Treatment Regimens for Autoimmune and Inflammatory Diseases

Abstract

The present disclosure relates to novel treatment regimens for the treatment of autoimmune and other inflammatory diseases with BTK (Bruton's tyrosine kinase) inhibitors. In particular, the present disclosure relates to treatments that combine BTK inhibitor therapy with vaccination in order to avoid infection, reduce the risk of contracting an infection, or alleviate an infection. Further, the present disclosure relates to vaccination in the presence of a BTK inhibitor.

Description

Technical Field

[0001] Field of the Invention The present disclosure relates to novel treatment regimens for the treatment of autoimmune and other inflammatory diseases with BTK (Bruton's tyrosine kinase) inhibitors. In particular, the present disclosure relates to treatments that combine BTK inhibitor therapy with vaccination in order to avoid infection, reduce the risk of contracting an infection, or alleviate an infection. Furthermore, the present disclosure relates to vaccination in the presence of a BTK inhibitor.

Background Art

[0002] Background of the Invention Autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis (MG), chronic spontaneous urticaria (CSU) and idiopathic thrombocytopenic purpura (ITP), as well as certain other inflammatory diseases such as graft-versus-host disease (GVHD), large vessel vasculitis (LVV) and asthma, result from the overactivation of the body's own immune system. Thus, suppression or regulation of at least a part of the immune system can lead to an improvement in the clinical picture of each disease.

[0003] Accordingly, a variety of drugs that are directly or indirectly immunosuppressive and immunomodulatory are widely used in the treatment of autoimmune and inflammatory diseases, including, but not limited to, corticosteroids such as cortisol, glucocorticoids such as prednisone, dexamethasone and hydrocortisone, cell division inhibitors such as nitrogen mustards (e.g., cyclophosphamide), nitrosoureas, platinum compounds, methotrexate, azathioprine, mercaptopurine, antimetabolites such as fluorouracil and cladribine, antibodies targeting B and / or T cell receptors such as obinutuzumab, rituximab, ocaratuzumab, ofatumumab and muromonab, drugs acting on immunophilins such as cyclosporine, tacrolimus, sirolimus and everolimus, and other drugs targeting the immune system such as interferons, opioids, TNF binding proteins such as infliximab, etanercept and adalimumab, and mycophenolic acid.

[0004] Similarly, Bruton's tyrosine kinase (BTK) inhibitors are one class of immunomodulatory drugs that show great promise for the clinical treatment of autoimmune diseases 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 result in the condition of X-linked agammaglobulinemia (XLA) (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 levels of immunoglobulins and peripheral B cells, decreased T cell-independent immune responses, and attenuated calcium mobilization after BCR stimulation.

[0006] Evidence regarding 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 show a marked 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) show 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 involved in the disease process. BTK is an important component of Fc-gamma signaling in myeloid cells. For example, BTK is expressed by mast cells, and BTK-deficient bone marrow-derived mast cells show impaired antigen-induced degranulation (Iwaki et al., J. Biol. Chem. (2005), vol. 280, p. 40261). This indicates that BTK may be useful for treating pathological mast cell responses such as allergy and asthma. Monocytes from XLA patients lacking BTK activity also show a decrease in TNF-alpha production after stimulation (Horwood et al., J. Exp. Med. (2003), vol. 197, p. 1603). Thus, TNF-alpha-mediated inflammation can be regulated by small molecule BTK inhibitors.

[0008] Such findings suggest that BTK inhibitors may be useful in the treatment of autoimmune diseases and other inflammatory diseases involving the activation of multiple B cell subtypes and / or macrophages.

[0009] Indeed, several BTK inhibitors already show great potential for the treatment of autoimmune and other inflammatory diseases, or clinical trials for such diseases are currently underway (reviewed in Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223). Specifically, at least 13 compounds targeting BTK in nine indications have achieved Phase II or higher clinical trial status. These studies relate to indications including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis including relapsing MS (RMS) and progressive (PMS), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), chronic idiopathic urticaria, idiopathic thrombocytopenia, graft-versus-host disease, and asthma. Eleven 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 13 BTK inhibitors tested clinically, only two, MS-986142 and fenebrutinib, have a mechanism of action of non-covalent inhibition. A new trial of tolebrutinib for myasthenia gravis (MG) was recently published (NCT05132569). Two BTK inhibitors, evobrutinib and tolebrutinib, have shown positive results in Phase II trials for 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] Among treatments, patients being treated for an autoimmune or inflammatory disease are particularly vulnerable to infection, especially if the medication used for the disease or treatment interferes with the normal immune response. Thus, it is highly desirable that such patients avoid infection or have their risk of contracting such infections reduced, and that, if they do actually contract an infection, the course of the infection is improved as much as possible.

