10 μl) of the incubation solution onto the membrane strip near one end, and allowing the incubation solution to dry for transport and/or storage before use. Due to the presence of reagents, such as the inert proteins and Tween-20, the incubation and detection antibodies become soluble to facilitate diffusion of the antibody/antigen complexes to the sequentially arranged reaction zones as the membrane becomes wet during the course of the assay. Pharmaceutical Compositions Compositions comprising at least one anti-SARS CoV-22E8 antibody are also described herein. In a particular embodiment, the composition comprises at least one anti- SARS CoV-22E8 antibody or antibody fragment that binds a spike protein epitope having the residue N501, as described herein, and at least one pharmaceutically acceptable carrier. The composition may further comprise at least one other therapeutic compound for the inhibition, treatment, and/or prevention of COVID-19. Alternatively, at least one other therapeutic compound may be contained within a separate composition(s) with at least one pharmaceutically acceptable carrier. The present invention also encompasses kits comprising a first composition comprising at least one anti-SARS CoV-2 antibody or antibody fragment and a second composition comprising at least one other therapeutic compound for the inhibition, treatment, and/or prevention of COVID-19, as known in the art, and further described herein. The first and second compositions may further comprise at least one pharmaceutically acceptable carrier. As explained hereinabove, the compositions of the instant invention are useful for treating autoantibody related diseases or disorders. A therapeutically effective amount of the composition may be administered to the subject. The dosages, methods, and times of administration are readily determinable by persons skilled in the art, given the teachings provided herein. In yet another aspect, a pharmaceutical composition for the treatment of COVID-19 comprises at least one antibody or epitope-binding fragment as described above and a pharmaceutically acceptable carrier. In one embodiment, the composition contains one or more antibodies, as described above. In another embodiment, the composition contains a fragment or other of the above-noted modifications of one or more of these antibodies. In still another embodiment, the pharmaceutical composition comprises one of more of a heavy chain variable domain sequence of SEQ ID NOs: 14, or a sequence having at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to one of the sequences; or having a light chain variable domain sequence at least 80, 85, 90, 95 or 99% identity to an amino acid sequence of SEQ ID NO: 21, or combinations thereof. Other pharmaceutical compositions can be generated by use of the corresponding chain encoding nucleotide sequences SEQ ID NOs: 8 and 1, or sequences having at least 80, 85, 90, 95 or 99% identity thereto, e.g., for delivery in vectors, viruses and the like. Still another pharmaceutical compositions contain a mixture of two or more of the antibodies or epitope binding antibody fragments as described above and a pharmaceutically acceptable carrier. In these compositions, the antibodies, fragments or modifications are present in an amount effective to bind a SARS-CoV-2 variant having an N501 residue and neutralize or inhibit the effect of the virus. In another embodiment, the composition contains a fragment or other of the above- noted modifications of one or more of these antibodies. In still another embodiment, the pharmaceutical composition comprises one of more of a heavy chain variable domain sequence identified herein, one of more of a light chain variable domain sequence identified herein, or a sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to one of these sequences, or a fragment or modification thereof. Suitable pharmaceutical carriers or excipients for such compositions include, without limitation, the diluent, adjuvant, excipient, auxiliary agent, carrier or vehicle with which an antibody, fragment or modification thereof is administered, as described above. Methods of Treatment The compositions comprising these anti-SARS-CoV-2 spike variant with N501 antibodies may be used in methods for the inhibition, prevention, and/or treatment of COVID-19. The methods comprise administering at least one anti-SARS-CoV-2 antibody to a subject. The methods of the instant invention may further comprise the administration of at least one other therapeutic for COVID-19. For example, the anti-SARS-CoV-2 antibodies may be co-administered with an anti-inflammatory agent and/or immunosuppressant. The agents administered to the subject may be contained within a composition comprising at least one pharmaceutically acceptable carrier. When more than one agent is being administered (e.g., anti-SARS-CoV-2 antibody with an additional therapeutic), the agents may be administered consecutively (before or after) and/or at the same time (concurrently). The agents may be administered in the same composition or in separate compositions. As stated hereinabove, the methods (and compositions) described herein comprise administering at least one antibody or antibody fragment which is immunologically specific for SARS-CoV-2 spike protein with N501 (anti-SARS-CoV-2 antibody) to a subject. In a particular embodiment, the anti-SARS-CoV-2 antibody is immunologically specific for SARS-CoV-2 spike protein with N501 to the exclusion of SARS-CoV-2 spike protein with N501Y. The antibodies, fragments and modifications of the anti-SARS-CoV-2 antibody described herein are useful in methods for treating COVID-19, that comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments. In another aspect, a method for treating a subject suspected of having COVID-19, comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments as described herein. In another aspect, a method for treating a subject with such a disease comprises administering an effective amount of a single antibody or epitope binding fragment or a mixture of antibodies or fragments as described herein. In one embodiment, the antibody comprises antibody 2E8 or fragments or modifications thereof. In another embodiment, the antibody comprises any of the heavy chain sequences of SEQ ID NOs: 14, an epitope binding fragment or a modification thereof. In another embodiment, the antibody comprises any of the light chain sequences of SEQ ID NOs: 21, an epitope binding fragment or a modification thereof. In one embodiment, the antibody and antibody fragment may comprise at least one domain from the 2E8 monoclonal antibody described herein. See FIG.8A and FIG.8B and Table 1 for the sequences of the heavy, chain, light chains, CDRs, framework regions, and encoding nucleic acid sequence of these above referenced antibodies. These exemplified sequences can be used to generate the same antibodies or modifications or fragments thereof. For example, the antibody or antibody fragment may comprise at least one, two, three, four, five, or all six complementarity-determining region (CDR) domains of the 2E8 monoclonal antibodies. In another embodiment, the antibody or antibody fragment may comprise CDRs from these antibodies. In an embodiment, the antibody or antibody fragment comprises at least one or both of the CDR3 domains. In an embodiment, the domains of the antibody or antibody fragment have at least 90%, 95%, 97%, 99%, or 100% homology or identity with the domains present in the anti-human IDO2 antibodies or modifications as discussed above. Suitable routes of administering the antibody compositions described herein (e.g., human monoclonal antibodies, multi-specific and bispecific molecules and immune- conjugates, fragments or modifications) are in vivo and in vitro are well known in the art and can be selected by those of ordinary skill. In one embodiment, the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous). Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition. In general, regulatory agencies require that a protein reagent to be used as a therapeutic is formulated so as to have acceptably low levels of pyrogens. Accordingly, therapeutic formulations will generally be distinguished from other formulations in that they are substantially pyrogen free, or at least contain no more than acceptable levels of pyrogen as determined by the appropriate regulatory agency (e.g., FDA). Therapeutic compositions may be administered with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be parenteral (e.g., intravenous, subcutaneous), oral, or topical, or intravenous, or by inhalation, as non-limiting examples. In addition, any gene therapy technique, using nucleic acids encoding the polypeptides of the invention, may be employed, such as naked DNA delivery, recombinant genes and vectors, cell-based delivery, including ex vivo manipulation of patients' cells, and the like. The concentration of the compound in the formulation varies depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration. The antibodies as described herein will generally be administered to a patient as a pharmaceutical preparation. The term “patient” as used herein refers to human or animal subjects. These antibodies may be employed therapeutically, under the guidance of a physician for the treatment of the indicated disease or disorder. The pharmaceutical preparation comprising the antibody molecules of the invention may be conveniently formulated for administration with an acceptable medium (e.g., pharmaceutically acceptable carrier) such as water, buffered saline, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), dimethyl sulfoxide (DMSO), oils, detergents, suspending agents or suitable mixtures thereof. The concentration of the agents in the chosen medium may be varied and the medium may be chosen based on the desired route of administration of the pharmaceutical preparation. Except insofar as any conventional media or agent is incompatible with the agents to be administered, its use in the pharmaceutical preparation is contemplated. The dose and dosage regimen of an antibody according to the invention that is suitable for administration to a particular patient may be determined by a physician considering the patient's age, sex, weight, general medical condition, and the specific condition and severity thereof for which the antibody is being administered. The physician may also consider the route of administration of the antibody, the pharmaceutical carrier with which the antibody may be combined, and the antibody's biological activity. Selection of a suitable pharmaceutical preparation depends upon the method of administration chosen. For example, the antibodies of the invention may be administered by direct injection into any desired tissue or into the surrounding area. In this instance, a pharmaceutical preparation comprises the antibody molecules dispersed in a medium that is compatible with the target tissue. Antibodies may also be administered parenterally, by intravenous injection into the blood stream, or by subcutaneous, intramuscular or intraperitoneal injection. Pharmaceutical preparations for parenteral injection are known in the art. If parenteral injection is selected as a method for administering the antibodies, steps must be taken to ensure that sufficient amounts of the molecules reach their target cells to exert a biological effect. The lipophilicity of the antibodies, or the pharmaceutical preparation in which they are delivered, may have to be increased so that the molecules can arrive at their target locations. Furthermore, the antibodies may have to be delivered in a cell-targeting carrier so that sufficient numbers of molecules will reach the target cells. Methods for increasing the lipophilicity of a molecule are known in the art. If a small form of the antibody is to be administered, including but not limited to a Fab fragment, a Dab, an scFv or a diabody, it may be conjugated to a second (carrier) molecule such as, but not limited to polyethylene glycol (PEG) or an albumin-binding antibody or peptide to prolong its retention in O blood. Pharmaceutical compositions containing an antibody of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral. In preparing the antibody in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. A pharmaceutical preparation of the invention may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment. Each dosage should contain a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier. Procedures for determining the appropriate dosage unit are well known to those skilled in the art. Dosage units may be proportionately increased or decreased based on the weight of the patient. Appropriate concentrations for alleviation of a particular pathological condition may be determined by dosage concentration curve calculations, as known in the art. The appropriate dosage unit for the administration of anti-SARS-CoV-2 antibody molecules may be determined by evaluating the toxicity of the antibody molecules in animal models. Various concentrations of antibody pharmaceutical preparations may be administered to murine models of the disease or disorder and the minimal and maximal dosages may be determined based on the results and side effects as a result of the treatment. Appropriate dosage unit may also be determined by assessing the efficacy of the antibody molecule treatment in combination with other standard drugs. The dosage units of anti-SARS-CoV-2 antibody molecules may be determined individually or in combination with another treatment. The pharmaceutical preparation comprising the anti-SARS-CoV-2 antibody molecules may be administered at appropriate intervals, for example, at least twice a day or more until the pathological symptoms are reduced or alleviated, after which the dosage may be reduced to a maintenance level. The appropriate interval in a particular case would normally depend on the condition of the patient. The methods of the instant invention may further comprise monitoring the disease or disorder in the subject after administration of the composition(s) described herein to monitor the efficacy of the method. Antibody Co-administration with other Therapies for COVID-19 and/or SARS-CoV-2 In one embodiment, a patient with an active infection of SARS-CoV-2 or a patient with COVID-19, receives a treatment comprising at least one of the antibodies described herein in addition to an antiviral therapy, such as molnupiravir (Merck & Co., Inc. and Ridgeback Biotherapeutics) or remdesivir (Gilead Sciences, Inc.). In yet another embodiment, a patient with an active infection of SARS-CoV-2 or COVID-19 receives a treatment comprising at least one of the antibodies described herein in addition to at least one anti-inflammatory agent, such as tocilizumab (Genentech USA, Inc.) and lenzilumab (Humanigen, Inc.). In another embodiment, a patient with an active infection of SARS-CoV- 2 or COVID-19 receives a treatment comprising at least one of the antibodies described herein in addition to at least one steroid, such as glucocorticosteroids, methylprednisolone, and dexamethasone. Other anti-inflammatory agents include, without limitation, non- steroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin, ibuprofen, naproxen, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ketoprofen, ketorolac, carprofen, fenoprofen, mefenamic acid, piroxicam, meloxicam, methotrexate, celecoxib, valdecoxib, parecoxib, etoricoxib, and nimesulide ), corticosteroids (e.g., prednisone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, tramcinolone, and fluticasone), rapamycin, acetaminophen, glucocorticoids, steroids, beta- agonists, anticholinergic agents, methyl xanthines, gold injections (e.g., sodium aurothiomalate), sulphasalazine, and dapsone. In another embodiment, a patient with an active infection of SARS-CoV-2 or COVID-19 receives a treatment comprising at least one of the antibodies described herein in addition to at least one of the following: convalescent plasma or serum, intravenous immunoglobulins, eculizumab, heparin or another anticoagulant, angiotensin-converting enzyme (ACE) inhibitors, vitamin C, vitamin D, zinc, or n-acetylcysteine. Therapies for COVID-19 and/or SARS-CoV-2 In one embodiment, a patient diagnosed with a SARS-CoV-2 infection or COVID-19 using the methods described herein, receives a treatment comprising at least one of an antiviral therapy, such as molnupiravir (Merck & Co., Inc. and Ridgeback Biotherapeutics) or remdesivir (Gilead Sciences, Inc.); a neutralizing monoclonal antibody that targets SARS- CoV-2, such as sotrovimab (GlaxoSmithKline plc.), bamlanivimab (Eli Lilly and Co.), etesevimab (Eli Lilly and Co.), casirivimab (Regeneron Pharmaceuticals Inc.), and imdevimab (Regeneron Pharmaceuticals Inc.).; an anti-inflammatory agent, such as tocilizumab (Genentech USA, Inc.) and lenzilumab (Humanigen, Inc.); a steroid, such as glucocorticosteroids, methylprednisolone, and dexamethasone. Other treatments include anti- inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin, ibuprofen, naproxen, methyl salicylate, diflunisal, indomethacin, sulindac, diclofenac, ketoprofen, ketorolac, carprofen, fenoprofen, mefenamic acid, piroxicam, meloxicam, methotrexate, celecoxib, valdecoxib, parecoxib, etoricoxib, and nimesulide ), corticosteroids (e.g., prednisone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, tramcinolone, and fluticasone), rapamycin, acetaminophen, glucocorticoids, steroids, beta-agonists, anticholinergic agents, methyl xanthines, gold injections (e.g., sodium aurothiomalate), sulphasalazine, and dapsone. In another embodiment, a patient with an active infection of SARS-CoV-2 or COVID-19 receives a treatment comprising at least one of the following: convalescent plasma or serum, intravenous