Treatment regimens for autoimmune and inflammatory diseases

Abstract

The present disclosure relates to novel therapeutic regimens for the treatment of autoimmune and other inflammatory diseases using BTK (Bruton's Tyrosine Kinase) inhibitors. In particular, the present disclosure relates to treatments that combine BTK inhibitor treatments with vaccination to avoid, reduce the risk of staining, or ameliorate infection. In addition, the present disclosure relates to vaccination in the presence of a BTK inhibitor.

Description

Technical Field

[0001] The present disclosure relates to novel treatment regimens for treating autoimmune and other inflammatory diseases using BTK (Bruton's tyrosine kinase) inhibitors. In particular, the present disclosure relates to combining BTK inhibitor therapy with vaccination to prevent, reduce the risk of contracting, or improve the treatment of an infection. Additionally, the present disclosure relates to vaccination in the presence of a BTK inhibitor. Background Art

[0002] Autoimmune disorders, such as multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), neuromyelitis optica spectrum disorders (NMOSD) and myasthenia gravis (MG), chronic spontaneous urticaria (CSU) and idiopathic thrombocytopenia (ITP), as well as certain other inflammatory diseases, such as graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma, are caused by overactivation of the body's own immune system. Therefore, suppressing or modulating at least a portion of the immune system can lead to an improvement in the clinical picture of each disease.

[0003] Thus, a variety of direct or indirect immunosuppressive and immunomodulatory drugs are widely used to treat autoimmune disorders and inflammatory diseases, including, but not limited to, corticosteroids such as Cortisol, glucocorticoids such as prednisone, dexamethasone and hydrocortisone, cytostatics such as nitrogen mustards (e.g., cyclophosphamide), nitrosoureas, platinum compounds, antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil and cladribine, B and / or T cell receptor directed antibodies such as obinutuzumab, rituximab and rituximab. These include tuximab, ocaratuzumab, ocrelizumab, and muromonab; drugs that act on immunostatins, such as cyclosporine, tacrolimus, sirolimus, and everolimus; and other drugs that target the immune system, such as interferons, opioids, TNF-binding proteins, such as infliximab, etanercept, and adalimumab, and mycophenolate mofetil.

[0004] Similarly, Bruton's tyrosine kinase (BTK) inhibitors are a class of immunomodulatory drugs that have shown great potential for the clinical treatment of autoimmune and other inflammatory diseases.

[0005] Bruton's tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases and is expressed in B cells, macrophages, and monocytes, but not in T cells. Mutations in BTK in humans lead to the condition X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al., New Eng. J. Med. (1995), vol. 333, p. 431 and Lindvall et al., Immunol. Rev. (2005), vol. 203, p. 200). These patients are immunocompromised and show impaired B cell maturation, reduced immunoglobulin and peripheral B cell levels, diminished T cell-independent immune responses, and diminished calcium mobilization following BCR stimulation.

[0006] Evidence for the role of BTK in autoimmune and inflammatory diseases has also been provided by BTK-deficient mouse models. In preclinical mouse models of SLE, BTK-deficient mice showed significant improvement in disease progression. In addition, BTK-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl, Clin. Exp. Immunol. (1993), vol. 94, p. 459). Selective BTK inhibitors (BTKi) have shown dose-dependent efficacy in mouse arthritis models (Pan et al., Chem. Med Chem. (2007), vol. 2, p. 58-61).

[0007] BTK is also expressed by cells other than B cells that may be relevant to the disease process. BTK is a key component of Fc-γ signaling in myeloid cells. For example, BTK is expressed by mast cells, and BTK-deficient bone marrow-derived mast cells show damaged antigen-induced degranulation (Iwaki et al., J.Biol.Chem. (2005), vol.280, p.40261). This suggests that BTK can be used to treat pathological mast cell reactions, such as allergies and asthma. Similarly, monocytes from XLA patients (in which BTK activity is absent) show reduced TNFα production after stimulation (Horwood et al., J.Exp.Med. (2003), vol.197, p.1603). Therefore, TNFα-mediated inflammation can be regulated by small molecule BTK inhibitors.

[0008] This finding suggests that BTK inhibitors may be useful in treating autoimmune and other inflammatory diseases that involve activation of several B cell subtypes and / or macrophages.

[0009] In fact, several BTK inhibitors have shown great potential for the treatment of autoimmune diseases and other inflammatory diseases, or are currently in clinical trials for such diseases (reviewed in Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223). Specifically, at least 13 compounds targeting BTK in 9 indications have reached Phase II or above clinical trial status. These studies involve indications including: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, including relapsing MS (RMS) and progressive form (PMS), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), chronic spontaneous urticaria, idiopathic thrombocytopenia, graft-versus-host disease and asthma. 11 of these BTK inhibitor clinical drug candidates are covalent alkylating agents that form an irreversible bond with cysteine ​​481 in the ATP binding pocket. Of the thirteen BTK inhibitors tested in the clinic, only two have a non-covalent inhibition mechanism of action, BMS-986142 and fenebrutinib. A new trial using tolebrutinib in myasthenia gravis (MG) has recently been announced (NCT05132569). Two BTK inhibitors, evobrutinib and tolebrutinib, have shown positive results in a phase II trial of RMS (Montalban et al., New Engl. J. of Medicine (2019), vol. 380, p. 2406; Reich et al., Lancet Neurology (2021), vol. 20, p. 729).

[0010] Patients being treated for autoimmune or inflammatory diseases are particularly susceptible to infection during treatment, particularly if the disease or the medical agent used to treat it interferes with the normal immune response. Therefore, it is highly desirable to avoid infection or reduce the risk of contracting such an infection in such patients, and to ameliorate the course of the infection if an infection does occur.

[0011] One of the most effective ways to prevent or ameliorate infection is to vaccinate against the agent that causes the infection. However, vaccination usually also requires the body to mount a proper immune response.

[0012] The successful vaccine response that leads to vaccine-mediated protection is a complex immune process. Most antigens trigger B cells (humoral immunity) and T cell responses (cellular immunity). Early protection efficacy is mainly given by the induction of immune effectors and antigen-specific antibodies produced by B cells that can bind to pathogens or toxins. Long-term protection requires the maintenance of immune memory that can quickly and effectively reactivate the vaccine antibodies that exceed the protection threshold.

[0013] Memory B cells are produced during the primary response to vaccines that rely on T cells. They continue to exist in the absence of antigens, and being exposed to antigens again drives them to differentiate into plasma cells that produce antibodies. This reactivation is rapid, so that the booster response is characterized by a rapid increase to higher titers of antibodies, the antibody affinity for the antigen is higher than the antibody produced during the primary response (Siegrist, Vaccines-Vaccine Immunology, in "Vaccines" book chapters, editors: Plotkin, Orenstein and Offit, published by Saunders / Elsevier, 5th edition (2008), p.16-34; Papp et al., J.of Cutaneous Medicine and Surgery (2019), vol.32, p.50-74). Therefore, the vaccine response also depends on the type of response (recall response compared to the response to new antigens).

[0014] In addition, the response to the vaccine also depends on the type of vaccine. For example, for the following vaccines, the protective efficacy is mainly mediated by the antibodies of the following vaccines: cholera, diphtheria toxoid, hepatitis A and B, Haemophilus influenzae type B (haemophilus influenzae), influenza, Japanese encephalitis, meningococcal polysaccharide (PS) and conjugates, papillomavirus, pneumococcal PS and conjugates, polio (Sabin and Salk), rabies, rotavirus, rubella, tetanus toxoid, typhoid PS and yellow fever (YF). For tuberculosis (BCG), the effect is only produced by T cells, or for measles and intranasal influenza vaccination, the effect is produced by a combination of antibodies and T (Zrzavry et al., Frontiers in Immunology (2019), vol. 10, p. 1883).

[0015] Furthermore, the response to vaccines depends on the effects of individual disease-modifying therapies on humoral and cellular immunity, as immunosuppressive and immunomodulatory therapies often interfere with a proper vaccination response.

[0016] For example, based on scientific considerations, there is reason to believe that BTK inhibitors may be incompatible with vaccination, most notably because of their effects on B cell receptor signaling in germinal centers, B / T cell interactions and antigen presentation, and T follicular helper cell (Tfh) / B cell interactions, leading to altered B cell maturation, reduced class switching and immunoglobulin synthesis, a mode of action that may translate into reduced primary and secondary humoral responses, and lower levels of antibodies produced against new and recall target antigens (Rijvers et al., AAN (2021), abstract; Bogers et al., ECTRIMS (2022), abstract; Rijvers et al., JCI Insight (2022, in press).

[0017] Consistent with the hypothesis, Li et al. (Acta Neuropathologica (2022), vol. 143, p. 505) showed, using an autologous antigen-specific B cell:T cell co-culture system, that BTK inhibitors significantly reduced the proliferation of B cells and T cells in response to recall vaccine-associated tetanus toxoid and limited the expression of T cell proinflammatory cytokines IFNγ and TNFα.

[0018] In addition, in a recent study by Parry et al. (J. of Hematology & Oncology (2022), vol. 15, p. 3), antibody responses after dual COVID-19 vaccination were tested in 279 untreated CLL patients under surveillance and 208 patients who had received therapy (20% of whom were currently receiving BTKi therapy). Post-vaccine spike-specific seroconversion was highest in untreated CLL patients under surveillance (79%). The overall antibody response rate in CLL patients under BTKi therapy was significantly lower than that in untreated patients (32%) and was also significantly lower than the overall antibody response of all previously treated patients (43%).

[0019] Douglas et al., Haematologica (2017), vol. 102, p. e398, tested the serological response of patients with chronic lymphocytic leukemia (CLL) and Waldenstrom's macroglobulinemia (WM) before and after influenza vaccination while being treated with the BTK inhibitor ibrutinib. The authors concluded that their results showed that there was no serological response to influenza vaccination in patients treated with the BTK inhibitor.

[0020] These results appear inconsistent with the findings reported by Sun et al. (JAMA Oncology (2016), vol. 2(12), p. 1656-1657) after studying a similar question. However, as Douglas et al. point out, the study by Sun et al. suffers from multiple flaws, such as the unclear extent of previous treatment in their population, the unclear proportion of patients receiving high-dose versus low-dose influenza vaccine, and, in particular, the lack of a control arm, which makes the results of Sun et al. difficult to interpret and raises doubts about the validity of their conclusions.

[0021] In Pleyer et al., Blood (2021), vol. 137(2), p. 185-189, vaccination with recombinant adjuvanted hepatitis B vaccine (HepB-CpG) or recombinant adjuvanted zoster vaccine (RZV, recombinant zoster vaccine) was studied in patients with CLL under BTK inhibitor therapy with the BTK inhibitors ibrutinib or acalabrutinib. Regarding hepatitis vaccination, the authors concluded that de novo immune responses to hepatitis B vaccine were “almost absent” in CLL patients under BTKi and impaired in previously untreated patients. Although the effect of BTK inhibitor therapy on RZV response rates was much weaker (the authors of Pleyer et al. concluded that responses were “not significantly different” overall), seroconversion was detected at a significantly lower rate in patients under BTK inhibitor therapy than in patients not treated with BTK inhibitors.

[0022] In a second, more recent study, Pleyer et al. (Blood Advances (2022), vol. 6, p. 1733-1740) showed that recombinant zoster vaccine (RZV) induced both humoral and cellular immune responses in treated and untreated CLL patients, although the response rate was lower in patients on BTKi therapy compared with previously untreated CLL patients. The antibody response rate in the previously untreated (TN) cohort (76.8%) was significantly higher than that in patients receiving BTKi (40.0%). The cellular response rate in the TN cohort (70.0%) was also significantly higher than that in the BTKi group (41.3%).

[0023] Therefore, the current in vitro and in vivo data on the mode of action of evobrutinib and other BTK inhibitors, as well as vaccination data obtained with selected BTK inhibitors in patients with CLL, suggest that, in general, and also in other situations where administration of BTK inhibitors may be beneficial, such as in autoimmune or other inflammatory diseases, the results of de novo and recall vaccinations may be attenuated by BTK inhibitors.

[0024] In the case where the correct immune response to the vaccine can not be expected, it is generally recommended to vaccinate well before and / or after immunosuppression or immunomodulation therapy begins. Generally, in order to have a safety margin, a gap or interval with a duration of several weeks to several months is applied between vaccination and the start and / or end of immunosuppression therapy. The general recommendation for vaccination in patients who will undergo immunosuppression / immunomodulation therapy is that vaccination should provide at least two weeks for inactivated vaccines, and should provide ≥4 weeks for live vaccines. Importantly, the refractory period after immunosuppression must also be considered, which may be up to a full year depending on the type of drug (e.g., rituximab or alemtuzumab (alemtuzumab)). Except for a few treatments that only cause mild immunosuppression, live vaccines are strongly contraindicated in the case of immunosuppressive therapy (Zrzavry et al., Frontiers in Immunology (2019), vol. 10, p. 1883).

[0025] These recommendations are consistent with Papp et al., Journal of Cutaneous Medicine and Surgery (2019), vol. 32, p. 50-74. The authors of the publication recommend that before starting immunosuppressive therapy in patients newly diagnosed with immune-mediated diseases, the immunization status should be assessed and a vaccine appropriate for age and condition should be administered. In order to optimize the immunogenicity of inactivated or live attenuated herpes zoster vaccines in patients with immune-mediated conditions who have not received treatment before, they recommend immunization at least 2 to 4 weeks before starting immunosuppressive therapy.

[0026] However, in many treatment situations, when vaccination is desired, immunosuppression or immunomodulation therapy is already underway. Due to the severity and unpredictability of many autoimmune diseases and immune-related inflammatory diseases that can exert serious disease activity outbreaks, sudden or recurring diseases at any given time, the treatment of such diseases often cannot be interrupted to provide a gap or interval as a safety margin for vaccination. In addition, since many of these diseases are generally incurable, but chronic, lifelong diseases, it is often necessary to continue to administer immunosuppression / immunomodulation drugs during several years (or otherwise decades). In these cases, vaccination before treatment begins or after treatment ends is impossible.

[0027] It would therefore be highly desirable to find ways of vaccinating patients with autoimmune and other inflammatory diseases while they are continuously treated with immunosuppressive / immunomodulatory drugs, i.e., how such patients could be continuously treated with immunosuppressive or immunomodulatory drugs but still be successfully vaccinated.

[0028] Therefore, there is a need in the art for improved methods for treating autoimmune and inflammatory diseases. In addition, there is a need in the art for improved methods for treating autoimmune diseases, such as SLE and MS, particularly MS. In addition, there is a need in the art for improved methods for treating autoimmune diseases using BTK inhibitors. In addition, there is a need in the art for improved methods for treating autoimmune or inflammatory diseases that allow for successful vaccination during treatment of such diseases. In addition, there is a need in the art for improved methods for vaccinating patients suffering from autoimmune or inflammatory diseases. In addition, there is a need in the art for improved methods for vaccinating patients with autoimmune diseases who are being treated with immunomodulatory drugs.

[0029] The present disclosure overcomes the aforementioned problems and addresses the aforementioned needs. Summary of the Invention

[0030] The present disclosure is based in part on the surprising observation that patients treated with BTK inhibitors, in particular patients treated with the BTK inhibitor evobrutinib, can mount a humoral response similar to that of untreated patients when vaccinated against seasonal influenza or COVID-19. It was further observed that humoral responses similar to those of untreated patients were elicited in different autoimmune diseases such as SLE and MS, implying that successful vaccination with evobrutinib treatment (and possibly with the closely related BTK inhibitor treatment) may also occur for other autoimmune diseases and, potentially, other inflammatory diseases. Furthermore, our analyses indicate that humoral responses with BTK inhibitor treatment, in particular with evobrutinib, are obtainable for vaccination with recall antigens as well as with neoantigens.

[0031] These surprising findings enable new therapeutic approaches combining BTK inhibitor administration with vaccination, which allow the above needs to be addressed through various aspects and embodiments of the present disclosure: In one aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor (Bruton's tyrosine kinase inhibitor) to the patient, and (b) vaccinating the patient against infection.

[0032] In one aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering a BTK inhibitor to the patient.

[0033] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) treating the disease by administering a BTK inhibitor to the patient.

[0034] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0035] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0036] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0037] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) optionally administering a BTK inhibitor to said patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering the BTK inhibitor to the patient, with the proviso that the method comprises one or more treatment periods in which the BTK inhibitor is administered to treat the patient for the disease and reduce the patient's risk of contracting the infection.

[0038] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the treatment comprising administering a BTK inhibitor to the patient, wherein the patient is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0039] In another aspect, the present disclosure relates to a method for reducing the risk of a subject contracting an infection, the method comprising: (a) administering a BTK inhibitor to the subject, and (b) vaccinating the subject against the infection.

[0040] In another aspect, the present disclosure relates to a method for reducing the risk of a subject contracting an infection, the method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0041] In another aspect, the present disclosure relates to a method for treating a disease and reducing the patient's risk of infection in a patient in need thereof, the method comprising (a) administering a BTK inhibitor to the patient, and (b) vaccinating the patient against the infection.

[0042] In another aspect, the present disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0043] In another aspect, the present disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0044] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0045] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0046] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0047] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering to said patient said BTK inhibitor, with the proviso that said method comprises one or more treatment periods in which said BTK inhibitor is administered.

[0048] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising administering the BTK inhibitor to a patient having the disease, the method comprising vaccinating the patient against infection while the patient is under ongoing treatment with the BTK inhibitor.

[0049] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein a patient suffering from the disease is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0050] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered in combination with a vaccine.

[0051] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0052] In another aspect, the disclosure relates to a vaccine for preventing an infection by a method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0053] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) identifying a subject at risk of contracting the infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0054] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject.

[0055] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0056] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0057] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0058] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0059] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0060] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering to said patient said BTK inhibitor, with the proviso that said method comprises one or more treatment periods in which said BTK inhibitor is administered.

[0061] In another aspect, the disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method wherein a patient suffering from the disease is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0062] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0063] In another aspect, the disclosure relates to use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0064] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) identifying subjects at risk of contracting an infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0065] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Reference is made hereinafter to the accompanying drawings.

[0067] Figure 1 The study design of study NCT02975336 (NCT number; EudraCT number: 2016-002950-19) and relevant information about the study as conducted and post hoc analysis of vaccination are shown. * Before vaccine (can be before treatment start), as available; As indicated (not by experimental design); 3-17 weeks after vaccination, as available. ACR, American College of Rheumatology; BID, twice daily; dsDNA, anti-double-stranded DNA; HI, hemagglutination inhibition; QD, once daily; R, randomized; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SLICC, Systemic Lupus Erythematosus International Collaborating Clinics.

[0068] Figure 2 and Figure 3 Baseline characteristics of patients included in the post hoc analysis of influenza vaccination are summarized. BID, twice daily; BILAG, British Isles Lupus Assessment Group; QD, once daily; SD, standard deviation; SLE, systemic lupus erythematosus.

[0069] Figure 4 An overview of the vaccination of patients in the studies described is provided, and the proportion of subjects vaccinated with a specific strain class and type is indicated.

[0070] Figure 5 The results of the hemagglutination inhibition serum antibody titer measurements before and after vaccination (GM before / after) and the ratio of the post-vaccination to pre-vaccination titer levels (GM ratio) obtained in Example 1 are summarized. BID, twice daily; GM, geometric mean; HI, hemagglutination inhibition; QD, once daily Figure 6 Figure 5. Seroconversion rate data obtained for the different patient groups in the analysis. BID, twice daily; CI, confidence interval; QD, once daily.

[0071] Figure 7 A tabular overview of the seroconversion rates determined in Example 1 is provided.

[0072] Figure 8 Seroprotection rate data obtained for the different patient groups included in the analysis are shown. For each patient group, the seroprotection rate value before vaccination is depicted by the left bar, and the value after vaccination is depicted by the right bar. BID, twice daily; CI, confidence interval; QD, once daily.

[0073] FIG. 9 provides a tabular overview of the seroprotection rates determined in Example 1 ( 9A : Part 1 ; 9B : Part 2 ).

[0074] Figure 10 The study design of study NCT02975349 (NCT number; EudraCT number: 2016-001448-21) and relevant information about the study as conducted and post hoc analyses of mRNA vaccines against COVID are shown. *As available, before vaccine; As indicated (not by trial design); §At least 4 weeks after the second dose of vaccine, as available. BID, twice daily; DBP, double-blind period; DMF, dimethyl fumarate; Evo, evobrutinib; OLE, open-label extension; QD, once daily; R, randomized.

[0075] Figure 11 Box plots showing the S1 / S2 IgG antibody levels (measured as single values) of pre- and post-vaccination plasma samples determined in Example 2 (for all patients who received two doses of the mRNA vaccine against COVID while on treatment with 75 mg of evobrutinib twice daily).

[0076] Figure 12 Box plots are shown of the S1 / S2 IgG antibody levels of pre- and post-vaccination plasma samples determined in Example 2 for all patients who received two doses of the mRNA vaccine against COVID while on treatment with 75 mg of evobrutinib twice daily, divided into (A) seronegative and (B) seropositive patient subgroups.

[0077] Figure 13 A table is shown summarizing the results of measurements of S1 / S2 IgG antibody levels for pre- and post-vaccination samples determined for patients who received two doses of an mRNA vaccine against COVID while on twice-daily treatment with 75 mg of evobrutinib. SD, standard deviation; CI, confidence interval; Q1, 25% quantile; Q3, 75% quantile; Min, minimum; Max, maximum.

[0078] Figure 14 Shown are the frequencies and summary statistics of the fold change in S1 / S2 IgG antibody levels for pre- and post-vaccination samples of patients who received two doses of an mRNA vaccine against COVID while on twice-daily treatment with 75 mg of evobrutinib. SD, standard deviation; CI, confidence interval; Q1, 25% quantile; Q3, 75% quantile; Min, minimum; Max, maximum.

[0079] Figure 15A table is shown summarizing the frequency and summary statistics of the time between the second dose of the mRNA vaccine against COVID-19 and the assessment of S1 / S2 IgG antibody levels after vaccination in the context of twice-daily treatment with 75 mg of evobrutinib in the study. SD, standard deviation; Q1, 25% quantile; Q3, 75% quantile; Min, minimum; Max, maximum.

[0080] Figure 16 Shown are boxplots of S1 / S2 IgG antibody levels from pre- and post-vaccination samples of patients who received two doses of an mRNA vaccine against COVID while on treatment, divided into categories defined by the time between the second dose of the mRNA COVID-19 vaccine and the assessment of S1 / S2 IgG antibody levels after vaccination (all patients were on treatment with evobrutinib 75 mg BID). CI, confidence interval.

[0081] Figure 17 A table is shown summarizing the frequency in different categories of fold change in S1 / S2 IgG antibody levels of pre- and post-vaccination samples depending on the time between the second dose of mRNA vaccine against COVID and the assessment of S1 / S2 IgG antibody levels after vaccination (all patients were on evobrutinib 75 mg BID treatment).

[0082] Figure 18 A table is shown summarizing the S1 / S2 IgG antibody levels (AU / ml) and fold changes in pre- and post-vaccination samples from participants (N=45) in the VAC-OLE II study who received a full cycle of either mRNA or non-mRNA vaccines against COVID-19 while on twice-daily treatment with 75 mg of evobrutinib. a) Pre-vaccination time point sample collection date occurred before the date of the first vaccination. b) Post-vaccination time point sample collection date occurred ≥ the date of the full vaccination cycle plus 28 days. c) Fold change to post-vaccination is the ratio of the geometric mean of S1 / S2 IgG antibodies post-vaccination to the geometric mean of S1 / S2 IgG antibodies pre-vaccination. AU, arbitrary units; CI, confidence interval; Min, minimum value; Max, maximum value; SD, standard deviation.

[0083] Figure 19 Shown are boxplots of S1 / S2 IgG antibody levels at pre- and post-vaccination time points for participants in the VAC-OLE II study (N=45).

[0084] Figure 20A table is shown summarizing the frequencies within different categories of fold change in S1 / S2 IgG antibody levels from pre- to post-vaccination for participants in the VAC-OLE II study (N=45). The fold change to post-vaccination is the ratio between the geometric mean post-vaccination S1 / S2 IgG antibody levels and the geometric mean pre-vaccination S1 / S2 IgG antibody levels, as determined for each individual participant.

[0085] Figure 21 A table summarizing S1 / S2 IgG antibody levels in pre- and post-vaccination samples among participants in the VAC-OLE II study, when subgrouped based on their pre-vaccination serostatus; seropositive = S1 / S2 antibody level ≥15 AU / mL, and seronegative = S1 / S2 antibody level <15 AU / mL. a) Pre-vaccination timepoint sample collection date occurred before the first vaccination date. b) Post-vaccination timepoint sample collection date occurred ≥ the date of the full vaccination cycle plus 28 days. AU, arbitrary units; CI, confidence interval; Min, minimum value; Max, maximum value; SD, standard deviation.

[0086] Figure 22 Shown are boxplots of S1 / S2 IgG antibody levels at pre- and post-vaccination time points for participants in the VAC-OLE II study who were subgrouped based on their pre-vaccination serostatus (N=13 for pre-vaccination seropositive; N=32 for pre-vaccination seronegative).

