Vaccine for inducing antibodies to inhibit native interleukin-11 signaling

Abstract

The present disclosure pertains to antigens comprising an epitope of IL-11, fused to a peptide tag capable of forming an isopeptide bond. Additionally, the disclosure encompasses vaccines containing said antigen, their uses, and methods of manufacturing. The IL-11 antigen is designed in such a way that the vaccine induces antibodies which neutralise IL-11 by preventing its interaction with IL-11Rα but does not induce gp130 signaling.

Description

[0001] P7421 PC00

[0002] Vaccine for Inducing Antibodies to Inhibit Native lnterleukin-11 Signaling

[0003] Technical field

[0004] The present invention relates to a vaccine composed of particles that display multiple copies of an IL-11 antigen in a repetitive, unidirectional arrangement. This vaccine is specifically designed to overcome B-cell tolerance and elicit strong anti-IL-11 autoantibody responses. The IL-11 antigen may be designed in such a way that the vaccine induces antibodies which neutralise IL-11 by preventing its interaction with IL- 11 Ra but does not induce antibodies binding to the gp130binding site.

[0005] Background

[0006] Many fatal diseases result from organ failure due to excessive fibrosis. Fibrotic disorders include rare conditions like scleroderma and idiopathic pulmonary fibrosis, as well as common ones like atrial fibrillation and diabetic kidney disease. With their significant impact on global health, developing therapies to inhibit these conditions is crucial.

[0007] A key feature of fibrosis is the abnormal activation of resident fibroblasts, leading them to transition from a quiescent state to proliferating, secretory, and contractile myofibroblasts. Fibroblasts can be activated by stimuli like mechanical stress and pro- fibrotic cytokines. lnterleukin-11 (IL-11) is part of the IL-6 cytokine family, which includes IL-6, leukemia inhibitory factor (LIF), oncostatin-M (OSM), and others. These cytokines signal through a shared receptor, gp130. However, signaling specificity is determined by the binding of IL-11 to its unique IL-11 receptor a subunit. While IL-11 shares similarities with IL-6, it also has distinct roles, including involvement in inflammation, cancer, and tissue fibrosis.

[0008] Elevated levels of lnterleukin-11 (IL-11) have been implicated in a wide range of diseases, including fibrosis, cancer, and cardiovascular conditions, positioning IL-11 as a promising therapeutic target. Increased expression of IL-11 has been observed in various fibro-inflammatory diseases, such as systemic sclerosis, rheumatoid arthritis, idiopathic pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug- induced liver injury, and metabolic dysfunction-associated steatohepatitis (MASH). P7421 PC00

[0009] A Versatile Therapeutic Target Across Multiple Diseases

[0010] IL-11's role has been particularly pronounced in lung inflammation. For example, it is one of the most upregulated genes in pulmonary fibroblasts of patients with scleroderma-associated interstitial lung disease. Elevated IL-11 levels have also been observed in asthma patients and those with idiopathic pulmonary fibrosis, with IL-11 expression correlating directly with the extent of fibrosis and inversely with lung function. Targeting IL-11 with therapeutic antibodies has shown significant benefits, reducing collagen levels and demonstrating anti-inflammatory effects in the lungs.

[0011] In liver diseases such as MASH (previously known as nonalcoholic steatohepatitis (NASH)), alcoholic liver disease, and primary biliary cholangitis, IL-11 is markedly elevated. Preclinical models targeting IL-11 in MASH have demonstrated promising outcomes, significantly improving fibrosis, inflammation, and steatosis.

[0012] IL-11 also plays a significant role in connective tissue diseases, including atopic dermatitis, psoriasis, and systemic sclerosis (SSc). Its expression is notably elevated in chronic skin lesions of atopic dermatitis patients and in the lung and skin fibroblasts of SSc patients. Targeting IL-11 in SSc may offer a new therapeutic strategy due to its pivotal role in fibroblast activation driven by TGF-p.

[0013] In rheumatoid arthritis (RA), IL-11 is highly expressed in the synovial fluid and membranes, particularly in synovial fibroblasts and endothelial cells, but not macrophages. IL-11 has been identified as the most upregulated gene in macrophage- activated synovial fibroblasts in RA, underscoring its potential as a therapeutic target.

[0014] IL-11 in Cancer and Other Conditions

[0015] In ulcerative colitis (UC), where up to 40% of patients fail to respond to anti-tumor necrosis factor (anti-TNF) therapy, IL-11 has emerged as a key player. IL-11 and IL-13 receptor expression are significantly elevated in UC patients who do not respond to anti-TNF therapy. These findings position IL-11 as a valuable target in UC and Crohn's disease, particularly for patients resistant to conventional therapies.

[0016] IL-11's role in cancer is equally significant, particularly in cancer-associated fibroblasts (CAFs). Tumor-derived IL-11 promotes stromal cell activity, driving neutrophil-related P7421 PC00 tumor growth and metastasis. This indirect role of IL-11 in cancer highlights its importance as a target for therapies aimed at reducing tumor progression.

[0017] Implications for Therapeutic Development

[0018] IL-11's involvement in such a wide array of diseases makes it a promising candidate for therapeutic intervention. Targeting IL-11 with monoclonal antibodies (mAbs) has shown efficacy in animal models, especially for lung diseases. However, mAb therapy comes with limitations, such as high costs, frequent dosing, and the risk of anti-drug immunity. These challenges underscore the need for alternative approaches, such as vaccines. Studies have shown that long-term deletion of IL-11 in mice, as well as the use of IL- 11 -neutralizing antibodies or IL-11 receptor knockout models, has no significant adverse effects, supporting the feasibility of developing therapies that block IL-11 signaling.

[0019] In summary, the development of a vaccine that induces antibodies to block IL-11 signaling offers a novel and potentially transformative therapeutic strategy for a wide range of diseases, including fibrosis, cancer, and autoimmune conditions.

[0020] Summary

[0021] While monoclonal antibodies (mAbs) have shown promise in targeting IL-11, their clinical application comes with limitations. High-dose mAb therapy can be costly and requires frequent administration, raising concerns about accessibility and the potential development of anti-drug immunity. To overcome these challenges, vaccine-based therapies present an interesting alternative. Vaccines that induce antibodies to block IL-11 signaling could provide a more cost-effective, long-lasting solution, reducing the burden on healthcare systems.

[0022] However, developing a vaccine against self-antigens, such as IL-11, presents significant challenges due to the immune system's inherent tolerance mechanisms designed to prevent autoimmunity. This tolerance reduces the immunogenicity of selfantigens, making it difficult to elicit a strong and specific immune response.

[0023] To address these challenges, the approach of the present disclosure leverages a modular split-protein (Tag / Catcher)-based antigen-display platform allowing multivalent and unidirectional presentation of IL-11 antigens on the surface of particles, in P7421 PC00 particular nanoparticles, including capsid virus-like particles. Surprisingly, the present disclosure describes that this approach can effectively overcome B-cell tolerance and promote the production of potent, polyclonal anti-IL-11 autoantibodies.

[0024] In addition, the present inventors have found that vaccines which target IL-11 Ra binding without inducing specificity towards gp130 binding site exhibit some advantages, as detailed below.

[0025] For example, because gp130 is a shared signaling receptor employed by multiple cytokines, and IL-11 engages gp130 through structural domains that are conserved within this cytokine family, the use of full-length IL-11 as an immunogen could give rise to antibodies that recognize not only the I L-11— gp130 interface but also homologous regions present in other gp130-utilizing cytokines. Such cross-reactivity may inadvertently disrupt parallel signaling pathways and provoke unwanted immune responses against physiologically unrelated cytokines. By contrast, constructs engineered to focus the immune response specifically on the I L-11 Ra— IL-11 interaction restrict antibody recognition to the unique receptor-binding determinants of IL-11. This targeted approach improves antigenic precision, enhances safety, and reduces / minimizes the likelihood of eliciting antibodies that interfere with broader gp130-mediated signaling networks.

[0026] The modular Tag / Catcher vaccine platform technology (doi: 10.1186 / s12951-016-0181- 1.) has already demonstrated efficacy in clinical trials for other conditions (DOI: 10.1016 / S2666-5247(22)00337-8) .

[0027] Targeting native self-antigens, such as IL-11 , through active vaccination may rise safety concerns. To address this, the present inventors have also developed IL-11 antigen designs aimed at minimizing antibody off-target effects and avoiding the activation of harmful cytotoxic T cells. These IL-11 antigens are based on truncated human IL-11 protein sequences, optionally with specific mutations introduced to further reduce off-target risks. Additionally, the present inventors have used artificial intelligence to create de novo antigens containing specific IL-11 epitopes, which specifically block IL-11 Ra binding without inducing gp130 blocking antibodies.

[0028] In an aspect, the present disclosure concerns a vaccine comprising: P7421 PC00 i. a particle-forming protein comprising a first peptide tag, and ii. an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of lnterleukin-11 (IL-11), wherein the antigen and particle-forming protein are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, and wherein i - ii form a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

[0029] In an aspect, the present disclosure concerns a vaccine comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of Interleukin-11 (IL- 11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, thereby forming a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

[0030] In an aspect, the present disclosure concerns an antigen as described herein fused to a (second) peptide tag as described herein, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

[0031] In an aspect, the present disclosure concerns a polynucleotide encoding an antigen as described herein fused to a (second) peptide tag as described herein.

[0032] In an aspect, the present disclosure concerns a vaccine for use in medicine, wherein the vaccine is as described herein.

[0033] In an aspect, the present disclosure concerns a vaccine for use in the prophylaxis and / or treatment of a disease, wherein the vaccine is as described herein, and wherein the disease is a fibrotic disorder and / or a fibro-inflammatory disease, an P7421 PC00 inflammatory disease, a cancer, a cardiovascular disease, an age-related disease and / or a lung-related disorder.

[0034] In an aspect, the present disclosure concerns an expression system, such as a vector, comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, thereby forming a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

[0035] In an aspect, the present disclosure concerns a cell expressing: i. a first polynucleotide encoding a particle-forming protein fused to a first peptide tag, preferably as described herein; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and the particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first peptide tag and the second peptide tag, thereby forming a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to I L-11 Ra, but does not bind to gp130.

[0036] In an aspect, the present disclosure concerns a host cell, wherein the host cell comprises an expression system as described herein.

[0037] In an aspect, the present disclosure concerns a method of administering a vaccine for the prophylaxis and / or treatment of a disease in a subject in need thereof, comprising the step of: i. administering at least one composition as described herein to a subject at least once for prophylaxis and / or treatment of a disease as described herein. P7421 PC00

[0038] In an aspect, the present disclosure concerns a kit of parts comprising i. a vaccine as described herein or an expression system as described herein, and ii. optionally, a medical instrument or other means for administering the vaccine, and iii. instructions for use.

[0039] In an aspect, the present disclosure concerns a method of manufacturing the vaccine, comprising the step of: i. Providing an expression system as described herein.

[0040] 1. In an aspect, the present disclosure concerns a method of manufacturing a vaccine targeting the IL-11 -IL-11Ra interaction, comprising the steps of: a) Designing an antigen sequence, wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to or activate gp130; b) Producing a polynucleotide encoding the antigen or producing a polypeptide comprising or consisting of the antigen; c) Formulating the polynucleotide or the polypeptide as a vaccine, wherein the vaccine comprises a particle-forming protein comprising a first peptide tag, and wherein the vaccine comprises the antigen fused to a second peptide tag, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130, and / or preferably wherein the antigen, the epitope, the mimotope, the vaccine, the first peptide tag and the second peptide tags are as defined herein.

[0041] Description of Figures

[0042] Throughout the figures and examples, SpyC refers to SpyCatcher; SpyT refers to SpyTag.; MC refers to MoonCake; RT refers to RumTrunk.

[0043] Figure 1: Recombinant expression of IL- 11 antigens in different expression systems.

[0044] A. 6xHis-Mooncake-mulL11(22-199) expressed in the baculo virus expression system. Virus stock was prepared by transfecting Spodoptera fruigiperda Sf9 cells followed by infection of Trichioplusiani High-Five insect cells for protein production. P7421 PC00

[0045] 6xHis-Mooncake-mulL11(22-199) was purified by Immobilised metal affinity chromatography (IMAC).

[0046] B. 6xHis-Mooncake-mulL11(22-199) expressed in HEK293-Freestyle cells and purified by IMAC.

[0047] C. 6xHis-Mooncake-gplL11(22-199) expressed in HEK293-Freestyle cells and purified by IMAC, (gp: guinea pig).

[0048] Figure 2: Vaccine formulation of murine IL-11.

[0049] A) Tag-VLP (RumtrunkD9N-AP205) was mixed with Mooncake-mulL11 (HEK produced) in a 1 :0.75 molar ratio and incubated overnight at 4°C in PBS + 100mM L-Arginine. VLP-IL11 was purified by density gradient ultracentrifugation (UC), where particulate particles are expected to be present in UC fractions 4-5, as indicated by the boxes.

[0050] B) Fractions containing the VLP-mulL11 vaccine were dialysed into PBS and investigated by Dynamic light scattering (DLS) estimating the homogeneity of the sample. Triplicate measurements of the vaccine show an average diameter of 65nm, with a polydispersity of 25-30%.

[0051] C) By densitometry the antigen coupling efficiency was estimated to -30%, corresponding to -54 IL-11 antigens per VLP.

[0052] A) Tag-VLP (RumtrunkD9N-AP205) was mixed with Mooncake-gplL11 (HEK produced) in a 1 : 1 molar ratio and incubated overnight at 4°C in PBS. VLP-I L11 was purified by density gradient ultracentrifugation, where particulate particles are expected to be present in UC fractions 5-7, as indicated by the box. Excess and unconjugated gplL11 antigen is present in the high-density fractions (F12- F14)

[0053] B) Fractions containing the VLP-mulL11 vaccine were dialysed into PBS and investigated by Dynamic light scattering (DLS) estimating the homogeneity of the sample. Triplicate measurements of the vaccine show an average diameter of 45nm, with a polydispersity of 10%.

[0054] C) By densitometry the antigen coupling efficiency was estimated to -33%, corresponding to -60 IL-11 antigens per VLP. P7421 PC00

[0055] Figure 4: Induction of IL-11 specific antibodies in mice.

[0056] Balb / c mice were immunized in a 2-week prime-boost-boost (total of 3 doses) regime with two different doses of the murine IL-11 vaccine (RumtrunkD9N-AP205 + Mooncake-mulL11) (2.75pg (n=8) or 1 g (n=4) IL-11 displayed on VLP per dose). As a control, mice were immunised with 3pg non-displayed Mooncake-mulL11 (n=4). All vaccines were formulated with extrinsic adjuvant (Addavax). Blood samples were taken 10 days after each immunization.

[0057] A) IL-11 specific antibody levels measured in serum from immunized mice depicted as area under the curve (AUC) with mean ± SD for individual mice.

[0058] B) IL-11 specific antibody levels measured in serum from immunized mice depicted as area under the curve (AUC) with mean ± SD for grouped mice.

[0059] C) IL-11 specific antibody levels measured in serum from mice immunized with VLP-mulL11 depicted as area under the curve (AUC) with mean ± SD detected using an MBP-mulL11 compared to a commercial recombinant mulL11 protein.

[0060] Figure 5: Induction of IL-11 specific antibodies in guinea pigs.

[0061] Female guinea pigs (n=4) were immunized in a 3-week prime-boost-boost-boost (total of 4 doses) regime with the guinea pig IL-11 vaccine (RumtrunkD9N-AP205 + Mooncake-gplL11), with a dose of 10pg IL11 displayed on VLP. The vaccine was administered without extrinsic adjuvant. Blood samples were taken on the day of immunization. As a control, blood samples from a naive guinea pig (of similar age) was investigated in parallel. The level of I L11 -specific antibodies was investigated in serum from immunized guinea pigs or control animals and depicted as area under the curve (AUC) with mean ± SD.

[0062] Figure 6: Induction of IL-11 specific antibodies in guinea pigs fed on a high-fat diet.

[0063] Female guinea pigs were immunized in a 3-week immunization regime over the course of 25 weeks (not all time points are shown, see Figure 19B). All animals were fed a high-fat-diet throughout the study. I L11 -specific antibody levels were measured in serum from female guinea pigs immunized with 1) VLP (5.5pg, corresponding to the VLP dose in the VLP-gplL11 group) (n=5), 2) VLP-gplL11 (6.5pg IL11) (n=5), 3) prime with VLP, boost with VLP-gplL11 and continuous booster immunizations with VLP (n=3) (i.e. representing a one-dose immunization regime) or 4) prime with VLP-gplL11, boost with VLP and continuous booster immunizations with VLP-gplL11 (n=3) (i.e. representing a 6-week prime-boost interval, followed by 3-week booster intervals) and P7421 PC00 depicted as area under the curve (AUC) with mean ± SD. For all vaccines, the VLP is RumtrunkD9N-AP205 and the IL11 antigen is Mooncake-gplL11. All vaccines were formulated in extrinsic adjuvant (Addavax). Blood samples were taken on each day of immunization.

[0064] Figure 7: Catcher-mulL 11 antigens express, secrete, and couple to different nanoparticles in vitro.

[0065] A-B) HEK293tt cells single or co-transfected with DNA encoding Rumtrunk- nanoparticle and / or SpyCatcher-mulL11 (SpyCatcher or Mooncake genetically fused to mulL11). Cell fraction (C) and supernatant (S) were harvested 3 days post transfection for western blot analysis and detected by an anti-l L11 antibody (fig 7A) or anti- SpyCatcher-mi3 (Fig. 7B). Cells transfected with DNA encoding Rumtrunk-mi3 (lane 1- 2), Mooncake-mulL11 (lane 3-4), Rumtrunk-mi3 and Mooncake-mulL11 (lane 5-6), SpyCatcher-mulL11 (lane 7-8) or SpyT-mi3 and SpyCatcher-mulL11 (lane 9-10).

[0066] Bands corresponding to Catcher-mulL11 (SpyCatcher or Mooncake genetically fused to mulL11) are indicated by dashed lined boxes and bands corresponding to the mi3- mulL11 product are indicated by the dotted line boxes.

[0067] C) HEK293tt cells co-transfected with DNA encoding for SpyCatcher-mulL11 and different Rumtrunk-nanoparticles. Cell fraction (C) and supernatant (S) were harvested 3 days post transfection for western blot analysis and detected by anti-SpyCatcher-mi3. Lanes show SpyC-mulL11 co-transfected with DNA encoding LS-SpyT (lane 1-2), SpyT-E2 (lane 3-4), Norovirus-SpyT (lane 5-6) and Encapsulin-SpyT (lane 7-8). Positive protein control (lane 9).

[0068] Figure 8: Coupling of IL-11 Antigen to Nanoparticles and Secretion of Antigen:Nanoparticle Complexes In Vitro.

[0069] HEK293TT cells were co-transfected with DNA encoding SpyC-mulL11 and SpyTag- NP (nanoparticle). The supernatant was harvested 3 days post transfection and purified by density gradient ultracentrifugation and investigated by Western blot analysis detected by anti-SpyC. Assembled nanoparticles coupled to IL11 are expected in gradient fractions between UC fractions 4- 8. As indicated by black boxes, SpyC- IL11 expressed, coupled, secreted and assembled into particles when co-transfected with LS-SpyTag (figure 8A), SpyTag-E2 (figure 8B) and Encapsulin-SpyTag (Figure 8C). P7421 PC00

[0070] Figure 9: Immunization with DNA encoding SpyC-mulL-11 and SpyTag-nanoparticles overcomes immune tolerance and induce IL-11 -specific antibodies in mice.

[0071] Balb / c mice were immunized in a 3-week prime-boost-boost (total of 3 doses) regime with 60pg total DNA (30pg antigen+30pg nanoparticle) encoding SpyT-LS + SpyC- mulL11 (n=6), SpyT-encapsulin + SpyC-mulL11 (n=6), or unconjugated SpyC-mulL11 (n=4). Blood samples were taken 10 and 21 days after each immunization.

[0072] A) I L11 -specific antibody levels measured in serum from mice after one immunization (+14 days = 1stbleed, +20 days = 2ndbleed) depicted as area under the curve (AUG).

[0073] B) I L11 -specific antibody levels measured in serum from mice after booster immunization (+14 days = 3rdbleed, +20 days = 4thbleed) and a second booster immunization (+14 days = 5th bleed, +20 days = final bleed) depicted as end-point titer (cut off OD450=0.2). To compare the levels of IL-11 specific antibody levels, serum from mice immunized with 3 doses of a protein-based VLP-mulL11 vaccine (2.75pg IL11 dose) (n=4) was run in parallel (“C”).

[0074] Figure 10: cVLP-gplL11(FL) vaccine reduce hepatic fibrosis in a guinea pig MASH model

[0075] Female guinea pigs were immunized in a 3-week immunization regime over the course of 25 weeks with 1) cVLP (5.5 pg, corresponding to the VLP dose in the VLP-gplL11 group) (n=5), 2) VLP-gplL11 (6.5 pg IL11) (n=5) or 3) prime with VLP-gplL11, boost with VLP and continuous booster immunizations with VLP-gplL11 (n=3) (i.e. representing a 6-week prime-boost interval, followed by 3-week booster intervals). As the IL-11 specific antibody levels are equally high after 3 doses of vaccine (A), animals from group 3 are pooled with group 1 for analysis, marked as light grey for identification. Guinea pigs primed with VLP, boosted with VLP-gplL11 and continuous booster immunizations with VLP (n=3) (i.e. representing a one-dose immunization regime) have been excluded from this analysis. All animals were fed a high-fat-diet throughout the study. A) The body weight was followed over the course of the study, demonstrating a higher body weight increase for guinea pigs immunized with the cVLP- gpl L11 vaccine. B) Livers were collected at termination and weighed. There is no statistically significant difference in the liver weight between the two immunization groups. C) The ratio of liver weight to body weight (BW), (LW:BW%) was calculated as a measure of liver enlargement. There is no statistically significant difference in the P7421 PC00 relative liver weight between the two immunization groups. D) Liver sections were collected for histological analysis. The fibrosis score (F1-F4) was determined based on visual inspections of the histology samples. Guinea pigs immunized with the cVLP- gpl L11 vaccine demonstrate a statistically significant reduction of hepatic fibrosis (p=0.0283). E) Steatosis was scored as %hepatocytes with lipid accumulation (e.g. <5%: 01 score 3:>66%) from the histology liver samples. No statistically significant difference was observed between the two immunization groups. F) Lobular inflammation (i.e. inflammatory foci within the liver lobule). Scores reflect the presence of foci (e.g. >2 ; 2-4 etc.), G) Portal inflammation (i.e. inflammatory foci specifically around portal areas), scored as present (1) or not present (0), H) Ballooning cells (i.e. enlarged hepatocytes), scored between 1-3 (none, few, many), I) NAS-index: cumulative score (Steatosis, lobular inflammation and ballooning cells). A measure of MASH severity. A score of 5, is a common cut-off for + / - MASH.

[0076] Figure 11: Test expression of Al-generated IL-11 antigens in HEK293tt cells HEK293tt cells transfected with DNA encoding Al-generated IL-11 antigens. Supernatant was harvested 3 days post transfection for western blot analysis and detected by an anti-cTag. All samples were run in a reduced (+DTT) and non-reduced (-DTT) state.

[0077] Figure 12: Recombinant expression of L-11 Al antigens from HEKexpi Al-generated IL-11 antigens were expressed in HEK293expi cells and purified by cTag chromatography. Eluted protein peaks were run on an SDS-PAGE, successful expression is shown by a black arrow.

[0078] Al-generated IL-11 antigens were designed with a N-terminal Catcher (i.e. Mooncake) for cVLP display. HEK293tt cells transfected with DNA encoding Catcher-fused Al- generated IL-11 antigens. Supernatant was harvested 3 days post transfection for western blot analysis and detected by an anti-cTag.

[0079] All samples were run in a reduced (+DTT) and non-reduced (-DTT) state. P7421 PC00

[0080] Figure 14: Recombinant expression of Catcher Al IL11 antigens

[0081] 3 Al-generated IL-11 antigens fused to an N-terminal Catcher (Mooncake) was expressed in HEK293expi cells and purified by cTag chromatography. Eluted peaks from the chromatogram (Fraction 1 (F1), lane 2-3 and fraction 2 (F2), lane 4-5) were analyzed by SDS-PAGE in reduced (+DTT) and non-reduced (-DTT) state. cTag chromatography input and run through (RT), are loaded in lane 1 and 6, respectively.