immunoglobulins, eculizumab, heparin or another anticoagulant, angiotensin-converting enzyme (ACE) inhibitors, vitamin C, vitamin D, zinc, or n-acetylcysteine. Still other aspects and advantages of these compositions and methods are described further in the following detailed description of the preferred embodiments thereof. EXAMPLES The invention is now described with reference to the following examples. These examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these examples but rather should be construed to encompass any and all variations that become evident as a result of the teaching provided herein. The SARS-CoV-2 diagnostic paradigm has been challenged by the emergence of rapidly spreading variant strains that have important consequences for clinical and epidemiological decision making. Variant detection generally relies on Nucleic Acid Amplification Tests (NAATs). Immunoassays that detect viral antigens, e.g., antigen- detection rapid diagnostic tests (Ag-RDTs), may also be able to contribute by recognizing variant-specific epitopes, but monoclonal antibodies suitable for use in these assays have not been described. Described herein is a human mAb that binds N501 but not Y501 and can thus distinguish delta from other VBMs in an ELISA or other diagnostic assay. Furthermore, among the Y501-containing VOCs, the previously described human mAb CB6 binds alpha and gamma, but not beta. Diagnostic assays incorporating these two mAbs are useful for variant-specific SARS-CoV-2 POC testing. The foundation of the present work is a pair of human mAbs (2E8 and CB6) that differentially recognize SARS-CoV-2 VOCs and VOIs in an ELISA. Most of the VOCs and VOIs have acquired mutations in their spike glycoprotein, which mediates receptor binding and is one of the major targets of the adaptive immune response to SARS-CoV-2. Four hotspots within the receptor binding domain (RBD) undergo common mutations that may be targetable in Ag-RDTs (K417, L452, E484, N501) (Table 5).2E8 is a human mAb specific for N501; it does not bind spike RBDs that contain N501Y in an ELISA. CB6 is a previously described mAb that binds B.1.1.7 and P.1, but not B.1.351, in the ELISA, consistent with its previously described binding activities. Significantly, both mAbs bind to B.1.427, B.1.429, and B.1.617. When used together, these two mAbs discriminate between clinically important SARS-CoV-2 VOCs and VBMs. Example 1: 2E8, a human mAb that neutralizes SARS-CoV-2 through spike RBD binding The 2E8 mAb was cloned from a male in his 50s who had a confirmed case of COVID-19 contracted in New York City in March 2020. A peripheral blood sample was obtained 42 days after his first symptom. The 2E8 mAb was cloned using the human hybridoma method described previously [36]. As antigens, we used VSV-G:S1 particles (pseudotyped with the SARS-CoV-2 spike protein S1 domain) and a trimeric, S1 protein (S1 trimer), both based on the reference sequence Wuhan-Hu-1 (L, NC_045512) [35]. We tested the hybridoma-expressed mAb for binding to commercial antigens (spike S1, spike D614G, and nucleocapsid) and the VSV-G:S1. In a direct ELISA, the 2E8 bound all four S1 antigens, with somewhat less binding to the VSV-G:S1 and the S1 trimer at the 0.1 µg/mL level (FIG. 1A). We then made a recombinant IgG12E8 molecule, which was used for all subsequent studies, as well as recombinant IgG1 mAbs, CB6 and CR3022 [32,41]. The 2E8 inhibited the binding of S1 to the 293T-hsACE2 cell line, reducing the amount of right-shifted cells from ~33% to 7.5%, compared to the 4G1 isotype control (FIG. 1B). The CB6 mAb also inhibited S1 binding (5%), whereas the CR3022 did not inhibit S1 binding despite adhering to S1 at the cell surface. To test viral neutralization, we used a reporter viral particle (RVP) assay, in which 293T-hsACE2 cells were incubated with SARS- CoV-2 (Wuhan-Hu-1 strain) pseudotyped virions that contain a luciferase transgene (FIG. 1C). Cells were infected in triplicate. The data were normalized to the negative control wells and calculated as the % infection. The 2E8 substantially reduced luciferase expression (80% reduction at 10 µg/mL) compared to the 6A non-binding control mAb, the non-neutralizing CR3022 mAb, and a polyclonal IgG (P24) from the B cell donor sampled for 2E8 mAb cloning. However, its activity was 100-fold less than that of the CB6 mAb (85% reduction at 0.1 µg/mL). We measured the binding kinetics of the 2E8 with the Wuhan-Hu-1 S1 using the OpenSPR™ Benchtop SPR System (Nicoya Lifesciences, Kitchener, ON, Canada). The Kinetic analysis is shown in FIG.1D: K_D = 7.4 ± 0.58 nM, k_on = 1.4 × 10⁵ M⁻¹ s⁻¹ ± 2.0 × 10³ M⁻¹ s⁻¹, k_off = 9.6 × 10⁻⁴ ± 5.6× 10⁻⁵ s⁻¹ (FIG.1D). This is approximately a three-fold lower affinity than that of the CD6 mAb, 2.49 ± 1.65 nM [32]. The full immobilization sequence of the SARS-CoV-2 S1 domain and 2E8 binding to the immobilized S1 domain are shown in FIG.6 and FIG.7A – FIG.7C, respectively. To gain more insight into the nature of S1 binding, we epitope binned the 2E8 in comparison to the CB6 and CR3022 mAbs and a neutralizing, pan-specific anti-spike mouse mAb (Sino Biologicals, RRID: AB_2857934) on the Wuhan-Hu-1 S1 and RBD proteins. We used a binding assay that analyzes mAb competition at the linear portion of an antigen binding curve [43,44]. The 2E8 epitope on S1 and RBD clearly overlaps with CB6 but not CR3022 or the mouse mAb (FIG.2A, FIG.2B). This is consistent with the observations that CB6 binds S1 in a configuration that overlies the N501 residue and that CB6 and CR3022 bind non-overlapping epitopes [32,41]. Murine mAb binding was not inhibited by 2E8 or CB6, suggesting that it can be used in combination with these mAbs in a SARS-CoV-2 sandwich ELISA (FIG.2C, FIG.2D). Example 2: 2E8 binding to SARS-CoV-2 Variants of Concern Present and previously designated VOCs contain mutations in the RBD that can affect binding by mAbs. We used a direct ELISA to compare the binding of 2E8 and CB6 to recombinant S1 and RBD proteins, including S1 proteins corresponding to L, alpha, beta, gamma, and epsilon (B.1.429; L452R, E484Q). We also tested RBDs corresponding to delta, kappa (B.1.617.1; L452R, E484Q), and the single mutant K417N. The 2E8 bound all the spike proteins tested, except for alpha, beta, and gamma (FIG.3A). As these VBMs share the N501Y RBD mutation, and the alpha contains only the N501Y mutation, we also tested 2E8 binding to an N501Y RBD; no binding was observed (data not shown). In contrast, 2E8 binding to RBDs with a single K417N or E484K mutation was not impaired (FIG.3B). This suggests that the 2E8 interacts with N501 but not substantially with E484 or K417. Equivalent binding to delta, kappa, and epsilon S1 proteins further indicates that 2E8 does not recognize L452 or T478. This indicates that the 2E8 can distinguish between N501 and N501Y independent of changes affecting class I (K417) and class II (E484) neutralizing antibodies. CB6 is a well characterized, potent neutralizing mAb that shows reduced neutralization activity against many VBMs. CB6 shows no binding to beta and reduced binding to gamma but no reduction in binding to alpha, delta, kappa, or epsilon (FIG.3B). We explored the difference between binding to the beta and gamma RBDs, which differ only at K417 (beta, K417N; gamma, K417T). K417N by itself significantly reduces binding (FIG. 3B). This is consistent with the observations of others [45] and suggests that CB6 is useful to differentiate N501Y-containing variants alpha and gamma from beta in an ELISA. The murine mAb bound to every antigen tested, indicating its suitability as a capture mAb in variant-specific sandwich ELISAs (FIG.3C). Example 3: Spike variant binding in a sandwich ELISA Sandwich ELISAs can be used to evaluate mAbs for use in LFAs, as both formats use a pair of non-overlapping mAbs for antigen capture and detection. We tested 2E8 and CB6 binding to variants in a sandwich ELISA format, including an anti-6X His tag antibody (Abcam, Cat: ab18184) as a positive control for antigen capture. The mAbs were used to capture the spike antigens, which were then detected with the biotinylated murine mAb (FIG. 4A). We tested binding to the same antigens tested in FIG.3A – FIG.3C. The 2E8 ELISA bound to L, delta, the K417N mutant, kappa, and epsilon but not to any of the Y501- containing variant proteins: alpha, beta, and gamma. CB6 bound every antigen except beta. As in the direct ELISA, reduced CB6 binding was seen with the gamma and K417N RBDs. The Anti-6X His tag antibody gave an equivalent signal with all antigens. These results are summarized in Table 5. Taken together, these results confirm the utility of the 2E8 mAb to differentiate variants by distinguishing N501 from Y501 in the spike RBD. They further show that CB6 can be used in this format to differentiate Y501-containing VBMs alpha and gamma from beta. Table 5. Antibody binding in sandwich ELISAs to SARS-CoV-2 variants

