Single domain antibodies against beta coronavirus spike protein s2 domain

Abstract

The present invention relates to novel single domain antibodies which bind to the S2 subunit of the spike glycoprotein of beta-coronaviruses. The invention also relates to binding molecules comprising the single domain antibodies. Also provided are uses of the single domain antibodies and binding molecules, and pharmaceutical compositions comprising the single domain antibodies and binding molecules.

Description

[0001] SINGLE DOMAIN ANTIBODIES AGAINST BETA CORONAVIRUS SPIKE PROTEIN S2 DOMAIN

[0002] Field of the Invention

[0003] The present invention relates to novel single domain antibodies which bind to the S2 subunit of the spike glycoprotein of beta-coronaviruses. The invention also relates to binding molecules comprising the single domain antibodies. Also provided are uses of the single domain antibodies and binding molecules, and pharmaceutical compositions comprising the single domain antibodies and binding molecules.

[0004] Background to the Invention

[0005] The spike (S) proteins of SARS-CoV-2 and other beta-coronaviruses play a key role in receptor recognition and in the cell membrane fusion and viral internalisation process. The spike protein forms trimers on the surface of the virions and comprise two subunits, SI and S2. The SI subunit contains a receptor-binding domain (RBD) that recognises and binds to the host receptor angiotensin-converting enzyme 2 (ACE-2). Following receptor binding through the S1 subunit, the spike proteins undergo cleavage between SI and S2 followed by conformational re-arrangement of the S2 subunit to expose the fusion peptide. This leads to fusion of the host and viral membranes and internalisation of the viral genome.

[0006] There is a need for identifying further treatment methods for preventing, treating and / or diagnosing beta-coronavirus infections, and diseases and / or complications associated with beta-coronavirus infections (e.g. COVID-19).