[0082] Figure 15: Binding of IL- 11 specific antibodies to Al-designed IL-11 antigens

[0083] To investigate whether IL-11 secific antibodies binds the Al-generated antigen, a 96- well ELISA plate was coated with 0.1 pg IL-11 protein per well. Plates were blocked in 0.5% skimmed milk in PBS, pH7.4. A 3-fold dilution of serum from mice immunized with cVLP-mulL11(FL) starting from 1 :50 was added to the plate. Level of Catcher-IL11 specific antibodies were measured at OD450. Data show that out of the 7 Al-designed IL-11 antigens (without Catcher), 6 demonstrate some binding of IL-11 specific antibodies. For the 3 Catcher-designs (#48, #50 and #51), the signal is significantly higher, as both the Catcher-specific, as well as the IL-11 specific antibodies are measured.

[0084] Figure 16: Vaccine formulation #48

[0085] #48 was mixed with Tag-cVLP in a 1:1.3 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and post-spin samples were loaded on an SDS-PAGE gel, to assess potential loss in the post-spin sample due to precipitation or aggregation (B). The antigen coupling efficiency was estimated to 45% (corresponding to ~81 IL-11 antigens per VLP) by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. (C) Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~44nm, with low percent polydispersity (%Pd<15) (C). P7421 PC00

[0086] Figure 17: Vaccine formulation #50

[0087] #48 was mixed with Tag-cVLP in a 1:1 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and post-spin samples were loaded on an SDS-PAGE gel, to assess potential loss in the post-spin sample due to precipitation or aggregation (B). The antigen coupling efficiency was estimated to 43% (corresponding to ~77 IL-11 antigens per VLP)by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~45nm, with low percent polydispersity (%Pd<15) (C).

[0088] Figure 18: Vaccine formulation #51

[0089] #48 was mixed with Tag-cVLP in a 1:1 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and post-spin samples were loaded on an SDS-PAGE gel, to assess potential loss in the post-spin sample due to precipitation or aggregation (B). The antigen coupling efficiency was estimated to 51% (corresponding to ~92 IL-11 antigens per VLP) by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~43nm, with low percent polydispersity (%Pd<15) (C). P7421 PC00

[0090] Figure 19: cVLP-gplL11 (full length) induce high levels of IL11 specific antibodies in a guinea pig MASH model

[0091] (A) Total IgG was purified from plasma from guinea pigs (not fed on a high fat diet, pilot immunogenicity study, figure 5) immunized with the cVLP-gplL11 vaccine. As control, total IgG was purified from age-matched, non-immunized guinea pigs, as well as control guinea pigs (non-immunized). The biological activity of the vaccine-induced antibody response was investigated by measuring the ability of IgG purified from plasma from immunized guinea pigs to inhibit IL-11 receptor activation in a HEK293 hulL-11 reporter cell line (Hek-blue, Invivogen). 1 ng / mL MBP-hulL11 was incubated with IgG from immunized mice in a 2-fold dilution starting from 1 pM, before added to 50.000 cells seeded in a 96-well plate. Cells were incubated overnight at 37°C, 5% CO2. SEAP reporter activity was measured plotted as percentage activity (% activity). As negative controls, cells were unstimulated / blank (i.e. PBS) or stimulated in the presence of IgG from non-immunized guinea pigs. (B) Female guinea pigs were immunized in a 3-week immunization regime over the course of 25 weeks. All animals were fed a high-fat-diet throughout the study.

[0092] IL-11 -specific antibody levels were measured in serum from female guinea pigs immunized with 1) cVLP (5.5 pg, corresponding to the VLP dose in the VLP-gplL-11 group) (n=4) (black triangle), 2) VLP-gplL-11 (6.5 pg IL-11) (n=5) (black circle) or 3) prime with VLP-gpl L-11 , boost with VLP and continuous booster immunizations with VLP-gplL-11 (n=3) (i.e. representing a 6-week prime-boost interval, followed by 3-week booster intervals) (grey circle) and depicted as area under the curve (AUC) with mean ± SD. As the IL-11 specific antibody levels are equally at week 9, animals from group 3 are pooled with group 2 for analysis, marked as light grey for identification. Guinea pigs primed with VLP, boosted with VLP-gplL-11 and continuous booster immunizations with VLP (n=3) (i.e. representing a one-dose immunization regime) have been excluded from this analysis (included in initial ELISA data in Figure 5). For all vaccines, the VLP is RumtrunkD9N-AP205 and the IL-11 antigen is Mooncake-gplL-11. All vaccines were formulated in extrinsic adjuvant (Addavax). Blood samples were taken on each day of immunization. P7421 PC00

[0093] Figure 20:

[0094] IL-11 antigens activate IL11 receptor signalling in vitro

[0095] The biological activity of different IL-11 proteins was investigated by measuring the ability of the IL-11 proteins to inhibit hulL-11 receptor activation in a HEK293 hulL-11 reporter cell line (Hek-blue, Invivogen). 50.000 cells seeded in a 96-well plate was incubated with IL-11 protein in a 2-fold dilution starting from 100 ng / mL. Cells were incubated overnight at 37°C, 5% CO2. SEAP reporter activity was measured at OD620. As negative controls, cells were stimulated with 10 ng / mL mulL33 or PBS. Data is shown as dilution curves (Fig. A) or plotted as Area under the curve (AUC) with mean ± SD (Fig. B).

[0096] Figure 21:

[0097] Al-generated hulL-11 antigens induce IL- 11 specific antibodies

[0098] Balb / c mice (n=4) were immunized in a 2-week prime-boost-boost regime with a 5 pg IL-11 antigen dose displayed on cVLP. Blood samples were taken 12 days after each immunization. hulL11 -specific IgG was measured in serum from immunized mice after one dose (1st bleed) and second dose (2nd bleed). Groups were immunized with vaccines displaying a single Al-generated hulL11 antigen (i.e. cVLP-#48, cVLP-#50 and cVLP-#51). For benchmark, a group received a cVLP-hulL11(FL) vaccine.

[0099] Detailed description

[0100] Definitions

[0101] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied to facilitate the understanding of the present invention.

[0102] The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. In addition, as used in the specification and claims, the language "comprising" can include analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of”.

[0103] As used in the specification and claims, the term "and / or" used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A", and "B". The term “or” P7421 PC00 as used herein does not necessarily imply that the elements are mutually exclusive; i.e. “A or B” is intended to include either A alone, B alone, or both A and B, unless it is apparent that A and B are mutually exclusive.

[0104] As used in the specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Similarly, terms such as “one or more” or “at least one” include both the singular and plural form of the respective feature.

[0105] As used herein, the term “particle-forming protein” refers to proteins that are capable of self-assembling into defined, three-dimensional structures, such as nanoparticles, virus-like particles, viral capsid proteins, or other ordered macromolecular assemblies. These proteins naturally or through engineering possess the inherent ability to organize into particulate forms under suitable conditions without forming disordered aggregates or inclusion bodies. The skilled person will recognize that particle-forming proteins are distinct from proteins that aggregate non-specifically, as they maintain structural fidelity and functional properties within the assembled particle, unlike for instance proteins which aggregate in e.g. inclusion bodies.

[0106] Epitope: As used herein, the term "epitope" refers to the specific part of an antigen recognized by an antibody, B-cell receptor, or T-cell receptor. Epitopes can be classified as either linear or conformational.

[0107] Linear epitope: A linear epitope, also referred to as a sequential epitope, consists of a continuous sequence of amino acids in the primary structure of a protein. These epitopes are recognized based on the specific order of amino acids, and their antigenic properties remain intact even if the protein is denatured, as the sequence remains unaltered.

[0108] Conformational epitope: A conformational epitope, also known as a discontinuous epitope, is composed of amino acids that are not contiguous in the primary sequence of a protein but are brought into proximity by the protein’s three-dimensional folding. These epitopes are typically recognized by antibodies when the protein maintains its native conformation. Denaturation of the protein may disrupt the structure of a conformational epitope, rendering it unrecognizable by the immune system. P7421 PC00

[0109] The number of amino acids in a conformational epitope can vary, but it typically consists of 5 to 20 amino acids. However, there is no strict number, as conformational epitopes are defined by the spatial arrangement of amino acids rather than a specific sequence.

[0110] As used herein, the term “immunogenic fragments thereof” refers to portions of a polypeptide that retain immunological relevance. Such fragments include sequences that comprise one or more epitopes capable of eliciting an immune response, such as antibody generation or T-cell activation. The skilled person will understand that these fragments are of sufficient length and structural integrity to preserve the immunogenic properties of the full-length polypeptide, thereby ensuring their functionality in immunological applications.

[0111] As used herein, the term 'at least 70% sequence identity' encompasses sequences with 71% sequence identity, 72% sequence identity, 73% sequence identity, 74% sequence identity, 75% sequence identity, 76% sequence identity, 77% sequence identity, 78% sequence identity, 79% sequence identity, 80% sequence identity, 81% sequence identity, 82% sequence identity, 83% sequence identity, 84% sequence identity, 85% sequence identity, 86% sequence identity, 87% sequence identity, 88% sequence identity, 89% sequence identity, 90% sequence identity, 91% sequence identity, 92% sequence identity, 93% sequence identity, 94% sequence identity, 95% sequence identity, 96% sequence identity, 97% sequence identity, 98% sequence identity, 99% sequence identity, and 100% sequence identity.

[0112] The Vaccine of the present disclosure

[0113] Interleukin-11 (IL-11) is a cytokine involved in various physiological and pathological processes, including cell proliferation, differentiation, and immune modulation, with emerging evidence highlighting its pivotal role in the progression of conditions such as fibrotic disorders and / or fibro-inflammatory diseases, inflammatory diseases, cancer, cardiovascular diseases, and / or lung-related disorders.

[0114] Thus, in some aspects, the disclosure provides a protein vaccine or a DNA / RNA vaccine against Interleukin-11 (IL-11). P7421 PC00

[0115] As a self-antigen, IL-11 is recognized by the immune system as "self," resulting in tolerance that prevents immune activation against it. This tolerance presents a significant challenge in developing immunotherapies or vaccines aimed at modulating IL- 11 activity.

[0116] The inventors of the present disclosure have found that, in contrast to a vaccine comprising only an antigen of IL-11 , a strong immune response against IL-11 can be elicited by administering a vaccine which comprises: i. a particle-forming protein containing a first peptide tag, and ii. an antigen comprising an epitope or a mimotope of lnterleukin-11 (IL-11), fused to a second peptide tag.

[0117] The particle-forming protein and the antigen are covalently linked through an isopeptide bond or an ester bond between the first and second peptide tags, resulting in the assembly of a particle that displays the antigen.

[0118] In an aspect, the present disclosure concerns a vaccine comprising: i. a particle-forming protein comprising a first peptide tag, and ii. an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of lnterleukin-11 (IL-11), wherein the antigen and particle-forming protein are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, and wherein i - ii form a particle displaying said antigen.

[0119] In an aspect, the present disclosure concerns a vaccine comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of Interleukin-11 (IL- 11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, thereby forming a particle displaying said antigen. P7421 PC00

[0120] In some embodiments, the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond.

[0121] In some embodiments, the antigen and particle-forming protein upon expression in a cell are linked via an ester bond.

[0122] In some embodiments, IL-11 human IL-11. In some embodiments, IL-11 is as set forth in SEQ ID NO: 45, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

[0123] In some embodiments, IL-11 is murine IL-11. In some embodiments, IL-11 is murine IL-11 as set forth in SEQ ID NO: 47, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

[0124] In some embodiments, IL-11 is guinea pig IL-11. In some embodiments, IL-11 is guinea pig IL-11 as set forth in SEQ ID NO: 48, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

[0125] The epitope, the antigen, the first and the second peptide tag, the particle-forming protein, fusion of the antigen to the particle-forming protein, and further elements of the vaccine are further described herein in the corresponding sections of the disclosure.

[0126] It will be evident to the skilled person that the different sections of the present disclosure are provided to facilitate understanding and clarity. However, the teachings and embodiments described in these sections are not intended to be read in isolation. Rather, they are to be considered in conjunction with one another, and the various features, aspects, and embodiments disclosed herein are intended to be combined in any manner that would be understood as technically feasible and beneficial by the skilled person.

[0127] In some embodiments, the first and / or second polynucleotide is DNA. In some embodiments, the first and / or second polynucleotide is RNA. In some embodiments, one of the first and / or second polynucleotide is DNA, and the other one of the first and / or second polynucleotide is RNA. P7421 PC00

[0128] In some embodiments, the RNA is formulated in a lipid particle formulation.

[0129] In an aspect, the present disclosure is directed to a composition comprising the vaccine described herein. In some embodiments, the compositions may further comprise an acceptable carrier.

[0130] The Epitope

[0131] As described herein, the present disclosure is directed in some aspects to a vaccine which results in the display on a particle of an antigen comprising an epitope of IL-11.

[0132] In some embodiments, the epitope is comprised in an antigen as described in the section “the antigen” of the present disclosure.

[0133] In some embodiments, the epitope is a linear epitope.

[0134] In some embodiments, the epitope is a conformational epitope of Interleukin-11 (IL-11). A conformational epitope, also known as a discontinuous epitope, is composed of amino acid residues that are not contiguous in the primary sequence of a protein but are brought into spatial proximity through the three-dimensional folding of the protein. These epitopes are typically recognized by antibodies when the protein maintains its native conformation, as their structural arrangement is critical for immune recognition.

[0135] Interleukin-11 (IL-11) is relatively conserved among species, particularly in mammals. This conservation reflects the cytokine's fundamental role in various physiological processes, such as hematopoiesis, inflammation, and tissue remodeling. The structure of IL-11, including its four-helix bundle topology characteristic of IL-6 family cytokines, and key functional domains involved in receptor binding are well preserved across species. In several species, including human, mouse, and guinea pig the precursor protein is 199 amino acids long.

[0136] The first 21 amino acids of human IL-11 correspond to the signal peptide, which directs the nascent IL-11 protein to the secretory pathway. This peptide is cleaved during the maturation process, and the mature IL-11 protein is secreted. Similarly, the first 21 amino acids of IL-11 encode for a signal peptide in other animals, such as mice and guinea pigs. P7421 PC00

[0137] Thus, in some embodiments, the epitope of Interleukin-11 is amino acids 22 to 199 of IL-11 or an immunogenic fragment thereof. It will be understood that in the context of the present disclosure, an immunogenic fragment (of an epitope or of an antigen) also targets IL-11 and induces an immune response, preferably by inducing antibodies which prevent the interaction of IL-11 with IL-11 Ra. Preferably, the immunogenic fragment does not bind the gp130binding site of IL-11 , as described herein in detail.

[0138] In some embodiments, the epitope of lnterleukin-11 is SEQ ID NO: 45 or an immunogenic fragment of amino acids of SEQ ID NO: 45.

[0139] In some embodiments, the epitope of lnterleukin-11 is SEQ ID NO: 47 or an immunogenic fragment of amino acids of SEQ ID NO: 47.

[0140] In some embodiments, the epitope of lnterleukin-11 is SEQ ID NO: 48 or an immunogenic fragment of amino acids of SEQ ID NO: 48.

[0141] It will be understood by a skilled person that any reference to an amino acid residue number within SEQ ID NO: 45, 47, or 48 refers to the position of the residue in the sequence of the mature protein. For example, residue P1 of SEQ ID NO: 45 corresponds to the first amino acid residue of the mature protein sequence (i.e. , SEQ ID NO: 45) and aligns with residue 22 of the precursor protein sequence (SEQ ID NO: 46), accounting for the presence of the signal peptide. This numbering system applies consistently across all referenced sequences unless otherwise specified.

[0142] IL-11 exerts its biological effects through interaction with a specific receptor complex, consisting of the IL-11 receptor alpha subunit (IL-11Ra) and the signal transducing glycoprotein 130 (gp130). This interaction initiates a cascade of intracellular signaling pathways, including JAK / STAT, MAPK, and PI3K / AKT, which mediate the cytokine's diverse roles in cellular and tissue processes. Structurally, IL-11 engages its receptor components through distinct binding sites, referred to as Site I, Site II, and Site III, which collectively facilitate the assembly, stability, and signaling activity of the receptor complex. P7421 PC00

[0143] Site I of IL-11 facilitates the initial high-affinity binding of the cytokine to its specific receptor, IL-11 receptor alpha (IL-11 Ra). This interaction is crucial for determining the specificity of IL-11 signaling and initiating the receptor assembly process. Modulating Site I can inhibit the formation of the IL-11 / IL-11 Ra complex, thereby blocking downstream signaling.

[0144] Site II mediates the critical interaction between the preformed IL-11 / IL-11 Ra complex and the shared signal transducer gp130. This binding event is essential for signal transduction through pathways such as JAK / STAT, MAPK, and PI3K / AKT, which drive IL-11 -mediated cellular effects. Targeting Site II provides a means to disrupt the signaling cascade, preventing the propagation of IL-11 activity.

[0145] Site III contributes to the stabilization of the hexameric receptor signaling complex, which comprises two molecules each of IL-11 , IL-11 Ra, and gp130. Stabilization at Site III ensures the proper assembly and alignment of the receptor complex, enhancing the efficiency of signal transduction. Interfering with Site III can destabilize the complex, effectively reducing or abolishing IL-11 activity.

[0146] The glycoprotein 130 (gp130) serves as a shared signal transducer for multiple members of the interleukin-6 (IL-6) cytokine family, including but not limited to IL-11 and IL-6. gp130 plays an integral role in various cytokine-mediated signalling pathways that regulate key physiological and pathological processes. Due to its involvement in multiple pathways, therapeutic strategies targeting gp130 directly, such as at Site II or Site III of the IL-11 receptor complex, may interfere with the activity of other cytokines within the IL-6 family. Such disruptions could result in unintended off-target effects, compromising the broader cytokine signalling network.

[0147] In contrast, Site I on IL-11 mediates its specific interaction with the IL-11 receptor alpha subunit (IL-11 Ra), a step that precedes gp130 engagement. Thus, without being bound by theory, Targeting Site I may allow for the selective modulation of IL-11 activity without disrupting gp130's interactions with other cytokines. This approach should ensure specificity in regulating IL-11 signalling, minimizing the risk of off-target effects associated with broader gp130 inhibition, while preserving the functionality of other gp130-dependent cytokine pathways. P7421 PC00

[0148] The person of skill in the art will know how to determine whether an antigen as disclosed herein binds to the gp130 binding site. For instance determining whether the IL-11 epitopes or antigens bind to a recombinant IL-11 Ra protein, would demonstrate binding and integrity of the IL-11 Ra binding region. This ability, combined with an inability for that same epitope or antigen to activate IL-11 receptor activation (e.g. reporter cell line, cell-based assay etc), would demonstrate that the absence of the gp130 site is required for full activation of the receptor complex. The skilled person may further test the ability of that vaccine to induce 11-11 specific antibodies, as described for instance in the examples, to confirm the integrity of the IL-11 part of such antigen.

[0149] In order to obtain IL-11 epitopes which bind to IL-11, and in particular site I as further defined below, several strategies are available to the skilled person.

[0150] The first strategy entails retaining specific regions or residues of IL-11 involved in the targeting, as described in further detail below, and building a scaffold protein around those regions or residues as is known in the art, for instance using RFdiffusion (Watson et al., 2023).

[0151] Another strategy would be to conjugate glycans to generate steric hindrance and shield the region responsible for binding gp130 and / or the region responsible for binding IL- 11 Ra (Martina et al., 2023).

[0152] Another strategy would be to scramble the native IL-11 sequence around the specific regions or residues involved in the targeting and described in further detail below, for instance using ProteinMPNN (Dauparas et al., 2022).

[0153] Besides the use of the above methods, the skilled person knows that the scaffold may need to meet some structural requirements. In particular, the inclusion of charged residues (such as K, R, D), or of polar and hydrophobic residues (such as F, L) may increase solubility of the antigen and / or recognition by antibodies. G and D residues can be included to increase flexibility of the antigen and / or exposure of the epitope. Should more rigidity be desired, proline or charged residues can be added to one or both termini. It may be advantageous to include a disordered central region, which may favour epitope accessibility, and / or to prevent the inclusion of strong beta sheet motifs to reduce the risk of aggregation. Cysteine residues can be avoided to prevent P7421 PC00 formation of disulphide bonds, and may also simplify expression and folding of the antigen. Including aromatic residues may also help boost immunogenicity.

[0154] For all strategies, the skilled person can readily determine whether the obtained epitopes have the desired properties of inducing antibodies targeting IL-11 , in particular preventing its interaction with I L-11 Ra, without targetinggp130 binding site, for instance as described herein above.

[0155] The specific regions or residues of interest, of which one or more are retained in the final epitope and / or in the antigen or antigenic fragment, independently of the strategy used, will now be further detailed.

[0156] Thus, in some embodiments, the epitope comprise one or more residues of site / of IL- 11 , preferably wherein IL-11 is as set forth in SEQ ID NO: 45.

[0157] The binding interface known as Site I of IL-11 , responsible for its interaction with the IL- 11 receptor alpha subunit (IL-11 Ra), comprises the following structural elements: i. Helix IV, where the region spanning G158-L178 (SEQ ID NO: 49) has been conserved in our Al-driven designs to maintain critical binding functionality. ii. The full AB loop, comprising residues F43-G65 (SEQ ID NO: 50), which plays a key role in stabilizing the interaction and providing flexibility for receptor engagement. iii. A smaller region spanning A66-G71 (SEQ ID NO: 52), which complements the AB loop and contributes to the specificity and stability of the IL-11 / 1 L-11 Ra interaction.

[0158] Thus, in some embodiments, the epitope is a conformational epitope of site / of IL-11 .

[0159] Thus, in some embodiments, the epitope comprises: i. Helix IV of IL-11 , or an immunogenic fragment thereof; ii. AB loop of IL-11 , or an immunogenic fragment thereof; and / or P7421 PC00 iii. the region which complements the AB loop and contributes to the specificity and stability of the I L-11 / 1 L-11 Ra interaction.

[0160] Thus, in some embodiments, the epitope comprises Helix IV of IL-11, or an immunogenic fragment thereof. In some embodiments, the epitope or the immunogenic fragment thereof comprises or consists of two or more amino acid residues of IL-11, such as 2 to 20 residues, such as 5 to 20 residues, such as 8 to 20 residues, such as 2, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, such as 20 or more amino acid residues of Helix IV of IL-11.

[0161] In some embodiments, the epitope comprises the AB loop of IL-11, or an immunogenic fragment thereof. In some embodiments, the epitope or the immunogenic fragment thereof comprises or consists of two or more amino acid residues of the AB loop of IL- 11, such as 2 to 20 residues, such as 5 to 20 residues, such as 8 to 20 residues, such as 2, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, such as 20 or more amino acid residues of the AB loop of IL-11

[0162] In some embodiments, the epitope comprises the region which complements the AB loop and contributes to the specificity and stability of the IL-11 / 1 L-11Ra interaction. In some embodiments, the epitope or the immunogenic fragment thereof comprises or consists of two or more amino acid residues of comprises the region which complements the AB loop and contributes to the specificity and stability of the IL-11 / IL- 11Ra interaction, such as 2 to 20 residues, such as 5 to 20 residues, such as 8 to 20 residues, such as 2, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, such as 20 or more amino acid residues of the region which complements the AB loop and contributes to the specificity and stability of the IL-11 / 1 L-11Ra interaction.

[0163] In some embodiments, the epitope or immunogenic fragment thereof comprises or consists of some residues of each of i., ii., and iii. above.

[0164] In some embodiments, the epitope comprises or consists of two or more amino acid residues of IL-11, such as 2 to 20 residues, such as 5 to 20 residues, such as 8 to 20 residues, such as 2, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, such as 20 or more amino acid residues of IL-11, preferably wherein IL-11 is as set forth in SEQ ID NO: 45. P7421 PC00

[0165] In some embodiments, the conformational epitope of IL-11 comprises: i. amino acid residues 158 to 178 of IL-11 ; ii. amino acid residues 43 to 65 of IL-11; and / or iii. amino acid residues 66 to 71 of IL-11.