The emergence of SARS-CoV-2 variants has greatly complicated the efforts to control and treat the disease. The variants differ in their ability to evade antibody immunity provided by vaccination or passive immunization and, therefore, may dramatically impact health care facilities, congregate housing settings, public transportation hubs, and high-risk occupational environments. Variant-specific POC testing is necessary to protect individuals in these settings, as well as to screen populations for shifts in SARS-CoV-2 epidemiology. This study advances the concept of using variant-specific Ag-RDTs as a component of the SARS-CoV-2 screening and diagnostic paradigm. Detection of the N501Y spike mutation with the 2E8 mAb is an efficient way distinguish delta from variants with the N501Y meta-signature [11], such as beta, gamma, mu, C.1.2, and novel N501Y-containing variants yet to emerge. The N501Y mutation has originated independently within multiple viral lineages and is positively selected because it increases infectivity through enhanced ACE2 binding [11,12]. Mutagenesis and modeling experiments suggest that the N501Y mutation will support the evolution of SARS-CoV-2 variants with increased infectivity and resistance to vaccines and therapeutics [13,45]. As the delta variant is currently the dominant strain globally, an Ag-RDT to detect infections with N501Y meta-signature variants will be a powerful tool for disease monitoring and control. The N501 residue lies on the “right shoulder” of the RBD and directly interacts with ACE2 during cell binding [11,12]. The N501Y mutation does not dramatically alter the overall RBD structure. This suggests that 2E8 binds N501 and/or may be sterically inhibited by Y501. The 2E8 binding site overlaps the CB6 site, yet its binding is not affected by changes at K417, and CB6 binding is largely insensitive to the N501Y change [12]. Furthermore, 2E8 has ~100-fold less neutralizing activity than that of CB6, even though its affinity is only 3-fold lower than that of the CB6 (7.38 ± 0.58 nM vs.2.49 ± 1.65 nM) [32]. These data highlight the structural independence of these two epitopes in variant RBDs. The CB6 interaction with the spike has been defined using X-ray crystallography [32]. CB6 is a type I neutralizing mAb that contacts the K417 and N501 residues. CB6 neutralization is unaffected by the N501Y RBD mutation, consistent with the relative unimportance of this residue to CB6 binding. In contrast, the gamma and beta variant changes essentially eliminate CB6 binding and neutralization [46,47,48]. Published data show that CB6 binding affinities for the beta and gamma variants are 42.6-fold and 18.7-fold lower, respectively, in comparison to the wild-type spike. This is attributable to the K417N mutation, which alone reduces affinity 21.9-fold compared to a 13.8-fold reduction from the K417T change. Our results are consistent with these data, which explain how CB6 distinguishes beta from alpha and gamma in our ELISAs. The 2E8 and CB6 mAbs provide qualitatively different information, because the 2E8 is a poorly neutralizing non-clinical antibody, whereas the CB6 is part of the etesevimab/bamlanivimab therapeutics. A lack of 2E8 binding to a clinical sample suggests additional mutations associated with an increased risk of breakthrough infections and treatment failures. In contrast, a lack of CB6 binding strongly suggests that either the beta or gamma variant is present; furthermore, it predicts resistance to etesevimab. In the current delta-dominant milieu, either finding would ideally trigger a follow-up characterization using an NAAT test. This study supports a paradigm for the detection of SARS-CoV-2 variants using an Ag-RDT with variant-specific mAbs. The mAb capture/detection pairs used can be readily adaptable for use in LFAs. Ideally, the 2E8 mAb would be used in a multiplexed assay in parallel with a mAb or ACE2 reagents capable of binding all variants [49,50,51]. Such tests can be an important adjunct to NAATs, as they are ideal for POC testing to protect vulnerable populations and broaden epidemiological surveillance. Both 2E8 and CB6 have immediate applicability for testing while delta is the most prevalent variant. However, additional mAbs will be needed as the variant landscape evolves. This objective should be achievable, as the repertoire of potential variant-specific mutations is well-defined, a large number of anti-spike mAbs have been cloned, and extensive structural data describing mAb–spike interactions have been generated. Example 4: Materials and Methods SARS-CoV-2 spike antigens and antibodies A Wuhan-Hu-1 SARS-CoV-2 spike protein cDNA was cloned into the XhoI and NheI sites of a modified recombinant VSV vector containing an additional transcription start/stop signal between the G and L genes. The recombinant virus was recovered on 293T cells as described previously [33] and filtered through 0.22 µm PVDF filters (MilliporeSigma, Burlington, MA, USA)). The filtered virus was then used to inoculate human BEAS-2B lung cells (gift from R. Plemper, University of Georgia) seeded in Cellstack culture chambers (Corning, Corning, NY, USA). The infected cells were cultured in serum-free Optipro medium (Invitrogen, Waltham, MA, USA). Cell culture supernatant was harvested three days post-inoculation, clarified by centrifugation at 3000 g, and filtered through 0.45 µm PES membrane filters (Nalgene, Rochester, NY, USA). The filtered supernatant was layered on 20% sucrose in DPBS, and particles were sedimented by ultracentrifugation in a SW32 rotor (Beckman, Brea, CA, USA) for 1.5 h at 25,000 rpm. Viral particles were resuspended in phosphate-buffered saline and inactivated with 0.05% beta-propiolactone (BPL). After