[0087] Figure 23 Tables are shown summarizing the frequencies and summary statistics (i.e., S1 / S2 antibody levels (AU / mL) and fold change by time between completed vaccination cycle and post-vaccination sampling) for participants in subgroups based on the time elapsed between the completion of a vaccination cycle and analysis of their post-vaccination samples. a) Pre-vaccination time point sample collection date occurred before the first vaccination date. b) Post-vaccination time point sample collection date occurred ≥ the date of the completed vaccination cycle plus 28 days. c) Fold change to post-vaccination is the ratio of the geometric mean of S1 / S2 IgG antibodies post-vaccination to the geometric mean of S1 / S2 IgG antibodies pre-vaccination. AU, arbitrary units; CI, confidence interval; Min, minimum value; Max, maximum value; SD, standard deviation.

[0088] Figure 24Box plots showing S1 / S2 IgG antibody levels at pre- and post-vaccination time points for participants in the VAC-OLE II study, who were subgrouped based on the time elapsed between receipt of a complete cycle of mRNA or non-mRNA COVID-19 vaccine and analysis of their post-vaccination samples.

[0089] Figure 25 A table is shown summarizing the fold change in S1 / S2 antibody levels in the VAC-OLE II study for participants in subgroups based on the time elapsed between receiving a full cycle of mRNA or non-mRNA COVID-19 vaccines and analysis of their post-vaccination samples. a) The fold change to post-vaccination is the ratio of the geometric mean post-vaccination S1 / S2 IgG antibody levels to the geometric mean pre-vaccination S1 / S2 IgG antibody levels, as determined for each individual participant.

[0090] Figure 26 Shown are box plots of S1 / S2 IgG antibody levels at pre-vaccination, post-vaccination, and post-boost vaccination time points in the subgroup of participants who received a booster vaccination in the VAC-OLE II study (N=14).

[0091] Figure 27 A table is shown listing S1 / S2 IgG antibody levels after booster vaccination, fold change from post-vaccination to post-boost, and pre-vaccination to post-boost in a subset of participants in the VAC-OLE II study (N=14). a) Post-boost sample collection date occurred 7 or more days after the booster vaccination date. b) Fold change from post-vaccination to post-boost vaccination is the ratio of the geometric mean S1 / S2 IgG antibody level after booster vaccination to the geometric mean S1 / S2 IgG antibody level after vaccination. c) Fold change from pre-vaccination to post-boost vaccination is the ratio of the geometric mean S1 / S2 IgG antibody level after booster vaccination to the geometric mean S1 / S2 IgG antibody level before vaccination. d) Summary statistics are based on participants who received the booster vaccine. AU, arbitrary units; CI, confidence interval; Min, minimum; Max, maximum; SD, standard deviation. DETAILED DESCRIPTION

[0092] Although the present disclosure is described in detail above and below, it should be understood that the disclosure is not limited to the specific methods, procedures and reagents described in the disclosure, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the disclosure, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0093] Hereinafter, some elements of the present disclosure will be described in more detail, including the description of specific embodiments. However, the various described embodiments and preferred embodiments should not be interpreted as limiting the present disclosure to only the embodiments clearly described. The description should be understood to support and include embodiments that combine the embodiments clearly described with any number of disclosed and / or preferred elements in any way. In addition, any arrangement and combination of all described elements in this application should be considered to be disclosed by the specification sheet of the application, except that this causes logical contradiction or the context otherwise indicates.

[0094] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present disclosure should have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature and techniques referred to in the present disclosure, such as the nomenclature and techniques of organic chemistry, chemical synthesis, biology, pharmaceutical and medicinal chemistry, medicine, pharmacology or toxicology, are those well-known and commonly used in the art. Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well-known in the art and as described in the references cited and discussed throughout the present disclosure.

[0095] Autoimmune diseases The immune system protects the body from infection. When the immune system malfunctions, it can attack the body's healthy cells. Autoimmune diseases are conditions in which the body's immune system mistakes its own healthy tissue for foreign and attacks it, causing inflammation that can affect many parts of the body, depending on the specific type of autoimmune disease a person has.

[0096] An overview of autoimmune diseases, the current scientific understanding of the underlying mechanisms, and detailed information on their treatment in clinical practice can be obtained from common textbooks in the field, such as "The Autoimmune Diseases Book" (2014), 5th edition, edited by Rose and Mackay, published by Elsevier Inc., ISBN: 978-0-12-384929-8, https: / / doi.org / 10.1016 / C2009-0-64586-4; or "Autoimmune Diseases, Acute and Complex Situations" (2011), 1st edition; edited by Khamashta and Ramos-Casals, published by Springer London, ISBN: 978-0-85729-358-9, https: / / doi.org / 10.1007 / 978-0-85729-358-9.

[0097] There are ~100 different types of autoimmune diseases. Some are more common, such as type 1 diabetes, multiple sclerosis, lupus, and rheumatoid arthritis, while others are rare. Most autoimmune diseases are incurable, and some require lifelong treatment to manage symptoms or prevent further damage to healthy tissue (Lleo et al., Autoimmunity Reviews (2010), vol. 9, p. A259-266).

[0098] Research into the treatment of autoimmune diseases has made tremendous progress in improving our understanding of the disease mechanisms that drive pathology. Dysregulation of B lymphocytes plays a major role in many rheumatic and neuroinflammatory diseases, but T cells and innate immune cells also play a crucial role in autoimmune diseases.

[0099] Systemic lupus erythematosus (SLE) SLE is a potentially fatal chronic multisystem autoimmune disorder that generally affects women from adolescence to menopause. SLE can affect connective tissue, joints, skin, brain, lungs, kidneys, and blood vessels. Lupus cannot be cured, and the severity of the disease can range from mild to life-threatening. The cause of SLE is unknown, but is believed to be a combination of environmental, genetic, and hormonal factors. Some of the strongest genetic links to SLE are rare single gene defects in the complement components C1Q and C4. In most patients, SLE is a quantitative trait in which several genes contribute to the risk of developing the disease; genome-wide association studies have implicated several candidate loci, including interferon (IFN) regulatory factor 5 (IRF5), mutations of which are associated with elevated levels of type 1 IFN family molecules in patients with SLE. For a review, see Kaul et al., Nature Reviews Disease Primers (2016), vol. 2(1), art. 16039.

[0100] Rheumatoid arthritis (RA) RA is a chronic disease and the most common form of autoimmune arthritis. About 75% of RA patients are women, and more than one million Americans are affected. Although less affected, symptoms tend to be more severe in men. RA causes joint pain, stiffness, swelling, and leads to reduced joint mobility and long-term damage to cartilage tissue and surrounding bones. In most cases, the small joints of the hands and feet are most commonly affected, and over time, other organs such as the eyes, skin or lungs may also be affected to a lesser extent in some patients. What causes RA is unclear, among which infection, smoking and heredity are risk factors that can affect RA. Current treatments include medications, balance exercises and directed rest on the affected joints, as well as surgery to deal with joint and bone damage (Bullock et al., Med. Princ. Pract. (2018), vol. 27, p. 501-507).

[0101] Pemphigus vulgaris (PV) PV manifests itself as blisters and sores on the skin and mucous membranes, caused by autoantibodies against specific proteins in these tissues. The exact cause of the disease is unclear, but several medications, including penicillamine, ACE (angiotensin-converting enzyme) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs), may be contributing factors. If left untreated, PV can be dangerous, and in some cases, complications, including severe infection, can be fatal. Treatment generally includes the use of corticosteroids to suppress the immune system, wound care similar to that of severe burns, and treatment aimed at preventing infection (see Scully & Challacombe, Crit. Rev. Oral. Biol. Med. (2002), vol. 13, p. 397).

[0102] Sjögren's syndrome (SJ) In Sjögren's syndrome, the body's immune cells attack the glands in the body that produce tears, saliva, and other body fluids. The amount of water produced by the glands decreases, resulting in dryness of the mouth, eyes, nose, throat, and skin, but the disease can also affect other parts of the body, including the joints, lungs, kidneys, blood vessels, digestive organs, and nerves. Most people affected by Sjögren's syndrome are women. The disease is sometimes associated with other autoimmune conditions, such as rheumatoid arthritis and lupus. Current treatments mainly address individual symptom relief, depending on the affected tissues. Interventions may include eye drops and sprays to keep the eyes moist, medicinal candies and gels to keep the mouth moist, and medications to support the body in producing more tears and saliva. For a review, see Venables, Best. Pract. Res. Clin. Rheumatol. (2004), vol. 18(3), p. 313-329.

[0103] Multiple sclerosis (MS) MS is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). MS is a multifactorial immune-mediated disease caused by a complex gene-environment interaction. The pathological characteristic of MS is the accumulation of demyelinating lesions in the white and gray matter of the brain and spinal cord. The clinical manifestations and progression of MS are diverse; in most patients, the initial stage of the disease is characterized by reversible episodes of neurological deficits (called relapses) that usually last for days or weeks (clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS)). Over time, the development of permanent neurological deficits and the progression of clinical disability become significant (called secondary progressive MS (SPMS)). A small number of patients have a progressive disease course since onset, which is called primary progressive MS (PPMS)). Each MS subtype can be divided into active or inactive based on clinical assessment of relapses or lesion activity detected using MRI; in addition, patients with PPMS or SPMS can be classified according to whether disability has progressed within a given time. MS generally affects young adults, with an onset age between 20 and 40 years, and has a higher prevalence in women, although some patients experience their initial demyelinating event in childhood or adolescence, generally with RRMS (Filippi et al., Nature Reviews Disease Primers (2018), vol. 4, art. 43).

[0104] Idiopathic thrombocytopenia (ITP) ITP is a hematological condition characterized by a low platelet count of less than 100,000 per microliter. The platelet deficiency can be caused by the production of thrombocytopenia, immune-mediated destruction, or increased splenic sequestration, but generally involves autoantibodies against glycoproteins expressed on megakaryocytes, the precursor cells of platelets. The symptoms of ITP can vary, but generally tend to be those of thrombocytopenia, such as petechiae, purpura, mucosal bleeding such as epistaxis, and in the most severe cases, fatal intracranial hemorrhage. ITP is idiopathic in 80% of cases, and primary ITP is often considered an autoimmune condition. However, 20% of ITP cases may be secondary to coexisting diseases. For example, ITP is often seen after infection. For a review, see Samson et al., Cureus (2019), vol. 11(10), p. e5849.

[0105] Chronic urticaria (CU) CU is characterized by wheals, angioedema, or both that last longer than 6 weeks. CU can be further divided into chronic spontaneous urticaria (CSU) and chronic induced urticaria (CIndU). CSU is defined as the absence of a specific trigger for the skin lesions, whereas CIndU lesions are activated by specific stimuli (e.g., symptomatic dermatographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibration angioedema, cholinergic urticaria, contact urticaria, or aquagenic urticaria).

[0106] The pathophysiology underlying CSU involves mast cell and basophil degranulation with the release of histamine, leukotrienes, prostaglandins (PGs) and different inflammatory mediators. Wheals are characterized by edema, mast cell degranulation and a perivascular mixed infiltration fluid consisting mainly of CD4+ lymphocytes, monocytes, neutrophils, eosinophils and basophils, similar to the late reaction mediated by allergens. The cytokine profile is characterized by an increase in interleukin (IL) -4, IL-5 and interferon-γ, which suggests a mixed type 1 T helper cell (Th1) / type 2 T helper cell (Th2) response (Choi et al., Immunol.Allergy Clin.North Am. (2010), vol.30, p.75-101; Min et al., Allergy Asthma Immunol. Res. (2019), vol.11, p.470).

[0107] Myasthenia gravis (MG) Myasthenia gravis (MG) is an autoimmune disease that affects the postsynaptic membrane at the neuromuscular junction. Its primary manifestation is muscle weakness. Respiratory muscle weakness can rarely occur, leading to a life-threatening condition requiring intensive care and respiratory support. However, with adequate treatment, most patients with MG remain stable with only mild muscle weakness and are fully able to carry out their daily functions.

[0108] 80% of patients with MG have detectable antibodies to acetylcholine (ACh) receptors (AChRs), while a minority instead have antibodies to muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4). Anti-LRP4 antibodies may be less specific for MG than those to AChRs and MuSKs, and this MG subgroup is less well established than other subgroups. In 10%-15% of patients with systemic MG, no antibodies are detected, usually because the sensitivity of the assay used is too low.

[0109] MG is divided into subtypes based on clinical presentation, age of onset, autoantibody patterns, and thymic pathology. These subgroups reflect differences in epidemiology, disease mechanisms, severity, and treatment response, and help guide personalized treatment. Ocular MG and MG with anti-LRP4 antibodies tend to be milder, while MuSK MG and possibly thymoma MG tend to be more severe. The thymus plays a key role in AChR-mediated MG, and thymectomy is the treatment of choice for patients with these subtypes. In 10% of patients, MG is induced by a thymoma, and thymectomy is the treatment of choice for patients with thymoma or thymic hyperplasia (Gilhus et al., Nature Reviews Disease Primers (2019), vol. 5, art. 30).

[0110] Neuromyelitis optica (NMO) / neuromyelitis optica spectrum disorder (NMOSD) Neuromyelitis optica (NMO) is characterized by simultaneous or sequential attacks of acute optic neuritis (ON) and transverse myelitis (TM). In ≥80% of cases, NMO is caused by pathogenic IgG autoantibodies against aquaporin 4 (AQP4-IgG), the most abundant water channel protein in the central nervous system (CNS). Approximately 10%-40% of individuals with NMO who lack AQP4-IgG have IgG autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG); notably, MOG-IgG is also present in a subset of patients (primarily children) with acute disseminated encephalomyelitis (ADEM).

[0111] AQP4-IgG-positive NMO is primarily an autoimmune astrocytopathy, although secondary damage to oligodendrocytes and neurons occurs as a result of astrocyte dysfunction and loss and, most likely, bystander inflammation. In contrast, primary demyelination is found in those with MOG-IgG. NMO has also been described in patients with sarcoidosis, infectious diseases, connective tissue disorders (CTDs), and paraneoplastic neurological disorders, although cases are rare. In a small subset of patients, the cause remains unknown (referred to as idiopathic NMO).

[0112] AQP4-IgG-positive and MOG-IgG-positive NMO typically have a relapsing disease course without major disease progression between episodes, although cases of monophasic MOG-IgG-positive disease have been reported. Untreated NMO may lead to severe, persistent visual and motor dysfunction due to incomplete recovery from acute episodes (Jarius et al., Nature Reviews Disease Primers (2020), vol 6, art. 85).

[0113] In 2015, when physicians defined a large range of clinical manifestations as NMOSD, including spinal cord and / or optic nerve involvement and other indications, the term "spectrum disorder" was added to the official name NMO because they are all attributed to the same immune mechanism. NMOSD is a term used to include NMO (with both optic neuritis and myelitis) and limited phenotypes such as relapsing optic neuritis or myelitis. It is an autoimmune disorder that is mediated by antibodies against aquaporin-4 (AQP4) water channels in most cases, and for most patients, serum AQP4 antibodies can be detected by immunoassay. Making a clear diagnosis of antibody-negative NMOSD can be challenging because the more popular relapsing-remitting multiple sclerosis (RRMS) may behave similarly. For a review, see Matthews et al., Neurology (2013), vol. 80, p. 1330.

[0114] The term spectrum disorder was added to the formal name NMO in 2015 when physicians defined a broad spectrum of clinical manifestations as NMOSD, including spinal cord and / or optic nerve involvement, among other indications, because they are all attributed to the same immune mechanism.

[0115] Other inflammatory diseases There are further inflammatory diseases that, even if not autoimmune diseases, nevertheless show similarities to autoimmune diseases in terms of misdirected inflammation and its clinical manifestations and the underlying inflammatory response. Examples of such inflammatory diseases that are particularly relevant with respect to the present disclosure are discussed below.

[0116] Large vessel vasculitis (LVV) LVV is characterized by inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV includes two different conditions, giant cell arteritis (GCA) and Takayasu's arteritis (TAK), although the phenotypic spectrum of primary LVV is complex. Nonspecific symptoms often predominate, and therefore patients with LVV present to a range of healthcare providers and locations. Rapid diagnosis, expert treatment arrangements, and early treatment are key to good patient outcomes. Unfortunately, disease recurrence remains common, and chronic vascular complications are a significant source of morbidity. Although accurately monitoring disease activity is challenging, advances in vascular imaging technology and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity and disease activity.

[0117] GCA is an idiopathic inflammatory condition characterized by granulomatous arteritis in temporal artery biopsy (TAB) specimens. It is now recognized that GCA encompasses a broad phenotypic spectrum of inflammation of medium- and large-arteries. Nomenclature has evolved to reflect this, and the terms large-vessel GCA (LV-GCA), cranial GCA (C-GCA), and LV-GCA with cranial involvement are now suggested, depending on the site of inflammation.

[0118] TAK was first described in 1908 as a series of retinal vascular abnormalities. Its association with absent or weakened peripheral pulses led to the term "pulseless disease", and autopsy studies have shown panarteritis involving the aorta and its major branches. Although early descriptions of the disease involved individuals of Japanese descent, it is now recognized that TAK occurs worldwide. Further, advances in our understanding of disease pathophysiology have paved the way for new biological treatments targeting important disease mediators in both giant cell arteritis and Takayasu's arteritis (Pugh et al., Nature Reviews Disease Primers (2021), vol. 7 (1), art. 93).

[0119] Graft-versus-host disease (GVHD) Allogeneic hematopoietic cell transplantation (HCT) is an important treatment option for a variety of malignant and non-malignant conditions. As the number of allogeneic HCTs continues to increase, there is increasing attention being paid to improvements in supportive care, infection prevention, immunosuppressive drugs, and DNA-based tissue typing. However, graft-versus-host disease (GVHD) remains the most common and serious complication after allogeneic HCT.

[0120] GVHD has acute and chronic forms. Acute GVHD is characterized by damage to the skin, liver, and gastrointestinal tract, while chronic GVHD has a more diverse presentation and may resemble autoimmune syndromes with, for example, eosinophilic fasciitis, scleroderma-like skin disease, and salivary and lacrimal gland involvement. For epidemiological purposes, acute GVHD occurs within the first 100 days after transplantation, while chronic GVHD occurs after day 100 after transplantation. However, it is now recognized that the clinical features of chronic GVHD can appear within 100 days after transplantation, and that the features of acute GVHD and chronic GVHD may coexist, leading to a new definition in which the diagnosis focuses on the constellation of symptoms rather than the time of onset (Choi et al., Immunol. Allergy Clin. North Am. (2010), vol. 30 (1), p. 75-101).

[0121] asthma Asthma is a heterogeneous disease characterized by chronic airway inflammation and variable remodeling that leads to a range of clinical manifestations, treatment responses, and natural histories throughout the patient's life course. Asthma involves a range of respiratory symptoms, including wheezing, shortness of breath, chest tightness, and cough, which vary in intensity over time, as well as variable expiratory airflow limitation and airway hyperresponsiveness to a range of stimuli, such as exercise and inhaled irritants. At the population level, a subset of individuals with asthma exhibit an accelerated decline in lung function over their lifetime, which manifests as fixed airflow obstruction in severe chronic disease. This decline is particularly pronounced in late-onset asthma. The origin and severity of asthma are driven by strong genetic and environmental factors. Although most cases of asthma begin in childhood and are associated with IgE-dependent sensitization to common environmental allergens, asthma can also occur later in life. Adult-onset asthma often occurs in the absence of an allergic reaction, but may be accompanied by intolerance to NSAIDs, sinusitis, and nasal polyps. Intolerance to NSAIDs is likely due to reduced production of the anti-bronchial constrictor prostaglandin E2 in inflammatory conditions. For a review, see Holgate et al., Nature Reviews Disease Primers (2015), vol. 25(1), art. 15025.

[0122] In clinical practice, there is a considerable need for the use of immunosuppressive or immunomodulatory agents for the medical treatment of autoimmune or other inflammatory diseases. However, at the same time, such patients are at risk due to infections, especially viral and / or bacterial infections.

[0123] bacterial infectionIt is known that various types of bacteria, in particular various types of pathogenic bacteria, can potentially infect, more particularly pathologically infect, one or more host species, including warm-blooded animals, mammals and humans. Generally, when the body of an organism (i.e., the body of a host) is invaded by one or more pathogenic bacteria, and the host's body is unable to control or is unable to adequately control the replication and spread of the pathogens within the host's body or a part or organ thereof, infection by (pathological) bacteria often leads to a bacterial disease or infectious bacterial disease in the host, and thereby causes a bacterial disease or condition.

[0124] Other bacteria are characterized as opportunistic pathogens and cause disease primarily in people with immunosuppression or cystic fibrosis. Examples of these opportunistic pathogens include Pseudomonas aeruginosa (causing diseases such as hospital-acquired infection, ventilator-associated pneumonia, a type of lung infection that occurs in people who use mechanical ventilators in hospitals, and various sepsis syndromes), Burkholderia cenocepacia, and Mycobacterium avium (found in fresh and salt water, household dust, and soil, causing a disease in humans called Mycobacterium avium-intracellulare infection or Mycobacterium avium complex infection, usually only in immunocompromised patients or those with severe lung disease).

[0125] Preferably, the bacterial infection, disease or condition includes, but is preferably not limited to, anthrax, cholera, diphtheria, Haemophilus influenzae, meningococcal meningitis, pertussis, plague, pneumococcal disease, Streptococcus pneumoniae, tetanus, tuberculosis and typhus.

[0126] Antibacterial vaccines that can be used in the present disclosure include, but are not limited to, one or more of the following vaccines, but are preferably not limited to the following vaccines: 23-polyvalent pneumococcal vaccines, such as Pneumovax 23 or Pneumovax 23 (Pro), 13-valent pneumococcal vaccines, such as Prevnar 13 or Prevnar 13(Pro), meningococcal conjugate vaccines, such as Menactra or Menactra(Pro), Haemophilus b conjugate (prp-t) vaccines, such as ActHIB or ActHIB(Pro), serogroup B meningococcal vaccines, such as Bexsero or Bexsero(Pro), adsorbed anthrax vaccines, such as Biothrax or Biothrax(Pro), Haemophilus b conjugate (prp-t) vaccines, such as Hiberix or Hiberix(Pro), Haemophilus b conjugate (prp-omp) vaccines, such as liquid PedvaxHIB or liquid PedvaxHIB(Pro), Haemophilus b conjugate (prp-t) vaccines / meningococcal conjugate vaccines, such as MenHibrix, meningococcal polysaccharide vaccines, such as Menomune A / C / Y / W-135, meningococcal conjugate vaccine, such as Menveo or Menveo (Pro), 7-valent pneumococcal vaccine, such as Prevnar or Prevnar (Pro), tetanus toxoid, such as Te Anatoxal Berna, tetanus toxoid, such as Tetanus Toxoid Adsorbed, group B meningococcal vaccine, such as Trumenba or Trumenba (Pro) typhoid vaccine, inactivated, such as Typhim Vi or Typhim Vi (Pro) cholera vaccine, live, such as Vaxchora or Vaxchora (Pro), and / or typhoid vaccine, live, such as Vivotif Berna.

[0127] Viral infection Many types of viruses are known that can potentially infect, more specifically pathologically infect, one or more host species, including warm-blooded animals, mammals, and humans. Generally, a viral infection, often resulting in a viral disease or infectious viral disease, occurs in a host when the body of an organism (i.e., the body of a host) is invaded by a pathogenic virus and infectious viral particles (e.g., virions) attach to and enter susceptible cells of the body of the host or subject.

[0128] Basic structural features, such as genome type, virion shape, and replication site, are often shared among viral species within the same family: Double-stranded DNA families: Three are non-enveloped (Adenoviridae, Papillomaviridae, and Polyomaviridae), and two are enveloped (Herpesviridae and Poxviridae). All non-enveloped families have icosahedral capsids.

[0129] Some double-stranded DNA viruses: Hepadnaviridae. These viruses are enveloped.

[0130] A family of single-stranded DNA viruses infects humans: Parvoviridae. These viruses are non-enveloped.

[0131] Positive single-stranded RNA families: Three are non-enveloped (Astroviridae, Caliciviridae, and Picornaviridae), and four are enveloped (Coronaviridae, Flaviviridae, Retroviridae, and Togaviridae). All non-enveloped families have icosahedral nucleocapsids.

[0132] Negative single-stranded RNA families: Arenaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae. All are enveloped with a helical nucleocapsid.

[0133] Double-stranded RNA genome: Reoviridae.

[0134] Hepatitis D virus has not yet been assigned to a family but is clearly distinct from other families that infect humans.

[0135] Viruses known to infect humans but not yet associated with disease: Family Anelloviridae and Genus Dependovirus. Both taxa are non-enveloped, single-stranded DNA viruses.

[0136] The family of viruses that infect humans provides rules that may help physicians and medical microbiologists / virologists.

[0137] Generally speaking, DNA viruses replicate in the nucleus, while RNA viruses replicate in the cytoplasm. Exceptions to this rule are known: poxviruses replicate in the cytoplasm, while orthomyxoviruses and hepatitis D virus (RNA viruses) replicate in the nucleus.

[0138] Some types of viruses have segmented genomes, such as the Bunyaviridae, Orthomyxoviridae, Arenaviridae, and Reoviridae (known by the acronym BOAR). All of these are RNA viruses.