[0007] Summary of the Invention

[0008] Immune escape of SARS-CoV-2 has compromised many neutralising antibodies that bind to the ACE-2 receptor binding region of the virus spike protein (S1). The amino acid sequences of the S2 subunit of SARS-Cov-2 variants are highly conserved (98-100 % identity) compared to the SI subunit (46 % vs 29 %). This conservation extends to other beta- coronaviruses. Therefore, targeting the S2 subunit for the development of vaccines and antibody-based therapeutics may lead to greater resistance to escape mutants and have the prospect of generating broadly cross-reactive antibodies against current and possible future beta-coronaviruses. The present inventors have identified new single domain antibodies that bind to the spike glycoprotein of beta-coronaviruses with high affinity and have shown neutralising activity for live virus in a cell-based infection assay. These single domain antibodies bind to the S2 subunit and are less vulnerable to immune escape. Furthermore, unlike known monoclonal antibodies that target the S2 subunit, the single domain antibodies of the invention do not bind to the fusion peptide or stem-helix sequence and may thus exhibit a new epitope and / or mode of binding. One theory is that by binding to the S2 of the pre- fusion state of the spike protein, the single domain antibodies of the invention prevent the conformational changes that are required to transition to a post-fusion state that exposes the fusion peptide in the S2 subunit required for fusion with the host cell following receptor engagement with the S1 subunit of the spike protein. The single domain antibodies of the invention therefore have use as therapeutics against a broad range of beta-coronaviruses by targeting the S2 subunit of the spike protein which is highly conserved between different viral subgroups. Accordingly, in a first aspect of the invention, there is provided a single domain antibody that binds to the S2 subunit of the spike glycoprotein of a beta-coronavirus. In a second aspect of the invention, there is provided a binding molecule comprising one or more of the single domain antibodies as described herein. In a third aspect, the present invention provides one or more polynucleotides encoding a single domain antibody or binding molecule as described herein. In a fourth aspect, the present invention provides a vector comprising the one or more polynucleotides as described herein. In a fifth aspect, the present invention provides a host cell comprising the one or more polynucleotides and / or the vector as described herein. In a sixth aspect, the present invention provides a pharmaceutical composition comprising the single domain antibody, binding molecule, one or more polynucleotides, vector, and / or host cell described herein, and optionally a pharmaceutically acceptable carrier and / or excipient. In a seventh aspect, the present invention provides the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein, for use in a method for treatment of a human or animal by therapy. In an eighth aspect, the present invention provides the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein, for use in a method of treating or preventing beta-coronavirus infection, or a disease or complication associated with beta-coronavirus infection. In a ninth aspect, the present invention provides a method of treating or preventing beta- coronavirus infection, or a disease or complication associated with beta-coronavirus infection, wherein the method comprises administering a therapeutically effective amount of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein, to said subject. In a tenth aspect, the present invention provides use of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein for preventing, treating and / or diagnosing beta-coronavirus infection, or a disease or complication associated therewith. In an eleventh aspect, the present invention provides use of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein for the manufacture of a medicament for treating or preventing beta-coronavirus infection, or a disease or complication associated therewith. In a twelfth aspect, the present invention provides a method of detecting beta-coronavirus in a subject, comprising: contacting a sample obtained from the subject with the single domain antibody and / or the binding molecule as described herein, and detecting the presence or absence of an antibody-antigen or binding molecule-antigen complex, wherein the presence of the antibody-antigen or binding molecule-antigen complex indicates the presence of beta- coronavirus in the subject. In a thirteenth aspect, the present invention provides a method for diagnosing beta- coronavirus infection in a subject, comprising: contacting a sample obtained from the subject with the single domain antibody and / or the binding molecule as described herein, and detecting the presence or absence of an antibody-antigen or binding molecule-antigen complex, wherein the presence of the antibody-antigen or binding molecule-antigen complex provides a positive diagnosis of beta-coronavirus in the subject. In a fourteenth aspect, the present invention provides a method of treating or preventing beta- coronavirus infection, or a disease or complication associated therewith, in a subject, the method comprising detecting the presence of beta-coronavirus according to the method of detecting coronavirus described herein in a sample, and treating the subject with the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell, and / or pharmaceutical composition as described herein, an anti-viral drug, or an anti-inflammatory agent. Description of the Figures Figure 1 - Venn diagram showing the number of VHH sequences that were either common or unique from panning the spike VHH libraries with either SARS-CoV-2 or MERS-CoV S2 trimers. Figure 2 – Titration ELISA of VHH-Fcs (MERS C9-Fc, MERS A4-Fc and BA.1 A7-Fc) (0.0001 – 1000 µg / ml) binding to either MERS-CoV S2 trimer or monomer proteins detected with an anti-human IgG Fc -Horse Radish Protein (HRP) reporter giving a colorimetric readout at 405 nm. Figure 3 - Checkerboard of epitope binning results for anti-VHH monomers binding to SARS-CoV-2 BA.1 S2 trimers measured by Biolayer Interferometry (BLI). Competitive binding to BA.1 S2 trimers between two VHH-Fcs is shown by light grey shading and no competition by dark grey shading. Mid-grey shaded cells represent the results of competition between the same two VHH-Fcs which did not need to be tested. Figure 4 - Binding of various VHH-Fcs (100 µg / ml) to SARS-CoV-2 BA.1 S2 trimer in the presence of B6 Fab (10 µg / ml) with VHH-Fcs detected with an anti-human IgG1-HRP antibody conjugate and B6 with an anti-mouse light chain HRP conjugate giving a colorimetric readout at 405 nm. Figure 5 - Heptad Repeat 2 (HR2) sequences. (a) The HR2 sequence defined by Uniprot (re. PODCT2) is underlined. The positions of the residue changes in the escape mutants following passaging with either BA.1-C2 (Q1201K) or BA.1-D2 are indicated in bold (S1175P). (b) Alignment of the HR2 sequences of Hu-OC43-CoV, MERS-CoV and SARS- Cov-2 with identical residues shown in bold. Figure 6 – Microneutralisation assay of un-passaged JN.1 (•) compared to D3C2 passaged virus (▪) after 5 (left) and 10 passages (right). Measured as percentage of Focus Forming Units (FFU). Error bars demark standard deviation. N=1. Figure 7 - Neutralisation of live MERS-CoV virus by MERS-C9 (grey diamond). MERS- S1_F2-Fc (▪) and Mab B6 (•) are positive controls. Figure 8 - Structural localisation of the MERS-C9 epitope. (a) Cryo-EM structure of the trimeric spike protein of HuOC43-CoV in complex with nanobody, MERS-C9 showing location of the binding site. (b) Ribbon diagram of the spike (dark grey): MERS-C9 (white) interface showing key contact residues that from the hydrophobic pocket occupied by the F103 in the CDR3 of the nanobody. Figure 9 - Multiple sequence alignment of the carboxy terminal region of the spike proteins of HuOC43-CoV, MERS-CoV and SARS-CoV-2 (Uniprot IDs P36334, R9UQ53, PODCT2). Identical residues are shown in dark boxes and similar residues in outlined boxes. Arrows mark the residues involved in the interaction with the CDR3 of MERS-C9. The numbering in the alignment is based on the HuCoV-OC43 sequence. Detailed Description It is to be understood that different applications of the disclosed products and methods may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a single domain antibody” includes “single domain antibodies”, and the like. Single domain antibody The term “single domain antibody” is interchangeable with “sdAb”, “nanobody”, or “VHH”. A single domain antibody is a monomeric antigen-binding polypeptide comprising a single variable antibody domain and lacking the constant domains present in conventional immunoglobulins (‘antibodies’). Single domain antibodies typically achieve binding affinities on a par with conventional immunoglobulins. Binding properties are primarily conferred by three linear peptide portions known as the complementarity determining regions (CDRs) 1, 2 and 3 (from N-terminus to C-terminus) interspersed between four structural framework regions (FRs) 1, 2, 3 and 4. The sequences of the framework regions are relatively conserved within a species and serve to position and align the CDRs in three-dimensional space. The variable antibody domain is usually a heavy chain variable region (VH) but may also be a light chain variable region (VL). Single domain antibodies occur in nature as VHH (VHH or VHH) in camelids (camels, llamas, alpacas etc.) and VNAR (or ‘VNAR’) in cartilaginous fish (e.g. sharks) or can be engineered from, for example, conventional immunoglobulins. Single domain antibodies, such as VHHs, have binding capabilities similar to those of conventional monoclonal antibodies but are typically less immunogenic and can target antigens and epitopes that are considered difficult or intractable for typical antibodies. Single domain antibodies canonically do not pair with a respective light (or heavy) chain, avoiding improper chain pairing. Their adaptability in formatting and engineering into multiple therapeutic formats, as well as their high thermal stability, make them an essential asset in drug development. The term “fragment” of a single domain antibody, typically refers to an “antigen binding fragment” of said antibody, i.e. one or more fragments of a single domain antibody that retain the ability to specifically bind to an antigen. Such a fragment retains the ability to bind to the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, Middle Eastern respiratory syndrome coronavirus (MERS-CoV), and / or hCoV-OC43) as described herein. These fragments or antigen binding fragments may be obtained using conventional techniques known to those of skill in the art. For example, fragments or antigen binding fragments can be produced by the modification of whole antibodies or synthesized de novo using recombinant DNA methodologies. The term “binding affinity” refers to the tendency of an antibody molecule to bind or not to bind to a target. Binding affinity may be quantified by determining the dissociation constant (Kd) for an antibody and its target. Similarly, the specificity of binding of an antibody to its target may be defined in terms of the comparative dissociation constants (Kd) of the antibody for its target as compared to the dissociation constant with respect to the antibody and another, non-target molecule. Typically, the Kd for the antibody with respect to the target will be 2-fold, preferably 5-fold, more preferably 10-fold less than Kd with respect to the other, non-target molecule. More preferably, the Kd will be 50- fold less, even more preferably 100-fold less, and yet more preferably 200-fold less. The value of this dissociation constant can be determined directly by well-known methods and can be computed even for complex mixtures by methods such as those, for example, set forth in Caceci et al. (Byte 9:340-362, 1984). Such methods may include, for example, ELISA or Biacore (i.e., surface plasmon resonance). Preferably, the binding affinities are measured by bio-layer interferometry (BLI). A single domain antibody of the invention binds (e.g. specifically binds) to the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43), that is it binds preferably to the S2 subunit of spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43), compared to other molecules, or binds at a lower affinity to other molecules. For example, the single domain antibody may bind to the S2 subunit of the spike glycoprotein, such as an S2 trimer. “Specifically binds” means that a single domain antibody binds the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV- OC43), with greater affinity than to another target. Specific binding can be determined by methods known in the art. A single domain antibody of the invention is preferably capable of binding to the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43) with an affinity that is at least two-fold, 10-fold, 50-fold, 100-fold or greater than its affinity for binding to another non-target molecule. Preferably, a single domain antibody described herein may have a binding affinity (i.e., Kd) for the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43) of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In one embodiment, the single domain antibody described herein has broad specificity for beta- coronaviruses and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein specifically binds to the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant) and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein specifically binds to the S2 subunit of the spike glycoprotein of SARS-CoV-1 and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein specifically binds to the S2 subunit of the spike glycoprotein of MERS-CoV and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein specifically binds to the S2 subunit of the spike glycoprotein of hCoV-OC43 and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant) and SARS-CoV-1, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant) and MERS-CoV, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant) and hCoV-OC43, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-1 and MERS-CoV, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-1 and hCoV-OC43 and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of MERS-CoV and hCoV-OC43 and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1 and MERS-CoV, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1 and hCoV-OC43, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), MERS-COV and hCoV-OC43, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of SARS-CoV-1, MERS-COV and hCoV-OC43, and does not bind or has a lower binding affinity for other targets. In one embodiment, the single domain antibody described herein has specificity for the S2 subunit of the spike glycoprotein of all of SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and hCoV-OC43, and does not bind or has a lower binding affinity for other targets. In some embodiments, the single domain antibody described herein binds to any beta- coronavirus. In some embodiments, the single domain antibody described herein binds to more than one beta-coronavirus. In some embodiments, the single domain antibody described herein binds to all beta-coronaviruses. In some embodiments, the single domain antibody described herein has neutralising activity against the beta-coronavirus. In some embodiments, the single domain antibody described herein has neutralising activity against more than one beta-coronavirus. For example, the single domain antibody described herein may be able to neutralise at least one biological activity of the beta-coronavirus, such as to neutralise virus infectivity. The ability of an antibody to neutralise virus infectivity may be measured using an appropriate assay, particularly using a cell-based neutralisation assay, as is known in the art and is described in Example 1. Neutralisation may be determined using a micro-neutralisation assay and measuring the neutralisation titre (NT50) values, e.g. the titre of VHH trimer that reduces the Foci forming unit (FFU) by 50% compared to control wells. For example, live viruses may be pre-incubated with serially diluted VHH trimer and then added to Vero E6 cells. Following incubation for approximately 24 hours, the number of infected cells is quantified by staining with an anti-SARS-CoV-2 nucleoprotein antibody. The beta-coronavirus may be from the subgenera Sarbevirus, Merbevirus or Embevirus. The beta-coronavirus may be SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2, hCoV-OC43 or HUK1. The single domain antibody described herein may bind SARS-CoV-2 variants such as the prototypical, for example Victoria, variant or the earliest identified Wuhan variant (hCoV- 19 / Wuhan / WIV04 / 2019 (WIV04); GISAID accession no. EPI_ISL_402124), an alpha variant (B.1.1.7 / UK or Kent variant), a beta variant (B.1.351 / South African variant), a gamma variant (P.1 / Brazilian variant), a delta variant (B.1.617.2 / Indian variant), an epsilon variant (B.1.427 / B.1.429 variant), a zeta variant (P.2 variant), an eta variant (B.1.525 variant), a theta variant (P.3 variant), an iota variant (B.1.526 variant), a kappa variant (B.1.617.1 variant), an omicron variant, BA.1, BA.1.1, BA.2, BA.2.10.1, BA.2.10.4, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4 / 5, BA.4.6, BQ.1, BQ.1.1, BJ.1, BS.1, BF.7, BN.1, XBB, XBB.1, XBB1.5, JN.1, EG.5.1, or a subvariant thereof. The variant or subvariant thereof may be an as-yet- unidentified variant or subvariant thereof of SARS-CoV-2 comprising mutations in the RBD and / or N-terminal domain (NTD) already identified in existing variants. The SARS-CoV-2 variant or subvariant may comprise one or more mutations, e.g. in the spike protein, compared to any of the variants and subvariants discussed herein. The single domain antibody described herein may also bind the S2 subunit of the spike glycoprotein of SARS-CoV-1 variants or subvariants thereof, hCoV-OC43 variants or subvariants thereof, or MERS-CoV variants or subvariants thereof from lineages of clades A, B and C. For example, the SARS-CoV-1 variants may be HSZ-2, CUHK-W1, or BJ01, or subvariants thereof. The OC43 variants may be HCoV-OC43-HK09, HCoV-OC43-HK04, HCoV-OC43-BE03, or HCoV-OC43-Paris, or subvariants thereof. The MERS-CoV variants may be EMC / 2012, Ethi-118S, or Nigeria, or subvariants thereof. The variant or subvariant thereof may be an as-yet-unidentified variant or subvariant thereof of SARS-CoV-1, hCoV- OC43 or MERS-CoV2 comprising mutations in the RBD and / or N-terminal domain (NTD) already identified in existing variants. The variant or subvariant may comprise one or more mutations, e.g. in the spike protein, compared to any of the variants and subvariants discussed herein. In some embodiments, the single domain antibody described herein binds to the Heptad Repeat 2 (HR2) sequence in the S2 subunit of the spike glycoprotein of a beta-coronavirus described herein. In some aspects, the beta-coronavirus is SARS-CoV-2. In some aspects, the beta-coronavirus is SARS-CoV-1. In some aspects, the antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 4. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 49. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 3. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 48. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 3, a CDR2 consisting of the sequence of SEQ ID NO: 4, and a CDR3 consisting of the sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 2 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 2. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 3, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 4, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 5, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 2. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 48, a CDR2 consisting of the sequence of SEQ ID NO: 49, and a CDR3 consisting of the sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 47 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 47. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 48, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 49, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 50, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 47. The term “epitope” generally refers to the site on a target antigen which is recognised by an antibody. Epitopes may be defined structurally or functionally. Functional epitopes are generally a subset of the structural epitopes and comprise residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non- linear (or discontinuous) amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and / or specific charge characteristics. A single domain antibody described herein may bind to an epitope comprising at least one amino acid residue selected from S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210 of SEQ ID NO: 131. The single domain antibody described herein may bind an epitope which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of these residues. The single domain antibody described herein may bind an epitope which comprises S794, F796, V999, L1006, I1007, Y1194, and Y1195. Preferably, the single domain antibody binds to an epitope comprising all of S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210. For example, single particle cryo-Electron Microscopy (EM) of spike protein-single domain antibody complexes may be used to map the epitope of the single domain antibody. Although these residues are provided for a particular sequence of the spike glycoprotein (i.e. SEQ ID NO: 131), the skilled person could readily extrapolate the positions of these residues to other corresponding spike glycoprotein sequences (e.g. from other beta-coronaviruses e.g. SARS-CoV-2, MERS-CoV, HuOC43-CoV, and variants or subvariants thereof) using routine techniques. For example, the skilled person could readily align the sequences of the various spike glycoproteins and extrapolate the relevant corresponding positions (see e.g. Figure 9 and Table 6). In some instances, the residues are highly conserved between different corresponding spike glycoprotein sequences which may suggest that a single domain antibody described herein is likely to bind to all the corresponding spike glycoprotein sequences (such as those shown in Figure 9). Single domain antibodies binding to epitopes comprising the corresponding residues within these other spike glycoprotein sequences are therefore also provided by the invention. For example, in some instances, the single domain antibody binds to an epitope comprising at least one amino acid residue at a position corresponding to a position selected from the group consisting of S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210 of SEQ ID NO: 131. The single domain antibody described herein may bind an epitope which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of these residues. The single domain antibody described herein may bind an epitope which comprises S794, F796, V999, L1006, I1007, Y1194, and Y1195. Preferably, the single domain antibody binds to an epitope comprising all of S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210. Amino acids “corresponding to” specified positions of a specified SEQ ID NO may be amino acids at the specified positions of the particular SEQ ID NO recited. For example, the amino acid “corresponding to position 794 of SEQ ID NO: 131” may be the amino acid at position 794 of SEQ ID NO: 131, namely a serine (S). Alternatively, amino acids “corresponding to” specified positions of a specified SEQ ID NO may be amino acids from an alternative amino acid sequence which correspond to the specified positions of the specified SEQ ID NO. For example, the amino acid “corresponding to position 794 of SEQ ID NO: 131” may be the amino acid from an alternative amino acid sequence which corresponds to position 794 of SEQ ID NO: 131. It is within the capabilities of the person skilled in the art to determine which amino acids in an alternative amino acid sequence “correspond to” the specified positions in the specified SEQ ID NO e.g. by sequence alignment or comparison of structures, including comparison of antibody:spike glycoprotein complexes. For example, the person skilled in the art merely needs to perform a sequence alignment of the alternative amino acid sequence with the specified SEQ ID NO using a suitable alignment algorithm such as that of Needleman and Wunsch described herein, and determine which region of the alternative amino acid sequence aligns to the specified positions in the specified SEQ ID NO. For example, the skilled person is able to align the alternative amino acid sequence with SEQ ID NO: 131 and determine which amino acid aligns, and therefore corresponds to, e.g. position 794 of SEQ ID NO: 131. The epitope may be determined by X-ray crystallography analysis and / or epitope binning using bio-layer interferometry (e.g. Rich & Myszka (2007), Anal. Biochem. 