Immunogenic polypeptides

Abstract

Immunogenic peptides are disclosed. Also disclosed are nucleic acids and expression vectors encoding, and cells, compositions and vaccines comprising the immunogenic peptides. Also provided are methods of using the immunogenic polypeptides in methods of medical treatment or prophylaxis.

Description

[0001] Immunogenic Polypeptides

[0002] This application claims priority from 10202302084W filed 21 July 2023, and 10202400781 S filed 20

[0003] March 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0004] Technical Field

[0005] The present disclosure relates to the fields of molecular biology and immunology, and in particular vaccine technology. The present disclosure also relates to methods of medical treatment and prophylaxis.

[0006] Background

[0007] The COVID-19 pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has had a profound impact worldwide. SARS-CoV-2 variants continue to circulate at high levels around the world, and there is a need to develop vaccines that are able to protect against or boost immunity against these variants and newly-emerging variants.

[0008] Furthermore, a very large number of coronaviruses circulate in wildlife reservoirs, such as the SARS- CoV-2-related coronaviruses (SC2r-CoVs) RaTG13, which circulates in bat populations, and GX-P5L, which circulated in pangolins (Wang et al. Curr Opin Virol (2019) 34:79-89; Zhou et al. Nature (2020) 579:270-273; Lam et al. Nature (2020) 583:282-285). Such reservoirs present significant potential for future outbreaks in humans caused by sarbecoviruses ( / .e. caused by SARS-CoV-3, et seq.) - see Calistri et al. Microorganisms (2021), 9(2):433).

[0009] According to the World Health Organization, in January 2023 there were 183 sarbecovirus vaccines in clinical development, including all of the currently-available vaccines Comirnaty (Pfizer / BioNTech), Spikevax (Moderna), Nuvaxovid (Novavax) and Corona Vac (Sinovac), and a further 199 vaccines in pre- clinical development. Many human subjects worldwide have been immunized with one or more (e.g. 2, 3 or more) doses of the currently-available vaccines. Where subjects have been administered multiple doses of COVID-19 vaccine, they have either been administered the same vaccine each time, or have been administered different vaccines.

[0010] There remains a need to develop vaccines and vaccination regimens providing protection against infection by circulating and newly-emerging SARS-CoV-2 variants, and also providing broad-spectrum protection against other sarbecoviruses.

[0011] Summary

[0012] In a first aspect, the present disclosure provides a polypeptide, optionally isolated, comprising an amino acid sequence that (i) has at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15; or (ii) has at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:9; and (iii) does not comprise the amino acid sequence of SEQ ID NQ:10.

[0013] In some embodiments, the amino acid sequence comprises ‘F’ at the position corresponding to position 358 of SEQ ID NO:15; and / or comprises ‘P’ at the position corresponding to position 360 of SEQ ID N0:15; and / or comprises ‘F’ at the position corresponding to position 362 of SEQ ID NO:15; and / or comprises ‘N’ at the position corresponding to position 392 of SEQ ID NO: 15; and / or comprises ‘S’ at the position corresponding to position 395 of SEQ ID NO:15.

[0014] In some embodiments, the amino acid sequence has at least 85% amino acid sequence identity to SEQ ID NOT, 8 or 9.

[0015] In some embodiments, the polypeptide further comprises an amino acid sequence forming a multimerization domain.

[0016] In some embodiments, the multimerization domain is a foldon domain, optionally wherein the foldon domain comprises, or consists of, an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence of SEQ ID NO:6.

[0017] In some embodiments, the multimerization domain is C-terminal to the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s).

[0018] In some embodiments, the polypeptide comprises, or consists of, (i) an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45, or (ii) an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:13. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:13.

[0019] In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:11 , 12 or 13. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:11 or 12. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:13.

[0020] The present disclosure also provides a nucleic acid, optionally isolated, encoding a polypeptide according to the present disclosure.

[0021] The present disclosure also provides a vector comprising a nucleic acid according to the present disclosure.

[0022] The present disclosure also provides a cell comprising a polypeptide, nucleic acid or vector according to the present disclosure. The present disclosure also provides a composition comprising a polypeptide, nucleic acid, vector or cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0023] The present disclosure also provides a vaccine, comprising a polypeptide, nucleic acid, vector, cell or composition according to the present disclosure.

[0024] The present disclosure also provides a polypeptide, nucleic acid, vector, cell, composition or vaccine according to the present disclosure, for use in a method of medical treatment or prophylaxis.

[0025] The present disclosure also provides a polypeptide, nucleic acid, vector, cell, composition or vaccine according to the present disclosure, for use in treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

[0026] The present disclosure also provides the use of a polypeptide, nucleic acid, vector, cell, composition or vaccine according to the present disclosure, in the manufacture of a medicament for treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

[0027] The present disclosure also provides a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, comprising administering to a subject a therapeutically- or prophylactically-effective amount of a polypeptide, nucleic acid, vector, cell, composition or vaccine according to the present disclosure, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

[0028] In some embodiments, the subject has previously been administered a COVID-19 vaccine, or has previously been infected with SARS-CoV-2 or a SARS-CoV-2 variant.

[0029] In some embodiments, the subject has previously been administered: (a) a polypeptide having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a).

[0030] In some embodiments, the subject has previously been infected with SARS-CoV-2 or a SARS-CoV-2 variant.

[0031] The present disclosure also provides a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, comprising:

[0032] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (i)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0033] (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (ii)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (ii)(a).

[0034] The present disclosure also provides an agent for use in a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject; wherein the agent is: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a); and wherein the method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject comprises:

[0035] (i) administering the agent to a subject; and

[0036] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (ii)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (ii)(a).

[0037] The present disclosure also provides an agent for use in a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject; wherein the agent is: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a); and wherein the method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject comprises:

[0038] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (i)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0039] (ii) administering the agent to the subject. The present disclosure also provides the use of an agent in the manufacture of a medicament for use in a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject; wherein the agent is: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a); and wherein the method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject comprises:

[0040] (i) administering the agent to a subject; and

[0041] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (ii)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (ii)(a).

[0042] The present disclosure also provides the use of an agent in the manufacture of a medicament for use in a method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject; wherein the agent is a second agent, and wherein the second agent is: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a); and wherein the method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject comprises:

[0043] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (i)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0044] (ii) administering the agent to the subject.

[0045] In some embodiments, the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 has at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45.

[0046] In some embodiments, the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NOT, 8, 10 or 51 has at least 85% amino acid sequence identity to an amino acid sequence identity to SEQ ID NO:11 , 12 or 14. In some embodiments, the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9 has at least 85% amino acid sequence identity to an amino acid sequence identity to SEQ ID NO:13.

[0047] Description

[0048] The present disclosure is based on the inventors’ development of novel sarbecovirus spike protein- derived polypeptides capable of inducing / upregulating immunity to sarbecovirus infection, and of nucleic acids encoding such polypeptides, vectors comprising such nucleic acids, and compositions / vaccines comprising such polypeptides / nucleic acids / vectors.

[0049] The present disclosure is also based on the inventors’ discovery that administration to a subject of multiple, different immunogenic sarbecovirus spike protein-derived polypeptides (or nucleic acids encoding the same, vectors comprising such nucleic acids, or compositions / vaccines comprising such polypeptides / nucleic acids / vectors) elicits broad-spectrum protection against infection by diverse sarbecoviruses.

[0050] A. Sarbecoviruses, SARSr-CoV, SARS-CoV-2 and SARS-CoV-2 variants

[0051] The present disclosure relates to sarbecoviruses. Sarbecoviruses are members of the subgenus Sarbecovirus of coronaviruses of the genus Betacoronavirus that infects humans, bats and certain other mammals. They are enveloped, positive-sense, single-stranded RNA viruses.

[0052] In some embodiments, a sarbecovirus according to the present disclosure is a betacoronavirus that uses angiotensin converting enzyme 2 (ACE2) for host cell entry. In some embodiments, a sarbecovirus according to the present disclosure is a betacoronavirus that uses human ACE2 for entry to human host cells.

[0053] Based on their evolutionary relationship, sarbecoviruses can be divided into three main clades: clades 1 , 2 and 3; see e.g. Xiang et al., Cell Rep. (2022) 39(13):111004 and Tortorici et al., Nature (2021) 597: 103-108.

[0054] Sarbecoviruses in clade 1 can be further grouped into clades 1 a, 1 b and 1 c. Clade 1 a sarbecoviruses include SARS-CoV (also known as SARS-CoV-1), WIV-1 , Rs2018B, LYRal 1 , Rs4231 , BtSY1 , RsSHC014 and Rs9401. Clade 1 b sarbecoviruses include SARS-CoV-2, SARS-CoV-2 variants, SARS- CoV-2 related coronaviruses (SC2r-CoVs; i.e. sarbecoviruses having >90% genomic identity with SARS- CoV-2, e.g. as described in Peng et al., Zool Res. (2021) 42(6):834-844), RaTG13, BANAL-20-51 , BANAL-20-52, BANAL-20-236, BANAL-20-103, Rc-o319, RsSTT182, BtSY2, GX-P5L and GD-1. Clade 1c sarbecoviruses include RaTG15 and RpYN04. Sarbecoviruses in clade 2 include RmYN02, RacCS203, SL-ZX45, SL-ZXC21 , BANAL-20-116, BANAL-20-247, PrC31 , RpYN06, Rm1 , Rf1 , Rp3, HKU3-1 , JTMC15, SX2013, HeB2013, Rs4237, 16BO133 and Anlong-103. Sarbecoviruses in clade 3 include BtKY72, BM48-31 and Khosta-2. In some embodiments, a sarbecovirus according to the present disclosure is a sarbecovirus of clade 1 , clade 2 or clade 3. In some embodiments, a sarbecovirus is a sarbecovirus of clade 1 or clade 3. In some embodiments, a sarbecovirus is a sarbecovirus of clade 1 b or clade 3. In some embodiments, a sarbecovirus is not a sarbecovirus of clade 2. In some embodiments, a sarbecovirus is a sarbecovirus of clade 1. In some embodiments, a sarbecovirus is a sarbecovirus of clade 1 a or 1 b. In some embodiments, a sarbecovirus is a sarbecovirus of clade 1 b.

[0055] In some embodiments, a sarbecovirus according to the present disclosure may be a sarbecovirus having a nucleotide sequence having at least 60% (e.g. one of >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the nucleotide sequence of GenBank: MN908947.3.

[0056] In some embodiments, a sarbecovirus according to the present disclosure is a severe acute respiratory syndrome-related coronavirus (SARSr-CoV). The virology of SARSr-CoV and epidemiology of disease associated with SARSr-CoV infection is reviewed, for example, in Cheng et al., Clin Microbiol Rev (2007) 20(4): 660-694 and de Wit et al., Nat Rev Microbiol (2016) 14: 523-534, both of which are hereby incorporated by reference in their entirety.

[0057] Two strains of SARSr-CoV have caused serious outbreaks of severe respiratory diseases in humans: SARS-CoV, which caused an outbreak of severe acute respiratory syndrome (SARS) between 2002 and 2003, and SARS-CoV-2, which has caused the coronavirus disease 2019 (COVID-19) pandemic. There are hundreds of strains of SARSr-CoV known only to infect non-human species; bats are a major reservoir of many strains of SARS-related coronaviruses.

[0058] In some embodiments, a sarbecovirus according to the present disclosure is SARS-CoV-2 or a SARS- CoV-2 variant.

[0059] As used herein, ‘SARS-CoV-2’ refers to the SARSr-CoV having the nucleotide sequence of GenBank: MN908947.3 (‘Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1 , complete genome’), reported in Wu et al., Nature (2020) 579: 265-269.

[0060] A large number of SARS-CoV-2 variants have been observed, and are described e.g. in Planas et al., Nat. Comm. (2023) 14: 824, Habib et al., Microbiol Resour Announc. (2023) 12(3): e00001-23, Katzmarzyk et al., Front Immunol. (2023) 14:1288794, Lasrado et al., Vaccine (2023) 41 (47): 6904-6909 and Rahman et al. Microbiol Resour Announc. (2023) 12(10): e00562-23.

[0061] A ‘SARSr-CoV’ according to the present disclosure may refer to a sarbecovirus having a nucleotide sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the nucleotide sequence of GenBank: MN908947.3. As used herein, a ‘SARS-CoV-2 variant’ refers to a SARSr-CoV having a nucleotide sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99%) sequence identity to the nucleotide sequence of GenBank: MN908947.3, wherein the nucleotide sequence is non-identical to the nucleotide sequence of GenBank: MN908947.3.

[0062] In some embodiments, a SARS-CoV-2 variant according to the present disclosure may be, or may previously have been, designated a variant of interest (VOI) or a variant of concern (VOC) by the World Health Organization. SARS-CoV-2 variants of particular interest in connection with the present disclosure include: BA.1 (also known as omicron; B.1.1.529; e.g. as represented by GISAID accession EPI_ISL_7358094.2); omicron subvariants such as BA.2 (e.g. as represented by GISAID accession EPI_ISL_6795834.2), BA.5 (GISAID accession EPI _ISL_12268495.2), BA.2.75 (e.g. as represented by GISAID accession EPI_ISL_13692860), BA.2.75.2 (e.g. as represented by GISAID accession

[0063] EPI _ISL_15731524), BA.4.6.1 (e.g. as represented by GISAID accession EPI _ISL_13925521), BF.7 (e.g. as represented by GISAID accession EPI_ISL_13972569), BQ.1.1 (e.g. as represented by GISAID accession EPI_ISL_15731523), XBB (e.g. as represented by GISAID accession EPI_ISL_15503011) XBB.1 (e.g. as represented by GISAID accession EPI_ISL_15503005); XBB.1.16 (e.g. as represented by GISAID accession EPI_ISL_17646715); XBB.2.3 (e.g. as represented by GISAID accession

[0064] EPI_ISL_17719186); EG.5 (e.g. as represented by EPI_ISL_17976635), EG.5.1 (e.g. as represented by GISAID accession EPI_ISL_18125149), B.1.1.7 (also known as alpha; GISAID accession

[0065] EPI_ISL_674612); B.1.351 (also known as beta, and 501Y.V2; GISAID accession EPI_ISL_940877); B.1.617.2 (also known as delta; GISAID accession EPI_ISL_1921353); and P.1 (also known as gamma; GISAID accession EPI_ISL_2777382).

[0066] Accordingly, in some embodiments, a SARS-CoV-2 variant according to the present disclosure is selected from: BA.1 , BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1 , BF.7, BQ.1 .1 , XBB, XBB.1 , XBB.1 .16, XBB.2.3, EG.5, EG.5.1 , B.1.1.7, B.1.351 , B.1.617.2 and P.1.

[0067] B. Sarbecovirus spike proteins

[0068] The sarbecovirus genome encodes four major structural proteins: the spike (S) protein, the envelope (E) protein, the membrane (M) protein, and the nucleocapsid (N) protein.

[0069] The canonical spike protein of SARS-CoV-2 ( / .e. the spike protein encoded by the nucleotide sequence of GenBank: MN908947.3) has the amino acid sequence shown in SEQ ID NO:16. SARS-CoV-2 spike protein comprises S1 (SEQ ID NO:21) and S2 (SEQ ID NO:24) subunits. The S1 subunit comprises a minimal receptor-binding domain (RBD; SEQ ID NO:22) through which SARS-CoV-2 binds to ACE2 expressed by host cells. The RBD in turn comprises the receptor binding motif (RBM; SEQ ID NO:23), which is the region of the RBD that contacts ACE2.

[0070] The sarbecovirus spike protein is a trimeric, class I fusion protein that exists in a metastable pre-fusion conformation. In order to fuse the viral membrane with the host membrane, the spike protein undergoes a substantial structural rearrangement that destabilizes the pre-fusion trimer, causing loss of the S1 subunit and transition of the S2 subunit to a stable post-fusion conformation, as described in Wrapp et al. Science (2020) 367(6483):1260-1263, which is hereby incorporated by reference in its entirety. The pre-fusion and post-fusion conformations therefore comprise different epitopes and can vary in immunogenicity.

[0071] In this specification, ‘SARS-CoV-2 spike protein’ refers to a polypeptide having the amino acid sequence of SEQ ID NO:16. The RBD of SARS-CoV-2 spike protein refers to the amino acid sequence of SEQ ID NO:22. The RBM of SARS-CoV-2 spike protein refers to the amino acid sequence of SEQ ID NO:23.