[0139] Some viruses are almost exclusively transmitted by arthropods: the bunyaviruses, flaviviruses, and togaviruses. Some reoviruses are transmitted from arthropod vectors. All of these are RNA viruses.

[0140] One family of enveloped viruses causes gastroenteritis (Coronaviridae). All other viruses associated with gastroenteritis are non-enveloped.

[0141] Table 1 below summarizes some of the most clinically important pathogenic viruses known to afflict a variety of hosts, including humans, along with the type, family, exemplary transmission pathway, and infection / disease generally attributed to the respective virus. However, the clinical characteristics of viruses can vary significantly among species within the same family.

[0142] Table 1: Preferably, all of the viruses and / or viral conditions given above are considered to be clinically relevant viruses and / or viral conditions in the context of the use according to the invention and / or in the context of the method of treatment according to the invention. More preferably, for example in MS, a number of vaccine-preventable infectious diseases are relevant because MS itself or its treatment increases the risk of infection or adverse outcomes. These mainly include hepatitis B virus (HBV) and varicella-zoster virus (VZV). Other infectious diseases may include measles, influenza, poliovirus, pneumococcus, diphtheria, tetanus and Bordetella pertussis, COVID-2 and / or COVID-19. Vaccines against COVID-2 and / or COVID-19 are now available and further alternative vaccines will soon be available.

[0143] Viral infections and / or the resulting illnesses can generally be detected by clinical manifestations, signs and / or symptoms, including but not limited to severe muscle and joint pain preceding a fever, or a skin rash and swollen lymph nodes. Standard laboratory investigations may help detect viral infections. Laboratory investigations may also be used to diagnose bacterial infections associated with viral infections. Viral infections generally have a limited duration, and treatment according to the prior art generally consists of relieving symptoms, and antipyretic and analgesic medications are usually prescribed.

[0144] However, the best protection for a subject from the potentially serious and harmful consequences of an infection is to prevent amelioration of the infection itself. It is currently believed that the most advantageous method of preventing or ameliorating the invention is vaccination of a subject at risk of the infection.

[0145] However, preventive measures against infections, such as vaccination, generally require a correct immune response of the respective body and are therefore generally recommended well before major medical interventions, i.e. surgery, chemotherapy, radiotherapy or the start of immunosuppressive treatment, and / or well after the end of the respective major medical intervention.

[0146] Therefore, if any, preventive measures against infections, such as vaccinations, which require a correct immune response of the respective body, are generally recommended long before the start of the respective immunosuppressive treatment and / or long after the end of the respective immunosuppressive treatment.

[0147] In this context, vaccination is preferably the administration of a vaccine to help the immune system develop protection against a disease, preferably an infectious disease. Vaccines generally contain the causative agent of the corresponding disease, preferably a microorganism or virus in a weakened, live or killed / dead state, or a protein or toxin from the corresponding organism. In stimulating the body's adaptive immunity, they help prevent disease from infectious diseases. Vaccination is the most effective method for preventing infectious diseases and is therefore generally considered important and advantageous / desirable in people whose immunity is reduced due to immunosuppressive therapy.

[0148] Infectious diseases for which vaccines are available or at least desirable include, but are not limited to, influenza and influenza-like illnesses, such as infections induced by parainfluenza viruses (causing croup, pneumonia, bronchiolitis and / or the common cold) and coronaviruses.

[0149] Antiviral vaccines that can be used in the present disclosure include, but are not limited to, one or more of the vaccines given below, but are preferably not limited to the vaccines given below: Influenza virus vaccine, inactivated, such as Afluria or Afluria (Pro), Influenza virus vaccine, inactivated, such as Fluarix Quadrivalent or Fluarix Quadrivalent (Pro), Influenza virus vaccine, inactivated, such as Flublok Quadrivalent or Flublok Quadrivalent (Pro), Influenza virus vaccine, inactivated, such as Fluvirin or Fluvirin (Pro), Hepatitis B vaccine for adults, such as Engerix-B, Influenza virus vaccine, inactivated, such as Flublok or Flublok (Pro), Herpes zoster vaccine, live, such as Zostavax or Zostavax (Pro), Human papillomavirus vaccine, such as Gardasil 9 or Gardasil 9 (Pro), Influenza virus vaccine, inactivated, such as Flucelvax Quadrivalent or Flucelvax Quadrivalent (Pro), Herpes zoster vaccine, inactivated, for example, Shingrix or Shingrix (Pro), Influenza virus vaccine, live, trivalent, for example, FluMist or FluMist (Pro), Influenza virus vaccine, inactivated, for example, Fluzone, Influenza virus vaccine, inactivated, for example, Fluzone High-Dose or Fluzone High-Dose (Pro), Influenza virus vaccine, inactivated, for example, Fluad or Fluad (Pro), Influenza virus vaccine, live, trivalent, for example, FluMist Quadrivalent, Yellow fever vaccine, for example, Stamaril or Stamaril (Pro), Smallpox vaccine, for example, ACAM2000 or ACAM2000 (Pro), Influenza virus vaccine, inactivated, for example, Afluria Quadrivalent or Afluria Quadrivalent (Pro), Influenza virus vaccine, inactivated, such as Agriflu, Measles virus vaccine, such as Attenuvax, Human papillomavirus vaccine, such as Cervarix or Cervarix (Pro), Smallpox vaccine, such as Dryvax, Hepatitis B pediatric vaccine, such as Engerix-B Pediatric, Influenza virus vaccine, inactivated, such as Fluarix or Fluarix (Pro), Influenza virus vaccine, inactivated, such as Flucelvax, Influenza virus vaccine, inactivated, such as FluLaval or FluLaval (Pro), Influenza virus vaccine, inactivated,For example, FluLaval Preservative-Free Quadrivalent, Influenza virus vaccine, inactivated, for example, FluLaval Quadrivalent or FluLaval Quadrivalent (Pro), Influenza virus vaccine, inactivated, for example, Fluzone High Dose Quadrivalent, Influenza virus vaccine, inactivated, for example, Fluzone Intradermal Quadrivalent, Influenza virus vaccine, inactivated, for example, Fluzone Quadrivalent or Fluzone Quadrivalent (Pro), Hepatitis A adult vaccine, for example, Havrix or Havrix (Pro), Hepatitis A pediatric vaccine, for example, Havrix Pediatric, Rabies vaccine, human diploid cells, for example, Imovax Rabies or Imovax Rabies (Pro), Poliovirus vaccine, inactivated, for example, Ipol or Ipol (Pro), Japanese encephalitis vaccine vacc)sa14-14-2, inactivated, such as Ixiaro or Ixiaro (Pro), Rubella virus vaccines, such as Meruvax II, Mumps virus vaccines, such as Mumpsvax, Rabies vaccines, purified chick embryo cells, such as RabAvert or RabAvert (Pro), Hepatitis B adult vaccines, such as Recombivax HB Adult, Hepatitis B adult vaccines, such as Recombivax HB Dialysis Formulation, Hepatitis B pediatric vaccines, such as Recombivax HB Pediatric / Adolescent, Rotavirus vaccine, such as Rotarix or Rotarix(Pro), Rotavirus vaccine, such as RotaTeq or RotaTeq(Pro), Hepatitis A adult vaccine, such as Vaqta or Vaqta(Pro), Hepatitis A pediatric vaccine, such as Vaqta Pediatric, Varicella virus vaccine, such as Varivax or Varivax(Pro), and / or Yellow fever vaccine, such as YF-Vax or YF-Vax(Pro).

[0150] Coronavirus Coronavirus-induced infections include epidemics or pandemics caused by SARS-CoV, HCoV NL63, HCoV HKU1, MERS-CoV and SARS-CoV-2 / COVID-19 and / or their mutants or successors.

[0151] Coronaviruses preferably constitute the subfamily Orthocoronavirinae, within the family Coronaviridae, order Nidovirales, and kingdom Riboviria. They are considered to be enveloped viruses with a positive-sense single-stranded RNA genome and / or a helically symmetrical nucleocapsid. The latter is generally enclosed in an icosahedral protein shell. The genome size of coronaviruses is believed to range from about 26 to 32 kilobases, making it one of the largest genomes among RNA viruses. In addition, they generally have a characteristic club-shaped spike protruding from their surface, which produces an image reminiscent of the solar corona in electron micrographs, and their name is believed to derive from this.

[0152] Human coronaviruses were discovered in the 1960s, including viruses called B814, 229E, IBV (infectious bronchitis virus), and OC43. The new virus group has become known as coronavirus due to its unique morphological appearance. Since then, a variety of other human coronaviruses have been identified, including SARS-CoV in 2003, HCoV NL63 in 2004, HCoV HKU1 in 2005, MERS-CoV in 2012, and SARS-CoV-2 in 2019. However, a large number of animal coronaviruses have also been identified since the 1960s.

[0153] The COVID-19 pandemic has caused unprecedented disruption to normal social and economic life worldwide. As of June 2022, over 500 million cases have occurred worldwide, with over 6 million deaths (https: / / covid19.who.int / ). The disease is caused by the novel coronavirus SARS-CoV-2, which infects cells through the angiotensin-converting enzyme receptor type 2, which is expressed on cells of the respiratory tract and also on critical tissues such as the brain.

[0154] For use according to the present disclosure, vaccines against COVID-19 and / or its mutants are highly desirable. Several vaccines against the virus that causes COVID-19 (i.e., SARS-COV-2) are now available, and further vaccines are in development, approaching approval by the Health Authority. Actual and / or candidate approaches include subunit vaccines containing viral proteins, particularly the surface membrane spike protein that mediates receptor attachment; nucleic acid-based vaccines that enable host cells to produce viral antigens, i.e., spike proteins, or immunogenic portions thereof; and whole microbial approaches, such as live attenuated vaccines, inactivated vaccines, or viral vector vaccines.

[0155] Particularly preferred for use as vaccines in the context of the present invention are coronavirus vaccines, in particular COVID-19 vaccines, including, but not limited to Vaccines based on mRNA technology, such as: mRNA-1273 (Moderna / NIAID vaccine), BNT162b2 (Pfizer / BioNTech vaccine); Vector-based vaccines, preferably adenovirus / vector-based vaccines, such as: Ad26.COV2.S (Johnson & Johnson / Janssen Pharmaceuticals vaccine), AZD1222 (ChAdOx1-S) (AstraZeneca / University of Oxford vaccine), Gam-COVID-Vac / SputnikV (Gamaleya Institute), Ad5-nCoV (CanSino Biologics); Vaccines based on virus-like particles (VLPs), such as: CVnCoV(CureVac), CoVLP (Medicago); DNA-based vaccines, such as: INO-4800 (Inovio Pharmaceuticals / International Vaccine Institute); Protein-based vaccines, such as: ZF2001 (Anhui Zhifei Longcom Biopharmaceutical Co., Ltd.), preferably with adjuvant, NVX-CoV2373 (Novavax), preferably with adjuvant; Inactivated virus-based or killed virus-based vaccines, such as: Covaxin / BBV152(Bharat Biotech / Indian Council of Medical Research(ICMR) / National Institute for Virology(NIV), CoronaVac (Sinovac), Sinopharm / Wuhan Institute of Biological Products Co., Ltd. BBIBP-CorV (Sinopharm Group / Beijing Institute of Biological Products); wait.

[0156] The same preferably applies to further coronavirus vaccines, in particular COVID-19 vaccines.

[0157] Particularly preferred are mRNA-based COVID-19 vaccines (mRNA vaccines against COVID-19), such as the mRNA vaccines against COVID-19 from BioNTech / Pfizer and Moderna.

[0158] mRNA-based vaccines contain mRNA that is introduced into cells in the vaccinated individual and instructs those cells to make a protein (or even just a portion of a protein) that triggers an immune response in the body.

[0159] In contrast, non-mRNA vaccines do not contain such mRNA, and instead may contain, for example, a viral vector that results in the production of a protein or portion of a protein within the cells of the vaccinated individual, or a protein or protein subunit that, in turn, may work with an adjuvant to elicit an immune response in the vaccinated individual.

[0160] An example of an mRNA vaccine is the BioNTech / Pfizer mRNA-based COVID-19 vaccine or Moderna's Examples of non-mRNA vaccines are non-mRNA COVID-19 vaccines (AstraZeneca) or (Janssen / Johnson&Johnson).

[0161] influenza Influenza, often called "the flu," is an infectious disease caused by the influenza virus. Symptoms can range from mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle and joint pain, headache, cough, and feeling tired. These symptoms generally begin two days after exposure to the virus and most last less than a week. However, a cough may persist for more than two weeks. In children, diarrhea and vomiting may be present, but these are uncommon in adults. Complications of influenza can include viral pneumonia, secondary bacterial pneumonia, sinus infection, and worsening of pre-existing health problems, such as asthma or heart failure.

[0162] There are four types of influenza viruses: A, B, C, and D. Generally, three of the four types affect humans: A, B, and C. To date, type D is not known to infect humans, but it is believed to have the potential to do so. Only influenza A and influenza B cause seasonal respiratory disease epidemics that occur each year. Influenza A viruses are further divided into different subgroups based on two proteins found on the surface of the virus: hemagglutinin (HA) and neuraminidase (NA). There are 18 different HA subtypes (H1-18) and 11 different NA subtypes (N1-11).

[0163] Each year, the annual flu vaccine protects against three or four influenza strains (the number depends on what research predicts will be the most common in the upcoming flu season). H1N1, H1N2, and H3N2 are the only influenza A virus subtypes known to currently circulate in humans and are included in the trivalent vaccine, while an additional influenza B strain is included in the quadrivalent vaccine.

[0164] H1N1 influenza is also known as swine influenza. The term swine influenza comes from a time when people who contracted the disease had direct contact with pigs. A few years ago, that changed when a new virus emerged that spread among people who hadn't been around pigs. In 2009, H1N1 spread so rapidly around the world that the World Health Organization declared it a pandemic.

[0165] The H3N2 virus continues to circulate worldwide as a seasonal influenza A virus. Seasonal H3N2 viruses, which are associated with severe illness in the elderly, undergo regular antigenic shifts. In years when H3N2 is the predominant strain, hospitalizations are more frequent, particularly among high-risk groups such as older adults and younger children.

[0166] The trivalent 2018-2019 Northern Hemisphere influenza vaccine contains an A / Michigan / 45 / 2015-like (H1N1)pdm09 virus, an A / Singapore / INFIMH-16-0019 / 2016 A(H3N2)-like virus, and a B / Colorado / 06 / 2017-like Victoria lineage virus. The quadrivalent vaccine also contains a B / Phuket / 3073 / 2013-like Yamagata lineage virus. Genetic characterization of the viruses has shown that the majority of circulating A(H3N2) viruses in the United States are antigenically distinct or divergent from the 2018-2019 Northern Hemisphere vaccine strains, while circulating A(H1N1)pdm9 viruses are a close match.

[0167] Influenza B viruses are known to infect only humans and seals. This limited host range is clearly the reason for the lack of related influenza pandemics compared to those caused by morphologically similar influenza A viruses, because both mutate through antigenic shift and reassortment. Based on the antigenic properties of the surface glycoprotein hemagglutinin, there are two known influenza B virus transmission lineages. The lineages are referred to as B / Yamagata / 16 / 88-like and B / Victoria / 2 / 87-like viruses. The quadrivalent influenza vaccine licensed by the CDC is currently designed to protect against two co-circulating lineages and has been shown to have greater effectiveness than previous trivalent vaccines in preventing influenza caused by influenza B viruses. Further weakening the impact of the virus is that "in humans, the evolution of influenza B viruses is slower than that of influenza A viruses, but faster than that of influenza C viruses." Influenza B viruses mutate at a rate of 1 / 2 to 1 / 3 that of influenza A viruses.

[0168] The injected trivalent inactivated influenza vaccine is the most commonly used worldwide.

[0169] The Magnify study used a quadrivalent inactivated influenza vaccine available during the 2014 / 2015 season.

[0170] In 2011, the EU / EEA approved a live attenuated influenza vaccine (LAIV) for intranasal use in children and adolescents (aged 2-17 years). All currently available live attenuated influenza vaccines are quadrivalent combination vaccines containing two influenza A strains (H1N1 and H3N2 subtypes) and two influenza B strains (Victoria and Yamagata lineages) as recommended by the WHO.

[0171] Because seasonal influenza vaccines are typically recommended for several susceptible groups who are poor immune responders due to age or illness, several attempts have been explored over the past 10-15 years to improve the vaccine, such as increasing the dose of antigen administered, intradermal administration to activate other arms of the immune system, and adding immunostimulatory compounds such as adjuvants.

[0172] Products utilizing these new technologies are now approved and available in some EU / EEA countries. See the table below. For human influenza vaccines, MF59 (squalene) and AS03 (squalene and alpha-tocopherol) have been approved as adjuvants by regulatory agencies in the EU, Canada, and the United States. Data from several observational studies showing improved performance and reductions in hospitalizations for influenza illness and hospitalizations in older adults have been included in the labels of adjuvanted trivalent influenza vaccines.

[0173] Most influenza vaccines (both inactivated and live attenuated) are based on the production of influenza virus / antigens in fertilized eggs. Therefore, these vaccines cannot be given to individuals with egg allergies who develop severe symptoms when exposed to egg protein. Therefore, a few manufacturers have developed cell-based influenza vaccines.

[0174] Influenza A virus subtype H1N2 (A / H1N2) is a subtype of the species influenza A virus (sometimes called avian influenza virus). It is currently prevalent in both human and swine populations. H1N1, H1N2, and H3N2 are the only influenza A virus subtypes known to be currently circulating in humans. The virus does not generally cause more severe illness than other influenza viruses, and no unusual increase in influenza activity has been associated with it.

[0175] H3N2 viruses continue to circulate worldwide as seasonal influenza A viruses. Seasonal H3N2 viruses associated with severe disease in the elderly undergo regular antigenic shifts.

[0176] Injectable trivalent inactivated influenza vaccines have been the most commonly used worldwide. Influenza antigen preparations vary among manufacturers. Inactivated influenza vaccines available in the EU / EEA may contain either segmented virion influenza virus products or subunit influenza products. Adjuvanted inactivated subunit influenza vaccines for older adults are available in some EU / EEA member states.

[0177] The quadrivalent inactivated influenza vaccine, available for injection in some EU / EEA countries from the 2014 / 2015 season, is expected to replace the trivalent vaccine over time. Although available on the private market in some European countries, vaccine approval, vaccine availability, observed vaccine effectiveness, and cost may affect the speed of such replacement.

[0178] In 2011, the EU / EEA approved a live attenuated influenza vaccine (LAIV) for intranasal use in children and adolescents (aged 2-17 years). All currently available live attenuated influenza vaccines are quadrivalent combination vaccines containing two influenza A strains (H1N1 and H3N2 subtypes) and two influenza B strains (Victoria and Yamagata lineages) as recommended by the WHO.

[0179] Universal paediatric programmes organized in Finland and the United Kingdom offer quadrivalent LAIV to young children aged 2–3 years or 2–11 years, respectively.

[0180] Table 2: Overview of seasonal influenza vaccines available in the EU / EEA (2019 / 20 season) Table 3: Seasonal influenza vaccines available in the UK (2020 / 2021 season) All flu vaccines available in the UK for the 2020-2021 season Suitable influenza (viral) vaccines include, but are not limited to: Mutagrip may contain traces of eggs used in the manufacturing process, such as ovalbumin, as well as neomycin, formaldehyde and octoxynol-9 (as per Spanish labeling).

[0181] Quadrivalent inactivated influenza vaccine (VaxigripTetra TM ): VaxigripTetra TM (IIV4; Sanofi Pasteur) is a quadrivalent segmented virion influenza vaccine approved in Europe in 2016 for use in individuals aged ≥3 years. The results are based on a well-established track record. IIV4 is immunogenic and well tolerated. Adding a second B strain to a trivalent segmented virion influenza vaccine provides a higher immune response to the additional strain without reducing the immune response to the three other strains or negatively impacting the safety profile. By providing broader protection against co-circulating influenza B lineages, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with the trivalent vaccine.

[0182] VaxigripTetra TMA buffered solution containing sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate, and water for injection. Some components such as egg (ovalbumin, chicken egg white), neomycin, formaldehyde, or octoxinol-9 may be present in very small amounts.

[0183] Alfuria quad - A single 0.5 ml dose of AFLURIA QUADRIVALENT contains sodium chloride (4.1 mg), monobasic sodium phosphate (80 mcg), disodium hydrogen phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride (20 mcg), and calcium chloride (0.5 mcg). Due to the manufacturing process, each 0.5 ml dose may also contain residual amounts of sodium taurodeoxycholate (≤10 ppm), ovalbumin (<1 mcg), sucrose (<10 mcg), neomycin sulfate (≤81.8 nanograms [ng]), polymyxin B (≤14 ng), beta-propiolactone (≤1.5 ng), and hydrocortisone (≤0.56 ng).

[0184] Trivalent inactivated influenza virus vaccine and quadrivalent inactivated influenza virus vaccine are preferred influenza (virus) vaccines for use according to the present invention.

[0185] Particularly preferred for use as a vaccine in the context of the present invention is a quadrivalent influenza vaccine (fragmented virions, inactivated), which is indicated for the prevention of influenza disease caused by two influenza A virus subtypes and two influenza B virus types contained in the vaccine. Quadrivalent influenza vaccine (fragmented virions, inactivated) is a vaccine that is administered to protect a subject or patient from influenza (influenza). Quadrivalent influenza vaccine (fragmented virions, inactivated) or vaccines of similar types are indicated for the prevention of influenza disease caused by two influenza A virus subtypes and two influenza B virus types contained in the vaccine. Typically, such influenza vaccines are administered only once a year, preferably before or during the influenza season. Preferably, the influenza vaccine is administered once a year or in connection with the influenza season, but preferably in accordance with the vaccination period of the present invention.

[0186] However, such influenza vaccines may also be administered more than once per year or per influenza season, preferably 2 or 3 times, more preferably 2 times, for example to boost or optimize the immunity achieved or achievable by the vaccine. If such a vaccine is to be administered twice, the first dose is preferably administered at any time within the vaccination timeframe described herein, preferably within the early vaccination timeframe described herein, followed by a second dose administered within 1-3 weeks of the first administration, preferably within 1-3 weeks of the same early vaccination timeframe, or within 4 weeks to 3 months after the first dose, preferably within a later or subsequent vaccination timeframe as described herein.

[0187] Varicella-zoster virus Shingles is caused by the same virus that causes chickenpox (varicella) in children. When the virus becomes active again in adults, it can cause herpes zoster, or shingles. (Zoster Live Vaccine) is a live vaccine that helps prevent herpes zoster, as is preferably an inactivated or recombinant VZV vaccine, e.g. or It's like that too.

[0188] Herpes zoster (HZ) often occurs after the reactivation of varicella-zoster virus (VZV) that has been latent in sensory and autonomic neurons. The incidence of HZ varies from 6-8 cases per 1000 person-years in people aged 50-59 years to >11 cases per 1000 person-years in people aged 70 years. The severity of HZ and its complications also increases with age, closely coinciding with the age-related decline in VZV-specific T-cell-mediated immunity (CMI), which is thought to be important in preventing the reactivation of latent VZV and the reproduction of reactivated virus. HZ vaccines are thought to boost VZV-specific memory T cells, thereby preventing them from falling below a currently unknown threshold required for protection from HZ.

[0189] Suitable varicella zoster vaccines are known in the art.

[0190] A live attenuated VZV vaccine (Zostavax, Merck Sharpe & Dohme Corp, hereinafter referred to as the Zoster Vaccine Live [ZVL]) is available to prevent HZ in individuals aged ≥50 years. However, ZVL has several limitations. Clinical trials have shown that vaccine efficacy against HZ is 70% in adults aged 50-59 years and decreases with age, from 64% in those aged 60-69 years to 18% in those aged ≥80 years. Furthermore, ZVL efficacy against HZ decreases over time, from 62% in the first year after vaccination to approximately 40% by the fifth year after vaccination.

[0191] A recombinant glycoprotein E (gE) subunit vaccine (HZ / su) was developed to overcome the unmet medical need for a better vaccine. HZ / su consists of recombinant VZV gE and an AS01B adjuvant system. gE was selected as the vaccine antigen because it is the most abundant glycoprotein expressed by VZV-infected cells and it induces both neutralizing antibodies and CD4 T-cell responses. AS01B contains Quillaja saponaria Molina, fraction 21 (QS-21; licensed by GSK from Antigenics LLC (a wholly owned subsidiary of Agenus Inc., Delaware, USA)) and 3-O-deacyl-4'-monophosphoryl lipid A (MPL). AS01B stimulates local and transient activation of the innate response, leading to the recruitment and activation of antigen-presenting dendritic cells. QS-21 is an adjuvant that induces transient local cytokine responses and activation of dendritic cells and macrophages in muscle and draining lymph nodes in animal models. The Toll-like receptor type 4 agonist MPL acts synergistically with QS-21 to enhance the immune response to co-administered antigens through the production of interferon-γ (IFN-γ).

[0192] Phase I and II trials demonstrated that a single HZ / su dose elicited substantial humoral and CMI responses, which were further increased after a second dose.