361(1):1-6). For example, the epitope of the single domain antibody described herein may be assessed through X-ray crystallography analysis of the single domain antibody bound to the spike glycoprotein of a beta-coronavirus. The crystal structure may for example be determined to resolutions of 1.97 Å. To screen for single domain antibodies that bind to a particular epitope, a routine cross-blocking assay such as that described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY) can be performed. Other methods include alanine scanning mutants, peptide blots (Reineke (2004) Methods Mol Biol 248:443-63), or peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487- 496). X-ray crystallography may also be used. Viral escape studies may also be used to help determine the binding site of the single domain antibodies. Furthermore, single particle cryo- Electron Microscopy (EM) of spike protein- single domain antibody complexes may also be used to map the epitope of a single domain antibody. Such methods are well known in the art. In some instances, the single domain antibody does not compete for binding with an antibody that binds to a linear epitope in the stem helix region or an epitope in the fusion peptide of the S2 subunit of a spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and hCoV-OC43). In some embodiments, the linear epitope in the stem helix corresponds to residues 1142 to 1247 of SARS-CoV-2 BA.1. In some embodiments, the epitope in the fusion peptide is accessible in a post-fusion state. In some embodiments, the epitope in the fusion peptide correspond to residues 796 to 828 of SARS-CoV-2 BA.1. Competition for binding can be easily determined using routine methods known in the art and as described herein. A single domain antibody of the invention may bind to the same epitope as, or compete for binding to the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and hCoV- OC43) with, any one of the single domain antibodies described herein. One can easily determine whether a test single domain antibody binds to the same epitope as, or competes for binding with, a reference antibody by using routine methods known in the art (e.g. epitope binning using bio-layer interferometry (BLI)). For example, to determine if a test antibody binds to the same epitope as a reference antibody, the reference antibody is allowed to bind to a protein or peptide (e.g. a SARS-CoV-2 BA.1 S2 trimer) under saturating conditions. The ability of a test antibody to bind to the protein or peptide (e.g. a SARS-CoV-2 BA.1 S2 trimer) is then assessed. If the test antibody is able to bind to the protein or peptide (e.g. a SARS-CoV-2 BA.1 S2 trimer) following saturation binding with the reference antibody, it can be concluded that there is no competition and therefore the test antibody binds to a different epitope than the reference antibody. On the other hand, if the test antibody is not able to bind to or binds less to protein or peptide following saturation binding with the reference antibody, then the test antibody may bind or partially bind to the same epitope as the epitope bound by the reference antibody. For example, in some instances, a single domain antibody comprising the sequence of SEQ ID NO: 2 may cross-compete for binding to the S2 subunit of the spike glycoprotein of a SARS-CoV-2 variant or subvariant thereof (e.g. BA.1) with the single domain antibody comprising the sequence of SEQ ID NO: 7. Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50%, 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res, 1990:50:1495-1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. In some embodiments, the single domain antibody of the invention may not bind to the same epitope as, or compete for binding to the spike glycoprotein of a beta-coronavirus (e.g. SARS- CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and hCoV-OC43) with, any one of the single domain antibodies described herein. For example, in some instances, a single domain antibody comprising the sequence of SEQ ID NO: 2 or 27 may not cross-compete for binding to the S2 subunit of the spike glycoprotein of a SARS- CoV-2 variant or subvariant thereof (e.g. BA.1) with the single domain antibody comprising the sequence of SEQ ID NO: 3. In some embodiments, the single domain antibody does not bind to a linear epitope in the stem helix region or an epitope in the fusion peptide of the S2 subunit of a spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and hCoV-OC43). In some embodiments, the linear epitope in the stem helix corresponds to residues 1142 to 1247 of SARS-CoV-2 BA.1. In some embodiments, the epitope in the fusion peptide is accessible in a post-fusion state. In some embodiments, the epitope in the fusion peptide correspond to residues 796 to 828 of SARS- CoV-2 BA.1. The complementarity-determining regions (CDRs) found within the heavy chain variable region of the single domain antibodies may be identified by any suitable method known in the art, for example using any suitable antibody numbering scheme. Suitable methods include the Kabat numbering scheme (Kabat et al., U.S. Department of Health and Human Services, 1991), the Chothia numbering scheme (Chothia C, Lesk A M. J Mol Biol. (1987) 196:901- 17), or the IMGT numbering scheme (Giudicelli V, et al. Nucleic Acids Res. (1997) 25:206- 11; Lefranc MP. Immunol Today (1997) 18:509). The skilled person will appreciate that these different CDR labelling systems can give slightly different results, but in each case the CDRs can be easily identified by the skilled person. Preferably, the CDRs are identified using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 3, 4, and 5 are the three CDRs of SEQ ID NO: 2 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 8, 9, and 10 are the three CDRs of SEQ ID NO: 7 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 13, 14, and 15 are the three CDRs of SEQ ID NO: 12 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 18, 19, and 20 are the three CDRs of SEQ ID NO: 17 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 23, 24, and 25 are the three CDRs of SEQ ID NO: 22 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 28, 29, and 30 are the three CDRs of SEQ ID NO: 27 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 33, 34, and 35 are the three CDRs of SEQ ID NO: 32 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 38, 39, and 40 are the three CDRs of SEQ ID NO: 37 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 43, 44, and 45 are the three CDRs of SEQ ID NO: 42 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 48, 49, and 50 are the three CDRs of SEQ ID NO: 47 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 53, 54, and 55 are the three CDRs of SEQ ID NO: 52 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 58, 59, and 60 are the three CDRs of SEQ ID NO: 57 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 63, 64, and 65 are the three CDRs of SEQ ID NO: 62 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 68, 69, and 70 are the three CDRs of SEQ ID NO: 67 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 73, 74, and 75 are the three CDRs of SEQ ID NO: 72 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 78, 79, and 80 are the three CDRs of SEQ ID NO: 77 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 83, 84, and 85 are the three CDRs of SEQ ID NO: 82 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 88, 89, and 90 are the three CDRs of SEQ ID NO: 87 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 93, 94, and 95 are the three CDRs of SEQ ID NO: 92 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 98, 99, and 100 are the three CDRs of SEQ ID NO: 97 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 103, 104, and 105 are the three CDRs of SEQ ID NO: 102 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 108, 109, and 110 are the three CDRs of SEQ ID NO: 107 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 113, 114, and 115 are the three CDRs of SEQ ID NO: 112 as defined using the IMGT numbering scheme. The CDR sequences set out in SEQ ID NOs: 118, 119, and 120 are the three CDRs of SEQ ID NO: 117 as defined using the IMGT numbering scheme. The present invention relates to single domain antibodies that bind to the S2 subunit of the spike glycoprotein of a beta-coronavirus. In some aspects, the antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 15. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 20. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 25. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 30. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 35. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 40. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 45. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 55. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 60. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 65. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 70. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 75. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 80. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 85. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 90. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 95. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 100. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 105. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 110. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 115. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 120. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 4. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 9. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 14. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 19. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 24. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 29. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 34. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 39. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 44. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 49. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 54. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 59. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 64. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 69. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 74. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 79. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 84. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 89. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 94. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 99. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 104. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 109. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 114. In some aspects, the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 119. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 3. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 13. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 18. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 23. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 28. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 33. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 38. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 43. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 48. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 53. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 58. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 63. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 68. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 73. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 78. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 83. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 88. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 93. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 98. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 103. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 108. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 113. In some aspects, the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 118. In some aspects, the single domain antibody comprises a CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120. The single domain antibody may further comprise a CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 4, 9, 14, 19, 24, 29, 34, 39, 44, 49, 54, 59, 64, 69, 74, 79, 84, 89, 94, 99, 104, 109, 114, or 119. The single domain antibody may further comprise a CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 53, 58, 63, 68, 73, 78, 83, 88, 93, 98, 103, 108, 113, or 118. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 3, a CDR2 consisting of the sequence of SEQ ID NO: 4, and a CDR3 consisting of the sequence of SEQ ID NO: 5. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 2 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 2. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 2. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 3, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 4, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 5, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 2. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 8, a CDR2 comprising the sequence of SEQ ID NO: 9, and a CDR3 comprising the sequence of SEQ ID NO: 10. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 8, a CDR2 consisting of the sequence of SEQ ID NO: 9, and a CDR3 consisting of the sequence of SEQ ID NO: 10. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 7 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 7. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 7. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 7. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 7. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 8, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 9, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 10, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 7. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 13, a CDR2 comprising the sequence of SEQ ID NO: 14, and a CDR3 comprising the sequence of SEQ ID NO: 15. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 13, a CDR2 consisting of the sequence of SEQ ID NO: 14, and a CDR3 consisting of the sequence of SEQ ID NO: 15. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 12 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 12. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 12. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 12. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 12. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 13, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 14, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 15, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 12. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 18, a CDR2 comprising the sequence of SEQ ID NO: 19, and a CDR3 comprising the sequence of SEQ ID NO: 20. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 18, a CDR2 consisting of the sequence of SEQ ID NO: 19, and a CDR3 consisting of the sequence of SEQ ID NO: 20. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 17 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 17. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 17. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 17. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 17. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 18, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 19, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 20, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 17. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 23, a CDR2 comprising the sequence of SEQ ID NO: 24, and a CDR3 comprising the sequence of SEQ ID NO: 25. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 23, a CDR2 consisting of the sequence of SEQ ID NO: 24, and a CDR3 consisting of the sequence of SEQ ID NO: 25. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 22 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 22. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 22. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 22. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 22. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 23, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 24, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 25, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 22. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 28, a CDR2 comprising the sequence of SEQ ID NO: 29, and a CDR3 comprising the sequence of SEQ ID NO: 30. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 28, a CDR2 consisting of the sequence of SEQ ID NO: 29, and a CDR3 consisting of the sequence of SEQ ID NO: 30. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 27 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 27. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 27. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 27. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 27. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 28, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 29, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 30, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 27. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 33, a CDR2 comprising the sequence of SEQ ID NO: 34, and a CDR3 comprising the sequence of SEQ ID NO: 35. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 33, a CDR2 consisting of the sequence of SEQ ID NO: 34, and a CDR3 consisting of the sequence of SEQ ID NO: 35. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 32 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 32. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 32. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 32. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 32. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 33, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 34, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 35, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 32. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 38, a CDR2 comprising the sequence of SEQ ID NO: 39, and a CDR3 comprising the sequence of SEQ ID NO: 40. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 38, a CDR2 consisting of the sequence of SEQ ID NO: 39, and a CDR3 consisting of the sequence of SEQ ID NO: 40. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 37 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 37. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 37. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 37. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 37. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 38, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 39, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 40, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 37. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 43, a CDR2 comprising the sequence of SEQ ID NO: 44, and a CDR3 comprising the sequence of SEQ ID NO: 45. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 43, a CDR2 consisting of the sequence of SEQ ID NO: 44, and a CDR3 consisting of the sequence of SEQ ID NO: 45. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 42 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 42. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 42. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 42. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 42. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 43, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 44, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 45, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 42. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 48, a CDR2 consisting of the sequence of SEQ ID NO: 49, and a CDR3 consisting of the sequence of SEQ ID NO: 50. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 47 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 47. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 47. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 48, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 49, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 50, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 47. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 53, a CDR2 comprising the sequence of SEQ ID NO: 54, and a CDR3 comprising the sequence of SEQ ID NO: 55. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 53, a CDR2 consisting of the sequence of SEQ ID NO: 54, and a CDR3 consisting of the sequence of SEQ ID NO: 55. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 52 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 52. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 52. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 52. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 52. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 53, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 54, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 55, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 52. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 58, a CDR2 comprising the sequence of SEQ ID NO: 59, and a CDR3 comprising the sequence of SEQ ID NO: 60. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 58, a CDR2 consisting of the sequence of SEQ ID NO: 59, and a CDR3 consisting of the sequence of SEQ ID NO: 60. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 57 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 57. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 57. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 57. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 57. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 58, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 59, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 60, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 57. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 63, a CDR2 comprising the sequence of SEQ ID NO: 64, and a CDR3 comprising the sequence of SEQ ID NO: 65. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 63, a CDR2 consisting of the sequence of SEQ ID NO: 64, and a CDR3 consisting of the sequence of SEQ ID NO: 65. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 62 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 62. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 62. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 62. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 62. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 63, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 64, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 65, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 62. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 68, a CDR2 comprising the sequence of SEQ ID NO: 69, and a CDR3 comprising the sequence of SEQ ID NO: 70. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 68, a CDR2 consisting of the sequence of SEQ ID NO: 69, and a CDR3 consisting of the sequence of SEQ ID NO: 70. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 67 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 67. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 67. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 67. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 67. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 68, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 69, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 70, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 67. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 73, a CDR2 comprising the sequence of SEQ ID NO: 74, and a CDR3 comprising the sequence of SEQ ID NO: 75. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 73, a CDR2 consisting of the sequence of SEQ ID NO: 74, and a CDR3 consisting of the sequence of SEQ ID NO: 75. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 72 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 72. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 72. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 72. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 72. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 73, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 74, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 75, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 72. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 78, a CDR2 comprising the sequence of SEQ ID NO: 79, and a CDR3 comprising the sequence of SEQ ID NO: 80. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 78, a CDR2 consisting of the sequence of SEQ ID NO: 79, and a CDR3 consisting of the sequence of SEQ ID NO: 80. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 77 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 77. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 77. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 77. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 77. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 78, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 79, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 80, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 77. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 83, a CDR2 comprising the sequence of SEQ ID NO: 84, and a CDR3 comprising the sequence of SEQ ID NO: 85. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 83, a CDR2 consisting of the sequence of SEQ ID NO: 84, and a CDR3 consisting of the sequence of SEQ ID NO: 85. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 82 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 82. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 82. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 82. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 82. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 83, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 84, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 85, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 82. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 88, a CDR2 comprising the sequence of SEQ ID NO: 89, and a CDR3 comprising the sequence of SEQ ID NO: 90. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 88, a CDR2 consisting of the sequence of SEQ ID NO: 89, and a CDR3 consisting of the sequence of SEQ ID NO: 90. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 87 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 87. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 87. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 87. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 87. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 88, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 89, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 90, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 87. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 93, a CDR2 comprising the sequence of SEQ ID NO: 94, and a CDR3 comprising the sequence of SEQ ID NO: 95. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 93, a CDR2 consisting of the sequence of SEQ ID NO: 94, and a CDR3 consisting of the sequence of SEQ ID NO: 95. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 92 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 92. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 92. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 92. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 92. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 93, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 94, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 95, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 92. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 98, a CDR2 comprising the sequence of SEQ ID NO: 99, and a CDR3 comprising the sequence of SEQ ID NO: 100. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 98, a CDR2 consisting of the sequence of SEQ ID NO: 99, and a CDR3 consisting of the sequence of SEQ ID NO: 100. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 97 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 97. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 97. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 97. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 97. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 98, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 99, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 100, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 97. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 103, a CDR2 comprising the sequence of SEQ ID NO: 104, and a CDR3 comprising the sequence of SEQ ID NO: 105. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 103, a CDR2 consisting of the sequence of SEQ ID NO: 104, and a CDR3 consisting of the sequence of SEQ ID NO: 105. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 102 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 102. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 102. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 102. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 102. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 103, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 104, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 105, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 102. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 108, a CDR2 comprising the sequence of SEQ ID NO: 109, and a CDR3 comprising the sequence of SEQ ID NO: 110. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 108, a CDR2 consisting of the sequence of SEQ ID NO: 109, and a CDR3 consisting of the sequence of SEQ ID NO: 110. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 107 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 107. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 107. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 107. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 107. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 108, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 109, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 110, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 107. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 113, a CDR2 comprising the sequence of SEQ ID NO: 114, and a CDR3 comprising the sequence of SEQ ID NO: 115. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 113, a CDR2 consisting of the sequence of SEQ ID NO: 114, and a CDR3 consisting of the sequence of SEQ ID NO: 115. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 112 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 112. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 112. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 112. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 112. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 113, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 114, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 115, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 112. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 118, a CDR2 comprising the sequence of SEQ ID NO: 119, and a CDR3 comprising the sequence of SEQ ID NO: 120. In some aspects, the single domain antibody comprises a CDR1 consisting of the sequence of SEQ ID NO: 118, a CDR2 consisting of the sequence of SEQ ID NO: 119, and a CDR3 consisting of the sequence of SEQ ID NO: 120. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 117 or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity thereto. In some aspects, the single domain antibody comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 117. In some aspects, the single domain antibody comprises a sequence having at least 95% identity to the sequence of SEQ ID NO: 117. In some aspects, the single domain antibody comprises a sequence of SEQ ID NO: 117. In some aspects, the single domain antibody consists of a sequence of SEQ ID NO: 117. In some aspects, the single domain antibody comprises a CDR1 comprising or consisting of the sequence of SEQ ID NO: 118, a CDR2 comprising or consisting of the sequence of SEQ ID NO: 119, and a CDR3 comprising or consisting of the sequence of SEQ ID NO: 120, and wherein the single domain antibody comprises, or consists of, a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% identity to SEQ ID NO: 117. In some aspects, a single domain antibody comprising or consisting of the sequences described herein may have a KD of less than 500n M, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM. In some aspects, the CDRs may comprise one or more modifications. The modifications may be substitutions, deletions or insertions as described below. In one aspect, the modifications are substitutions. CDRs that comprise one or more modifications still maintain their function / activity. In some aspects, the amino acid sequences of CDR3 may comprise between 0 and 7, 0 and 6, 0 and 5, 0 and 4, 0 and 3, 0 and 2, or 0 and 1 modifications. In some aspects, the amino acid sequences of CDR3 may comprise one, two, three, four, five, six, or seven modifications. In some aspects, the amino acid sequences of CDR2 may comprise between 0 and 4, 0 and 3, 0 and 2, or 0 and 1 modifications. In some aspects, the amino acid sequences of CDR2 may comprise one, two, three, or four modifications. In some aspects, the amino acid sequences of CDR1 may comprise between 0 and 4, 0 and 3, 0 and 2, or 0 and 1 modifications. In some aspects, the amino acid sequences of CDR1 may comprise one, two, three, or four modifications. For the purpose of this invention, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotides or amino acid residues at each position are then compared. When a position in the first sequence is occupied by the same nucleotide or amino acid at the corresponding position in the second sequence, then the nucleotides or amino acids are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100). Typically, the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence is 95% identical to SEQ ID NO: 2, SEQ ID NO: 2 would be the reference sequence. To assess whether a sequence is at least 95% identical to SEQ ID NO: 2 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: 2, and identify how many positions in the test sequence were identical to those of SEQ ID NO: 2. If at least 95% of the positions are identical, the test sequence is at least 95% identical to SEQ ID NO: 2. If the test sequence is shorter than SEQ ID NO: 2, the gaps or missing positions should be considered to be non-identical positions. The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In one embodiment, the alignment generated over a certain portion of the sequence aligned having sufficient identity but not over portions having low degree of identity (i.e., a local alignment). A preferred, non-limiting example of a local alignment algorithm utilised for the comparison of sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithm is incorporated into the BLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. In another embodiment, the alignment is optimised by introducing appropriate gaps and percent identity is determined over the length of the aligned sequences (i.e., a gapped alignment). To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25(17):3389-3402. In another embodiment, the alignment is optimised by introducing appropriate gaps and percent identity is determined over the entire length of the sequences aligned (i.e., a global alignment). A preferred, non- limiting example of a mathematical algorithm utilized for the global comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. In another embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. A “polypeptide” is used herein in its broadest sense to refer to a compound of two or more subunit amino acids, amino acid analogs, or other peptidomimetics. The term “polypeptide” thus includes short peptide sequences and also longer polypeptides and proteins. The terms “protein” and “polypeptide” are used interchangeably herein, and are intended to refer to a polymeric chain of amino acids of any length. As used herein, the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics. A single domain antibody of the invention may alternatively comprise a variant of one or more of the specified sequences. A “variant” may be a substitution, deletion or addition variant of any of the above amino acid sequences. A variant may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30 or more amino acid substitutions and / or deletions from the specific sequences and fragments discussed above, whilst maintaining the activity / function of the single domain antibodies described herein. “Deletion” variants may comprise the deletion of, for example, 1, 2, 3, 4 or 5 individual amino acids. “Substitution” variants preferably involve the replacement of one or more amino acids with the same number of amino acids and making conservative amino acid substitutions. For example, an amino acid may be substituted with an alternative amino acid having similar properties, for example, another basic amino acid, another acidic amino acid, another neutral amino acid, another charged amino acid, another hydrophilic amino acid, another hydrophobic amino acid, another polar amino acid, another aromatic amino acid or another aliphatic amino acid. Some properties of the 20 main amino acids which can be used to select suitable substituents are as follows: Ala aliphatic, hydrophobic, neutral Met hydrophobic, neutral Cys polar, hydrophobic, neutral Asn polar, hydrophilic, neutral Asp polar, hydrophilic, charged (-) Pro hydrophobic, neutral Glu polar, hydrophilic, charged (-) Gln polar, hydrophilic, neutral Phe aromatic, hydrophobic, neutral Arg polar, hydrophilic, charged (+) Gly aliphatic, neutral Ser polar, hydrophilic, neutral His aromatic, polar, hydrophilic, Thr polar, hydrophilic, neutral charged (+) Ile aliphatic, hydrophobic, neutral Val aliphatic, hydrophobic, neutral Lys polar, hydrophilic, charged(+) Trp aromatic, hydrophobic, neutral Leu aliphatic, hydrophobic, neutral Tyr aromatic, polar, hydrophobic The substituents may also be selected from the amino acids selenocysteine and pyrrolysine. Preferred “derivatives” or “variants” include those in which instead of the naturally occurring amino acid the amino acid which appears in the sequence is a structural analog thereof. Amino acids used in the sequences may also be derivatized or modified, e.g. labelled, providing the function of the single domain antibody is not significantly adversely affected. Derivatives and variants as described above may be prepared during synthesis of the single domain antibody or by post-production modification, or when single domain antibody is in recombinant form using the known techniques of site-directed mutagenesis, random mutagenesis, or enzymatic cleavage and / or ligation of nucleic acids. For example, a single domain antibody can be labelled with a radiolabeled amino acid. Examples of radiolabels include, but are not limited to, the following radioisotopes or radionucleotides:3H,14C,15N,35S,90Y,99Tc,111In,125I,131I. The radiolabel may be used for both diagnostic and therapeutic purposes. The single domain antibodies described herein can be derivatized or linked to another molecule (such as another peptide or protein). In general, the single domain antibody is derivatized such that the binding to a target polypeptide such as the S2 subunit of the spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43), is not affected adversely by the derivatization or labelling. For example, the single domain antibody can be functionally linked, for example, by chemical coupling, genetic fusion, noncovalent association or otherwise to one or more other molecular entities, such as another antibody (for example, a bispecific antibody or a diabody), a detection agent, a pharmaceutical agent, and / or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag). An antigen binding domain that specifically binds to the S2 subunit of a spike glycoprotein of a beta-coronavirus (e.g. SARS-CoV-2 (such as Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43), can be labelled with a detectable moiety or marker as described herein. Means of detecting labels are well known to those of skill in the art. Thus, for example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted illumination. Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the coloured label. A single domain antibody can also be derivatized with a chemical group such as polyethylene glycol (PEG), a methyl or ethyl group, or a carbohydrate group. These groups may be useful to improve the biological characteristics of the antigen binding domain, such as to increase serum half-life or to increase tissue binding. In some embodiments, the single domain antibodies of the invention are “humanised” or partially humanised. Humanisation is the modification of amino acid residues within non- human derived sequences to reduce immunogenicity when administered to a human subject. Humanisation may be by grafting of non-human functional sequences (e.g. CDRs) onto human structural or scaffolding sequences (e.g. FRs), but is now more commonly achieved by mutation of residues within a non-human sequence to a counterpart residue occupying the equivalent position in a corresponding human homolog (‘back-mutation’). Preferably only the structural (e.g. framework) regions are humanised such that binding capabilities are not affected. In preferred aspects all parts of a humanised single domain antibody, except the CDRs, are substantially identical to (i.e., have at least 90% and preferably at least 95% sequence identity with) corresponding parts of natural human sequences. Methods of humanisation of single domain antibodies are known to the skilled person, see for example Vincke et al. (2009), J Biol Chem, 284(5):3273-3284. Following the same principle, the single domain antibodies of the invention can be modified to reduce immunogenicity in other species, such as non-human primates, cats, dogs, horses, mice, rats, cows, birds and pigs. Binding molecule The present invention also relates to a binding molecule comprising one or more of the single domain antibodies described here. In one aspect, the binding molecule may comprise one, two, three, four, five or more single domain antibodies. In some aspects, the binding molecule is multivalent. The term “multivalent” can be used interchangeably with “polyvalent” and as used herein describes a binding molecule that has multiple antigen binding sites. The multiple antigen binding sites may bind the same epitope or overlapping epitopes. In some aspects, a multivalent binding molecule comprises two or more single domain antibodies described herein. In some aspects, the two or more single domain antibodies are the same. In some aspects, the binding molecule may be bivalent, trivalent, or tetravalent. A “bivalent” binding molecule refers to a binding molecule that has two antigen binding sites. In some aspects, a bivalent binding molecule comprises two single domain antibodies described herein. In some aspects, the two single domain antibodies are the same. A “trivalent” binding molecule refers to a binding molecule that has three antigen binding sites. In some aspects, a trivalent binding molecule comprises three single domain antibodies described herein. In some aspects, the three single domain antibodies are the same. A “tetravalent” binding molecule refers to a binding molecule that has four antigen binding sites. In some aspects, a tetravalent binding molecule comprises four single domain antibodies described herein. In some aspects, the four single domain antibodies are the same. In a preferred aspect, the binding molecule is trivalent, preferably comprising three copies of a single domain antibody described herein. For example, the binding molecule may comprise three copies of a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5, or three copies of a single domain antibody comprising a sequence of SEQ ID NO: 2 or a variant thereof as described herein. The binding molecule may comprise three copies of a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50, or three copies of a single domain antibody comprising a sequence of SEQ ID NO: 47 or a variant thereof as described herein. The binding molecule may comprise three copies of a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 8, a CDR2 comprising the sequence of SEQ ID NO: 9, and a CDR3 comprising the sequence of SEQ ID NO: 10, or three copies of a single domain antibody comprising a sequence of SEQ ID NO: 7 or a variant thereof as described herein. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence having at least 90% identity to SEQ ID NO: 2. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 2. In some aspects, the binding molecule binds to the S2 subunit of the spike glycoprotein of a SARS-CoV-2 omicron variant or subvariant thereof e.g. BA.1 or JN.1, and neutralises the virus. In some aspects, the single domain antibodies in the binding molecule are joined by a (GS)3linker. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence having at least 90% identity to SEQ ID NO: 47. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 47. In some aspects, the binding molecule binds to the S2 subunit of the spike glycoprotein of a SARS-CoV-2 omicron variant or subvariant thereof e.g. BA.1 or JN.1, and neutralises the virus. In some aspects, the single domain antibodies in the binding molecule are joined by a (GS)3linker. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 8, a CDR2 comprising the sequence of SEQ ID NO: 9, and a CDR3 comprising the sequence of SEQ ID NO: 10. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence having at least 90% identity to SEQ ID NO: 7. In some aspects, the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 7. In some aspects, the binding molecule binds to the S2 subunit of the spike glycoprotein of a SARS-CoV-2 omicron variant or subvariant thereof e.g. BA.1 or JN.1, and neutralises the virus. In some aspects, the single domain antibodies in the binding molecule are joined by a (GS)3linker. In some aspects, the binding molecule comprises two single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 68, a CDR2 comprising the sequence of SEQ ID NO: 69, and a CDR3 comprising the sequence of SEQ ID NO: 70. In some aspects, the binding molecule comprises two single domain antibodies, each single domain antibody comprising a sequence having at least 90% identity to SEQ ID NO: 67. In some aspects, the binding molecule comprises two single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 67. In some aspects, the binding molecule binds to the S2 subunit of the spike glycoprotein of MERS-CoV and neutralises the virus. In some aspects, the single domain antibodies in the binding molecule are joined by a (GS)3linker. In some aspects, the binding molecule is multiparatopic. The term “multiparatopic” as used herein describes a binding molecule that recognises two or more different binding sites or epitopes on the same target antigen (e.g. the spike glycoprotein of a beta-coronavirus such as SARS-CoV-2 (e.g. Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43). Typically, the binding sites or epitopes are distinct and non- overlapping. In some aspects, a multiparatopic binding molecule comprises two or more different single domain antibodies described herein. In some aspects the multiparatopic binding molecule comprises three or more single domain antibodies, where at least one single domain antibody is different from the others. In some aspects, the binding molecule may be biparatopic, triparatopic, or tetraparatopic. A “biparatopic” binding molecule refers to a binding molecule that binds to two different binding sites or epitopes on the same target antigen (e.g. the spike glycoprotein of a beta-coronavirus such as SARS-CoV-2 (e.g. Vic01 or omicron subvariant BA.1 or JN.1), SARS-CoV-1, MERS-CoV, and / or hCoV-OC43). In some aspects, a biparatopic binding molecule comprises two different single domain antibodies described herein. As an example, the biparatopic binding molecule may comprise a first single domain antibody (i) comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5, or (ii) comprising the sequence of SEQ ID NO: 2 or a variant thereof as described herein, and a second single domain antibody comprising a single domain antibody as described in International Publication Nos. WO / 2021 / 224606 and WO / 2022 / 053839 and International Application No. PCT / GB2024 / 050982. In some aspects, the first single domain antibody of the binding molecule is linked at the C- terminus to the N-terminus of the second single domain antibody. In some aspects, the second single domain antibody of the binding molecule is linked at the C-terminus to the N- terminus of the third single domain antibody. In some aspects, the second single domain antibody of the binding molecule is disposed between the first single domain antibody and the third single domain antibody (i.e., the second single domain antibody is linked at the N- terminus to the first single domain antibody and linked at the C-terminus to the third single domain antibody, or the second single domain antibody is linked at the N-terminus to the third single domain antibody and linked at the C-terminus to the first single domain antibody). In some aspects, the third single domain antibody of the binding molecule is disposed between the first single domain antibody and the second single domain antibody (i.e., the third single domain antibody is linked at the N-terminus to the first single domain antibody and linked at the C-terminus to the second single domain antibody, or the third single domain antibody is linked at the N-terminus to the second single domain antibody and linked at the C-terminus to the first single domain antibody). In some aspects, a biparatopic binding molecule may comprise three or more single domain antibodies described herein, wherein at least one single domain antibody recognises a first binding site or epitope, and where at least one single domain antibody recognises a second, different binding site or epitope. A biparatopic binding molecule may comprise two or more single domain antibodies, and overall only recognise two different binding sites or epitopes on the target antigen. Additional single domain binding molecules that may be included in the multiparatopic binding molecules described herein are disclosed in International Publication Nos. WO / 2021 / 224606 and WO / 2022 / 053839 and International Application No. PCT / GB2024 / 050982. A “triparatopic” binding molecule refers to a binding molecule that binds to three different binding sites or epitopes on the same target antigen (e.g. the spike glycoprotein of a beta- coronavirus such as SARS-CoV-2 (e.g. Vic01 or omicron subvariant BA.1 or JN.1), SARS- CoV-1, MERS-CoV, and / or hCoV-OC43). In some aspects, a triparatopic binding molecule comprises three different single domain antibodies described herein. In some aspects, a triparatopic binding molecule may comprise four or more single domain antibodies described herein, wherein at least one single domain antibody recognises a first binding site or epitope, at least one single domain antibody recognises a second, different binding site or epitope, and at least one single domain antibody recognises a third, different binding site or epitope. A triparatopic binding molecule may comprise three or more single domain antibodies, and overall only recognise three different binding sites or epitopes on the target antigen. A “tetraparatopic” binding molecule refers to a binding molecule that binds to four different binding sites or epitopes on the same target antigen (e.g. the spike glycoprotein of a beta- coronavirus such as SARS-CoV-2 (e.g. Vic01 or omicron subvariant BA.1 or JN.1), SARS- CoV-1, MERS-CoV, and / or hCoV-OC43). In some aspects, a tetraparatopic binding molecule comprises four different single domain antibodies described herein. In some aspects, a