overnight incubation at 4 °C, the particles were incubated at 37 °C for 45 min to hydrolyze BPL and filtered through 0.22 µm PES filters (MilliporeSigma). To separate the glycoproteins from the ribonucleoprotein complex, 2% beta-octyl-glucopyranoside (OGP) was added to the viral particles. After 15 min incubation at room temperature, the mixture was centrifuged for 1.5 h in a SW55 rotor (Beckman) at 45,000 rpm. After centrifugation, the supernatant was collected and filtered through 0.22 µm PES filters. For protein analysis, 3 µg particles and 1 µg OGP-solubilized glycoproteins were resolved on a denaturing SDS- polyacrylamide gel. (FIG.5). The gel was fixed and stained with SYPRORuby (Thermo Fisher Scientific, Waltham, MA, USA) according to the instructions provided by the manufacturer. Images of the stained gel were acquired on a Fluochem M instrument (Biotechne, Minneapolis, MN, USA). We also expressed a SARS-CoV-2 S1 domain fragment as a trimeric protein in Expi- 293F cells, in part following [34] (FIG.5). We used the original L strain sequence (GenBank: NC_045512) [35] and produced a fusion protein that included residues G283-F718 (eliminating the S1 amino terminal domain and extending to the S1–S2 boundary) and a mutated furin cleavage site. The fusion protein included a mu-phosphatase signal peptide (N- terminal) and a C-terminal fibritin T4 trimerization domain, followed by a Myc site and a 6XHis tag. A gene encoding this fusion protein was produced by Twist Bioscience (South San Francisco, CA, USA) and cloned into the pTwist CMV BetaGlobin expression vector. The construct was transiently transfected into Expi-293F cells (Thermo Fisher) following the manufacturer’s instructions. Due to limited secretion of the protein, on Day 5, we pelleted the cells by centrifugation at 3000 rpm at 4 °C for 20 min. The pellet was resuspended in Takara xTractor™ buffer (Takara Bio, Mountain View, CA, USA) with GenDEPOT Protease Inhibitor Cocktail II, EDTA Free (10X) (Thermo Fisher), incubated on ice with intermittent mixing for 15 min, and then centrifuged at 3500 rpm for 15 min at 4 °C. The supernatant was filtered through a 0.45 μm filter, and the protein was isolated with a Capturem™ His-Tagged Purification Column (Takara). The purity and integrity of S1 trimer were assessed by SDS:PAGE (data not shown) and Western blot (FIG.5) and detected with the Anti-6X His tag® antibody [HIS.H8] (Cat: ab18184; Abcam, Cambridge, MA, USA) and Peroxidase AffiniPure Goat Anti-Mouse IgG, Fcγ fragment specific (RRID: AB_2313585, Jackson ImmunoResearch, West Grove, PA, USA). A recombinant S1 fragment trimer (S1-trimer): We also expressed a SARS-CoV-2 S1 domain fragment as a trimeric protein in Expi-293F cells, in part following [32] (FIG.5). We used the original L strain sequence (GenBank: NC_045512) [21] and produced a fusion protein that includes residues G283-F718 (eliminating the S1 amino terminal domain and extending to the S1-S2 boundary) and a mutated furin cleavage site. The fusion protein included a mu-phosphatase signal peptide (N-terminal) and a C-terminal fibritin T4 trimerization domain, followed by a Myc site and a 6XHis tag. A gene encoding this fusion protein was synthesized by Twist Bioscience (South San Francisco, CA) and cloned into the pTwist CMV Beta Globin expression vector. The construct was transiently transfected into Expi-293F cells (Thermo Fisher Scientific, Waltham, MA) following the manufacturer’s instructions. Due to limited secretion of the protein, on Day 5 we pelleted the cells by centrifugation at 3000 rpm at 4 °C for 20 minutes. The pellet was resuspended in Takara xTractor™ buffer (Takara Bio, USA, Mountain View, CA) with GenDEPOT Protease Inhibitor Cocktail II, EDTA Free (10X) (Thermo Fisher), incubated on ice with intermittent mixing for 15 minutes, then centrifuged at 3500rpm for 15 minutes at 4 °C. The supernatant was filtered through a 0.45 μm filter and protein was isolated with a Capturem™ His-Tagged Purification Column (Takara). The purity and integrity of S1-F-trimer was assessed by SDS:PAGE (data not shown) and Western blot (FIG.5), and was detected with the Anti-6X His tag® antibody [HIS.H8] (Cat: ab18184; Abcam, Cambridge, MA) and Peroxidase AffiniPure Goat Anti-Mouse IgG, Fcγ fragment specific (RRID: AB_2313585, Jackson ImmunoResearch, West Grove, PA). Commercial antigens The following S1 antigens were obtained from Sino Biological, Chesterbrook, PA: Wuhan-Hu-1 S1 (L): SARS-CoV-2 (2019-nCoV) Spike S1-His Recombinant Protein (Cat: 40591-V08H); Wuhan-Hu-1 S1 with D614G: SARS-CoV-2 (2019-nCoV) Spike S1 (D614G)-His Recombinant Protein (Cat: 40591-V08H3); Wuhan-Hu-1 RBD (L): SARS- CoV-2 (2019-nCoV) Spike RBD-His Recombinant Protein (Cat: 40592-V08H); alpha S1 (B.1.1.7, UK): SARS-CoV-2 (2019-nCoV) Spike S1(HV69-70 deletion, Y144 deletion, N501Y, A570D, D614G, P681H)-His Recombinant Protein (Cat: 40591-V08H12); beta S1 (B.1.351, South Africa), only RBD and D614G changes: SARS-CoV-2 (2019-nCoV) Spike S1(K417N, E484K, N501Y, D614G)-His Recombinant Protein (Cat: 40591-V08H10); beta S1 (B.1.351, South Africa): SARS-CoV-2 (2019-nCoV) Spike S1 (L18F, D80A, D215G, LAL242-244 deletion, R246I, K417N, E484K, N501Y, D614G)-His Recombinant Protein (Cat# 40591-V08H15); gamma RBD (P.1, Brazil/Japan): SARS-CoV-2 (2019-nCoV) Spike RBD (K417T, E484K, N501Y) Protein (His Tag) (Cat: 40592-V08H86); gamma S1 (P.1, Brazil/Japan): SARS-CoV-2 (2019-nCoV) Spike S1 (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y) Protein (His Tag) (Cat# 40591-V08H14); epsilon S1 (B.1.429, California): SARS-CoV-2 (2019-nCoV) Spike S1 (W152C, L452R, D614G) Protein (His Tag) (Cat: 40591-V08H17); kappa RBD (B.1.617.1, India): SARS-CoV-2 (2019-nCoV) Spike RBD (L452R, E484Q) Protein (His Tag) (Cat# 40592-V08H88); delta RBD (B.1.617.2, India): SARS-CoV-2 Spike RBD (L452R, T478K) Protein (His Tag) (Cat# 40592-V08H90); N501Y (alpha) RBD: SARS-CoV-2 (2019-nCoV) Spike RBD (N501Y)- His Recombinant Protein (Cat# 40592-V08H82); E484K RBD: SARS-CoV-2 (2019-nCoV) Spike RBD(E484K)-His Recombinant Protein (Cat# 40592-V08H84); K417N RBD: SARS- CoV-2 (2019-nCoV) Spike RBD (K417N)-His Recombinant Protein (Cat# 40592-V08H59); Wuhan-Hu-1 S1 (L) biotinylated: SARS-CoV-2 (2019-nCoV) Spike S1-His Recombinant Protein, Biotinylated (Cat: 40591-V08H-B). Example 5: 2E8 monoclonal antibody isolation We collected sera and peripheral blood mononuclear cells (PBMCs) from 25 patients at least 14 days following complete recovery from a SARS-CoV-2 infection. All subjects provided signed informed consent under a protocol approved by the Main Line Hospitals Institutional Review Board. We assayed the sera for immunoreactivity with the SARS-CoV-2 S1 pseudotyped VSV (VSV G:S1) particles by ELISA. A male volunteer in his 50s was found to have anti-spike titers >1:8000. He was a Caucasian, without comorbid health conditions, diagnosed by RT-PCR testing in New York City in March 2020. He required hospitalization due to respiratory decompensation but was not intubated. Blood was sampled 25 days after his last COVID-19-related symptom. We fused CD27+ peripheral blood mononuclear cells and the LCX OCMS fusion partner cell line [36]. Hybridomas were screened for binding to the VSV G:S1 particles by ELISA. A positive well was subjected to three rounds of single-cell cloning to isolate a monoclonal cell expressing the anti-SARS CoV-2 mAb, 2E8. For scale up, the hybridoma was adapted to 5% Ultra Low IgG FBS (Thermo Fisher), and the mAb was isolated from the supernatant using a Pierce™ Protein G column (Cat: 89927; Thermo Fisher). The 6A control mAb was also produced from its hybridoma [37]. The 2E8 Ig variable domains were amplified by RT-PCR, using the Qiagen RNA extraction kit (Cat: 74124; Qiagen, Germantown, MD, USA), and reverse transcribed with the Omniscript RT Kit (Cat: 205111; Qiagen). Variable domain cDNA sequences were amplified with consensus primer sets specific for human immunoglobulin heavy and light chain genes [38]. Amplified sequences were isolated by agarose gel electrophoresis, purified with the QiaQuick Gel Extraction kit (Cat: 28706; Qiagen), sequenced by Psomagen, Inc. (Rockville, MD, USA), and analyzed with IMGT/V-QUEST [39]. We also isolated polyclonal IgG from plasma of the individual who provided the 2E8 mAb, using a Pierce™ Protein G column (Thermo Fisher). Production of recombinant antibodies For recombinant 2E8 production, full-length human IgG1 and Igλ cDNAs encoding the 2E8 mAb heavy and light chain variable regions were produced and subcloned into pTwist CMV BetaGlobin expression plasmids (Twist Bioscience) [40]. The plasmids were transiently transfected into Expi-293F cells following the manufacturer’s instructions. On day 4, cell culture supernatants were harvested and purified with the Pierce™ Protein G column (Thermo Fisher). Purity and size were confirmed by SDS:PAGE (data not shown). The 2E8 mAb concentration was measured with a NanoDrop1000 (Thermo Fisher). Recombinant human mAbs CB6 [32], CR3022 [41], and 4G1 [42] were produced by the same method. Surface Plasmon Resonance (SPR) Spectroscopy The binding kinetics of the 2E8 IgG with the SARS-CoV-2 S1 protein was determined using the 2-channel OpenSPR (Nicoya Lifesciences, Kitchener, ON). The assays were performed at 21 °C with buffer PBS 0.05% Tween-20 (PBST). The S1 protein (Wuhan-Hu-1 S1 (L): SARS-CoV-2 (2019-nCoV) Spike S1-His Recombinant Protein (Cat: 40591-V08H)) was immobilized on a nitrilotriacetic acid (NTA) sensor chip following EDTA conditioning. His-streptavidin (Abcam, Cat: ab78833) was immobilized in the reference channel as a control ligand. Purified recombinant 2E8 mAb was diluted in PBST supplemented with 0.1% BSA and injected for 5 min at a flow rate of 20 μL/min in a concentration series from 1.23 nM to 100 nM, with 10 min dissociation time. Sensors were regenerated with two injections of 500mM imidazole per regeneration step, with 40 s contact time and 270 s dissociation time. Sensorgrams were fitted with Trace Drawer analysis software (Ridgeview Instruments, Uppsala, Sweden). ELISAs Recombinant antibody binding to SARS-CoV-2 spike antigens: Recombinant antibody binding to SARS-CoV-2 spike antigens: NUNC high-binding ELISA plates (Thermo Fisher) were coated in PBS with 500 ng/well antigen at 4 °C overnight. Plates were washed three times with PBS containing 0.05% Tween-20 (PBST) and blocked with blocking buffer (BB) (PBST containing 5% non-fat dry milk) at 37 °C for one hour. Ten-fold serial dilutions of the mAbs were diluted in BB, added in triplicate, and incubated for 1 h at 37 °C. Following 3 washes with PBST, samples were incubated with horseradish peroxidase (HRP)-conjugated mouse anti-human IgG Fc fragment specific secondary antibody (RRID AB_2687484; Southern Biotech, Birmingham, AL, USA), diluted 1:1500 in BB, for one hour at 37 °C. After three washes, the plate was incubated with OPD substrate (P8287; Sigma Aldrich, St. Louis, MO, USA) for 10 min at RT. The reaction was stopped with 1N HCL, and the optical density (OD) at 490 nm was read with a Biotek Synergy II microplate reader (BioTek Instruments, Winooski, VT, USA). The mouse mAb positive control was SARS-CoV-2 (2019-nCoV) Spike Neutralizing Antibody (RRID:AB_2857934; Sino Biological) and was detected with Goat Anti-Mouse Ig, Human ads-HRP (Cat: 1010-05; Southern Biotech). Sandwich ELISAs for specific variant binding: Sandwich ELISAs for specific variant binding: NUNC high-binding ELISA plates were