[0193] Particularly preferred for use as a vaccine in the context of the present invention is an inactivated and / or recombinant herpes zoster vaccine or varicella zoster vaccine, preferably the vaccine having the European Medicines Agency (EMA) product number EMEA / H / C / 004336, wherein the active substance comprises recombinant varicella zoster virus glycoprotein E, has the International Non-proprietary Name (INN) or the common name "Zoster Vaccine" or "Zoster Vaccine (Recombinant, Adjuvanted)", whose therapeutic area (MeSH) includes herpes zoster, and / or whose Anatomical Therapeutic Chemical (ATC) code is J07BK03. Said vaccine is marketed under the trade name The following are known. Preferably, the inactivated and / or recombinant herpes zoster vaccine or varicella zoster vaccine is available as a powder and suspension, preferably mixed together by a doctor or nurse before administration to the patient, preferably by injection, for example by injection into the patient's upper arm muscle. In this regard, the vaccination preferably comprises two separate vaccinations, two separate injections or two separate shots, preferably given about 3 weeks to about 8 months apart, preferably about 4 weeks to about 6 months apart.

[0194] Typically, in this regard, the patient or subject is administered two separate vaccinations, two separate injections, or two separate injections. (i) Every 3 to 5 weeks or about one month (ii) at intervals of about 8 to 10 weeks or about 2 months, (iii) at intervals of about 24 to 28 weeks or about 6 months, or (iv) at intervals of about 4 to 28 weeks, about 6 to 26 weeks, or about 8 to 25 weeks, or substantially up to 6 months.

[0195] Thus, if desired or necessary in this regard, the second vaccination, dose, injection or shot may be given at an interval later than 3 to 10 weeks, but preferably within 6 months of the first vaccination, dose or shot. People whose immune systems are not functioning properly, who are on immunosuppressive therapy and / or who are being treated or are to be treated according to the treatment methods of the present invention, and who would therefore benefit from a shorter vaccination schedule, may receive a second dose one to two months after the first dose, preferably within the vaccination time period as outlined herein. This is particularly preferred for inactivated or recombinant herpes zoster vaccines, shingles vaccines, varicella zoster vaccines and / or VZV vaccines, especially such vaccines which are typically administered twice to the subject or patient to achieve optimal protection or immunity to the subject or patient. Administration is generally carried out by 2 separate vaccinations, 2 separate injections or 2 separate shots, preferably as known in the art, and in particular as described herein. A preferred example of such a vaccine is the recombinant herpes zoster vaccine, adjuvanted, for example available under the trade name VZV vaccine. The vaccine is preferably indicated for the prevention of herpes zoster (shingles), more preferably for the prevention of herpes zoster (shingles) in adults aged 50 years and over. This vaccine is also preferably used as a vaccine according to the present invention. The two doses of the vaccine are preferably administered via injection, preferably intramuscularly, and preferably according to the following schedule: a first dose at any time within the vaccination time period described herein, preferably within the early vaccination time period described herein, followed by a) any time between 1 and 6 months later than the first dose, or b) a second dose administered at any time between 2 and 6 months later than the first dose, preferably within the later vaccination time period described herein.

[0196] Vaccines Recombinant herpes zoster vaccine, adjuvanted, e.g. It is shown to boost the VZV-specific immune response, preferably if used according to the method of the present invention, and this boosting is believed to be the mechanism by which the subject or patient is protected from the varicella zoster and / or herpes zoster disease.

[0197] Particularly preferred in this regard are vaccines comprising recombinant varicella-zoster virus glycoprotein E, preferably vaccines having the International Nonproprietary Name (INN) or the common name "Zoster Vaccine" or "Zoster Vaccine (Recombinant, Adjuvanted)", e.g.

[0198] In the case of varicella zoster virus vaccines, live or live attenuated vaccines are preferred, e.g. (Herpes Zoster Live Vaccine), which can be used to prevent varicella zoster virus (shingles) in persons aged 50 years and older. Also preferred in this regard are non-live varicella zoster virus (VZV) vaccines, preferably including, but not limited to, inactivated VZV vaccines and recombinant VZV vaccines, such as or Also particularly preferred for use as a vaccine in the context of the present disclosure are live herpes zoster vaccines, which are preferably live attenuated virus vaccines, e.g. (Herpes zoster live vaccine), and is preferably indicated for the prevention of herpes zoster (shingles), more preferably for the prevention of herpes zoster (shingles) in individuals aged 50 years and older. Herpes zoster live vaccine, e.g. Preferred is a lyophilized preparation of a live attenuated varicella-zoster virus (VZV) strain, such as the Oka / Merck strain of live attenuated varicella-zoster virus (VZV). When reconstructed as indicated, it is a sterile suspension for subcutaneous administration. Generally, this herpes zoster live vaccine is used for single administration, and therefore according to the present invention, it is generally only applied once (i.e., as a single dose) to main body or patient. However, the treating physician can advise or prescribe a prescription for repeated administration. In any case, it is generally applied subcutaneously, preferably in the deltoid region of the upper arm of the main body or patient. Herpes zoster (HZ), often referred to as herpes zoster (shingles) or herpes zoster (zoster), is preferably the performance of varicella zoster virus (VZV) reactivation, which produces chickenpox (chickenpox) (chickenpox) as primary infection. After initial infection, the virus remains latent in dorsal root or cranial nerve sensory ganglia until it reactivates, thereby producing herpes zoster. Herpes zoster is characterized in that there is unilateral, painful, vesicular skin eruption with dermatome distribution. The risk of development herpes zoster and / or herpes zoster (shingles) seems to be relevant with VZV-specific immune decline. Varicella zoster virus vaccine (or varicella zoster vaccine), preferably a live herpes zoster vaccine and especially It has been shown to enhance VZV-specific immunity, which is thought to be the mechanism of protection against herpes zoster and its complications.

[0199] Other diseases for which vaccines are available or desired Further infectious diseases for which vaccines are available or at least desirable include, but are preferably not limited to, hepatitis B virus (HBV) and varicella zoster virus (VZV). Other infectious diseases may include hepatitis B, measles, influenza vaccine, poliovirus, pneumococcus, diphtheria, tetanus and Bordetella pertussis, and SARS-Covid 2. A vaccine against SARS Covid-2 is now available.

[0200] Other diseases, including smallpox, chickenpox, polio, tetanus, measles, mumps, rubella, whooping cough, and / or influenza-like illness, are also implicated.

[0201] Vaccination Vaccination is a method of artificially activating the immune system to protect against infectious diseases. Activation occurs by priming the immune system with an immunogen. Using an infectious agent to stimulate an immune response is called immunization. Vaccination involves various methods of administering the immunogen.

[0202] Various vaccine administration routes are known to those skilled in the art. Generally, vaccine administration can be oral, by injection (intramuscular, intradermal, subcutaneous), by puncture, transdermal or intranasal. Several recent clinical trials are intended to deliver vaccines via mucosal surfaces, to be absorbed by the common mucosal immune system, thereby avoiding the need for injection.

[0203] Most vaccines are given before a person has contracted the disease to help increase future protection. However, some vaccines are given after a person has already contracted the disease. Vaccines given after exposure to smallpox have been reported to provide some protection from the disease or to reduce the severity of the disease.

[0204] Most vaccines are given by injection because they are not reliably absorbed through the intestine. Live attenuated polio vaccine, rotavirus vaccine, some typhoid vaccines, and some cholera vaccines are given orally to produce immunity in the intestine. While vaccinations provide a long-lasting effect, they typically take several weeks to develop and require an immune system capable of mounting an appropriate immune response.

[0205] Vaccine type There are several different types of vaccines. Each type is designed to teach your immune system how to fight off certain types of germs—and the serious illnesses they cause. When scientists create vaccines, they consider: how your immune system responds to the germ, who needs to be vaccinated against the germ, and the best technology or method for creating the vaccine. Based on many of these factors, scientists decide which type of vaccine they will make. There are several main types of vaccines, such as live attenuated vaccines, inactivated vaccines, subunit, recombinant, polysaccharide and conjugate vaccines, and toxoid vaccines.

[0206] The most relevant vaccine types are described in more detail below: Live attenuated vaccines: Live vaccines use a weakened (or attenuated) form of the germ that causes a disease. Because these vaccines are so similar to the natural infection they help prevent, they produce a strong and long-lasting immune response. Just one or two doses of most live vaccines can give you lifelong protection against the germs and the diseases they cause. But live vaccines have some limitations. For example, because they contain a small amount of weakened, live virus, some people should talk to their healthcare provider before getting them, such as those with a weakened immune system, those with long-term health problems, or those who have received an organ transplant. They need to be kept cold, so they are not suitable for long-distance transportation. This means they cannot be used in countries where refrigeration is limited. Live vaccines are used to protect against: measles, mumps, and rubella (MMR combination vaccine), rotavirus, smallpox, chickenpox, yellow fever, and nasal flu vaccine.

[0207] Inactivated vaccines: Inactivated vaccines use a killed form of the germ that causes the disease. Inactivated vaccines usually do not provide as strong immunity (protection) as live vaccines. Therefore, you may need several doses over time to get continuous immunity against the disease. Inactivated vaccines are used to protect against: Hepatitis A, influenza (shot only), polio (shot only), and rabies.

[0208] Subunit, recombinant, polysaccharide, and conjugate vaccines: These vaccines use a specific part of the germ—such as its proteins, sugars, or capsid (the outer shell around the germ). Because these vaccines use only that specific part of the germ, they produce a very strong immune response that targets the key parts of the germ. They can also be used in almost anyone who needs them, including people with weakened immune systems and long-term health problems. One limitation of these vaccines is that you may need booster shots for continued protection from disease. These vaccines protect against: Hib (Haemophilus influenzae type b) disease, hepatitis B, HPV (human papillomavirus), pertussis (part of the DTaP combination vaccine), pneumococcal disease, meningococcal disease, and shingles.

[0209] Toxoid vaccines: Toxoid vaccines use toxins (harmful products) produced by disease-causing germs. They produce immunity against the part of the germ that causes disease, rather than the germ itself. This means the immune response targets the toxin rather than the whole germ. As with some other types of vaccines, you may need booster shots to get continued protection from disease. Toxoid vaccines are used to protect against: diphtheria, tetanus.

[0210] DNA plasmid vaccines: These vaccines contain small circular segments of DNA, called plasmids, that carry genes encoding proteins from the pathogen of interest. The manufacturing process for DNA plasmid vaccines is well-established, allowing for the rapid development of experimental vaccines to address emerging or re-emerging infectious diseases. NIAID's Vaccine Research Center has developed candidate DNA vaccines to address several viral disease threats during outbreaks, including SARS-CoV in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and Zika virus in 2016. The time from selecting the viral genes to be included in the vaccine to the start of clinical studies in humans has been reduced from 20 months for SARS-CoV to just over 3 months for Zika virus.

[0211] mRNA vaccines: Vaccines based on messenger RNA (mRNA), the intermediate between DNA and protein, are also being developed. Recent technological advances have largely overcome the problems associated with mRNA instability and the difficulty of delivering it into cells, and some mRNA vaccines have shown encouraging early results. For example, NIAID-supported researchers have developed an experimental mRNA vaccine that protected mice and monkeys from Zika virus infection after a single dose.

[0212] Recombinant vector vaccines (platform-based vaccines): Instead of delivering DNA or mRNA directly to cells, some vaccines use harmless viruses or bacteria as vectors or carriers to introduce genetic material into cells. Several such recombinant vector vaccines are approved to protect animals against infectious diseases, including rabies and distemper. Many of these veterinary vaccines are based on technology developed by NIAID researchers in the 1980s, which uses weakened forms of poxviruses to deliver the pathogen's genetic material. Now, NIAID-supported scientists are developing and evaluating recombinant vector vaccines to protect people against viruses such as HIV, Zika, and Ebola.

[0213] However, vaccination may lead to a serious clinical crisis in the vaccinated body, for example through vaccine failure. Generally, vaccine failure occurs when an organism, despite being vaccinated against a disease, still contracts the disease. Primary vaccine failure occurs when the organism's immune system does not produce antibodies when the vaccine is first administered. A vaccine may fail when several batches are given and an immune response fails to be generated. The term "vaccine failure" does not necessarily mean that the vaccine is defective. Most vaccine failures are simply due to variations in the individual immune response, but also occur in immunosuppressed bodies, for example in the case of immunosuppressive treatment of patients with autoimmune diseases.

[0214] Vaccine response Effect mechanism It is found that vaccine induction can quickly control the pathogen being replicated or inactivate the effector mechanism (cell or molecule) of its toxic components. Early protection efficacy is mainly given by the induction of immune effectors, antigen-specific antibodies produced by B cells that can be combined with pathogens or toxins. Long-term protection requires the maintenance of immune memory that can be quickly and effectively reactivated by the persistence of vaccine antibodies that exceed the protection threshold. Antigen-specific antibodies have been formally proven to be the protection induced by vaccines for many diseases. The main role of B cells in current vaccine efficacy should not obscure the importance of T cell response. Most antigens and vaccines trigger B cell response (humoral immunity) and T cell response (cellular immunity).

[0215] Most antibody responses require CD4+ T cells, and antibodies exert a significant influence on T cell responses to intracellular pathogens. T cells are essential for the induction of high-affinity antibodies and immunological memory. Cytotoxic CD8+ T lymphocytes are additional effectors that will limit the spread of infectious agents by recognizing and killing infected cells or secreting specific antiviral cytokines. CD4+ T helper (Th) cells provide support for the generation and maintenance of B cell and CD8 responses and contribute to protection through cytokine production (example: Th1 cells expressing IFN-γ). Other additional Th subtype effector cells are follicular Th cells (Tfh) that support potent B cell activation and differentiation into antibody-secreting cells or Th17 cells.

[0216] Table 4: Vaccine-triggered effector mechanisms The characteristics of the vaccine exert a direct influence on the type of immune effectors elicited that mediate protective activity. The hallmark of T-dependent responses (elicited by toxoids, proteins, inactivated or attenuated live virus vaccines) is the induction of higher affinity antibodies and immune memory. In addition, attenuated live vaccines / vectors typically produce CD8 cytotoxic T cells. Most current vaccines mediate their protective efficacy by inducing vaccine antibodies, while vaccine-induced CD4+ T cells contribute to macrophage activation and control of Mycobacterium tuberculosis. Current vaccines primarily mediate protection by inducing highly specific IgG serum antibodies. Live vaccines induce serum IgA and secretory IgA levels, which help limit viral release from mucosal surfaces. There is clear evidence that T cells are the primary effectors of BCG in infants vaccinated with BCG or adults vaccinated with herpes zoster. There is indirect evidence that vaccine-induced T cells contribute to the protection conferred by other vaccines.

[0217] Table 5: T-cell responses to vaccines.

[0218] Innate immunity and vaccination When exposed to pathogens in tissues or at the injection site, immature dendritic cells mature and migrate to secondary lymph nodes, where B cell and T cell responses are induced. The main role of mature DCs (dendritic cells) in inducing vaccine responses is to provide sufficient danger signals through vaccine antigens or adjuvants to trigger inflammatory reactions. DCs, monocytes, and neutrophils express pattern recognition receptors (such as Toll-like receptors, TLRs) that sense potential danger when they encounter pathogens and are activated. They regulate the expression of cell surface proteins and produce proinflammatory cytokines and chemokines. The inflammatory environment (milieux) drives monocytes to differentiate into macrophages and DCs to mature. In the absence of danger signals, DCs remain immature and when in contact with naive cells, CD4+ cells do not differentiate into effector cells. Live vaccines trigger the innate immune system most effectively in time and space via TLRs. Non-live vaccines (such as proteins, complex carbohydrates, inactivated microorganisms) may still contain pathogen recognition receptors, but vaccine-induced activation remains more limited to the injection site. Upon activation, DCs change their homing receptors and migrate to draining lymph nodes, where B and T cell responses occur.

[0219] Primary antibody response In response to protein antigens, the B cell experience of its surface immunoglobulin and the antigen combination is fast activated. Initial antigen exposure draws out follicular response, wherein B cell rapidly differentiates into the plasma cell that produces low-affinity antibody (IgM+ / -IgG isotype), which causes low Ig titer to occur quickly in serum in a few days after immunization. Antigen-specific T helper cells activated by DCs carrying antigen trigger antigen-specific B cells to migrate to follicular DCs, thereby initiating germinal center (GC) reaction. In GCs, B cells receive additional signals from T follicular helper (Tfh) cells, experience large-scale clonal proliferation and convert from IgM to IgG, IgA or IgE. Along with B cell proliferation in germinal center, IgG antibody titer increases to a maximum peak value, usually reaching 4 weeks after immunization. The short life of these plasma cells causes antibody titer to decline rapidly. The shortest interval of 3 weeks between two initial doses allows the generation of continuous Ag-specific initial response waves without interference.

[0220] Secondary antibody response In the secondary immune response, the reinforcement of antigen is exposed to reactivate immune memory and cause the fast increase of IgG titer. Short-lived plasma cells maintain peak levels for several weeks, and until the long-lived plasma cells that arrive in the bone marrow to survive in a niche continue to produce antigen-specific antibodies, which then decline with slower kinetics. The shortest interval of 4 months between initiation and reinforcement allows the affinity maturation of memory B cells and thereby higher secondary responses. The universal model may not be suitable for triggering the live vaccine that long-term IgG antibodies reach the time period of extension.

[0221] Table 6: Determinants of duration of vaccine antibody responses in healthy individuals Vaccine-induced B cell memory Memory B cells are generated during the primary response to T-dependent vaccines. They persist in the absence of antigen—reexposure to antigen drives their differentiation into antibody-producing plasma cells. This reactivation is rapid and does not require T cell help, resulting in a booster response characterized by a rapid increase to higher titers of antibodies with a higher affinity for the antigen than those produced during the primary response.

[0222] Table 7: Markers of memory B-cell responses Vaccine-induced T cell memory Table 8: Determinants of memory T-cell responses Table 9: In the elderly Vaccination issues in patients receiving immunosuppressive / immunomodulatory drugs Vaccination is a powerful tool for preventing infection, reducing the risk of contracting an infection and, if an infection does occur, increasing the chances that the infection will be mild. However, as detailed in the Background section, many immunosuppressive and immunomodulatory drugs affect the immune system in a way that does not result in a complete vaccination response. Therefore, in these cases, vaccination will not result in the desired immunity.

[0223] In view of the above, it is strongly recommended to avoid vaccination during or very close to treatment with drugs that have such modifying effects on the immune response. Instead, it is recommended that a gap or interval of several weeks to several months be always allowed between vaccination and the start and / or end of treatment with such immunosuppressive or immunomodulatory drugs (see Background section above).

[0224] Based on their mode of action, it seems likely that this problem will also occur for BTK inhibitors. This hypothesis is consistent with vaccination data obtained using selected BTK inhibitors, which suggest that vaccination results may be weakened in the case of treatment with BTK inhibitors (see the background section above). According to general recommendations, this means that in the case of BTK inhibitors, vaccination should also be avoided in the case of treatment very close to immunomodulatory drugs.

[0225] BTK inhibitors Bruton's tyrosine kinase (BTK) is a cytoplasmic kinase of the Tec family expressed by hematopoietic and plasma cells, which regulates diverse signaling, including the PI3K, MAPK, and NF-κB pathways.

[0226] As discussed in the Background section, BTK is expressed in almost all hematopoietic cells, particularly in B cells, but also in macrophages and monocytes, but not in T cells. In fact, it is an essential component of different B cell receptor (BCR) signaling pathways that regulate the differentiation of antibody-producing plasma cells as well as cell activation, proliferation, and survival. In addition, BTK plays a crucial role in the secretion of proinflammatory cytokines as well as degranulation and histamine release.

[0227] Thus, BTK inhibition results in the blockade of diverse downstream cell signaling pathways associated with the development of B-cell malignancies and autoimmune and inflammatory diseases.

[0228] BTK consists of 659 amino acids. The protein contains five domains. From N-terminus to C-terminus, these are: platelet leukocyte C kinase substrate homology (PH) domain, proline-rich TEC homology (TH) domain, SRC homology (SH) domain (referred to as SH3 and SH2) and finally the catalytic domain. The function of the PH domain is to mediate protein-phospholipid and protein-protein interactions. In contrast, the TH domain contains zinc finger motifs that are important for protein activity and stability. The autophosphorylation site Tyr223 is located in the SH2 and SH3 domains. The catalytic domain contains two phosphorylation sites (Tyr551 and Cys481).

[0229] Based on their mechanism of action and binding mode, BTK inhibitors can be divided into two categories: (i) irreversible inhibitors, which form a covalent bond with the conserved cysteine ​​481 residue in the ATP-binding site; and (ii) reversible inhibitors, which bind to a specific pocket in the SH3 domain through weak reversible interactions (e.g., hydrogen bonds or hydrophobic interactions), resulting in an inactive conformation of the enzyme.

[0230] Examples of irreversible BTK inhibitors include evobrutinib, spebrutinib, remibrutinib, torebutinib, olmutinib, branebrutinib, TAK-020 (prepared by Takeda), elsubrutinib, or rilzabrutinib. Examples of reversible BTK inhibitors include vecabrutinib, BMS-935177 (Bristol Meyers Squibb), BMS-986142 (Bristol Meyers Squibb), or nonibutinib, which are reviewed in, for example, Tasso et al., Molecules (2021), vol. 26, p. 7411 or Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223, the contents of which are incorporated herein by reference. See also the discussion and references in the Background section, the contents of which are also incorporated herein by reference.

[0231] BTK inhibitors have shown great potential in the treatment of clinical diseases.

[0232] Ibrutinib is the first BTK inhibitor approved by the FDA in 2013 for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL), and relapsed / refractory mantle cell lymphoma (MCL). Subsequently, it was also approved in 2017 for patients with chronic graft-versus-host disease (cGVHD). More recently, acalabrutinib and zanubrutinib were launched in 2017 and 2019, respectively, for the treatment of CLL, SLL, and MCL. Additionally, tirabrutinib is currently registered in Japan for the treatment of relapsed or refractory primary central nervous system lymphoma and has received supplemental approvals for WM and lymphoplasmacytic lymphoma. In December 2020, orelabrutinib received its first approval in China for the treatment of patients with MCL, CLL, and SLL who have received at least one prior therapy. Clinical development of orelabrutinib for various indications is ongoing in the United States and China. For a review of this compound and treatment, see, for example, Tasso et al.

[0233] As detailed in the background section, various BTK inhibitors have also shown great potential in the treatment of autoimmune diseases and other inflammatory diseases, or are currently being used in clinical trials for such diseases (reviewed in Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223). This includes the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, including relapsing MS (RMS) and progressive forms (PMS), pemphigus vulgaris, Sjögren's syndrome, chronic spontaneous urticaria, and idiopathic thrombocytopenia, as well as other inflammatory diseases such as graft-versus-host disease and asthma. The BTK inhibitors evobrutinib and torebutinib have shown positive results in Phase II trials for the treatment of RMS (Montalban et al., New Engl. J. of Medicine (2019), vol. 380, p. 2406; Reich et al., Lancet Neurology (2021), vol. 20, p. 729). In addition, a trial using torebrutinib in myasthenia gravis (MG) has recently been announced (NCT05132569).

[0234] Thus, BTK inhibitors can be successfully administered to treat a variety of diseases, including various autoimmune and other inflammatory diseases. For detailed information on these treatments, see, for example, Ringheim et al., Tasso et al., references cited therein, research posts on www.clinicaltrials.gov, and corresponding research publications.

[0235] Therefore, such BTK inhibitors are considered useful in practicing the present disclosure.

[0236] Evobrutinib Evobrutinib is a BTK inhibitor having the structure shown below in Formula (I): The chemical name of Evobrutinib is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one, or (synonymously) N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine.

[0237] Preferably, the nomenclature of the active ingredient, active principle (API), drug or its International Nonproprietary Name (INN) includes all prodrugs, salts and solvates thereof, especially those which are functionally equivalent and / or considered suitable alternatives from a clinical point of view.

[0238] Evobrutinib and its use in medical therapy are described, for example, in published international patent applications WO 2012 / 170976 A2, WO 2017 / 087445 A1, and WO 2020 / 016850 A1, or in publications on clinical trials with evobrutinib, for example in Montalban et al., the contents of which are incorporated herein by reference.

[0239] A related BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one, which is described, for example, in WO 2012 / 170976 A2, WO 2017 / 087445 A1 and WO 2017 / 079542 A1 (compound A225).

[0240] Evobrutinib is an irreversible BTK inhibitor that covalently binds to cysteine ​​481 in the BTK active site, leading to strong and sustained inhibition of BTK enzymatic activity.

[0241] Functional changes induced by BTK inhibition by evobrutinib include inhibition of B cell proliferation, activation, maturation, antigen presentation, cytokine / antibody production, and CNS homing. Due to inhibition of T cell and B cell interactions, evobrutinib also indirectly affects pathological T cell responses. In myeloid cells (monocytes, macrophages, dendritic cells) and CNS glia (microglia, astrocytes), evobrutinib acts downstream of various receptors (e.g., GM-CSF receptor, FcR), reducing pro-inflammatory signals and increasing anti-inflammatory signals, thereby potentially promoting a more anti-inflammatory state in peripheral and CNS compartments.