tetraparatopic binding molecule may comprise five or more single domain antibodies described herein, wherein at least one single domain antibody recognises a first binding site or epitope, at least one single domain antibody recognises a second, different binding site or epitope, at least one single domain antibody recognises a third, different binding site or epitope, and at least one single domain antibody recognises a fourth, different binding site or epitope. A tetraparatopic binding molecule may comprise four or more single domain antibodies, and overall only recognise four different binding sites or epitopes on the target antigen. In some aspects where the binding molecule comprises two or more single domain antibodies described herein, the two or more single domain antibodies may be joined by one or more linkers. A “linker” (or spacer) is a chemical or biochemical structure, typically a polymer, which spatially separates two or more functionally relevant domains. Linkers are preferably unstructured allowing the two or more domains to re-orientate relative to each other to accommodate relative configurations of binding partners. Many linkers are known in the art and suitable linkers will be immediately apparent to the skilled person. In some aspects, the one or more linkers can be selected from polyA linkers, GS linkers, ubiquitin linkers, ubiquitin-like linkers, SUMO linkers, and SUMO-like linkers. The linker may be joined to either the N-terminal, the N-terminal, or in the case that the multivalent binding molecules comprise multiple linkers, the linker may be joined at both the N- and the N-terminal of the single domain antibodies described herein. A GS linker may comprise two glycine-serine repeats (GSGS, SEQ ID NO: 121), three glycine-serine repeats (GSGSGS, SEQ ID NO: 122), four glycine-serine repeats (GSGSGSGS, SEQ ID NO: 123), or multiple glycine-serine repeats, represented by the general formula (GS)n, wherein n is the number of GS repeats present, for example n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Ubiquitin linkers and ubiquitin-like linkers have been extensively characterised and are well known to the skilled person. Such proteins comprise a ubiquitin-like folding motif. These linkers can be varied in composition and length to tailor the design to the optimal arrangement for linking the single domain antibodies described herein and positioning them in the optimal spatial arrangement for targeting the epitope(s). The linker can further be optimised in composition and length to optimise binding characteristics of the binding molecule or single domain antibodies, for example Kd, as described herein. In one aspect, the linker comprises a protein selected from the group consisting of ubiquitin, Small Ubiquitin-like Modifier 1 (SUMO-1, also known in humans as Smt3c, PIC1, GMP1, sentrin and Ubl1), Small Ubiquitin-like Modifier 2 (SUMO-2, also known in humans as Smt3a and Sentrin3), Small Ubiquitin-like Modifier 3 (SUMO-3, also known as Smt3b and Sentrin2), Small Ubiquitin- like Modifier 4 (SUMO-4), FAU, NEDD-8, UBL-1, and GDX, Rub1, APG8, ISG15, URM1, HUB1, elonginB, or PLIC2. In one aspect, the protein is ubiquitin. In one aspect, the protein is Small Ubiquitin-like Modifier (SUMO). In one aspect, the linker comprises two or more ubiquitins (Ub) or a ubiquitin-like proteins (ULP), optionally 2, 3, 4 or 5 ubiquitins (Ub) or a ubiquitin-like proteins (ULP). The linker may be extended to additionally comprise amino acids at both the N-terminal and the C-terminal ends of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, additional amino acids are joined to the N-terminal end of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, additional amino acids are joined to the C-terminal end of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, additional amino acids are joined to the C-terminal and the N-terminal end of the ubiquitin (Ub) or ubiquitin-like protein linker. The amino acids joined to either the N- terminal, the C-terminal, or both the N- and the C-terminal of the ubiquitin (Ub) or ubiquitin- like protein linker can comprise one or more additional amino acids. In one aspect, 5 to 50 amino acids may be joined to either the N-terminal, the C-terminal, or both the N- and the C- terminal of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, 4 to 8 amino acids may be joined to either the N-terminal, the C-terminal, or both the N- and the C- terminal of the ubiquitin (Ub) or ubiquitin-like protein linker, optionally 4, 5, 6, 7 or 8 amino acids. In one aspect, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 amino acids may be joined to either the N-terminal, the C-terminal, or both the N- and the C-terminal of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2 amino acids may be joined to either the N-terminal, the C- terminal, or both the N- and the C-terminal of the ubiquitin (Ub) or ubiquitin-like protein linker. In one aspect, 6 amino acid residues may be joined to either the N-terminal, the C- terminal, or both the N- and the C-terminal of the ubiquitin (Ub) or ubiquitin-like protein linker. In the case that amino acids are joined to both the N-terminal and the C-terminal of the ubiquitin (Ub) or ubiquitin-like protein linker, the number of amino acids at each terminal may be the same or different, i.e. the extensions at either side may be of the same length, or the extensions at each terminal may be of differing lengths. Additional description of suitable linkers is described in International Publication No. WO / 2022 / 053839. The binding molecule described herein may further comprise one or more moieties. In one aspect, the one or more moieties is a therapeutic moiety or a diagnostic moiety. In some aspects, the one or more single domain antibodies are conjugated to the one or more moieties, optionally via a linker described herein. Conjugation (or coupling) refers to the covalent linkage of molecules. Covalent conjugation may be achieved via genetic engineering of the encoding polynucleotides into a recombinant open reading frame, optionally separated via a polynucleotide sequence encoding a linker, or via post-translational chemical reaction, for example mediated by chemical tethering, ‘plug and play’ reagents, SpyTag / SpyCatcher reagents, and so on. Coupled or conjugated moieties may be a therapeutic and / or a diagnostic moiety in that they possess therapeutic and / or diagnostic capability, thereby enabling use of the single domain antibody:moeity construct in a therapeutic and / or diagnostic context. In some aspects, therapeutic and / or diagnostic agents may also be administered separately from (i.e. not coupled to) single domain antibodies described herein. Moieties (or agents) suitable for conjugation to the single domain antibodies described herein or binding molecules comprising the single domain antibodies described herein may include, but are not limited to, one or more antibodies or fragments (antigen-binding fragments) thereof, one or more enzymes, one or more single domain antibodies, one or more single domain antibodies described herein, one or more single chain variable fragments (scFvs), one or more chemical moieties, one or more small molecule drugs, one or more anti-viral drugs, one or more radioactive moieties, one or more fluorescent moieties, one or more cells, one or more receptors, one or more nucleic acids, one or more peptides, and / or one or more toxins. Single domain antibodies and binding molecules herein may additionally comprise tags for the purposes of protein detection and / or purification, for example but not limited to His tags, biotin, fluorescent markers and radiolabels. In some instances, the binding molecule described herein may be monospecific, where the antigen binding sites all bind to the same epitope. In some instances, the binding molecule described herein may be multispecific, where the binding molecule comprises one or more different antigen binding sites that bind to two different epitopes (either on the same or on different antigens). For example, the binding molecule may have specificity for two different beta-coronaviruses, such as MERS and SARS-CoV-2. In some instances, the binding molecule described herein is bispecific and has antigen binding sites that bind to two different epitopes (either on the same or on different antigens). In some instances, the binding molecule described herein is trispecific and has antigen binding sites that bind to three different epitopes (either on the same or on different antigens). In some instances, the binding molecule described herein is tetraspecific and has antigen binding sites that bind to four different epitopes (either on the same or on different antigens). Polynucleotides, vectors and host cells The present invention further provides one or more polynucleotides encoding a single domain antibody described herein. Also provided by the present invention are one or more polynucleotides encoding a binding molecule described herein. The terms “nucleic acid molecule” and “polynucleotide” are used interchangeably herein and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include a gene, a gene fragment, messenger RNA (mRNA), cDNA, recombinant polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A nucleic acid molecule of the invention may be provided in isolated or purified form. A polynucleotide sequence which “encodes” a selected polypeptide is a nucleic acid molecule which is transcribed (in the case of DNA) and translated (in the case of mRNA) into a polypeptide in vivo when placed under the control of appropriate regulatory sequences. The boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxy) terminus. For the purposes of the invention, such polynucleotide sequences can include, but are not limited to, cDNA from viral, prokaryotic or eukaryotic mRNA, genomic sequences from viral or prokaryotic DNA or RNA, and even synthetic DNA sequences. A transcription termination sequence may be located 3' to the coding sequence. In one aspect, a polynucleotide of the invention comprises or consists of a sequence of SEQ ID NOs: 1, 6, 11, 16, 21, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 76, 81, 86, 91, 96, 101, 106, 111, or 116. A suitable polynucleotide sequence may alternatively be a variant of one of these specific polynucleotide sequences. For example, a variant may be a substitution, deletion or addition variant of any of the above nucleic acid sequences. A variant polynucleotide may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 or more nucleic acid substitutions and / or deletions from the sequences given in the sequence listing. Suitable variants may be at least 70% homologous to a polynucleotide of any one of the nucleic acid sequences disclosed herein, preferably at least 80 or 90% and more preferably at least 95%, 97% or 99% homologous thereto. Preferably homology and identity at these levels is present at least with respect to the coding regions of the polynucleotides. Methods of measuring homology are well known in the art and it will be understood by those of skill in the art that in the present context, homology is calculated on the basis of nucleic acid identity. Calculation of homology is also described in the preceding sections. A variant sequence may vary from the specific sequences given in the sequence listing by virtue of the redundancy in the genetic code. The DNA code has 4 primary nucleic acid residues (A, T, C and G) and uses these to “spell” three letter codons which represent the amino acids the proteins encoded in an organism’s genes. The linear sequence of codons along the DNA molecule is translated into the linear sequence of amino acids in the protein(s) encoded by those genes. The code is highly degenerate, with 61 codons coding for the 20 natural amino acids and 3 codons representing “stop” signals. Thus, most amino acids are coded for by more than one codon - in fact several are coded for by four or more different codons. A variant polynucleotide of the invention may therefore encode the same polypeptide sequence as another polynucleotide of the invention, but may have a different nucleic acid sequence due to the use of different codons to encode the same amino acids. Polynucleotide “fragments” according to the invention may be made by truncation, e.g. by removal of one or more nucleotides from one or both ends of a polynucleotide. Up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 or more amino acids may be removed from the 3’ and / or 5’ end of the polynucleotide in this way. Fragments may also be generated by one or more internal deletions. Such fragments may be derived from a sequence as described herein or may be derived from a variant polynucleotide as described herein. Preferably such fragments are between 90 and 1000 residues in length, e.g.90 to 300, 90 to 500, 100 to 800, 200 to 900 or 300 to 100 residues. Alternatively, fragments of the invention may be longer sequences, for example comprising at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of a full length polynucleotide of the invention. A single domain antibody or binding molecule of the invention may thus be produced from or delivered in the form of a polynucleotide which encodes, and is capable of expressing, it. In some embodiments a single domain antibody of the invention is encoded by one polynucleotide. In some embodiments a binding molecule of the invention is encoded by one polynucleotide, and in others a binding molecule of the invention is encoded by more than one nucleotide whereby assembly of the resulting translated polypeptides into the binding molecule occurs post-translationally. Polynucleotides of the invention can be synthesised according to methods well known in the art, as described by way of example in Sambrook et al. (1989, Molecular Cloning - a laboratory manual; Cold Spring Harbor Press). The polynucleotides of the present invention may be provided in the form of an expression cassette which includes control sequences operably linked to the inserted sequence, thus allowing for expression of the single domain antibody or binding molecule of the invention in vivo. These expression cassettes, in turn, are typically provided within vectors (e.g., plasmids or recombinant viral vectors). Such an expression cassette may be administered directly to a host subject. Alternatively, a vector comprising a polynucleotide of the invention may be administered to a host subject. Preferably the polynucleotide is prepared and / or administered using a genetic vector. A suitable vector may be any vector which is capable of carrying a sufficient amount of genetic information, and allowing expression of a polypeptide of the invention. The present invention thus also provides a vector comprising the one or more polynucleotides described herein. Such expression vectors are routinely constructed in the art of molecular biology and may for example involve the use of plasmid DNA and appropriate initiators, promoters, enhancers and other elements, such as for example polyadenylation signals which may be necessary, and which are positioned in the correct orientation, in order to allow for expression of a polypeptide of the invention. Other suitable vectors would be apparent to persons skilled in the art. By way of further example in this regard we refer to Sambrook et al. The present invention also provides host cells comprising the one or more polynucleotides or vector described herein. The cells are modified to express a single domain antibody or binding molecule of the invention. Such cells include transient, or preferably stable higher eukaryotic cell lines, such as mammalian cells or insect cells, lower eukaryotic cells, such as yeast or prokaryotic cells such as bacterial cells. Particular examples of cells which may be modified by insertion of vectors or expression cassettes encoding for a single domain antibody or binding molecule of the invention include mammalian HEK293T, CHO, HeLa, NS0 and COS cells. Cell lines available as hosts for expression are well known in the art. Preferably the cell line selected will be one which is not only stable, but also allows for mature glycosylation. Such cell lines of the invention may be cultured using routine methods to produce a single domain antibody or binding molecule of the invention. Pharmaceutical compositions, methods and uses The present invention also provides pharmaceutical compositions comprising the single domain antibody, binding molecule, one or more polynucleotides, vector and / or host cell described herein. Optionally, the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier and / or excipient. As used herein, “pharmaceutically acceptable carrier” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier may be suitable for parenteral, e.g. intravenous, intramuscular or subcutaneous administration (e.g., by injection or infusion) or by inhalation such as nasal or oral inhalation. Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition, 1995, describes compositions and formulations suitable for pharmaceutical delivery of the single domain antibody, binding molecule, one or more polynucleotides, vector and / or host cell described herein. In general, the nature of the carrier or excipient will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids, which include, but are not limited to, water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. For nasal or oral inhalation, the pharmaceutical composition may include aerosols, fine particles or dust. In some instances, a base vehicle may be PBS and the excipients trehalose or sorbitol may be used. Preferred pharmaceutically acceptable carriers comprise aqueous carriers or diluents. Examples of suitable aqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, buffered water and saline. Examples of other carriers include aqueous dextrose, glycerol, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. Sterile injectable solutions can be prepared by incorporating the active agent (e.g. antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Pharmaceutical compositions of the invention may comprise additional active ingredients as well as the single domain antibody, binding molecule, one or more polynucleotides, vector and / or host cell described herein. For example, the pharmaceutical compositions may further comprise additional therapeutic or prophylactic agents. The present invention further provides the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein for use in a method for treatment of a human or animal by therapy. The method of treatment may be therapeutic of prophylactic. The present invention further provides the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein for use in a method for treating or preventing beta-coronavirus infection, or a disease or complication associated with beta-coronavirus infection. The present invention also provides a method of treating or preventing beta-coronavirus infection, or a disease or complication associated with beta-coronavirus infection in a subject, comprising administering a therapeutically effective amount of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein to said subject. An “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. Also provided is use of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein for preventing, treating and / or diagnosing beta-coronavirus infection, or a disease or complication associated therewith. Also provided is use of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein for the manufacture of a medicament for treating or preventing beta-coronavirus infection, or a disease or complication associated therewith. When a disease, disorder or infection (e.g. beta-coronavirus such as SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and / or hCoV-OC43) is “treated” as discussed herein (for example in the methods or uses of the invention), this means that one or more symptoms of the disease, disorder or infection (e.g. beta-coronavirus such as SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and / or hCoV-OC43) are ameliorated. It does not mean that the symptoms of the disease, disorder or infection (e.g. beta-coronavirus SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and / or hCoV-OC43) are completely remedied so that they are no longer present in the patient, although in some methods, this may be the case. Thus, in all instances the term “treatment” or “treating” can be replaced with the term “amelioration" or “ameliorating”, respectively. The methods or uses of the invention (such as the methods of treatment or treating) may result in one or more of the symptoms of the disease, disorder or infection (e.g. beta-coronavirus such as SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and / or hCoV-OC43) being less severe than before treatment. The methods and uses of the invention may comprise inhibiting the disease state, e.g. arresting its development; and / or relieving the disease state, e.g. causing regression of the disease state until a desired endpoint is reached. The methods and uses of the invention may comprise the amelioration or the reduction of the severity, duration or frequency of a symptom of the disease state (e.g. lessen the pain or discomfort), and such amelioration may or may not be directly affecting the disease. The symptoms or complications may be fever, headache, fatigue, loss of appetite, myalgia, diarrhoea, vomiting, abdominal pain, dehydration, respiratory tract infections, cytokine storm, acute respiratory distress syndrome (ARDS) sepsis, and / or organ failure (e.g. heart, kidneys, liver, GI, and / or lungs). The methods and uses of the invention may lead to a decrease in the viral load of beta- coronavirus (e.g. SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS- CoV-1, MERS-CoV-2 and / or hCoV-OC43), e.g. by ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, or 100% compared to pre-treatment. Methods of determining viral load are well known in the art, e.g. infection assays. The methods and uses of the invention may comprise preventing the beta-coronavirus infection from occurring in a subject (e.g. humans), in particular, when such subject is predisposed to complications associated with beta-coronavirus infection. The subject may or may not have been diagnosed to be infected with beta-coronavirus (e.g. SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS-CoV-1, MERS-CoV-2 and / or hCoV- OC43). The beta-coronavirus infection may be caused by any beta-coronavirus. The beta-coronavirus may be from the subgenera Sarbevirus, Merbevirus or Embevirus. For example, the beta- coronavirus may be SARS-CoV-2 (e.g. Vic01 or BA.1 or JN.1 omicron subvariant), SARS- CoV-1, MERS-CoV-2 and / or hCoV-OC43. The beta-coronavirus may also be a SARS-CoV- 2 variant such as the prototypical, for example Victoria, variant or the earliest identified Wuhan variant (hCoV-19 / Wuhan / WIV04 / 2019 (WIV04); GISAID accession no. EPI_ISL_402124), an alpha variant (B.1.1.7 / UK or Kent variant), a beta variant (B.1.351 / South African variant), a gamma variant (P.1 / Brazilian variant), a delta variant (B.1.617.2 / Indian variant), an epsilon variant (B.1.427 / B.1.429 variant), a zeta variant (P.2 variant), an eta variant (B.1.525 variant), a theta variant (P.3 variant), an iota variant (B.1.526 variant), a kappa variant (B.1.617.1 variant), an omicron variant, BA.1, BA.1.1, BA.2, BA.2.10.1, BA.2.10.4, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4 / 5, BA.4.6, BQ.1, BQ.1.1, BJ.1, BS.1, BF.7, BN.1, XBB, XBB.1, XBB1.5, JN.1, EG.5.1, or a subvariant thereof. The variant or subvariant thereof may be an as-yet-unidentified variant or subvariant thereof of SARS-CoV-2 comprising mutations in the RBD and / or N-terminal domain (NTD) already identified in existing variants. The SARS-CoV-2 variant or subvariant may comprise one or more mutations, e.g. in the spike protein, compared to any of the variants and subvariants discussed herein. The beta-coronavirus may also be a SARS-CoV-1, hCoV-OC43, or MERS-CoV variant or subvariant thereof. For example, the SARS-CoV-1 variants may be HSZ-2, CUHK-W1, or BJ01, or subvariants thereof. The OC43 variants may be HCoV-OC43-HK09, HCoV-OC43- HK04, HCoV-OC43-BE03, or HCoV-OC43-Paris, or subvariants thereof. The MERS-CoV variants may be EMC / 2012, Ethi-118S, or Nigeria, or subvariants thereof. The variant or subvariant thereof may be an as-yet-unidentified variant or subvariant thereof of SARS-CoV- 1, hCoV-OC43 or MERS-CoV2 comprising mutations in the RBD and / or N-terminal domain (NTD) already identified in existing variants. The variant or subvariant may comprise one or more mutations, e.g. in the spike protein, compared to any of the variants and subvariants discussed herein. In some aspects of the methods and uses described herein, the single domain antibody is a combination of (i) a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5; or a single domain antibody comprising a sequence of SEQ ID NO: 2 or a sequence having at least 90% identity thereto; and (ii) a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50; or a single domain antibody comprising a sequence of SEQ ID NO: 47 or a sequence having at least 90% identity thereto. A single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein may be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. Preferably, single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein may be administered by parenteral administration. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration. Preferred routes of administration for the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein include administration by inhalation, such as nasal inhalation or oral inhalation, and also intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. Alternatively, the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration. Local administration is also possible, including peritumoral, juxtatumoral, intratumoral, intralesional, perilesional, intra cavity infusion, intravesicle administration, and inhalation. A suitable dosage of a single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein may be determined by a skilled medical practitioner. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular antibody employed, the route of administration, the time of administration, the rate of excretion of the antibody, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A suitable dose of a single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein may be, for example, in the range of from about 100 ng / kg to about 25 mg / kg body weight of the patient to be treated per day or per week or from about 100 µg / kg to about 25 mg / kg body weight of the patient to be treated per day or per week. For example, a suitable dosage may be from about 1 µg / kg to about 10 mg / kg body weight per week, from about 100 µg / kg to about 10 mg / kg body weight per week, or from about 10 µg / kg to about 5 mg / kg body weight per week. A suitable dosage may be from about 1 µg / kg to about 10 mg / kg body weight per day, from about 100 µg / kg to about 10 mg / kg body weight per day, or from about 10 µg / kg to about 5 mg / kg body weight per day. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. It is especially advantageous to formulate compositions for parenteral administration in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic or conditioning effect in association with the required pharmaceutical carrier. The single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein may be administered in a single dose or in multiple doses. The multiple doses may be administered via the same or different routes and to the same or different locations. Alternatively, they can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency may vary depending on the half-life in the patient and the duration of treatment that is desired. The pharmaceutical composition may comprise any single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein. In some aspects, the pharmaceutical composition may comprise a single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein. In some aspects, the pharmaceutical composition may comprise two or more different species of the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein within the same composition. The present invention also provides for the concurrent administration of two different pharmaceutical compositions each comprising a single but different species of single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein. The present invention also provides a method of detecting beta-coronavirus in a subject, comprising (i) contacting a sample obtained from the subject with the single domain antibody and / or binding molecule described herein, and (ii) detecting the presence or absence of an antibody-antigen complex or binding molecule-antigen complex, wherein the presence of the antibody-antigen complex or binding molecule-antigen complex indicates the presence of beta-coronavirus in the subject. The present invention also provides a method for diagnosing beta-coronavirus infection in a subject, the method comprising (i) contacting a sample obtained from the subject with the single domain antibody and / or binding molecule described herein, and (ii) detecting the presence or absence of an antibody-antigen complex or binding molecule-antigen complex, wherein the presence of the antibody-antigen or binding molecule-antigen complex provides a positive diagnosis of beta-coronavirus in the subject. Methods of determining or detecting the presence of an antibody-antigen or binding molecule-antigen complex are known in the art. For example, in vitro detection techniques include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In some instances, the single domain antibody acts as capture agents allowing detection of beta-coronavirus in a sample. In vivo techniques include introducing into a subject a labelled anti-analyte protein antibody. For example, the antibody can be labelled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. The detection techniques may provide a qualitative or a quantitative readout depending on the assay employed. Typically, the invention relates to methods and uses for a human subject in need thereof. However, non-human animals such as rats, rabbits, sheep, pigs, cows, cats, or dogs is also contemplated. The sample may be a biological sample. For example, the sample may be tissue, cells, or biological or bodily fluids, such as blood, blood serum, lymph, nasal secretions, sputum, blood plasma, urine or spinal fluid. The sample may be obtained from a subject or present within a subject. Typically, the sample is from a throat swab, nasal swab, or saliva. The detection or diagnosis assays may be performed in situ, in which case the sample is a tissue section (fixed and / or frozen) of the tissue obtained from biopsies or resections from a subject. The invention also provides a method of treating or preventing beta-coronavirus infection, or a disease or complication associated therewith, in a subject, the method comprising detecting the presence of beta-coronavirus according to the method described herein in a sample, and treating the subject with the single domain antibody, binding molecule, one or more polynucleotides, vector, host cell and / or pharmaceutical composition described herein, an anti-viral drug, or an anti-inflammatory agent. Examples of anti-viral drugs include, for example, remdesivir, lopinavir, ritonavir, APN01, and favilavir. Examples of anti- inflammatory agents include, for example, a corticosteroid (e.g. dexamethasone) or a non- steroidal anti-inflammatory drug (e.g. tocilizumab). The invention is illustrated by the following Examples: Examples Example 1 – Materials and Methods Production of VHHs Llama immunisation, VHH library construction and screening were carried out according to the protocols of Eyssen et al. (2024). VHHs were expressed and purified as previously described (Le Bas et al. 2022). The Fc and trimeric versions of the VHHs were constructed by inserting the VHH sequences into the vector pOPINTTG-3C-Fc using Infusion® cloning (19). VHH-Fcs, VHH trimers and biotinylated S2 proteins were expressed in Expi293™ cells and purified, as previously described (Huo et al.2020). ELISA 96-well ELISA plates were coated overnight with 1 ug / well neutravidin in PBS and then washed x 5 with PBS containing Tween 20 (300 µl 0.05 % v / v) (PBST) Biotinylated S2 trimers (50 nM) were added to each well (100 µl) and allowed to bind for 1 h. at RT on a vibrating shaking platform. Plates were blocked for 1 h at RT by adding 2 % milk powder in PBST 250 washed x 5 with PBST, and then tenfold serial dilutions of VHH-Fcs (100 to 0.0001 ug / well) added to the plate. Following further incubation for 1 h. at RT with agitation, plates were washed, and bound VHH-Fcs detected by the addition of an anti-human IgGFc- HRP conjugate using ABTS substrate (mix solution A: solution B in a 1:1 ratio). Colour development was measured by absorbance at 405 nm. For epitope mapping, binding of VHH- Fcs (100 µg / ml) was assayed in the presence of Fab B6 (10 µg / ml). Biolayer interferometry Biolayer interferometry was used to measure the binding constants of the VHHs and VHH- Fcs to BA.1 S2, MERS-CoV, HuOC43-CoV and epitope binning (Cornish et al. 2024). All assays were performed using a Sartorius Octet R8 system and designed using Octet BLI Discovery 12.2.2.20 software for normalization of the association and dissociation steps and Savitzky-Golay filtering. Curve fitting was applied using a global fit method and the association and dissociation rates calculated using a best fit method. All graphs were plotted using GraphPad Prism. Micro-neutralisation assay SARS-CoV-2 microneutralisation assays were carried out as previously described (Cornish et al. 2024). The neutralisation titre (NT50) was defined as the titre of VHH trimer or Fc dimer that reduced the Foci forming unit (FFU) by 50% compared to the control wells. Micro- neutralisation assays for HCoV-OC43 and MERS-CoV were carried out in a similar way. Example 2 – Screening for VHHs that bind to the S2 spike subunit of SARS-CoV-2 & MERS-CoV A VHH phage display library was constructed from the peripheral blood mononuclear cells of a llama immunised with a cocktail of three beta-coronavirus spike proteins (SARS-CoV-2 Omicron BA.1, MERS-CoV and hCoV-OC43). The spike proteins were produced as stabilised trimers by substitution of proline residues into the S2 sequences and fusion to the T4 fibritin foldon sequence at the carboxy terminus (Hsieh et al. 2020; Pallesen et al. 2017; Wang et al. 2022). The primary phage display library was screened with the trimerized and proline stabilised S2 fragment of the SARS-CoV-2 Omicron BA.1 spike protein (residues 681 to 1200) from which VHH binders were identified by phage ELISA using biotinylated BA.1 S2 to coat plates. The sub-library generated by panning with BA.1 S2 was re-screened with the corresponding S2 fragment of MERS-CoV (residues 749 to 1291), and further binders identified by MERS S2 phage ELISA. A second display sub-library was generated by panning the primary library with the spike protein of huOC43 and this in turn was panned with MERS S2. Sequencing and clustering of phage ELISA positive clones from the three panning experiments gave a total 24 different VHH sequences, 13 of which were unique to the BA.1 S2 screen, 11 were found in the two sub-libraries screened with MERS S2, of which 5 were common to both screening with BA.1 S2 and MERS S2 (Figure 1). Example 3 – Binding profiles and virus neutralisation activity of anti-S2 VHHs Focusing on the BA.1 S2 screen, human IgG1 Fc fusions were constructed from selected VHHs, expressed in expi293™ cells and purified by a combination of IMAC-SEC. The binding of the Fc fusions to either the spike and / or S2 proteins of BA.1 Omicron, MERS-CoV and huOC43 was assayed by ELISA. The results summarised in Table 1 showed that all expressed VHH-Fcs bound to the S2 subunit of both SARS-CoV-2 (BA.1) and SARS-CoV-1 presumptively to common conserved epitopes. Only four of these VHH-Fcs also bound to MERS-CoV S2, of which only two showed binding to the spike protein of OC43 (MERS-C9 and MERS-A4). Of the VHHs that bound both SARs-CoV-1 / 2 and MERS-CoV S2 subunits, MERS-C9 and BA.1-A7 are of particular interest as they showed binding to both MERS-CoV S2 trimers and monomers indicating that they recognise an epitope that may be accessible in both pre and post fusion configurations of the S2 subunit. By contrast MERS-A4-Fc only showed binding to the MERS S2 trimer (Figure 2). The observation that MERS-C9 and MERS-A4 both bound the spike protein of hCoV-OC43 indicates that these epitopes are conserved between different lineages of beta-coronaviruses. Table 1 – Summary of ELISA results from screening VHH-Fc binding to spike proteins SARS- CoV-2 SARS- SARS- BA.1 CoV-2 CoV-1 MERS OC43 Spike BA.1 S2 S2 S2 Spike Screening reagent Nanobody-Fc Trimer Trimer Trimer Trimer trimer BA.1 S2 Trimer BA.1 A1-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 A5-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 A7-Fc ✓ ✓ ✓ ✓ XBA.1 S2 Trimer BA.1 B1-Fc ✓ ✓ ✓ ✓ XBA.1 S2 Trimer BA.1 B3-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 B10-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 C1-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 C2-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 D3-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 D12-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 E1-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer Ba.1 E7-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 E11-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 F2-Fc ✓ ✓ ✓ X XBA.1 S2 Trimer BA.1 D2-Fc ND ✓ ✓ X XBA.1 S2 Trimer BA.1 D10-Fc ND ✓ ✓ X XBA.1 S2 Trimer BA.1 G9-Fc ND ✓ ✓ X X MERS S2 Trimer MERS C9-Fc ✓ ✓ ✓ ✓ ✓ MERS S2 Trimer MERS A4-Fc ND ✓ ✓ ✓ ✓MERS S2 Trimer MERS A8-Fc ND ✓ ✓ X XMERS S2 Trimer MERS B8-Fc ND (✓) ✓ X ✓MERS S2 Trimer MERS F6-Fc ND (✓) ✓ (✓) XMERS S2 Trimer MERS G9-Fc ND (✓) ✓ (✓) XNA Mab B6 ND ✓ X ✓ XND = not determined NA =not applicable ✓ = binding (@ > / = 1 µg / ml) (✓) = weak binding (@ > / = 100 µg / ml) X = no binding The nanobody Fc fusions were tested for neutralisation of both an ancestral SARS-CoV-2 virus (strain Vic01), the more recent Omicron BA.1 variant and huOC43 in live virus assays. Four nanobodies showed low nanomolar half maximal neutralisation titres with BA.1-C2 and D3 the most potent, both with NT50s of 1.6 nM against BA.1 (Table 2). The only VHH-Fc fusion that showed a sub-micromolar NT50 against huOC43 was BA.1-B1. The other VHH- Fcs had either weak (NT50s > 1 µM) or no measurable neutralising activity against this virus (Table 2). These results show that not all the epitopes recognised by the anti-S2 VHHs are neutralising, presumably reflecting the location of the binding sites on the S2 subunit. Table 2 – Half-maximal live virus neutralisation values SARS-CoV-2 SARS-CoV-2 Vic01 Omicron BA.1 HCoV-OC43 Nanobody-Fc NT50 (µM) NT50 (µM) NT50 (µM) BA.1 A1-Fc 5 1.25 >100BA.1 A5-Fc 0.8 0.2 >100BA.1 A7-Fc >100 20 1.2BA.1 B1-Fc 0.8 2 0.1BA.1 B3-Fc 20 16 6.4BA.1 B10-Fc 0.06 0.06 16BA.1 C1-Fc >100 >100 >100BA.1 C2-Fc 0.0013 0.0016 2BA.1 D3-Fc 0.02 0.0016 3BA.1 D12-Fc 0.04 0.02 1.6BA.1 E1-Fc >100 25 >100BA.1 E7-Fc 1 0.8 2.5BA.1 E11-Fc 5 5 5BA.1 F2-Fc >100 25 2MERS C9-Fc 50 4 20MERS A4-Fc 32 2.5 1Several neutralising monoclonal antibodies have been isolated from either COVID-19 patients (Hurlburt et al. 2022; Zhou et al. 2023) or mice immunised with spike proteins (Wang et al. 2021; Sauer et al. 2021) that bind to a linear epitope in the S2 domain of the spike protein around the stem-helix region encompassing residues 1142 -1247. This sequence is highly conserved between beta-coronaviruses and some of these anti-S2 antibodies showed broad neutralisation activity against SARS-CoV-2, MERS-CoV and hCoV-OC43 (Wang et al. 2021; Sauer et al. 2021). A second class of human monoclonal antibodies that bind to the fusion peptide have also been reported which show neutralisation activity (Dacon et al. 2022; Sun et al. 2022). To assess whether any of the anti-S2 nanobodies bound to either the of these neutralising S2 epitopes, two reference antibodies were cloned and expressed as Fab fragments that have been reported to bind to the stem-helix, B6, (Sauer et al. 2021)) and fusion peptide, CoV-91.27 (Dacon et al. 2022), respectively. No binding of CoV-91.27 to the antigen was observed, presumably due to a lack of exposure of the fusion peptide in the stabilised S2 trimer and confirming that it corresponds to a pre-fusion state. Given that the nanobodies bound to the S2 trimer we deduce that none bind to the fusion peptide. All the nanobodies bound to BA.1 S2 trimer in the presence of the stem-helix binding Fab B6 indicating that they do not bind to the stem-helix sequence (Figure 4). Example 4 – Binding affinities and competition between selected anti-S2 VHHs The binding affinities of the three most potent neutralising nanobodies, BA.1_D3, BA.1_D12 and BA.1C2 as Fc fusions, were measured by BLI confirming as both monomers and dimers (Fc-fusions). The results confirmed their tight binding to BA.1 S2 trimers and indicated that both monomer and Fc fusions interact with the S2 trimer with a similar stoichiometry, i.e., one VHH to each S2 chain of the trimer. No gain in affinity for the divalent Fc due to avidity was observed (Table 3). A competition experiment was then carried out by BLI to determine whether the four nanobodies bound to the same or different epitopes in the S2 subunit of the spike protein. The results showed that BA.1S2-NbC2 and BA.1S2-NbD12 bound to the same or overlapping epitopes whereas BA.1S2-NbD3 and BA.1S2-NbB10 each bound to a different epitope (Figure 3). Table 3 – Dissociation constants (Kd) determined from the kinetics of VHH and VHH-Fc fusions binding to SARS-CoV-2 BA.1 S2 trimers measured by Biolayer Interferometry Monomers Fc fusions (dimers)Nb KD (nM) Ka (1 / Ms) Kdis (1 / s) KD (nM) Ka (1 / Ms) Kdis (1 / s)C2 0.176 1.11x106 1.96x10-4 0.644 5.95x104 3.84x10-5D3 0.001 3.26 x105 1x10-7 0.001 8.36x104 1x10-7D12 0.001 1.17x106 1x10-7 0.0116 3.41x106 3.97x10-5Example 5 – Comparison of neutralisation by anti-S2 VHH monomers and trimers of SARS-CoV-2 variants Trimeric version of VHHs that bound to the Receptor Binding Domain (RBD) of the spike protein of SARS-CoV-2 have previously been shown to neutralise potently the virus both in vitro and in an animal of COVID-19 (Huo et al. 2021; Cornish et al. 2024). Therefore, trimeric versions of BA.1_C2 and BA.1_D3 were constructed by joining VHHs end-to-end with six residue linkers comprising alternating glycine and serine residues, [GS]3. The live neutralisation activity of these trimers was compared to the corresponding VHH monomers and unexpectedly the single VHHs showed similar potency to the trimeric versions (Table 4). This contrasts with published results for single domain antibodies that target the RBD of beta- coronaviruses for which dimeric and trimeric versions showed increased neutralisation activity compared to the corresponding monomers (He et al. 2019; Hultberg et al. 2011; Koenig et al.2021). Both BA.1_C2 and BA.1_D3 in both monomer and trimer formats neutralised all SARs-CoV-2 variants with BA.1_C2 showing approximately tenfold greater potency than BA.1_D3 in both monomer and trimer formats (Table 4). These results indicate that only one VHH of the trimer binds to each S2 chain of the trimeric S2. VHH binding presumably prevents the conformational transition of the spike protein from a pre-fusion trimer to the post-fusion state and hence prevents viral entry into the cells. The neutralisation results of the SARS-CoV-2 Omicron sub-variants, including the most recent JN.1 strain, confirm that targeting the highly conserved S2 subunit of the spike protein leads to broad cross-reactivity. Therefore, these VHHs have the prospect of generating protection against all current and possible future SARS-CoV-2 variants. Table 4 – Neutralisation of SARS-CoV-2 Omicron sub-variants by monomeric and trimeric anti-S2 VHHs SARS-CoV-2 Omicron BA.1_C2 VHH BA.1 C2_VHH BA.1_D3 VHH BA.1_D3 VHH sub-variant monomer trimer monomer trimer (NT50 nM) (NT50 nM) (NT50 nM) (NT50 nM) BA.1 0.16 0.04 1.30 1.07XBB.1.5 0.06 0.03 0.83 1.64XBB.1.6 0.90 0.24 2.23 3.85EG.5.1 0.35 0.11 1.52 9.16JN.1 0.08 0.11 2.38 12.13Example 6 – Localising the binding site of BA.1-C2 and BA.1-D3 nanobodies on SARS- CoV-2 A viral escape study was carried out as a first approach to determining where the SARS-CoV- 2 neutralising nanobodies, BA.1-C2 and D3 bound to the spike protein. VeroE6 cells infected with SARS-CoV-2 Omicron variant JN.1, were serially passaged in the presence of either BA.1-D3 (monomer) or BA.1-C2 (trimer). After eight (for BA.1-D3) or nine passages (for BA.1-C2), neutralisation of the passaged viruses was assessed by BA.1-D3 and BA.1-C2 respectively in a micro-neutralisation assay. The results showed that BA.1-D3 had selected for viruses that were no longer neutralised by this nanobody whereas for viruses passaged in the presence of BA.1-C2, viruses remained susceptible to the nanobody, though with an approximately seven-fold higher ED50 (0.07 nM vs 0.48nM). Sequencing of the spike proteins of the escape mutants showed that one mutation (S1175P) in the S2 region of the spike protein conferred resistance to neutralisation by BA.1-D3, and one residue change led to a reduced activity of BA.1-C2 (Q1201K). Both amino acid changes are in the membrane proximal second heptad repeat (HR2) of the spike protein. This sequence is highly conserved between all known variants of SARS-CoV-2 and is identical in SARS-CoV but not MERS- CoV or HuOC43-CoV which accounts for the lack of binding to the spike proteins of these viruses (Figure 5). This sequence forms a triple helix at the base of the spike trimer, and the mutated residues are located at opposite ends of the helices, confirming the experimental result that the epitopes for the BA.1-C2 and D3 nanobodies do not overlap. The D3 escape mutation (S1175P) would prevent N-glycosylation at N1173 by disrupting the NXS / T acceptor sequence. Given that the epitopes of BA.1-C2 and D3 are distinct, a second escape mutant study was carried out in which the SARS-CoV-2 Omicron JN.1 virus was passaged in the presence of an equimolar mixture of the two nanobodies as described above. After 5 and 10 passages, the susceptibility of the virus to neutralisation by the mixture of BA.1-C2 and D3 was tested in a microneutralisation assay. The results showed no reduction in the potency of the nanobodies demonstrating that combining nanobodies with different binding sites prevented viral escape (Figure 6). The results show that a combination of BA.1-C2 and D3 targeting the HR2 sequence in the S2 region of the spike protein has potential for the effective treatment of Covid-19 with a reduced risk of virus escape compared to many antibodies that bind to the S1 region. Further, the data point to the HR2 sequence as a target for designing a vaccine that would provide protection against all currently known SARS-CoV-2 variants. Example 7 – Neutralisation of MERS-CoV by nanobody MERS-C9 and localisation of the binding site MERS-C9 is unique among the anti-S2 nanobodies that were identified as it binds to the S2 regions of all three of the coronaviruses, MERS-CoV, HCoV-OC43 and SARS-CoV-2 (Table 1) with high affinities (Table 5). However, compared to some of the other nanobodies shows only very weak neutralisation activity against SARS-CoV-2 and HCoV-OC43 (Table 2). By contrast, MERS-C9, produced as an Fc dimer, potently neutralised MERS-CoV (NT50 = 0.7 nM) (Figure 7). Table 5 – Binding affinities of MERS-C9 to MERS-CoV, SARS-CoV-2 and OC43 spike proteins determined by Biolayer Interferometry KD (nM) Kon (1 / Ms) Koff (1 / s) MERS- CoV 0.6642 1.54E+05 1.02E-04 (S2 monomer) SARS-CoV-2 0.001 4.96E+04 1.00E-07 (BA.1 S2 Trimer) Hu-OC43CoV 43.63 8.26E+04 3.61E-03 (Spike timer) Single particle cryo-Electron Microscopy (EM) of spike protein-nanobody complexes was used to map the epitope of the nanobody, MERS-C9. This nanobody binds to the S2 regions of MERS-CoV, HCoV-OC43 and SARS-CoV-2, but only potently neutralises the MERS CoV virus. To date, the structure of the HCoV-OC43 spike-nanobody complex has been determined and showed that MERS-C9 bound to a discontinuous epitope formed by the membrane proximal end of Heptad Repeat 1 (HR1) and coiled coil linker between HR1 and HR2 (Figure 8a). The paratope of the nanobody consists exclusively of residues in the CDR3 loop (Table 6). A key feature of the epitope revealed by the structure is a hydrophobic pocket into which F103 in the CDR3 of MERS-C9 is docked (Figure 8b). The residues that form the pocket are conserved between HuOC43-CoV, MERs-CoV and SARS-CoV2 (Table 6) and comparison of published spike protein structures shows that the pocket is structurally similar in all three proteins (Figure 9). Therefore, it seems likely that MERS-C9 binds in a similar way to all three viral spike proteins. However, this does not readily explain the unexpected observation that while MERS-C9 binds to all the spike proteins (Table 5) it only potently neutralizes the MERS-CoV virus (Figure 7). Further work will be required to determine whether there are differences in the interaction between the nanobody and the spike proteins and / or the mechanism of inhibition of infection that are involved. Table 6 – The residues in HuCoV-OC43 and corresponding residues in MERS-CoV and SARS-CoV2 from multiple sequence alignment that form the epitope of MERS-C9. The residues at the HuOC43-CoV: MERS C9 interface that are conserved are in bold and therefore include the residues that interact with the CDR3 of MERS-C9 for all three spike proteins. HuOC43-CoV MERS-CoV SARS-CoV2 Nanobody MERS-C9: Contact residues Corresponding residue Corresponding residue HuOC43 spike CDR3 contact residue S794 T784 T716 Y100 E795 N785 N717 Y100 F796 F786 F717 F103 V999 V989 V915 F103 L1006 L996 L922 Part of hydrophobic pocket I1007 I997 I923 Part of hydrophobic pocket K1155 N1145 Q1071 Y100 V1183 T1175 N1098 Y109 M1188 S1185 F1103 Y109 Y1194 F1191 F1109 F103 Y1195 Y1192 Y1110 Y100 Y1196 A1193 E1111 S105, N107 Adjacent chain of trimer D1170 N1160 K1086 R106 T1210 P1207 N1125 R106 References - Le Bas A, Mikolajek H, Huo J, Dormon J, Naismith JH, Owens RJ. 