coated with 100 ng/well 2E8 or CB6 or 500 ng/well anti-6X His tag® antibody [HIS.H8] (RRID:AB_444306; Abcam), in PBS overnight at 4 °C. Plates were washed and blocked as above. S1 or RBD proteins were added to the plates (500 ng/well) and incubated for 1 h at 37 °C, followed by 3 washes. Biotinylated mouse anti-S1 (RRID:AB_2857934; Sino Biological), biotinylated with EZ-Link Sulfo-NHS- Biotin, (Thermo Fisher), was added (500 ng/well) and incubated for 1 h at 37 °C followed by 3 washes. Pierce Streptavidin-HRP substrate (Thermo Fisher) was added at 1:2000 dilution and incubated for 1 h at 37 °C and washed as above, and then the plates were washed and detected with OPD substrate as above. Example 7: Flow cytometry-based receptor-binding inhibition assay Antibody interference of S1 binding to human ACE2 receptor on the cell surface of 293T cells was measured by flow cytometry. Briefly, 0.1 μg/mL biotinylated SARS-CoV-2 spike S1 (Cat: 40591-V08H-B; Sino Biological) was incubated with 1 μg/mL recombinant mAb or a human ACE2-Fc fusion protein (Cat fc-hace2: Invivogen, San Diego, CA, USA) at 37 ºC for one hour. The S1:mAb mixtures were added to 5 × 105293T-hsACE2 cells (Cat: C-HA101; Integral Molecular) and incubated for 30 min at room temperature. Following incubation, cells were washed twice with PBS containing 2% fetal bovine serum (PBSF) and incubated with Alexa Flour 488 Streptavidin (RRID: AB_2337249; Jackson ImmunoResearch) (1:200 dilution) to detect S1 binding and Goat Anti-Human IgG (H + L) Antibody, Alexa Fluor 647 Conjugated (RRID:AB_2535862; Thermo Fisher) to detect human IgG binding. After 30 min incubation, cells were washed twice with PBSF and analyzed using a BD FACS Canto II (Becton Dickson, Franklin Lakes, NJ, USA). Data were analyzed using FlowJo 10.6.1. software (Tree Star, Ashland, OR, USA). Example 8: Pseudotyped SARS-CoV-2 antibody neutralization assay The antibody neutralization assay was obtained from Integral Molecular and performed following their protocol, using the 293T-hsACE2 cell line (Cat: C-HA101; Integral Molecular, Philadelphia, PA, USA) and the pseudotyped SARS-CoV-2 (Wuhan-Hu- 1 strain) reporter viral particles (RVPs) with luciferase (Cat: RVP-701L, Lot CL-114B, Integral Molecular). Briefly, in a 96-well plate, 5-fold serially diluted mAbs were combined with 10 μL RVPs and incubated for 1 h at 37 °C. Following incubation, 2 × 104293T- hsACE2 cells were added to each well, mixed gently by pipetting, and then incubated at 37° C with 5% CO2. After 72 h, SARS-CoV-2 RVP infection was quantified using the Renilla- Glo® Luciferase Assay System (Cat: E2710, Promega, Madison, WI, USA). Briefly, we centrifuged the plate for 5 min at 2000 rpm, aspirated the supernatants, and added 30 μL PBS to each well, followed by 30 µL Renilla-Glo® Assay Substrate (1:100 dilution). After 10 min, relative luminescence values were measured using the Synergy 2 plate reader (BioTek Instruments). The values from the negative control wells were normalized and used to calculate the percent infection for each concentration. All samples were run in triplicate. Example 9: Epitope binning We performed competitive binding assays to test whether biotinylated 2E8 could bind SARS-CoV-2 spike antigens (S1 and RBD) in the presence of the human mAbs CB6, CR3022, and the murine SARS-CoV-2 (2019-nCoV) Spike Neutralizing Antibody (RRID:AB_2857934; Sino Biological) [43,44]. Black NUNC MaxiSorP 96-well plates (Thermo Fisher) were incubated overnight with 500 ng/well S1 or RBD, then washed three times with PBST, and blocked with BB for 1 h at 37 °C. The 2E8 was biotinylated with the EZ-Link Sulfo-NHS-Biotin kit (Thermo Fisher), and the S1 and sRBD antigen binding curves were found to be linear between 2.5 pg/mL and 2.5 μg/mL. In the experiments shown, 500 ng/well of the competing mAb was added to half of the antigen wells and PBS to the other half and then incubated for 1 h at 37 °C, followed by 3 PBST washes. The 2E8 serial dilution was added to the entire plate. 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Cantera J.L., Cate D.M., Golden A., Peck R.B., Lillis L.L., Domingo G.J., Murphy E., Barnhart B.C., Anderson C.A., Alonzo L.F., et al. Screening antibodies raised against the spike glycoprotein of SARS-CoV-2 to support the development of rapid antigen assays. ACS Omega.2021;6:20139–20148. doi: 10.1021/acsomega.1c01321. 51. Lee J.H., Choi M., Jung Y., Lee S.K., Lee C.S., Kim J., Kim J., Kim N.H., Kim B.T., Kim H.G. A novel rapid detection for SARS-CoV-2 spike 1 antigens using human angiotensin converting enzyme 2 (ACE2) Biosens. Bioelectron.2021;171:112715. doi: 10.1016/j.bios.2020.112715. Each and every patent, patent application, and publication, including websites cited throughout the specification are incorporated herein by reference. Similarly, the SEQ ID NOs which are referenced herein and which appear in the appended Sequence Listing are incorporated by reference. US Provisional Patent Application No.63/253,178, filed October 7, 2021, is incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS: 1. An antibody that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan S1 protein variant at N501, but does not bind a SARS-CoV-2 S1 protein variant that has a spike protein mutation N501Y, said antibody comprising: (a) a heavy chain variable region (V_H) comprising (i) a complementarity- determining region 1 (CDR1) of SEQ ID NO: 15, (ii) a complementarity-determining region 2 (CDR2) of SEQ ID NO: 17, and (iii) a complementarity-determining region 3 (CDR3) of SEQ ID NO: 18; and/or (b) a light chain variable region (V_L) comprising, (i) a CDR1 of SEQ ID NO: 22, (ii) a CDR2 having the amino acid sequence Asp-Asp-Ser (DDS), and (iii) a CDR3 of SEQ ID NO: 23.