[0242] Evobrutinib is currently in clinical studies for autoimmune disorders, and when administered orally, it shows good efficacy in RA and SLE mouse models, as demonstrated by reductions in disease severity and histological lesions (Caldwell et al., J. Med. Chem. (2019), vol. 62, p. 7643–7655; Haselmayer et al., J. Immunol. (2019), vol. 202, p. 2888–2906).

[0243] Furthermore, evobrutinib has shown efficacy in the treatment of patients with relapsing forms of multiple sclerosis (Montalban et al.).

[0244] Evobrutinib (and similarly the related BTK inhibitor 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one) may be contemplated for use in practicing the teachings of the present disclosure.

[0245] BTK inhibitors, and in particular Evobrutinib, can be formulated into any pharmaceutical formulation, wherein preferably such pharmaceutical formulations are suitable for oral administration. Representative oral formulations of BTK inhibitors are described in the product features of BTK inhibitors that have obtained FDA or EMA marketing authorization (see, respectively, the U.S. Prescription Information (USPI) approved by the U.S. Food and Drug Administration (FDA) or the Summary of Product Characteristics (SmPC) approved by the European Health Authority (EMA)). Examples of oral formulation ingredients are provided below.

[0246] Methods for preparing Evobrutinib are known in the art. For example, the preparation of Evobrutinib is described in published international patent application WO 2012 / 170976 A2.

[0247] BTK inhibitors can be used in the form of free alkali, pharmaceutically acceptable salts, solvates or solvates of salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. Therefore, BTK inhibitors containing one or more basic groups (such as Evobrutinib), that is, protonatable groups, can exist in the form of salts and can be used according to the present invention in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art. Similarly, BTK inhibitors containing one or more acidic groups can exist in salt form and can be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts formed with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.

[0248] Oral administration of Evobrutinib can be in the form of capsules, tablets, oral suspensions, or syrups. Tablets or capsules can contain about 10 to 500 mg of the BTK inhibitor (e.g., Evobrutinib). Preferably, they can contain 30 to about 300 mg of Evobrutinib, more preferably about 40 to 150 mg of Evobrutinib. Tablets can contain the aforementioned amounts of the compound and a binder, which can be a gelatin solution, starch paste in water, polyethylene polyvinyl alcohol in water, etc., with a typical sugar coating.

[0249] Preferably, the term "evobrutinib" as used in the context of the present invention, if not explicitly defined otherwise, preferably refers to "oral evobrutinib", i.e. the active ingredient evobrutinib administered orally according to the present invention. Preferably, the evobrutinib administered orally according to the present invention is administered in the form of an oral dosage form, such as a capsule, e.g., a capsule filled with evobrutinib solution, a capsule filled with evobrutinib powder, or a tablet containing evobrutinib.

[0250] The composition of Evobrutinib may further comprise one or more pharmaceutically acceptable additional ingredients, such as alum, stabilizers, antimicrobial agents, buffers, colorants, fragrances, adjuvants, and the like.

[0251] The composition can be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration can contain conventional excipients, including, but not limited to, binders, fillers, lubricants, disintegrants, and wetting agents. Binders include, but are not limited to, syrup, gum arabic, gelatin, sorbitol, gum tragacanth, starch syrup, and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silicon dioxide. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate. The tablets can be coated according to methods well known in the art.

[0252] The composition can also be a liquid formulation, including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The composition can also be formulated as a dry product for constitution with water or other suitable vehicles before use. Such liquid formulations may contain additives, including, but not limited to, suspending agents, emulsifiers, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifiers include, but are not limited to, lecithin, sorbitan monooleate, and gum arabic. Non-aqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethanol. Preservatives include, but are not limited to, methyl or propyl parahydroxybenzoate and sorbic acid.

[0253] The above information regarding the composition, formulation in any pharmaceutical formulation or formulation for oral administration applies accordingly to other BTK inhibitors.

[0254] Post-hoc analysis of clinical study data In the experimental part of this article, a post hoc analysis of data obtained from two phase II clinical studies with the BTK inhibitor (evobrutinib) has been performed.

[0255] In the context of treating different autoimmune diseases (SLE, MS) with the BTK inhibitor, it was surprisingly found that different vaccinations (flu, COVID-19) during treatment with the BTK inhibitor resulted in a humoral immune response similar to that of patients treated with placebo (SLE / flu vaccine), or induced antibody levels consistent with published data (MS / mRNA COVID-19 vaccine). Contrary to general advice to date, it has thus been surprisingly found that subjects with autoimmune disorders can undergo BTK inhibitor treatment, in particular evobrutinib treatment, and can still be safely vaccinated and / or immunized against infection at any time when such vaccination is considered necessary or desirable. The fact that this observation was made in the treatment of different autoimmune diseases and with different types of vaccines (flu vaccine, which is thought to reflect a recall response; and COVID-19 vaccine, which is an mRNA vaccine and is thought to reflect a response to new antigens due to the recent emergence of the virus) suggests that these findings are also more broadly applicable to other autoimmune diseases and potentially even other inflammatory diseases, as well as different types of vaccines and antigens.

[0256] Thus, despite the presumed negative effects of BTK inhibitor administration on the parts of the immune system responsible for mounting an immune response to vaccination, it has been found that such an immune response to vaccination can be mounted in a variety of settings during BTK inhibitor treatment.

[0257] Advantageously, these findings allow for much greater applicability of vaccination in the context of BTK inhibitor treatment, particularly evobrutinib treatment, as well as much greater flexibility in when to vaccinate in the context of treatment with such BTK inhibitors.

[0258] Thus, in various aspects, the present disclosure further relates to the following: In one aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor (Bruton's tyrosine kinase inhibitor) to the patient, and (b) vaccinating the patient against infection.

[0259] BTK inhibitors are known to those skilled in the art and are further described in this disclosure. Additional information about BTK inhibitors and their use in treating diseases can be obtained from published literature, such as Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223; Tasso et al., Molecules (2021), vol. 26, p. 7411; and references cited therein. The appropriate dosage will depend on the specific patient and clinical situation, and will therefore be determined by the responsible physician.

[0260] Vaccination occurs by administering the vaccine to the patient. Vaccines and their use to prevent infection are part of the skilled practitioner's expertise. The exact vaccination protocol will be determined by the responsible physician based on the clinical prescription of the vaccine used and the specific circumstances of the case.

[0261] As described herein, the present disclosure relates to BTK inhibitor treatment and vaccination in close temporal proximity or even simultaneously, without requiring a specific order of the BTK inhibitor treatment and vaccination steps. Thus, the words (a) and (b) in the above methods (or similar words in further methods below relating to BTK inhibitor treatment and vaccination) should not be understood in the sense of being arranged in a chronological order. Unless expressly provided otherwise, administration of the BTK inhibitor according to the treatment method and vaccination of the patient can occur in any order, at overlapping times, or simultaneously.

[0262] As used herein, the term "patient" refers to a human to be treated by the methods of the present invention.

[0263] As used herein, the term "treating" or "treatment" includes any effect that results in an improvement of a disease, such as alleviation, reduction, modulation, improvement, or elimination.

[0264] Corresponding considerations apply to the further aspects of the disclosure below.

[0265] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering a BTK inhibitor to the patient.

[0266] The step of "identifying a patient at risk of contracting an infection" (or "determining that a patient is at risk of contracting an infection") is a routine step for a person skilled in the art. Typically, it will be performed by a skilled physician (e.g., a physician in general medicine, immunology, and / or autoimmune disorders) using standard laboratory procedures, including, for example, determining antibody titers. Based on this antibody titer, it is possible to assess the extent to which a patient has been immunized against the infection, and accordingly, whether the patient is at risk of contracting the infection.

[0267] With respect to the step of determining whether a patient is at risk of contracting an infection and the step of vaccinating said patient, it is understood that the determining step precedes the vaccinating step because the patient to be vaccinated is determined by the determining step.

[0268] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) treating the disease by administering a BTK inhibitor to the patient.

[0269] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0270] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0271] As used herein, "repeated" administration of the BTK inhibitor or "repeated" treatment with the BTK inhibitor means administering the BTK inhibitor at regular time intervals as dictated by the BTK inhibitor and the treatment regimen for the disease (as may be defined, for example, in the drug labeling for the BTK inhibitor), e.g., daily.

[0272] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0273] As will be understood by those skilled in the art, the step of "continuing to administer the BTK inhibitor" will be performed after the step of "administering the BTK inhibitor." There may be a period of time between the step of completing the administration of the BTK inhibitor and the step of continuing to administer the BTK inhibitor (i.e., there is a break in treatment with the BTK inhibitor; features defining the length of such a break are further disclosed below) or the step of continuing to administer the BTK inhibitor may begin immediately upon completion of the step of administering the BTK inhibitor (i.e., the patient is treated continuously). The step of vaccinating the patient may overlap in whole or in part with the step of administering the BTK inhibitor, the step of continuing to administer the BTK inhibitor, or both.

[0274] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising: (a) optionally administering a BTK inhibitor to said patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering said BTK inhibitor to said patient, Provided is a proviso that said method comprises one or more treatment periods wherein said BTK inhibitor is administered to thereby treat said patient for said disease and reduce said patient's risk of contracting said infection.

[0275] As used herein, "reducing the risk of said patient contracting said infection" may be a complete reduction (ie, the patient becomes completely immune to said infection) or a partial reduction.

[0276] In another aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the treatment comprising administering a BTK inhibitor to the patient, wherein the patient is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0277] There is no particular limitation on the route of administration of the BTK inhibitor. Administration can occur by any route that allows for successful treatment of the disease. Typically, the administration of the BTK inhibitor will be by oral administration, for example in the form of tablets, or by injection.

[0278] If the disclosure states that a patient is "ongoing treatment" with a BTK inhibitor at a certain time, this means that treatment with the BTK inhibitor was started before the certain time and continued without interruption until the certain time or longer. In some embodiments, it means that at the certain time, the most recent administration of the BTK inhibitor occurred no more than 72 hours ago. In some embodiments, it means that at the certain time, the most recent administration of the BTK inhibitor occurred no more than 48 hours ago. In some embodiments, it means that at the certain time, the most recent administration of the BTK inhibitor occurred no more than 36 hours ago. In some embodiments, it means that at the certain time, the most recent administration of the BTK inhibitor occurred no more than 24 hours ago.

[0279] Similarly, if the disclosure states that an event occurs while a patient is “undergoing treatment” with a BTK inhibitor (e.g., vaccination), this means that the treatment with the BTK inhibitor has begun before the event and continues without interruption to the date of the event or longer (e.g., treatment of the patient with the BTK inhibitor has begun and continues without interruption until the patient has received at least one dose of the corresponding vaccine). In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor occurred no more than 72 hours ago. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor occurred no more than 48 hours ago. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor occurred no more than 36 hours ago. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor occurred no more than 24 hours ago. Treatment will generally involve repeated administration of the BTK inhibitor at regular intervals, e.g., daily, according to a protocol.

[0280] In another aspect, the present disclosure relates to a method for reducing the risk of a subject contracting an infection, the method comprising: (a) administering a BTK inhibitor to the subject, and (b) vaccinating the subject against the infection.

[0281] In some embodiments, the subject is a patient suffering from a disease.

[0282] In some embodiments, the administering of a BTK inhibitor to the subject is for treating a disease in the subject.

[0283] In some embodiments, the subject is a patient in need of such treatment.

[0284] In another aspect, the present disclosure relates to a method for reducing the risk of a subject contracting an infection, the method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0285] In some embodiments, the subject is a patient suffering from a disease.

[0286] In some embodiments, the treatment with the BTK inhibitor is for treating a disease in a patient in need thereof.

[0287] In some embodiments, the treating comprises administering the BTK inhibitor to the subject.

[0288] In another aspect, the present disclosure relates to a method for treating a disease and reducing the patient's risk of infection in a patient in need thereof, the method comprising (a) administering a BTK inhibitor to the patient, and (b) vaccinating the patient against the infection.

[0289] In another aspect, the present disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0290] In another aspect, the present disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0291] In some embodiments, the patient is a patient suffering from the disease.

[0292] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0293] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0294] In some embodiments, the patient is a patient suffering from the disease.

[0295] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0296] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0297] In some embodiments, the patient is a patient suffering from the disease.

[0298] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0299] In some embodiments, the patient is a patient suffering from the disease.

[0300] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0301] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering said BTK inhibitor to said patient, With the proviso that the method comprises one or more treatment periods wherein the BTK inhibitor is administered.

[0302] In some embodiments, the patient is a patient suffering from the disease.

[0303] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0304] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease by a method comprising administering the BTK inhibitor to a patient having the disease, the method comprising vaccinating the patient against infection while the patient is under ongoing treatment with the BTK inhibitor.

[0305] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein a patient suffering from the disease is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0306] In some embodiments, the treatment with the BTK inhibitor comprises administering the BTK inhibitor to the patient.

[0307] In some embodiments, the method comprises administering the BTK inhibitor to a patient suffering from the disease.

[0308] In another aspect, the disclosure relates to a BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered in combination with a vaccine.

[0309] In some embodiments, the treating is by administering the BTK inhibitor to a patient in need thereof.

[0310] In some embodiments, the vaccine is a vaccine against an infection.

[0311] In some embodiments, the patient is vaccinated against an infection with the vaccine.

[0312] In some embodiments, the vaccine is administered to the patient.

[0313] In some embodiments, the treatment with the BTK inhibitor and the vaccination with the vaccine occur simultaneously or sequentially.

[0314] In some embodiments, the administration of the BTK inhibitor and the vaccination with the vaccine occur simultaneously or sequentially.

[0315] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0316] As used herein, "prevention" of an infection may mean complete prevention of the infection or partial prevention of the infection. Thus, "prevention" of an infection may mean that, through the vaccination, the subject becomes fully or partially immune to the infection. Thus, "prevention" of an infection may mean that, upon vaccination, the infection is avoided, the risk of contracting the infection is reduced, or, if the patient contracts the infection, the infection is ameliorated (compared to what would have occurred without such vaccination).

[0317] In some embodiments, the subject is a patient suffering from a disease.

[0318] In some embodiments, said administering a BTK inhibitor to said subject is for treating said disease.

[0319] In some embodiments, the administering of a BTK inhibitor to the subject is for treating a disease in the subject.

[0320] In some embodiments, the subject is a patient in need of such treatment.

[0321] In another aspect, the disclosure relates to a vaccine for preventing an infection by a method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0322] In some embodiments, the subject is a patient suffering from a disease.

[0323] In some embodiments, the treatment with the BTK inhibitor is for treating a disease in the patient.

[0324] In some embodiments, the patient is a patient suffering from the disease.

[0325] In some embodiments, the treating comprises administering the BTK inhibitor to the subject.

[0326] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) identifying a subject at risk of contracting the infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0327] In some embodiments, the BTK inhibitor is administered to treat a disease.

[0328] In some embodiments, the subject is a patient suffering from a disease.

[0329] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0330] In another aspect, the disclosure relates to a vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject.

[0331] In some embodiments, the BTK inhibitor is administered to treat a disease.

[0332] In some embodiments, the subject is a patient suffering from a disease.

[0333] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0334] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0335] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0336] In some embodiments, the patient is a patient suffering from the disease.

[0337] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0338] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0339] In some embodiments, the patient is a patient suffering from the disease.

[0340] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0341] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0342] In some embodiments, the patient is a patient suffering from the disease.

[0343] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0344] In some embodiments, the patient is a patient suffering from the disease.

[0345] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0346] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering to said patient said BTK inhibitor, with the proviso that said method comprises one or more treatment periods in which said BTK inhibitor is administered.

[0347] In some embodiments, the patient is a patient suffering from the disease.

[0348] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0349] In another aspect, the disclosure relates to the use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method wherein a patient suffering from the disease is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0350] In some embodiments, the method comprises administering the BTK inhibitor to a patient suffering from the disease.

[0351] In some embodiments, the treatment with the BTK inhibitor comprises administering the BTK inhibitor to the patient.

[0352] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0353] In some embodiments, the subject is a patient suffering from a disease.

[0354] In some embodiments, said administering a BTK inhibitor to said subject is for treating said disease.

[0355] In some embodiments, the administering of a BTK inhibitor to the subject is for treating a disease in the subject.

[0356] In some embodiments, the subject is a patient in need of such treatment.

[0357] In another aspect, the disclosure relates to use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0358] In some embodiments, the subject is a patient suffering from a disease.

[0359] In some embodiments, said treatment with said BTK inhibitor is for treating said disease.

[0360] In some embodiments, the treating comprises administering the BTK inhibitor to the subject.

[0361] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) identifying subjects at risk of contracting an infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0362] In some embodiments, the BTK inhibitor is administered to treat a disease.

[0363] In some embodiments, the subject is a patient suffering from a disease.

[0364] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0365] In another aspect, the disclosure relates to the use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject.

[0366] In some embodiments, the subject is a human.

[0367] In some embodiments, the BTK inhibitor is administered to treat a disease.

[0368] In some embodiments, the subject is a patient suffering from a disease.

[0369] In some embodiments, the BTK inhibitor is administered to treat the disease.

[0370] The following embodiments relate to any of the above-disclosed aspects (i.e., to any method for treating a disease, method for reducing the risk of a subject contracting an infection, BTK inhibitor for use, vaccine for use, use of a BTK inhibitor for the preparation of a medicament, or use of a vaccine for the preparation of a medicament) or any of the above-disclosed embodiments.

[0371] In some embodiments, the patient is vaccinated while the patient is on ongoing BTK inhibitor treatment.

[0372] In some embodiments, the vaccine is administered while the patient is on ongoing BTK inhibitor treatment.

[0373] In some embodiments, at least one dose of the vaccine is administered during treatment with the BTK inhibitor.

[0374] In some embodiments, at least one dose of the vaccine is administered while the patient is on ongoing BTK inhibitor treatment.

[0375] In some embodiments, at least a portion of the vaccination program is performed while the patient / subject is under treatment with the BTK inhibitor.

[0376] In some embodiments, the BTK inhibitor treatment begins before the vaccination begins and continues until after the vaccination begins.

[0377] As will be understood by those skilled in the art, in this context, the expression "the vaccination has begun" or "the vaccination has been completed" refers to a complete vaccination program (which may include the administration of multiple individual doses to the patient). Thus, in this context, the term "vaccination" includes the administration of all doses required to complete the vaccination program.

[0378] In some embodiments, wherein the BTK inhibitor treatment begins before the vaccination begins and continues until after the vaccination has been completed.

[0379] In some embodiments, the BTK inhibitor treatment begins after the vaccination has begun and before the vaccination has been completed, and continues until after the vaccination has been completed.

[0380] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine and continues at least until administration of the vaccine.

[0381] In this context, "administering the vaccine" refers to administering individual doses of the vaccine. Depending on the specific vaccine, in some cases, administering a single dose of the vaccine may be sufficient to complete the vaccination program, while in other cases, more than one dose of the vaccine may be needed to complete the vaccination program.

[0382] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine and continues until after administration of the vaccine.

[0383] In some embodiments, the BTK inhibitor is administered before, during, and after administration of the vaccine.

[0384] In some embodiments, the vaccine is administered at a time when treatment with the BTK inhibitor has already begun and is still ongoing.

[0385] In some embodiments, there is a temporal overlap between the vaccination program and the BTK inhibitor treatment.

[0386] In some embodiments, the BTK inhibitor is administered during the vaccination.

[0387] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor does not end before administration of the vaccine begins or ends less than 4 weeks before administration of the vaccine begins.

[0388] As used herein, treatment with the BTK inhibitor starts at a first time and ends “not before” a second time means that the treatment starts at the first time and continues at least until the second time, i.e., from the first time at least until the second time, there is repeated administration of the BTK inhibitor (wherein, preferably, repeated administration of the BTK inhibitor means administration substantially once or more per day).

[0389] As used herein, "substantially daily" administration means that administration occurs every day or almost every day (i.e., only on a very exceptional basis, there may be one day when administration does not occur). "Substantially daily" administration is not limited in terms of the number of doses administered per day, i.e., it can be one or more doses per day.

[0390] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor does not end before administration of the vaccine begins or ends less than 3 weeks before administration of the vaccine begins.

[0391] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor does not end before administration of the vaccine begins or ends less than 2 weeks before administration of the vaccine begins.

[0392] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor does not end before administration of the vaccine begins or ends less than 1 week before administration of the vaccine begins.

[0393] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the BTK inhibitor is administered substantially daily from that time until less than 4 weeks or later before administration of the vaccine begins.

[0394] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the BTK inhibitor is administered substantially daily from that time until less than 3 weeks or later before administration of the vaccine begins.

[0395] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the BTK inhibitor is administered substantially daily from that time until less than 2 weeks or later before administration of the vaccine begins.

[0396] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the BTK inhibitor is administered substantially daily from that time until less than 1 week or later before administration of the vaccine begins.

[0397] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the BTK inhibitor is administered substantially daily from that time until administration of the vaccine begins or later.

[0398] In some embodiments, the substantially daily administration can be one or more than one dose of the BTK inhibitor administered substantially daily.

[0399] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor ends less than 4 weeks before administration of the vaccine begins.

[0400] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor ends no more than 3 weeks before administration of the vaccine begins.

[0401] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor ends no more than 2 weeks before administration of the vaccine begins.

[0402] In some embodiments, treatment with the BTK inhibitor begins before administration of the vaccine begins, and the treatment with the BTK inhibitor ends no more than 1 week before administration of the vaccine begins.

[0403] In some embodiments, treatment with the BTK inhibitor begins after the vaccination has begun, and the treatment with the BTK inhibitor begins less than 4 weeks after the vaccination has been completed.

[0404] In some embodiments, treatment with the BTK inhibitor begins after the vaccination has begun, and the treatment with the BTK inhibitor begins no more than 3 weeks after the vaccination has been completed.

[0405] In some embodiments, treatment with the BTK inhibitor begins after the vaccination has begun, and the treatment with the BTK inhibitor begins no more than 2 weeks after the vaccination has been completed.

[0406] In some embodiments, treatment with the BTK inhibitor begins after the vaccination has begun, and the treatment with the BTK inhibitor begins no more than 1 week after the vaccination has been completed.

[0407] In some embodiments, the time period between administration of the BTK inhibitor and vaccination is less than 4 weeks.

[0408] In some embodiments, the time period between administration of the BTK inhibitor and vaccination is less than 3 weeks.

[0409] In some embodiments, the time period between administration of the BTK inhibitor and vaccination is less than 2 weeks.

[0410] In some embodiments, the time period between administration of the BTK inhibitor and vaccination is less than 1 week.

[0411] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 8 weeks due to administration of the vaccine.

[0412] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 6 weeks due to administration of the vaccine.

[0413] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 4 weeks due to administration of the vaccine.

[0414] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 2 weeks due to administration of the vaccine.

[0415] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 1 week due to administration of the vaccine.

[0416] In some embodiments, vaccination occurs while the patient is on BTK inhibitor therapy, and treatment with the BTK inhibitor is not interrupted due to administration of the vaccine.

[0417] In some embodiments, the BTK inhibitor is administered to the patient substantially daily during the period in which the patient is on treatment with the BTK inhibitor.

[0418] In some embodiments, the BTK inhibitor is administered to the patient daily during the period in which the patient is on BTK inhibitor therapy.

[0419] In some embodiments, the patient receives repeated administrations of the BTK inhibitor substantially every day during treatment with the BTK inhibitor.

[0420] In some embodiments, the patient receives repeated administrations of the BTK inhibitor every day during treatment with the BTK inhibitor.

[0421] In some embodiments, repeated treatment with a BTK inhibitor means administering the BTK inhibitor substantially every day.

[0422] In some embodiments, repeated administration of the BTK inhibitor means that administration of the BTK inhibitor occurs substantially every day.

[0423] In some embodiments, step (d) begins less than 8 weeks after the completion of step (a).

[0424] In some embodiments, step (d) begins less than 6 weeks after the completion of step (a).

[0425] In some embodiments, step (d) begins less than 4 weeks after the completion of step (a).

[0426] In some embodiments, step (d) begins less than 2 weeks after the completion of step (a).

[0427] In some embodiments, step (d) begins less than 1 week after the completion of step (a).

[0428] In some embodiments, step (d) begins immediately upon completion of step (a).

[0429] In some embodiments, the subject is a human.

[0430] In some embodiments, the patient is a human.

[0431] In some embodiments, the subject / patient is an adult.

[0432] In some embodiments, the subject / patient is between 18 and 75 years old.

[0433] In some embodiments, the patient / subject is determined to be at risk for contracting the infection by testing the patient / subject for a history of infection.

[0434] In some embodiments, the patient / subject is identified as being at risk for contracting the infection by determining the titer of one or more antibodies indicative of immunity against the infection in the patient / subject's blood, serum, or plasma.

[0435] In some embodiments, the step of identifying a patient at risk of contracting an infection comprises measuring one or more antibody titers, preferably from a blood, serum or plasma sample.

[0436] In some embodiments, the disease in the patient is treated by the method.

[0437] In some embodiments, by the method, symptoms of the disease are alleviated.

[0438] In some embodiments, the administering of the BTK inhibitor is for treating a disease in a patient in need thereof.

[0439] In some embodiments, the disease in the patient is treated by administering the BTK inhibitor to the patient.

[0440] In some embodiments, by administering the BTK inhibitor to the patient, symptoms of the disease are alleviated.

[0441] In some embodiments, by said treatment, said disease in said patient is treated.