[0072] Many variants of SARS-CoV-2 spike protein ( / .e. encoded by SARS-CoV-2 variants) have been reported, i.e. comprising one or more amino acid substitutions, deletions or insertions in the amino acid sequence of the spike protein. Such proteins may be referred to herein as SARS-CoV-2 variant spike proteins.

[0073] A ‘sarbecovirus spike protein’ according to the present disclosure refers to a polypeptide having an amino acid sequence having at least 60% (e.g. one of >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to SEQ ID NO:16. Sarbecovirus spike proteins according to the present disclosure include SARSr-CoV spike proteins, SARS-CoV-2 spike protein and SARS-CoV-2 variant spike proteins.

[0074] A ‘SARSr-CoV spike protein’ according to the present disclosure refers to a polypeptide having an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to SEQ ID NO:16. ‘SARS-CoV-2 spike protein' refers to a polypeptide having the amino acid sequence of SEQ ID NO:16. A ‘SARS-CoV-2 variant spike protein’ according to the present disclosure refers to a polypeptide having an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99%) amino acid sequence identity to SEQ ID NO:16, wherein the amino acid sequence is nonidentical to SEQ ID NO:16.

[0075] In some embodiments, a SARS-CoV-2 variant spike protein comprises an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99%) amino acid sequence identity to SEQ ID NO:22, wherein the amino acid sequence is non-identical to SEQ ID NO:22. In some embodiments, a SARS- CoV-2 variant spike protein comprises an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99%) amino acid sequence identity to SEQ ID NO:23, wherein the amino acid sequence is nonidentical to SEQ ID NO:23.

[0076] The following table summarises variations (i.e. amino acid substitutions and deletions (A) in the amino acid sequences of the spike proteins encoded by SARS-CoV-2 variants of particular interest. The variations of the SARS-CoV-2 variant spike proteins shown in the Table 1 are obtained from outbreak.info (Gangavarapu et al., Nature Methods (2023) 20:512-522). The numbering of positions of SARS-CoV-2 spike protein residues and variants can be determined relative to SEQ ID NO:16 according to the present disclosure.

[0077] Table 1

[0078] In some embodiments, a SARS-CoV-2 variant spike protein according to the present disclosure has an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises one or more of the variations shown in Table 1 above.

[0079] In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises the variation(s) shown in column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 of Table 1 above. By way of illustration, in some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises N440K, S477N, T478K, E484A, Q493R, Q498R, N501 Y, Y505H, G446S and G496S ( / .e. the RBM variations of BA.1 , as shown in row 1). In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises the variation(s) shown in column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 of Table 1 above. In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises the variation(s) shown in column C of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16 or 17 of Table 1 above.

[0080] In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises the variation(s) shown in columns A and B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 of Table 1 above. By way of illustration, in some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, G446S, G496S, G339D, S373P, S375F, K417N and S371 L ( / .e. the RBD variations of BA.1 , as shown in row 1).

[0081] In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises the variation(s) shown in columns A, B and C of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17 or 18 of Table 1 above. By way of illustration, in some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:16, and comprises N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, G446S, G496S, G339D, S373P, S375F, K417N, S371 L, A67V, A69, A70, T95I, G142D, A143, A144, A145, A211 , L212I, +214EPE, T547K, D614G, H655Y, N679K, P681 H, N764K, D796Y, N856K, Q954H, N969K and L981 F ( / .e. the spike protein variations of BA.1 , as shown in row 1).

[0082] In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, the amino acid sequence of the spike protein encoded by a SARS-CoV-2 variant selected from: BA.1 , BA.2, BA.5, BA.2.75, BA.2.75.2, BA.4.6.1 , BF.7, BQ.1 .1 , XBB, XBB.1 , XBB.1 .16, XBB.2.3, EG.5, EG.5.1 , B.1 .1 .7, B.1.351 , B.1.617.2 and P.1.

[0083] In some embodiments, a SARS-CoV-2 variant spike protein according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42.

[0084] In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:26, and comprises the variation(s) shown in (i) column A of row 1 of Table 1 ; or (ii) columns A and B of row 1 of Table 1 ; or (iii) columns A, B and C of row 1 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:27, and comprises the variation(s) shown in (i) column A of row 2 of Table 1 ; or (ii) columns A and B of row 2 of Table 1 ; or (iii) columns A, B and C of row 2 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:28, and comprises the variation(s) shown in (i) column A of row 3 of Table 1 ; or (ii) columns A and B of row 3 of Table 1 ; or (iii) columns A, B and C of row 3 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:29, and comprises the variation(s) shown in (i) column A of row 4 of Table 1 ; or (ii) columns A and B of row 4 of Table 1 ; or (iii) columns A, B and C of row 4 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NQ:30, and comprises the variation(s) shown in (i) column A of row 5 of Table 1 ; or (ii) columns A and B of row 5 of Table 1 ; or (iii) columns A, B and C of row 5 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:31 , and comprises the variation(s) shown in (i) column A of row 6 of Table 1 ; or (ii) columns A and B of row 6 of Table 1 ; or (iii) columns A, B and C of row 6 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:32, and comprises the variation(s) shown in (i) column A of row 7 of Table 1 ; or (ii) columns A and B of row 7 of Table 1 ; or (iii) columns A, B and C of row 7 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:33, and comprises the variation(s) shown in (i) column A of row 8 of Table 1 ; or (ii) columns A and B of row 8 of Table 1 ; or (iii) columns A, B and C of row 8 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:34, and comprises the variation(s) shown in (i) column A of row 9 of Table 1 ; or (ii) columns A and B of row 9 of Table 1 ; or (iii) columns A, B and C of row 9 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:35, and comprises the variation(s) shown in (i) column A of row 10 of Table 1 ; or (ii) columns A and B of row 10 of Table 1 ; or (iii) columns A, B and C of row 10 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:36, and comprises the variation(s) shown in (i) column A of row 11 of Table 1 ; or (ii) columns A and B of row 11 of Table 1 ; or (iii) columns A, B and C of row 11 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:37, and comprises the variation(s) shown in (i) column A of row 12 of Table 1 ; or (ii) columns A and B of row 12 of Table 1 ; or (iii) columns A, B and C of row 12 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:38, and comprises the variation(s) shown in (i) column A of row 13 of Table 1 ; or (ii) columns A and B of row 13 of Table 1 ; or (iii) columns A, B and C of row 13 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:39, and comprises the variation(s) shown in (i) column A of row 14 of Table 1 ; or (ii) columns A and B of row 14 of Table 1 ; or (iii) columns A, B and C of row 14 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NQ:40, and comprises the variation(s) shown in (i) column A of row 15 of Table 1 ; or (ii) columns A and B of row 15 of Table 1 ; or (iii) columns A, B and C of row 15 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:41 , and comprises the variation(s) shown in (i) column A of row 16 of Table 1 ; or (ii) columns A and B of row 15 of Table 1 ; or (iii) columns A, B and C of row 16 of Table 1 . In some embodiments, a SARS-CoV-2 variant spike protein comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:42, and comprises the variation(s) shown in (i) column A of row 17 of Table 1 ; or (ii) columns A and B of row 17 of Table 1 ; or (iii) columns A, B and C of row 15 of Table 1 . In some embodiments, a sarbecovirus spike protein according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:16, 26, 28, 38, 39, 52, 53, 54, 55 or 56.

[0085] In some embodiments, a sarbecovirus spike protein according to the present disclosure is provided in the form of a trimeric spike protein complex. In some embodiments, the sarbecovirus spike protein is provided in the pre-fusion conformation. In some embodiments, the sarbecovirus spike protein comprises one or more amino acid substitutions to stabilise the pre-fusion conformation. Examples of such stabilising mutations are described, for example, in Hsieh et al. Science (2020) 369(6510):1501 -1505 (hereby incorporated by reference in its entirety). In some embodiments, the sarbecovirus spike protein comprises one or more amino acid substitutions selected from amino acid substitutions described in Hsieh et al. Science (2020) 369(6510):1501-1505.

[0086] C. Polypeptides

[0087] Aspects and embodiments according to the present disclosure relate to polypeptides. As used herein, a ‘peptide’ refers to a chain of two or more amino acid monomers linked by peptide bonds. A peptide typically has a length in the region of about 2 to 50 amino acids. A ‘polypeptide’ is a polymer chain of two or more peptides. Polypeptides typically have a length greater than about 50 amino acids. The polypeptides according to the present disclosure may be provided in isolated or substantially purified form.

[0088] The polypeptides according to the present disclosure comprise or consist of an amino acid sequence derived from amino acid sequence(s) of one or more (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) sarbecovirus spike protein(s). As used herein, an amino acid sequence which is ‘derived from’ a reference amino acid sequence comprises an amino acid sequence having at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the reference amino acid sequence.

[0089] An amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) may have at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence(s) of the sarbecovirus spike protein(s) from which it is derived. It will be appreciated that where an amino acid sequence is derived from the amino acid sequences or two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) sarbecovirus spike proteins, individual spike proteins of the two or more spike proteins may have non-identical amino acid sequences, and the amino acid sequence derived from the amino acid sequence(s) of those two or more spike proteins independently has at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of each sarbecovirus spike protein from which it is derived. By way of illustration, an amino acid sequence derived from the amino acid sequences of a first sarbecovirus spike protein and a second sarbecovirus spike protein (wherein the first spike protein and the second spike protein have non-identical amino acid sequences) has at least 50% amino acid sequence identity to the amino acid sequence of the first sarbecovirus spike protein, and also has at least 50% amino acid sequence identity to the amino acid sequence of the second sarbecovirus spike protein.

[0090] Amino acid sequences derived from amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure include the amino acid sequences of SEQ ID NO:15, 7, 8, 9, 1 , 2 and 3.

[0091] In some embodiments, an amino acid sequence derived from amino acid sequence(s) of one or more sarbecovirus spike protein(s) may comprise, or may consist of, an amino acid sequence having at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to SEQ ID NO:23. In some embodiments, an amino acid sequence derived from amino acid sequence(s) of one or more sarbecovirus spike protein(s) may comprise, or may consist of, an amino acid sequence having at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to SEQ ID NO:22. In some embodiments, an amino acid sequence derived from amino acid sequence(s) of one or more sarbecovirus spike protein(s) may comprise, or may consist of, an amino acid sequence having at least 50% (e.g. one of >55%, >60%, >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to SEQ ID NO:18.

[0092] In some embodiments, a polypeptide according to the present disclosure comprises an amino acid sequence having at least 60% (e.g. one of >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of the receptor binding motif (RBM) of a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 a, 1 b or 1 c), clade 2 or clade 3. The RBM of a given spike protein refers to the region corresponding to positions 437 to 508 of SEQ ID NO:16, which can be identified by sequence alignment of the subject sequence to the amino acid sequence formed by positions 437 to 508 of SEQ ID NO:16, e.g. using sequence alignment software such as ClustalOmega (Soding, J. 2005, Bioinformatics 21 , 951-960).

[0093] In some embodiments, a polypeptide according to the present disclosure comprises an amino acid sequence having at least 60% (e.g. one of >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of the receptor binding domain (RBD) of a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 a, 1 b or 1 c), clade 2 or clade 3. The RBD of a given spike protein refers to the region corresponding to positions 319 to 541 of SEQ ID NO:16, which can be identified by sequence alignment of the subject sequence to the amino acid sequence formed by positions 319 to 541 of SEQ ID NO:16, e.g. using sequence alignment software such as ClustalOmega. In some embodiments, a polypeptide according to the present disclosure comprises an amino acid sequence having at least 60% (e.g. one of >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of the extracellular domain of a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 a, 1 b or 1 c), clade 2 or clade 3. The extracellular domain of a given spike protein refers to the region corresponding to positions 13 to 1213 of SEQ ID NO:16, which can be identified by sequence alignment of the subject sequence to the amino acid sequence formed by positions 13 to 1213 of SEQ ID NO:16, e.g. using sequence alignment software such as ClustalOmega.

[0094] In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 a, 1 b or 1 c) is the spike protein encoded by SARS-CoV, WIV-1 , LYRal 1 , Rs4231 , BtSY1 , RsSHC014, Rs9401 , SARS- CoV-2, a SARS-CoV-2 variant (e.g. a SARS-CoV-2 variant described herein), a SC2r-CoV, RaTG13, BANAL-20-51 , BANAL-20-52, BANAL-20-236, BANAL-20-103, Rc-o319, RsSTT182, BtSY2, GX-P5L, GD-1 , RaTG15 or RpYN04. In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 a is the spike protein encoded by SARS-CoV, WIV-1 , LYRal 1 , Rs4231 , BtSY1 , RsSHC014 or Rs9401 . In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 b is the spike protein encoded by SARS-CoV-2, a SARS-CoV-2 variant (e.g. a SARS-CoV-2 variant described herein), a SC2r- CoV, RaTG13, BANAL-20-51 , BANAL-20-52, BANAL-20-236, BANAL-20-103, Rc-o319, RsSTT182, BtSY2, GX-P5L or GD-1 . In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 c is the spike protein encoded by RaTG15 or RpYN04.

[0095] In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 b) comprises the amino acid sequence of SEQ ID NO:23, or comprises the amino acid sequence of SEQ ID NO:23 and additionally comprises the combination of amino acid substitutions shown in column A of one of rows 1 to 18 of Table 1 herein. In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 b) comprises the amino acid sequence of SEQ ID NO:22, or comprises the amino acid sequence of SEQ ID NO:22 and additionally comprises the combinations of amino acid substitutions shown in columns A and B of one of rows 1 to 18 of Table 1 herein. In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 b) comprises the amino acid sequence of SEQ ID NO:22, or comprises the amino acid sequence of SEQ ID NO:22 and additionally comprises the combinations of amino acid substitutions shown in columns A and B of one of rows 1 to 18 of Table 1 herein. In some embodiments, a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1 b) comprises the amino acid sequence of SEQ ID NO:18, or comprises the amino acid sequence of SEQ ID NO:18 and additionally comprises the combinations of amino acid substitutions shown in columns A and B and C of one of rows 1 to 18 of Table 1 herein.

[0096] In some embodiments, a spike protein encoded by a sarbecovirus of clade 2 is the spike protein encoded by RmYN02, RacCS203, SL-ZX45, SL-ZXC21 , BANAL-20-116, BANAL-20-247, PrC31 , RpYN06, Rm1 , Rf1 , Rp3, HKU3-1 , JTMC15, SX2013, HeB2013, Rs4237, 16BO133 or Anlong-103. In some embodiments, a spike protein encoded by a sarbecovirus of clade 3 is the spike protein encoded by BtKY72, BM48-31 or Khosta-2.

[0097] The polypeptides according to the present disclosure are preferably immunogenic polypeptides. As used herein, ‘immunogenicity’ refers to the capability to stimulate an immune response, in particular an adaptive immune response. Thus, an immunogenic polypeptide is a polypeptide capable of stimulating an immune response (e.g. an adaptive immune response).

[0098] The polypeptides according to the present disclosure are also preferably antigenic polypeptides. As used herein, ‘antigenicity’ refers to the ability to interact specifically with an antigen-binding molecule produced by an adaptive immune response, e.g. an antibody or a T cell receptor. Thus, an antigenic polypeptide is a polypeptide capable of interacting specifically with an antigen-binding molecule (e.g. an antibody or a T cell receptor), or comprising a peptide capable of interacting specifically with an antigen-binding molecule (e.g. an antibody or a T cell receptor).

[0099] In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating a B cell-mediated immune response. In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating a T cell-mediated immune response. In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating the expression of an antigen-binding molecule (e.g. an antibody and / or T cell receptor). In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating the expression of an antibody capable of binding to the polypeptide. In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating the expression of a T cell receptor capable of binding to a peptide:MHC complex comprising a peptide of the polypeptide. In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating the proliferation / expansion of B cells producing antibodies capable of binding to the polypeptide. In some embodiments, an immunogenic / antigenic polypeptide is capable of stimulating the proliferation / expansion of T cells expressing a T cell receptor capable of binding to a peptide:MHC complex comprising a peptide of the polypeptide. In some embodiments, an immunogenic / antigenic polypeptide comprises or consist of a sequence of amino acids which forms a B cell epitope. In some embodiments, an immunogenic / antigenic polypeptide comprises or consist of a sequence of amino acids which forms a T cell epitope.

[0100] In some embodiments, an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15, 7, 8, or 9. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:7. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:9.

[0101] In some embodiments, an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure does not comprise, or consist of, the amino acid sequence of SEQ ID NO:14. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) does not comprise, or consist of, the amino acid sequence of SEQ ID NO:4. does not comprise, or consist of, the amino acid sequence of SEQ ID NQ:10.