[0166] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises: i. G158 to L178 of IL-11 (SEQ ID NO: 49); ii. F43 to G65 of IL-11 (SEQ ID NO: 50); and / or iii. A66 to G71 of IL-11 (SEQ ID NO: 52), or a region corresponding to the region defined by any of i. to iii.

[0167] It will be evident to the skilled person that targeting the corresponding region in other organisms is expected to achieve the same effect. The skilled person knows how to identify the regions corresponding to G158 to L178 of IL-11 (SEQ ID NO: 49);

[0168] F43 to G65 of IL-11 (SEQ ID NO: 50); and / or A66 to G71 of IL-11 (SEQ ID NO: 52) in other organisms.

[0169] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises: i. one or more amino acid residues of G158 to L178 of IL-11 (SEQ ID NO: 49); ii. one or more amino acid residues of F43 to G65 of IL-11 (SEQ ID NO: 50); and / or iii. one or more amino acid residues of A66 to G71 of IL-11 (SEQ ID NO: 52), or a region corresponding to the region defined by any of i. to iii.

[0170] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises: i. two or more amino acid residues of G158 to L178 of IL-11 (SEQ ID NO: 49); ii. two or more amino acid residues of F43 to G65 of IL-11 (SEQ ID NO: 50); and / or iii. two or more amino acid residues of A66 to G71 of IL-11 (SEQ ID NO: 52), or a region corresponding to the region defined by any of i. to iii. P7421 PC00

[0171] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises: i. three or more amino acid residues of G158 to L178 of IL-11 (SEQ ID NO: 49); ii. three or more amino acid residues of F43 to G65 of IL-11 (SEQ ID NO: 50); and / or iii. three or more amino acid residues of A66 to G71 of IL-11 (SEQ ID NO: 52), or a region corresponding to the region defined by any of i. to iii.

[0172] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises: i. G158 to L178 of IL-11 (SEQ ID NO: 49); ii. L54 to G65 of IL-11 (SEQ ID NO: 51); and / or iii. A66 to G71 of IL-11 (SEQ ID NO: 52), or a region corresponding to the region defined by any of i. to iii.

[0173] In some embodiments, the conformational epitope comprises: i. Asp165; Trp166; Arg169; Leu172; or Leu173 ii. Met59; Ala61 ; Gly62; Leu64; Leu67; and / or iii. Arg75, or a region corresponding to the region defined by any of i. to iii.

[0174] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises G158-L178 (SEQ ID NO: 49), or a region corresponding to the region defined by residues 158 to 178 of SEQ ID NO: 45.

[0175] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises F43-G65 (SEQ ID NO: 50), or a region corresponding to the region defined by residues 43 to 65 of SEQ ID NO: 45.

[0176] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises L54-G65 (SEQ ID NO: 51) , or a region corresponding to the region defined by residues 54 to 65 of SEQ ID NO: 45. P7421 PC00

[0177] In some embodiments, the conformational epitope of IL-11 as set forth in SEQ ID NO: 45 comprises A66-G71 (SEQ ID NO: 52), or a region corresponding to the region defined by residues 66 to 71 of SEQ ID NO: 45.

[0178] In some embodiments, the epitope is a conformational epitope of IL-11 as set forth in SEQ ID NO: 45, wherein the epitope comprises: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0179] In some embodiments, the epitope comprises a residue of IL-11 as set forth in SEQ ID NO: 45, wherein the residue is: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu173.

[0180] In some embodiments, the epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein the two or more residues are selected from: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0181] In some embodiments, the epitope comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues of IL-11 as set forth in SEQ ID NO: 45, said residues being selected from: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0182] In some embodiments, the epitope comprises: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0183] In some embodiments, the epitope comprises two or more amino acid residues unique to Site I of IL-11. Importantly, the spatial arrangement of these residues in the antigen displayed by the vaccine is preserved to replicate their configuration in the native three- dimensional structure of IL-11. This conservation of the epitope’s structural integrity ensures that the antigen can effectively mimic the native protein, eliciting an immune response specifically targeting Site I IL-11.

[0184] Thus, in some embodiments, the epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61; Gly62; Leu 64;

[0185] Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and P7421 PC00 ii. the two or more residues maintain the same spatial arrangement between each other as in the three-dimensional structure of IL-11 , wherein IL-11 is as set forth in SEQ ID NO: 45.

[0186] In some embodiments, the epitope comprises two or more amino acid residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173; and ii. the two or more residues maintain the same spatial arrangement between each other as in the three-dimensional structure of IL-11 , wherein IL-11 is as set forth in SEQ ID NO: 45.

[0187] In some embodiments, i. the epitope comprises Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173 of IL-11 , as set forth in SEQ ID NO: 45; and ii. the residues of the epitope maintain the same spatial arrangement between each other as in the three-dimensional structure of IL-11 , wherein IL-11 is as set forth in SEQ ID NO: 45.

[0188] Methods to determine whether two or more amino acid residues maintain the same spatial arrangement are known in the art. Thus, the skilled person may employ any of these methods.

[0189] For example, the skilled person may employ the Root Mean Square Deviation (RMSD) of the two or more amino acid residues within the three-dimensional structure of the antigen and the corresponding two or more amino acid residues within the three- dimensional structure of IL-11. If the RMSD is less than, e.g. 2 A, is assessed that said amino acid residues in the antigen maintain the same spatial arrangement as in IL-11 , such IL-11 as set forth in SEQ ID NO: 45, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

[0190] Root Mean Square Deviation (RMSD) is a widely accepted and routinely used parameter in structural biology for quantifying the similarity between three-dimensional P7421 PC00 conformations of proteins or of selected amino acid residues thereof. RMSD has long been employed in the fields of protein engineering, homology modelling, structural alignment, and molecular dynamics to evaluate whether two structures maintain the same spatial arrangement. Numerous software packages commonly used in the art (e.g., PyMOL, Chimera, VMD, MOE, and various MD analysis suites) provide built-in RMSD calculation tools, and the parameter is considered a standard descriptor of structural equivalence. Thus, the use of RMSD to assess whether two or more amino acid residues maintain a comparable spatial orientation is conventional and immediately accessible to the skilled person. Further guidance on how to use RSMD can be found for example at the corresponding Wikipedia page: https: / / en.wikipedia.org / wiki / Root_mean_square_deviation_of_atomic_positions.

[0191] In some embodiments, the conformational epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the Root Mean Square Deviation (RMSD) of the two or more residues within the three-dimensional structure the antigen and the corresponding two or more residues within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1.9 A, such as less than 1.8 A, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.2, such as less than 1 A, wherein IL-11 is as set forth in SEQ ID NO: 45.

[0192] In some embodiments, the conformational epitope comprises two or more residues of IL-11 such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid residues of IL-11, as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the Root Mean Square Deviation (RMSD) of the two or more residues within the three-dimensional structure the antigen and the corresponding two or more residues within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1.9 A, such as less than 1.8 A, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.2, such as less than 1 A, wherein IL-11 is as set forth in SEQ ID NO: 45.

[0193] In some embodiments: P7421 PC00 i. the conformational epitope comprises Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173 of IL-11 , as set forth in SEQ ID NO: 45, and ii. the Root Mean Square Deviation (RMSD) of amino acid residues of the conformation epitope within the three-dimensional structure of the antigen and the corresponding amino acid residues of the conformation epitope within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1 .9 A, such as less than 1 .8 A, 1.7, 1 .6, 1 .5, 1.4, 1.3, 1 .2, 1 .2, such as less than 1 A, wherein IL-11 is as set forth in SEQ ID NO: 45.

[0194] In some embodiments, the epitope does not comprise a polypeptide consisting of Arg111 to Arg118 (SEQ ID NO: 53) of IL-11 , or the antigen does not comprise a polypeptide corresponding to the region defined by residues 111 to 118 of SEQ ID NO: 45, as set forth in SEQ ID NO: 53, nor immunogenic fragments thereof.

[0195] In some embodiments, the epitope does not comprise the helix C region of site II. In particular, the antigen in some embodiments does not comprise a polypeptide consisting of the region defined by residues 20 to 27 of SEQ ID NO: 45, or a polypeptide corresponding to the region defined by residues 20 to 27 of SEQ ID NO: 45, nor immunogenic fragments thereof.

[0196] Thus, in some embodiments, the Root Mean Square Deviation (RMSD) of the amino acid residues within the three-dimensional structure of the antigen and the corresponding amino acid residues within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1.9 A, such as less than 1 .8 A, 1.7, 1 .6, 1 .5, 1.4, 1.3, 1.2, 1.2, such as less than 1 A.

[0197] In some embodiments, the conformational epitope comprises two or more amino acid residues of IL-11 , such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid residues of IL-11.

[0198] In some embodiments, the conformational epitope comprises two or more amino acid residues of Site I IL-11 , such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid residues of Site I IL-11. P7421 PC00

[0199] The three-dimensional structure of human IL-11 is publicly available and can be retrieved for example from PDB:6O4O, PDB: 8DPS, or PDB: 8DPT. Alternatively a prediction of the three-dimensional structure of IL-11 can be used instead.

[0200] It will be evident to the skilled person that where a three-dimensional structure of the antigen displaying the epitope is not available, a prediction of the three-dimensional structure of the antigen might be used instead. Thus, in some embodiments, the structure of the antigen and / or of IL-11 is a predicted three-dimensional structure. The skilled person knows how to generate a prediction of the three-dimensional structure of a polypeptide given the corresponding sequence. Any known method to generate a three-dimensional structure of a polypeptide might be employed.

[0201] Three-dimensional structures to be used with the present invention may be available through various databases or can be predicted structures. AlphaFold3, referred to herein as AlphaFold, represents a state-of-the-art artificial intelligence (Al) system developed by DeepMind for predicting the three-dimensional (3D) structures of proteins from their amino acid sequences. This system is detailed in the publication: Jumper, J., Evans, R., Pritzel, A. et al. "Highly accurate protein structure prediction with AlphaFold." Nature 596, 583-589 (2021). https: / / doi.org / 10.1038 / s41586-021-03819-2.

[0202] AlphaFold DB is an online database which hosts over 200 million entries, encompassing the human proteome as well as the proteomes of 47 other key organisms relevant to research and global health. These entries are freely accessible at https: / / alphafold.ebi.ac.uk / . The (predicted) structure of can be retrieved by inputting identifiers such as the protein name, gene name, or UniProt accession number.

[0203] Structures of polypeptides not included in the AlphaFold DB may for example be predicted using the source code available at https: / / github.com / google- deepmind / alphafold, and / or a Colab notebook accessible at https: / / colab.research.google.com / github / deepmind / alphafold / blob / main / notebooks / Alp haFold.ipynb. To generate a three-dimensional structure using the Colab notebook, the amino acid sequence of the antigen can be inserted. P7421 PC00

[0204] The skilled person will understand that any similar software to predict the three- dimensional structure of a protein, such as previous or future iterations of AlphaFold, might be equally employed.

[0205] The Antigen

[0206] The vaccines described herein comprise a particle-forming protein comprising a first peptide tag and an antigen fused to a second peptide tag. Any of the epitopes described herein above may be comprised within the antigen. In particular, the antigen prevents the interaction of IL-11 with I L-11 Ra, without binding gp130, thus activating the IL-R11a / gp130 receptor complex; for instance the antigen interacts to IL-11 Ra. The antigen preferably comprises one or more epitopes of the IL-11 region that binds to IL- 11 Ra. The antigen can be designed using any of the strategies described for the epitope in the above section, and tested for the desired properties in the same way. For instance, a scaffold can be built around the specific regions or residues described in detail herein above, glycans can be conjugated as described herein above, or the residues surrounding the specific regions or residues described herein above can be scrambled. Further, an advantage of using a scaffold is that residues which should not be targeted by the antibodies induced by the construct are omitted. This ensures that the resulting immune response focuses on the intended epitope(s), minimizes recognition of irrelevant or undesired regions, and improves both the precision and functional relevance of the antibodies generated.

[0207] The antigen is described in further detail in the present section.

[0208] In addition, in an aspect, the present disclosure concerns an antigen as described herein, fused to a (second) peptide tag as described herein.

[0209] In some embodiments, said antigen may be displayed by any particle capable of displaying the antigen via an isopeptide bond, or an ester bond, such as those described in the section “the particle-forming protein” of the present disclosure.

[0210] In some embodiments, said antigen may comprise an epitope of IL-11, such as an epitope of Site I, as described in the section “the epitope” of the present disclosure. P7421 PC00

[0211] In some embodiments, said antigen is fused to a second peptide tag, such as those described in the section “the first and second peptide tag” of the present disclosure.

[0212] In an aspect, the present disclosure concerns a polynucleotide encoding an antigen as described herein fused to a (second) peptide tag as described herein. Said polynucleotide may be employed in the process of manufacturing the vaccine as described herein, and / or may be employed as a component of a DNA / RNA vaccine as described herein.

[0213] In some embodiments, the antigen comprises an epitope of IL-11.

[0214] In some embodiments, the antigen comprises a mimotope of IL-11

[0215] In some embodiments, the antigen is a polypeptide comprising SEQ ID NO: 45 or an immunogenic fragment thereof.

[0216] In some embodiments, the antigen comprises the full-length sequence of IL-11 as set forth in SEQ ID NO: 45; a sequence having at least 95% identity to SEQ ID NO: 45 such as 96%, 97%, 98% or 99% sequence identity thereto; or one or more immunogenic fragments thereof.

[0217] In some embodiments, the antigen is a polypeptide comprising SEQ ID NO: 47 or an immunogenic fragment thereof.

[0218] In some embodiments, the antigen comprises the full-length sequence of IL-11 as set forth in SEQ ID NO: 47; a sequence having at least 95% identity to SEQ ID NO: 47 such as 96%, 97%, 98% or 99% sequence identity thereto; or one or more immunogenic fragments thereof.

[0219] In some embodiments, the antigen is a polypeptide comprising SEQ ID NO: 48 or an immunogenic fragment thereof.

[0220] In some embodiments, the antigen comprises the full-length sequence of IL-11 as set forth in SEQ ID NO: 48; a sequence having at least 95% identity to SEQ ID NO: 48 such as 96%, 97%, 98% or 99% sequence identity thereto, or one or more immunogenic fragments thereof. P7421 PC00

[0221] In some embodiments, the antigen comprises: i. G158-L178 (SEQ ID NO: 49); and / or ii. F43-G65 (SEQ ID NO: 50); and / or iii. A66-G71 (SEQ ID NO: 52), and / or immunogenic fragments thereof.

[0222] In some embodiments, the antigen comprises: i. G158-L178 (SEQ ID NO: 49); and / or ii. L54-G65 (SEQ ID NO: 51); and / or iii. A66-G71 (SEQ ID NO: 52) and / or immunogenic fragments thereof.

[0223] In some embodiments, the second polynucleotide encodes: i. G158-L178 (SEQ ID NO: 49); and / or ii. F43-G65 (SEQ ID NO: 51); and / or iii. A66-G71 (SEQ ID NO: 52), and / or immunogenic fragments thereof.

[0224] In some embodiments, the second polynucleotide encodes: i. G158-L178 (SEQ ID NO: 49); and / or ii. L54-G65 (SEQ ID NO: 51); and / or iii. A66-G71 (SEQ ID NO: 52) and / or immunogenic fragments thereof.

[0225] In some embodiments, the vaccine aims to induce antibodies against an epitope of Site / of IL-11 , as described in the sections “The Epitope” and “Antibodies induced by the vaccine” of the present disclosure. Thus, in some embodiments, the vaccine comprises an epitope of Site / of IL-11.

[0226] In some embodiments, the antigen comprises G158-L178 (SEQ ID NO: 49), or immunogenic fragments thereof. In some embodiments, the antigen comprises or consists of a region corresponding to the region defined by residues 158 to 178 of SEQ ID NO: 45, as set forth in SEQ ID NO: 49, or an immunogenic fragment thereof. In some embodiments, the antigen comprises F43-G65 (SEQ ID NO: 50) or immunogenic P7421 PC00 fragments thereof. In some embodiments, the antigen comprises or consists of a region corresponding to the region defined by residues 43 to 65 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 50, or an immunogenic fragment thereof. In some embodiments, the antigen comprises L54-G65 (SEQ ID NO: 51) or immunogenic fragments thereof. In some embodiments, the antigen comprises or consists of a region corresponding to the region defined by residues 54 to 65 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 51, or an immunogenic fragment thereof. In some embodiments, the antigen comprises A66-G71 (SEQ ID NO: 52), or immunogenic fragments thereof. In some embodiments, the antigen comprises or consists of a region corresponding to the region defined by residues 66 to 71 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 52, or an immunogenic fragment thereof. Such antigens preferably comprise one or more epitopes of the IL-11 region that binds IL-11 Ra, and do not activating gp130 signaling.

[0227] The skilled person knows how to identify the regions corresponding to Site II and Site III in other organisms.

[0228] As described herein, in some embodiments, the vaccine aims to induce antibodies which do not bind to Site II or Site III of IL-11, as described in the sections “The Epitope” and “Antibodies induced by the vaccine” of the present disclosure.

[0229] In some embodiments, the antigen or antigenic fragment does not comprise the helix C region of site II. In particular, the antigen in some embodiments does not comprise a polypeptide consisting of the region defined by residues 20 to 27 of SEQ ID NO: 45, or a polypeptide corresponding to the region defined by residues 20 to 27 of SEQ ID NO: 45, nor immunogenic fragments thereof.

[0230] Thus, in some embodiments, the antigen does not comprise an amino acid residue of site II or site III of IL-11.

[0231] In some embodiments, the antigen does not comprise the binding site of IL-11 to gp130 of Site II of IL-11. Thus, in some embodiments, the antigen does not comprise a polypeptide consisting of Arg111 to Arg118 (SEQ ID NO: 53) of IL-11 , or the antigen does not comprise a polypeptide corresponding to the region defined by residues 111 P7421 PC00 to 118 of SEQ ID NO: 45, as set forth in SEQ ID NO: 53, nor immunogenic fragments thereof.

[0232] In some embodiments, the antigen does not comprise the binding site of IL-11 to gp130 of Site II of IL-11. Thus, in some embodiments, the antigen does not comprise a polypeptide consisting of amino acid residues 111 to 118 of IL-11.

[0233] In some embodiments, the antigen does not comprise the binding site of IL-11 to gp130 of Site III of IL-11. Thus, in some embodiments, the antigen does not comprise a polypeptide consisting of Ser145 to Arg151 (SEQ ID NO: 54) of IL-11.

[0234] In some embodiments, the antigen does not comprise the binding site of IL-11 to gp130 of Site III of IL-11. Thus, in some embodiments, the antigen does not comprise a polypeptide consisting of amino acid residues 145 to 151 of IL-11.

[0235] In some embodiments, the antigen does not comprise a polypeptide consisting of Arg111 to Arg118 (SEQ ID NO: 53) and / or Ser145 to Arg151 (SEQ ID NO: 54).

[0236] In some embodiments, the antigen does not comprise a polypeptide comprising Arg111 ; Arg114; Leu115, Arg117; Arg118; Ser145; Trp147; or Arg151.

[0237] In some embodiments, the antigen does not comprise a polypeptide comprising one or more of: Arg111 ; Arg114; Leu115; Arg117; Arg118; Ser145; Trp147; or Arg151 .

[0238] In some embodiments, the antigen does not comprise a polypeptide comprising any one of: Arg111 ; Arg114; Leu115, Arg117; Arg118; Ser145; Trp147; and Arg151.

[0239] In some embodiments, the antigen does not comprise: Arg111 ; Arg114; Leu115, Arg117; Arg118; Ser145; Trp147; or Arg151.

[0240] In some embodiments, the antigen does not comprise one or more of: Arg111; Arg114; Leu115; Arg117; Arg118; Ser145; Trp147; or Arg151 .

[0241] In some embodiments, the antigen does not comprise any one of: Arg111; Arg114;

[0242] Leu115, Arg117; Arg118; Ser145; Trp147; and Arg151. P7421 PC00

[0243] A skilled person would understand that references to an antigen not comprising a specific residue are meant, in some embodiments, to correspond to the designated amino acid residues within the native structure of IL-11, defined by their sequence position and three-dimensional orientation in relation to the epitope of IL-11.

[0244] In some embodiments, the antigen is a scaffold, such as minimal scaffold, comprising a conformational epitope of Interleukin-11 (IL-11).

[0245] Scaffold proteins are structural frameworks that can display epitopes in a defined spatial arrangement, thereby preserving their conformational integrity and improving their immunogenic potential.

[0246] A scaffold protein, particularly a minimal scaffold protein, provides a compact and stable platform for presenting the epitope of IL-11 in a manner that closely mimics its native conformation. This might be of particular relevance for vaccine against a selfantigen such as IL-11 , because the scaffold itself does not share the three-dimensional structure of IL-11 and, thus, the likelihood of cross-reactivity with parts of IL-11 other than the displayed epitope is minimized. Thus, in some embodiments, this structural distinction may ensure that antibodies elicited by the vaccine specifically target Site I of IL-11 without interfering with the binding of gp130 to other members of the IL-6 family. Scaffold-based antigens can also facilitate efficient production and enhance the structural resilience of the vaccine, contributing to its overall efficacy and safety.

[0247] Nevertheless, it will be evident to the skilled person that a scaffold protein, such as a minimal scaffold protein, might be used to present any epitope of IL-11 , such as an epitope of human IL-11 , mice IL-11, guinea pig IL-11 , or any other IL-11 known in the art.

[0248] A “minimal scaffold refers to a structural framework or protein that is engineered or selected to provide a simplified configuration sufficient to stably present an epitope or functional domain. A minimal scaffold maintains the conformational integrity of the epitope while excluding non-essential regions or sequences that are not required for stability, folding, or function. P7421 PC00

[0249] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, comprising an epitope of IL-11 , such as an epitope of Site / of IL-11. The skilled person knows how to design such a scaffold protein in which an epitope of IL-11 as described herein above has been introduced.

[0250] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, comprising a conformational epitope of IL-11. The skilled person knows how to design such a scaffold protein in which a conformational epitope of IL-11 as described herein above has been introduced.

[0251] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, comprising said epitope of IL-11 , and wherein the amino acid residues of said epitope in the vaccine maintain the same spatial arrangement between each other as in the corresponding three-dimensional structure of IL-11 , such as how described in the section “The Epitope” of the present disclosure.

[0252] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, wherein the scaffold protein does not comprise an epitope of site II of IL, such as site / / of IL as set forth in SEQ ID NO: 45.

[0253] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, wherein the scaffold protein does not comprise an epitope of site III of IL, such as site III of IL as set forth in SEQ ID NO: 45.

[0254] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, wherein the scaffold protein does not comprise an epitope of site II or site III of IL, such as site II or site III of IL as set forth in SEQ ID NO: 45.

[0255] In some embodiments, the antigen is a scaffold protein, such as a minimal scaffold protein, wherein the scaffold protein does not comprise Site II of IL-11 , preferably wherein Site II is as set forth in SEQ ID NO: 53, and / or Site III of IL-11 , preferably wherein Site III is as set forth in SEQ ID NO: 54.

[0256] In some embodiments, the scaffold protein comprising the epitope has a length of 100 to 300 amino acids, such as 100 to 200 amino acids, such as 110 to 190 amino acids, P7421 PC00 such as 120 to 180 amino acids, such as 130 to 170 amino acids, such as 140 to 160 amino acids, such as around 150 amino acids, or such as 100 to 190 amino acids, 100 to 180 amino acids, 100 to 170 amino acids, 100 to 160 amino acids, 100 to 150 amino acids, 100 to 140 amino acids, 100 to 130 amino acids, 100 to 120 amino acids, such as around 110 amino acids, around 120 amino acids, around 130 amino acids, around 140 amino acids, around 150 amino acids, around 160 amino acids, around 170 amino acids. In some embodiments, the scaffold protein comprising the epitope has a length of 200 to 300 amino acids, such as 210 to 290 amino acids, such as 220 to 280 amino acids, such as 230 to 270 amino acids, such as 240 to 260 amino acids, such as around 250 amino acids, or such as 200 to 290 amino acids, 200 to 280 amino acids, 200 to 270 amino acids, 200 to 260 amino acids, 200 to 250 amino acids, 200 to 240 amino acids, 200 to 230 amino acids, 200 to 220 amino acids, such as around 210 amino acids, around 220 amino acids, around 230 amino acids, around 240 amino acids, around 250 amino acids, around 260 amino acids or around 280 amino acids.