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Sequences SEQ ID NO: 1 – Nucleotide sequence of BA.1_C2 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTTGGTGCAGACTGGGGACTCTCTGAGACTCTCCTGTGT AGCCTCTGGACTGTACTTCAGGTACCATGCCATGGGCTGGTTCCGCCAGGCTCCAGGAAAGGAGCGTG AATTTATAGCAGGTATTAGCGGGAATGGTAGAACCACGGACTATGCAGACTCCGTGAACGGCCGATTC ACCATCTCCAGAGACAACGACAAGAACACGATGTACCTGCAAATGAACAGCCTGAAACCTGACGACAC GGCCGTTTATTACTGCGCTGGCCGTGGTCGCAATTTTGTTATAATCGCGCGACACAGGGCGGAGTATG TCCACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 2 – Amino acid sequence of BA.1_C2 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQTGDSLRLSCVASGLYFRYHAMGWFRQAPGKEREFIAGISGNGRTTDYADSVNGRF TISRDNDKNTMYLQMNSLKPDDTAVYYCAGRGRNFVIIARHRAEYVHWGQGTQVTVSS SEQ ID NO: 3 – CDR1 amino acid sequence of BA.1_C2 (as defined by the IMGT system) GLYFRYHA SEQ ID NO: 4 – CDR2 amino acid sequence of BA.1_C2 (as defined by the IMGT system) ISGNGRTT SEQ ID NO: 5 – CDR3 amino acid sequence of BA.1_C2 (as defined by the IMGT system) AGRGRNFVIIARHRAEYVH SEQ ID NO: 6 – Nucleotide sequence of BA.1_D12 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGCCTGGGGACTCTCTGACACTCTCCTGTGC AGCCTCTGGGCGCGGCTTCGATGCCTACGGCATGATGTGGTTCCGCCAGGCTCCAGGGAAGGAACGTG AATTTGTAACAGGAATTAACTGGGGTGGTACTACATACTATGCGGACTCCGCGAAGGGCCGATTCACC ATCTCCAGAACCAGTGACAAGACCACGGTATATCTACAAATGACCAGCCTGAAACCTGAGGACTCGGC CATTTATTACTGTGCAGCAGCTCCCACCAGCACAGTGGTGACTAGACCCTCTCGTCCGAAGTACTGGG GCCAGGGGACCCAGGTCACCGTCTCCTCG SEQ ID NO: 7 – Amino acid sequence of BA.1_D12 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQPGDSLTLSCAASGRGFDAYGMMWFRQAPGKEREFVTGINWGGTTYYADSAKGRFT ISRTSDKTTVYLQMTSLKPEDSAIYYCAAAPTSTVVTRPSRPKYWGQGTQVTVSS SEQ ID NO: 8 – CDR1 amino acid sequence of BA.1_D12 (as defined by the IMGT system) GRGFDAYG SEQ ID NO: 9 – CDR2 amino acid sequence of BA.1_D12 (as defined by the IMGT system) INWGGTT SEQ ID NO: 10 – CDR3 amino acid sequence of BA.1_D12 (as defined by the IMGT system) AAAPTSTVVTRPSRPKY SEQ ID NO: 11 – Nucleotide sequence of BA.1_A7 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATCGGTGCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGT AGCCTCCGGACGCACCGTCAGTCTTTTTGACATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGTG AATTTGTAGCGCGTATTACGTTGAAGGAAGGTAAACTAAACTATGCAGACTCCGTGAAGGGCCGATTC ACCATCTCCAGAGGCAACCCCGAGAACACGGTGTATCTGCAGATGGATAGTCTGAAACCGGAGGACAC GGCCGTTTATTACTGTGCAGCAGACCAAACGGTAGTACGTATGACTGGGACCGGGATCGACTACTGGG GCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 12 – Amino acid sequence of BA.1_A7 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGSVQAGGSLRLSCVASGRTVSLFDMGWFRQAPGKEREFVARITLKEGKLNYADSVKGRF TISRGNPENTVYLQMDSLKPEDTAVYYCAADQTVVRMTGTGIDYWGQGTQVTVSS SEQ ID NO: 13 – CDR1 amino acid sequence of BA.1_A7 (as defined by the IMGT system) GRTVSLFD SEQ ID NO: 14 – CDR2 amino acid sequence of BA.1_A7 (as defined by the IMGT system) ITLKEGKL SEQ ID NO: 15 – CDR3 amino acid sequence of BA.1_A7 (as defined by the IMGT system) AADQTVVRMTGTGIDY SEQ ID NO: 16 – Nucleotide sequence of BA.1_D2 CAGGTGCAGCTGCAGGAGTCTGGGGGTGGCGTGGTGCAGGCCGGGGGCTCTCTGAGACTCTCCTGTGC AGCCTCTGGACGCGCCTTCAGCGTCACTACTGTGGCCTGGTTCCGCCAGTCTCCAGGGAAGGAGCGTG AGTACATAGCACGCTCCGACGCCAGAGGCGGTAAATATTATACAGACTCCGTGAAGGGCCGATTCACC ATCTCCGACGAACGTGACAAGATGACAGTATATCTACAAATGAACGACCTCGAAACTAGCGACACGGC CGTTTATTATTGTGCAGCCGGCCCGTTTGGAGTCAGCGCTAGAGAAGATGACTATGCTTACTGGGGGC AGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 17 – Amino acid sequence of BA.1_D2 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGVVQAGGSLRLSCAASGRAFSVTTVAWFRQSPGKEREYIARSDARGGKYYTDSVKGRFT ISDERDKMTVYLQMNDLETSDTAVYYCAAGPFGVSAREDDYAYWGQGTQVTVSS SEQ ID NO: 18 – CDR1 amino acid sequence of BA.1_D2 (as defined by the IMGT system) GRAFSVTT SEQ ID NO: 19 – CDR2 amino acid sequence of BA.1_D2 (as defined by the IMGT system) SDARGGK SEQ ID NO: 20 – CDR3 amino acid sequence of BA.1_D2 (as defined by the IMGT system) AAGPFGVSAREDDYAY SEQ ID NO: 21 – Nucleotide sequence of BA.1_A5 CAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGCCACCTC TGGACGCATTCTCAGTAACTATGTGATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGTGCGTTAC TTGGAGCTATTACCTGGAGCGCAGGTAGAACAGCCTATGCGGAGTCCGTGAAGGGCCGATTCACCATC TCCAGAGACATCGCCGAGAACGCGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACGGCCGT TTATTACTGTGCGGCACGAATTGTATCCGCATCTGAATATACCTACTGGGGCCAGGGGACCCAGGTCA CCGTCTCCTCA SEQ ID NO: 22 – Amino acid sequence of BA.1_A5 (CDRs 1-3 based on the IMGT system in bold) QLQESGGGLVQAGGSLRLSCATSGRILSNYVMGWFRQAPGKERALLGAITWSAGRTAYAESVKGRFTI SRDIAENAVYLQMNSLKPEDTAVYYCAARIVSASEYTYWGQGTQVTVSS SEQ ID NO: 23 – CDR1 amino acid sequence of BA.1_A5 (as defined by the IMGT system) GRILSNYV SEQ ID NO: 24 – CDR2 amino acid sequence of BA.1_A5 (as defined by the IMGT system) ITWSAGRT SEQ ID NO: 25 – CDR3 amino acid sequence of BA.1_A5 (as defined by the IMGT system) AARIVSASEYTY SEQ ID NO: 26 – Nucleotide sequence of BA.1_B10 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGAGGCTCTCTGAGGCTCTCCTGTAA AGCCTCTGGACGTACCGTCAACCAGAACATGGCGTGGTTCCGCCAGCCTCCAGGGAAGGAGCGTGAGT TTGTGTCAGCTATTGAGTGGAGTGTTGGAATGACAAGATATAAAGACTCCGTGAAGGGCCGATTCACC ATCTCCAGAGACATCGCCAAGGGCACGGTGTATCTGCAAATGAACAGCCTGAAACCTGACGACACGGC CGTTTATTACTGTGCAGCAAGTAACTCAGGCGTTGGCGCGTATGGGTATGATTATTGGGGCCAGGGGA CCCAGGTCACCGTCTCCTCA SEQ ID NO: 27 – Amino acid sequence of BA.1_B10 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLRLSCKASGRTVNQNMAWFRQPPGKEREFVSAIEWSVGMTRYKDSVKGRFT ISRDIAKGTVYLQMNSLKPDDTAVYYCAASNSGVGAYGYDYWGQGTQVTVSS SEQ ID NO: 28 – CDR1 amino acid sequence of BA.1_B10 (as defined by the IMGT system) GRTVNQNM SEQ ID NO: 29 – CDR2 amino acid sequence of BA.1_B10 (as defined by the IMGT system) EWSVGMT SEQ ID NO: 30 – CDR3 amino acid sequence of BA.1_B10 (as defined by the IMGT system) AASNSGVGAYGYDY SEQ ID NO: 31 – Nucleotide sequence of BA.1_F2 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCAGGGGGCTCTCTGAGACTCTCCTGTGC AGCCTCTGGACTGCGATTCAGTAACTATAACATGGGCTGGTTCCGCCGGGCTCCAGGGAAGGACCGTG AGTTTGTAGCATATATTAGCTGGAGTGATGATACCACAGCTTATGCAGACTCCGTGAAGGGCCGATTC ACCATCTCCAGAGACAACGCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAATTCTGAGGACAC GGCCGTTTACTACTGTGCAGCAGTTGGTGGTTACTACCAGGCGGGAGATCGGCCCTCGTCGGAATATG AGTATGACTACTGGGGTCAGGGGACCCGGGTCACCGTCTCCTCA SEQ ID NO: 32 – Amino acid sequence of BA.1_F2 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLRLSCAASGLRFSNYNMGWFRRAPGKDREFVAYISWSDDTTAYADSVKGRF TISRDNAKNTVYLQMNSLNSEDTAVYYCAAVGGYYQAGDRPSSEYEYDYWGQGTRVTVSS SEQ ID NO: 33 – CDR1 amino acid sequence of BA.1_F2 (as defined by the IMGT system) GLRFSNYN SEQ ID NO: 34 – CDR2 amino acid sequence of BA.1_F2 (as defined by the IMGT system) ISWSDDTT SEQ ID NO: 35 – CDR3 amino acid sequence of BA.1_F2 (as defined by the IMGT system) AAVGGYYQAGDRPSSEYEYDY SEQ ID NO: 36 – Nucleotide sequence of BA.1_A1 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGTTCTCTGAGACTCTCCTGTGC GACCTCTGGATTCACTTTGGATAATTATGCCATAGGCTGGTTCCGCCAGGCCCCAGGGAAGGAGCGCG AGGGGGTCTCATGTATTAGGAGTAGTGATGGTACCACATACTATGCAGATTCCGTGAAGGGCCGATTC ACCATGTCCAGTGACAACGCCAAGAATATGTATCTGCAAATGAATAACCTGAAACCCGAGGACACGGC CGTTTATTACTGTGCAGCAGGGGGTCAAACGTGTTCGGAGACGGTAGTACGTGGTTGGCTGCTGGGTG ACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 37 – Amino acid sequence of BA.1_A1 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQPGGSLRLSCATSGFTLDNYAIGWFRQAPGKEREGVSCIRSSDGTTYYADSVKGRF TMSSDNAKNMYLQMNNLKPEDTAVYYCAAGGQTCSETVVRGWLLGDYWGQGTQVTVSS SEQ ID NO: 38 – CDR1 amino acid sequence of BA.1_A1 (as defined by the IMGT system) GFTLDNYA SEQ ID NO: 39 – CDR2 amino acid sequence of BA.1_A1 (as defined by the IMGT system) IRSSDGTT SEQ ID NO: 40 – CDR3 amino acid sequence of BA.1_A1 (as defined by the IMGT system) AGGQTCSETVVRGWLLGDY SEQ ID NO: 41 – Nucleotide sequence of BA.1_E11 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGACTCTCTGAACCTCTCCTGTGT AGTGTCTGGAGGTACTTTCAGCAGGTATACCCTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCG AGTTTGTAAGTGGTATTAATTGGAGTGGTATCAGCGCAACAATTCCAGCCGTGAAGGGCCGGTTCACC ATCGGGAGAGACAACACCAAGAACACGGGATATTTGCAAATGCACAGGTTGGAACCTGAGGACACGGC CGTTTATTACTGTGCATTAGACACGACATTTCCATCTGGCGCCTTGACTGAAGCTTCAGAATATGACT ACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 42 – Amino acid sequence of BA.1_E11 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGDSLNLSCVVSGGTFSRYTLGWFRQAPGKEREFVSGINWSGISATIPAVKGRFT IGRDNTKNTGYLQMHRLEPEDTAVYYCALDTTFPSGALTEASEYDYWGQGTQVTVSS SEQ ID NO: 43 – CDR1 amino acid sequence of BA.1_E11 (as defined by the IMGT system) GGTFSRYT SEQ ID NO: 44 – CDR2 amino acid sequence of BA.1_E11 (as defined by the IMGT system) INWSGIS SEQ ID NO: 45 – CDR3 amino acid sequence of BA.1_E11 (as defined by the IMGT system) ALDTTFPSGALTEASEYDY SEQ ID NO: 46 – Nucleotide sequence of BA.1_D3 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTCGGTGCAGCCTGGGGGATCTCTGAGACTCTCCTGTGC AGCCTCTGGGTTCACCTTCGGTATTTATGGCATGACCTGGGTCCGTCAGGCTCCAGGAAAGGGGCACG AATGGATCTCTACTATTACCGCCGGTGGTGAGATTACCCACTATGCAGACTCCGTTCGGGGCCGATTC TCCATCTCCAGAGACAACGCCAAAAATACGCTGTATTTGGAGATGAACAGCCTGAAACTGGAGGACAC GGCCCGTTATTACTGTGCACGGACTCCTGGCATAGTAGTACGTGGACCCAATACATACGACTACCTGG GCCAGGGAACCCAGGTCACCGTCTCCTCA SEQ ID NO: 47 – Amino acid sequence of BA.1_D3 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGSVQPGGSLRLSCAASGFTFGIYGMTWVRQAPGKGHEWISTITAGGEITHYADSVRGRF SISRDNAKNTLYLEMNSLKLEDTARYYCARTPGIVVRGPNTYDYLGQGTQVTVSS SEQ ID NO: 48 – CDR1 amino acid sequence of BA.1_D3 (as defined by the IMGT system) GFTFGIYG SEQ ID NO: 49 – CDR2 amino acid sequence of BA.1_D3 (as defined by the IMGT system) ITAGGEIT SEQ ID NO: 50 – CDR3 amino acid sequence of BA.1_D3 (as defined by the IMGT system) ARTPGIVVRGPNTYDY SEQ ID NO: 51 – Nucleotide sequence of BA.1_D10 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGGGGGTCTCTGAGACTCTCCTGTGC AGCCTCGGGATTCACCTTCGGTATTTATGGTATGAGCTGGCTCCGCCAGGCTCCAGGAAAGGGGCGAG AGTGGGTCTCAACTATTACCGCTGGCGGTGAGATCCAACACTATGCAGACTCCGTGAAGGGCCGATTC ACCATCTCCAAAGACAACGCCAAGAACATGCTGTATCTGCAAATGACTAGCCTGGAAGTTGAGGACAC GGCCGTTTATTACTGTGCACGAGTTCCAGGGATAGTAGTACGGGGGTCCAATGCGTATGACCACGTGG GTCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 52 – Amino acid sequence of BA.1_D10 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGSVQAGGSLRLSCAASGFTFGIYGMSWLRQAPGKGREWVSTITAGGEIQHYADSVKGRF TISKDNAKNMLYLQMTSLEVEDTAVYYCARVPGIVVRGSNAYDHVGQGTQVTVSS SEQ ID NO: 53 – CDR1 amino acid sequence of BA.1_D10 (as defined by the IMGT system) GFTFGIYG SEQ ID NO: 54 – CDR2 amino acid sequence of BA.1_D10 (as defined by the IMGT system) ITAGGEIQ SEQ ID NO: 55 – CDR3 amino acid sequence of BA.1_D10 (as defined by the IMGT system) ARVPGIVVRGSNAYDH SEQ ID NO: 56 – Nucleotide sequence of BA.1_E7 CAGGTGCAGCTGCAGGAGTCTGGAGGACGACTGGCGCAGCCTGGGGACTCTCTGAGACTCTCCTGTGC AGCCTCTGGCCTCAACTTCAGCGATTACACCATGGGATGGTTCCGCCAGGCTCCAGGAGAGGAGCGTG AATTAGTGGCGCATATCACCCTGACTGGTTTTACATTGCGTGGTAGAAGTCCATACTATGCAGACTCC GTGAAGGACCGATTCACCATCTCCAGAGACATTGTCAAGAACGCGGTTTATCTGCAAATGAACAACCT GAAATTTGAGGATTCGGCTGTTTATTACTGTGCAGCAGGTGCTTACCCACTCTCATTGACGGCTGTTG CCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 57 – Amino acid sequence of BA.1_E7 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGRLAQPGDSLRLSCAASGLNFSDYTMGWFRQAPGEERELVAHITLTGFTLRGRSPYYADS VKDRFTISRDIVKNAVYLQMNNLKFEDSAVYYCAAGAYPLSLTAVAYWGQGTQVTVSS SEQ ID NO: 58 – CDR1 amino acid sequence of BA.1_E7 (as defined by the IMGT system) GLNFSDYT SEQ ID NO: 59 – CDR2 amino acid sequence of BA.1_E7 (as defined by the IMGT system) ITLTGFTL SEQ ID NO: 60 – CDR3 amino acid sequence of BA.1_E7 (as defined by the IMGT system) AAGAYPLSLTAVAY SEQ ID NO: 61 – Nucleotide sequence of BA.1_G9 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGCCTGGGGGCTCTCTGAGACTCTCCTGTGC AATCTCCGGACGCGCCTCCGATTTCTATGCCATGGGCTGGTTCCGCCAAACTCCAGGAGAGGAACGTG AGTTTCTAGCAGCCATTACCTTGAAGACTTTTCGCACGCGCTATGCGGCCTCCGTGGAGGGTCGATTC CGCTTCTCCAGAGACAATCCCGAGAACACGGTATATCTGCAATTGAACGAACTGACACCTGACGATAC GGCCGTTTATTACTGTGGTCTTACCGAGGTTATGAGTCTTTCGCCAATGCCACATGACTATCAGTACT GGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 62 – Amino acid sequence of BA.1_G9 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQPGGSLRLSCAISGRASDFYAMGWFRQTPGEEREFLAAITLKTFRTRYAASVEGRF RFSRDNPENTVYLQLNELTPDDTAVYYCGLTEVMSLSPMPHDYQYWGQGTQVTVSS SEQ ID NO: 63 – CDR1 amino acid sequence of BA.1_G9 (as defined by the IMGT system) GRASDFYA SEQ ID NO: 64 – CDR2 amino acid sequence of BA.1_G9 (as defined by the IMGT system) ITLKTFRT SEQ ID NO: 65 – CDR3 amino acid sequence of BA.1_G9 (as defined by the IMGT system) GLTEVMSLSPMPHDYQY SEQ ID NO: 66 – Nucleotide sequence of MERS_C9 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTCCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGC AGCCACTGGACGCGGTTTCAGTGACAGAGCCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCGTG AGTTTGTGGCTGCTATTAACATGGGTGCCTTTGACACAGTGTATGGAGACTCTGTCAAGGACCGATTC GCCATCTCCAGAGACGACGCCAAGAACACAATGTATCTGCAAATGAACAGCCTGATACCTGAGGACAC GGCCGTTTATTACTGTGCAGTCGGGTATGGATCGTTCCTCAGTCGTAATCAATATTCTTATGAAGTCT GGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 67 – Amino acid sequence of MERS_C9 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLRLSCAATGRGFSDRAMGWFRQAPGKGREFVAAINMGAFDTVYGDSVKDRF AISRDDAKNTMYLQMNSLIPEDTAVYYCAVGYGSFLSRNQYSYEVWGQGTQVTVSS SEQ ID NO: 68 – CDR1 amino acid sequence of MERS_C9 (as defined by the IMGT system) GRGFSDRA SEQ ID NO: 69 – CDR2 amino acid sequence of MERS_C9 (as defined by the IMGT system) INMGAFDT SEQ ID NO: 70 – CDR3 amino acid sequence of MERS_C9 (as defined by the IMGT system) AVGYGSFLSRNQYSYEV SEQ ID NO: 71 – Nucleotide sequence of BA.1_B3 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGG AGTCTCTGGAGGCTACTTCACTAACTATGCCATGGGCTGGTTCCGCCAGCCTCCCGGGAAGGAGCGGA GTGAATTTGTGGCAGGCATTCAGTGGAGTGGCGGTTACGAATATTATTTCGACTCCGTGAAGGGCCGA TTCGCCATCTCCACAGACAACGCCAGGAACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGA CACGGCCGTTTATTACTGCGCAGCCGCGAAGCTCGAACATTACGATAGCCACTTTCCAATGGAGTCAT ATGAGTATAACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 72 – Amino acid sequence of BA.1_B3 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLRLSCGVSGGYFTNYAMGWFRQPPGKERSEFVAGIQWSGGYEYYFDSVKGR FAISTDNARNTVYLQMNSLKPEDTAVYYCAAAKLEHYDSHFPMESYEYNYWGQGTQVTVSS SEQ ID NO: 73 – CDR1 amino acid sequence of BA.1_B3 (as defined by the IMGT system) GYFTNYAM SEQ ID NO: 74 – CDR2 amino acid sequence of BA.1_B3 (as defined by the IMGT system) IQWSGGYE SEQ ID NO: 75 – CDR3 amino acid sequence of BA.1_B3 (as defined by the IMGT system) AAAKLEHYDSHFPMESYEYNY SEQ ID NO: 76 – Nucleotide sequence of BA.1 _E1 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGACTCTCTGACACTGTCCTGTGC GGTCTCTGGACGCACCTCCGGCACCACCATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGATCGTGACT TTGTAGGCGCTATTAATTGGTATGTTGGCGGCCCTCACTATGCAGACTCCGTTAAGGGCCGATTCAGT ATCTCGAGAGACAACACCAACAACATCTTGTATCTGCAAATGAACACCCTACAGCCTGACGACACGGC CGTTTATTACTGTGCAGCAAAAGACTGGCAACCGGCCCTCAAATCACGGCCAGATGACTATCCCTACT GGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 77 – Amino acid sequence of BA.1_E1 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGDSLTLSCAVSGRTSGTTMAWFRQAPGKDRDFVGAINWYVGGPHYADSVKGRFS ISRDNTNNILYLQMNTLQPDDTAVYYCAAKDWQPALKSRPDDYPYWGQGTQVTVSS SEQ ID NO: 78 – CDR1 amino acid sequence of BA.1_E1 (as defined by the IMGT system) GRTSGTTM SEQ ID NO: 79 – CDR2 amino acid sequence of BA.1_E1 (as defined by the IMGT system) NWYVGGP SEQ ID NO: 80 – CDR3 amino acid sequence of BA.1_E1 (as defined by the IMGT system) AAKDWQPALKSRPDDYPY SEQ ID NO: 81 – Nucleotide sequence of BA.1_C1 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGAAGGCTGGGGACTCTCTGACACTCTCCTGTGC AGTCTCTGGACGCACCTCCGGCACCACCATGGCCTGGTTCCGCCAGGCGCCAGAGAAGGACCGTGAGT TTGTAGCTGCTATTAACTGGAACTTTGGTGGCCCACACTATGCAGACTCCGTGCAGGGCCGATTCACC ATCTCCAGAAACAACGCCGAGAATACACTGACTCTGCAAATGAACATCCTGGAACCTGACGACACGGC CGTTTATTACTGTGCAGCAAGAGACTGGACACCGGGCCTCAAAACGCGACCAGATGACTATGCCTACT GGGGCCAGGGGATTCAGGTCACCGTCTCCTCG SEQ ID NO: 82 – Amino acid sequence of BA.1_C1 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVKAGDSLTLSCAVSGRTSGTTMAWFRQAPEKDREFVAAINWNFGGPHYADSVQGRFT ISRNNAENTLTLQMNILEPDDTAVYYCAARDWTPGLKTRPDDYAYWGQGIQVTVSS SEQ ID NO: 83 – CDR1 amino acid sequence of BA.1_C1 (as defined by the IMGT system GRTSGTTM SEQ ID NO: 84 – CDR2 amino acid sequence of BA.1_C1 (as defined by the IMGT system NWNFGGP SEQ ID NO: 85 – CDR3 amino acid sequence of BA.1_C1 (as defined by the IMGT system AARDWTPGLKTRPDDYAY SEQ ID NO: 86 – Nucleotide sequence of BA.1_B1 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGACTGGGGGCTCCCTGAGACTCTCCTGTGC AGCCTCTGGACGCACCTCTAGTAGGTATGACATGGACTGGTACCGCCAGGCTCCAGGGAAGGAGCGTG AGTTCGTAGCGGGTTTCAGCCGGAATGGTATTAGCACATATTATGAAGACTCCGTGAAGGGCCGATTC ACCATCTCCAGAGACAACGCCAAGAACACAGTGTATCTGCAAATGAGCAGCCTGAAACCTGAGGACAC GGCCGTTTATTACTGTGGAGCACGTGTACGTGGCAGCTTAACGTATGATTCGTGGGGCCAGGGGACCC AGGTCACCGTCTCCTCA SEQ ID NO: 87 – Amino acid sequence of BA.1_B1 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQTGGSLRLSCAASGRTSSRYDMDWYRQAPGKEREFVAGFSRNGISTYYEDSVKGRF TISRDNAKNTVYLQMSSLKPEDTAVYYCGARVRGSLTYDSWGQGTQVTVSS SEQ ID NO: 88 – CDR1 amino acid sequence of BA.1_B1 (as defined by the IMGT system GRTSSRYD SEQ ID NO: 89 – CDR2 amino acid sequence of BA.1_B1 (as defined by the IMGT system FSRNGIST SEQ ID NO: 90 – CDR3 amino acid sequence of BA.1_B1 (as defined by the IMGT system GARVRGSLTYDS SEQ ID NO: 91 – Nucleotide sequence of MERS_B8 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGC AGCCTCCGGACGCACCTTTAGTAGCTATACAATGGGGTGGTTCCGCCAGGCTCCAGGGAAGGAGCGTG AGTTTGTAGCAGCTATTAATAGGAGTGGAGATAGGACATCGTACGCAGACTCCGCGAAGGGCCGATTT ACTATCTCCAGAGACAACGCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACAC GGCCACTTATTACTGTGCAGCGCACGAATCTGCTAATGCTCAGGCTATGGCTGTTATGAGGGGTCGTG GGATTAACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 92 – Amino acid sequence of MERS_B8 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYTMGWFRQAPGKEREFVAAINRSGDRTSYADSAKGRF TISRDNAKNTVYLQMNSLKPEDTATYYCAAHESANAQAMAVMRGRGINYWGQGTQVTVSS SEQ ID NO: 93 – CDR1 amino acid sequence of MERS_B8 (as defined by the IMGT system GRTFSSYT SEQ ID NO: 94 – CDR2 amino acid sequence of MERS_B8 (as defined by the IMGT system INRSGDRT SEQ ID NO: 95 – CDR3 amino acid sequence of MERS_B8 (as defined by the IMGT system AAHESANAQAMAVMRGRGINY SEQ ID NO: 96 – Nucleotide sequence of MERS_F6 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGACTCTCTAGGACTCTCCTGTGT AGCCTCCGGACGCGGCCTAGATTCTCTAATAGTGGCCTGGTTCCGCCAGGCTCCCGGAAAGGAGCGTG AGTTTGTAGCAGGTATCGTCTGGAGTGATGAATTTACATCGTATGGCAAGTTCGCGCAGGGCCGATTT ACCATCTCCAGAGACAAGGGCAAGAACACGATATTTCTGCAAATTAACAGCCTGAAACCTGAGGACAC GGCCGTTTATTACTGTGCCGGACGTTACGGGAATCTTATTCATGAAAACGAGAATGAGTACCAAGTTT GGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 97 – Amino acid sequence of MERS_F6 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGDSLGLSCVASGRGLDSLIVAWFRQAPGKEREFVAGIVWSDEFTSYGKFAQGRF TISRDKGKNTIFLQINSLKPEDTAVYYCAGRYGNLIHENENEYQVWGQGTQVTVSS SEQ ID NO: 98 – CDR1 amino acid sequence of MERS_F6 (as defined by the IMGT system GRGLDSLI SEQ ID NO: 99 – CDR2 amino acid sequence of MERS_F6 (as defined by the IMGT system IVWSDEFT SEQ ID NO: 100 – CDR3 amino acid sequence of MERS_F6 (as defined by the IMGT system AGRYGNLIHENENEYQV SEQ ID NO: 101 – Nucleotide sequence of MERS_D1 CAGGTGCAGCTGCAGGAGTCTGgGGGAGGATTGgTGCAGGCTGGGGACTCTCTGAGACTCACCTGTAC AGCCTCTGGATATATTCACGAGACGCATGTCGTGGGCTGGTTCCGCCAGGCTCCAGGAAAGGAGCGTG AGTTTGTGGCACATATTACATGGGGTCTTGGCTACACAGCCTATGAGGACGCCGTGAAGGGCCGCTTC ACCATTACCAGAGACAACGCCAAAAACACGATTTATCTGCAAATGAACAGCCTGAAACCTGAGGACAC GGCCAGATATTACTGTGCAGTTCGGCCAGGCGGGATTCACTTTGGTTCCTGGGGTCCGGGGACCCAGG TCACCGTCTCCTCA SEQ ID NO: 102 – Amino acid sequence of MERS_D1 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGDSLRLTCTASGYIHETHVVGWFRQAPGKEREFVAHITWGLGYTAYEDAVKGRF TITRDNAKNTIYLQMNSLKPEDTARYYCAVRPGGIHFGSWGPGTQVTVSS SEQ ID NO: 103 – CDR1 amino acid sequence of MERS_D1 (as defined by the IMGT system GYIHETHV SEQ ID NO: 104 – CDR2 amino acid sequence of MERS_D1 (as defined by the IMGT system ITWGLGYT SEQ ID NO: 105 – CDR3 amino acid sequence of MERS_D1 (as defined by the IMGT system AVRPGGIHFGS SEQ ID NO: 106 – Nucleotide sequence of MERS_G9 CAGGTGCAGCTGCAGGAGTCTGGGGGAGGATTGGTACAGGCTGGGGGCTCTTTGACACTCTCCTGTGC AGCCTCTGGACTACCCTTCAGTACATATACCGTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAACGTG AATTTGTAGCGCGGATTACTCGGAACATTTATAACACAATTTATGCAGATTCCGTACAGGGCCGCTTC ACCATCTCCAGAGACACCACCAAAAACACGGTGTATCTGCAAATGAACAGCCTGAAATTTGAGGACAC GGCCGTTTATTTCTGCGCAGCGCGCCCGTCCGGAAGTACCATGATAGCCTCAGACTATGACTACTGGG GCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 107 – Amino acid sequence of MERS_G9 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGGLVQAGGSLTLSCAASGLPFSTYTVGWFRQAPGKEREFVARITRNIYNTIYADSVQGRF TISRDTTKNTVYLQMNSLKFEDTAVYFCAARPSGSTMIASDYDYWGQGTQVTVSS SEQ ID NO: 108 – CDR1 amino acid sequence of MERS_G9 (as defined by the IMGT system GLPFSTYT SEQ ID NO: 109 – CDR2 amino acid sequence of MERS_G9 (as defined by the IMGT system ITRNIYNT SEQ ID NO: 110 – CDR3 amino acid sequence of MERS_G9 (as defined by the IMGT system AARPSGSTMIASDYDY SEQ ID NO: 111 – Nucleotide sequence of MERS_A8 CAGGTGCAGCTGCAGGAGTCTGGGGGAGAATTCGTGCAGCCCGGGGACTCGCTGAGACTCTCCTGCGC GACCTCTGGATTCACTTTGGATAATTATGCCATAGGCTGGTTCCGCCAGGCCCCAGGGAAGGAGCGCG AGGGGGTCTCATGTATTAGGAGTAGTGATAGTACCACATACTATGCAGATTCCGTGAAGGGCCGATTC ACCATGTCCAGTGACAACGCCAAGAATATGTATCTGCAAATGAACAACCTGAAACCCGAGGACACGGC CGTTTATTACTGTGCAGCAGGGGGTCAAACGTGTTCGGAGACGGTAGTACGTGGTTGGCTGCTGGGTG ACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCG SEQ ID NO: 112 – Amino acid sequence of MERS_A8 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGEFVQPGDSLRLSCATSGFTLDNYAIGWFRQAPGKEREGVSCIRSSDSTTYYADSVKGRF TMSSDNAKNMYLQMNNLKPEDTAVYYCAAGGQTCSETVVRGWLLGDYWGQGTQVTVSS SEQ ID NO: 113 – CDR1 amino acid sequence of MERS_A8 (as defined by the IMGT system GFTLDNYA SEQ ID NO: 114 – CDR2 amino acid sequence of MERS_A8 (as defined by the IMGT system IRSSDSTT SEQ ID NO: 115 – CDR3 amino acid sequence of MERS_A8 (as defined by the IMGT system AGGQTCSETVVRGWLLGDY SEQ ID NO: 116 – Nucleotide sequence of MERS_A4 CAGGTGCAGCTGCAGGAGTCTGGGGGAGAATTCGTGCAGCCCGGGGACTCGCTGAGACTCTCCTGCGC GACCTCTGGATTCACTTTGGATAATTATGCCATAGGCTGGTTCCGCCAGGCCCCAGGGAAGGAGCGCG AGGGGGTCTCATGTATTAGGAGTAGTGATAGTACCACATACTATGCAGATTCCGTGAAGGGCCGATTC ACCATGTCCAGTGACAACGCCAAGAATATGTATCTGCAAATGAACAACCTGAAACCCGAGGACACGGC CGTTTATTACTGTGCAGCAGGGGGTCAAACGTGTTCGGAGACGGTAGTACGTGGTTGGCTGCTGGGTG ACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCG SEQ ID NO: 117 – Amino acid sequence of MERS_A4 (CDRs 1-3 based on the IMGT system in bold) QVQLQESGGEFVQPGDSLRLSCATSGFTLDNYAIGWFRQAPGKEREGVSCIRSSDSTTYYADSVKGRF TMSSDNAKNMYLQMNNLKPEDTAVYYCAAGGQTCSETVVRGWLLGDYWGQGTQVTVSS SEQ ID NO: 118 – CDR1 amino acid sequence of MERS_A4 (as defined by the IMGT system GFTLDNYA SEQ ID NO: 119 – CDR2 amino acid sequence of MERS_A4 (as defined by the IMGT system IRSSDSTT SEQ ID NO: 120 – CDR3 amino acid sequence of MERS_A4 (as defined by the IMGT system AGGQTCSETVVRGWLLGDY SEQ ID NO: 121 – linker GSGS SEQ ID NO: 122 – linker GSGSGS SEQ ID NO: 123 – linker GSGSGSGS SEQ ID NO: 124 – peptide sequence from the spike protein of SARS- CoV-2 in Figure 5(a) (Uniprot ID PODCT2), with HR2 sequence underlined HTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEGKYEQYIK SEQ ID NO: 125 – HR2 sequence in the spike protein of SARS-CoV-2 defined by Uniprot PODCT2 in Figure 5(a) and (b) and HR2 sequence in the spike protein of SARS-CoV in Figure 5(b) DVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQE SEQ ID NO: 126 – HR2 sequence in the spike protein of MERS-CoV in Figure 5(b) IPNFGSLTQINTTLLDLTYEMLSLQQVVKALNESYIDLKE SEQ ID NO: 127 - HR2 sequence in the spike protein of HuOC43-CoV in Figure 5(b) APDLSLDYINVTFLDLQVEMNRLQEAIKVLNQSYINLKD SEQ ID NO: 128 - carboxy terminal region of the spike protein of HuOC43-CoV (Uniprot ID P36334) in Figure 9 YCVDYSKNRRSRGAITTGYRFTNFEPFTVNSVNDSLEPVGGLYEIQIPSEFTIGNMVEFIQTSSPKVT IDCAAFVCGDYAACKSQLVEYGSFCDNINAILTEVNELLDTTQLQVANSLMNGVTLSTKLKDGVNFNV DDINFSPVLGCLGSECSKASSRSAIEDLLFDKVKLSDVGFVEAYNNCTGGAEIRDLICVQSYKGIKVL PPLLSENQISGYTLAATSASLFPPWTAAAGVPFYLNVQYRINGLGVTMDVLSQNQKLIANAFNNALYA IQEGFDATNSALVKIQAVVNANAEALNNLLQQLSNRFGAISASLQEILSRLDALEAEAQIDRLINGRL TALNAYVSQQLSDSTLVKFSAAQAMEKVNECVKSQSSRINFCGNGNHIISLVQNAPYGLYFIHFSYVP TKYVTARVSPGLCIAGDRGIAPKSGYFVNVNNTWMYTGSGYYYPEPITENNVVVMSTCAVNYTKAPYV MLNTSIPNLPDFKEELDQWFKNQTSVAPDLSLDYINVTFLDLQVEMNRLQEAIKVLNQSYINLKDIGT YEYYVKWPWYVWLLICLAGVAMLVLLFFICCCTGCGTSCFKKCGGCCDDYTGYQELVIKTSHDD SEQ ID NO: 129 - carboxy terminal region of the spike protein of MERS-CoV (Uniprot ID R9UQ53) in Figure 9 LCALPDTPSTLTPRSVRSVPGEMRLASIAFNHPIQVDQLNSSYFKLSIPTNFSFGVTQEYIQTTIQKV TVDCKQYVCNGFQKCEQLLREYGQFCSKINQALHGANLRQDDSVRNLFASVKSSQSSPIIPGFGGDFN LTLLEPVSISTGSRSARSAIEDLLFDKVTIADPGYMQGYDDCMQQGPASARDLICAQYVAGYKVLPPL MDVNMEAAYTSSLLGSIAGVGWTAGLSSFAAIPFAQSIFYRLNGVGITQQVLSENQKLIANKFNQALG AMQTGFTTTNEAFRKVQDAVNNNAQALSKLASELSNTFGAISASIGDIIQRLDVLEQDAQIDRLINGR LTTLNAFVAQQLVRSESAALSAQLAKDKVNECVKAQSKRSGFCGQGTHIVSFVVNAPNGLYFMHVGYY PSNHIEVVSAYGLCDAANPTNCIAPVNGYFIKTNNTRIVDEWSYTGSSFYAPEPITSLNTKYVAPHVT YQNISTNLPPPLLGNSTGIDFQDELDEFFKNVSTSIPNFGSLTQINTTLLDLTYEMLSLQQVVKALNE SYIDLKELGNYTYYNKWPWYIWLGFIAGLVALALCVFFILCCTGCGTNCMGKLKCNRCCDRYEEYDLE PHKVHVH SEQ ID NO: 130 - carboxy terminal region of the spike protein of SARS-CoV-2 (Uniprot ID PODCT2) in Figure 9 ICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVD CTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQI LPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQY TSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSST ASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVT QQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTT APAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPEL DSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWP WYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT SEQ ID NO: 131 - spike glycoprotein sequence of HuOC43-CoV (Uniprot ID P36334) MFLILLISLPTAFAVIGDLKCTSDNINDKDTGPPPISTDTVDVTNGLGTYYVLDRVYLNTTLFLNGYY PTSGSTYRNMALKGSVLLSRLWFKPPFLSDFINGIFAKVKNTKVIKDRVMYSEFPAITIGSTFVNTSY SVVVQPRTINSTQDGDNKLQGLLEVSVCQYNMCEYPQTICHPNLGNHRKELWHLDTGVVSCLYKRNFT YDVNADYLYFHFYQEGGTFYAYFTDTGVVTKFLFNVYLGMALSHYYVMPLTCNSKLTLEYWVTPLTSR QYLLAFNQDGIIFNAEDCMSDFMSEIKCKTQSIAPPTGVYELNGYTVQPIADVYRRKPNLPNCNIEAW LNDKSVPSPLNWERKTFSNCNFNMSSLMSFIQADSFTCNNIDAAKIYGMCFSSITIDKFAIPNGRKVD LQLGNLGYLQSFNYRIDTTATSCQLYYNLPAANVSVSRFNPSTWNKRFGFIEDSVFKPRPAGVLTNHD VVYAQHCFKAPKNFCPCKLNGSCVGSGPGKNNGIGTCPAGTNYLTCDNLCTPDPITFTGTYKCPQTKS LVGIGEHCSGLAVKSDYCGGNSCTCRPQAFLGWSADSCLQGDKCNIFANFILHDVNSGLTCSTDLQKA NTDIILGVCVNYDLYGILGQGIFVEVNATYYNSWQNLLYDSNGNLYGFRDYIINRTFMIRSCYSGRVS AAFHANSSEPALLFRNIKCNYVFNNSLTRQLQPINYFDSYLGCVVNAYNSTAISVQTCDLTVGSGYCV DYSKNRRSRGAITTGYRFTNFEPFTVNSVNDSLEPVGGLYEIQIPSEFTIGNMVEFIQTSSPKVTIDC AAFVCGDYAACKSQLVEYGSFCDNINAILTEVNELLDTTQLQVANSLMNGVTLSTKLKDGVNFNVDDI NFSPVLGCLGSECSKASSRSAIEDLLFDKVKLSDVGFVEAYNNCTGGAEIRDLICVQSYKGIKVLPPL LSENQISGYTLAATSASLFPPWTAAAGVPFYLNVQYRINGLGVTMDVLSQNQKLIANAFNNALYAIQE GFDATNSALVKIQAVVNANAEALNNLLQQLSNRFGAISASLQEILSRLDALEAEAQIDRLINGRLTAL NAYVSQQLSDSTLVKFSAAQAMEKVNECVKSQSSRINFCGNGNHIISLVQNAPYGLYFIHFSYVPTKY VTARVSPGLCIAGDRGIAPKSGYFVNVNNTWMYTGSGYYYPEPITENNVVVMSTCAVNYTKAPYVMLN TSIPNLPDFKEELDQWFKNQTSVAPDLSLDYINVTFLDLQVEMNRLQEAIKVLNQSYINLKDIGTYEY YVKWPWYVWLLICLAGVAMLVLLFFICCCTGCGTSCFKKCGGCCDDYTGYQELVIKTSHDD