[0102] In preferred embodiments, an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure does not comprise, or consist of, the amino acid sequence of a spike protein of a sarbecovirus.

[0103] In some embodiments, an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15, 7, 8, or 9, and has ‘F’ at the position corresponding to position 358 of SEQ ID NO:15; and / or has ‘P’ at the position corresponding to position 360 of SEQ ID NO:15; and / or has ‘F’ at the position corresponding to position 362 of SEQ ID NO:15; and / or has ‘N’ at the position corresponding to position 392 of SEQ ID NO:15; and / or has ‘S’ at the position corresponding to position 395 of SEQ ID NO:15.

[0104] In some embodiments, an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) according to the present disclosure does not comprise the amino acid sequence of SEQ ID NO:43. In some embodiments, the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) does not comprise the amino acid sequence of SEQ ID NO:44.

[0105] In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15, 7, 8, or 9. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:7. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:9.

[0106] In some embodiments, a polypeptide according to the present disclosure does not comprise, or consist of, the amino acid sequence of SEQ ID NO:14. In some embodiments, the polypeptide does not comprise, or consist of, the amino acid sequence of SEQ ID NO:4. does not comprise, or consist of, the amino acid sequence of SEQ ID NQ:10.

[0107] In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:15, 7, 8, or 9, and has ‘F’ at the position corresponding to position 358 of SEQ ID NO:15; and / or has ‘P’ at the position corresponding to position 360 of SEQ ID NO:15; and / or has ‘F’ at the position corresponding to position 362 of SEQ ID NO:15; and / or has ‘N’ at the position corresponding to position 392 of SEQ ID NO:15; and / or has ‘S’ at the position corresponding to position 395 of SEQ ID NO:15.

[0108] In some embodiments, a polypeptide according to the present disclosure does not comprise the amino acid sequence of SEQ ID NO:43. In some embodiments, the polypeptide does not comprise the amino acid sequence of SEQ ID NO:44.

[0109] In some embodiments, a polypeptide according to the present disclosure comprises one or more amino acid substitutions selected from amino acid substitutions described in Hsieh et al. Science (2020) 369(6510):1501-1505.

[0110] In some embodiments, a polypeptide according to the present disclosure comprises a domain providing for association of plural monomers of the polypeptide to form a multipolypeptide complex. Such domains may also be referred to as multimerization domains. Accordingly, in some embodiments, the polypeptide comprises a multimerization domain. In some embodiments, the multimerization domain is a trimerization domain. In some embodiments, the multimerization domain is, or is derived from, the C-terminal domain of T4 fibritin, which is also referred to in the scientific literature as ‘foldon’. The foldon domain of T4 fibritin consists of the amino acid sequence shown in SEQ ID NO:6. The C-terminal domain of T4 fibritin is required for the formation of trimeric fibritin polypeptide complexes, and has been employed as an artificial trimerization domain in the production of trimeric polypeptide complexes. See, for example, Meier et al., J Mol Biol. (2004) 344(4):1051-1069; Wang et al., BMC Biotechnology volume 17, Article number: 57 (2017).

[0111] In some embodiments, the multimerization domain (e.g. trimerization domain, e.g. foldon domain) comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:6.

[0112] In some embodiments, the multimerization domain (e.g. trimerization domain, e.g. foldon domain) is C- terminal to ( / .e. downstream of) an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), in the amino acid sequence of the polypeptide according to the present disclosure. In some embodiments, the polypeptide according to the present disclosure has the structure: N-term-[...]-[amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s)]-[foldon domain]-[...]-C-term; wherein ‘N-term’ represents the N-terminus of the polypeptide, ‘C-term’ represents the C-terminus of the polypeptide, ‘[...]’ indicates the optional presence of further amino acid sequence(s) / protein domain(s), and each indicates an optional linker sequence.

[0113] In some embodiments, the multimerization domain (e.g. trimerization domain, e.g. foldon domain) is provided at or proximal to the C-terminus of the polypeptide according to the present disclosure. In some embodiments, the C-terminal position of the amino acid sequence of the multimerization domain (e.g. trimerization domain, e.g. foldon domain) is the C-terminal position of the amino acid sequence of the polypeptide. In some embodiments, the C-terminal residue of the multimerization domain (e.g. trimerization domain, e.g. foldon domain) is provided within 1-40, e.g. one of 1-30, 1-25, 1-20, 1-15, 1-10 or 1-5 amino acids of C-terminal position of the amino acid sequence of the polypeptide.

[0114] In some embodiments, the polypeptides according to the present disclosure assemble into multimeric polypeptide complexes. That is, plural monomers of the polypeptide according to the present disclosure may associate to form a multimeric polypeptide complex. In some embodiments, the multimeric polypeptide complex is a trimeric polypeptide. In some embodiments, the polypeptide of the present disclosure is provided in the form of a multimeric (e.g. trimeric) polypeptide complex comprising the polypeptide.

[0115] In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:45. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:11 . In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:12. In some embodiments, the polypeptide comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:13.

[0116] In some embodiments, a polypeptide according to the present disclosure comprises, or consists of, an amino acid sequence having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of SEQ ID NO:45, 11 , 12, or 13, and has ‘F’ at the position corresponding to position 358 of SEQ ID NO:45; and / or has ‘P’ at the position corresponding to position 360 of SEQ ID NO:45; and / or has ‘F’ at the position corresponding to position 362 of SEQ ID NO:45; and / or has ‘N’ at the position corresponding to position 392 of SEQ ID NO:45; and / or has ‘S’ at the position corresponding to position 395 of SEQ ID NO:45.

[0117] In some embodiments, the polypeptide according to the present disclosure comprises further amino acids or sequences of amino acids.

[0118] The polypeptides according to the present disclosure may comprise one or more linker sequences between sequences of amino acids. For example, a linker sequence may be provided between an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), and an amino acid sequence forming a foldon domain, providing linkage between the sequences. For example, a linker sequence may be provided between an amino acid sequence forming a foldon domain, and a 10XHis sequence ( / .e. consisting of 10 histidines).

[0119] Linker sequences are known to the skilled person, and are described, for example in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369, which is hereby incorporated by reference in its entirety. In some embodiments, a linker sequence may be a flexible linker sequence. Flexible linker sequences allow for relative movement of the amino acid sequences which are linked by the linker sequence. Flexible linkers are known to the skilled person, and several are identified in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369. Flexible linker sequences often comprise high proportions of glycine and / or serine residues.

[0120] In some embodiments, the linker sequence comprises at least one glycine residue and / or at least one serine residue. In some embodiments, the linker sequence comprises or consists of glycine and serine residues. In some embodiments, the linker sequence has the structure: (GxS)n or (GxS)nGm; wherein G = glycine, S = serine, x = 3 or 4, n = 2, 3, 4, 5 or 6, and m = 0, 1 , 2 or 3. In some embodiments, the linker sequence comprises one or more (e.g. 1 , 2, 3, 4, 5 or 6) copies (e.g. in tandem) of the sequence motif G4S. In some embodiments, the linker sequence comprises or consists of (G4S)4 or (G4S)6. In some embodiments, the linker sequence has a length of 1-2, 1-3, 1-4, 1-5, 1-10, 1-15, 1-20, 1-25, or 1-30 amino acids.

[0121] The polypeptides according to the present disclosure may comprise amino acid sequence(s) to facilitate expression, folding, trafficking, processing, purification or detection of the polypeptide. For example, polypeptides according to the present disclosure may additionally comprise a sequence of amino acids forming a detectable moiety, e.g. as described hereinbelow.

[0122] The polypeptides according to the present disclosure may additionally comprise a signal peptide (also known as a leader sequence or signal sequence). Signal peptides normally consist of a sequence of 5-30 hydrophobic amino acids, which form a single alpha helix. Secreted proteins and proteins expressed at the cell surface often comprise signal peptides. Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt and Ensembl, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 2011 Nature Methods 8: 785- 786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172-2176).

[0123] The signal peptide may be present at the N-terminus of the polypeptide, and may be present in the newly synthesised polypeptide. The signal peptide provides for efficient trafficking of the polypeptide. Signal peptides are often removed by cleavage, and thus are not comprised in the mature polypeptide.

[0124] Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl, and InterPro, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 2011 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172- 2176).

[0125] In some embodiments, the polypeptide according to the present disclosure comprises a detectable moiety.

[0126] In some embodiments, a detectable moiety is an immuno-detectable label (e.g. an epitope tag), a fluorescent label, phosphorescent label, luminescent label, radiolabel, chemical, nucleic acid or enzymatic label. The polypeptide may be covalently or non-covalently labelled with the detectable moiety.

[0127] In some embodiments, the polypeptide comprises an epitope tag, e.g. a His, (e.g. 1-10XHis, e.g. 6XHis, 10XHis), FLAG, c-Myc, StrepTag, haemagglutinin, E, calmodulin-binding protein (CBP), glutathione-s- transferase (GST), maltose-binding protein (MBP), thioredoxin, S-peptide, T7 peptide, SH2 domain, avidin, streptavidin, and haptens (e.g. biotin, digoxigenin, dinitrophenol), optionally at the N- or C- terminus of the polypeptide.

[0128] In some embodiments, the polypeptide comprises a 1-10XHis tag. In some embodiments, the polypeptide comprises a 1-10XHis tag at the C-terminus of the polypeptide. Fluorescent labels include e.g. fluorescein, rhodamine, allophycocyanin, eosine and NDB, green fluorescent protein (GFP), chelates of rare earths such as europium (Eu), terbium (Tb) and samarium (Sm), tetramethyl rhodamine, Texas Red, 4-methyl umbelliferone, 7-amino-4-methyl coumarin, Cy3, and Cy5. Radiolabels include radioisotopes such as Hydrogen3, Sulfur35, Carbon14, Phosphorus32, Iodine123, Iodine125, Iodine126, lodinel 31 , Iodine133, Bromine77, Technetium99m, Indiuml 11 , Indium113m, Gallium67, Gallium68, Ruthenium95, Ruthenium97, Ruthenium103, Ruthenium105, Mercury207, Mercury203, Rhenium99m, Rhenium101 , Rhenium105, Scandium47, Tellurium121 m, Tellurium122m, Tellurium125m, Thulium165, Thuliuml167, Thulium168, Copper67, Fluorine18, Yttrium90, Palladiuml OO, Bismuth217 and Antimony211. Luminescent labels include as radioluminescent, chemiluminescent (e.g. acridinium ester, luminol, isoluminol) and bioluminescent labels. Immuno- detectable labels include haptens, peptides / polypeptides, antibodies, receptors and ligands such as biotin, avidin, streptavidin or digoxigenin. Nucleic acid labels include aptamers.

[0129] In some embodiments, the polypeptide comprises a moiety having a detectable activity, e.g. an enzymatic moiety. Enzymatic moieties include e.g. luciferases, glucose oxidases, galactosidases (e.g. betagalactosidase), glucorinidases, phosphatases (e.g. alkaline phosphatase), peroxidases (e.g. horseradish peroxidase) and cholinesterases.

[0130] In some embodiments, the polypeptide according to the present disclosure comprises a chemical moiety. In some embodiments, the polypeptide according to the present disclosure is conjugated to a chemical moiety. The chemical moiety may be a moiety for providing a therapeutic effect, i.e. a drug moiety. A drug moiety may be a small molecule (e.g. a low molecular weight (< 1000 daltons, typically between ~300- 700 daltons) organic compound). Drug moieties are described e.g. in Parslow et al., Biomedicines. 2016 Sep; 4(3):14 (hereby incorporated by reference in its entirety).

[0131] D. Nucleic acids and vectors

[0132] The present disclosure also provides nucleic acids encoding the polypeptides according to the present disclosure. The nucleic acids according to the present disclosure may be provided in isolated or substantially purified form.

[0133] The nucleic acid may be a polynucleotide. A 'polynucleotide' refers to a polymer chain of a plurality of nucleotide monomers linked by bonds between the monomers, typically phosphodiester bonds (e.g. in the case of polynucleotides formed by naturally-occurring nucleotide monomers). Polynucleotides include oligonucleotides, which generally comprise <50 nucleotides. A polynucleotide may be single-stranded, or may be double-stranded (j.e. may comprise a duplex formed by hydrogen-bonding between complementary nucleotides).

[0134] In some embodiments, a nucleic acid according to the present disclosure comprises or consists of DNA. In some embodiments, the nucleic acid is a polydeoxyribonucleotide. In some embodiments, the nucleic acid comprises or consists of double-stranded DNA. In some embodiments, the nucleic acid according to the present disclosure comprises or consists of RNA. In some embodiments, the nucleic acid is a polyribonucleotide. In some embodiments, the nucleic acid comprises or consists of single-stranded RNA. In some embodiments, the nucleic acid comprises or consists of messenger RNA (mRNA).

[0135] In some embodiments, a nucleic acid according to the present disclosure is, is comprised in, or is encoded by, a vector. Herein, a ‘vector’ refers to an agent used as a vehicle to transfer exogenous nucleic acid into a cell. A vector according to the present disclosure may comprise a nucleic acid according to the present disclosure, and may facilitate delivery of the nucleic acid into a cell.

[0136] Nucleic acids / vectors may be administered to a subject in order to express a polypeptide according to the present disclosure. The nucleic acid / vector may provide for recombinant expression of the polypeptide.

[0137] A vector may be a vector for expression of a polypeptide encoded by the vector in a cell into which the vector has been introduced. Such vectors may include a polynucleotide encoding a promoter sequence, operably-linked to a nucleotide sequence encoding the polypeptide to be expressed. A vector may also include a sequences of nucleotides forming a termination codon and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express a polypeptide from a vector according to the present disclosure. The term ‘operably-linked’ may include the situation where a selected nucleotide sequence and regulatory nucleotide sequence (e.g. promoter and / or enhancer) are covalently linked in such a way as to place the expression of nucleotide sequence under the influence or control of the regulatory sequence (thereby forming an expression cassette). Thus a regulatory sequence is operably-linked to the selected nucleotide sequence if the regulatory sequence is capable of effecting transcription of the selected nucleotide sequence. The resulting transcript(s) may then be translated into desired peptide(s) / polypeptide(s). Suitable vectors contemplated in connection with the present disclosure include DNA vectors, RNA vectors, plasmids (e.g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g. retroviral vectors, e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors, e.g. SFG vector), lentiviral vectors, adenovirus vectors, adeno-associated virus vectors, vaccinia virus vectors and herpesvirus vectors), transposon-based vectors, and artificial chromosomes (e.g. yeast artificial chromosomes), e.g. as described in Maus et al., Annu Rev Immunol. (2014) 32:189-225 and Morgan and Boyerinas, Biomedicines (2016) 4:9, which are both hereby incorporated by reference in their entirety. In some embodiments, the vector may be a eukaryotic vector, e.g. a vector comprising the elements necessary for expression of a polypeptide encoded by nucleic acid of the vector in a eukaryotic cell.

[0138] In some embodiments, the nucleic acid / vector comprises a nucleotide sequence forming a promoter sequence, for expression of a polypeptide encoded by the nucleic acid / vector in a eukaryotic cell (e.g. a cytomegalovirus (CMV) or SV40 promoter sequence).

[0139] In some embodiments, the nucleic acid / vector comprises a nucleotide sequence providing for expression of the polypeptide by cells of a particular type or tissue. For example, the nucleic acid / vector may comprise a nucleotide sequence forming a cell type- or tissue-specific promoter. E. Cells comprisinq / expressinq the antigen-binding molecules and polypeptides

[0140] The present disclosure also provides cells comprising or expressing a polypeptide / nucleic acid / vector according to the present disclosure.

[0141] It will be appreciated that where cells are referred to herein in the singular ( / .e. ‘a / the cell’), pluralities / populations of such cells are also contemplated.

[0142] The cell may be a eukaryotic cell, e.g. a mammalian cell. The mammal may be a primate (rhesus, cynomolgous, non-human primate or human) or a non-human mammal (e.g. rabbit, guinea pig, rat, mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cows, e.g. dairy cows, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate). In some embodiments, the cell is, or is derived from, a cell type commonly used for the expression of polypeptides for use in therapy / prophylaxis in humans. Exemplary cells are described e.g. in Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100:3451- 3461 (hereby incorporated by reference in its entirety), and include e.g. CHO, HEK 293, PER.C6, NSO and BHK cells. In some embodiments, the cell is a human cell.