[0257] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO: 96.

[0258] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 82.

[0259] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 68. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 70. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 72. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 74. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 78. In some embodiments, the antigen comprises or consists of an amino acid sequence as set P7421 PC00 forth in SEQ ID NO: 80. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 82. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 84. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 86. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 88. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 90. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 92. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 94. In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 96.

[0260] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO: 96, and a peptide tag, such as a first or second peptide tag as described herein, fused to the N-terminal end of said antigen.

[0261] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 82, and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N- terminal end of said antigen.

[0262] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0263] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 68 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen. P7421 PC00

[0264] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 70 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0265] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 72 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0266] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 74 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0267] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0268] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 78 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0269] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 80 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0270] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 82 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0271] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 84 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0272] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 86 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen. P7421 PC00

[0273] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 88 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0274] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 90 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0275] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 92 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0276] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 94 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0277] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 96 and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0278] Thus, in some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID

[0279] NO: 72, SEQ ID NO: 74, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID

[0280] NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID

[0281] NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO: 96., and a peptide tag is fused to the N-terminal of said antigen, wherein said peptide tag is SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25);

[0282] SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, P7421 PC00 such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0283] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 82, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0284] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as P7421 PC00 at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0285] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 80, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0286] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 82, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); P7421 PC00 or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0287] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO: 96., wherein a peptide tag is fused to the N- terminal of said antigen, and wherein said peptide tag is MoonCake (SEQ ID NO: 28); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0288] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 82, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is MoonCake (SEQ ID NO: 28); P7421 PC00 or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0289] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 76, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is MoonCake (SEQ ID NO: 28); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0290] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 80, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is MoonCake (SEQ ID NO: 28); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least P7421 PC00

[0291] 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0292] In some embodiments, the antigen comprises or consists of an amino acid sequence as set forth SEQ ID NO: 82, wherein a peptide tag is fused to the N-terminal of said antigen, and wherein said peptide tag is MoonCake (SEQ ID NO: 28); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue.

[0293] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71,

[0294] SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81,

[0295] SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91,

[0296] SEQ ID NO: 93, SEQ ID NO: 95, or SEQ ID NO: 97, or a homologue thereof.

[0297] Degenerate sequences encoding the corresponding antigens as encoded by these sequences can also be used as an alternative.

[0298] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 77, SEQ ID NO: 81, or SEQ ID NO: 83, or a homologue thereof. Degenerate sequences encoding the corresponding antigens as encoded by these sequences can also be used as an alternative. P7421 PC00

[0299] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 67. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 69. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 71. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 73. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 75. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 77. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 79. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 81. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 83. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 85. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 87. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 89, In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 91. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 93. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 95. In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 97.

[0300] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71,

[0301] SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81,

[0302] SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91,

[0303] SEQ ID NO: 93, SEQ ID NO: 95, or SEQ ID NO: 97, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal of said antigen. P7421 PC00

[0304] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 77, SEQ ID NO: 81, or SEQ ID NO: 83, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0305] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 67, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0306] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 69, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0307] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 71, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0308] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 73, and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0309] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 75, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0310] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 77, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen. P7421 PC00

[0311] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 79, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0312] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 81, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0313] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 83, and wherein a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0314] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 85, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0315] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 87, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0316] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 89, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0317] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 91, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen. P7421 PC00

[0318] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 93, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0319] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 95, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0320] In some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 97, and a peptide tag, such as a first or second peptide tag as described herein is fused to the N-terminal end of said antigen.

[0321] Thus, in some embodiments, the antigen is encoded by a polynucleotide comprising a nucleotide sequence as set forth in SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 95, or SEQ ID NO: 97, a peptide tag is fused to the N- terminal of said antigen, and said peptide tag is SpyCatcher (SEQ ID NO: 23);

[0322] Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or with the proviso that said homologues or fragments comprise a an Asparagine (N) as reactive residue, in the position where said peptide tag comprise an Aspartic acid (D) as reactive residue. P7421 PC00

[0323] In some embodiments, the antigen is capable of eliciting an immune reaction in an animal, such as a mammal, such as a Homo sapiens, a dog, a cat, a cow, a pig, a horse, a sheep, a goat, a llama, a mouse, a rat, a monkey, and / or a bird, such as a chicken and / or a fish, such as a salmon.

[0324] In some embodiments, the antigen further comprises an additional tag.

[0325] In some embodiments, the antigen further comprises a polyhistidine tag or cTag.

[0326] In some embodiments, the antigen further comprises a polyhistidine tag.

[0327] In some embodiments, the antigen further comprises a cTag.

[0328] In some embodiments, a linker connects the (second) peptide and the antigen. Suitable likers are known in the art. A polypeptide of sequence GGS is an example of such suitable linker.

[0329] In some embodiments, the antigen fused to a second peptide tag comprises or consists of: i. SEQ ID NO: 55 ii. SEQ ID NO: 56 iii. SEQ ID NO: 57 iv. SEQ ID NO: 58 and / or v. SEQ ID NO: 59

[0330] In some embodiments, the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 55. In some embodiments, the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 56. In some embodiments, the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 57. In some embodiments, the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 58. In some embodiments, the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 59.

[0331] In some embodiments, the polynucleotide encoding the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 60. In some embodiments, the P7421 PC00 polynucleotide encoding the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 61. In some embodiments, the polynucleotide encoding the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 62. In some embodiments, the polynucleotide encoding the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 63. In some embodiments, the polynucleotide encoding the antigen fused to a second peptide tag comprises or consists of SEQ ID NO: 64.

[0332] Antibodies induced by the vaccine

[0333] As described herein, the present disclosure is directed in some aspects to a vaccine which is capable of displaying an antigen comprising an epitope of IL-11 on a particle .

[0334] Thus, in some embodiments the vaccine is capable of inducing in a subject one or more antibodies which have affinity for an epitope of IL-11 , as described herein such as in the section “The Epitope” of the present disclosure. Thus, in some embodiments, the vaccine is capable of inducing in a subject one or more antibodies specific to IL-11.

[0335] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 as described herein.

[0336] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 , wherein the conformational epitope comprises one or more of: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu173.

[0337] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 , wherein the conformational epitope comprises two or more residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues, selected from: Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0338] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 , wherein the conformational epitope comprises Met59; Ala61; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173. P7421 PC00

[0339] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises one or more of: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu173.

[0340] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises two or more residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues, selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0341] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0342] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for, and / or are capable to bind to, a conformational epitope of IL-11 , wherein the conformational epitope comprises: i. Asp165; Trp166; Arg169; Leu172; or Leu173 ii. Met59; Ala61 ; Gly62; Leu 64; Leu67; and / or iii. Arg75.

[0343] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for, and / or are capable to bind to, a conformational epitope of IL-11 , wherein the conformational epitope comprises: i. G158-L178 (SEQ ID NO: 49); and / or ii. F43-G65 (SEQ ID NO: 50); and / or iii. A66-G71 (SEQ ID NO: 52), and / or immunogenic fragments thereof.

[0344] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have affinity for, and / or are capable to bind to, a conformational epitope of IL-11 , wherein the conformational epitope comprises: P7421 PC00 i. G158-L178 (SEQ ID NO: 49); and / or ii. F43-G65 (SEQ ID NO: 50); and / or iii. A66-G71 (SEQ ID NO: 52), and / or immunogenic fragments thereof.

[0345] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies which have an affinity for IL-11 which is at least 2-fold, 3-fold, 5-fold, 10-fold greater than the affinity for one or more of: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCF1); Neuropoietin; Interleukin- 27 (IL-27); and / or Interleukin-31 (IL-31).

[0346] In some embodiments, the vaccine is not cross-reactive.

[0347] In some embodiments, the vaccine is not cross-reactive with lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCF1); Neuropoietin; Interleukin-27 (IL-27); and / or Interleukin-31 (IL-31)

[0348] In some embodiments, the vaccine is not capable of inducing in a subject one or more antibodies which bind to: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF);

[0349] Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCF1); Neuropoietin; Interleukin-27 (IL- 27); and / or Interleukin-31 (IL-31).

[0350] In some embodiments, the vaccine is capable of inducing one or more antibodies which have a Kd (Dissociation Constant) for IL-11 which is at least 2-fold, 3-fold, 5-fold, 10-fold lower, 50-fold lower, 100-fold lower, 200-fold lower, 500-fold lower, 1000 fold lower, than the Kd for one or more of: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCF1); Neuropoietin; Interleukin-27 (IL- 27); and / or Interleukin-31 (IL-31).

[0351] In some embodiments, the vaccine is capable of inducing one or more antibodies which are not capable of binding to Site II of IL-11 , preferably wherein Site II is as set P7421 PC00 forth in SEQ ID NO: 53, and / or Site III of IL-11 , preferably wherein Site III is as set forth in SEQ ID NO: 54.

[0352] In some embodiments, the vaccine is capable of inducing in a subject one or more antibodies, and wherein the Kd (Dissociation constant) of IL-11 to gp130 in the subject is increased no more than 10%, such as 5%, such as 4%, 3%, 2%, 1%, 0.5%, 0.1% compared to the Kd of IL-11 to gp130 in the absence of said antibodies.

[0353] In some embodiments, the vaccine does not induce, or has a decreased risk of inducing, an IL-11 specific T-cell response in a subject.

[0354] The particle-forming protein

[0355] As described herein, the present disclosure is directed in some aspects to a vaccine which results in the display on a particle of an antigen comprising an epitope of IL-11. This is achieved by the binding of an antigen fused to a first peptide tag as described herein to a particle-forming protein as described herein via an isopeptide bond or an ester bond.

[0356] In some embodiments, the particle-forming protein is fused to a first peptide tag as described in the section “the first and second peptide tag” disclosure.

[0357] In some embodiments, the particle-forming protein forms a particle displaying the antigen as described in the section “the antigen” of the present disclosure.

[0358] In some embodiments, the particle-forming protein is: a nanoparticle-forming protein; a virus protein, in particular a virus capsid protein. In some embodiments, the particle is a nanoparticle or a virus-like particle.

[0359] In some embodiments, the particle-forming protein is a nanoparticle-forming protein.

[0360] In some embodiments, the particle-forming protein is a virus protein, such an adenovirus protein, in particular an adenovirus capsid protein.

[0361] In some embodiments, the particle is a virus-like particle. P7421 PC00

[0362] In some embodiments the particle is a capsid virus-like particle (cVLP).

[0363] In some embodiments the particle-forming protein is a protein from a virus, such as an adenovirus. In some embodiments, the particle-forming protein is a protein from a hepatitis virus such as hepatitis B or E, for example a core protein from hepatitis B virus. In some embodiments, the particle-forming protein is a protein from a norovirus such as NoV. In some embodiments, the particle-forming protein is a protein from a papilloma virus such as Human Papilloma Virus (HPV), preferably HPV16 or HPV18, such as HPV L1. In some embodiments, the particle-forming protein a protein from a polyomavirus such as polyomavirus vp1 (PyV). In some embodiments, the particleforming protein is a protein from a calicivirus such as feline calicivirus (FCV), preferably FCV VP1. In some embodiments, the particle-forming protein is a protein from a circovirus such as a porcine circovirus (PCV), preferably PCV2 ORF2. In some embodiments, the particle-forming protein is a protein from a nervous necrosis virus (NNV), such as NNV coat protein. In some embodiments, the particle-forming protein is a protein from a parvovirus such as canine parvovirus (CVP), preferably CPV VP2, goose parvovirus (GPV) or porcine parvovirus (PPV), preferably structural proteins from GPV or PPV, or parvovirus B19. In some embodiments, the particle-forming protein is a protein from a protoparvovirus such as an enteritis virus, for example mink enteritis virus (MEV), preferably MEV VP2, or duck plague virus (DPV), preferably a DPV structural protein.

[0364] The protein may be a particle-forming protein from a plant virus, such as a cowpea virus, a tobacco virus, a tomato virus, a cucumber virus or a potato virus. In some embodiments, the plant virus is a mosaic virus, preferably Cowpea mosaic virus (CPMV). In some embodiments, the plant virus is a tobacco mosaic virus (TMV). In some embodiments, the plant virus is a tomato spotted wilt virus (TSWV). In some embodiments, the plant virus is a tomato yellow leaf curl virus (TYLCV). In some embodiments, the plant virus is a cucumber mosaic virus (CMV). In some embodiments, the plant virus is a potato virus Y (PVY).

[0365] In some embodiments, the particle-forming protein is a bacteriophage protein, such as a protein from Salmonella virus P22, MS2, QBeta, PRR1 , PP7, bacteriophage R17, bacteriophage fr, bacteriophage GA, bacteriophage SP, bacteriophage M11, P7421 PC00 bacteriophage MX1 , bacteriophage NL95, bacteriophage f2 or Cb5. Additional relevant bacteriophage proteins are described in Lieknina et al., 2019.

[0366] In some embodiments, the particle-forming protein has at least 70% sequence identity, such as 75%, such as 80%, such as 85%, such as 90%, such as 95% such as 99%, such as 100% sequence identity to:

[0367] MsDps2 as set forth in SEQ ID NO: 33;

[0368] AP205 as set forth in SEQ ID NO: 34; ferritin as set forth in SEQ ID NO: 35; i301 as set forth in SEQ ID NO: 36; replicase polyprotein 1a (pp1a); a lumazine synthase as set forth in SEQ ID NO: 38;

[0369] Hbc as set forth in SEQ ID NO: 39; tandemHBc as set forth in SEQ ID NO: 40; the 2-oxo acid dehydrogenase subunit E2 as set forth in SEQ ID NO: 41 ; or the norovirus capsid protein as set forth in SEQ ID NO: 42.

[0370] In some embodiments, the particle-forming protein has at least 70% sequence identity to MsDps2 as set forth in SEQ ID NO: 33.

[0371] In some embodiments, the particle-forming protein has at least 70% sequence identity to AP205 as set forth in SEQ ID NO: 34.

[0372] In some embodiments, the particle-forming protein has at least 70% sequence identity to ferritin as set forth in SEQ ID NO: 35.

[0373] In some embodiments, the particle-forming protein has at least 70% sequence identity to i301 as set forth in SEQ ID NO: 36.

[0374] In some embodiments, the particle-forming protein has at least 70% sequence identity to replicase polyprotein 1a (pp1a).

[0375] In some embodiments, the particle-forming protein has at least 70% sequence identity to a lumazine synthase as set forth in SEQ ID NO: 38. P7421 PC00

[0376] In some embodiments, the particle-forming protein has at least 70% sequence identity to Hbc as set forth in SEQ ID NO: 39.

[0377] In some embodiments, the particle-forming protein has at least 70% sequence identity to tandemHBc as set forth in SEQ ID NO: 40.

[0378] In some embodiments, the particle-forming protein has at least 70% sequence identity to the 2-oxo acid dehydrogenase subunit E2 as set forth in SEQ ID NO: 41.

[0379] In some embodiments, the particle-forming protein has at least 70% sequence identity to the norovirus capsid protein as set forth in SEQ ID NO: 42.

[0380] In some embodiments, the particle-forming protein is a viral capsid protein or a viral envelope protein such as a glycoprotein.

[0381] In some embodiments, the particle-forming protein is a protein of a recombinant adenovirus. In some embodiments, the particle-forming protein is an adenovirus and the first peptide tag is SpyTag. In some embodiments, the particle-forming protein is an adenovirus and the first peptide tag is SpyCatcher.

[0382] In an aspect, the present disclosure discloses a vaccine wherein the antigen as described herein is directly fused to a particle forming protein as described herein, and wherein the antigen is not fused to a second peptide as described herein. In some embodiments the antigen is fused genetically to the particle forming protein, or it is conjugated via chemical or enzymatic conjugation.

[0383] The first and second peptide tags

[0384] The first and the second peptide tags can bind to one another either by the formation of an isopeptide bond, or via an ester bond.

[0385] Peptide pairs, consisting of a first peptide tag and a second peptide tag which are capable of binding to one another via the (spontaneous) formation of an isopeptide bond, are known in the art, or can be designed or obtained by methods known in the art, in particular as described in Zakeri et al., 2012, and in Zakeri et al., 2010. P7421 PC00

[0386] As described herein, the first peptide tag is fused to a particle-forming protein, such as the particle-forming protein described in the corresponding section of the present disclosure.

[0387] As described herein, the second peptide tag is fused to an antigen, such as the antigen described in the corresponding section of the present disclosure.

[0388] The term "peptide tag" as used herein in some embodiments refers to a small peptide fragment which may be designed or derived directly from a particle-forming protein which naturally forms an intramolecular isopeptide bond. Peptide tags may also be identified by using a known binding partner, for example derived from a particle-forming protein naturally forming an intramolecular isopeptide bond, to screen a peptide library. The candidate peptide tags may thus be from a library, e.g. a peptide library, which can be screened for candidate peptide tags. They may also be designed in silico.

[0389] A peptide pair as understood herein thus in some embodiments consists of two peptide tags which can interact via the spontaneous formation of an isopeptide bond.

[0390] Generally, these are also called a “tag and catcher” system, where the longer of the two peptide tags is termed “catcher” while the shorter of the two peptide tags is termed “tag”. For instance, the SpyTag / SpyCatcher system consists of a first peptide tag (SpyTag) and a second peptide tag (SpyCatcher).

[0391] In some embodiments, the peptide pair as understood herein consists of two peptide tags which can interact via the spontaneous formation of an ester bond. Useful peptide tags able to form such spontaneous ester bonds are further described in Young et al., 2017. An example of an esther-forming split-protein pair is the fragment corresponding to amino acid residues 439-587 of cpe0147 (Uniprot B1 R775) (SEQ ID NO: 32) and the fragment corresponding to amino acid residues 565-587 of cpe0147 (Uniprot B1R775) (SEQ ID NO: 22).

[0392] The “tag” may be between 5-50 amino acids in length e.g. from 10, 20, 30, 40 to 50 amino acids in length and may bind covalently via an isopeptide bond to a binding partner as defined herein. Thus, the “tag” may comprise one reactive residue involved in an isopeptide bond in the isopeptide protein used to design the binding partner (and P7421 PC00 the binding partner may comprise the other reactive residue involved in that bond), as described herein.

[0393] In some embodiments, the “tag” has a length between 7 and 47 amino acids, such as between 8 and 46 amino acids, such as between 9 and 45 amino acids, such as between 10 and 44 amino acids, such as between 11 and 43 amino acids, such as between 12 and 42 amino acids, such as between 13 and 41 amino acids, such as between 14 and 40 amino acids, such as between 15 and 39 amino acids, such as between 16 and 38 amino acids, such as between 17 and 37 amino acids, such as between 18 and 36 amino acids, such as between 19 and 35 amino acids, such as between 20 and 34 amino acids, such as between 21 and 33 amino acids, such as between 22 and 32 amino acids, such as between 23 and 31 amino acids, such as between 24 and 30 amino acids, such as between 25 and 29 amino acids, such as between 26 and 28 amino acids, such as 27 amino acids. In some embodiments, the “tag” has a length of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46 amino acids.

[0394] In some embodiments, the “catcher” is at least 20 amino acids in length. Preferably, the “catcher” has a length of 5 amino acids or more, such as 10 amino acids or more, such as 15 amino acids or more, such as 20 amino acids or more, such as 25 amino acids, such as 30 amino acids, such as 35 amino acids, such as 40 amino acids, such as 45 amino acids, such as 50 amino acids, such as 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 or 350 amino acids or more. In preferred embodiments, the “catcher” is at least 20 amino acids in length. In some embodiments, the “catcher” is between 75 to 125 amino acids in length.

[0395] Preferably, the “catcher” has an amino acid sequence which consists of more amino acid residues than the “tag”.

[0396] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is: SpyTag (SEQ ID NO: 1); SdyTag (SEQ ID NO: 2); SnoopTag (SEQ ID NO: 3); PhoTag (SEQ ID NO: 4); EntTag (SEQ ID NO: 5); RumTag (SEQ ID NO: 6); Rum2Tag (SEQ ID NO: 7); Rum3Tag (SEQ ID NO: 8); Rum4Tag (SEQ ID NO: 9); Rum5Tag (SEQ ID NO: 10); Rum6Tag (SEQ ID P7421 PC00

[0397] NO: 11); Rum7Tag (SEQ ID NO: 12); Rumtrunk D9N (SEQ ID NO: 13); RumTrunkTag (SEQ ID NO: 14); BacTag (SEQ ID NO: 15); Bac2Tag (SEQ ID NO: 16); Bac3Tag (SEQ ID NO: 17); Bac4Tag (SEQ ID NO: 18); Bac5Tag (SEQ ID NO: 19); PsCsTag (SEQ ID NO: 20); Clib9 (SEQ ID NO: 21); Ktag (SEQ ID NO: 65) or a homologue or fragment thereof having at least 70% homology or identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologue or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or wherein where the reactive amino acid residue is an Aspartic acid (D), the reactive amino acid residue is mutated to an Asparagine (N).

[0398] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is: SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or homologues or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said homologues or fragments comprise the reactive amino acid residue involved in the formation of the isopeptide bond, or wherein where the reactive amino acid residue is an Aspartic acid (D), the reactive amino acid residue is mutated to an Asparagine (N).

[0399] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is SpyCatcher (SEQ ID NO: 23), or homologues or fragments thereof having at least 70% identity thereto P7421 PC00

[0400] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is Spycatcherv2 (SEQ ID NO:

[0401] 24), or homologues or fragments thereof having at least 70% identity thereto

[0402] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is Spycatcherv3 (SEQ ID NO:

[0403] 25), or homologues or fragments thereof having at least 70% identity thereto

[0404] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is SdyCatcher (SEQ ID NO:

[0405] 26), or homologues or fragments thereof having at least 70% identity thereto

[0406] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is SnoopCatcher (SEQ ID NO:

[0407] 27), or homologues or fragments thereof having at least 70% identity thereto

[0408] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is MoonCake (SEQ ID NO: 28), or homologues or fragments thereof having at least 70% identity thereto

[0409] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is Katl (SEQ ID NO: 29), or homologues or fragments thereof having at least 70% identity thereto

[0410] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is QueenCatcher (SEQ ID NO:

[0411] 30), or homologues or fragments thereof having at least 70% identity thereto

[0412] In some embodiments where an isopeptide bond is formed between the first and the second peptide tags, the first or the second peptide tag is PsCsCatcher (SEQ ID NO:

[0413] 31), or homologues or fragments thereof having at least 70% identity thereto

[0414] In some embodiments, the isopeptide bond between the first and second peptide tag is an isopeptide bond between: i. SEQ ID NO: 28 (MoonCake) and P7421 PC00 a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); or variants thereof having at least 70% homology or identity thereto; and / or ii. SEQ ID NO: 28 (Katl) and a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or P7421 PC00 p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); or variants thereof having at least 70% homology or identity thereto; and / or iii. SEQ ID NO: 29 (QueenCatcher) and a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); or variants thereof having at least 70% homology or identity thereto.

[0415] In some embodiments, the one or more first peptide tags are fused to the N-terminal end, to the C-terminal end of the particle-forming protein and / or inserted in-frame into the coding sequence of the particle-forming protein, optionally by a linker.

[0416] In some embodiments, one or more second peptide tags are fused to the N-terminal end, to the C-terminal end of the antigen and / or inserted in-frame into the coding sequence of the antigen, optionally by a linker.

[0417] In some embodiments, the peptide pair comprises or consists of truncated or modified versions of any of the above, i.e. further engineered peptide pairs, which however retain the ability to form an isopeptide bond. P7421 PC00

[0418] A peptide tag may be altered, e.g. mutations or alterations may be introduced in any one or any two of the first or second peptide tag, i.e. in any one or any two of the tag and catcher. The peptide tag, i.e. the first, or the second peptide tag, should be able to covalently bind to a corresponding binding partner via an isopeptide bond, or via an ester bond, spontaneously. In this respect, each peptide tag preferably comprises one of the reactive amino acid residues involved in the formation of an isopeptide bond in the isopeptide protein. Hence, each peptide tag comprises only one reactive residue from the isopeptide bond and does not comprise both reactive residues involved. Further, if the peptide tag is modified or mutated, the reactive residue in that fragment preferably remains unchanged. This means that when a homologue of a peptide tag is used, the homologue preferably still contains the reactive residue which was originally present in the original peptide tag. In some embodiments, however, the reactive residue in that fragment is also changed if the peptide tag is modified or mutated.