[0442] In some embodiments, the symptoms of the disease are alleviated by the treatment.

[0443] In some embodiments, the frequency of clinical exacerbations of the autoimmune disease is reduced by the treatment.

[0444] In some embodiments, the progression of the autoimmune disease is slowed or stopped by the treatment.

[0445] In some embodiments, administering the BTK inhibitor to the patient results in successful treatment of the patient.

[0446] In some embodiments, by using the method, the patient's risk of contracting the infection is reduced.

[0447] In some embodiments, the method achieves prevention of the infection.

[0448] In some embodiments, by the methods, an immune response in the patient is achieved against the agent causing the infection.

[0449] In some embodiments, by administering the vaccine to the patient, the patient's risk of contracting the infection is reduced.

[0450] In some embodiments, by administering the vaccine to the patient, prevention against the infection is achieved.

[0451] In some embodiments, by administering the vaccine to the patient, an immune response in the patient is achieved against the agent causing the infection.

[0452] In some embodiments, the risk of the patient contracting the infection is reduced by vaccinating the patient against the infection.

[0453] In some embodiments, prevention against the infection is achieved by vaccinating the patient against the infection.

[0454] In some embodiments, an immune response in the patient against the agent causing the infection is achieved by vaccinating the patient against the infection.

[0455] In some embodiments, full or partial immunization against the infection is achieved by vaccinating the patient against the infection.

[0456] In some embodiments, complete immunization against the infection is achieved by vaccinating the patient against the infection.

[0457] In some embodiments, prevention of an infection means that the subject becomes fully or partially immune to the infection.

[0458] In some embodiments, prevention of an infection means that the subject becomes completely immune to the infection.

[0459] In some embodiments, prevention of an infection means that the infection is avoided, the risk of contracting the infection is reduced, or if a patient contracts the infection, the infection is ameliorated (compared to where it would have been if such prevention had not occurred).

[0460] In some embodiments, the method is a method for vaccinating the subject rather than a method for treating a disease.

[0461] In some embodiments, the method is a method for vaccinating the subject rather than a method for treating a disease.

[0462] In some embodiments, the BTK inhibitor is selected from evobrutinib, torebrutinib, fennibrutinib, and ribrutinib.

[0463] In some embodiments, the BTK inhibitor is an irreversible BTK inhibitor.

[0464] In some embodiments, the BTK inhibitor is a BTK inhibitor that covalently binds to cysteine ​​481 of BTK.

[0465] In some embodiments, the BTK inhibitor has been shown in clinical studies to allow successful treatment of the disease.

[0466] In some embodiments, the BTK inhibitor has been granted marketing authorization for treating the disease by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0467] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or Mixtures of any of the above in any proportions.

[0468] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0469] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt thereof, or 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, or a mixture of any of these in any ratio.

[0471] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0472] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0473] In some embodiments, the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one.

[0474] In some embodiments, the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, or a mixture of any of these in any ratio.

[0475] In some embodiments, the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0477] In some embodiments, the BTK inhibitor is evobrutinib or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, or a mixture of any of these in any ratio.

[0478] In some embodiments, the BTK inhibitor is evobrutinib or a pharmaceutically acceptable salt thereof.

[0479] In some embodiments, the BTK inhibitor is evobrutinib.

[0480] In some embodiments, the BTK inhibitor is a compound according to formula (I): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0481] In some embodiments, the BTK inhibitor is a compound according to formula (I): or a pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the BTK inhibitor is a compound according to formula (I):

[0483] In some embodiments, the disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP), chronic spontaneous urticaria (CSU), graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma.

[0484] In some embodiments, the disease is selected from an autoimmune disease and an inflammatory disease.

[0485] In some embodiments, the disease is selected from an autoimmune disease, graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma.

[0486] In some embodiments, the inflammatory disease is selected from graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma.

[0487] In some embodiments, the disease is an autoimmune disease.

[0488] In some embodiments, the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP), and chronic spontaneous urticaria (CSU).

[0489] In some embodiments, the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP) and chronic spontaneous urticaria (CSU).

[0490] In some embodiments, the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD), and myasthenia gravis (MG).

[0491] In some embodiments, the autoimmune disease is SLE (systemic lupus erythematosus) or MS (multiple sclerosis).

[0492] In some embodiments, the autoimmune disease is SLE (systemic lupus erythematosus).

[0493] In some embodiments, the autoimmune disease is MS (multiple sclerosis).

[0494] In some embodiments, the autoimmune disease is multiple sclerosis (MS), including one or more indications selected from relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

[0495] In some embodiments, the autoimmune disease is selected from relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

[0496] In some embodiments, the autoimmune disease is relapsing multiple sclerosis (RMS).

[0497] In some embodiments, the disease is a disease that can be treated with the BTK inhibitor.

[0498] In some embodiments, treatment with the BTK inhibitor has been ongoing for a certain period of time means that, at least for that period of time, the BTK inhibitor has been administered substantially every day.

[0499] In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 72 hours ago.

[0500] In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 48 hours ago.

[0501] In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 36 hours ago.

[0502] In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 24 hours ago.

[0503] In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 72 hours ago.

[0504] In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 48 hours ago.

[0505] In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 36 hours ago.

[0506] In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 24 hours ago.

[0507] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 20 mg to 300 mg.

[0508] As will be appreciated by those skilled in the art, the daily dose can be administered in a single administration or in multiple administrations that together result in the full daily dose being administered. For example, a daily dose of 100 mg can be administered by the patient taking one 100 mg tablet in the morning, or by the patient taking one 50 mg tablet in the morning and one 50 mg tablet in the evening for a total daily dose of 100 mg.

[0509] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 20 mg to 200 mg.

[0510] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 25 mg to 150 mg.

[0511] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 85 mg to 95 mg.

[0512] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 25 mg to 50 mg.

[0513] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 50 mg to 75 mg.

[0514] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 75 mg to 100 mg.

[0515] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 100 mg to 150 mg.

[0516] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 100 mg to 125 mg.

[0517] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 125 mg to 150 mg.

[0518] In some embodiments, the BTK inhibitor is administered in a daily amount ranging from 90 mg to 130 mg.

[0519] In some embodiments, the BTK inhibitor is administered in a daily amount of about 90 mg.

[0520] As used herein, the term "about" with respect to a number, range, or amount is used to mean "approximately" or "approximately" the number, range, or amount. The meanings of those terms are well known in the art and indicate that variance, deviation, and / or variability are included in the corresponding number, range, or amount, for example, up to plus or minus 15% variance, deviation, and / or variability. In some embodiments, the term "about" indicates up to plus or minus 5% variance, deviation, and / or variability.

[0521] In some embodiments, the BTK inhibitor is administered in a daily amount of 90 mg.

[0522] In some embodiments, the daily amount of the BTK inhibitor is administered as a single unit formulation.

[0523] The unit dosage form can be, for example, a tablet (in the case of oral administration) or a single injection (in the case of administration by injection). Thus, if a patient takes a 100 mg daily dose by taking one 100 mg tablet in the morning, this would be a single unit dosage form for daily administration. On the other hand, if a patient takes a 50 mg tablet in the morning and one 50 mg tablet in the evening for daily administration of 100 mg, this would be two unit dosage forms for daily administration.

[0524] In some embodiments, the daily amount of the BTK inhibitor is administered as two unit formulations, which are administered separately and together comprise the daily amount.

[0525] In some embodiments, the daily amount of the BTK inhibitor is administered as two or more unit formulations, which are administered independently and together comprise the daily amount.

[0526] In some embodiments, the daily amount of the BTK inhibitor is administered as a single unit formulation or two unit formulations that are administered separately and together comprise the daily amount.

[0527] In some embodiments, each unit formulation administered each day contains the same amount of the BTK inhibitor.

[0528] In some embodiments, one or more unit dosage forms are tablets or capsules.

[0529] In some embodiments, 65 to 85 mg of the BTK inhibitor is administered once daily.

[0530] In some embodiments, 70 to 80 mg of the BTK inhibitor is administered once daily.

[0531] In some embodiments, about 75 mg of the BTK inhibitor is administered once daily.

[0532] In some embodiments, 75 mg of the BTK inhibitor is administered once daily.

[0533] In some embodiments, the once-daily administration of the BTK inhibitor is administered as a single unit dose.

[0534] In some embodiments, 40 to 85 mg of the BTK inhibitor is administered twice daily.

[0535] In some embodiments, 45 to 80 mg of the BTK inhibitor is administered twice daily.

[0536] In some embodiments, about 50 to about 75 mg of the BTK inhibitor is administered twice daily.

[0537] In some embodiments, 50 to 75 mg of the BTK inhibitor is administered twice daily.

[0538] In some embodiments, 40 to 60 mg of the BTK inhibitor is administered twice daily.

[0539] In some embodiments, 45 to 55 mg of the BTK inhibitor is administered twice daily.

[0540] In some embodiments, about 50 mg of the BTK inhibitor is administered twice daily.

[0541] In some embodiments, 50 mg of the BTK inhibitor is administered twice daily.

[0542] In some embodiments, 65 to 85 mg of the BTK inhibitor is administered twice daily.

[0543] In some embodiments, 70 to 80 mg of the BTK inhibitor is administered twice daily.

[0544] In some embodiments, about 75 mg of the BTK inhibitor is administered twice daily.

[0545] In some embodiments, 75 mg of the BTK inhibitor is administered twice daily.

[0546] In some embodiments, about 45 mg of the BTK inhibitor is administered twice daily.

[0547] In some embodiments, 45 mg of the BTK inhibitor is administered twice daily.

[0548] In some embodiments, administering the BTK inhibitor twice daily means administering two single unit doses of the same amount per day.

[0549] In some embodiments, the BTK inhibitor is administered in such a manner that the resulting concentration of the BTK inhibitor in the patient's plasma is similar to the concentration of the BTK inhibitor in the patient's plasma that would be achieved if the BTK inhibitor were administered orally as a tablet via a dosing / administration regimen as defined in any of the above embodiments.

[0550] In some embodiments, the BTK inhibitor is administered in a manner such that the resulting concentration of the BTK inhibitor in the patient's plasma is similar to the concentration of the BTK inhibitor in the patient's plasma that would be achieved if the BTK inhibitor were administered orally at 40 mg to 85 mg twice daily as a tablet.

[0551] In some embodiments, the BTK inhibitor is administered in a manner such that the resulting concentration of the BTK inhibitor in the patient's plasma is similar to the concentration of the BTK inhibitor in the patient's plasma that would be achieved if the BTK inhibitor were administered orally at 40 mg to 85 mg twice daily as a tablet under fed conditions.

[0552] In some embodiments, the BTK inhibitor is administered in such a manner that the therapeutic effect of the BTK inhibitor is similar to the therapeutic effect achieved if the BTK inhibitor is administered orally as a tablet via a dosing / administration regimen as defined in any one of the above embodiments.

[0553] In some embodiments, administering "in such a manner" means administering "in such an amount, in such a formulation, and by such an administration regimen."

[0554] In some embodiments, the BTK inhibitor is administered with a meal on each occasion in which the BTK inhibitor is administered.

[0555] In some embodiments, the BTK inhibitor is administered without a meal on each occasion in which the BTK inhibitor is administered.

[0556] In some embodiments, the BTK inhibitor is administered to a patient who has consumed food within 1 hour prior to receiving the BTK inhibitor.

[0557] In some embodiments, the BTK inhibitor is administered to a patient who has consumed food within 1 hour before administration of the BTK inhibitor and / or to a patient who has consumed food within 1 hour after administration of the BTK inhibitor.

[0558] In some embodiments, the BTK inhibitor is administered to a patient who has not consumed food within 1 hour before administration of the BTK inhibitor and who will not consume food within 1 hour after administration of the BTK inhibitor.

[0559] In some embodiments, the BTK inhibitor is administered orally.

[0560] In some embodiments, the BTK inhibitor is administered as one or more tablets or one or more capsules.

[0561] In some embodiments, the BTK inhibitor is administered as one or more tablets.

[0562] In some embodiments, the vaccination is performed by administering a vaccine.

[0563] In some embodiments, the vaccination is performed by administering a vaccine to the subject / patient.

[0564] In some embodiments, the patient is vaccinated by administering a vaccine to the patient.

[0565] In some embodiments, the vaccine is selected from an inactivated vaccine, a live attenuated vaccine, a live vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine, and a toxoid vaccine, or a combination thereof.

[0566] In some embodiments, the vaccine is selected from a live attenuated vaccine and a live vaccine, or a combination thereof.

[0567] In some embodiments, the vaccine is an inactivated vaccine.

[0568] In some embodiments, the vaccination is performed with a vaccine selected from the group consisting of: In some embodiments, the vaccination is performed with a vaccine selected from the group consisting of: inactivated vaccines, live attenuated vaccines, live vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines, and toxoid vaccines, or a combination thereof.

[0569] In some embodiments, the vaccination is performed using a vaccine selected from a live attenuated vaccine and a live vaccine, or a combination thereof.

[0570] In some embodiments, the vaccination is performed using a vaccine that is an inactivated vaccine.

[0571] In some embodiments, the vaccine is selected from anthrax preventive vaccine, cholera preventive vaccine, diphtheria preventive vaccine, Haemophilus influenzae preventive vaccine, meningococcal meningitis preventive vaccine, pertussis preventive vaccine, plague preventive vaccine, pneumococcal disease preventive vaccine, Streptococcus pneumoniae preventive vaccine, tetanus preventive vaccine, tuberculosis preventive vaccine, typhoid preventive vaccine.

[0572] In some embodiments, the vaccine is selected from the group consisting of: a varicella-zoster virus vaccine, a live attenuated varicella-zoster virus vaccine, an inactivated varicella-zoster virus vaccine, and an inactivated and / or recombinant varicella-zoster virus vaccine.

[0573] In some embodiments, the vaccine is a recombinant adjuvanted herpes zoster vaccine.

[0574] In some embodiments, the vaccine is a recombinant adjuvanted zoster vaccine comprising recombinant varicella-zoster virus glycoprotein E.

[0575] In some embodiments, the vaccine is

[0576] In some embodiments, the patient is antibody negative for varicella-zoster virus, preferably prior to said vaccination and / or prior to initiation of said BTK inhibitor treatment.

[0577] In some embodiments, the vaccine is an influenza virus vaccine selected from a monovalent influenza virus vaccine, a bivalent influenza virus vaccine, a trivalent influenza virus vaccine, a quadrivalent influenza virus vaccine, and a multivalent influenza virus vaccine.

[0578] In some embodiments, the vaccine is a quadrivalent influenza virus vaccine.

[0579] In some embodiments, the vaccine is selected from a coronavirus vaccine, a COVID-19 vaccine, a SARS-COVID-19 vaccine, and a SARS-CoV-2 vaccine.

[0580] In some embodiments, the vaccine is a coronavirus vaccine.

[0581] In some embodiments, the vaccine is a COVID-19 vaccine.

[0582] In some embodiments, the vaccine is an mRNA vaccine.

[0583] In some embodiments, the vaccine is not an mRNA vaccine.

[0584] In some embodiments, the vaccine is a non-mRNA vaccine.

[0585] In some embodiments, the vaccine is a non-mRNA COVID-19 vaccine.

[0586] In some embodiments, the vaccine is an mRNA-based vaccine.

[0587] In some embodiments, the vaccine is a viral vector-based vaccine.

[0588] In some embodiments, the vaccine is a protein-based vaccine.

[0589] In some embodiments, the vaccine is not an mRNA-based vaccine.

[0590] In some embodiments, the vaccine is an mRNA-based COVID-19 vaccine.

[0591] In some embodiments, the vaccine is not an mRNA-based COVID-19 vaccine.

[0592] In some embodiments, the vaccine is BioNTech / Pfizer's mRNA vaccine against COVID-19 or Moderna's mRNA vaccine against COVID-19.

[0593] In some embodiments, the vaccine is BioNTech / Pfizer's or Moderna's or the same vaccine distributed under a different name.

[0594] In some embodiments, the vaccine is BioNTech / Pfizer's or Moderna's or the same vaccine.

[0595] In some embodiments, the vaccine is BioNTech / Pfizer's mRNA vaccine against COVID-19.

[0596] In some embodiments, the vaccine is (AstraZeneca) or the same vaccine distributed under a different name.

[0597] In some embodiments, the vaccine is (AstraZeneca) or equivalent vaccine.

[0598] In some embodiments, the vaccine is (Janssen / Johnson & Johnson) or the same vaccine distributed under a different name.

[0599] In some embodiments, the vaccine is (Janssen / Johnson & Johnson) or equivalent vaccine.

[0600] In some embodiments, the patient is antibody negative prior to said vaccination for antibodies directed against the target antigen of said vaccination.

[0601] In some embodiments, the patient is seronegative for antibodies produced in an immune response to the vaccine prior to the vaccination.

[0602] In some embodiments, the antigen to which the patient is exposed upon vaccination is a novel antigen to the patient.

[0603] In some embodiments, the patient's immune response to the vaccination is a de novo response.

[0604] In some embodiments, the patient is antibody positive for antibodies to the target antigen of the vaccination prior to the vaccination.

[0605] In some embodiments, the patient is seropositive for antibodies produced in an immune response to the vaccine prior to said vaccination.

[0606] In some embodiments, the antigen to which the patient was exposed at the time of vaccination is a recall antigen for the patient.

[0607] In some embodiments, the patient's immune response to the vaccination is an anamnestic response.

[0608] In some embodiments, the vaccine is a vaccine against an infection.

[0609] In some embodiments, the infection is a viral infection.

[0610] In some embodiments, the viral infection is selected from hepatitis, chickenpox (varicella), shingles (herpes zoster), measles, influenza, poliovirus, human papillomavirus (HPV)-related diseases, SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and COVID-19 (coronavirus disease 2019).

[0611] In some embodiments, the hepatitis is hepatitis A and / or hepatitis B.

[0612] In some embodiments, the hepatitis is hepatitis B.

[0613] In some embodiments, the infection is a bacterial infection.

[0614] In some embodiments, the bacterial infection is selected from anthrax infection, cholera, diphtheria, Haemophilus influenzae infection, meningococcal meningitis, pertussis, plague, pneumococcal disease, Streptococcus pneumoniae infection, pneumococcal pneumonia, tetanus, tuberculosis, and typhus.

[0615] In some embodiments, the infection is a coronavirus infection.

[0616] In some embodiments, the infection is selected from SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and COVID-19 (Coronavirus Disease 2019).

[0617] In some embodiments, the infection is COVID-19.

[0618] In some embodiments, the infection is caused by a virus belonging to the Ribovirus domain.

[0619] In some embodiments, the infection is caused by a virus belonging to the domain Ribovirus and within the kingdom Nidovirales.

[0620] In some embodiments, the infection is caused by a virus belonging to the domain Ribovirus, within the kingdom Nidovirales, and within the order Coronaviridae.

[0621] In some embodiments, the infection is caused by a virus belonging to the Ribovirus domain, within the kingdom, to the order Nidovirales, within the order, to the family Coronaviridae, and within the family, to the subfamily Orthocoronavirinae.

[0622] In some embodiments, the infection is caused by a coronavirus.

[0623] In some embodiments, the infection is caused by a virus selected from SARS-CoV-1 (severe acute respiratory syndrome coronavirus 1), MERS-CoV (Middle East respiratory syndrome-related coronavirus), and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0624] In some embodiments, the infection is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0625] In some embodiments, the infection is influenza.

[0626] In some embodiments, the infection is seasonal influenza.

[0627] In some embodiments, the infection is varicella zoster infection.

[0628] In some embodiments, the infection is a herpes zoster infection.

[0629] In some embodiments, the infection is varicella.

[0630] In some embodiments, the infection is herpes zoster.

[0631] In some embodiments, the vaccine is a vaccine against an infectious agent.

[0632] In some embodiments, the infection is an infection caused by an infectious agent.

[0633] In some embodiments, the infection is caused by an infectious agent.

[0634] In some embodiments, the infectious agent is a virus belonging to the Ribovirus domain.

[0635] In some embodiments, the infectious agent is a virus belonging to the Riboviridae domain and to the order Nidovirales.

[0636] In some embodiments, the infectious agent is a virus belonging to the Riboviridae domain, the Nidovirales order, and the Coronaviridae family.

[0637] In some embodiments, the infectious agent is a virus belonging to the Riboviridae domain, the Nidovirales order, the Coronaviridae family, and the Orthocoronavirinae subfamily.

[0638] In some embodiments, the infectious agent is a coronavirus.

[0639] In some embodiments, the infectious agent is a virus selected from SARS-CoV-1 (severe acute respiratory syndrome coronavirus 1), MERS-CoV (Middle East respiratory syndrome-related coronavirus), and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0640] In some embodiments, the infectious agent is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0641] In some embodiments, the vaccine is selected from: an mRNA-based SARS-CoV-2 / COVID-19 virus vaccine, a vector-based SARS-CoV-2 / COVID-19 virus vaccine, an adenovirus / vector-based SARS-CoV-2 / COVID-19 virus vaccine, a virus-like particle (VLP)-based SARS-CoV-2 / COVID-19 virus vaccine, a DNA-based SARS-CoV-2 / COVID-19 virus vaccine, a protein-based SARS-CoV-2 / COVID-19 virus vaccine, an inactivated virus-based SARS-CoV-2 / COVID-19 virus vaccine, and a killed virus-based SARS-CoV-2 / COVID-19 virus vaccine.

[0642] In some embodiments, the vaccine is selected from: an mRNA-based SARS-CoV-2 / COVID-19 virus vaccine, a vector-based SARS-CoV-2 / COVID-19 virus vaccine, and an adenovirus / vector-based SARS-CoV-2 / COVID-19 virus vaccine.

[0643] In some embodiments, the vaccine is an mRNA-based SARS-CoV-2 / COVID-19 viral vaccine.

[0644] In some embodiments, the vaccine is (made by BioNTech / Pfizer) or (Made by Moderna).

[0645] In some embodiments, the vaccine is

[0646] In some embodiments, the vaccine is

[0647] In some embodiments, the infectious agent is influenza virus.

[0648] In some embodiments, the infectious agent is an influenza virus of strain HI A (human influenza A) or HI B (human influenza B).

[0649] In some embodiments, the infectious agent is influenza virus of strain HIA (human influenza A).

[0650] In some embodiments, the infectious agent is influenza virus of strain HI A (human influenza A), subtype A (H1N1).

[0651] In some embodiments, the infectious agent is influenza virus of strain HI A (human influenza A), subtype A (H3N2).

[0652] In some embodiments, the infectious agent is influenza virus of strain HI B (human influenza type B).

[0653] In some embodiments, the infectious agent is influenza virus of strain HI B (human influenza B), lineage B / Yamagata.

[0654] In some embodiments, the infectious agent is influenza virus of strain HI B (human influenza B), lineage B / Victoria.

[0655] In some embodiments, the infectious agent is varicella-zoster virus.

[0656] In some embodiments, the vaccine is administered by intramuscular injection.

[0657] In some embodiments, the vaccine is administered by oral administration.

[0658] In some embodiments, the vaccine is administered as a nasal spray.

[0659] In some embodiments, the vaccination consists of administering a single dose of the vaccine.

[0660] In some embodiments, the vaccination consists of administering two separate doses of the vaccine administered on different days.

[0661] In some embodiments, the vaccination consists of administering one dose of the vaccine or two separate doses of the vaccine administered on different days.

[0662] In some embodiments, the vaccination consists of administering a single dose of the vaccine or 2 to 6 separate doses of the vaccine administered on different days.

[0663] In some embodiments, said administering one or more of said doses of the vaccine is administering one or more of said doses to a patient.

[0664] In some embodiments, the two doses or the 2 to 6 doses are administered on different days over 1 week to 12 months.

[0665] In some embodiments, the two doses or the 2 to 6 separate doses are administered on different days over a period of 1 week to 6 months.

[0666] In some embodiments, the two doses or the 2 to 6 separate doses are administered on different days over 1 to 12 weeks.

[0667] In some embodiments, the two doses or the 2 to 6 separate doses are administered on different days within 1 to 6 weeks.

[0668] In some embodiments, the two doses or the 2 to 6 separate doses are administered on different days within 1 to 4 weeks.

[0669] In some embodiments, the two separate doses or the 2 to 6 separate doses are administered on different days separated by a period of at least 2 weeks.

[0670] In some embodiments, the two separate doses or the 2 to 6 separate doses are administered on different days separated by a period of at least 4 weeks.

[0671] In some embodiments, the two separate doses are administered to the patient on different days separated by a period of at least 2 months.

[0672] In some embodiments, the vaccination optionally includes administering a booster vaccination.

[0673] In some embodiments, the vaccination comprises administering a booster vaccination.

[0674] In some embodiments, the vaccination does not include administering a booster vaccination.

[0675] In some embodiments, administration of the vaccine optionally includes administration of a booster vaccination.

[0676] In some embodiments, administration of the vaccine comprises administration of a booster vaccination.

[0677] In some embodiments, the administration of the vaccine does not include the administration of a booster vaccination.