[0143] In some embodiments, the cell is an antigen-presenting cell (APC). APCs are cells that express MHC molecules (e.g. MHC class I and / or MHC class II molecules), and are capable of presenting MHC:peptide complexes. APCs according to the present disclosure may be professional APCs. Professional APCs are specialised for presenting antigens to T cells; they are efficient at processing and presenting MHC- peptide complexes at the cell surface, and express high levels of costimulatory molecules. Professional APCs include dendritic cells (DCs), macrophages, and B cells. Non-professional APCs are other cells capable of presenting MHC-peptide complexes to T cells, in particular MHC Class l-peptide complexes to CD8+ T cells. In some embodiments, an APC according to the present disclosure is a dendritic cell, a macrophage or B cell.

[0144] The present disclosure also provides a method for producing a cell comprising or expressing a polypeptide / nucleic acid / vector according to the present disclosure, comprising introducing a nucleic acid or vector according to the present disclosure into a cell. In some embodiments, introducing a nucleic acid or vector according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. retroviral transduction).

[0145] In some embodiments, the methods additionally comprise culturing the cell under conditions suitable for expression of the polypeptide from the nucleic acid / vector by the cell.

[0146] In some embodiments, the methods are performed in vitro. In some embodiments, the methods are performed ex vivo.

[0147] In some embodiments, the methods are performed in vivo. In some embodiments, a cell a nucleic acid or vector according to the present disclosure is introduced into a cell of a subject in vivo. The present disclosure also provides cells obtained or obtainable by the methods according to the present disclosure.

[0148] F. Compositions

[0149] The polypeptides, nucleic acids and vectors according to the present disclosure may be provided in the form of a composition comprising the relevant agent. Such compositions may be pharmaceutical compositions or medicaments suitable for clinical use, and may additionally comprise a pharmaceutically- acceptable carrier, diluent, excipient or adjuvant.

[0150] It will be appreciated that the compositions according to the present disclosure are preferably immunogenic compositions. That is, the compositions are preferably capable of stimulating an immune response (e.g. an adaptive immune response) in a subject, e.g. to a constituent of the composition (e.g. a polypeptide according to the present disclosure comprised in the composition), or a molecule encoded by a constituent of the composition (e.g. a polypeptide encoded by a nucleic acid / vector according to the present disclosure, comprised in the composition).

[0151] The compositions according to the present disclosure may comprise one or more pharmaceutically- acceptable carriers (e.g. liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium stearate, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, acetic acid, tromethamine, tromethamine hydrochloride), adjuvants, fillers, buffers, preservatives (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), anti-oxidants (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium), lubricants (e.g. magnesium stearate, talc, silica, stearic acid, vegetable stearin), binders (e.g. sucrose, glucose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilisers, solubilisers, surfactants (e.g. wetting agents), masking agents or colouring agents (e.g. titanium oxide).

[0152] The term ‘pharmaceutically-acceptable’ as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent of a composition according to the present disclosure must also be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, binders, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents or sweetening agents can be found in standard pharmaceutical texts, for example, Remington’s ‘The Science and Practice of Pharmacy’ (Ed. A. Adejare), 23rd Edition (2020), Academic Press. The pharmaceutical compositions / medicaments according to the present disclosure may be formulated for administration to a subject, e.g. administration via a route of administration as appropriate for the nature of the therapeutic agent and the disease to be treated / prevented. In some embodiments, a pharmaceutical composition / medicament may be formulated for parenteral, systemic, intravascular, intravenous, intra-arterial, intramuscular, topical, intracavitary, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral or transdermal administration. In some embodiments, a pharmaceutical composition / medicament may be formulated for administration by injection or infusion, or administration by ingestion.

[0153] Suitable formulations may comprise a polypeptide / nucleic acid / vector according to the present disclosure in a sterile or isotonic medium. Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via cannula) to a selected region of the human or animal body. The pharmaceutical compositions / medicaments may also be provided in solid form, e.g. in lyophilised form. Medicaments and pharmaceutical compositions may be formulated for administration to a blood vessel, or to a tissue / organ of interest (e.g. a tissue / organ affected by the disease / condition (e.g. a tissue / organ in which symptoms of the disease / condition manifest).

[0154] The present disclosure also provides methods for producing pharmaceutical compositions / medicaments according to the present disclosure. Such methods may comprise mixing a polypeptide / nucleic acid / vector described herein with a pharmaceutically-acceptable carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent. Such methods generally include the step of bringing into association the polypeptide / nucleic acid / vector with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

[0155] G. Delivery / uptake

[0156] The polypeptides, nucleic acids, vectors and compositions according to the present disclosure may comprise one or more moieties, and / or may be formulated, to facilitate their delivery to and / or uptake by cells / tissue (e.g. cells of a cell-type / tissue to which it is desired to deliver the polypeptide according to the present disclosure, or in which is it is desired to express the polypeptide).

[0157] Strategies for targeted delivery of such species are reviewed e.g. in Li et al., Int. J. Mol. Sci. (2015) 16: 19518-19536 and Fu et al., Bioconjug Chem. (2014) 25(9): 1602-1608, which are hereby incorporated by reference in their entirety.

[0158] In some embodiments, the polypeptides, nucleic acids, vectors or compositions may be encapsulated in a nanoparticle or a liposome. In some embodiments, the polypeptides, nucleic acids, vectors or compositions may be (covalently or non-covalently) associated with a cell-penetrating peptide (e.g. a protein transduction domain, trojan peptide, arginine-rich peptide, vectocell peptide), a cationic polymer, a cationic lipid or a viral carrier.

[0159] Nanoparticles may be organic, e.g. micelles, liposomes, proteins, solid-lipid particles, solid polymer particles, dendrimers, and polymer therapeutics. Nanoparticles may be inorganic, e.g. such as nanotubes or metal particles, optionally with organic molecules added. In some embodiments, a nanoparticle is a nanoparticle described in Chen et al., Mol Ther Methods Clin Dev. (2016) 3:16023, which is hereby incorporated by reference in its entirety. In some embodiments, a nanoparticle is a PLGA, polypeptide, poly(p-amino ester), DOPE, p-cyclodextrin-containing polycation, linear PEI, PAMAM dendrimer, branched PEI, chitosan or polyphosphoester nanoparticle.

[0160] Moieties facilitating delivery to, and / or uptake by, cell-types or tissues of interest are described e.g. in Benizri et al., Bioconjug Chem. (2019) 30(2): 366-383, which is hereby incorporated by reference in its entirety. Such moieties include e.g. N-acetylgalactosamine (GalNAc), a-tocopherol, cell-penetrating peptides, nucleic acid aptamers, antibodies and antigen-binding fragments / derivatives thereof, cholesterol, squalene, polyethylene glycol (PEG), fatty acids (e.g. palmitic acid) and nucleolipid moieties.

[0161] The polypeptides, nucleic acids, vectors or compositions according to the present disclosure may be formulated in a sustained release delivery system, in order to release the polypeptide, nucleic acid, vector, cell or composition at a predetermined rate. Sustained release delivery systems may maintain a constant drug / therapeutic / prophylactic concentration for a specified period of time. In some embodiments, articles according to the present disclosure are formulated in a liposome, gel, implant, device, or drug- polymer conjugate e.g. hydrogel.

[0162] HL Vaccines

[0163] Aspects and embodiments according to the present disclosure pertain to the use of the polypeptides, nucleic acids, vectors and compositions according to the present disclosure in methods for the treatment and / or prevention of diseases and conditions by vaccination.

[0164] As used herein, ‘vaccination’ refers to administration of an agent to a subject in order to induce / elicit or upregulate an immune response in the subject to an agent that is pathologically-implicated in a disease / condition (e.g. an infectious agent, or a disease / condition-associated molecule). Herein, a ‘vaccine’ refers to an agent, or a composition comprising an agent, capable of inducing / eliciting or upregulating an immune response in a subject, to an agent that is pathologically-implicated in a disease / condition (e.g. an infectious agent, or a disease / condition-associated molecule).

[0165] Accordingly, the present disclosure provides a vaccine comprising a polypeptide, nucleic acid, vector or composition according to the present disclosure.

[0166] Vaccines may be classified into different platforms based on their composition. Vaccine platforms contemplated in connection with the present disclosure include virus-based vaccines, protein vaccines, nucleic acid vaccines (including RNA vaccines, e.g. mRNA vaccines), viral vector vaccines and antigen presenting cell (APC) vaccines. Exemplary vaccine platforms are described e.g. in Bayani et al. Prog Biophys Mol Biol (2023) 178:32-49, and Nagy and Alhatlani, Comput Struct Biotechnol J. (2021) 19:2508- 2517, both of which are hereby incorporated by reference in their entirety.

[0167] In some embodiments, a vaccine according to the present disclosure is a protein vaccine, a nucleic acid vaccine (e.g. an RNA vaccine, e.g. an mRNA vaccine), a viral vector vaccine or an APC vaccine. In some embodiments, the vaccine is a protein vaccine or a nucleic acid vaccine. In some embodiments, the vaccine is a nucleic acid vaccine, e.g. an RNA vaccine. In some embodiments, the vaccine is an mRNA vaccine.

[0168] Protein vaccines include purified viral protein vaccines, virus-like particle (VLP) vaccines, and recombinant protein vaccines. The present disclosure provides a virus-like particle vaccine comprising a polypeptide according to the present disclosure. The present disclosure also provides a recombinant protein vaccine comprising a polypeptide according to the present disclosure.

[0169] In some embodiments, a vaccine according to the present disclosure is a virus-like particle vaccine. Virus-like particle (VLP) vaccines mimic the structure of a virus without containing any viral genetic material, making them non-infectious. They are composed of proteins that self-assemble into structures resembling the virus upon which they are based, prompting an immune response without causing disease. Virus-like particles may be homologous (assembled using proteins derived from the native pathogen only) or heterologous (assembled using proteins or peptides from different sources). Virus-like particle vaccines are reviewed e.g. in Prates-Syed et al. Vaccines (Basel) (2021) 9(12):1409, which is hereby incorporated by reference in its entirety.

[0170] Nucleic acid vaccines comprise polynucleotide(s) encoding a polypeptide to which it is desired to induce / elicit or upregulate an immune response. The present disclosure provides a nucleic acid vaccine comprising nucleic acid encoding a polypeptide according to the present disclosure. A nucleic acid vaccine according to the present disclosure may comprise, or consist of, DNA. A nucleic acid vaccine according to the present disclosure may comprise, or consist of, RNA (e.g. mRNA). Following uptake by a cell, the nucleic acid is transcribed and subsequently translated (in the case of DNA vaccines), or simply translated (in the case of mRNA vaccines) into the polypeptide to which it is desired to induce / elicit or upregulate an immune response.

[0171] DNA vaccines may be administered in conjunction with electroporation, in order to enhance cellular uptake (see e.g. Sardesai and Weiner, Curr Opin Immunol. (2011) 23(3):421-429, which is hereby incorporated by reference in its entirety).

[0172] In some embodiments, a nucleic acid vaccine according to the present disclosure is an mRNA vaccine. In some embodiments an mRNA vaccine comprises mRNA encoding a polypeptide according to the present disclosure. mRNA is susceptible to degradation, and so techniques for stabilising mRNA molecules are often employed in mRNA vaccines to improve stability. mRNA stabilising modifications are reviewed in e.g. Chang Kim etal. Mol Cell Toxicol. (2022) 18(1):1 -8, which is hereby incorporated by reference in its entirety. An mRNA vaccine according to the present disclosure may comprise one or more such modifications to increase stability. In some embodiments, an mRNA vaccine according to the present disclosure comprises one or more modified nucleosides. mRNA vaccines may further comprise one or more carriers to facilitate introduction of the mRNA into a cell. Such carriers may be or comprise comprise, for example, protamine-based carriers, polymeric nanoparticles, inorganic nanoparticles, peptide carriers, peptide nanoparticles, lipid carriers (e.g. lipidoids), liposomes, lipoplexes, nanotubes and lipid nanoparticles. Accordingly, in some embodiments an mRNA vaccine according to the present disclosure comprises a protamine-based carrier, a polymeric nanoparticle, an inorganic nanoparticle, a peptide carrier, a peptide nanoparticle, a lipid carrier, a lipidoid, a liposome, a lipoplex, a nanotube or a lipid nanoparticle. The mRNA may be encapsulated by / enclosed in a carrier.

[0173] In some embodiments, a nucleic acid vaccine (e.g. mRNA vaccine) according to the present disclosure comprises a lipid nanoparticle. In some embodiments, a nucleic acid vaccine (e.g. mRNA vaccine) according to the present disclosure comprises a nucleic acid (e.g. mRNA) according to the present disclosure encapsulated in a lipid nanoparticle.

[0174] In some embodiments, a vaccine according to the present disclosure is a viral vector vaccine. Viral vector vaccines employ harmless viruses to deliver nucleic acid encoding a polypeptide to which it is desired to induce / elicit or upregulate an immune response into target cells. The polypeptide is then expressed by the cells, triggering an immune response. Accordingly, the present disclosure provides a viral vector vaccine comprising nucleic acid encoding a polypeptide according to the present disclosure ( / .e., a viral vector vaccine comprising a nucleic acid according to the present disclosure).

[0175] In some embodiments, a viral vector vaccine according to the present disclosure is, or comprises, an adenovirus vector, an adeno-associated virus vector, a vesicular stomatitis virus (VSV) vector, a poxvirus vector (e.g. a vaccinia virus vector, variola virus vector, or modified vaccinia Ankara virus vector), a measles virus vector, Newcastle disease virus vector or influenza virus vector. In some embodiments, a viral vector vaccine according to the present disclosure is, or comprises, a replicating or non-replicating virus vector.

[0176] In some embodiments, a vaccine according to the present disclosure is an antigen-presenting cell (APC) vaccine. APC vaccines comprise APCs comprising nucleic acid encoding a polypeptide to which it is desired to induce / elicit or upregulate an immune response. APCs are described hereinabove. In some embodiments, the APC of an APC vaccine according to the present disclosure is a dendritic cell, a macrophage or B cell. Accordingly, the present disclosure provides an APC vaccine that comprises, or consists of, an APC comprising nucleic acid encoding a polypeptide according to the present disclosure ( / .e., an APC comprising a nucleic acid according to the present disclosure). In order to augment the immune response, vaccines may be formulated in combination with adjuvants. The use of adjuvants in vaccines is reviewed, for example, in Facciola et al. Vaccines (Basel) (2022) 10(5):819, which is hereby incorporated by reference in its entirety.

[0177] In some embodiments, a vaccine according to the present disclosure comprises one or more pharmaceutically-acceptable adjuvants. Pharmaceutically-acceptable adjuvants include alum, immunostimulatory complexes (ISCOMs), CpG oligodeoxynucleotides (e.g. CpG 1018), squalene, MF59, Adjuvant System 03 (AS03), Sigma Adjuvant System (S6322), bacterial toxins or monophosphoryl lipid A. In some embodiments, a vaccine according to the present disclosure comprises Sigma Adjuvant System (S6322).

[0178] Vaccines may be formulated with additional components to improve efficacy, stability, safety or other desired characteristics. Typical vaccine compositions are reviewed, for example, in Kocourkova et al. Mini Rev Med Chem. (2017) 17(5):451 -466, which is hereby incorporated by reference in its entirety.

[0179] Vaccines according to the present disclosure may comprise one or more pharmaceutically-acceptable buffers (e.g. tris, phosphate, phosphate-citrate, potassium chloride, sodium chloride), diluents (e.g. sterile water, saline), preservatives (e.g. phenol, 2-phenoxyethanol, thiomersal), stabilizers (e.g. sugars (e.g. sucrose, lactose, sorbitol), amino acids (e.g. glycine, monosodium salt of glutamic acid), proteins (e.g. gelatin, human or bovine serum albumin)), inactivators (e.g. formaldehyde, p-propiolactone, glutaraldehyde), antibiotics (e.g. neomycin, streptomycin, polymyxin B, gentamicin, chlortetracycline, amphotericin B) or other trace elements.

[0180] In some embodiments, a vaccine according to the present disclosure may be a composition according to the present disclosure. That is, a composition according to the present disclosure (e.g. as described in section F herein) may be a vaccine.

[0181] L Known polypeptides, nucleic acids, vectors, compositions and vaccines

[0182] Aspects and embodiments according to the present disclosure relate to known polypeptides comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), known nucleic acids encoding such polypeptides, known vectors comprising such nucleic acids, known compositions comprising such polypeptides, nucleic acids and vectors, and known vaccines comprising such polypeptides, nucleic acids, vectors and compositions.