[0419] Preferably, the reactive residue present in the tag is an asparagine or an aspartate residue, which can form an isopeptide bond with the reactive residue of the binding partner or modified binding partner (the catcher), as described above. Thus, one peptide tag contains one reactive residue while the other peptide tag contains the other reactive residue, and thus no single peptide tag contain both reactive residues.

[0420] In some embodiments, both reactive residues are involved in the formation of an isopeptide bond. In some embodiments, the reactive residue of the first peptide tag is different than the reactive residue of the second peptide tag. Preferably, the reactive residue present in the “catcher” is a lysine residue. In some embodiments, the reactive residue present in the “catcher” is an asparagine or an aspartate residue. Preferably, the reactive residue present in the “tag” is an asparagine or an aspartate residue. In some embodiments, the reactive residue present in the “tag” is a lysine residue. These residues together may form the isopeptide bond.

[0421] Fusion of the first peptide tag to the protein and fusion of the second peptide tag to the antigen

[0422] Changing the position where the first peptide tag is fused to the protein may allow changing the orientation of the antigen on the particle. This may be performed to P7421 PC00 enable the best possible display of the most important epitopes of the antigen. The best possible orientation may be different from antigen to antigen.

[0423] Epitopes of specific monoclonal antibodies may be mapped on the antigen structure, whereby it is possible to determine which epitopes are accessible after conjugation of the antigen to the particle-forming protein. Specifically, one may measure binding between a specific monoclonal antibody and the complex of the antigen bound to the particle forming protein (antigen: particle complex), such as by using ELISA or another affinity-measuring technique (e.g. Attana), and thereby determine the orientation of the antigen. Cryo-electron microscopy may also be used to determine the structure of the entire antigemparticle complex. If the antigen contains a functional binding epitope, binding-assays may be conducted to determine if the epitope is exposed or hidden in the final antigemparticle complex.

[0424] Changing the position where the second peptide tag is fused to the antigen will allow changing the orientation of the antigen on the particle. This may be performed to enable the best possible display of the most important epitopes of the antigen. The best possible orientation may be different from antigen to antigen.

[0425] In some embodiments, the first peptide tag is fused to the N-terminus of the protein. In other embodiments, the first peptide tag is fused to the C-terminus of the protein. In other embodiments, the first polynucleotide is inserted in-frame in the coding sequence of the protein. The fusion protein may comprise a linker between the first peptide tag and the protein.

[0426] Similarly, in some embodiments, the second peptide tag is fused to the N-terminus of the antigen. In other embodiments, the second peptide tag is fused to the C-terminus of the antigen. In other embodiments, the second polynucleotide is inserted in-frame in the coding sequence of the antigen. The fusion protein may comprise a linker between the second peptide tag and the antigen.

[0427] In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 101 ; SEQ ID NO: 103; SEQ ID NO: 105; SEQ ID NO: 107; SEQ ID NO: 109; SEQ ID NO: 111; SEQ ID NO: 113; SEQ ID NO: 115; SEQ ID NO: P7421 PC00

[0428] 117; SEQ ID NO: 119; SEQ ID NO: 121 ; SEQ ID NO: 123; SEQ ID NO: 125; or SEQ ID NO: 127.

[0429] In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 109; SEQ ID NO: 113; or SEQ ID NO: 115.

[0430] In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 101. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 103. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 105. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 107. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 109. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 111. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 113. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 115. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 117. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 119. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 121. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 123. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 125. In some embodiments, the second peptide tag is fused to the N-terminus of the antigen as set forth in SEQ ID NO: 127.

[0431] In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 102; SEQ ID NO: 104; SEQ ID NO: 106; SEQ ID NO: 108; SEQ ID NO: 110; SEQ ID NO: 112; SEQ ID NO: 114; SEQ ID NO: 116; SEQ ID NO: 118; SEQ ID NO: 120; SEQ ID NO: 122; SEQ ID NO: 124; SEQ ID NO: 126; or SEQ ID NO: 128. P7421 PC00

[0432] In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 110; SEQ ID NO: 114; or SEQ ID NO: 116.

[0433] In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 102. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 104. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 106. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 108. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 110. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 112. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 114. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 116. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 118. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 120. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 122. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 124. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 126. In some embodiments, the second peptide tag fused to the N-terminus of the antigen is encoded by a polynucleotide as set forth in SEQ ID NO: 128.

[0434] Further elements of the vaccine

[0435] In some embodiments, the first polynucleotide further comprises a secretion or excretion signal, whereby the particle forming protein fused to the first peptide tag is secreted or excreted from the endoplasmic reticulum of the cell. P7421 PC00

[0436] In some embodiments, the secretion or excretion signal comprises or consists of: MFPFALLYVLSVSFRKIFILQLVGLVLT (SEQ ID NO: 43).

[0437] In some embodiments, the secretion or excretion signal comprises or consists of MGSAALLLWVLLLWVPGSNG (SEQ ID NO: 44).

[0438] It will be evident to the skilled person that the sequences above are merely examples, and that any known secretion or excretion signal known in the art to promote secretion or extraction from the endoplasmic reticulum of the cell might be used. Thus, any signal sequence described herein might substitute by other suitable signal sequence.

[0439] Expression systems

[0440] Herein is also provided an expression system such as a vector comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, thereby forming a particle displaying said antigen.

[0441] The expression system may consist of or comprise a polycistronic RNA construct and / or a DNA construct, from which the transcribed mRNA is polycistronic. Thus, in some embodiments, the first and the second polynucleotides of the expression system are encoded on the same ribonucleic acid molecule. In some embodiments, the first and the second polynucleotides of the expression system lie within the same open reading frame, whereby only one promoter sequence is needed to transcribe both polynucleotides. In some embodiments, the first and the second polynucleotides of the expression system lie within separate open reading frames and may thus be regulated by separate promoters.

[0442] The first peptide tag, the second peptide tag, the protein and / or the antigen may be as defined herein elsewhere. P7421 PC00

[0443] The term “expression system” refers to a genetic construct designed to produce a protein and / or an RNA inside a cell. Thus, the expression system may comprise RNA and / or DNA, which is translated or transcribed to a protein or DNA, respectively, inside the cell.

[0444] The expression system may comprise the sequences necessary for gene expression in the cell. These may include a promoter, a translation initiation sequence such as a ribosomal binding site, a start codon, a termination codon, and a transcription termination sequence. There are differences in the enzymes responsible for protein synthesis between prokaryotes and eukaryotes, therefore the expression vectors must comprise elements for expression that are appropriate for the chosen host. For example, prokaryotic expression systems may comprise a Shine-Dalgarno sequence at the translation initiation site for the binding of ribosomes, while eukaryotic expression systems may contain a Kozak consensus sequence.

[0445] The expression system may additionally comprise a marker, such as a selectable marker, i.e. a gene that confers a trait suitable for artificial selection, whereby cells comprising the expression system may be selected for, or a screenable marker, such as a reporter gene, i.e. a gene that allows for differentiation between cells comprising or not comprising the expression system, whereby cells comprising the expression system may be identified. Examples of such markers include antibiotic resistance genes, auxotrophic markers and genes expressing detectable compounds, such as coloured and / or fluorescent compounds.

[0446] In some embodiments, the first polynucleotide and the second polynucleotide are both DNA polynucleotides. In some embodiments, the first polynucleotide and the second polynucleotide are both RNA polynucleotides. In some embodiments, the first polynucleotide or the second polynucleotide is a DNA polynucleotide and the other is an RNA polynucleotide.

[0447] The first polynucleotide and / or the second polynucleotide may be under the control of a promoter, such as an inducible promoter or a constitutive promoter. The first and / or the second polynucleotide may each be under the control of a first and / or second promoter, respectively, which may be identical or different. They may also be under the control of a single promoter. P7421 PC00

[0448] The first and the second polynucleotides of the expression system may be comprised within the same molecule. The first and the second polynucleotides of the expression system may alternatively be comprised within different molecules, such as within two or more separate molecules.

[0449] The first and / or the second polynucleotide may further comprise a secretion or excretion signal to obtain a fusion protein comprising such a signal, whereby the protein fused to the first peptide tag and / or the antigen fused to the second peptide tag is secreted or excreted from the endoplasmic reticulum and optionally also from the cell.

[0450] In some embodiments, the first and second polynucleotides are comprised within one vector such as a viral vector or a plasmid, or wherein the first and second polynucleotides are comprised within two vectors such as two viral vectors; two plasmids; or one viral vector and one plasmid.

[0451] In some embodiments, the viral vector is an adenoviral vector, such as a modified adenoviral vector, e.g. the replication-deficient simian adenovirus vector ChAdOxI , or a modified vaccinia Ankara (MVA) vector.

[0452] The present expressions systems can be used for prophylaxis and / or treatment of a wide range of diseases as disclosed herein.

[0453] In some embodiments, the expression system comprises or consists of a plasmid. In some embodiments, the expression system comprises or consists of an mRNA.

[0454] Cells

[0455] The invention further relates to a cell, such as a host cell, comprising one or more polynucleotides and / or an expression system as disclosed herein. The one or more polynucleotides and / or expression system may have a sequence that is codon- optimised. Codon optimisation methods are known in the art and allow optimised expression in a heterologous host organism or cell. P7421 PC00

[0456] Thus, in an aspect, the present disclosure concerns a cell comprising the polynucleotide as described herein.

[0457] In some embodiments the cell comprises the expression system as described herein.

[0458] In an aspect, the present disclosure concerns a cell expressing: i. a first polynucleotide encoding a particle-forming protein fused to a first peptide tag, preferably as defined in any one of the preceding items; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and the particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first peptide tag and the second peptide tag, thereby forming a particle displaying said antigen.

[0459] In some embodiments the cell may be selected from the group comprising a bacterial cell, yeast cell, a fungal cell, a plant, a mammalian cell, and / or an insect cell.

[0460] In some embodiments, the cell is a bacterial cell. In some embodiments, the cell is a yeast cell. In some embodiments, the cell is a fungal cell. In some embodiments, the cell is a plant cell. In some embodiments, the cell is a mammalian cell, such as a human cell. In some embodiments, the cell is an insect cell.

[0461] In some embodiments, the cell is a microorganism.

[0462] In an aspect, the present disclosure concerns a host cell, wherein the host cell comprises an expression system as described herein.

[0463] In some embodiments the host cell may be selected from the group comprising a bacterial cell, yeast cell, a fungal cell, a plant, a mammalian cell, and / or an insect cell.

[0464] In some embodiments, the host cell is a bacterial cell. In some embodiments, the host cell is a yeast cell. In some embodiments, the host cell is a fungal cell. In some embodiments, the host cell is a plant cell. In some embodiments, the host cell is a mammalian cell, such as a human cell. In some embodiments, the host cell is an insect cell. P7421 PC00

[0465] Methods for expressing a polypeptide as described herein, such as a first polypeptide and / or a second polypeptide in a cell, such as a host cell, are known in the art. The first or second polypeptide may be heterologously expressed from corresponding polynucleotide sequences cloned into the genome of the cell or they may be comprised within a vector. For example, a first and / or second polynucleotide coding for the first and / or second polypeptide is cloned into the genome, and a first and / or second polynucleotide coding for the first and / or second polypeptide is comprised within a vector transformed or transfected into the cell.

[0466] Expression of a polypeptide, such as the first and second polypeptides in the cell may occur in a transient manner. When the polynucleotide encoding one of the polypeptides is cloned into the genome, an inducible promoter may be cloned as well to control expression of the polypeptides. Such inducible promoters are known in the art. Alternatively, genes coding for suppressors of gene silencing may also be cloned into the genome or into a vector transfected within the cell.

[0467] In some embodiments, the cell, such as the host cell, may be selected from Escherichia coli, Spodoptera frugiperda (sf9), Trichoplusia ni (BTI-TN-5B1-4), Pichia Pastoris, Saccharomyces cerevisiae, Hansenula polymorpha, Drosophila Schneider 2 (S2), Lactococcus lactis, Chinese hamster ovary (CHO), Human Embryonic Kidney 293, Nicotiana tabacum cv. Samsun NN or Solanum tuberosum cv. Solara. Thus in some embodiments, the cell is Escherichia coli. In another embodiment, the cell is Spodoptera frugiperda. In some embodiments, the cell is Pichia Pastoris. In some embodiments, the cell is Saccharomyces cerevisiae. In some embodiments, the cell is Hansenula polymorpha. In some embodiments, the cell is Drosophila Schneider 2. In some embodiments, the cell is Lactococcus lactis. In some embodiments, the cell is Chinese hamster ovary (CHO). In some embodiments, the cell is Human Embryonic Kidney 293. In some embodiments, the cell is Trichoplusiani (BTI-TN-5B1-4). In In some embodiments, the cell is Nicotiana tabacum cv. Samsun NN. In some embodiments, the cell is Solanum tuberosum cv. Solara.

[0468] Use of the vaccine in medicine

[0469] In an aspect, the present disclosure concerns a vaccine for use in medicine, wherein the vaccine is as described herein. P7421 PC00

[0470] In an aspect, the present disclosure concerns a vaccine for use in the prophylaxis and / or treatment of a disease, wherein the vaccine is as described herein, and wherein the disease is a fibrotic disorder and / or a fibro-inflammatory disease, an inflammatory disease, a cancer, a cardiovascular disease, and / or a lung-related disorder.

[0471] It will be evident to the skilled person that, in some embodiments, a specific disease might be categorized in multiple ways. Thus, the skilled person will understand that the categories mentioned above are not to be considered as mutually exclusive

[0472] In some embodiments, the fibrotic disorder is: idiopathic pulmonary fibrosis (IFF), systemic sclerosis (scleroderma), liver fibrosis, cardiac fibrosis, renal fibrosis (kidney fibrosis), cystic fibrosis (CF), diabetic kidney disease (diabetic nephropathy), atrial fibrosis, Dupuytren's contracture, cirrhosis, myocardial fibrosis, interstitial lung disease (ILD), radiation-induced fibrosis, primary myelofibrosis (PMF), peritoneal fibrosis, Peyronie's disease, keloids, chronic pancreatitis, bronchiolitis obliterans, retroperitoneal fibrosis, and / or radiation or chemotherapy induced fibrosis.

[0473] In some embodiments, the fibro-inflammatory disease is idiopathic pulmonary fibrosis (I PF), systemic sclerosis (SSc), liver cirrhosis, chronic kidney disease (CKD), crohn's disease, ulcerative colitis, metabolic dysfunction-associated steatohepatitis (MASH), primary biliary cholangitis (PBC), chronic pancreatitis, rheumatoid arthritis (RA), psoriasis, atherosclerosis, heart failure with preserved ejection fraction (HFpEF), myocardial fibrosis, keloids and hypertrophic scarring, cystic fibrosis (CF), dupuytren's contracture, graves' ophthalmopathy, lymphangioleiomyomatosis (LAM), sarcoidosis (SAR), and / or drug-induced liver injury.

[0474] In some embodiments, the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, glioblastoma, bone cancer, skin cancer and uterine serous carcinoma.

[0475] In some embodiments, the lung-related disorder is idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD), asthma, lung cancer (NSCLC), acute lung injury (ALI), acute respiratory distress syndrome (ARDS). P7421 PC00

[0476] In an aspect, the present disclosure concerns a method of administering a vaccine for the prophylaxis and / or treatment of a disease in a subject in need thereof, comprising the step of i. administering at least one composition comprising the vaccine as described herein to a subject at least once for prophylaxis and / or treatment of a disease as described herein.

[0477] In an aspect, the present disclosure concerns a method of administering a vaccine to improve the lifespan of a subject, comprising the step of: i. administering at least one composition comprising the vaccine as described herein to a subject.

[0478] In an aspect, the present disclosure concerns a method of administering a vaccine to delay ageing of a subject, comprising the step of: i. administering at least one composition comprising the vaccine as described herein to a subject.

[0479] In some embodiments, the composition is boosted by administration in a form or body part different from the previous administration.

[0480] In some embodiments, the vaccine is administered to the area most likely to be the receptacle of a given disease.

[0481] In some embodiments, the antigen is capable of eliciting an immune reaction in an animal, such as a mammal, such as a Homo sapiens, a dog, a cat, a cow, a pig, a horse, a sheep, a goat, a llama, a mouse, a rat, a monkey, and / or a bird, such as a chicken and / or a fish, such as a salmon.

[0482] In some embodiments, the composition is administered in combination with any other vaccine.

[0483] In some embodiments, the composition forms a part of a vaccine cocktail.

[0484] Kits of parts

[0485] In an aspect, the present disclosure concerns a kit of parts comprising P7421 PC00 i. a vaccine as described herein, or an expression system as described herein, and ii. optionally, a medical instrument or other means for administering the vaccine, and iii. instructions for use.

[0486] In some embodiments, the kit of parts comprises a second active ingredient.

[0487] Isolation of the antigen and manufacture of the vaccine

[0488] In an aspect, the present disclosure concerns a method of isolating an antigen as described herein, said antigen being fused to a peptide tag as described herein, wherein the method comprises expressing said antigen fused to a peptide tag in a cell, such as the cell as described herein.

[0489] The skilled person will understand that any method known in the art which is suitable for isolating a polypeptide expressed by a cell might be employed to isolate the antigen described herein. This includes for example lysis of the host cell using mechanical, chemical, or enzymatic methods to release the expressed antigen. Depending on the nature of the host cell and expression system, methods such as sonication, bead milling, or the use of detergents or lysozyme may be employed to disrupt the cell membrane while preserving the structural integrity of the antigen.

[0490] Following cell lysis, techniques such as centrifugation or filtration may be used to separate soluble components from cell debris. The antigen fused to a peptide tag can then be isolated using affinity purification techniques, which exploit the specific binding properties of the tag. For instance, if the tag is a polyhistidine tag, immobilized metal affinity chromatography (IMAC) can be used.

[0491] In cases where the antigen forms inclusion bodies or insoluble aggregates, solubilization followed by refolding protocols may be applied to recover the antigen in its functional form. Further purification steps, such as size exclusion chromatography or ion exchange chromatography, may be employed to ensure the antigen meets the required purity standards for downstream applications. P7421 PC00

[0492] Alternative methods, including automated purification systems or cell-free expression platforms, may also be utilized depending on the scale and application of the antigen. These methods allow for scalability, reproducibility, and compliance with regulatory standards while ensuring that the antigen retains its intended structure and functionality.

[0493] In an aspect, the present disclosure concerns a method of manufacturing the vaccine as described herein, comprising the step of: i. Providing an expression system as described herein; and ii. Recovering the vaccine.

[0494] The skilled person will understand that any method known in the art which is suitable for manufacturing a vaccine might be employed. This includes for example methods involving recombinant protein expression in host cells, such as bacterial, yeast, insect, or mammalian cells, followed by purification steps to isolate the antigen or antigenic particle. The expression system may be configured to ensure proper folding, post- translational modifications, and assembly of the antigen or antigen-particle complex to maintain immunogenicity and structural fidelity.

[0495] In addition to traditional expression and purification techniques, advanced methodologies such as cell-free expression systems or in vivo assembly of nanoparticles may also be employed. Downstream processes, including chromatographic purification, ultrafiltration, and sterile filtration, may be utilized to ensure the final vaccine product meets required purity and safety standards.

[0496] Furthermore, techniques such as encapsulation, lyophilization, or formulation into nanoparticles or lipid vesicles might be applied to enhance the vaccine’s stability, delivery, or immunogenic efficacy. The method of manufacturing may be tailored to the specific antigen and its intended application, ensuring scalability, reproducibility, and compliance with regulatory requirements for vaccine production.

[0497] Methods for manufacturing a vaccine targeting IL-11

[0498] Also disclosed herein is a method of manufacturing a vaccine targeting IL-11, comprising the steps of: P7421 PC00 a) Designing an antigen sequence comprising an epitope or mimotope of IL-11 and is a sequence derived from IL-11 which binds and activates IL-11 Ra but does not bind or activate gp130 nor the IL-11Ra / gp130 complex; b) Producing a polynucleotide encoding the antigen or producing a polypeptide comprising or consisting of the antigen; c) Formulating the polynucleotide or the polypeptide as a vaccine.

[0499] All the elements of such vaccines have been described herein above. In some embodiments, the vaccine comprises a particle-forming protein comprising a first peptide tag, and the vaccine comprises the antigen fused to a second peptide tag.

[0500] In some embodiments the antigen comprises a scaffold protein, which can be designed for instance using RFdiffusion, ProteinMPNN or glycan masking strategies, as described herein elsewhere.

[0501] Items

[0502] 1. A vaccine comprising: i. a particle-forming protein comprising a first peptide tag, and ii. an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of lnterleukin-11 (IL-11), wherein the antigen and particle-forming protein are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, and wherein i - ii form a particle displaying said antigen.

[0503] 2. A vaccine comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of Interleukin- 11 (IL-11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, and thereby forming a particle displaying said antigen. P7421 PC00

[0504] 3. The vaccine according to any one of the preceding items, wherein the epitope is a conformational epitope of Interleukin-11 (IL-11).

[0505] 4. The vaccine according to any one of the preceding items, wherein the antigen and / or the epitope / mimotope does not bind to gp130 and induces antibodies preventing interaction of IL-11 with IL-11 Ra, preferably the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra and / or the antigen and / or the epitope / mimotope binds to IL-11 Ra.

[0506] 5. The vaccine according to any one of the preceding items, wherein the antigen further comprises a scaffold protein comprising the epitope or mimotope.

[0507] 6. The vaccine according to any one of the preceding items, wherein the scaffold protein has a length of 100 to 300 amino acids, such as 100 to 200 amino acids, such as 110 to 190 amino acids, such as 120 to 180 amino acids, such as 130 to 170 amino acids, such as 140 to 160 amino acids, such as around 150 amino acids, or such as 100 to 190 amino acids, 100 to 180 amino acids, 100 to 170 amino acids, 100 to 160 amino acids, 100 to 150 amino acids, 100 to 140 amino acids, 100 to 130 amino acids, 100 to 120 amino acids, such as around 110 amino acids, around 120 amino acids, around 130 amino acids, around 140 amino acids, around 150 amino acids, around 160 amino acids, around 170 amino acids; or such as 200 to 300 amino acids, such as 210 to 290 amino acids, such as 220 to 280 amino acids, such as 230 to 270 amino acids, such as 240 to 260 amino acids, such as around 250 amino acids, or such as 200 to 290 amino acids, 200 to 280 amino acids, 200 to 270 amino acids, 200 to 260 amino acids, 200 to 250 amino acids, 200 to 240 amino acids, 200 to 230 amino acids, 200 to 220 amino acids, such as around 210 amino acids, around 220 amino acids, around 230 amino acids, around 240 amino acids, around 250 amino acids, around 260 amino acids or around 280 amino acids.

[0508] 7. The vaccine according to any one of the preceding items, wherein the antigen and / or the epitope / mimotope comprises the residues or regions of IL-11 which bind to IL-11 Ra. P7421 PC00

[0509] 8. The vaccine according to any one of the preceding items, wherein the antigen and / or the epitope / mimotope does not comprise the residues or regions of IL-11 which bind to gp130.

[0510] 9. The vaccine according to any one of the preceding items, wherein the scaffold protein has a sequence designed using RFdiffusion.

[0511] 10. The vaccine according to any one of the preceding items, wherein the scaffold protein is a scrambled sequence, such as scrambled using ProteinMPNN.

[0512] 11. The vaccine according to any one of the preceding items, wherein the scaffold protein comprises an amino acid sequence to which glycans have been conjugated.

[0513] 12. The vaccine according to any one of the preceding items, wherein IL-11 is as set forth in SEQ ID NO: 45, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

[0514] 13. The vaccine according to any one of the preceding items, wherein the antigen comprises: SEQ ID NO: 49; SEQ ID NO: 50; and / or SEQ ID NO: 51, or immunogenic fragments thereof.