2. The antibody of claim 1, comprising a V_H having an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 14 and a V_L having an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 21.

3. The antibody of claim 1 or 2, wherein the V_H comprises the amino acid sequence of SEQ ID NO: 14 and the V_L comprises the amino acid sequence of SEQ ID NO: 21.

4. The antibody of any one of claims 1 to 3, wherein the antibody is an IgG, an IgM, an IgE, an IgA, or an IgD isotype, or is derived therefrom.

5. The antibody of any one of claims 1 to 4, wherein the antibody comprises a monoclonal antibody, a grafted antibody, a chimeric antibody, a human antibody, or a non- human antibody.

6. The antibody of any one of claims 1 to 4, wherein the antigen-binding fragment is a Fab, F(ab’)₂, Fab’, scFv, di-scFv, tri-functional antibody, chemically linked F(ab’)₂, BiTE, or single domain antibody.

7. The antibody of any one of claims 1 to 6, which is synthetic or recombinant.

8. The antibody of any one of claims 1 to 7, which is conjugated to a synthetic molecule.

9. The antibody of claim 8, wherein the synthetic molecule is a label, a contrast agent, a magnetic nanoparticle, a cytotoxic agent, a cytostatic agent, an anti-angiogenic agent, or a radioisotope.

10. The antibody of claim 6, which is formatted as a non-human antibody, wherein the V_H CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 15, 17, and 18 respectively and wherein the V_L CDR1, CDR2, and CDR3 are SEQ ID No: 22, amino acid sequence DDS and SEQ ID No: 23, respectively.

11. A method of diagnosing a subject as being infected with a SARS-CoV-2 virus, the method comprising contacting a sample obtained from the subject with the antibody of any one of claims 1 to 10, to form an antibody/SARS-CoV-2 virus complex when the antigen is present in the sample, diagnosing the subject as being infected with a SARS-CoV-2 virus variant having the residue N501 and not N501Y, when the antibody/SARS-CoV-2 virus complex is detected.

12. A method of diagnosing a subject as being infected with a SARS-CoV-2 virus, the method comprising contacting a sample obtained from the subject with a panel of antibodies that bind selected S1 antigens in SARS-CoV-2 variants to form an antibody/SARS-CoV-2 virus complex when the antigen is present in the sample, wherein one antibody in the panel of antibodies is the antibody of any one of claims 1 to 10 that binds S1 antigens having only N501, not mutations at that site; detecting the pattern of binding between said antibodies by the presence or absence of an antibody/SARS-CoV-2 virus complex; and diagnosing the subject as being infected with a specific SARS-CoV-2 virus variant based upon the pattern of binding between the panel of antibodies and the viral S1 protein.

13. The method of claim 11 or 12, wherein the sample comprises a nasal swab, a tissue sample, saliva, or blood.

14. The method of claims 11 to 13, wherein detecting the presence or absence of the antibody/SARS-CoV-2 virus complex or the antigen-binding fragment/SARS-CoV-2 virus complex comprises an enzyme linked immunosorbent assay (ELISA), an immunospot assay, a lateral flow assay, flow cytometry, immunohistochemistry, or a western blot.

15. The method of any one of claims 11 to 14, wherein said test is an Antigen Diagnostic Test immunoassay directed to detect at pattern of spike RBD polymorphisms at S1 amino acid residues K417, L452, E484, and N501, wherein the pattern detected by the selected antibodies or antigen binding fragments thereof distinguishes among SARS-CoV-2 variant infections.

16. The method of any one of claims 11 to 15, wherein said test further comprises a pan- SARS-CoV-2 specific antibody.

17. A diagnostic composition comprising the antibody of any one of claims 1 to 10 conjugated to or associated with a detectable label.

18. A cell transformed to express the antibody of any one of claims 1 to 10.

19. A diagnostic kit for the diagnosis of a SARS-CoV-2 variant comprising the antibody of any of claims 1 to 10 conjugated to or associated with a detectable label.

20. The diagnostic kit of claim 19, further comprising (b) a pan-SARS-CoV-2 specific antibody, conjugated to or associated with a detectable label.

21. The kit of claim 19 or 20, further comprising antibodies of (a) and/or (b), packaged in a container, a vial or bottle, further reagents essential for performing an ELISA, and a label attached to or packaged with the container, the label describing the contents of the container and providing indications and/or instructions regarding use of the contents of the container.

22. A pharmaceutical composition comprising the antibody of any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, further comprising a second therapeutic agent.

24. A method of preventing or treating a SARS-CoV-2 viral infection or COVID19 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 22 or 23.