[0183] To be clear, where reference is made herein to ‘a polypeptide according to the present disclosure’ or ‘a nucleic acid according to the present disclosure’ or ‘a vector according to the present disclosure’ or ‘a composition according to the present disclosure’ or ‘a vaccine according to the present disclosure’, reference to such known polypeptides / nucleic acids / vectors / compositions / vaccines is not intended. Reference herein to ‘a polypeptide according to the present disclosure’ preferably refers to a polypeptide described in section C or G herein. Reference herein to ‘a nucleic acid according to the present disclosure’ preferably refers to a nucleic acid described in section D or G herein. Reference herein to ‘a vector according to the present disclosure’ preferably refers to a vector described in section D or G herein. Reference herein to ‘a composition according to the present disclosure’ preferably refers to a composition described in section F or G herein. Reference herein to ‘a vaccine according to the present disclosure’ preferably refers to a vaccine described in section H herein.

[0184] Known vaccines comprising nucleic acid encoding an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) include BNT162b2 (also known as Tozinameran and Comirnaty; DrugBank Acc. No. DB15696) and mRNA1273 (also known as Spikevax; DrugBank Acc. No. DB15654). BNT162b2 and mRNA1273 each comprise single-stranded RNA molecules encoding a polypeptide having the amino acid sequence of SEQ ID NO:51 (see e.g. Jeong et al., “Assemblies-of-Putative-SARS-CoV2-Spike-Encoding-mRNA-Sequences-for-Vaccines-BNT-162b2- and-mRNA-1273”; available from virological.org).

[0185] Known vaccines comprising an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) include those described in WO 2022 / 245287 A1 , such as the polypeptide having the amino acid sequence of SEQ ID NO:50.

[0186] In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID NO:23. In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID NO:22. In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID N0:21. In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID N0:18. In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID N0:51. In some embodiments, a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of the amino acid sequence of SEQ ID NQ:50.

[0187] In some embodiments, a known composition according to the present disclosure comprises a polypeptide according to the preceding paragraph. In some embodiments, a known vaccine comprises a polypeptide according to the preceding paragraph, and / or a composition according to the preceding sentence.

[0188] In some embodiments, a known nucleic acid encoding a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of nucleic acid encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:23. In some embodiments, a known nucleic acid encoding a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of nucleic acid encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:22. In some embodiments, a known nucleic acid encoding a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of nucleic acid encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:18. In some embodiments, a known nucleic acid encoding a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of nucleic acid encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:51. In some embodiments, a known nucleic acid encoding a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s) comprises or consists of nucleic acid encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NQ:50.

[0189] In some embodiments, a known vector according to the present disclosure comprises a nucleic acid according to the preceding paragraph. In some embodiments, a known composition according to the present disclosure comprises a nucleic acid according to the preceding paragraph, and / or a vector according to the preceding paragraph. In some embodiments, a known vaccine comprises a nucleic acid according to the preceding paragraph, and / or a composition according to the preceding sentence.

[0190] J. Therapy and prophylaxis

[0191] The polypeptides, nucleic acids, vectors, compositions and vaccines described herein find use in therapeutic and prophylactic methods.

[0192] The present disclosure provides a polypeptide, nucleic acid, vector, composition or vaccine described herein for use in a method of medical treatment or prophylaxis. Also provided is a polypeptide, nucleic acid, vector, composition or vaccine described herein for use in a method of treating or preventing a disease or condition described herein. Also provided is the use of a polypeptide, nucleic acid, vector, composition or vaccine described herein in the manufacture of a medicament for treating or preventing a disease or condition described herein. Also provided is a method of treating or preventing a disease or condition described herein, comprising administering to a subject a therapeutically or prophylactically effective amount of a polypeptide, nucleic acid, vector, composition or vaccine described herein.

[0193] The articles, methods and uses according to the present disclosure may be effective to reduce the development or progression of a disease / condition, alleviation of the symptoms of a disease / condition or reduction in the pathology of a disease / condition. The articles, methods and uses may be effective to prevent progression of the disease / condition, e.g. to prevent worsening of, or to slow the rate of development of, the disease / condition. In some embodiments, the articles, methods and uses may lead to an improvement in the disease / condition, e.g. a reduction in the symptoms of the disease / condition or reduction in some other correlate of the severity / activity of the disease / condition. In some embodiments, the articles, methods and uses may prevent development of the disease / condition a later stage (e.g. a chronic stage). It will be appreciated that the articles according to the present disclosure may be used for the treatment / prevention of any disease / condition that would derive therapeutic or prophylactic benefit from an increased immune response to a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant). For example, the disease / condition may be a disease / condition in which infection with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant) is pathologically-implicated, e.g. a disease / condition for which infection with a sarbecovirus (e.g. a SARSr-CoV, , e.g. SARS-CoV-2 / a SARS-CoV-2 variant) is positively associated with the onset, development or progression of the disease / condition, and / or severity of one or more symptoms of the disease / condition, or for which infection with a sarbecovirus (e.g. a SARSr-CoV, e.g. , e.g. SARS-CoV-2 / a SARS-CoV-2 variant) is, is a risk factor for the onset, development or progression of the disease / condition.

[0194] In some embodiments, the disease / condition to be treated / prevented in accordance with the present disclosure is a disease / condition characterised by infection with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant), e.g. COVID-19. In some embodiments, the disease / condition is a disease / condition caused by infection with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS- CoV-2 variant), e.g. COVID-19.

[0195] The clinical features of COVID-19 are described e.g. in Lechien et al., Journal of Internal Medicine (2020) 288(3): 335-344, International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC). COVID-19 Report: 19 May 2020: ISARIC; 2020, Docherty et al., BMJ (2020) 369:m1985 and Bhardwaj et al., Int Rev Immunol. (2021) 2021 : 1 — 36, which are hereby incorporated by reference in their entirety. Common symptoms include cough, fever, headache, dyspnoea, anosmia, pharyngitis, nasal obstruction, rhinorrhoea, asthenia, myalgia, joint pain, gustatory dysfunction, abdominal pain, vomiting, and diarrhoea. The majority patients present with mild / moderate disease, however hospitalisation is sometimes required in particularly in elderly patients and / or patients having comorbidities such as diabetes and cardiovascular disease. A major complication in COVID-19 is progression to acute respiratory distress syndrome (ARDS), which presents as dyspnoea and acute respiratory failure, with patients requiring mechanical ventilation. A proportion of infected subjects are asymptomatic.

[0196] Treatment in accordance with the methods according to the present disclosure may achieve one or more of: a reduction in the level or viral load of a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS- CoV-2 variant) in a subject or in a tissue / organ of the subject (e.g. the lungs), a reduction in the level of expression of a proinflammatory factor (e.g. IL-6, CCL2 and / or CXCL10) in a subject or in a tissue / organ of the subject (e.g. the lungs), an increase in the level of expression of IFNy in the subject or in a tissue / organ of the subject (e.g. the lungs), a reduction in the number / proportion of cells infected with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant), inhibition of the development / progression of a disease / condition caused by infection with a sarbecovirus (e.g. a SARSr- CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant), e.g. COVID-19, in the subject, a reduction in the severity of symptoms of a disease / condition caused by infection with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant), e.g. COVID-19, in the subject, inhibition of the development / progression of acute respiratory distress syndrome (ARDS) in the subject, and an increase in survival of the subject. In some embodiments, a subject may be selected for prophylactic intervention as described herein based on determination that the subject is at risk of being exposed to / infected by a sarbecovirus (e.g. a SARSr- CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant).

[0197] In some embodiments, a subject may be selected for prophylactic or therapeutic intervention as described herein based on determination that the subject is at risk of having been infected with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant). For example, the subject might have been in close contact with a subject infected with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant).

[0198] In some embodiments, a subject may be selected for prophylactic or therapeutic intervention described herein based on the determination that the subject is infected with a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant), e.g. by detection of a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS-CoV-2 / a SARS-CoV-2 variant) in a sample obtained from the subject.

[0199] Administration of the articles according to the present disclosure is preferably in a ‘therapeutically- effective’ or ‘prophylactically-effective’ amount, this being sufficient to show therapeutic / prophylactic benefit to the subject. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease / condition and the particular article administered.

[0200] Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disease / disorder to be treated, the condition of the individual subject, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s ‘The Science and Practice of Pharmacy’ (ed. A. Adejare), 23rd Edition (2020), Academic Press.

[0201] Administration of the articles according to the present disclosure may be parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intravitreal, intraconjunctival, subretinal, suprachoroidal, subcutaneous, intradermal, intrathecal, oral, nasal, topical or transdermal. Administration may be by any suitable mode of nasal delivery, e.g. nasal drops, nasal spray, nebulizer, etc. Administration may be by injection or infusion.

[0202] Multiple doses of the polypeptides, nucleic acids, vectors, compositions and vaccines described herein may be provided. Multiple doses may be separated by a predetermined time interval, which may be selected to be one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 months.

[0203] Administration of the articles according to the present disclosure may be alone, or in combination with a further prophylactic / therapeutic agent, either simultaneously or sequentially dependent upon the disease / condition to be treated. The polypeptide, nucleic acid, vector, composition or vaccine described herein and further prophylactic / therapeutic agent may be administered simultaneously or sequentially. Simultaneous administration refers to administration of the polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure and the further prophylactic / therapeutic agent together, for example as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other and optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel. Sequential administration refers to administration of one of (1) the polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure, or (2) the further prophylactic / therapeutic agent, followed after a given time interval by separate administration of the other of (1 ) / (2). It is not required that (1) and (2) are administered by the same route, although this is the case in some embodiments. The time interval may be any time interval.

[0204] The present disclosure also provides a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure for use in a method of treating or preventing a disease / condition described herein, wherein the method further comprises administering a known polypeptide / nucleic acid / vector / composition / vaccine described section I. Also provided is a known polypeptide / nucleic acid / vector / composition / vaccine described in section I for use in a method of treating or preventing a disease / condition described herein, wherein the method further comprises administering a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure.

[0205] Also provided is the use of a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure in the manufacture of a medicament for use in a method of treating or preventing a disease / condition described herein, wherein the method further comprises administering a known polypeptide / nucleic acid / vector / composition / vaccine described in section I. Also provided is the use of a known polypeptide / nucleic acid / vector / composition / vaccine described in section I in the manufacture of a medicament for use in a method of treating or preventing a disease / condition described herein, wherein the method further comprises administering a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure.

[0206] In some embodiments, a subject according to the present disclosure is a subject that has previously been administered a vaccine for the treatment / prevention of disease / condition characterised by infection with a sarbecovirus (e.g. COVID-19).

[0207] In some embodiments, the subject has previously been administered one or more of: BNT162b2 (DrugBank Acc. No. DB15696), mRNA1273 (DrugBank Acc. No. DB15654), andusomeran (DrugBank Acc. No. DB18227), ChAdOxI nCoV-19 (also known as AZD1222; DrugBank Acc. No. DB15656), Ad26.COV2.S (DrugBank Acc. No. DB15857), CoronaVac (also known as PiCoVacc; DrugBank Acc. No. DB15806) or nuvaxovid (also known as NVX-CoV2373; DrugBank Acc. No. DB15810).

[0208] In some embodiments, the subject has previously been administered more than one dose (e.g. 2, 3 or more) of a vaccine listed in the preceding paragraph. In some embodiments, the subject has previously been administered more than one (e.g. 2, 3 or more) of the vaccines listed in the preceding paragraph. In some embodiments, the subject has been administered a vaccine listed in the preceding paragraph within 15 years, e.g. within 10 years, 5 years, 3 years, 2 years, 18 months, 12 months, 6 months, 3 months or 1 month of therapeutic / prophylactic intervention in accordance with the present disclosure.

[0209] In some embodiments, the subject has previously been administered: (a) a polypeptide having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine or composition comprising the polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a). In some embodiments, the subject has previously been administered in accordance with the preceding sentence on more than one occasion (e.g. on 2, 3 or more occasions). In some embodiments, the subject has been administered in accordance with the first sentence of this paragraph within 15 years, e.g. within 10 years, 5 years, 3 years, 2 years, 18 months, 12 months, 6 months, 3 months or 1 month of therapeutic / prophylactic intervention in accordance with the present disclosure.

[0210] In some embodiments, the subject has previously been infected with a sarbecovirus. In some embodiments, the subject has previously been infected with a sarbecovirus of clade 1 (e.g. clade 1a or clade 1 b). In some embodiments, the subject has previously been infected with SARS-CoV, SARS-CoV-2 or a SARS-CoV-2 variant. In some embodiments, the subject has previously been infected with SARS- CoV-2 or a SARS-CoV-2 variant.

[0211] In some embodiments, the subject has previously been infected with a sarbecovirus (e.g. SARS-CoV-2 or a SARS-CoV-2 variant) on one more than one occasion (e.g. on 2, 3 or more occasions). In some embodiments, the subject has previously been infected with more than one (e.g. 2, 3 or more), nonidentical sarbecovirus (e.g. selected from SARS-CoV-2 and SARS-CoV-2 variants). In some embodiments, the subject has been infected with a sarbecovirus (e.g. SARS-CoV-2 or a SARS-CoV-2 variant) within 15 years, e.g. within 10 years, 5 years, 3 years, 2 years, 18 months, 12 months, 6 months, 3 months or 1 month of therapeutic / prophylactic intervention in accordance with the present disclosure.

[0212] In accordance with the preceding paragraph, a subject having previously been infected with a sarbecovirus may have previously been diagnosed with infection with a sarbecovirus (e.g. SARS-CoV-2 or a SARS-CoV-2 variant) e.g. using an appropriate diagnostic test. The subject may have previously been diagnosed with COVID-19.

[0213] Further provided is a method of treating or preventing a disease / condition described herein, the method comprising administering a therapeutically- or prophylactically-effective amount of (1) a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure, and (2) a known polypeptide / nucleic acid / vector / composition / vaccine described in section I to a subject in need of treatment. The present disclosure also provides (1) a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure, and (2) a known polypeptide / nucleic acid / vector / composition / vaccine described in section I, for use in a method of treating or preventing a disease / condition described herein in a subject. Also provided is the use of (1) a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure, and (2) a known polypeptide / nucleic acid / vector / composition / vaccine described in section I, in the manufacture of a medicament for use in treating or preventing a disease / condition described herein in a subject. Also provided is a method of treating or preventing a disease / condition described herein in a subject, comprising administering to the subject a therapeutically- or prophylactically-effective amount of (1) a polypeptide, nucleic acid, vector, composition or vaccine according to the present disclosure, and (2) a known polypeptide / nucleic acid / vector / composition / vaccine described in section I.

[0214] In embodiments in accordance with aspects of the preceding paragraph, provision of (1) and (2) may be as a combination therapy. In some embodiments, (1) and (2) may be provided simultaneously or sequentially. In preferred embodiments, (1) and (2) are provided sequentially.

[0215] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises:

[0216] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0217] (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0218] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises:

[0219] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a);

[0220] (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); and

[0221] (iii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), (b) a vaccine / composition comprising the polypeptide of (iii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (iii)(a); and wherein the amino acid sequences of the polypeptides of (i)(a), (ii)(a) and (iii)(a) are nonidentical.

[0222] In preferred embodiments, (i), (ii) and (iii) (as applicable) are performed sequentially. In some embodiments, (i), (ii) and (iii) (as applicable) in accordance with treatment / prophylaxis as described herein are separated by a time interval sufficient for a subject to raise an immune response to the polypeptide comprised in the composition / vaccine encoded by the nucleic acid / vector, of a given administration. In some embodiments, administration according to (i), (ii) and (iii) (as applicable) in accordance with treatment / prophylaxis as described herein is separated by a time interval of >2 weeks and <20 years, e.g. >2 weeks and <15 years, >2 weeks and <10 years, >2 weeks and <5 years, >1 month and <2 years, >1 month and <18 months, >1 month and <12 months, or >1 month and <6 months.

[0223] In some embodiments, an administration according to (i), (ii) or (iii) (as applicable) may be performed on a subject on multiple occasions. In some embodiments, administration according to (i) may be performed on a subject on multiple occasions. By way of illustration, in vaccine regimen 1 as summarised in Table A of Example 1 herein, BNT162b2 is administered to the subject twice.