[0515] 14. The vaccine according to any one of the preceding items, wherein the antigen comprises the full-length sequence of IL-11 as set forth in SEQ ID NO: 45; a sequence having at least 95% identity to SEQ ID NO: 45 such as 96%, 97%, 98% or 99% sequence identity thereto, or one or more immunogenic fragments thereof.

[0516] 15. The vaccine according to any one of the preceding items, wherein the antigen is a scaffold, such as minimal scaffold, comprising a conformational epitope of Interleukin-11 (IL-11).

[0517] 16. The vaccine according to any one of the preceding items, wherein the epitope comprises one or more residues of site / of IL-11, preferably wherein IL-11 is as set forth in SEQ ID NO: 45. P7421 PC00

[0518] 17. The vaccine according to any one of the preceding items, wherein the epitope comprises a residue of IL-11 as set forth in SEQ ID NO: 45, wherein the residue is: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu 173.

[0519] 18. The vaccine according to any one of the preceding items, wherein the epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0520] 19. The vaccine according to any one of the preceding items, wherein the epitope comprises, wherein 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues are selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu 173.

[0521] 20. The vaccine according to any one of the preceding items, wherein the epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the two or more residues maintain the same spatial arrangement between each other as in the three-dimensional structure of IL-11 , wherein IL-11 is as set forth in SEQ ID NO: 45.

[0522] 21 . The vaccine according to any one of the preceding items, wherein the conformational epitope comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the Root Mean Square Deviation (RMSD) of the two or more residues within the three-dimensional structure the antigen and the corresponding two or more residues within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1.9 A, such as less than 1.8 A, 1 .7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.2, such as less than 1 A, wherein IL-11 is as set forth in SEQ ID NO: 45. P7421 PC00

[0523] 22. The vaccine according to any one of the preceding items, wherein the conformational epitope comprises: i. Asp165; Trp166; Arg169; Leu172; or Leu173 ii. Met59; Ala61 ; Gly62; Leu64; Leu67; and / or iii. Arg75.

[0524] 23. The vaccine according to any one of the preceding items, wherein the conformational epitope comprises: i. SEQ ID NO: 49; ii. SEQ ID NO: 51 ; and / or iii. SEQ ID NO: 52

[0525] 24. The vaccine according to any one of the preceding items, wherein the epitope is a conformational epitope of IL-11 as set forth in SEQ ID NO: 45, wherein the epitope comprises: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0526] 25. The vaccine according to any one of the preceding items, wherein the antigen does not comprise an amino acid residue of site II or site III of IL-11.

[0527] 26. The vaccine according to any one of the preceding items, wherein the antigen comprises one or more of: a) the region corresponding to residues 158 to 178 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 49; b) the region corresponding to residues 43 to 65 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 50; and c) a region corresponding to residues 66 to 71 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 52, or immunogenic fragments thereof.

[0528] 27. The vaccine according to any one of the preceding items, wherein the antigen does not comprise: SEQ ID NO: 53 and / or SEQ ID NO: 54. P7421 PC00

[0529] 28. The vaccine according to any one of the preceding items, wherein the antigen does not comprise: Arg111 ; Arg114; Leu115, Arg117; Arg118; Ser145; Trp147; or Arg151.

[0530] 29. The vaccine according to any one of the preceding items, wherein the antigen does not comprise one or more of: Arg111 ; Arg114; Leu115; Arg117; Arg118; Ser145; Trp147; or Arg151 .

[0531] 30. The vaccine according to any one of the preceding items, wherein the antigen does not comprise any one of: Arg111 ; Arg114; Leu115, Arg117; Arg118; Ser145; Trp147; and Arg151.

[0532] 31 . The vaccine according to any one of the preceding items, wherein the antigen does not comprise site II or site III of IL-11.

[0533] 32. The vaccine according to any one of the preceding items, wherein the antigen does not comprise a polypeptide consisting of the region defined by residues 20 to 27 of SEQ ID NO: 45, or a polypeptide corresponding to the region defined by residues 20 to 27 of SEQ ID NO: 45, nor immunogenic fragments thereof.

[0534] 33. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies specific to IL-11.

[0535] 34. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 , wherein the conformational epitope comprises one or more of: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu173.

[0536] 35. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies which have affinity for a conformational epitope of IL-11 , wherein the conformational epitope comprises two or more residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues, selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173. P7421 PC00

[0537] 36. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises one or more of: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; or Leu173.

[0538] 37. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises two or more residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues, selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

[0539] 38. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies which have affinity for, and / or are capable to bind to, a conformational epitope of IL-11 , wherein the conformational epitope comprises: i. Asp165; Trp166; Arg169; Leu172; or Leu173 ii. Met59; Ala61 ; Gly62; Leu 64; Leu67; and / or iii. Arg75.

[0540] 39. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies which have affinity for, and / or are capable to bind to, a conformational epitope of IL-11 , wherein the conformational epitope comprises: i. SEQ ID NO: 49; ii. SEQ ID NO: 50; and / or iii. SEQ ID NO: 51.

[0541] 40. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies which have an affinity for IL-11 which is at least 2-fold, 3-fold, 5-fold, 10-fold greater than the affinity for one or more of: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin- P7421 PC00 like cytokine factor 1 (CLC or CLCFI); Neuropoietin; Interleukin-27 (IL-27); and / or Interleukin-31 (IL-31).

[0542] 41. The vaccine according to any one of the preceding items, wherein the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66,

[0543] SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76,

[0544] SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86,

[0545] SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO:

[0546] 96.

[0547] 42. The vaccine according to any one of the preceding items, wherein the first or second peptide tag is fused to the N-terminal end of the antigen.

[0548] 43. The vaccine according to any one of the preceding items, wherein the vaccine is not cross-reactive.

[0549] 44. The vaccine according to any one of the preceding items, wherein the vaccine is not capable of inducing in a subject one or more antibodies which bind to: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCFI); Neuropoietin; Interleukin-27 (IL-27); and / or Interleukin-31 (IL-31).

[0550] 45. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing one or more antibodies which have a Kd (Dissociation Constant) for IL-11 which is at least 2-fold, 3-fold, 5-fold, 10-fold lower, 50-fold lower, 100-fold lower, 200-fold lower, 500-fold lower, 1000 fold lower, than the Kd for one or more of: lnterleukin-6 (IL-6); Leukemia inhibitory factor (LIF); Oncostatin M (OSM); Ciliary neurotrophic factor (CNTF); Cardiotrophin-1 (CT-1); Cardiotrophin-like cytokine factor 1 (CLC or CLCFI); Neuropoietin; Interleukin-27 (IL-27); and / or Interleukin-31 (IL-31).

[0551] 46. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing one or more antibodies which are not capable of binding to site P7421 PC00

[0552] II of IL-11 , preferably wherein site II is as set forth in SEQ ID NO: 53, and / or site III of IL-11 , preferably wherein site III is as set forth in SEQ ID NO: 54.

[0553] 47. The vaccine according to any one of the preceding items, wherein the vaccine is capable of inducing in a subject one or more antibodies, and wherein the Kd (Dissociation constant) of IL-11 to gp130 in the subject is increased no more than 10%, such as 5%, such as 4%, 3%, 2%, 1 %, 0.5%, 0.1% compared to the Kd of IL- 11 to gp130 in the absence of said antibodies.

[0554] 48. The vaccine according to any one of the preceding items, wherein the vaccine does not induce, or has a decreased risk of inducing, an IL-11 specific T-cell response in a subject.

[0555] 49. The vaccine according to any one of the preceding items, wherein the particle is a nanoparticle.

[0556] 50. The vaccine according to any one of the preceding items, wherein the protein is a particle forming protein.

[0557] 51. The vaccine according to any one of the preceding items, wherein the protein is a particle forming protein having at least 70% sequence identity, such as 75%, such as 80%, such as 85%, such as 90%, such as 95% such as 99%, such as 100% sequence identity to:

[0558] MsDps2 as set forth in SEQ ID NO: 33;

[0559] AP205 as set forth in SEQ ID NO: 34; ferritin as set forth in SEQ ID NO: 35; i301 as set forth in SEQ ID NO: 36; replicase polyprotein 1a (pp1a); a lumazine synthase as set forth in SEQ ID NO: 38;

[0560] Hbc as set forth in SEQ ID NO: 39; tandemHBc as set forth in SEQ ID NO: 40; the 2-oxo acid dehydrogenase subunit E2 as set forth in SEQ ID NO: 41 ; or the norovirus capsid protein as set forth in SEQ ID NO: 42. P7421 PC00

[0561] 52. The vaccine according to any one of the preceding items, wherein the particle is a virus-like particle.

[0562] 53. The vaccine according to any one of the preceding items, wherein the protein is a viral capsid protein or a viral envelope protein such as a glycoprotein.

[0563] 54. The vaccine according to any one of the preceding items, wherein the first or the second peptide tag is: SpyTag (SEQ ID NO: 1); SdyTag (SEQ ID NO: 2); SnoopTag (SEQ ID NO: 3); PhoTag (SEQ ID NO: 4); EntTag (SEQ ID NO: 5); RumTag (SEQ ID NO: 6); Rum2Tag (SEQ ID NO: 7); Rum3Tag (SEQ ID NO: 8); Rum4Tag (SEQ ID NO: 9); Rum5Tag (SEQ ID NO: 10); Rum6Tag (SEQ ID NO: 11); Rum7Tag (SEQ ID NO: 12); Rumtrunk D9N (SEQ ID NO: 13); RumTrunkTag (SEQ ID NO: 14); BacTag (SEQ ID NO: 15); Bac2Tag (SEQ ID NO: 16); Bac3Tag (SEQ ID NO: 17); Bac4Tag (SEQ ID NO: 18); Bac5Tag (SEQ ID NO: 19); PsCsTag (SEQ ID NO: 20); Clib9 (SEQ ID NO: 21); Ktag (SEQ ID NO: 65) or a fragment thereof having at least 70% homology or identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said fragments comprise the reactive residue involved in the formation of the isopeptide bond, or wherein where the reactive residue is an Aspartic acid (D), the reactive residue is mutated to an Asparagine (N).

[0564] 55. The vaccine according to any one of the preceding items, wherein the first or the second peptide tag is: SpyCatcher (SEQ ID NO: 23); Spycatcherv2 (SEQ ID NO: 24); Spycatcherv3 (SEQ ID NO: 25); SdyCatcher (SEQ ID NO: 26); SnoopCatcher (SEQ ID NO: 27); MoonCake (SEQ ID NO: 28); Katl (SEQ ID NO: 29); QueenCatcher (SEQ ID NO: 30); PsCsCatcher (SEQ ID NO: 31); or fragments thereof having at least 70% identity thereto, such as at least 75%, such as at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such P7421 PC00 as at least 91 %, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% identity thereto, with the proviso that said fragments comprise the reactive residue involved in the formation of the isopeptide bond, or wherein where the reactive residue is an Aspartic acid (D), the reactive residue is mutated to an Asparagine (N).

[0565] 56. The vaccine according to any one of the preceding items wherein the isopeptide bond between the first and second peptide tag is an isopeptide bond between: i. SEQ ID NO: 27 (MoonCake) and a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); or variants thereof having at least 70% homology or identity thereto; and / or ii. SEQ ID NO: 28 (Katl) and a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); P7421 PC00 e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); or variants thereof having at least 70% homology or identity thereto; and / or iii. SEQ ID NO: 29 (QueenCatcher) and a) SEQ ID NO: 13 (RumTrunkD9NTag); b) SEQ ID NO: 12 (Rum7Tag); c) SEQ ID NO: 8 (Rum3Tag); d) SEQ ID NO: 7 (Rum2Tag); e) SEQ ID NO: 9 (Rum4Tag); f) SEQ ID NO: 10 (Rum5Tag); g) SEQ ID NO: 11 (Rum6Tag); h) SEQ ID NO: 14 (RumTrunkTag); i) SEQ ID NO: 1 (SpyTag); j) SEQ ID NO: 2 (SdyTag); k) SEQ ID NO: 6 (RumTag); l) SEQ ID NO: 15 (BacTag); m) SEQ ID NO: 16 (Bac2Tag); n) SEQ ID NO: 17 (Bac3Tag); o) SEQ ID NO: 18 (Bac4Tag); or p) SEQ ID NO: 19 (Bac5Tag); q) SEQ ID NO: 21 (Clib9); P7421 PC00 or variants thereof having at least 70% homology or identity thereto.

[0566] 57. The vaccine according to any one of the preceding items, wherein the first and / or second polynucleotide is DNA.

[0567] 58. The vaccine according to any one of the preceding items, wherein the first and / or second polynucleotide is RNA.

[0568] 59. The vaccine according to item 59, wherein the RNA is formulated in a lipid particle formulation.

[0569] 60. The vaccine according to any one of the preceding items, wherein one or more first peptide tags are fused to the N-terminal end, to the C-terminal end of the protein and / or inserted in-frame into the coding sequence of the protein, optionally by a linker.

[0570] 61. The vaccine according to any one of the preceding items, wherein one or more second peptide tags are fused to the N-terminal end, to the C-terminal end of the antigen and / or inserted in-frame into the coding sequence of the antigen, optionally by a linker.

[0571] 62. The vaccine according to any one of of the preceding items, wherein the first polynucleotide further comprises a secretion or excretion signal, whereby the protein fused to the first peptide tag is secreted or excreted from the endoplasmic reticulum of the cell.

[0572] 63. The vaccine according to item 62, wherein the secretion or excretion signal comprises or consists of MGSAALLLWVLLLWVPGSNG (SEQ ID NO: 44).

[0573] 64. The vaccine according to any one of the preceding items, wherein the antigen further comprises a polyhistidine tag or a cTag.

[0574] 65. The vaccine according to any one of the preceding items, wherein the antigen fused to a second peptide tag comprises: P7421 PC00 i. SEQ ID NO: 55; ii. SEQ ID NO: 56; iii. SEQ ID NO: 57; iv. SEQ ID NO: 58; or v. SEQ ID NO: 59

[0575] 66. The vaccine according to any one of the preceding items, wherein the second polynucleotide comprises: i. SEQ ID NO: 60; ii. SEQ ID NO: 61 ; iii. SEQ ID NO: 62; iv. SEQ ID NO: 63; or v. SEQ ID NO: 64.

[0576] 67. The vaccine according to any one of the preceding items, wherein the antigen is capable of eliciting an immune reaction in an animal, such as a mammal, such as a Homo sapiens, cow, pig, horse, sheep, goat, llama, mouse, rat, monkey, and / or a bird, such as a chicken and / or a fish, such as a salmon.

[0577] 68. A vaccine for use in medicine, wherein the vaccine is according to any one of the preceding items.

[0578] 69. A vaccine for use in the prophylaxis and / or treatment of a disease, wherein the vaccine is according to any one of the preceding items, and wherein the disease is a fibrotic disorder and / or a fibro-inflammatory disease, an inflammatory disease, a cancer, a cardiovascular disease, and / or a lung-related disorder.

[0579] 70. The vaccine for the use according to item 69, wherein the fibrotic disorder is: idiopathic pulmonary fibrosis (I PF), systemic sclerosis (scleroderma), liver fibrosis, cardiac fibrosis, renal fibrosis (kidney fibrosis), cystic fibrosis (CF), diabetic kidney disease (diabetic nephropathy), atrial fibrosis, Dupuytren's contracture, cirrhosis, myocardial fibrosis, interstitial lung disease (ILD), radiation-induced fibrosis, primary myelofibrosis (PMF), peritoneal fibrosis, Peyronie's disease, keloids, chronic pancreatitis, bronchiolitis obliterans, retroperitoneal fibrosis, and / or radiation or chemotherapy induced fibrosis. P7421 PC00

[0580] 71 . The vaccine for the use according to item 69, wherein the fibro-inflammatory disease is idiopathic pulmonary fibrosis (IFF), systemic sclerosis (SSc), liver cirrhosis, chronic kidney disease (CKD), crohn's disease, ulcerative colitis, metabolic dysfunction-associated steatohepatitis (MASH), primary biliary cholangitis (PBC), chronic pancreatitis, rheumatoid arthritis (RA), psoriasis, atherosclerosis, heart failure with preserved ejection fraction (HFpEF), myocardial fibrosis, keloids and hypertrophic scarring, cystic fibrosis (CF), dupuytren's contracture, graves' ophthalmopathy, lymphangioleiomyomatosis (LAM), sarcoidosis (SAR), and / or drug-induced liver injury.

[0581] 72. The vaccine for the use according to item 69, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, glioblastoma, bone cancer, skin cancer and uterine serous carcinoma.

[0582] 73. The vaccine for the use according to item 69, wherein the lung-related disorder is idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD), asthma, lung cancer (NSCLC), acute lung injury (ALI), acute respiratory distress syndrome (ARDS).

[0583] 74. A method for prevention or treatment of a disease, comprising administering to a subject in need thereof a vaccine according to any one of the preceding items, optionally wherein the disease is a fibrotic disorder and / or a fibro-inflammatory disease, an inflammatory disease, a cancer, a cardiovascular disease, and / or a lung-related disorder.

[0584] 75. The method according to item 74, wherein the fibrotic disorder is: idiopathic pulmonary fibrosis (IPF), systemic sclerosis (scleroderma), liver fibrosis, cardiac fibrosis, renal fibrosis (kidney fibrosis), cystic fibrosis (CF), diabetic kidney disease (diabetic nephropathy), atrial fibrosis, Dupuytren's contracture, cirrhosis, myocardial fibrosis, interstitial lung disease (ILD), radiation-induced fibrosis, primary myelofibrosis (PMF), peritoneal fibrosis, Peyronie's disease, keloids, chronic pancreatitis, bronchiolitis obliterans, retroperitoneal fibrosis, and / or radiation or chemotherapy induced fibrosis. P7421 PC00

[0585] 76. The vaccine for the use according to any one of items 74 to 75, wherein the fibro- inflammatory disease is idiopathic pulmonary fibrosis (I PF), systemic sclerosis (SSc), liver cirrhosis, chronic kidney disease (CKD), crohn's disease, ulcerative colitis, metabolic dysfunction-associated steatohepatitis (MASH), primary biliary cholangitis (PBC), chronic pancreatitis, rheumatoid arthritis (RA), psoriasis, atherosclerosis, heart failure with preserved ejection fraction (HFpEF), myocardial fibrosis, keloids and hypertrophic scarring, cystic fibrosis (CF), dupuytren's contracture, graves' ophthalmopathy, lymphangioleiomyomatosis (LAM), sarcoidosis (SAR), and / or drug-induced liver injury.

[0586] 77. The vaccine for the use according to any one of items 74 to 76, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, glioblastoma, bone cancer, skin cancer and uterine serous carcinoma.

[0587] 78. The vaccine for the use according to any one of items 74 to 77, wherein the lung- related disorder is idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD), asthma, lung cancer (NSCLC), acute lung injury (ALI), acute respiratory distress syndrome (ARDS).

[0588] 79. An expression system such as a vector comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide bond or an ester bond between the first and second peptide tag, thereby forming a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL- 11 Ra, but does not bind to gp130.

[0589] 80. The expression system according to item 79, wherein the first peptide tag, the second peptide tag, the protein and / or the antigen are as defined in any one of items 2 to Fejl! Henvisningskilde ikke fundet. P7421 PC00

[0590] 81. The expression system according to any one of items 79 to 80, wherein the first polynucleotide and the second polynucleotide are comprised within the same nucleic acid molecule, or within two different nucleic acid molecules.

[0591] 82. The expression system according to any one of items 79 to 81 , wherein the first polynucleotide and the second polynucleotide are both DNA polynucleotides or RNA polynucleotides.

[0592] 83. The expression system according to any one of items 79 to 82, wherein the first and second polynucleotides are comprised within one vector such as a viral vector or a plasmid, or wherein the first and second polynucleotides are comprised within two vectors such as two viral vectors; two plasmids; or one viral vector and one plasmid.

[0593] 84. The expression system according to item 83, wherein the viral vector is an adenoviral vector, such as a modified adenoviral vector, e.g. the replicationdeficient simian adenovirus vector ChAdOxI, or a modified vaccinia Ankara (MVA) vector.

[0594] 85. The expression system according to any one of items 79 to 84, wherein the expression system comprises or consists of a plasmid.

[0595] 86. The expression system according to any one of items 79 to 85, wherein the expression system comprises or consists of an mRNA.

[0596] 87. A cell expressing: i. a first polynucleotide encoding a particle-forming protein fused to a first peptide tag, preferably as defined in any one of the preceding items; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and the particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first peptide tag and the second peptide tag, thereby forming a particle displaying said antigen, P7421 PC00 preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to I L-11 Ra, but does not bind to gp130.

[0597] 88. The cell according to item 87, comprising the expression system according to any one of items 2 to 67.

[0598] 89. A host cell, wherein the host cell comprises an expression system according to any one of items 79 to 86.

[0599] 90. The host cell according to item 90, wherein the host cell is a bacterial cell, a yeast cell, a fungal cell, a plant cell, a mammalian cell, or an insect cell.

[0600] 91 . A method of administering a vaccine for the prophylaxis and / or treatment of a disease in a subject in need thereof, comprising the step of i. administering at least one composition as defined in any one of items 1 to 67 to a subject at least once for prophylaxis and / or treatment of a disease as defined in any one of the preceding items.

[0601] 92. The method of administering a vaccine for the use according to item 91 , wherein the composition is boosted by administration in a form or body part different from the previous administration.

[0602] 93. The method of administering a composition for the use according to any one of items 91 to 92, wherein the vaccine is administered to the area most likely to be the receptacle of a given disease.

[0603] 94. The method of administering a vaccine for the use according to any one of items 91 to 93, wherein the subject is an animal, such as a mammal, such as a cow, pig, horse, sheep, goat, llama, mouse, rat, monkey, most preferably such as a human being; or a bird, such as a chicken or a fish, such as a salmon.

[0604] 95. The method of administering a vaccine for the use according to any one of items 91 to 94, wherein the composition is administered in combination with any other vaccine. P7421 PC00

[0605] 96. The method of administering a vaccine for the use according to any one of items 91 to 95, wherein the composition forms a part of a vaccine cocktail.

[0606] 97. A kit of parts comprising i. a vaccine as defined in any one of the preceding items or an expression system according to any one of items 79 to 86, and ii. optionally, a medical instrument or other means for administering the vaccine, and iii. instructions for use.

[0607] 98. The kit of parts according to item 97, comprising a second active ingredient.

[0608] 99. A method of manufacturing a vaccine targeting IL-11 , comprising the steps of: a) Designing an antigen sequence, wherein the antigen comprises an epitope or mimotope of IL-11 and is a sequence derived from IL-11 which binds and activates IL-11 Ra, but does not bind to or activate gp130; b) Producing a polynucleotide encoding the antigen or producing a polypeptide comprising or consisting of the antigen; c) Formulating the polynucleotide or the polypeptide as a vaccine.

[0609] 100. The method according to item 99, wherein the vaccine comprises a particle-forming protein comprising a first peptide tag, and wherein the vaccine comprises the antigen fused to a second peptide tag.

[0610] 101. The method according to any one of items 99 to 100, wherein the antigen, the epitope, the mimotope, the vaccine, the first peptide tag and the second peptide tags are as defined in any one of items 1 to 98.

[0611] 102. The method according to any one of items 99 to 101 , wherein the antigen comprises a scaffold protein, and wherein step a) comprises designing the scaffold protein using RFdiffusion, Prate in MP NN or glycan masking. P7421 PC00

[0612] 103. A method of manufacturing the vaccine according to any one of the preceding items, comprising the step of: i. Providing an expression system as defined in any one of items 79 to 86.

[0613] Examples

[0614] Example 1 : Recombinant expression of IL-11 antigens in different expression systems.

[0615] As shown in figure 1A-C, the inventors of the present invention successfully expressed and purified IL-11 antigens of different origins (murine, mulL11 , and guinea pig, gpl L11) in different eukaryotic expression systems (insect and human cells). To mediate VLP display, the IL-11 antigens were designed with a split-protein Catcher binding-partner (Mooncake). For purification, the IL-11 antigens contained a hexahistidine tag for affinity chromatography.

[0616] Example 2: Vaccine formulation of murine IL-11.