[0678] A booster vaccination is a dose of vaccine administered to an individual who has already received a primary vaccination (or series of vaccinations). A booster vaccination is recommended when the protection from the primary vaccination decreases over time, and it helps maintain or increase the protective immune response achieved by the primary vaccination. For example, after the primary vaccination against tetanus, a booster vaccination against tetanus is generally recommended every 10 years, at which point the memory cells specific for tetanus lose their function or undergo apoptosis. The recommended time interval between the primary vaccination and the administration of a booster vaccination for a particular vaccine is known to physicians with expertise in the corresponding medical field and is also available from the vaccine's product label or from the company that produces and sells the vaccine. In the case of mRNA-based COVID-19 vaccines such as BioNTech / Pfizer's or Moderna's In the case of COVID-19, the booster vaccination can be administered, for example, about 6 months after the previous COVID-19 vaccination dose.

[0679] In some embodiments, the booster vaccination is administered prior to administering the BTK inhibitor.

[0680] In some embodiments, the booster vaccination is administered after administration of the BTK inhibitor.

[0681] In some embodiments, the booster vaccination is administered while the patient is on repeat treatment with the BTK inhibitor.

[0682] In some embodiments, the booster vaccination is administered while the patient is on ongoing BTK inhibitor treatment.

[0683] In some embodiments, treatment with the BTK inhibitor continues for at least 2 weeks.

[0684] In some embodiments, treatment with the BTK inhibitor continues for at least 1 month.

[0685] In some embodiments, treatment with the BTK inhibitor continues for at least 2 months.

[0686] In some embodiments, treatment with the BTK inhibitor continues for at least 3 months.

[0687] In some embodiments, treatment with the BTK inhibitor continues for at least 6 months.

[0688] In some embodiments, treatment with the BTK inhibitor continues for at least 12 months.

[0689] Due to the fact that most of the autoimmune diseases and other inflammatory diseases discussed herein are rarely ultimately curable and are therefore of a chronic nature, the duration of treatment with the BTK inhibitor may span one or more years, typically several years, wherein the BTK inhibitor is administered to the patient, preferably as described herein above and / or below, without significant pauses or interruptions, or substantially without significant pauses or interruptions. However, there may be exceptional circumstances in which the treatment period is limited as defined in the embodiments below.

[0690] In some embodiments, treatment with the BTK inhibitor continues for no more than 12 months.

[0691] In some embodiments, treatment with the BTK inhibitor continues for no more than 6 months.

[0692] In some embodiments, treatment with the BTK inhibitor lasts no longer than 3 months.

[0693] In some embodiments, treatment with the BTK inhibitor lasts no longer than 2 months.

[0694] In some embodiments, treatment with the BTK inhibitor lasts no longer than 1 month.

[0695] In some embodiments, treatment with the BTK inhibitor lasts no longer than 2 weeks.

[0696] In some embodiments, during the duration of said treatment with said BTK inhibitor, the patient is on continuous treatment with said BTK inhibitor, without intermittent periods in which treatment with said BTK inhibitor does not occur.

[0697] In some embodiments, the disease in the patient or subject is treated by administering the BTK inhibitor to the patient or subject.

[0698] In some embodiments, the disease in the patient or subject is treated by administering the BTK inhibitor to the patient or subject.

[0699] In some embodiments, BTK inhibitor treatment is performed by administering a BTK inhibitor.

[0700] In some embodiments, the patient is treated with a BTK inhibitor by administering the BTK inhibitor.

[0701] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 1 week at the time of initiation of said vaccination.

[0702] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 2 weeks at the time of initiation of said vaccination.

[0703] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 1 month at the time of initiation of said vaccination.

[0704] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 2 months at the time of initiation of said vaccination.

[0705] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 3 months at the time of initiation of said vaccination.

[0706] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 6 months at the time of initiation of said vaccination.

[0707] In some embodiments, treatment with the BTK inhibitor has been ongoing for at least 12 months at the time of initiation of said vaccination.

[0708] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 12 months at the time of initiation of said vaccination.

[0709] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 6 months at the time of initiation of said vaccination.

[0710] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 3 months at the time of initiation of said vaccination.

[0711] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 2 months at the time of initiation of said vaccination.

[0712] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 1 month at the time of initiation of said vaccination.

[0713] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 2 weeks at the time of initiation of said vaccination.

[0714] In some embodiments, treatment with the BTK inhibitor has been ongoing for no more than 1 week at the time of initiation of the vaccination.

[0715] In some embodiments, treatment with the BTK inhibitor continues for at least 1 week after the time when the vaccination is completed.

[0716] In some embodiments, treatment with the BTK inhibitor continues for at least 2 weeks after the time when the vaccination is completed.

[0717] In some embodiments, treatment with the BTK inhibitor continues for at least 1 month after the time when the vaccination is completed.

[0718] In some embodiments, treatment with the BTK inhibitor continues for at least 2 months after the time when the vaccination is completed.

[0719] In some embodiments, treatment with the BTK inhibitor continues for at least 3 months after the time when the vaccination is completed.

[0720] In some embodiments, treatment with the BTK inhibitor continues for at least 6 months after the time when the vaccination is completed.

[0721] In some embodiments, treatment with the BTK inhibitor continues for at least 12 months after the time when the vaccination is completed.

[0722] In some embodiments, treatment with the BTK inhibitor continues for no more than 12 months after the time when the vaccination is completed.

[0723] In some embodiments, treatment with the BTK inhibitor continues for no more than 6 months after the time when the vaccination is completed.

[0724] In some embodiments, treatment with the BTK inhibitor continues for no more than 3 months after the time when the vaccination is completed.

[0725] In some embodiments, treatment with the BTK inhibitor continues for no more than 2 months after the time when the vaccination is completed.

[0726] In some embodiments, treatment with the BTK inhibitor continues for no more than 1 month after the time when the vaccination is completed.

[0727] In some embodiments, treatment with the BTK inhibitor continues for no more than 2 weeks after the time when the vaccination is completed.

[0728] In some embodiments, treatment with the BTK inhibitor continues for no more than 1 week after the time when the vaccination is completed.

[0729] The following is also disclosed with respect to the above subject matter: [1] A method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor (Bruton's tyrosine kinase inhibitor) to the patient, and (b) vaccinating the patient against infection.

[0730] [2] A method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering a BTK inhibitor to the patient.

[0731] [3] A method for treating a disease in a patient in need thereof, the method comprising: (a) identifying patients at risk of contracting an infection who require treatment for the disease, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) treating the disease by administering a BTK inhibitor to the patient.

[0732] [4] A method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0733] [5] A method for treating a disease in a patient in need thereof, the method comprising: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0734] [6] A method for treating a disease in a patient in need thereof, the method comprising: (a) administering a BTK inhibitor to the patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0735] [7] A method for treating a disease in a patient in need thereof, the method comprising: (a) optionally administering a BTK inhibitor to said patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering the BTK inhibitor to the patient, with the proviso that the method comprises one or more treatment periods in which the BTK inhibitor is administered to treat the patient for the disease and reduce the patient's risk of contracting the infection.

[0736] [8] A method for treating a disease in a patient in need thereof, the treatment comprising administering a BTK inhibitor to the patient, wherein the patient is vaccinated against an infection while the patient is on ongoing treatment with the BTK inhibitor.

[0737] [9] A method for reducing the risk of a subject contracting an infection, the method comprising: (a) administering a BTK inhibitor to the subject, and (b) vaccinating the subject against the infection.

[0738]

[10] The method according to item [9], wherein the subject is a patient suffering from a disease.

[0739]

[11] The method according to any one of items [9] or

[10] , wherein the administration of the BTK inhibitor to the subject is for treating a disease of the subject.

[0740]

[12] The method according to any one of items [9] to

[11] , wherein the subject is a patient in need of such treatment.

[0741]

[13] A method for reducing the risk of a subject contracting an infection, the method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while on ongoing treatment with a BTK inhibitor.

[0742]

[14] The method according to item

[13] , wherein the subject is a patient suffering from a disease.

[0743]

[15] The method according to any one of items

[13] or

[14] , wherein the treatment with the BTK inhibitor is for treating a disease in a patient in need thereof.

[0744]

[16] The method according to any one of items

[13] to

[15] , wherein the treatment comprises administering the BTK inhibitor to the subject.

[0745]

[17] A method for treating a disease in a patient in need thereof and reducing the risk of infection in the patient, the method comprising (a) administering a BTK inhibitor to the patient, and (b) vaccinating the patient against the infection.

[0746]

[18] A BTK inhibitor for use in treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0747]

[19] A BTK inhibitor for use in treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0748]

[20] The BTK inhibitor for use according to item

[19] , wherein the patient is a patient suffering from the disease.

[0749]

[21] The BTK inhibitor for use according to any one of items

[19] or

[20] , wherein the BTK inhibitor is administered to treat the disease.

[0750]

[22] A BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0751]

[23] The BTK inhibitor for use according to item

[22] , wherein the patient is a patient suffering from the disease.

[0752]

[24] The BTK inhibitor for use according to any one of items

[22] or

[23] , wherein the BTK inhibitor is administered to treat the disease.

[0753]

[25] A BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0754]

[26] The BTK inhibitor for use according to item

[25] , wherein the patient is a patient suffering from the disease.

[0755]

[27] A BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0756]

[28] The BTK inhibitor for use according to item

[27] , wherein the patient is a patient suffering from the disease.

[0757]

[29] The BTK inhibitor for use according to any one of items

[27] or

[28] , wherein the BTK inhibitor is administered to treat the disease.

[0758]

[30] A BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering to said patient said BTK inhibitor, with the proviso that said method comprises one or more treatment periods in which said BTK inhibitor is administered.

[0759]

[31] The BTK inhibitor for use according to item

[30] , wherein the patient is a patient suffering from the disease.

[0760]

[32] The BTK inhibitor for use according to any one of items

[30] or

[31] , wherein the BTK inhibitor is administered to treat the disease.

[0761]

[33] A BTK inhibitor for use in treating a disease by a method comprising administering the BTK inhibitor to a patient suffering from the disease, the method comprising vaccinating the patient against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0762]

[34] A BTK inhibitor for use in treating a disease, wherein the patient is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0763]

[35] The BTK inhibitor for use according to item

[34] , wherein the treatment with the BTK inhibitor comprises administering the BTK inhibitor to the patient.

[0764]

[36] The BTK inhibitor for use according to any one of items

[34] or

[35] , wherein the method comprises administering the BTK inhibitor to a patient suffering from the disease.

[0765]

[37] A BTK inhibitor for use in treating a disease, wherein the BTK inhibitor is administered in combination with a vaccine.

[0766]

[38] The BTK inhibitor for use according to item

[37] , wherein the treatment is by administering the BTK inhibitor to a patient in need thereof.

[0767]

[39] The BTK inhibitor for use according to any one of

[37] of item

[38] , wherein the vaccine is a vaccine against an infection.

[0768]

[40] The BTK inhibitor for use according to any one of items

[37] to

[39] , wherein the patient is vaccinated against an infection with the vaccine.

[0769]

[41] The BTK inhibitor for use according to any one of items

[37] to

[40] , wherein the vaccine is administered to the patient.

[0770]

[42] The BTK inhibitor for use according to any one of items

[37] to

[41] , wherein the treatment with the BTK inhibitor and the vaccination with the vaccine occur simultaneously or sequentially.

[0771]

[43] The BTK inhibitor for use according to any one of items

[37] to

[42] , wherein administration of the BTK inhibitor and vaccination with the vaccine occur simultaneously or sequentially.

[0772]

[44] A vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0773]

[45] The vaccine for use according to item

[44] , wherein the subject is a patient suffering from a disease.

[0774]

[46] The vaccine for use according to item

[45] , wherein the administration of the BTK inhibitor to the subject is for treating the disease.

[0775]

[47] The vaccine for use according to any one of items

[44] to

[46] , wherein the administration of the BTK inhibitor to the subject is for treating a disease in the subject.

[0776]

[48] ​​A vaccine for use according to any one of items

[44] to

[47] , wherein the subject is a patient in need of such treatment.

[0777]

[49] A vaccine for preventing an infection by a method comprising vaccinating the subject against the infection, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0778]

[50] The vaccine for use according to item

[49] , wherein the subject is a patient suffering from a disease.

[0779]

[51] The vaccine for use according to any one of items

[49] or

[50] , wherein the treatment with the BTK inhibitor is for treating a disease in the patient.

[0780]

[52] The vaccine for use according to item

[51] , wherein the patient is a patient suffering from the disease.

[0781]

[53] The vaccine for use according to any one of items

[49] to

[52] , wherein the treatment comprises administering the BTK inhibitor to the subject.

[0782]

[54] A vaccine for preventing infection by a method comprising: (a) identifying a subject at risk of contracting the infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0783]

[55] The vaccine for use according to item

[54] , wherein the BTK inhibitor is administered to treat a disease.

[0784]

[56] The vaccine for use according to any one of items

[54] or

[55] , wherein the subject is a patient suffering from a disease.

[0785]

[57] The vaccine for use according to any one of items

[54] to

[56] , wherein the BTK inhibitor is administered to treat the disease.

[0786]

[58] A vaccine for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject.

[0787]

[59] The vaccine for use according to item

[58] , wherein the BTK inhibitor is administered to treat a disease.

[0788]

[60] A vaccine for use according to any one of items

[58] or

[59] , wherein the subject is a patient suffering from a disease.

[0789]

[61] The vaccine for use according to any one of items

[58] to

[60] , wherein the BTK inhibitor is administered to treat the disease.

[0790]

[62] Use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient suffering from the disease, and (b) vaccinating the patient against infection.

[0791]

[63] Use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method comprising: (a) identify patients at risk of contracting an infection, (b) vaccinating said patient at risk of contracting said infection against said infection, and (c) administering the BTK inhibitor to the patient.

[0792]

[64] The use according to item

[63] , wherein the patient is a patient suffering from the disease.

[0793]

[65] The use according to any one of items

[63] or

[64] , wherein the BTK inhibitor is administered to treat the disease.

[0794]

[66] Use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, and (c) vaccinating the patient against the infection.

[0795]

[67] The use according to item

[66] , wherein the patient is a patient suffering from the disease.

[0796]

[68] The use according to any one of items

[66] or

[67] , wherein the BTK inhibitor is administered to treat the disease.

[0797]

[69] Use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the disease in the patient, (b) determining that the patient is at risk of contracting an infection if placed on repeat treatment with the BTK inhibitor, and (c) vaccinating said patient against said infection while under repeated treatment with said BTK inhibitor, and optionally (d) continuing said repeated treatment with said BTK inhibitor.

[0798]

[70] The use according to item

[69] , wherein the patient is a patient suffering from the disease.

[0799]

[71] Use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0800]

[72] The use according to item

[71] , wherein the patient is a patient suffering from the disease.

[0801]

[73] The use according to any one of items

[71] or

[72] , wherein the BTK inhibitor is administered to treat the disease.

[0802]

[74] Use of a BTK inhibitor for the preparation of a medicament for treating a disease, wherein the BTK inhibitor is administered by the following method: (a) optionally administering the BTK inhibitor to the patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering to said patient said BTK inhibitor, with the proviso that said method comprises one or more treatment periods in which said BTK inhibitor is administered.

[0803]

[75] The use according to item

[74] , wherein the patient is a patient suffering from the disease.

[0804]

[76] The use according to any one of items

[74] or

[75] , wherein the BTK inhibitor is administered to treat the disease.

[0805]

[77] Use of a BTK inhibitor for the preparation of a medicament for treating a disease by a method wherein a patient suffering from the disease is vaccinated against an infection while the patient is under ongoing treatment with the BTK inhibitor.

[0806]

[78] The use according to item

[77] , wherein the method comprises administering the BTK inhibitor to a patient suffering from the disease.

[0807]

[79] The use according to any one of items

[77] or

[78] , wherein the treatment with the BTK inhibitor comprises administering the BTK inhibitor to the patient.

[0808]

[80] Use of a vaccine for the preparation of a medicament for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infection.

[0809]

[81] The use according to item

[80] , wherein the subject is a patient suffering from a disease.

[0810]

[82] The use according to any one of items

[80] or

[81] , wherein the administration of the BTK inhibitor to the subject is for treating the disease.

[0811]

[83] The use according to any one of items

[80] to

[82] , wherein the administration of the BTK inhibitor to the subject is for treating a disease of the subject.

[0812]

[84] The use according to any one of items

[80] to

[83] , wherein the subject is a patient in need of such treatment.

[0813]

[85] Use of a vaccine for the preparation of a medicament for preventing an infection by a method comprising vaccinating said subject against said infection, wherein said subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0814]

[86] The use according to item

[85] , wherein the subject is a patient suffering from a disease.

[0815]

[87] The use according to item

[86] , wherein the treatment with the BTK inhibitor is for treating the disease.

[0816]

[88] The use according to any one of items

[85] to

[87] , wherein the treatment comprises administering the BTK inhibitor to the subject.

[0817]

[89] Use of a vaccine for the preparation of a medicament for preventing infection by a method comprising: (a) identifying subjects at risk of contracting an infection, (b) vaccinating said subject at risk of contracting said infection with said vaccine against said infection, and (c) administering a BTK inhibitor to the subject.

[0818]

[90] The use according to item

[89] , wherein the BTK inhibitor is administered to treat a disease.

[0819]

[91] The use according to any one of items

[89] or

[90] , wherein the subject is a patient suffering from a disease.

[0820]

[92] The use according to any one of items

[89] to

[91] , wherein the BTK inhibitor is administered to treat the disease.

[0821]

[93] Use of a vaccine for the preparation of a medicament for preventing infection by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating said subject against said infection with said vaccine, and (c) continuing to administer the BTK inhibitor to the subject.

[0822]

[94] The use according to item

[93] , wherein the subject is a human.

[0823]

[95] The use according to any one of items

[93] or

[94] , wherein the BTK inhibitor is administered to treat a disease.

[0824]

[96] The use according to any one of items

[93] to

[95] , wherein the subject is a patient suffering from a disease.

[0825]

[97] The use according to any one of items

[93] to

[96] , wherein the BTK inhibitor is administered to treat the disease.

[0826]

[98] The method according to any one of items [1] to

[17] or the BTK inhibitor for use according to any one of items

[18] to

[43] or the vaccine for use according to any one of items

[44] to

[61] or the use according to any one of items

[62] to

[97] , wherein the patient is vaccinated while the patient is under ongoing BTK inhibitor treatment.

[0827]

[99] The method according to any one of items [1] to

[17] or

[98] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] or the vaccine for use according to any one of items

[44] to

[61] or

[98] or the use according to any one of items

[62] to

[98] , wherein the vaccine is administered while the patient is under ongoing BTK inhibitor treatment.

[0828]

[100] The method according to any one of items [1] to

[17] or

[98] to

[99] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[99] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[99] or the use according to any one of items

[62] to

[99] , wherein at least one dose of the vaccine is administered during treatment with the BTK inhibitor.

[0829]

[101] The method according to any one of items [1] to

[17] or

[98] to

[100] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[100] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[100] or the use according to any one of items

[62] to

[100] , wherein at least one dose of the vaccine is administered while the patient is under ongoing BTK inhibitor treatment.

[0830]

[102] The method according to any one of items [1] to

[17] or

[98] to

[101] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[101] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[101] or the use according to any one of items

[62] to

[101] , wherein at least part of the vaccination procedure is performed while the patient / subject is under treatment with the BTK inhibitor.

[0831]

[103] The method according to any one of items [1] to

[17] or

[98] to

[102] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[102] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[102] or the use according to any one of items

[62] to

[102] , wherein the BTK inhibitor treatment is started before the start of the vaccination and continues until after the start of the vaccination.

[0832]

[104] The method according to any one of items [1] to

[17] or

[98] to

[103] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[103] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[103] or the use according to any one of items

[62] to

[103] , wherein the BTK inhibitor treatment is started before the vaccination is started and continues until after the vaccination has been completed.

[0833]

[105] The method according to any one of items [1] to

[17] or

[98] to

[104] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[104] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[104] or the use according to any one of items

[62] to

[104] , wherein the BTK inhibitor treatment starts after the vaccination has started and before the vaccination has been completed and continues until after the vaccination has been completed.

[0834]

[106] The method according to any one of items [1] to

[17] or

[98] to

[105] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[105] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[105] or the use according to any one of items

[62] to

[105] , wherein treatment with the BTK inhibitor is started before administration of the vaccine and continues at least until administration of the vaccine.

[0835]

[107] The method according to any one of items [1] to

[17] or

[98] to

[106] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[106] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[106] or the use according to any one of items

[62] to

[106] , wherein treatment with the BTK inhibitor is started before administration of the vaccine and continues until after administration of the vaccine.

[0836]

[108] The method according to any one of items [1] to

[17] or

[98] to

[107] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[107] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[107] or the use according to any one of items

[62] to

[107] , wherein the BTK inhibitor is administered before, during and after administration of the vaccine.

[0837]

[109] The method according to any one of items [1] to

[17] or

[98] to

[108] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[108] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[108] or the use according to any one of items

[62] to

[108] , wherein the vaccine is administered at a time when treatment with the BTK inhibitor has started and is still ongoing.

[0838]

[110] The method according to any one of items [1] to

[17] or

[98] to

[109] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[109] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[109] or the use according to any one of items

[62] to

[109] , wherein there is a temporal overlap between the vaccination program and the BTK inhibitor treatment.

[0839]

[111] The method according to any one of items [1] to

[17] or

[98] to

[110] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[110] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[110] or the use according to any one of items

[62] to

[110] , wherein the BTK inhibitor is administered during the vaccination.

[0840]

[112] The method according to any one of items [1] to

[17] or

[98] to

[111] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[111] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[111] or the use according to any one of items

[62] to

[111] , wherein the treatment with the BTK inhibitor is started before the start of administration of the vaccine, and wherein the treatment with the BTK inhibitor does not end before the start of administration of the vaccine or ends less than 4 weeks before the start of administration of the vaccine.

[0841]

[113] The method according to any one of items [1] to

[17] or

[98] to

[112] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[112] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[112] or the use according to any one of items

[62] to

[112] , wherein the treatment with the BTK inhibitor is started before the start of administration of the vaccine, and wherein the treatment with the BTK inhibitor does not end before the start of administration of the vaccine or ends less than 3 weeks before the start of administration of the vaccine.

[0842]

[114] The method according to any one of items [1] to

[17] or

[98] to

[113] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[113] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[113] or the use according to any one of items

[62] to

[113] , wherein the treatment with the BTK inhibitor is started before the start of administration of the vaccine, and wherein the treatment with the BTK inhibitor does not end before the start of administration of the vaccine or ends less than 2 weeks before the start of administration of the vaccine.

[0843]

[115] The method according to any one of items [1] to

[17] or

[98] to

[114] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[114] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[114] or the use according to any one of items

[62] to

[114] , wherein the treatment with the BTK inhibitor is started before the start of administration of the vaccine, and wherein the treatment with the BTK inhibitor does not end before the start of administration of the vaccine or ends less than 1 week before the start of administration of the vaccine.

[0844]

[116] The method according to any one of items [1] to

[17] or

[98] to

[115] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[115] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[115] or the use according to any one of items

[62] to

[115] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and the BTK inhibitor is administered substantially daily from that time until less than 4 weeks or later before the start of administration of the vaccine.

[0845]

[117] The method according to any one of items [1] to

[17] or

[98] to

[116] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[116] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[116] or the use according to any one of items

[62] to

[116] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and the BTK inhibitor is administered substantially daily from that time until less than 3 weeks or later before the start of administration of the vaccine.

[0846]

[118] The method according to any one of items [1] to

[17] or

[98] to

[117] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[117] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[117] or the use according to any one of items

[62] to

[117] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and the BTK inhibitor is administered substantially daily from that time until less than 2 weeks or later before the start of administration of the vaccine.

[0847]

[119] The method according to any one of items [1] to

[17] or

[98] to

[118] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[118] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[118] or the use according to any one of items

[62] to

[118] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and the BTK inhibitor is administered substantially daily from that time until less than 1 week or later before the start of administration of the vaccine.

[0848]

[120] The method according to any one of items [1] to

[17] or

[98] to

[119] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[119] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[119] or the use according to any one of items

[62] to

[119] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and the BTK inhibitor is administered substantially daily from that time until the start of administration of the vaccine or later.

[0849]

[121] The method according to any one of items [1] to

[17] or

[98] to

[120] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[120] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[120] or the use according to any one of items

[62] to

[120] , wherein the substantially daily administration may be one dose or more than one dose of the BTK inhibitor administered substantially every day.

[0850]

[122] The method according to any one of items [1] to

[17] or

[98] to

[121] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[121] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[121] or the use according to any one of items

[62] to

[121] , wherein treatment with the BTK inhibitor starts before the start of administration of the vaccine and wherein the treatment with the BTK inhibitor ends less than 4 weeks before the start of administration of the vaccine.

[0851]

[123] The method according to any one of items [1] to

[17] or

[98] to

[122] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[122] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[122] or the use according to any one of items

[62] to

[122] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and wherein the treatment with the BTK inhibitor is ended no more than 3 weeks before the start of administration of the vaccine.

[0852]

[124] The method according to any one of items [1] to

[17] or

[98] to

[123] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[123] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[123] or the use according to any one of items

[62] to

[123] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and wherein the treatment with the BTK inhibitor is ended no more than 2 weeks before the start of administration of the vaccine.