[0224] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises:

[0225] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 (e.g. clade 1a, 1 b or 1 c), (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0226] (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 (e.g. clade 1a, 1 b or 1 c), (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0227] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises:

[0228] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 (e.g. clade 1a, 1 b or 1 c), (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0229] (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 2 or clade 3, (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0230] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises:

[0231] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 (e.g. clade 1a, 1 b or 1 c), (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and (ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 (e.g. clade 1a, 1 b or 1 c), (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); and

[0232] (iii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 2 or clade 3, (b) a vaccine / composition comprising the polypeptide of (iii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (iii)(a); wherein the amino acid sequences of the polypeptides of (i)(a), (ii)(a) and (iii)(a) are nonidentical.

[0233] In some embodiments, ‘a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 ’ comprises, or consists of, an amino acid sequence having at least 60% (e.g. one of >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of the RBM / RBD / extracellular domain of a spike protein encoded by a sarbecovirus of clade 1 (e.g. clade 1a, 1 b or 1c).

[0234] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 is a polypeptide according to the present disclosure ( / .e. a polypeptide according to an embodiment described in section C or G herein).

[0235] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 is a known polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein(s), e.g. as described in section I herein.

[0236] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 comprises, or consists of: an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:7; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:8; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NQ:10; or an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:11 ; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:12; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:14; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:51.

[0237] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 comprises, or consists of: an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:7; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:8; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NQ:10; or an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:11 ; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:12; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:14.

[0238] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 comprises, or consists of an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 .

[0239] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 comprises, or consists of: an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:7; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:8; or an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:11 ; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:12.

[0240] In some embodiments, ‘a polypeptide that comprises or consists of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 2 or clade 3’ comprises, or consists of, an amino acid sequence having at least 60% (e.g. one of >65%, >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of the RBM / RBD / extracellular domain of a spike protein encoded by a sarbecovirus of clade 2 or clade 3.

[0241] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 2 or clade 3 is a polypeptide according to the present disclosure ( / .e. a polypeptide according to an embodiment described in section C or G herein).

[0242] In some embodiments, a polypeptide comprising or consisting of an amino acid sequence derived from the amino acid sequence(s) of one or more spike protein(s) encoded by one or more sarbecoviruses of clade 1 comprises, or consists of: an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:9; or an amino acid sequence having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:13.

[0243] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0244] (i) administering to a subject: (a) polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0245] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 10, 11 , 12 or 14, (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0246] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0247] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0248] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 11 or 12, (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0249] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0250] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0251] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:9 or 13, (b) a vaccine / composition comprising the polypeptide of (ii) (a) , or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0252] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0253] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 10, 11 , 12 or 14, (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:9 or 13, (b) a vaccine / composition comprising the polypeptide of (ii) (a) , or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0254] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0255] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 11 or 12, (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a); and

[0256] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:9 or 13, (b) a vaccine / composition comprising the polypeptide of (ii) (a) , or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); wherein the amino acid sequences of the polypeptides of (i)(a) and (ii)(a) are non-identical.

[0257] In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0258] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a);

[0259] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 10, 11 , 12 or 14, (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); and

[0260] (iii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:9 or 13, (b) a vaccine / composition comprising the polypeptide of (iii) (a) , or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (iii)(a); wherein the amino acid sequences of the polypeptides of (i)(a), (ii)(a) and (iii)(a) are non- identical. In some embodiments, treatment / prophylaxis in accordance with the present disclosure comprises administering to a subject:

[0261] (i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine / composition comprising the polypeptide of (i)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (i)(a);

[0262] (ii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 or SEQ ID NO:45, or to the amino acid sequence of SEQ ID NO:7, 8, 11 or 12, (b) a vaccine / composition comprising the polypeptide of (ii)(a), or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (ii)(a); and

[0263] (iii) administering to the subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 70% (e.g. >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) amino acid sequence identity to the amino acid sequence of SEQ ID NO:9 or 13, (b) a vaccine / composition comprising the polypeptide of (iii) (a) , or (c) a vaccine / composition / vector comprising nucleic acid encoding the polypeptide of (iii)(a); wherein the amino acid sequences of the polypeptides of (i)(a), (ii)(a) and (iii)(a) are nonidentical.

[0264] K. Effects achieved by the therapeutic / prophylactic intervention

[0265] Therapeutic and prophylactic intervention in accordance with the present disclosure may be characterised by reference to one or more effects achieved by the intervention.

[0266] In some embodiments, therapeutic / prophylactic intervention as described herein is associated with one or more of the following:

[0267] Stimulates production in the subject of a population of antibodies that binds to one or more sarbecovirus spike proteins;

[0268] Stimulates production in the subject of a population of antibodies that inhibits interaction between ACE2 and one or more sarbecovirus spike proteins; and / or

[0269] Stimulates production in the subject of a population of antibodies that inhibits infection of ACE2- expressing cells by one or more sarbecoviruses.

[0270] It will be appreciated that therapeutic / prophylactic intervention according to the present disclosure may stimulate the production in the recipient subject of a population of antibodies displaying more than one of the properties recited in the preceding paragraph. A population of antibodies produced in a subject following therapeutic / prophylactic intervention in accordance with the present disclosure may be evaluated for the properties recited in the preceding paragraph using suitable assays. For example, the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. In some embodiments, the assays may be e.g. in vivo assays, i.e. performed in non-human animals. In some embodiments, the assays may be e.g. ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject.

[0271] The analysis may involve evaluating an antibody-containing sample (e.g. a blood or serum sample) obtained from the subject, e.g. obtained from the subject after a suitable period of time for a population of antibodies to have been produced by the subject in response to the therapeutic / prophylactic intervention.

[0272] The properties described in this section are contemplated in connection with populations of antibodies comprising a diversity of non-identical antibodies. As such, the properties of the population of antibodies may arise from the combined properties of the different constituent antibodies of the population of antibodies. For example, where a population of antibodies is described as comprising antibodies that bind e.g. to two different polypeptides, this encompasses both (a) the scenario in which the population of antibodies comprises an antibody that binds cross-reactively to the two different proteins, and (b) the scenario in which the population of antibodies comprises a first antibody that binds to one of the proteins (and which does not bind to the other protein), and a second antibody that binds to the other protein (and which does not bind to the protein bound by the first antibody). In both scenarios, the population of antibodies comprises antibodies that bind to the two different polypeptides.

[0273] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to a plurality of non-identical sarbecovirus spike proteins (i.e. plural sarbecovirus spike proteins having amino acid sequences that are non-identical).

[0274] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to: (i) the spike protein of SARS-CoV-2, or the spike protein of a SARS-CoV-2 variant; or (ii) the spike protein of a SC2r-CoV; or (iii) the spike protein of SARS-CoV-1 ; or (iv) the spike protein of a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to one or more (e.g. 1 , 2, 3 or all 4) of (i) to (iv) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to: (i) the spike protein of a SC2r- CoV; or (ii) the spike protein of SARS-CoV-1 ; or (iii) the spike protein of a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to the spike protein of a SC2r-CoV. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to the spike protein of a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to: (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:16; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:26; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:28; or (iv) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:38; or (v) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:39; or (vi) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (vii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (viii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (ix) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (x) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:56; or (xi) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to one or more (e.g. 1 , 2, 4, 5, 6, 7, 8, 9, 10 or all 11) of (i) to (xi) of the preceding sentence.

[0275] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to: (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iv) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (v) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to one or more (e.g. 1 , 2, 3, 4 or all 5) of (i) to (v) of the preceding sentence.

[0276] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to: (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to one or more (e.g. 1 , 2, or all 3) of (i) to (iii) of the preceding sentence.

[0277] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that bind to a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57.

[0278] Whether an antibody-containing sample comprises antibodies that bind to a given peptide / polypeptide can be determined by analysis according to methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol (2012) 907:411-442), Bio-Layer Interferometry (BLI; see e.g. Lad et al., (2015) J Biomol Screen 20(4): 498-507), flow cytometry, or by a radiolabelled antigen-binding assay (RIA) enzyme-linked immunosorbent assay.

[0279] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and a plurality of non-identical sarbecovirus spike proteins.

[0280] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and: (i) the spike protein of SARS-CoV-2, or the spike protein of a SARS-CoV- 2 variant; or (ii) the spike protein of a SC2r-CoV; or (iii) the spike protein of SARS-CoV-1 ; or (iv) the spike protein of a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and one or more (e.g. 1 , 2, 3 or all 4) of (i) to (iv) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and: (i) the spike protein of a SC2r-CoV; or (ii) the spike protein of SARS-CoV-1 ; or (iii) the spike protein of a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and the spike protein of a SC2r-CoV. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and a spike protein of a sarbecovirus of clade 2 or clade 3.

[0281] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:16; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:26; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:28; or (iv) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:38; or (v) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:39; or (vi) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (vii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (viii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (ix) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (x) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:56; or (xi) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and one or more (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or all 11) of (i) to (xi) of the preceding sentence.

[0282] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iv) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (v) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and one or more (e.g. 1 , 2, 3, 4 or all 5) of (i) to (v) of the preceding sentence.

[0283] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and (i) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (ii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iii) a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:55. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence.

[0284] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit interaction between ACE2 and a polypeptide comprising, or consisting of, the amino acid sequence of SEQ ID NO:57.

[0285] Antibodies that inhibit interaction between ACE2 and a given sarbecovirus spike protein may be described as inhibitors / antagonists of such interaction, and may be referred to as neutralising antibodies to sarbecoviruses comprising the relevant spike protein.

[0286] The ability of a population of antibodies to inhibit interaction between ACE2 and a given sarbecovirus spike protein can be determined for example by analysis of interaction in the presence of, or following incubation of one or both of the interaction partners with, the population of antibodies. A population of antibodies that inhibits interaction between ACE2 and a given sarbecovirus spike protein is identified by the observation of a reduction / decrease in the level of interaction between the interaction partners in the presence of - or following incubation of the interaction partners with - the population of antibodies, as compared to the level of interaction observed in the absence of the population of antibodies (or in the presence of an appropriate control population of antibodies known not to affect interaction between the sarbecovirus spike protein and ACE2). Suitable analysis can be performed in vitro, e.g. using recombinant interaction partners, or using cells expressing the interaction partners. Cells expressing the interaction partners may do so endogenously, or may do so from nucleic acid introduced into the cell. For the purposes of such assays, one or both of the interaction partners may be labelled or used in conjunction with a detectable entity for the purposes of detecting and / or measuring the level of interaction.

[0287] The ability of a given population of antibodies to inhibit interaction between ACE2 and a given sarbecovirus spike protein can be evaluated in a pseudovirus neutralisation assay. Pseudovirus neutralisation assays employ e.g. vesicular stomatitis virus (VSV) or retrovirus (RV) vectors pseudotyped with the sarbecovirus spike protein. Pseudovirus neutralisation assays that may be employed to evaluate the ability of a given population of antibodies to inhibit interaction between ACE2 and a given sarbecovirus spike protein are described e.g. in Donofrio et al., Vaccines (Basel) (2021) 9(4): 389, Nie et al., Emerg. Microbes Infect. (2020) 9:680-686, Chia et al., Sci Adv. (2023) 9(30):eade3470 and Tan et al., Nature Biotechnology (2020) 38: 1073-1078, all of which are hereby incorporated by reference in their entirety.

[0288] The ability of a given population of antibodies to inhibit interaction between ACE2 and a sarbecovirus spike protein can also be evaluated in a surrogate virus neutralization test (sVNT). Surrogate virus neutralization tests investigate binding of sarbecovirus spike proteins (or a domain thereof, e.g. the RBD thereof) to ACE2, using labelled species in an ELISA-based assay, to infer inhibition of interaction. Surrogate virus neutralization tests that may be employed to evaluate the ability of a given population of antibodies to inhibit interaction between ACE2 and a sarbecovirus spike protein are described e.g. in Chia et al., Sci Adv. (2023) 9(30):eade3470, Tan et al., Nature Biotechnology (2020) 38: 1073-1078, Springer et al., Diagnostics (Basel). (2023) 13(13): 2278, Tan et al., N Engl J Med (2021) 385:1401-1406 and Wang et al., Res Sq. (2022) Feb 23:rs.3. rs-1362541 (hereby incorporated by reference in their entirety).

[0289] In some embodiments, the ability of a population of antibodies to inhibit interaction between ACE2 and a sarbecovirus spike protein is analysed essentially as described in Example 1 herein.

[0290] In some embodiments, a population of antibodies according to the present disclosure reduces / inhibits interaction between a given sarbecovirus spike protein and ACE2 to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of interaction observed in the absence of the population of antibodies (or in the presence of an appropriate control population of antibodies known not to affect interaction between the sarbecovirus spike protein and ACE2).

[0291] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by a plurality of different sarbecoviruses, wherein the different sarbecoviruses comprise non-identical spike proteins. Such populations of antibodies may be described as inhibiting / antagonising infection of ACE2-expressing cells, or may be referred to as neutralising infection of such cells, by the sarbecoviruses.

[0292] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) SARS-CoV-2, or a SARS-CoV-2 variant; or (ii) a SC2r-CoV; or (iii) SARS-CoV-1 ; or (iv) a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by one or more (e.g. 1 , 2, 3 or all 4) of (i) to (iv) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by: (i) a SC2r-CoV; or (ii) SARS-CoV-1 ; or (iii) a sarbecovirus of clade 2 or clade 3. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2- expressing cells by one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2- expressing cells by a SC2r-CoV. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by a sarbecovirus of clade 2 or clade 3.

[0293] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:16; or (ii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:26; or (iii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:28; or (iv) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:38; or (v) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:39; or (vi) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (vii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (viii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (ix) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (x) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:56; or (xi) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:57;. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by one or more (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or all 11) of (i) to (xi) of the preceding sentence. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:52; or (ii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (iii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iv) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:55; or (v) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:57. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by one or more (e.g. 1 , 2, 3, 4 or all 5) of (i) to (v) of the preceding sentence.

[0294] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:53; or (ii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:54; or (iii) a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:55. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2- expressing cells by one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence.

[0295] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by a sarbecovirus comprising a spike protein comprising, or consisting of, the amino acid sequence of SEQ ID NO:57.

[0296] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) SARS-CoV-2, (ii) BA.1 , (iii) BA.5, (iv) B.1.351 , (v) B.1.617.2, (vi) SARS-CoV-1 , (vii) GX-P5L, (viii) Rs2018B, (ix) RsSHC014, (x) XBB, or (xi) Khosta-2. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2- expressing cells by one or more (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or all 11) of (i) to (xi) of the preceding sentence.

[0297] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) SARS-CoV-1 , (ii) GX-P5L, (iii) Rs2018B, (iv) RsSHC014, or (v) Khosta-2. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by one or more (e.g. 1 , 2, 3, 4 or all 5) of (i) to (v) of the preceding sentence.

[0298] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by: (i) GX-P5L, (ii) Rs2018B or (iii) RsSHC014. In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of ACE2-expressing cells by one or more (e.g. 1 , 2 or all 3) of (i) to (iii) of the preceding sentence.

[0299] In some embodiments, therapeutic / prophylactic intervention according to the present disclosure stimulates production in the subject of a population of antibodies comprising antibodies that inhibit infection of AC E2-ex pressing cells by Khosta-2.

[0300] The ability of a given population of antibodies to inhibit infection of AC E2-ex pressing cells by a given sarbecovirus (e.g. comprising a given spike protein) can be analysed by detecting / quantifying infection of ACE2-expressing cells by the sarbecovirus (or a pseudovirus pseudotyped with the spike protein encoded by the sarbecovirus) in the presence of the population of antibodies, and comparing the level of infection to the level observed in the absence of the population of antibodies (and / or the level of infection observed in presence of an appropriate control population of antibodies known not to affect infection of ACE2-expressing cells by the sarbecovirus). Such methods may comprise determining the absolute number of, or the proportion of, cells infected with (e.g. comprising) the sarbecovirus.

[0301] The ability of a given population of antibodies to inhibit infection of AC E2-ex pressing cells by a given sarbecovirus (e.g. comprising a given spike protein) can be analysed in a pseudovirus neutralisation assay, e.g. as described in Chia et al., Sci Adv. (2023) 9(30):eade3470 or Tan et al., Nature Biotechnology (2020) 38: 1073-1078.

[0302] In some embodiments, a population of antibodies according to the present disclosure reduces / inhibits infection of AC E2-ex pressing cells by a given sarbecovirus (or a pseudovirus pseudotyped with the spike protein encoded by the sarbecovirus) to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of infection of ACE2-expressing cells observed in the absence of the population of antibodies (or in the presence of an appropriate control population of antibodies known not to affect infection of AC E2-ex pressing cells by the sarbecovirus).