[0617] Mixing of Mooncake-mulL11 to RumtrunkD9N-VLP (AP205) enables unidirectional display of mulL11 on VLPs. The vaccine was purified by density gradient ultracentrifugation, where VLP-mulL11 located to post-UC gradient fractions 4-5, which is expected to contain particulate structures (figure 2A). DLS demonstrated a homogeneous vaccine sample with particles of ~65nm (figure 2B). A spin stability test demonstrated that the vaccine was stable (non aggregating) in solution (figure 2C, lane 1-2). Densitometry analysis estimated the antigen coupling efficiency to be -30%, corresponding to approximately 54 mulL-11 antigens per VLP (figure 2C).

[0618] Example 3: Vaccine formulation of guinea pig IL-11.

[0619] Mixing of Mooncake-gplL11 to RumtrunkD9N-VLP (AP205) enables unidirectional display of gpl L11 on VLPs. The vaccine was purified by density gradient, where VLP- mulL11 located to gradient fractions 5-7, which are expected to contain particulate structures (figure 3A). DLS demonstrate a homogeneous vaccine sample with particles of ~45nm (figure 3B). A spin stability test demonstrated that the vaccine was stable (i.e. not aggregating) in solution (figure 3C, lane 1-4). Densitometry analysis estimated the antigen coupling efficiency to be -33%, corresponding to approximately 60 gplL-11 antigens per VLP (figure 3C). P7421 PC00

[0620] Example 4 : Induction of IL-11 specific antibodies in mice.

[0621] Balb / c mice were immunized in a 2-week prime-boost-boost (total of 3 doses) regimen with two different doses of the murine IL-11 vaccine (2.75pg (n=8) or 1 pg (n=4) of VLP-displayed IL-11 antigen per dose exploiting the Mooncake-RumtrunkD9N split protein binding pair). As a control, mice were immunised with 3pg non-displayed Mooncake-mulL11 (n=4). All vaccines were formulated with extrinsic adjuvant (Addavax). Blood samples were taken 10 days after each immunization. The data demonstrate that all mice immunized with the VLP-IL-11 vaccine seroconverted and produced high levels of murine IL-11 -specific antibodies. Furthermore, no statistically significant difference in antibody levels was observed between the 2.75 pg and 1 pg doses. In contrast, mice immunized with the nondisplayed murine IL-11 antigen generated very low levels of IL-11 -specific antibodies (Fig. 4A-B). For detection, a maltose-binding protein (MBP)-fusion of murine IL-11 (MBP-mulL-11) was used. Figure 4C illustrates that the antibodies binding to the MBP- mulL-11 protein are specifically directed against IL-11, as confirmed by comparison with a commercial recombinant murine IL-11 protein.

[0622] Antibody levels are presented as the area under the curve (AUC) and expressed as mean ± standard deviation (SD)."

[0623] Female guinea pigs (n=4) were immunized using a 3-week prime-boost-boost-boost regimen (a total of four doses) with a guinea pig IL-11 vaccine. Each dose contained 10 pg of IL-11 displayed VLP RumtrunkD9N-AP205 and was administered without an extrinsic adjuvant. Blood samples were collected on the day of each immunization. As a control, blood samples from a naive guinea pig of similar age were analyzed in parallel. The levels of IL-11 -specific antibodies in the serum of immunized guinea pigs were quantified and represented as the area under the curve (AUC), expressed as mean ± standard deviation (SD).

[0624] The results demonstrate that the IL-11 vaccine successfully overcame immune tolerance in guinea pigs, inducing high levels of guinea pig IL-11 -specific antibodies after just two doses. Repeated immunizations maintained a high level of circulating IL- 11 -specific antibodies. No IL-11 -specific antibodies were detected in blood samples from the non-vaccinated control guinea pig. P7421 PC00

[0625] Example 6: Induction of IL-11 -Specific Antibodies in Guinea Pigs Using the MASH Model.

[0626] Female guinea pigs were immunized following a 3-week immunization schedule over a 25-week period. Throughout the study, all animals were maintained on a high-fat diet. IL-11 -specific antibody levels in serum were measured from guinea pigs immunized with one of the following regimens (for all groups, RumtrunkD9N-AP205 was used as the VLP and the antigen was Mooncake-gplL11):

[0627] 1. VLP-gplL11 (6.5 pg IL-11) (n=5),

[0628] 2. VLP only (5.5 pg, matching the VLP dose in the VLP-gplL11 group) (n=5),

[0629] 3. Prime with VLP, boost with VLP-gplL11, followed by continuous booster immunizations with VLP (n=3) (representing a single-dose immunization protocol),

[0630] 4. Prime with VLP-gplL11, boost with VLP, followed by continuous booster immunizations with VLP-gplL11 (n=3) (representing a 6-week prime-boost interval, with subsequent 3-week booster intervals).

[0631] All antibody levels were quantified as the area under the curve (AUC) and expressed as mean ± standard deviation (SD). All vaccines were formulated with the extrinsic adjuvant Addavax. Blood samples were collected on each day of immunization.

[0632] The results demonstrate that the IL-11 vaccine effectively overcame immune tolerance in guinea pigs fed a high-fat diet, inducing high levels of IL-11 -specific antibodies after only two doses of the VLP-gplL11 vaccine, regardless of whether the prime-boost interval was 3 or 6 weeks. Guinea pigs receiving a single dose of the VLP-gplL11 vaccine seroconverted, although they exhibited lower overall levels of I L-11 -specific antibodies compared to those receiving multiple administrations. No IL-11 -specific antibodies were detected in guinea pigs immunized with VLP only. Induction of high levels of IL-11 specific antibodies in guinea pigs, are further supported by Fig. 19B, showing the IL-11 specific antibody response measured in guinea pigs throughout the 25 week study.

[0633] Example 7: Coupling of IL-11 Antigen to Nanoparticles and Secretion of Antigen:Nanoparticle Complexes In Vitro.

[0634] HEK293TT cells were either singly or co-transfected with DNA encoding (1) a nanoparticle genetically fused to a split-protein (RumtrunkDD) and (2) a murine IL-11 P7421 PC00

[0635] (mulL11) antigen genetically fused to a split-protein Catcher (SpyCatcher or Mooncake). Three days post-transfection, cell fractions (C) and supernatants (S) were collected for analysis via Western blot, using anti-l L11 antibodies (Figure 7A) or SpyC- mi3 antibodies (Figures 7B and 7C) for detection.

[0636] The results demonstrate that HEK293TT cells transfected with Catcher-mulL11 successfully expressed and secreted the antigen (Figures 7A and 7B). Additionally, cotransfection with a Tagged nanoparticle (NP) resulted in the coupling of the Catcher- mulL11 antigen to the NP, forming an antigen:NP complex that was subsequently secreted. The tested nanoparticles included mi3, LS, E2, Norovirus, and encapsulin.

[0637] Example 8: Induction of IL-11 -Specific Autoantibodies in Mice via DNA Immunization with Catcher-mu I L11 and SpyTag-Nanoparticles.

[0638] BALB / c mice were immunized using a 3-week prime-boost-boost regimen (three doses total) with 60 pg of DNA (30 pg encoding the antigen + 30 pg encoding the nanoparticle). The groups included: SpyTag-LS + SpyCatcher-mulL11 (n=6), SpyTag- Encapsulin + Catcher-mulL11 (n=6), and unconjugated SpyCatcher-mulL11 (n=4). Blood samples were collected 10 and 21 days after each immunization.

[0639] Results:

[0640] 1 . After one immunization: Seroconversion was observed in only one mouse immunized with DNA encoding SpyTag-Encapsulin + SpyCatcher-mulL11 after 20 days (Figure 9A).

[0641] 2. After the second and third doses: o All mice immunized with nanoparticle-displayed SpyCatcher-mulL11 (both SpyTag-LS and SpyTag-Encapsulin) seroconverted and produced IL-11 -specific autoantibodies. o Antibody levels increased significantly after the third immunization (fifth and final bleed) compared to the second immunization (third and fourth bleeds).

[0642] 3. Mice immunized with unconjugated SpyCatcher-mulL11 failed to seroconvert and did not produce IL-11 -specific antibodies.

[0643] 4. Comparison to protein-based vaccine: Serum from mice immunized with three doses of a protein-based VLP-mulL11 vaccine (2.75 pg IL-11 dose) was analyzed in parallel as a control ("C"). Antibody levels induced by the DNA P7421 PC00 vaccine were significantly lower than those induced by the protein-based IL-11 vaccine.

[0644] These results demonstrate that DNA vaccines encoding SpyCatcher-mulL11 coupled to SpyTag-nanoparticles successfully overcome immune tolerance and induce IL-11- specific autoantibodies in mice, with nanoparticle display being critical for immunogenicity.

[0645] Example 9: cVLP-gplL11(FL) vaccine reduce hepatic fibrosis in a guinea pig MASH model

[0646] Female guinea pigs were immunized in a 3-week immunization regime over the course of 25 weeks with 1) cVLP (5.5 pg, corresponding to the VLP dose in the VLP-gplL11 group) (n=5), 2) VLP-gplL11 (6.5 pg IL11) (n=5) or 3) prime with VLP-gplL11, boost with VLP and continuous booster immunizations with VLP-gplL11 (n=3) (i.e. representing a 6-week prime-boost interval, followed by 3-week booster intervals). As the IL-11 specific antibody levels are equally high after 3 doses of vaccine (figure 19B), animals from group 3 are pooled with group 1 for analysis, marked as light grey for identification. Guinea pigs primed with VLP, boosted with VLP-gplL11 and continuous booster immunizations with VLP (n=3) (i.e. representing a one-dose immunization regime) have been excluded from this analysis. All animals were fed a high-fat-diet throughout the study. Fig. 10A) The body weight was followed over the course of the study, demonstrating a body weight increase for guinea pigs immunized with the cVLP-gplL11 vaccine. Fig. 10B) Livers were collected at termination and weighed. There is no statistically significant difference in the liver weight between the two immunization groups. Fig. 10C) The ratio of liver weight to body weight (BW), (LW:BW%) was calculated as a measure of liver enlargement. There is no statistically significant difference in the relative liver weight between the two immunization groups. Fig. 10D) Liver sections were collected for histological analysis. The fibrosis score (F1- F4) was determined based on visual inspections of the histology samples. Guinea pigs immunized with the cVLP-gplL11 vaccine demonstrate a statistically significant reduction of hepatic fibrosis (p=0.0334). Fig. 10E) Steatosis was scored as %hepatocytes with lipid accumulation (e.g. <5%: 01 score 3:>66%) from the histology liver samples. No statistically significant difference was observed between the two immunization groups. Fig. 10F) Lobular inflammation (i.e. inflammatory foci within the P7421 PC00 liver lobule). Scores reflect the presence of foci (e.g. >2 ; 2-4 etc.), Fig. 10G) Portal inflammation (i.e. inflammatory foci specifically around portal areas), scored as present (1) or not present (0), Fig. 10H) Ballooning cells (i.e. enlarged hepatocytes), scored between 1-3 (none, few, many), Fig. 101) NAS-index: cumulative score (Steatosis, lobular inflammation and ballooning cells). A measure of MASH severity. A score of 5, is a common cut-off for + / - MASH.

[0647] Conclusion: This data demonstrates that immunizing guinea pigs with the cVLP- gpl L11 vaccine significantly reduces the level of hepatic fibrosis.

[0648] Example 10: Test expression of Al- enerated IL-11 antigens in HEK293tt cells

[0649] HEK293tt cells transfected with DNA encoding Al-generated IL-11 antigens.

[0650] Supernatant was harvested 3 days post transfection for western blot analysis and detected by an anti-cTag. All samples were run in a reduced (+DTT) and non-reduced (-DTT) state (Figure 11).

[0651] Strategy 1.2 refers to designs where only a minimal epitope was included in the epitope. Strategy 1.3 refers to designs with a longer epitope, wherein a longer scaffold P7421 PC00 is included. Strategy 2 refers to designs obtained after the native IL-11 sequence around the epitope were scrambled ProteinMPNN models trained on proteins with specific characteristics (more soluble proteins, hyperstable proteins etc).

[0652] Conclusion: Data demonstrates successful expression of 11 / 17 as soluble protein from small-scale HEK expression. Example 11: Recombinant expression of IL-11 Al antigens from HEKexpi Al-generated IL-11 antigens were expressed in HEK293expi cells and purified by cTag chromatography. Eluted protein peaks were run on an SDS-PAGE, successful expression is shown by a black arrow (Figure 12). Conclusion: This data demonstrates successful expression and purification of 7 / 11 Al- generated IL-11 antigens. P7421 PC00

[0653] Example 12: Test expression of Al-generated IL-11 antigens fused to an N-terminal Catcher

[0654] Al-generated IL-11 antigens were designed with a N-terminal Catcher (i.e Mooncake) for cVLP display. HEK293tt cells transfected with DNA encoding Catcher-fused Al- generated IL-11 antigens. Supernatant was harvested 3 days post transfection for western blot analysis and detected by an anti-cTag. All samples were run in a reduced (+DTT) and non-reduced (-DTT) state (Figure 13).

[0655] Conclusion: This data demonstrates successful design and expression of several Catcher versions of Al-generated IL-11 antigens from small-scale HEK expression.

[0656] Example 13: Recombinant expression of Catcher Al IL11 antigens

[0657] 3 Al-generated IL-11 antigens fused to an N-terminal Catcher (Mooncake) was expressed in HEK293expi cells and purified by cTag chromatography. Eluted peaks from the chromatogram (Fraction 1 (F1), lane 2-3 and Frcation 2 (F2), lane 4-5) were analyzed by SDS-PAGE in reduced (+DTT) and non-reduced (-DTT) state. cTag chromatography input and run through (RT), are loaded in lane 1 and 6, respectively (Figure 14).

[0658] Conclusion: This data demonstrates successful expression and purification of 3 Catcher-versions of Al-generated IL-11 antigens. P7421 PC00

[0659] To investigate whether IL-11 specific antibodies binds the Al-generated antigen, a 96- well ELISA plate was coated with 0.1 pg IL-11 protein per well. Plates were blocked in 0.5% skimmed milk in PBS, pH7.4. A 3-fold dilution of serum from mice immunized with cVLP-mulL11(FL) starting from 1 :50 was added to the plate. Level of Catcher-IL11 specific antibodies were measured at OD450. Data show that out of the 7 Al-designed IL-11 antigens (without Catcher), 6 demonstrate some binding of IL-11 specific antibodies. For the 3 Catcher-designs (#48, #50 and #51), the signal is significantly higher, as both the Catcher-specific, as well as the IL-11 specific antibodies are measured (Figure 15).

[0660] Conclusion: This data demonstrates the integrity of the conformational fold of the IL- 11 region present in some of the Al designed proteins. Specifically, data shows that the IL-11 antigen designs of #19 and #21 contain conformational folds detected by IL-11 specific polyclonal antibodies.

[0661] Example 15: Vaccine formulation #48

[0662] #48 was mixed with Tag-cVLP in a 1:1.3 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (Fig. 16A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and postspin samples were loaded on an SDS-PAGE gel, to assess potential loss in the postspin sample due to precipitation or aggregation (Fig. 16B). The antigen coupling efficiency was estimated to 45% (corresponding to ~81 IL-11 antigens per VLP)by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~44nm, with low percent polydispersity (%Pd<15) (data not shown).

[0663] Conclusion: This data demonstrates successful vaccine formulation for #48. P7421 PC00

[0664] Example 16: Vaccine formulation #50

[0665] #48 was mixed with Tag-cVLP in a 1:1 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (Fig. 17A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and postspin samples were loaded on an SDS-PAGE gel, to assess potential loss in the postspin sample due to precipitation or aggregation (Fig. 17B). The antigen coupling efficiency was estimated to 43% (corresponding to ~77 IL-11 antigens per VLP)by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~45nm, with low percent polydispersity (%Pd<15) (data not shown).

[0666] Conclusion: This data demonstrates successful vaccine formulation for #50.

[0667] Example 17: Vaccine formulation #51

[0668] #48 was mixed with Tag-cVLP in a 1:1 molar excess. The vaccine was incubated overnight at 4°C before excess antigen was removed by density gradient ultracentrifugation (UC) using an Optiprep™ gradient (23, 29, 35%) (Fig. 18A). Fractions containing the vaccine (indicated by black box) were dialysed into PBS. To assess stability, the vaccine was subjected to a spin stability test. Specifically, a vaccine sample was spun at 16.000g for 2min and an equal volume of pre- and postspin samples were loaded on an SDS-PAGE gel, to assess potential loss in the postspin sample due to precipitation or aggregation (Fig. 18B). The antigen coupling efficiency was estimated to 51% (corresponding to ~92 IL-11 antigens per VLP) by calculating the percentage conjugation (i.e. number of bound antigens divided by the total available binding sites (=180) per cVLP) by densitometric analysis using ImageLab. Purified vaccine was quality checked Dynamic Light scattering (DLS) analysis. Triplicate measurements of the vaccine show a monodisperse population with a diameter of ~43nm, with low percent polydispersity (%Pd<15) (data not shown).

[0669] Conclusion: This data demonstrates successful vaccine formulation for #51. P7421 PC00

[0670] Total IgG was purified from plasma from guinea pigs (not fed on a high fat diet, pilot immunogenicity study, Figure 5) immunized with the cVLP-gplL11 vaccine. As control, total IgG was purified from age-matched, non-immunized guinea pigs, as well as control guinea pigs (non-immunized). The biological activity of the vaccine-induced antibody response was investigated by measuring the ability of IgG purified from plasma from immunized guinea pigs to inhibit IL-11 receptor activation in a HEK293 hulL-11 reporter cell line (Hek-blue, Invivogen). 1 ng / mL MBP-hulL11 was incubated with IgG from immunized mice in a 2-fold dilution starting from 1 pM, before being added to 50.000 cells seeded in a 96-well plate. Cells were incubated overnight at 37°C, 5% CO2. SEAP reporter activity was measured plotted as percentage activity (% activity).

[0671] As negative controls, cells were unstimulated / blank (i.e. PBS) or stimulated in the presence of IgG from non-immunized guinea pigs. The data shown in Fig. 19A demonstrate, that the vaccine-induced antibody response in guinea pigs immunized with the cVLP-gplL11 vaccine completely inhibit IL11 receptor activation until the highest tested dilution (i.e. 0.001 pM IgG). In contrast, IgG from non-immunized guinea pigs show no inhibition of the IL-11 receptor.

[0672] Conclusion: Data demonstrate that the IL-11 specific antibody response induced in guinea pigs immunized with the cVLP-gplL-11 vaccine, can block IL-11 receptor activation in a HEK293 reporter cell line in ad dose-dependent manner. Only at the highest dilution tested, can some receptor activation be measured, suggesting very high efficacy of the vaccine-induced antibody response.

[0673] Example 19: IL- 11 receptor activation assay demonstrate biological activity of IL- 11 proteins and antigens.

[0674] The biological activity of different IL-11 proteins was investigated by measuring the ability of the IL-11 proteins to inhibit hulL-11 receptor activation in a HEK293 hulL- 11 reporter cell line (Hek-blue, Invivogen). 50.000 cells seeded in a 96-well plate were incubated with IL-11 protein in a 2-fold dilution starting from 100 ng / mL. Cells were incubated overnight at 37°C, 5% CO2. SEAP reporter activity was measured at P7421 PC00

[0675] OD620. As negative controls, cells were stimulated with 10ng / mL mulL33 or PBS. Data is shown as dilution curves (Figure 20A) or plotted as Area under the curve (AUG) with mean ± SD (Figure 20B).

[0676] Data demonstrate that the HEK-blue IL-11 reporter cell line can be effectively stimulated by both commercial recombinant murine and human IL11. Moreover, MBP fusion proteins of murine, guinea pig, and human IL-11 all stimulate receptor activation in a dose-dependent manner, to a comparable level as the commercial mulL11 and hulL11.

[0677] Moreover, Mooncake-mulL11 (i.e. the antigen used for cVLP-display in murine immunogenicity studies, see example 4), also demonstrates receptor activation. However, in contrast two designs (#42 and #19) did not activate the IL11 receptor. Note that #19 is the antigen of vaccine formulation #50, which induces I L-11 -specific antibodies (see Example 14).

[0678] This demonstrates that antigens only containing the IL11Ra site, and not the gp130 binding site, cannot activate downstream signalling from the IL-11 receptor complex.

[0679] Example 20: Al-generated IL-11 vaccine induces IL- 11 specific antibodies in mice Balb / c mice (n=4) were immunized in a 2-week prime-boost-boost regime with a 5 pg IL-11 antigen dose displayed on cVLP. Blood samples were taken 12 days after each immunization. hulL11 -specific IgG was measured in serum from immunized mice after one dose (1st bleed) and second dose (2nd bleed). Groups were immunized with vaccines displaying a single Al-generated hulL11 antigen (i.e. cVLP-#48, cVLP-#50 and cVLP-#51). For benchmark, a group received a cVLP-hulL11(FL) vaccine. The results are shown in Figure 21. After one dose, only mice immunized with the FL IL11 vaccine (i.e. cVLP-hulL11(FL) demonstrated seroconversion in all mice.

[0680] After a second dose, mice immunized with cVLP-#50 and cVLP-#51 seroconverted, inducing hulL11 specific antibody levels comparable to measured in mice immunized with cVLP-hulL11(FL) after one dose.

[0681] Surprisingly, mice immunized with cVLP-#48 showed no seroconversion after two P7421 PC00 doses of the vaccines, suggesting that the IL11 receptor binding site does not fold in its native fold in this Al-generated antigen design.