Claims

CLAIMS 1. A single domain antibody that binds to the S2 subunit of the spike glycoprotein of a beta-coronavirus.

2. The single domain antibody according to claim 1, wherein the single domain antibody binds to more than one beta-coronavirus.

3. The single domain antibody according to claims 1 or 2, wherein the single domain antibody has neutralising activity against the beta-coronavirus, optionally wherein the single domain antibody has neutralising activity against more than one beta-coronavirus.

4. The single domain antibody according to any one of the preceding claims, wherein the beta-coronavirus is SARS-CoV-2, SARS-CoV-1, MERS-CoV, and / or hCoV-OC43, further optionally wherein the SARS-CoV-2 is a Vic01 or BA.1 omicron subvariant.

5. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120.

6. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO: 4, 9, 14, 19, 24, 29, 34, 39, 44, 49, 54, 59, 64, 69, 74, 79, 84, 89, 94, 99, 104, 109, 114, or 119.

7. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 53, 58, 63, 68, 73, 78, 83, 88, 93, 98, 103, 108, 113, or 118.

8. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody comprises:i. a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5; or ii. a CDR1 comprising the sequence of SEQ ID NO: 8, a CDR2 comprising the sequence of SEQ ID NO: 9, and a CDR3 comprising the sequence of SEQ ID NO: 10; or iii. a CDR1 comprising the sequence of SEQ ID NO: 13, a CDR2 comprising the sequence of SEQ ID NO: 14, and a CDR3 comprising the sequence of SEQ ID NO: 15; or iv. a CDR1 comprising the sequence of SEQ ID NO: 18, a CDR2 comprising the sequence of SEQ ID NO: 19, and a CDR3 comprising the sequence of SEQ ID NO: 20; or v. a CDR1 comprising the sequence of SEQ ID NO: 23, a CDR2 comprising the sequence of SEQ ID NO: 24, and a CDR3 comprising the sequence of SEQ ID NO: 25; or vi. a CDR1 comprising the sequence of SEQ ID NO: 28, a CDR2 comprising the sequence of SEQ ID NO: 29, and a CDR3 comprising the sequence of SEQ ID NO: 30; or vii. a CDR1 comprising the sequence of SEQ ID NO: 33, a CDR2 comprising the sequence of SEQ ID NO: 34, and a CDR3 comprising the sequence of SEQ ID NO: 35; or viii. a CDR1 comprising the sequence of SEQ ID NO: 38, a CDR2 comprising the sequence of SEQ ID NO: 39, and a CDR3 comprising the sequence of SEQ ID NO: 40; or ix. a CDR1 comprising the sequence of SEQ ID NO: 43, a CDR2 comprising the sequence of SEQ ID NO: 44, and a CDR3 comprising the sequence of SEQ ID NO: 45; or x. a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50; or xi. a CDR1 comprising the sequence of SEQ ID NO: 53, a CDR2 comprising the sequence of SEQ ID NO: 54, and a CDR3 comprising the sequence of SEQ ID NO: 55; or xii. a CDR1 comprising the sequence of SEQ ID NO: 58, a CDR2 comprising the sequence of SEQ ID NO: 59, and a CDR3 comprising the sequence of SEQ ID NO: 60; or xiii. a CDR1 comprising the sequence of SEQ ID NO: 63, a CDR2 comprising the sequence of SEQ ID NO: 64, and a CDR3 comprising the sequence of SEQ ID NO: 65; or xiv. a CDR1 comprising the sequence of SEQ ID NO: 68, a CDR2 comprising the sequence of SEQ ID NO: 69, and a CDR3 comprising the sequence of SEQ ID NO: 70; or xv. a CDR1 comprising the sequence of SEQ ID NO: 73, a CDR2 comprising the sequence of SEQ ID NO: 74, and a CDR3 comprising the sequence of SEQ ID NO: 75; or xvi. a CDR1 comprising the sequence of SEQ ID NO: 78, a CDR2 comprising the sequence of SEQ ID NO: 79, and a CDR3 comprising the sequence of SEQ ID NO: 80; orxvii. a CDR1 comprising the sequence of SEQ ID NO: 83, a CDR2 comprising the sequence of SEQ ID NO: 84, and a CDR3 comprising the sequence of SEQ ID NO: 85; or xviii. a CDR1 comprising the sequence of SEQ ID NO: 88, a CDR2 comprising the sequence of SEQ ID NO: 89, and a CDR3 comprising the sequence of SEQ ID NO: 90; or xix. a CDR1 comprising the sequence of SEQ ID NO: 93, a CDR2 comprising the sequence of SEQ ID NO: 94, and a CDR3 comprising the sequence of SEQ ID NO: 95; or xx. a CDR1 comprising the sequence of SEQ ID NO: 98, a CDR2 comprising the sequence of SEQ ID NO: 99, and a CDR3 comprising the sequence of SEQ ID NO: 100; or xxi. a CDR1 comprising the sequence of SEQ ID NO: 103, a CDR2 comprising the sequence of SEQ ID NO: 104, and a CDR3 comprising the sequence of SEQ ID NO: 105; or xxii. a CDR1 comprising the sequence of SEQ ID NO: 108, a CDR2 comprising the sequence of SEQ ID NO: 109, and a CDR3 comprising the sequence of SEQ ID NO: 110; or xxiii. a CDR1 comprising the sequence of SEQ ID NO: 113, a CDR2 comprising the sequence of SEQ ID NO: 114, and a CDR3 comprising the sequence of SEQ ID NO: 115; or xxiv. a CDR1 comprising the sequence of SEQ ID NO: 118, a CDR2 comprising the sequence of SEQ ID NO: 119, and a CDR3 comprising the sequence of SEQ ID NO:

120.

9. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody comprises: i. a sequence of SEQ ID NO: 2 or a sequence having at least 90% identity thereto; or ii. a sequence of SEQ ID NO: 7 or a sequence having at least 90% identity thereto; or iii. a sequence of SEQ ID NO: 12 or a sequence having at least 90% identity thereto; or iv. a sequence of SEQ ID NO: 17 or a sequence having at least 90% identity thereto; or v. a sequence of SEQ ID NO: 22 or a sequence having at least 90% identity thereto; or vi. a sequence of SEQ ID NO: 27 or a sequence having at least 90% identity thereto; or vii. a sequence of SEQ ID NO: 32 or a sequence having at least 90% identity thereto; or viii. a sequence of SEQ ID NO: 37 or a sequence having at least 90% identity thereto; or ix. a sequence of SEQ ID NO: 42 or a sequence having at least 90% identity thereto; or x. a sequence of SEQ ID NO: 47 or a sequence having at least 90% identity thereto; or xi. a sequence of SEQ ID NO: 52 or a sequence having at least 90% identity thereto; or xii. a sequence of SEQ ID NO: 57 or a sequence having at least 90% identity thereto; or xiii. a sequence of SEQ ID NO: 62 or a sequence having at least 90% identity thereto; or xiv. a sequence of SEQ ID NO: 67 or a sequence having at least 90% identity thereto; orxv. a sequence of SEQ ID NO: 72 or a sequence having at least 90% identity thereto; or xvi. a sequence of SEQ ID NO: 77 or a sequence having at least 90% identity thereto; or xvii. a sequence of SEQ ID NO: 82 or a sequence having at least 90% identity thereto; or xviii. a sequence of SEQ ID NO: 87 or a sequence having at least 90% identity thereto; or xix. a sequence of SEQ ID NO: 92 or a sequence having at least 90% identity thereto; or xx. a sequence of SEQ ID NO: 97 or a sequence having at least 90% identity thereto; or xxi. a sequence of SEQ ID NO: 102 or a sequence having at least 90% identity thereto; or xxii. a sequence of SEQ ID NO: 107 or a sequence having at least 90% identity thereto; or xxiii. a sequence of SEQ ID NO: 112 or a sequence having at least 90% identity thereto; or xxiv. a sequence of SEQ ID NO: 117 or a sequence having at least 90% identity thereto.

10. The single domain antibody according to any one of claims 1 to 4, wherein the single domain antibody binds to the Heptad Repeat 2 (HR2) sequence in the S2 subunit of the spike glycoprotein of the beta-coronavirus.

11. The single domain antibody according to claim 10, wherein the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:

5.

12. The single domain antibody according to claim 10 or 11, wherein the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO:

4.

13. The single domain antibody according to any one of claims 10 to 12, wherein the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:

3.

14. The single domain antibody according to any one of claims 10 to 13, wherein the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4 and a CDR3 comprising the sequence of SEQ ID NO:

5.

15. The single domain antibody according to any one of claims 10 to 14, wherein the single domain antibody comprises a sequence of SEQ ID NO: 2 or a sequence having at least 90% identity thereto.

16. The single domain antibody according to claim 10, wherein the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:

50.

17. The single domain antibody according to claim 10 or 16, wherein the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO:

49.

18. The single domain antibody according to any one of claims 10, 16 and 17, wherein the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:

48.

19. The single domain antibody according to any one of claims 10 and 16 to 18, wherein the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49 and a CDR3 comprising the sequence of SEQ ID NO:

50.

20. The single domain antibody according to any one of claims 10 and 16 to 19, wherein the single domain antibody comprises a sequence of SEQ ID NO: 47 or a sequence having at least 90% identity thereto.

21. The single domain antibody according to any one of claims 10 to 20, wherein the beta-coronavirus is SARS-CoV-2 or SARS-CoV-1.

22. The single domain antibody according to any one of claims 1 to 4, wherein the single domain antibody binds to an epitope comprising at least one amino acid residue selected from S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210 of SEQ ID NO:

131.

23. The single domain antibody according to claim 22, wherein the single domain antibody binds to an epitope comprising S794, F796, V999, L1006, I1007, Y1194, and Y1195.

24. The single domain antibody according to claim 22 or 23, wherein the single domain antibody binds to an epitope comprising all of S794, E795, F796, V999, L1006, I1007, K1155, V1183, M1188, Y1194, Y1195, Y1196, D1170, and T1210.

25. The single domain antibody according to any one of claims 22 to 24, wherein the single domain antibody comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:

70.

26. The single domain antibody according to any one of claims 22 to 25, wherein the single domain antibody comprises a CDR2 comprising the amino acid sequence of SEQ ID NO:

69.

27. The single domain antibody according to any one of claims 22 to 26, wherein the single domain antibody comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:

68.

28. The single domain antibody according to any one of claims 22 to 27, wherein the single domain antibody comprises a CDR1 comprising the sequence of SEQ ID NO: 68, a CDR2 comprising the sequence of SEQ ID NO: 69 and a CDR3 comprising the sequence of SEQ ID NO:

70.

29. The single domain antibody according to any one of claims 22 to 28, wherein the single domain antibody comprises a sequence of SEQ ID NO: 67 or a sequence having at least 90% identity thereto.

30. The single domain antibody according to any one of claims 22 to 29, wherein the beta-coronavirus is MERS-CoV.

31. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody does not compete for binding with an antibody that binds to a linear epitope in the stem helix region or an epitope in the fusion peptide of the S2 subunit of a spike glycoprotein of a beta-coronavirus.

32. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody does not bind to a linear epitope in the stem helix region or an epitope in the fusion peptide of the S2 subunit of a spike glycoprotein of a beta-coronavirus.

33. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody is humanised or partially humanised.

34. The single domain antibody according to any one of the preceding claims, wherein the single domain antibody has a KD of less than 500nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 1 nM, less than 0.7 nM, less than 0.2 nM, less than 0.1 nM, or less than 0.01 nM, optionally measured by bio-layer interferometry.

35. A binding molecule comprising one or more of the single domain antibodies according to any one of the preceding claims.

36. The binding molecule according to claim 35, wherein the binding molecule is multivalent, optionally wherein the binding molecule is bivalent or trivalent.

37. The binding molecule according to claim 35 or 36, wherein the binding molecule is trivalent.

38. The binding molecule according to claim 35, wherein the binding molecule is multiparatopic, optionally wherein the molecule is biparatopic, triparatopic, or tetraparatopic.

39. The binding molecule according to any one of claims 35 to 38, wherein the two or more single domain antibodies are joined by one or more linkers, optionally wherein the one or more linkers can be selected from polyA linkers, GS linkers, ubiquitin linkers, ubiquitin- like linkers, SUMO linkers, and SUMO-like linkers.

40. The binding molecule according to any one of claims 35 to 39, further comprising one or more moieties, optionally wherein the one or more moieties is a therapeutic moiety or a diagnostic moiety, further optionally wherein the single domain antibody is conjugated to the one or more moieties.

41. The binding molecule according to claim 40, wherein the one or more moieties is one or more antibodies or fragments thereof, one or more enzymes, one or more single domain antibodies, one or more single domain antibodies according to any one of claims 1 to 34, one or more single chain variable fragments (scFvs), one or more chemical moieties, one or more small molecule drugs, one or more anti-viral drugs, one or more radioactive moieties, one or more fluorescent moieties, one or more cells, one or more receptors, one or more nucleic acids, one or more peptides, and / or one or more toxins.

42. The binding molecule according to any one of claims 35 to 41, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO:

5.

43. The binding molecule according to any one of claims 35 to 42, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 2 or a sequence having at least 90% identity thereto.

44. The binding molecule according to any one of claims 35 to 41, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO:

50.

45. The binding molecule according to any one of claims 35 to 41 and 44, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 47 or a sequence having at least 90% identity thereto.

46. The binding molecule according to any one of claims 35 to 41, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 8, a CDR2 comprising the sequence of SEQ ID NO: 9, and a CDR3 comprising the sequence of SEQ ID NO: 10.

47. The binding molecule according to any one of claims 35 to 41 and 46, wherein the binding molecule comprises three single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 7 or a sequence having at least 90% identity thereto.

48. The binding molecule according to any one of claims 42 to 47, wherein the binding molecule binds to the spike glycoprotein of a SARS-CoV-2 omicron variant or subvariant thereof.

49. The binding molecule according to any one of claims 35 to 41, wherein the binding molecule comprises two single domain antibodies, each single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 68, a CDR2 comprising the sequence of SEQ ID NO: 69, and a CDR3 comprising the sequence of SEQ ID NO:

70.

50. The binding molecule according to any one of claims 35 to 41 and 49, wherein the binding molecule comprises two single domain antibodies, each single domain antibody comprising a sequence of SEQ ID NO: 67 or a sequence having at least 90% identity thereto.

51. The binding molecule according to claim 49 or 50, wherein the binding molecule binds to the spike glycoprotein of MERS-CoV.

52. The binding molecule according to any one of claims 42 to 51, wherein the single domain antibodies are joined by a (GS)3linker.

53. One or more polynucleotides encoding a single domain antibody according to any one of claims 1 to 34 and / or a binding molecule according to any one of claims 35 to 52.

54. A vector comprising the one or more polynucleotides according to claim 53.

55. A host cell comprising the one or more polynucleotides according to claim 53 and / or the vector according to claim 54.

56. A pharmaceutical composition comprising the single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, theone or more polynucleotides according to claim 53, the vector according to claim 54, and / or the host cell according to claim 55, optionally wherein the composition further comprises a pharmaceutically acceptable carrier and / or excipient.

57. The single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, the one or more polynucleotides according to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56, for use in a method for treatment of a human or animal by therapy.

58. The single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, the one or more polynucleotides according to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56, for use in a method of treating or preventing beta-coronavirus infection, or a disease or complication associated with beta- coronavirus infection.

59. A method of treating or preventing beta-coronavirus infection, or a disease or complication associated with beta-coronavirus infection in a subject, comprising administering a therapeutically effective amount of the single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, the one or more polynucleotides according to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56 to said subject.

60. Use of the single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, the one or more polynucleotides according to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56, for preventing, treating and / or diagnosing beta-coronavirus infection, or a disease or complication associated therewith.

61. Use of the single domain antibody according to any one of claims 1 to 34, the binding molecule according to any one of claims 35 to 52, the one or more polynucleotidesaccording to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56, for the manufacture of a medicament for treating or preventing beta-coronavirus infection, or a disease or complication associated therewith.

62. The single domain antibody, the binding molecule, the one or more polynucleotides, the vector, the host cell, and / or the pharmaceutical composition for use of claim 57 or 58, the method of claim 59, or the use of claim 60 or 61, wherein the single domain antibody is a combination of: (i) a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 3, a CDR2 comprising the sequence of SEQ ID NO: 4, and a CDR3 comprising the sequence of SEQ ID NO: 5; or a single domain antibody comprising a sequence of SEQ ID NO: 2 or a sequence having at least 90% identity thereto; and (ii) a single domain antibody comprising a CDR1 comprising the sequence of SEQ ID NO: 48, a CDR2 comprising the sequence of SEQ ID NO: 49, and a CDR3 comprising the sequence of SEQ ID NO: 50; or a single domain antibody comprising a sequence of SEQ ID NO: 47 or a sequence having at least 90% identity thereto.

63. A method of detecting beta-coronavirus in a subject, comprising: i. contacting a sample obtained from the subject with the single domain antibody according to any one of claims 1 to 34 and / or the binding molecule according to any one of claims 35 to 52, and ii. detecting the presence or absence of an antibody-antigen or binding molecule-antigen complex, wherein the presence of the antibody-antigen or binding molecule-antigen complex indicates the presence of beta-coronavirus in the subject.

64. A method for diagnosing beta-coronavirus infection in a subject, comprising: i. contacting a sample obtained from the subject with the single domain antibody according to any one of claims 1 to 34 and / or the binding molecule according to any one of claims 35 to 52, and ii. detecting the presence or absence of an antibody-antigen or binding molecule-antigen complex,wherein the presence of the antibody-antigen or binding molecule-antigen complex provides a positive diagnosis of beta-coronavirus in the subject.

65. A method of treating or preventing beta-coronavirus infection, or a disease or complication associated therewith, in a subject, the method comprising detecting the presence of beta-coronavirus according to the method of claim 63 in a sample, and treating the subject with the single domain antibody according to any one of claims 1 to 34 and / or the binding molecule according to any one of claims 35 to 52, the one or more polynucleotides according to claim 53, the vector according to claim 54, the host cell according to claim 55, and / or the pharmaceutical composition according to claim 56, an anti-viral drug, or an anti-inflammatory agent.

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