[0303] L. Subjects

[0304] A subject in accordance with the various aspects according to the present disclosure may be any animal or human. Therapeutic and prophylactic applications may be in human or animals (veterinary use). The subject to be administered with an article according to the present disclosure (e.g. in accordance with therapeutic or prophylactic intervention described herein) may be a subject in need of such intervention. The subject is preferably mammalian, more preferably human. The subject may be a non-human mammal, but is more preferably human. The subject may be male or female. The subject may be a patient.

[0305] A subject may be at risk of developing / contracting a disease or condition described herein, may have (e.g. may have been diagnosed with) a disease or condition described herein, or may be suspected of having such a disease / condition.

[0306] In some embodiments, a subject may be selected for therapeutic / prophylactic intervention in accordance with the present disclosure based on evaluation as described hereinabove.

[0307] In some embodiments, a subject may be selected for therapeutic / prophylactic intervention in accordance with the present disclosure based on characterisation for one or more markers of a disease / condition described herein. In some embodiments, a subject may be selected for therapeutic or prophylactic intervention as described herein based on the detection of a sarbecovirus (e.g. a SARSr-CoV, e.g. SARS- CoV-2 / a SARS-CoV-2 variant) and / or a sarbecovirus spike protein (e.g. SARS-CoV-2 spike protein / a SARS-CoV-2 variant spike protein), e.g. in a sample obtained from the subject.

[0308] M. Kits

[0309] The present disclosure also provides kits of parts.

[0310] In some embodiments, the kit may have at least one container having a predetermined quantity of a polypeptide, nucleic acid, vector, composition or vaccine described herein.

[0311] In some embodiments, the kit may comprise materials for producing a polypeptide, nucleic acid, vector, composition or vaccine described herein. In some embodiments, the kit of parts may comprise materials for formulating a polypeptide, nucleic acid, vector, composition or vaccine described herein to a pharmaceutical composition / medicament, e.g. in a composition further comprising a pharmaceutically- acceptable carrier, diluent, excipient or adjuvant.

[0312] The kit may provide the polypeptide, nucleic acid, vector, composition or vaccine together with instructions for administration to a patient in order to treat a specified disease / condition (e.g. a disease / condition described herein).

[0313] Kits according to the present disclosure may include instructions for use, e.g. in the form of an instruction booklet or leaflet. The instructions may include a protocol for performing any one or more of the methods described herein. N. Sequence identity

[0314] As used herein, sequence identity’ refers to the percent of nucleotides / amino acid residues in a subject sequence that are identical to nucleotides / amino acid residues in a reference sequence, after aligning the sequences and, if necessary, introducing gaps, to achieve the maximum percent sequence identity

[0315] 5 between the sequences. Pairwise and multiple sequence alignment for the purposes of determining percent sequence identity between two or more amino acid or nucleic acid sequences can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalOmega (Soding, J. 2005, Bioinformatics 21 , 951-960), T-coffee (Notredame etal. 2000, J. Mol. Biol. (2000) 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298))

[0316] 10 and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4) 772-780) software. When using such software, the default parameters, e.g. for gap penalty and extension penalty, are preferably used.

[0317] O. Sequences

[0318] P. Further aspects and embodiments according to the present disclosure

[0319] The present disclosure provides an amino acid construct comprising amino acid sequence having at least 90% sequence identity to SEQ ID NO:3. In some embodiments, the amino acid sequence having at least 90% sequence identity to SEQ ID NO:3 may have 91 % sequence identity to SEQ ID NO:3, or 92% sequence identity to SEQ ID NO:3, or 93% sequence identity to SEQ ID NO:3, or 94% sequence identity to SEQ ID NO:3, or 95% sequence identity to SEQ ID NO:3, or 95% sequence identity to SEQ ID NOS, or 96% sequence identity to SEQ ID NOS, or 97% sequence identity to SEQ ID NOS, or 98% sequence identity to SEQ ID NOS or 99% sequence identity to SEQ ID NOS, or 100% sequence identity to SEQ ID NOS. In some embodiments, the amino acid sequence of an amino acid construct according to the present disclosure comprises the sequence set forth in SEQ ID NOS. In some embodiments, the amino acid sequence having at least 90% sequence identity to SEQ ID NOS may be selected from the group consisting of SEQ ID NOS, SEQ ID NO:1 and SEQ ID NOS. SEQ ID NO:1 is also referred to as c1 .26, and comprises mutations similar to the Omicron mutations on c1.25 backbone (SEQ ID NO: 4). SEQ ID NOS is also referred to as d .27, and further modified amino acid sequence of the c1.25 (SEQ ID NO:4) and c1.26 (SEQ ID NO:1) backbones.

[0320] In some embodiments, the amino acid sequence further comprises a foldon and a linker sequence. In some embodiments, the foldon and linker sequence replace the C-terminal 60 positions of SEQ ID NOs:3, 1 , 2 and 4 i.e. positions 1202 to 1261 of SEQ ID NOS, and positions 1196 to 1255 of SEQ ID NOs:1 , 2 and 4). In some embodiments, the foldon and linker sequence comprises SEQ ID NOS.

[0321] The present disclosure also provides nucleic acid encoding the amino acid construct described hereinabove. In some embodiments, the nucleic acid comprises a messenger ribonucleic acid (mRNA). The present disclosure also provides an immunogenic composition comprising the amino acid construct as described hereinabove or the nucleic acid as described hereinabove. In some embodiments, the immunogenic composition comprises the amino acid construct as described hereinabove, or the nucleic acid as described hereinabove is enclosed in a lipid nanoparticle. In some embodiments, the immunogenic composition is a mRNA vaccine comprising lipid nanoparticles. In some embodiments, the immunogenic composition comprises a pre-fusion stabilized amino acid sequence having at least 90% sequence identity to SEQ ID NO:3.

[0322] In some embodiments, the immunogenic composition comprises a carrier. In various embodiments, the carrier is any one of a lipid nanoparticle (LNP), a polymeric nanoparticle, a lipid carrier such as a lipidoid, a liposome, a lipoplex, a peptide carrier, a nanoparticle mimic, a nanotube, or a conjugate.

[0323] In some embodiments, the immunogenic composition further comprises an adjuvant. In various embodiments, the adjuvant may comprise MF59, Adjuvant System 03 (AS03), CpG 1018 or Sigma Adjuvant System (S6322). In some embodiments, the adjuvant comprises a Sigma Adjuvant System (S6322).

[0324] In some embodiments, the immunogenic composition is an RNA vaccine. RNA vaccines include vaccines comprising an RNA polynucleotide having an open reading frame encoding an amino acid construct capable of inducing an immune response against sarbecovirus infection, as described hereinabove. In some embodiments, the immunogenic composition includes at least one RNA polynucleotide having an open reading frame that encodes amino acid sequence having at least 90% sequence identity to SEQ ID NO:3 and an adjuvant that can elicit an immune response against sarbecovirus infection. In some embodiments, the immunogenic composition includes at least one RNA polynucleotide having an open reading frame that encodes amino acid sequence having at least 90% sequence identity to SEQ ID NO:3, a foldon, a linker sequence and an adjuvant that can elicit an immune response against sarbecovirus infection. In some embodiments, the immunogenic composition includes at least one RNA polynucleotide having an open reading frame that encodes amino acid sequence of SEQ ID NO:3 and an adjuvant that can elicit an immune response against sarbecovirus infection. In some embodiments, the immunogenic composition includes at least one RNA polynucleotide having an open reading frame that encodes amino acid sequence of SEQ ID NO:3, a foldon, a linker sequence and an adjuvant that can elicit an immune response against sarbecovirus infection.

[0325] The present disclosure also provides a viral vector comprising nucleic acid as described hereinabove. In some embodiments, the vector is selected from: a recombinant measles virus vector, a vesicular stomatitis virus (VSV) vector, a vaccinia virus vector and an adenovirus vector.

[0326] The present disclosure provides an amino acid construct as described hereinabove, an immunogenic composition as described hereinabove, a nucleic acid as described hereinabove or a viral vector as described hereinabove for use in the treatment or prevention of SARS-CoV-2 infection or other sarbecovirus infection. Also provided is the use of an amino acid construct as described hereinabove, an immunogenic composition as described hereinabove, a nucleic acid as described hereinabove or a viral vector as described hereinabove in the manufacture of a medicament for the treatment and / or prevention of SARS-CoV-2 infection or other sarbecovirus infection.

[0327] Also provided is a method of treating and / or preventing an infection caused by SARS-CoV-2 or other sarbecovirus comprising administering to a subject a vaccine molecule comprising a) an amino acid construct comprising amino acid sequence having at least 90% sequence identity to SEQ ID NO:3, b) an immunogenic composition comprising the amino acid construct, c) a nucleic acid encoding the amino acid construct, or d) a viral vector comprising the nucleic acid encoding the amino acid construct.

[0328] In some embodiments, the subject has been previously administered a different vaccine for preventing an infection caused by SARS-CoV-2 or other sarbecovirus. In some embodiments, the subject has been previously administered with two or more doses of either the same commercially-available vaccine or with two or more different commercially-available vaccines.

[0329] The present disclosure provides a method of making an amino acid construct for the treatment and / or prevention of SARS-CoV-2 infections or other sarbecovirus infections, comprising: a) forming the amino construct having at least 90% sequence identity to SEQ ID NO:3. In some embodiments, the method further comprises modifying the amino acid sequence with a foldon and a linker sequence as described hereinabove. The C-terminal domain of T4 fibritin (foldon) is known for the formation of the fibritin trimer structure and can be used as an artificial trimerization domain. In some embodiments, the linker comprises a His6-tag. In some embodiments, forming the amino construct in step a) comprises forming a nucleic acid encoding the amino acid construct able to express the amino acid construct. In some embodiments, the nucleic acid comprises mRNA. In some embodiments, the amino acid construct or a nucleic acid encoding the amino acid construct able to express the amino acid construct is prepared as an immunogenic composition. In some embodiments, the immunogenic composition comprises an adjuvant. In some embodiments, the adjuvant is a Sigma Adjuvant system. In some embodiments, the nucleic acid is prepared in a viral vector. In some embodiments, the nucleic acid is prepared in the viral vector selected from a recombinant measles virus vector, a VSV vector, a vaccinia virus vector or an adenovirus vector.

[0330] The following numbered paragraphs (paras) describe particular aspects and embodiments of the present disclosure:

[0331] 1 . An amino acid construct comprising amino acid sequence having at least 90% sequence identity to SEQ ID NO:3.

[0332] 2. The amino acid construct according to para 1 , wherein the amino acid sequence further comprises a foldon and a linker sequence.

[0333] 3. The amino acid construct according to para 1 , wherein the amino acid sequence having at least 90% sequence identity to SEQ ID NO:3 is selected from the group consisting of SEQ ID NO:3; SEQ ID NO:1 ; and SEQ ID NO:2. 4. The amino acid construct according to para 1 , wherein the amino acid sequence comprises sequence set forth in SEQ ID NO:3.

[0334] 5. A nucleic acid encoding the amino acid construct of any one of paras 1 to 4.

[0335] 6. The nucleic acid according to para 5, comprising a messenger ribonucleic acid (mRNA)

[0336] 7. An immunogenic composition comprising the amino acid construct according to any one of paras 1 to 4 or the nucleic acid according to para 5 or para 6.

[0337] 8. The immunogenic composition according to para 7, further comprising an adjuvant.

[0338] 9. The immunogenic composition according to para 8, wherein the adjuvant is a Sigma Adjuvant System (S6322).

[0339] 10. A viral vector comprising a nucleic acid of para 5 or 6.

[0340] 11 . The viral vector according to para 10, wherein the vector is selected from a recombinant measles virus vector, a vesicular stomatitis virus (VSV) vector, a vaccinia virus vector or an adenovirus vector.

[0341] 12. An amino acid construct according to any one of paras 1 to 4 for use in the treatment or prevention of SARS-CoV-2 infection.

[0342] 13. An immunogenic composition according to any one of paras 7 to 9 for use in the treatment and / or prevention of SARS-CoV-2 infection.

[0343] 14. A nucleic acid according to para 5 or 6 for use in the treatment and / or prevention of SARS-CoV-2 infection.

[0344] 15. A viral vector according to para 10 or 11 for use in the treatment and / or prevention of SARS-CoV-2 infection.

[0345] 16. Use of the amino acid construct according to any one of paras 1 to 4 in the manufacture of a medicament for the treatment and / or prevention of SARS-CoV-2 infection.

[0346] 17. Use of the immunogenic composition according to any one of paras 7 to 9 in the manufacture of a medicament for the treatment and / or prevention of SARS-CoV-2 infections.

[0347] 18. Use of the nucleic acid according to para 5 or 6 in the manufacture of a medicament for the treatment and / or prevention of sarbecovirus infections.

[0348] 19. Use of a viral vector according to para 10 or 11 in the manufacture of a medicament for the treatment and / or prevention of sarbecovirus infections.

[0349] 20. A method of treating and / or preventing an infection caused by SARS-CoV-2 comprising administering to a subject a vaccine molecule comprising 21 . an amino acid construct comprising amino acid sequence having at least 90% sequence identity to SEQ ID NO:3;

[0350] 22. an immunogenic composition comprising the amino acid construct;

[0351] 23. a nucleic acid encoding the amino acid construct; or

[0352] 24. a viral vector comprising the nucleic acid encoding the amino acid construct.

[0353] 25. The method according to para 20, wherein the subject has been previously administered a different vaccine for preventing an infection caused by SARS-CoV-2.

[0354] 26. The method according to para 20, wherein the amino acid sequence further comprises a foldon and a linker sequence.

[0355] 27. The method according to para 20, wherein the amino acid sequence having at least 90% sequence identity to SEQ ID NO:3is selected from the group consisting of SEQ ID NO:3; SEQ ID NO:1 ; and SEQ ID NO:2.

[0356] 28. The method according to para 20, wherein the amino acid sequence comprises sequence set forth in SEQ ID NO:3.

[0357] 29. The method according to para 20, wherein the nucleic acid encoding the amino acid construct comprises a messenger ribonucleic acid (mRNA)

[0358] 30. The method according to para 20, wherein the immunogenic composition comprises an adjuvant.

[0359] 31 . The method according to para 20, wherein the immunogenic composition comprises a Sigma Adjuvant System (S6322).

[0360] 32. The method according to para 20, wherein the vector is selected from a recombinant measles virus vector, a vesicular stomatitis virus (VSV) vector, a vaccinia virus vector or an adenovirus vector.

[0361] ***

[0362] The present disclosure includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0363] The section headings used herein are for organisational purposes only and are not to be construed as limiting the subject matter described.

[0364] Aspects and embodiments according to the present disclosure will now be illustrated, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0365] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word ‘comprise,’ and variations such as ‘comprises’ and ‘comprising,’ will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0366] As used herein, an amino acid sequence, or a region of a polypeptide which ‘corresponds’ to a specified reference amino acid sequence or region of a polypeptide has at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of the amino acid sequence / polypeptide / region. An amino acid sequence / region / position of a subject polypeptide / amino acid sequence which ‘corresponds’ to a specified reference amino acid sequence / region / position of a reference polypeptide / amino acid sequence can be identified by sequence alignment of the subject sequence to the reference sequence, e.g. using sequence alignment software such as ClustalOmega (Soding, J. 2005, Bioinformatics 21 , 951-960).

[0367] It must be noted that, as used in the specification and the appended claims, the singular forms ‘a,’ ‘an,’ and ‘the’ include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from ‘about’ one particular value, and / or to ‘about’ another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent ‘about,’ it will be understood that the particular value forms another embodiment.

[0368] Where a nucleic acid sequence is disclosed herein, the reverse complement thereof is also expressly contemplated.

[0369] Methods described herein may preferably be performed in vitro. The term ‘in vitro’ is intended to encompass procedures performed with cells in culture whereas the term ‘in vivo’ is intended to encompass procedures with / on intact multi-cellular organisms.

[0370] Brief Description of the Figures

[0371] Figure 1 : (a) Schematic representation of Multiplex sVNT on the Luminex platform, (b) Graph showing the ability of RBD proteins derived from the spike proteins of different sarbecoviruses to bind human ACE2.

[0372] Figure 2: Schematic illustrating vaccination regimens and the schedule of vaccination.