[0682] Sequence overview

[0683] SEQ ID NO: 45 - mature human IL-11 (22-199)

[0684] PGPPPGPPRVSPDPRAELDSTVLLTRSLLADTRQLAAQLRDKFPADGDHNLDSLPTLA

[0685] MSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRL LRRLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLL LKTRL

[0686] SEQ ID NO: 47 - mature murine IL-11 (22-199)

[0687] PGPPAGSPRVSSDPRADLDSAVLLTRSLLADTRQLAAQMRDKFPADGDHSLDSLPTL

[0688] AMSAGTLGSLQLPGVLTRLRVDLMSYLRHVQWLRRAGGPSLKTLEPELGALQARLER

[0689] LLRRLQLLMSRLALPQAAPDQPVIPLGPPASAWGSIRAAHAILGGLHLTLDWAVRGLLL LKTRL

[0690] SEQ ID NO: 48 - mature guinea pig IL-11 (22-199)

[0691] RGPPPGPSRATPDPRAELDSAVLLTRSLLVDTRQLAAQLRDKFPVDGDHSLDSLPTP

[0692] AMSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGPSLKTLEPELGALQARLDR LLRRLQLLMSGLALPQVPPEPPAPPLAPPASAWGGIRAAHAILGGLHLTLDWAVRGLL LLKTRL

[0693] SEQ ID NO: 55

[0694] >#1 sign8_Mooncake_ggs_mulL11(22-199) (amino acids) - codon optimized for human, including a secretion signal (sign8)

[0695] MAFLWLLSCWALLGTTFGMGIDTMSGLSGETGQSGNTTIEEDSTTHVKFSKRDSNGK

[0696] ELAGAMIELRNLSGQTIQSWVSDGTVKDFYLMPGTYQFVETAAPEGYELAAPITFTVQ

[0697] DNGEVIIQGRLTRGDVHIGGSPGPPAGSPRVSSDPRADLDSAVLLTRSLLADTRQLAA

[0698] QMRDKFPADGDHSLDSLPTLAMSAGTLGSLQLPGVLTRLRVDLMSYLRHVQWLRRA GGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAPDQPVIPLGPPASAWGSIR AAHAILGGLHLTLDWAVRGLLLLKTRL

[0699] SEQ ID NO: 60 P7421 PC00

[0700] >#1 Sign8_Mooncake_ggs_mulL11(22-199) (nucleotides) - codon optimized for human, including a secretion signal (sign8)

[0701] TTTGAATTCGCCACCATGGCCTTTCTGTGGCTGCTGTCTTGTTGGGCCCTGCTGG

[0702] GCACAACATTCGGCATGGGCATCGACACCATGAGCGGCCTGTCTGGCGAAACAG

[0703] GCCAGAGCGGCAATACCACCATCGAAGAGGACAGCACCACACACGTGAAGTTCA

[0704] GCAAGCGGGACAGCAACGGCAAAGAACTGGCTGGCGCCATGATCGAGCTGAGAA

[0705] ATCTGAGCGGCCAGACCATCCAGAGCTGGGTGTCAGATGGCACCGTGAAGGACT

[0706] TCTACCTGATGCCTGGCACCTACCAGTTCGTGGAAACAGCCGCTCCTGAGGGCTA

[0707] TGAGCTGGCTGCCCCTATCACATTCACAGTGCAGGACAACGGCGAAGTGATCATC

[0708] CAGGGCAGACTGACCAGAGGCGACGTGCACATTGGAGGATCTCCAGGACCTCCT

[0709] GCCGGCTCTCCTAGAGTGTCTAGCGATCCTAGAGCCGACCTGGATTCTGCCGTG

[0710] CTGCTGACAAGAAGCCTGCTGGCCGATACCAGACAGCTGGCAGCCCAGATGAGA

[0711] GACAAGTTCCCTGCCGATGGCGACCACTCTCTGGACTCACTGCCTACACTGGCCA

[0712] TGTCTGCCGGCACACTGGGATCTCTTCAACTGCCTGGCGTGCTGACCAGACTGA

[0713] GAGTGGACCTGATGAGCTACCTGCGGCATGTGCAATGGCTGCGTAGAGCTGGCG

[0714] GCCCTAGCCTGAAAACACTGGAACCTGAACTGGGAGCCCTGCAGGCCAGACTGG

[0715] AAAGACTGCTGAGAAGGCTGCAGCTGCTGATGAGCAGACTGGCTCTGCCTCAGG

[0716] CTGCTCCTGACCAGCCTGTTATTCCTCTGGGACCTCCAGCTTCTGCCTGGGGCTC

[0717] TATTAGAGCTGCCCACGCCATTCTCGGCGGCCTGCATCTTACACTGGATTGGGCC

[0718] GTTAGAGGCCTGCTGCTGCTCAAGACCAGACTCTGAGCGGCCGCTTT

[0719] SEQ ID NO: 56

[0720] >#2 sign8_SpyCatcher_ggs_mulL11(22-199) (amino acids) - codon optimized for human, including a secretion signal (sign8)

[0721] MAFLWLLSCWALLGTTFGGAMVDTLSGLSSEQGQSGDMTIEEDSATHIKFSKRDEDG

[0722] KELAGATMELRDSSGKTISTWISDGQVKDFYLYPGKYTFVETAAPDGYEVATAITFTV

[0723] NEQGQVTVNGKATKGDAHIGGSPGPPAGSPRVSSDPRADLDSAVLLTRSLLADTRQL

[0724] AAQMRDKFPADGDHSLDSLPTLAMSAGTLGSLQLPGVLTRLRVDLMSYLRHVQWLR RAGGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAPDQPVIPLGPPASAWGS IRAAHAILGGLHLTLDWAVRGLLLLKTRL

[0725] SEQ ID NO: 61

[0726] >#2 sign8_SpyCatcher_ggs_mulL11(22-199) (nucleotides) - codon optimized for human, including a secretion signal (sign8) P7421 PC00

[0727] TTTGAATTCGCCACCATGGCCTTTCTGTGGCTGCTGTCTTGTTGGGCCCTGCTGG

[0728] GCACAACATTTGGCGGCGCTATGGTGGATACACTGAGCGGCCTGTCTAGCGAGC

[0729] AGGGACAGTCTGGCGACATGACCATCGAAGAGGACAGCGCCACACACATCAAGT

[0730] TCAGCAAGAGAGATGAGGACGGCAAAGAGCTGGCTGGCGCCACAATGGAACTGA

[0731] GAGACAGCTCCGGCAAGACCATCAGCACCTGGATCTCTGACGGCCAAGTGAAGG

[0732] ACTTCTATCTGTACCCCGGCAAGTACACCTTCGTGGAAACAGCCGCTCCTGACGG

[0733] ATACGAGGTGGCCACAGCCATCACCTTCACCGTGAATGAGCAGGGGCAAGTGAC

[0734] CGTGAACGGCAAGGCTACAAAGGGCGACGCCCACATCGGAGGATCTCCAGGACC

[0735] TCCTGCCGGCTCTCCTAGAGTGTCTAGCGATCCTAGAGCCGACCTGGATTCTGCC

[0736] GTGCTGCTGACAAGAAGCCTGCTGGCCGATACCAGACAGCTGGCAGCCCAGATG

[0737] AGAGACAAGTTCCCTGCCGATGGCGACCACTCTCTGGACTCACTGCCTACACTGG

[0738] CCATGTCTGCCGGCACACTGGGATCTCTTCAACTGCCTGGCGTGCTGACCAGACT

[0739] GAGAGTGGACCTGATGAGCTACCTGCGGCATGTGCAATGGCTGCGTAGAGCTGG

[0740] CGGCCCTAGCCTGAAAACACTGGAACCTGAACTGGGAGCCCTGCAGGCCAGACT

[0741] GGAAAGACTGCTGAGAAGGCTGCAGCTGCTGATGAGCAGACTGGCTCTGCCTCA

[0742] GGCTGCTCCTGACCAGCCTGTTATTCCTCTGGGACCTCCAGCTTCTGCCTGGGGC

[0743] TCTATTAGAGCTGCCCACGCCATTCTCGGCGGCCTGCATCTTACACTGGATTGGG

[0744] CCGTTAGAGGCCTGCTGCTGCTCAAGACCAGACTCTGAGCGGCCGCTTT

[0745] SEQ ID NO: 57

[0746] >#2 6xHis_TEV_Mooncake_ggs_mulL11(22-199) for baculo (amino acids) - codon optimized for baculo, including a GP64 secretion signal

[0747] MVSAIVLYVLLAAAAHSAFAADPMHHHHHHENLYFQGMGIDTMSGLSGETGQSGNTT

[0748] IEEDSTTHVKFSKRDSNGKELAGAMIELRNLSGQTIQSWVSDGTVKDFYLMPGTYQFV

[0749] ETAAPEGYELAAPITFTVQDNGEVIIQGRLTRGDVHIGGSPGPPAGSPRVSSDPRADL

[0750] DSAVLLTRSLLADTRQLAAQMRDKFPADGDHSLDSLPTLAMSAGTLGSLQLPGVLTRL

[0751] RVDLMSYLRHVQWLRRAGGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAP

[0752] DQPVIPLGPPASAWGSIRAAHAILGGLHLTLDWAVRGLLLLKTRL

[0753] SEQ ID NO: 62

[0754] >#2 6xHis_TEV_Mooncake_ggs_mulL11(22-199) for baculo (nucleotides) - codon optimized for baculo, including a GP64 secretion signal

[0755] ATGGTAAGCGCTATTGTTTTATATGTGCTTTTGGCGGCGGCGGCGCATTCTGCCT

[0756] TTGCGGCGGATCCGATGCACCACCACCATCACCACGAGAACCTGTACTTCCAAGG

[0757] CATGGGTATCGACACCATGTCCGGCCTGTCTGGCGAGACTGGTCAATCCGGCAA P7421 PC00

[0758] CACCACTATCGAAGAGGACTCCACCACTCACGTGAAGTTCTCCAAGCGCGACTCC

[0759] AACGGCAAAGAACTGGCTGGTGCTATGATCGAGCTGCGTAACCTGTCCGGCCAG

[0760] ACCATCCAATCTTGGGTGTCCGACGGAACCGTGAAGGACTTCTACCTGATGCCTG

[0761] GCACCTACCAGTTCGTGGAAACCGCTGCTCCTGAGGGTTACGAGCTGGCTGCTC

[0762] CCATCACCTTCACCGTGCAAGACAACGGCGAAGTGATCATCCAGGGTCGTCTGAC

[0763] TAGAGGCGACGTGCACATCGGTGGTTCTCCAGGTCCTCCTGCTGGTTCTCCCCGT

[0764] GTCTCTTCTGATCCTCGTGCTGACCTGGACTCCGCTGTGCTGCTGACTCGTTCTC

[0765] TGCTGGCTGACACTCGTCAGCTGGCCGCTCAAATGCGTGACAAGTTCCCTGCTGA

[0766] CGGCGACCACTCTTTGGACTCCCTGCCTACTCTGGCTATGTCCGCTGGTACTCTG

[0767] GGTTCTCTGCAGCTGCCTGGTGTCCTGACTAGACTGCGTGTGGACCTGATGTCCT

[0768] ACCTGCGTCACGTGCAATGGCTGCGTAGAGCTGGTGGTCCCAGCCTCAAGACTC

[0769] TGGAACCTGAACTGGGTGCCCTGCAGGCTCGTCTGGAACGTTTGTTGCGTCGTCT

[0770] GCAACTGCTGATGTCCCGTCTGGCTCTGCCTCAGGCTGCTCCAGACCAACCTGTG

[0771] ATCCCTTTGGGTCCTCCAGCTTCCGCTTGGGGTTCTATCAGAGCTGCTCACGCTA

[0772] TCCTCGGTGGCCTGCACTTGACTTTGGACTGGGCTGTGCGTGGACTGCTGCTGC

[0773] TCAAAACTAGGCTCTAAGCGGCCGCTTT

[0774] SEQ ID NO: 57

[0775] >#10 sign3_6xHis_Mooncake_ggs_mulL11(22-199) for HEK (amino acids) - codon optimized for Human, including secretion signal

[0776] MGMKWVTFISLLFLFSSSSRASHHHHHHMGIDTMSGLSGETGQSGNTTIEEDSTTHV

[0777] KFSKRDSNGKELAGAMIELRNLSGQTIQSWVSDGTVKDFYLMPGTYQFVETAAPEGY

[0778] ELAAPITFTVQDNGEVIIQGRLTRGDVHIGGSPGPPAGSPRVSSDPRADLDSAVLLTRS

[0779] LLADTRQLAAQMRDKFPADGDHSLDSLPTLAMSAGTLGSLQLPGVLTRLRVDLMSYL

[0780] RHVQWLRRAGGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAPDQPVIPLG

[0781] PPASAWGSIRAAHAILGGLHLTLDWAVRGLLLLKTRL

[0782] SEQ ID NO: 63

[0783] >#10 sign3_6xHis_Mooncake_ggs_mulL11(22-199) for HEK (nucleotides) - codon optimized for Human, including secretion signal

[0784] TTTCCATGGGCATGAAATGGGTCACCTTTATCAGCCTGCTGTTCCTGTTCAGCAGC

[0785] AGCTCCAGAGCCAGCCACCACCATCACCATCACATGGGCATCGACACCATGAGC

[0786] GGCCTGTCTGGCGAAACAGGCCAGAGCGGCAATACCACCATCGAAGAGGACAGC

[0787] ACCACACACGTGAAGTTCAGCAAGCGGGACAGCAACGGCAAAGAACTGGCTGGC GCCATGATCGAGCTGAGAAATCTGAGCGGCCAGACCATCCAGAGCTGGGTGTCA P7421 PC00

[0788] GATGGCACCGTGAAGGACTTCTACCTGATGCCTGGCACCTACCAGTTCGTGGAAA

[0789] CAGCCGCTCCTGAGGGCTATGAGCTGGCTGCCCCTATCACATTCACAGTGCAGG

[0790] ACAACGGCGAAGTGATCATCCAGGGCAGACTGACCAGAGGCGACGTGCACATTG

[0791] GAGGATCTCCAGGACCTCCTGCCGGCTCTCCTAGAGTGTCTAGCGATCCTAGAG

[0792] CCGACCTGGATTCTGCCGTGCTGCTGACAAGAAGCCTGCTGGCCGATACCAGAC

[0793] AGCTGGCAGCCCAGATGAGAGACAAGTTCCCTGCCGATGGCGACCACTCTCTGG

[0794] ACTCACTGCCTACACTGGCCATGTCTGCCGGCACACTGGGATCTCTTCAACTGCC

[0795] TGGCGTGCTGACCAGACTGAGAGTGGACCTGATGAGCTACCTGCGGCATGTGCA

[0796] ATGGCTGCGTAGAGCTGGCGGCCCTAGCCTGAAAACACTGGAACCTGAACTGGG

[0797] AGCCCTGCAGGCCAGACTGGAAAGACTGCTGAGAAGGCTGCAGCTGCTGATGAG

[0798] CAGACTGGCTCTGCCTCAGGCTGCTCCTGACCAGCCTGTTATTCCTCTGGGACCT

[0799] CCAGCTTCTGCCTGGGGCTCTATTAGAGCTGCCCACGCCATTCTCGGCGGCCTG

[0800] CATCTTACACTGGATTGGGCCGTTAGAGGCCTGCTGCTGCTCAAGACCAGACTCT GAGATATCTTT

[0801] SEQ ID NO: 59

[0802] >#5 6xHis_Mooncake_ggs_guienapiglL11(22-199) for HEK (amino acids) - codon optimized for Human, including secretion signal

[0803] MKWVTFISLLFLFSSSSRASHHHHHHMGIDTMSGLSGETGQSGNTTIEEDSTTHVKFS

[0804] KRDSNGKELAGAMIELRNLSGQTIQSWVSDGTVKDFYLMPGTYQFVETAAPEGYELA

[0805] APITFTVQDNGEVIIQGRLTRGDVHIGGSRGPPPGPSRATPDPRAELDSAVLLTRSLLV

[0806] DTRQLAAQLRDKFPVDGDHSLDSLPTPAMSAGALGALQLPGVLTRLRADLLSYLRHV

[0807] QWLRRAGGPSLKTLEPELGALQARLDRLLRRLQLLMSGLALPQVPPEPPAPPLAPPA

[0808] SAWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRL

[0809] SEQ ID NO: 64

[0810] >#5 6xHis_Mooncake_ggs_guienapiglL11(22-199) for HEK (nucleotide) - codon optimized for Human, including secretion signal

[0811] TTTCCATGGGCATGAAATGGGTCACCTTTATCAGCCTGCTGTTCCTGTTCAGCAGC

[0812] AGCTCCAGAGCCAGCCACCACCACCATCACCACATGGGCATCGATACCATGAGC

[0813] GGCCTGAGCGGAGAGACAGGCCAGTCTGGCAATACCACCATCGAAGAGGACAGC

[0814] ACCACACACGTGAAGTTCAGCAAGCGGGACAGCAACGGCAAAGAACTGGCTGGC

[0815] GCCATGATCGAGCTGAGAAATCTGAGCGGCCAGACCATCCAGAGCTGGGTGTCA

[0816] GATGGCACCGTGAAGGACTTCTACCTGATGCCTGGCACCTACCAGTTCGTGGAAA

[0817] CAGCCGCTCCTGAGGGCTATGAGCTGGCTGCCCCTATCACATTCACAGTGCAGG P7421 PC00

[0818] ACAACGGCGAAGTGATCATCCAGGGCAGACTGACCAGAGGCGACGTGCACATCG GAGGCTCTAGAGGACCTCCTCCAGGACCTTCTAGAGCCACACCTGATCCTAGAGC CGAGCTGGATTCTGCCGTGCTGCTGACCAGATCTCTGCTGGTGGATACCAGACA GCTGGCCGCACAGCTGAGAGACAAGTTCCCTGTGGATGGCGACCACAGCCTGGA CTCATTGCCTACACCAGCCATGTCTGCTGGCGCTCTGGGAGCACTTCAACTGCCT GGCGTTCTGACCAGACTGAGAGCCGATCTGCTGAGCTACCTGAGACACGTGCAA TGGCTGCGTAGAGCCGGCGGACCTAGCCTGAAAACACTGGAACCTGAACTGGGA GCCCTGCAGGCCAGACTCGATAGACTGCTGAGAAGGCTGCAGCTGCTGATGAGC GGACTGGCTCTGCCTCAAGTGCCTCCTGAACCTCCTGCTCCTCCATTGGCTCCTC CAGCATCTGCCTGGGGAGGAATTAGAGCCGCTCACGCCATTCTCGGCGGACTGC ATCTTACACTGGATTGGGCCGTTAGAGGCCTGCTGCTGCTGAAAACCAGACTCTA AGATATCTTT

[0819] References

[0820] Dauparas et al., 2022: Robust deep learning-based protein sequence design using ProteinMPNN. Science, 378 (6615), p. 49-56.

[0821] Watson et al., 2023: De novo design of protein structure and function with RFdiffusion.

[0822] Nature, 620, p. 1089-1100.

[0823] Martina et al., 2023: Glycan masking in vaccine design: Targets, immunogens and applications. Front Immunol. 2023 Mar 23;14:1126034. doi: 10.3389 / fimmu.2023.1126034

Claims

P7421 PC00Claims1. A vaccine comprising: i. a particle-forming protein comprising a first peptide tag, and ii. an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of Interleukin-11 (IL-11), wherein the antigen and nanoparticle are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, and wherein i - ii form a particle displaying said antigen, wherein the antigen comprises one or more epitopes of the IL- 11 region that binds to IL-11 Ra, but does not bind to gp130.

2. A vaccine comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope or a mimotope of Interleukin- 11 (IL-11), wherein the antigen and nanoparticle upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first and second peptide tag, thereby forming a particle displaying said antigen, wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

3. The vaccine according to any one of the preceding claims, wherein IL-11 is as set forth in SEQ ID NO: 45, or has at least 95% identity thereto, such as 96%, 97%, 98% or 99% identity thereto.

4. The vaccine according to any one of the preceding claims, wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, and / or wherein the antigen does not comprise the residues or regions of IL-11 which bind to gp130.

5. The vaccine according to any one of the preceding claims, wherein the antigen comprises: SEQ ID NO: 49; SEQ ID NO: 51 , such as SEQ ID NO: 50; and / or SEQ ID NO: 52, or immunogenic fragments thereof.P7421 PC006. The vaccine according to any one of the preceding claims, wherein the antigen is a scaffold, such as minimal scaffold, comprising a conformational epitope of Interleukin-11 (IL-11).

7. The vaccine according to any one of the preceding claims, wherein the epitope comprise one or more residues of site / of IL-11 , preferably wherein IL-11 is as set forth in SEQ ID NO: 45.

8. The vaccine according to any one of the preceding claims, wherein the antigen comprises one or more of: a) the region corresponding to residues 158 to 178 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 49; b) the region corresponding to residues 43 to 65 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 50; and c) a region corresponding to residues 66 to 71 of SEQ ID NO: 45, such as set forth in SEQ ID NO: 52, or immunogenic fragments thereof.

9. The vaccine according to any one of the preceding claims, wherein the epitope comprises two or more amino acid residues, wherein 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues are selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.

10. The vaccine according to any one of the preceding claims, wherein the epitope is a conformational epitope and comprises two or more residues of IL-11 as set forth in SEQ ID NO: X, wherein: i. the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the two or more residues maintain the same spatial arrangement between each other as in the three-dimensional structure of IL-11, wherein IL-11 is as set forth in SEQ ID NO: 45.P7421 PC0011 . The vaccine according to any one of the preceding claims, wherein the epitope is a conformational epitope and comprises two or more residues of IL-11 as set forth in SEQ ID NO: 45, wherein: i. the two or more residues are selected from: Met59; Ala61 ; Gly62; Leu64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173, and ii. the Root Mean Square Deviation (RMSD) of the two or more residues within the three-dimensional structure the antigen and the corresponding two or more residues within the three-dimensional structure of IL-11 is less than 2 A, such as less than 1.9 A, such as less than 1.8 A, 1 .7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.2, such as less than 1 A, wherein IL-11 is as set forth in SEQ ID NO: 45.

12. The vaccine according to any one of the preceding claims, wherein the conformational epitope comprises: i. SEQ ID NO: 49; ii. SEQ ID NO: 51 ; and / or iii. SEQ ID NO: 5213. The vaccine according to any one of the preceding claims, wherein the antigen does not comprise: SEQ ID NO: 53 and / or SEQ ID NO: 54.

14. The vaccine according to any one of the preceding claims, wherein the antigen does not comprise a polypeptide consisting of the region defined by residues 20 to 27 of SEQ ID NO: 45, or a polypeptide corresponding to the region defined by residues 20 to 27 of SEQ ID NO: 45, nor immunogenic fragments thereof.

15. The vaccine according to any one of the preceding claims, wherein the vaccine is capable of inducing in a subject one or more antibodies capable of binding a conformational epitope of IL-11 , wherein the conformational epitope comprises two or more residues, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 residues, selected from: Met59; Ala61 ; Gly62; Leu 64; Leu67; Arg75; Asp165; Trp166; Arg169; Leu172; and Leu173.121P7421 PC0016. The vaccine according to any one of the preceding claims, wherein the vaccine does not induce, or has a decreased risk of inducing, an IL-11 specific T-cell response in a subject.

17. The vaccine according to any one of the preceding claims, wherein the protein is a particle forming protein having at least 70% sequence identity, such as 75%, such as 80%, such as 85%, such as 90%, such as 95% such as 99%, such as 100% sequence identity to:MsDps2 as set forth in SEQ ID NO: 33;AP205 as set forth in SEQ ID NO: 34; ferritin as set forth in SEQ ID NO: 35; i301 as set forth in SEQ ID NO: 36; replicase polyprotein 1a (pp1a); a lumazine synthase as set forth in SEQ ID NO: 38;Hbc as set forth in SEQ ID NO: 39; tandemHBc as set forth in SEQ ID NO: 40; the 2-oxo acid dehydrogenase subunit E2 as set forth in SEQ ID NO: 41 ; or the norovirus capsid protein as set forth in SEQ ID NO: 42.

18. The vaccine according to any one of the preceding claims, wherein the antigen comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76,SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86,SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, or SEQ ID NO:96.

19. The vaccine according to any one of the preceding claims, wherein the first or second peptide tag is fused to the N-terminal end of the antigen.

20. A vaccine for use in the prophylaxis and / or treatment of a disease, wherein the vaccine is according to any one of the preceding claims, and wherein the disease is a fibrotic disorder and / or a fibro-inflammatory disease, an inflammatory disease, a cancer, a cardiovascular disease, and / or a lung-related disorder, wherein the vaccine is as defined in any one of the preceding claims.122P7421 PC0021 . An expression system such as a vector comprising: i. a first polynucleotide encoding a particle-forming protein comprising a first peptide tag; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, wherein the antigen comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and particle-forming protein upon expression in a cell are linked via an isopeptide, bond or an ester bond between the first and second peptide tag, thereby forming a particle displaying said antigen, wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130.

22. The expression system according to claim 21 , wherein the first peptide tag, the second peptide tag, the protein and / or the antigen are as defined in any one of the preceding claims.

23. A cell expressing: i. a first polynucleotide encoding a particle-forming protein fused to a first peptide tag, preferably as defined in any one of the preceding claims; and ii. a second polynucleotide encoding an antigen fused to a second peptide tag, comprises an epitope of Interleukin-11 (IL-11), wherein the antigen and the particle-forming protein upon expression in a cell are linked via an isopeptide bond, or an ester bond, between the first peptide tag and the second peptide tag, thereby forming a particle displaying said antigen, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to I L-11 Ra, but does not bind to gp130.

24. A host cell, wherein the host cell comprises an expression system according to any one of claims 21 to 22.

25. A kit of parts comprising i. a vaccine as defined in any one of the preceding items or an expression system according to any one of claims 21 to 22, and ii. optionally, a medical instrument or other means for administering the vaccine, and123P7421 PC00 iii. instructions for use, and optionally a second active ingredient.

26. A method of manufacturing a vaccine targeting the IL-11-IL-11 Ra interaction, comprising the steps of: a) Designing an antigen sequence, wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to or activate gp130; b) Producing a polynucleotide encoding the antigen or producing a polypeptide comprising or consisting of the antigen; c) Formulating the polynucleotide or the polypeptide as a vaccine, wherein the vaccine comprises a particle-forming protein comprising a first peptide tag, and wherein the vaccine comprises the antigen fused to a second peptide tag, preferably wherein the antigen comprises one or more epitopes of the IL-11 region that binds to IL-11 Ra, but does not bind to gp130, and / or preferably wherein the antigen, the epitope, the mimotope, the vaccine, the first peptide tag and the second peptide tags are as defined in any one of the preceding claims.

27. A method of manufacturing a vaccine according to any one of the preceding claims, comprising the step of providing an expression system as defined in any one of the preceding claims.

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