[0853]

[125] The method according to any one of items [1] to

[17] or

[98] to

[124] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[124] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[124] or the use according to any one of items

[62] to

[124] , wherein treatment with the BTK inhibitor is started before the start of administration of the vaccine and wherein the treatment with the BTK inhibitor is ended no more than 1 week before the start of administration of the vaccine.

[0854]

[126] The method according to any one of items [1] to

[17] or

[98] to

[125] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[125] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[125] or the use according to any one of items

[62] to

[125] , wherein treatment with the BTK inhibitor is started after the vaccination has started, and wherein treatment with the BTK inhibitor is started less than 4 weeks after the vaccination has been completed.

[0855]

[127] The method according to any one of items [1] to

[17] or

[98] to

[126] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[126] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[126] or the use according to any one of items

[62] to

[126] , wherein treatment with the BTK inhibitor is started after the vaccination has started, and wherein treatment with the BTK inhibitor is started no more than 3 weeks after the vaccination has been completed.

[0856]

[128] The method according to any one of items [1] to

[17] or

[98] to

[127] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[127] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[127] or the use according to any one of items

[62] to

[127] , wherein treatment with the BTK inhibitor is started after the vaccination has started, and wherein treatment with the BTK inhibitor is started no more than 2 weeks after the vaccination has been completed.

[0857]

[129] The method according to any one of items [1] to

[17] or

[98] to

[128] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[128] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[128] or the use according to any one of items

[62] to

[128] , wherein treatment with the BTK inhibitor is started after the vaccination has started, and wherein treatment with the BTK inhibitor is started no more than 1 week after the vaccination has been completed.

[0858]

[130] The method according to any one of items [1] to

[17] or

[98] to

[129] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[129] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[129] or the use according to any one of items

[62] to

[129] , wherein the period between administration of the BTK inhibitor and vaccination is less than 4 weeks.

[0859]

[131] The method according to any one of items [1] to

[17] or

[98] to

[130] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[130] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[130] or the use according to any one of items

[62] to

[130] , wherein the time period between administration of the BTK inhibitor and vaccination is less than 3 weeks.

[0860]

[132] The method according to any one of items [1] to

[17] or

[98] to

[131] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[131] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[131] or the use according to any one of items

[62] to

[131] , wherein the time period between administration of the BTK inhibitor and vaccination is less than 2 weeks.

[0861]

[133] The method according to any one of items [1] to

[17] or

[98] to

[132] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[132] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[132] or the use according to any one of items

[62] to

[132] , wherein the time period between administration of the BTK inhibitor and vaccination is less than 1 week.

[0862]

[134] The method according to any one of items [1] to

[17] or

[98] to

[133] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[133] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[133] or the use according to any one of items

[62] to

[133] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 8 weeks due to administration of the vaccine.

[0863]

[135] The method according to any one of items [1] to

[17] or

[98] to

[134] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[134] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[134] or the use according to any one of items

[62] to

[134] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 6 weeks due to administration of the vaccine.

[0864]

[136] The method according to any one of items [1] to

[17] or

[98] to

[135] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[135] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[135] or the use according to any one of items

[62] to

[135] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 4 weeks due to administration of the vaccine.

[0865]

[137] The method according to any one of items [1] to

[17] or

[98] to

[136] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[136] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[136] or the use according to any one of items

[62] to

[136] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 2 weeks due to administration of the vaccine.

[0866]

[138] The method according to any one of items [1] to

[17] or

[98] to

[137] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[137] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[137] or the use according to any one of items

[62] to

[137] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted or is interrupted for less than 1 week due to administration of the vaccine.

[0867]

[139] The method according to any one of items [1] to

[17] or

[98] to

[138] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[138] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[138] or the use according to any one of items

[62] to

[138] , wherein vaccination occurs while the patient is under treatment with a BTK inhibitor and treatment with the BTK inhibitor is not interrupted due to administration of the vaccine.

[0868]

[140] The method according to any one of items [1] to

[17] or

[98] to

[139] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[139] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[139] or the use according to any one of items

[62] to

[139] , wherein the BTK inhibitor is administered to the patient substantially every day during the period in which the patient is under treatment with the BTK inhibitor.

[0869]

[141] The method according to any one of items [1] to

[17] or

[98] to

[140] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[140] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[140] or the use according to any one of items

[62] to

[140] , wherein the BTK inhibitor is administered to the patient daily during the period in which the patient is under treatment with the BTK inhibitor.

[0870]

[142] The method according to any one of items [1] to

[17] or

[98] to

[141] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[141] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[141] or the use according to any one of items

[62] to

[141] , wherein during the BTK inhibitor treatment, the patient receives repeated administrations of the BTK inhibitor substantially every day.

[0871]

[143] The method according to any one of items [1] to

[17] or

[98] to

[142] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[142] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[142] or the use according to any one of items

[62] to

[142] , wherein during the BTK inhibitor treatment the patient receives repeated administrations of the BTK inhibitor every day.

[0872]

[144] The method according to any one of items [1] to

[17] or

[98] to

[143] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[143] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[143] or the use according to any one of items

[62] to

[143] , wherein repeated treatment with the BTK inhibitor means administration of the BTK inhibitor essentially every day.

[0873]

[145] The method according to any one of items [1] to

[17] or

[98] to

[144] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[144] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[144] , or the use according to any one of items

[62] to

[144] , wherein repeated administration of the BTK inhibitor means that administration of the BTK inhibitor occurs essentially every day.

[0874]

[146] The method of any one of items [5] or [7] or

[98] to

[145] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[145] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[145] , wherein step (d) is commenced less than 8 weeks after the end of step (a).

[0875]

[147] The method of any one of items [5] or [7] or

[98] to

[146] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[146] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[146] , wherein step (d) is commenced less than 6 weeks after the end of step (a).

[0876]

[148] The method of any one of items [5] or [7] or

[98] to

[147] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[147] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[147] , wherein step (d) is commenced less than 4 weeks after the end of step (a).

[0877]

[149] The method of any one of items [5] or [7] or

[98] to

[148] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[148] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[148] , wherein step (d) is commenced less than 2 weeks after the end of step (a).

[0878]

[150] The method of any one of items [5] or [7] or

[98] to

[149] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[149] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[149] , wherein step (d) is started less than 1 week after the end of step (a).

[0879]

[151] The method according to any one of items [5] or [7] or

[98] to

[150] or the BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[150] or the use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[150] , wherein step (d) is started immediately upon completion of step (a).

[0880]

[152] The method according to any one of items [1] to

[17] or

[98] to

[151] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[151] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or the use according to any one of items

[62] to

[151] , wherein the subject is a human.

[0881]

[153] The method according to any one of items [1] to

[17] or

[98] to

[152] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[152] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] or the use according to any one of items

[62] to

[152] , wherein the patient is a human.

[0882]

[154] The method according to any one of items [1] to

[17] or

[98] to

[153] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[153] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[153] or the use according to any one of items

[62] to

[153] , wherein the subject / patient is an adult.

[0883]

[155] The method according to any one of items [1] to

[17] or

[98] to

[154] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[154] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[154] or the use according to any one of items

[62] to

[154] , wherein the subject / patient is aged between 18 and 75 years.

[0884]

[156] The method according to any one of items [1] to

[17] or

[98] to

[155] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[155] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[155] or the use according to any one of items

[62] to

[155] , wherein the patient / subject is determined to be at risk of contracting the infection by testing the patient / subject for a history of infection.

[0885]

[157] The method according to any one of items [1] to

[17] or

[98] to

[156] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[156] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[156] or the use according to any one of items

[62] to

[156] , wherein the patient / subject is determined to be at risk of contracting the infection by determining one or more antibody titers indicative of immunity against the infection in the blood, serum or plasma of the patient / subject.

[0886]

[158] The method according to any one of items [1] to

[17] or

[98] to

[157] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[157] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[157] or the use according to any one of items

[62] to

[157] , wherein the step of determining a patient at risk of contracting an infection / determining a patient at risk of contracting an infection comprises measuring one or more antibody titers, preferably from a blood, serum or plasma sample.

[0887]

[159] The method according to any one of items [1] to

[17] or

[98] to

[158] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[158] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[158] or the use according to any one of items

[62] to

[158] , wherein the disease in the patient is treated by said method.

[0888]

[160] The method according to any one of items [1] to

[17] or

[98] to

[159] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[159] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[159] or the use according to any one of items

[62] to

[159] , wherein by said method the symptoms of the disease are alleviated.

[0889]

[161] The method according to any one of items [1] to

[17] or

[98] to

[160] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[160] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[160] or the use according to any one of items

[62] to

[160] , wherein the administration of the BTK inhibitor is for treating a disease in a patient in need thereof.

[0890]

[162] The method according to any one of items [1] to

[17] or

[98] to

[161] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[161] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[161] or the use according to any one of items

[62] to

[161] , wherein the disease in the patient is treated by administering the BTK inhibitor to the patient.

[0891]

[163] The method according to any one of items [1] to

[17] or

[98] to

[162] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[162] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[162] or the use according to any one of items

[62] to

[162] , wherein the symptoms of the disease are alleviated by administering the BTK inhibitor to the patient.

[0892]

[164] The method according to any one of items [1] to

[17] or

[98] to

[163] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[163] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[163] or the use according to any one of items

[62] to

[163] , wherein by said treatment the disease in said patient is treated.

[0893]

[165] The method according to any one of items [1] to

[17] or

[98] to

[164] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[164] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[164] or the use according to any one of items

[62] to

[164] , wherein the symptoms of the disease are alleviated by said treatment.

[0894]

[166] The method according to any one of items [1] to

[17] or

[98] to

[165] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[165] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[165] or the use according to any one of items

[62] to

[165] , wherein the frequency of clinical exacerbations of the autoimmune disease is reduced by said treatment.

[0895]

[167] The method according to any one of items [1] to

[17] or

[98] to

[166] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[166] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[166] or the use according to any one of items

[62] to

[166] , wherein by said treatment the progression of the autoimmune disease is slowed or stopped.

[0896]

[168] The method according to any one of items [1] to

[17] or

[98] to

[167] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[167] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[167] or the use according to any one of items

[62] to

[167] , wherein administration of the BTK inhibitor to the patient results in successful treatment of the patient.

[0897]

[169] The method according to any one of items [1] to

[17] or

[98] to

[168] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[168] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[168] or the use according to any one of items

[62] to

[168] , wherein by said method the risk of said patient contracting said infection is reduced.

[0898]

[170] The method according to any one of items [1] to

[17] or

[98] to

[169] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[169] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[169] or the use according to any one of items

[62] to

[169] , wherein by said method, prevention of said infection is achieved.

[0899]

[171] The method according to any one of items [1] to

[17] or

[98] to

[170] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[170] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[170] or the use according to any one of items

[62] to

[170] , wherein by said method an immune response of the patient against the agent causing the infection is achieved.

[0900]

[172] The method according to any one of items [1] to

[17] or

[98] to

[171] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[171] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[171] or the use according to any one of items

[62] to

[171] , wherein by administering the vaccine to the patient the risk of the patient contracting the infection is reduced.

[0901]

[173] The method according to any one of items [1] to

[17] or

[98] to

[172] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[172] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[172] or the use according to any one of items

[62] to

[172] , wherein prevention against the infection is achieved by administering the vaccine to the patient.

[0902]

[174] The method according to any one of items [1] to

[17] or

[98] to

[173] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[173] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[173] or the use according to any one of items

[62] to

[173] , wherein by administering the vaccine to the patient an immune response is achieved in the patient against the agent causing the infection.

[0903]

[175] The method according to any one of items [1] to

[17] or

[98] to

[174] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[174] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[174] or the use according to any one of items

[62] to

[174] , wherein the risk of the patient contracting the infection is reduced by vaccinating the patient against the infection.

[0904]

[176] The method according to any one of items [1] to

[17] or

[98] to

[175] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[175] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[175] or the use according to any one of items

[62] to

[175] , wherein prevention against the infection is achieved by vaccinating the patient against the infection.

[0905]

[177] The method according to any one of items [1] to

[17] or

[98] to

[176] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[176] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[176] or the use according to any one of items

[62] to

[176] , wherein an immune response of the patient against the agent causing the infection is achieved by vaccinating the patient against the infection.

[0906]

[178] The method according to any one of items [1] to

[17] or

[98] to

[177] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[177] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[177] or the use according to any one of items

[62] to

[177] , wherein full or partial immunity against the infection is achieved by vaccinating the patient against the infection.

[0907]

[179] The method according to any one of items [1] to

[17] or

[98] to

[178] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[178] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[178] or the use according to any one of items

[62] to

[178] , wherein complete immunization against the infection is achieved by vaccinating the patient against the infection.

[0908]

[180] The method according to any one of items [1] to

[17] or

[98] to

[179] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[179] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[179] or the use according to any one of items

[62] to

[179] , wherein prevention of infection means that the subject becomes fully or partially immune to the infection.

[0909]

[181] The method according to any one of items [1] to

[17] or

[98] to

[180] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[180] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[180] or the use according to any one of items

[62] to

[180] , wherein prevention of infection means that the subject becomes fully immune against the infection.

[0910]

[182] The method of any one of items [1] to

[17] or

[98] to

[181] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[181] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[181] or the use according to any one of items

[62] to

[181] , wherein prevention of an infection means that the infection is avoided, the risk of contracting the infection is reduced, or if the patient contracts the infection, the infection is ameliorated (compared to where such prevention has not occurred).

[0911]

[183] ​​The method according to any one of items [1] to

[17] or

[98] to

[182] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[182] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[182] or the use according to any one of items

[62] to

[182] , wherein the method is a method for vaccinating the subject and not a method for treating a disease.

[0912]

[184] The method according to any one of items [1] to

[17] or

[98] to

[183] ​​or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[183] ​​or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[183] ​​or the use according to any one of items

[62] to

[183] , wherein the BTK inhibitor is selected from evobrutinib, torebrutinib, fennibrutinib and ribuzinib.

[0913]

[185] The method according to any one of items [1] to

[17] or

[98] to

[184] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[184] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[184] or the use according to any one of items

[62] to

[184] , wherein the BTK inhibitor is an irreversible BTK inhibitor.

[0914]

[186] The method according to any one of items [1] to

[17] or

[98] to

[185] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[185] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[185] or the use according to any one of items

[62] to

[185] , wherein the BTK inhibitor is a BTK inhibitor covalently bound to cysteine ​​481 of BTK.

[0915]

[187] The method according to any one of items [1] to

[17] or

[98] to

[186] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[186] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[186] or the use according to any one of items

[62] to

[186] , wherein the BTK inhibitor has been shown in clinical studies to allow successful treatment of the disease.

[0916]

[188] The method according to any one of items [1] to

[17] or

[98] to

[187] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[187] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[187] or the use according to any one of items

[62] to

[187] , wherein the BTK inhibitor has been granted marketing authorization for the treatment of the disease by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0917]

[189] The method according to any one of items [1] to

[17] or

[98] to

[188] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[188] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[188] or the use according to any one of items

[62] to

[188] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or Mixtures of any of the above in any proportions.

[0918]

[190] The method according to any one of items [1] to

[17] or

[98] to

[189] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[189] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[189] or the use according to any one of items

[62] to

[189] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt thereof, or 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0919]

[191] The method according to any one of items [1] to

[17] or

[98] to

[190] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[190] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[190] , or the use according to any one of items

[62] to

[190] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a mixture of any of these in any ratio.

[0920]

[192] The method according to any one of items [1] to

[17] or

[98] to

[191] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[191] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[191] or the use according to any one of items

[62] to

[191] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0921]

[193] The method according to any one of items [1] to

[17] or

[98] to

[192] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[192] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[192] , or the use according to any one of items

[62] to

[192] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0922]

[194] The method according to any one of items [1] to

[17] or

[98] to

[193] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[193] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[193] , or the use according to any one of items

[62] to

[193] , wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one.

[0923]

[195] The method according to any one of items [1] to

[17] or

[98] to

[194] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[194] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[194] or the use according to any one of items

[62] to

[194] , wherein the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a mixture of any of these in any ratio.

[0924]

[196] The method according to any one of items [1] to

[17] or

[98] to

[195] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[195] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[195] or the use according to any one of items

[62] to

[195] , wherein the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0925]

[197] The method according to any one of items [1] to

[17] or

[98] to

[196] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[196] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[196] or the use according to any one of items

[62] to

[196] , wherein the BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0926]

[198] The method according to any one of items [1] to

[17] or

[98] to

[197] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[197] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[197] or the use according to any one of items

[62] to

[197] , wherein the BTK inhibitor is evobrutinib or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a mixture of any of these in any ratio.

[0927]

[199] The method according to any one of items [1] to

[17] or

[98] to

[198] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[198] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[198] or the use according to any one of items

[62] to

[198] , wherein the BTK inhibitor is evobrutinib or a pharmaceutically acceptable salt thereof.

[0928]

[200] The method according to any one of items [1] to

[17] or

[98] to

[199] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[199] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[199] or the use according to any one of items

[62] to

[199] , wherein the BTK inhibitor is evobrutinib.

[0929]

[201] The method according to any one of items [1] to

[17] or

[98] to

[199] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[199] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[199] , or the use according to any one of items

[62] to

[199] , wherein the BTK inhibitor is a compound according to formula (I): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0930]

[202] The method according to any one of items [1] to

[17] or

[98] to

[201] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[201] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[201] or the use according to any one of items

[62] to

[201] , wherein the BTK inhibitor is a compound according to formula (I): or a pharmaceutically acceptable salt thereof.

[0931]

[203] The method according to any one of items [1] to

[17] or

[98] to

[202] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[202] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[202] or the use according to any one of items

[62] to

[202] , wherein the BTK inhibitor is a compound according to formula (I):

[0932]

[204] The method according to any one of items [1] to

[17] or

[98] to

[203] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[203] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[203] or the use according to any one of items

[62] to

[203] , wherein the disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP), chronic spontaneous urticaria (CSU), graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma.

[0933]

[205] The method according to any one of items [1] to

[17] or

[98] to

[204] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[204] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[204] or the use according to any one of items

[62] to

[204] , wherein the disease is selected from an autoimmune disease and an inflammatory disease.

[0934]

[206] The method according to any one of items [1] to

[17] or

[98] to

[205] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[205] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[205] or the use according to any one of items

[62] to

[205] , wherein the disease is selected from an autoimmune disease, graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma.

[0935]

[207] The method according to any one of items [1] to

[17] or

[98] to

[206] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[206] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[206] or the use according to any one of items

[62] to

[206] , wherein the inflammatory disease is selected from graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma.

[0936]

[208] The method according to any one of items [1] to

[17] or

[98] to

[207] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[207] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[207] or the use according to any one of items

[62] to

[207] , wherein the disease is an autoimmune disease.

[0937]

[209] The method according to any one of items [1] to

[17] or

[98] to

[208] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[208] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[208] or the use according to any one of items

[62] to

[208] , wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP) and chronic spontaneous urticaria (CSU).

[0938]

[210] The method according to any one of items [1] to

[17] or

[98] to

[209] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[209] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[209] or the use according to any one of items

[62] to

[209] , wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenia (ITP) and chronic spontaneous urticaria (CSU).

[0939]

[211] The method according to any one of items [1] to

[17] or

[98] to

[210] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[210] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[210] or the use according to any one of items

[62] to

[210] , wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG).

[0940]

[212] The method according to any one of items [1] to

[17] or

[98] to

[211] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[211] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[211] or the use according to any one of items

[62] to

[211] , wherein the autoimmune disease is SLE (systemic lupus erythematosus) or MS (multiple sclerosis).

[0941]

[213] The method according to any one of items [1] to

[17] or

[98] to

[212] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[212] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[212] or the use according to any one of items

[62] to

[212] , wherein the autoimmune disease is SLE (systemic lupus erythematosus).

[0942]

[214] The method according to any one of items [1] to

[17] or

[98] to

[213] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[213] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[213] or the use according to any one of items

[62] to

[213] , wherein the autoimmune disease is MS (multiple sclerosis).

[0943]

[215] The method according to any one of items [1] to

[17] or

[98] to

[214] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[214] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[214] or the use according to any one of items

[62] to

[214] , wherein the autoimmune disease is multiple sclerosis (MS), including one or more indications selected from relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS).

[0944]

[216] The method according to any one of items [1] to

[17] or

[98] to

[215] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[215] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[215] or the use according to any one of items

[62] to

[215] , wherein the autoimmune disease is selected from relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS).

[0945]

[217] The method according to any one of items [1] to

[17] or

[98] to

[216] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[216] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[216] or the use according to any one of items

[62] to

[216] , wherein the autoimmune disease is relapsing multiple sclerosis (RMS).

[0946]

[218] The method according to any one of items [1] to

[17] or

[98] to

[217] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[217] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[217] or the use according to any one of items

[62] to

[217] , wherein the disease is a disease that can be treated with the BTK inhibitor.

[0947]

[219] The method according to any one of items [1] to

[17] or

[98] to

[218] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[218] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[218] or the use according to any one of items

[62] to

[218] , wherein the treatment with the BTK inhibitor has been carried out for a certain period of time means that, at least for said period of time, the BTK inhibitor has been administered essentially every day.

[0948]

[220] The method according to any one of items [1] to

[17] or

[98] to

[219] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[219] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[219] or the use according to any one of items

[62] to

[219] , wherein in the context of ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 72 hours ago.

[0949]

[221] The method according to any one of items [1] to

[17] or

[98] to

[220] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[220] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[220] or the use according to any one of items

[62] to

[220] , wherein in the context of ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 48 hours ago.

[0950]

[222] The method according to any one of items [1] to

[17] or

[98] to

[221] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[221] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[221] or the use according to any one of items

[62] to

[221] , wherein in the context of ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 36 hours ago.

[0951]

[223] The method according to any one of items [1] to

[17] or

[98] to

[222] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[222] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[222] or the use according to any one of items

[62] to

[222] , wherein in the context of ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 24 hours ago.

[0952]

[224] The method according to any one of items [1] to

[17] or

[98] to

[223] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[223] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[223] or the use according to any one of items

[62] to

[223] , wherein "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 72 hours ago.

[0953]

[225] The method according to any one of items [1] to

[17] or

[98] to

[224] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[224] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to

[224] or the use according to any one of items

[62] to

[224] , wherein "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor occurred no more than 48 hours ago.

[0954]

[226] The method according to any one of items [1] to

[17] or

[98] to

[225] or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[225] or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[145] or

[152] to ...

Claims

1. A BTK inhibitor for use in treating an autoimmune disease or an inflammatory disease, wherein the BTK inhibitor is administered by: (a) optionally administering the BTK inhibitor to a patient, (b) determining that the patient is at risk of contracting an infection, (c) vaccinating said patient against said infection, and (d) optionally administering said BTK inhibitor to said patient, Provided that the method comprises one or more treatment periods wherein the BTK inhibitor is administered, wherein the inflammatory disease is selected from the group consisting of graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma, And wherein the patient is vaccinated while the patient is under ongoing BTK inhibitor treatment or wherein the time period between administration of the BTK inhibitor and vaccination is less than 4 weeks.

2. The BTK inhibitor for use according to claim 1, wherein the BTK inhibitor is used to treat an autoimmune disease.

3. The BTK inhibitor for use according to any one of claims 1 or 2, wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis (MG), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), chronic spontaneous urticaria (CSU) and idiopathic thrombocytopenia (ITP).

4. The BTK inhibitor for use according to any one of claims 1 to 3, wherein the autoimmune disease is SLE or MS.

5. The BTK inhibitor for use according to any one of claims 1 to 4, wherein the BTK inhibitor is 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or 1-(4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or Mixtures of any of the above in any proportion.

6. The BTK inhibitor for use according to any one of claims 1-5, wherein the BTK inhibitor is evobrutinib.

7. The BTK inhibitor for use according to any one of claims 1-6, wherein the BTK inhibitor is administered in a daily amount ranging from 20 mg to 300 mg.

8. The BTK inhibitor for use according to any one of claims 1 to 7, wherein 40 to 85 mg of the BTK inhibitor is administered twice daily, Or wherein the BTK inhibitor is administered in such a manner that the resulting concentration of the BTK inhibitor in the patient's plasma is similar to the concentration of the BTK inhibitor in plasma that would be achieved if the BTK inhibitor were administered at 40 to 85 mg administered as a tablet by oral administration twice a day.

9. The BTK inhibitor for use according to any one of claims 1-8, wherein the vaccination is performed using a vaccine selected from an inactivated vaccine, a live attenuated vaccine, a live vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine and a toxoid vaccine or a combination thereof.

10. The BTK inhibitor for use according to any one of claims 1 to 9, wherein the infection is a viral infection, preferably selected from hepatitis, varicella (chickenpox), herpes zoster (shingles), measles, influenza, poliovirus, human papillomavirus (HPV) and other papillomavirus-related diseases, SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome) and COVID-19 (coronavirus disease 2019).

11. The BTK inhibitor for use according to any one of claims 1 to 9, wherein the infection is a bacterial infection, preferably selected from anthrax infection, cholera, diphtheria, Haemophilus influenzae infection, meningococcal meningitis, whooping cough, plague, pneumococcal disease, Streptococcus pneumoniae infection, pneumococcal pneumonia, tetanus, tuberculosis and typhus.

12. The BTK inhibitor for use according to any one of claims 1-10, wherein the infection is influenza or COVID-19.

Images