[0373] Figure 3: Graphs showing 50% neutralisation titre (NT50) values of sera from mice vaccinated according to Vaccination Regimens 1 to 4, 6 7 and 8 against various sarbecoviruses in sVNTs. Data shows NT50 for sera collected at time of Dose 3 and / or Dose 4, and sera collected 14 days later.

[0374] Figure 4: Graphs showing geometric mean neutralizing titer 50% (GMT50) of mouse serum from mice vaccinated according to one of Vaccine Regimens 1 to 5, against various sarbecoviruses in sVNTs. Top panel shows antibody titres taken from mice challenged with virus immediately after Dose 3. Bottom panel shows antibody titres taken from mice challenged with virus 14 days after Dose 3. Figure 5: Graphs showing NT50 values of sera from mice vaccinated according to Vaccination Regimen 6 to 9 against various sarbecoviruses in sVNTs. Data shows NT50 for sera collected at time of Dose 4, and sera collected 14 days later.

[0375] Figure 6: Graphs showing NT50 values of sera from mice vaccinated according to Vaccination Regimen6, 7, 8 and 10 against various sarbecoviruses in sVNTs. Data shows NT50 for sera collected at time of Dose 4, and sera collected 14 days later. Figure 7: Graphs showing GMT50 of mouse serum from mice vaccinated according to one of Vaccine Regimens 6 to 9 against various sarbecoviruses in sVNTs. Top panel shows antibody titres from serum collected at time of Dose 4. Bottom panel shows antibody titres from serum collected 14 days after Dose 4. Examples

[0376] Example 1

[0377] The inventors designed novel immunogenic sarbecovirus spike protein-derived polypeptides c1.26, c1.27 and c1 .28. c1 .26 (SEQ ID NO:47) and c1 .27 (SEQ ID NO:48) are based on the backbone of c1 .25 (SEQ ID NO:50), which is described in WO 2022 / 245287 A1 .

[0378] The majority of clade 2 and 3 sarbecoviruses do not use human ACE2 for cell entry. However, Khosta-2, a bat sarbecovirus discovered in Russian horseshoe bats and classified in clade 3, demonstrates binding to human ACE2 and resistance to current SARS-CoV-2 vaccines, and therefore presents a potential threat for future human infection (see e.g. Seifert et al. PLoS Pathog. (2022) 18(9):e1010828). c1 .28 (SEQ ID NO:49) was designed using clade 2 and 3 sarbecoviruses.

[0379] The inventors investigated the ability of vaccination regimens employing c1 .26, c1 .27 or c1 .28 to elicit the production of antibodies capable of inhibiting infection by various different sarbecoviruses, as determined by their ability to inhibit interaction between the RBD of the spike protein of the relevant sarbecovirus with human ACE2.

[0380] Mice were vaccinated according to the schedule represented schematically in Figure 2, and according to vaccination regimens 1 to 10 as summarised in Table A.

[0381] Table A.

[0382] BNT162b2 was administered by intramuscular injection, while c1 .25, c1 .26, c1 .27 and c1 .28 were administered by intraperitoneal injection. Mice in vaccination regimen groups 1 to 5 were given one dose of BNT162b2, followed by a second dose of BNT162b2 21 days after the first dose, and subsequently given a dose of c1 .25 protein (SEQ ID NO:50), c1 .26 protein (SEQ ID NO:47), or c1 .27 protein (SEQ ID NO:48) in 100 pl of Sigma adjuvant S6322, 142 days after the second dose. The third dose of BNT162b2 for groups 4, 5, 9 and 10 and fourth dose of BNT162b2 for groups 9 and 10 were administered without additional adjuvant, as the formulation contained mRNA in lipid nanoparticles (LNP), ready for use.

[0383] Mice in vaccination regimen groups 6 to 10 were additionally administered a dose of c1.28 protein (SEQ ID NO:49) in 100 pl of Sigma adjuvant S6322, 128 days after the third dose. For mice in vaccination regimen groups 1 to 5, sera were collected from each mouse at the time the third dose was given, and 14 days after the third dose was given. For mice in vaccination regimen groups 5 to 8, sera were collected from each mouse at the time the fourth dose was given, and 14 days after the fourth dose was given. The inventors first confirmed that the RBDs of the spike proteins of different sarbecoviruses bound to human ACE2. Polypeptides comprising the RBDs of the spike proteins of six different sarbecoviruses (SARS-CoV-2, the SARS-CoV-2 variants B.1.351 (Beta) and B.1.617.2 (Delta), the SC2r-CoVs GX-P5L and RaTG13, and SARS-CoV-1) fused to AviTag were immobilized on MagPlex -Avidin microspheres (Luminex) at 5 pg per 1 million beads. RBD-coated beads (600 per antigen) were incubated with varying concentrations (ranging from 1-1000 ng / ml) of phycoerythrin-conjugated human ACE2 (Genscript) for 15 minutes at 37°C, with agitation. After two washes with 1% BSA in PBS, the final readings were acquired using the MAGPIX system (Luminex), following manufacturer’s instructions.

[0384] The results are shown in Figure 1 . All sarbecovirus spike protein-derived RBDs were found to bind to human ACE2. From high to low affinity: SARS-CoV-2 B.1 .351 > SARS-CoV-2 B.1 .1 .7 = SC2r-CoV

[0385] GXP5L (pangolin) > SARS-CoV-2 > SARS-CoV > SC2r-CoV RaTG13 (bat).

[0386] The sera were analysed in order to determine whether they contained antibodies capable of neutralising interaction between the spike proteins of different sarbecoviruses and ACE2, using a multiplex surrogate virus neutralization test (sVNT), performed essentially as described in Tan et al., N Engl J Med (2021) 385:1401-1406 and Tan et al., Nature Biotechnology (2020) 38: 1073-1078. Briefly, polypeptides comprising the RBDs of the spike proteins of different sarbecoviruses (SARS-CoV-2, the SARS-CoV-2 variants BA.1 , BA.5, B.1.351 (Beta), B.1.617.2 (Delta) and XBB, the SC2r-CoVs GX-P5L, Rs2018B and RsSHC014, SARS-CoV-1 and Khosta-2) fused to AviTag were immobilized on MagPlex-Avidin microspheres (Luminex) at 5 pg per 1 million beads. RBD-coated beads (600 per antigen) were preincubated with test serum at final dilutions of 1 :20, 1 :80, 1 :320, 1 :1280) for 15 min at 37°C with agitation, followed by addition of 50 pl of phycoerythrin-conjugated human ACE2 (2 mg / ml; Genscript), and incubated for an additional 15 minutes at 37°C with agitation. After two washes with 1 % BSA in PBS, the final readings were acquired using the MAGPIX system (Luminex) following manufacturer’s instructions. sVNT percentage inhibition for each sample for each RBD were calculated by the following formula: Inhibition (%) = (1 - sample optical density value / negative control optical density value) x 100. Neutralizing titer 50% (NT50) values were calculated in GraphPad Prism (v9+), by modelling the dilution factors and sVNT percentage inhibition for each sample and each RBD in the non-linear regression analysis (Inhibitor vs. normalized response, Variable slope). Geometric Mean NT50 (GMT50) were calculated by using the geometric mean of NT50s for all samples per group, for each RBD.

[0387] The results are shown in Figures 3 to 7.

[0388] Figure 3 shows the Logio of the neutralizing titer 50% (NT50) for sera obtained from mice subjected to vaccination regimens 1 to 4, 6 7 and 8. The sera obtained from mice subjected to the different vaccination regimens were able to inhibit interaction between human ACE2 the RBDs of spike proteins of all of SARS-CoV-2, the SARS-CoV-2 variants BA.1 , BA.5, B.1.351 (Beta), B.1.617.2 (Delta) and XBB, the SC2r-CoVs GX-P5L, Rs2018B and RsSHC014, and SARS-CoV-1.

[0389] The reaction was stronger in sera collected 14 days after the third dose compared to sera collected at the time of the third dose. Similarly, for mice administered a fourth dose, the reaction was stronger in sera collected 14 days after the fourth dose compared to sera collected at the time of the fourth dose. The data also show that the fourth dose increases the titre of neutralizing antibodies to all of the different sarbecoviruses.

[0390] Figure 4 shows the geometric mean of the neutralizing titer 50% (GMT50) for sera obtained from mice subjected to vaccination regimens 1 to 5. Administration of c1 .26 or c1 .27 following 2 doses of BNT162b2 produced higher antibody titres to the zoonotic sarbecoviruses ( / .e. GX-P5L, Rs2018B and RsSHC014) and SARS-CoV-1 , as compared to when a third dose of BNT162b2 was administered.

[0391] These data illustrate that vaccination schedules employing c1 .25, c1 .26 or c1 .27 after initial doses of BNT162b2 elicit the production of antibodies displaying greater ability to neutralise a broad spectrum of sarbecoviruses than equivalent vaccination schedules instead employing a further dose of BNT162b2. The data also illustrate that vaccination schedules employing c1 .26 or c1 .27 elicit the production of antibodies displaying greater ability to neutralise SC2r-CoVs and SARS-CoV-1 than equivalent vaccination schedules instead employing c1.25. Figure 5 shows the Logio of the neutralizing titer 50% (NT50) for sera obtained from mice subjected to vaccination regimens 6 to 9. Statistical analyses were performed using T tests to compare the groups 6, 7 and 8 to group 9. The sera obtained from mice subjected to the different vaccination regimens were able to inhibit interaction between human ACE2 the RBDs of spike proteins of all of SARS-CoV-2, the SARS- CoV-2 variants BA.1 , BA.5, B.1.351 (Beta), B.1.617.2 (Delta) and XBB, the SC2r-CoVs GX-P5L, Rs2018B and RsSHC014, SARS-CoV-1 and the clade 3 sarbecovirus Khosta-2.

[0392] Administration of the booster dose of c1.28 in vaccination regimens 6, 7 and 8 greatly enhanced titres against the SC2r-CoVs GX-P5L, Rs2018B and RsSHC014, SARS-CoV-1 and Khosta-2, as compared to mice that received a fourth booster dose of BNT162b2 (vaccination regimen 9). Mice that received a booster dose of c1 .28 (vaccination regimens 6, 7 and 8) had increased antibody titres against 10 out of the 11 sarbecoviruses evaluated, relative to mice that received a fourth booster dose of BNT162b2 (vaccination regimen 9).

[0393] Figure 6 shows the Log of the neutralizing titer 50% (NT50) for sera obtained from mice subjected to vaccination regimens 6 to 8 and 10. Statistical analyses were performed using T tests to compare the groups 6, 7 and 8 to group 10. Mice administered 5 pg doses of BNT162b2 (vaccination regimen 10) displayed similar or improved neutralising antibody titres to SARS-CoV-2 and SARS-CoV-2 variants. However, mice administered vaccination regimens 6, 7 and 8 displayed improved neutralising antibody titres to the SC2r-CoVs GX-P5L, Rs2018B and RsSHC014, SARS-CoV-1 and Khosta-2, compared to the mice administered vaccination regimen 10.

[0394] Figure 7 shows the geometric mean of the neutralizing titer 50% (GMT50) for sera obtained from mice subjected to vaccination regimens 6 to 10. Vaccination according to regimens 6 to 8 stimulated the production of higher antibody titres to the zoonotic sarbecoviruses ( / .e. GX-P5L, Rs2018B and RsSHC014), SARS-CoV-1 and Khosta-2, as compared to vaccination regimens employing BNT162b2 alone (vaccination regimens 9 and 10).

[0395] These data illustrate that vaccination regimens employing c1 .25, c1 .26 or c1 .27 with c1 .28 provide enhanced protection against SC2r-CoVs, SARS-CoV-1 and the clade 2 / 3 sarbecovirus Khosta-2, as compared to vaccination regimens employing BNT162b2 alone.

Claims

Claims:1 . A polypeptide, optionally isolated, comprising an amino acid sequence that (i) has at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15; or (ii) has at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:9; and (iii) does not comprise the amino acid sequence of SEQ ID NQ:10.

2. The polypeptide according to claim 1 , wherein the amino acid sequence comprises ‘F’ at the position corresponding to position 358 of SEQ ID NO:15; and / or comprises ‘P’ at the position corresponding to position 360 of SEQ ID NO:15; and / or comprises ‘F’ at the position corresponding to position 362 of SEQ ID NO:15; and / or comprises ‘N’ at the position corresponding to position 392 of SEQ ID NO:15; and / or comprises ‘S’ at the position corresponding to position 395 of SEQ ID NO:15.

3. The polypeptide according to claim 1 or claim 2, wherein the amino acid sequence has at least 85% amino acid sequence identity to SEQ ID NO:7, 8 or 9.

4. The polypeptide according to any one of claims 1 to 3, wherein the polypeptide further comprises an amino acid sequence forming a multimerization domain.

5. The polypeptide according to claim 4, wherein the multimerization domain is a foldon domain, optionally wherein the foldon domain comprises, or consists of, an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence of SEQ ID NO:6.

6. The polypeptide according to claim 4 or claim 5, wherein the multimerization domain is C-terminal to the amino acid sequence derived from the amino acid sequence(s) of one or more sarbecovirus spike protein (s).

7. The polypeptide according to any one of claims 1 to 6, wherein the polypeptide comprises, or consists of, (i) an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45, or (ii) an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:13.

8. The polypeptide according to any one of claims 1 to 7, wherein the polypeptide comprises, or consists of, an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:11 , 12 or 13.

9. A nucleic acid, optionally isolated, encoding a polypeptide according to any one of claims 1 to 8.

10. A vector comprising a nucleic acid according to claim 9.11 . A cell comprising a polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, or a vector according to claim 10.

12. A composition comprising a polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, or a cell according to claim 11 , and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

13. A vaccine, comprising a polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, a cell according to claim 11 , or a composition according to claim 12.

14. A polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, a cell according to claim 11 , a composition according to claim 12, or a vaccine according to claim 13, for use in a method of medical treatment or prophylaxis.

15. A polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, a cell according to claim 11 , a composition according to claim 12, or a vaccine according to claim 13, for use in treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

16. Use of a polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, a cell according to claim 11 , a composition according to claim 12, or a vaccine according to claim 13 in the manufacture of a medicament for treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

17. A method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, comprising administering to a subject a therapeutically- or prophylactically- effective amount of a polypeptide according to any one of claims 1 to 8, a nucleic acid according to claim 9, a vector according to claim 10, a cell according to claim 11 , a composition according to claim 12, or a vaccine according to claim 13, optionally wherein the disease or condition characterised by infection with a sarbecovirus is COVID-19.

18. The polypeptide, nucleic acid, vector, cell, composition or vaccine for use according to claim 15, the use according to claim 16, or the method according to claim 17, wherein the subject has previously been administered a COVID-19 vaccine, or has previously been infected with SARS-CoV-2 or a SARS-CoV-2 variant.

19. The polypeptide, nucleic acid, vector, cell, composition or vaccine for use according to claim 15 or claim 18, the use according to claim 16 or claim 18, or the method according to claim 17 or claim 18, wherein the subject has previously been administered: (a) a polypeptide having at least 85% amino acid sequence identity to the amino acid sequence of SEQ ID NO:51 , (b) a vaccine or composition comprisingthe polypeptide of (a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (a).

20. The polypeptide, nucleic acid, vector, cell, composition or vaccine for use according to any one of claims 15, 18 or 19, the use according to any one of claims 16, 18 or 19, or the method according to any one of claims 17 to 19, wherein the subject has previously been infected with SARS-CoV-2 or a SARS- CoV-2 variant.21 . A method of treating or preventing a disease or condition characterised by infection with a sarbecovirus in a subject, comprising:(i) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15, or a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 ; or (b) a vaccine or composition comprising the polypeptide of (i)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (i)(a); and(ii) administering to a subject: (a) a polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9; or (b) a vaccine or composition comprising the polypeptide of (ii)(a); or (c) a vaccine or composition or vector comprising nucleic acid encoding the polypeptide of (ii)(a).

22. The method according to claim 21 , wherein the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:15 has at least 85% amino acid sequence identity to an amino acid sequence according to SEQ ID NO:45.

23. The method according to claim 21 , wherein the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:7, 8, 10 or 51 has at least 85% amino acid sequence identity to an amino acid sequence identity to SEQ ID NO:11 , 12 or 14.

24. The method according to any one of claims 21 to 23, wherein the polypeptide that comprises or consists of an amino acid sequence having at least 85% amino acid sequence identity to SEQ ID NO:9 has at least 85% amino acid sequence identity to an amino acid sequence identity to SEQ ID NO:13.

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