[0011] One of the most powerful approaches for preventing or ameliorating an infection is vaccination against the pathogen that causes the infection. However, vaccination generally requires the correct immune response of each body.

[0012] The successful vaccine response and the vaccine-mediated protection that results are complex immunological processes. Most antigens elicit B cell (humoral immunity) and T cell responses (cell-mediated immunity). The early protective effects are mainly provided by the induction of immune effectors produced by B cells and antigen-specific antibodies that can bind to pathogens or toxins. Long-term protection requires that vaccine antibodies persist above a protective threshold and / or the maintenance of immune memory that allows for rapid and effective reactivation.

[0013] Memory B cells are produced during the primary response to T cell-dependent vaccines. They persist in the absence of antigen, and re-exposure to antigen drives their differentiation into antibody-producing plasma cells. This reactivation is rapid, and the booster response is characterized by a rapid increase to higher antibody titers with higher affinity than the antibodies produced during the primary response to the antigen (Siegrist, Vaccines - Vaccine Immunology, chapter in Plotkin, Orenstein and Offit eds., "Vaccines", Saunders / Elsevier, 5th edition, (2008), p. 16-34; Papp et al., J. of Cutaneous Medicine and Surgery (2019), vol. 32, p. 50-74). Thus, the vaccine response also depends on the type of response (recall response vs. response to a new antigen).

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

[0015] Moreover, since immunosuppressive and immunomodulatory treatments often interfere with the correct vaccination response, the response to vaccines also depends on the impact of individual disease-modifying therapies on humoral and cellular immunity.

[0016] For example, there are reasons to believe that BTK inhibitors may be incompatible with vaccination from a scientific perspective. Most notably, B cell receptor signaling, B / T cell interaction and antigen presentation, and follicular helper T cell (Tfh) / B cell interaction in the germinal center lead to modification of B cell maturation, reduction of class switch, and immunoglobulin synthesis. This mechanism of action can lead to a decrease in primary and secondary humoral responses, as well as a decrease in the levels of antibodies produced against both novel 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] Along this hypothesis, Li et al. (Acta Neuropathologica (2022), vol. 143, p. 505) showed that through an autoantigen-specific B cell:T cell co-culture system, a BTK inhibitor significantly decreased the proliferation of B cells and T cells and restricted the expression of the pro-inflammatory cytokines IFN gamma and TNF alpha in response to recall vaccine-related tetanus toxoid.

[0018] In addition, in a recent study by Parry et al. (J. of Hematology & Oncology (2022), vol. 15, p. 3), the antibody response after two doses of COVID-19 vaccination was tested in 279 untreated CLL patients under monitoring and 208 treated patients (20% of whom were currently receiving BTKi therapy). Spike-specific seroconversion after vaccination was highest (79%) among untreated CLL patients under monitoring. The overall antibody response rate in CLL patients during BTKi therapy was significantly lower compared to untreated patients (32%) and also significantly lower compared to the overall antibody response (43%) in all previously treated patients.

[0019] The study by Douglas et al., Haematologica (2017), vol. 102, p. e398, verified the serological response before and after influenza vaccination in patients with chronic lymphocytic leukemia (CLL) and Waldenström's hypergammaglobulinemia (WM) treated with the BTK inhibitor ibrutinib. The authors concluded that their results indicated the absence of a serological response to influenza vaccination in patients treated with this BTK inhibitor.

[0020] These results were considered not to be consistent with findings reported by Sun et al. (JAMA Oncology (2016), vol. 2(12), p. 1656-1657) after studying similar issues. However, as pointed out by Douglas et al., the study by Sun et al. has multiple deficiencies, such as the degree of previous treatment in their population being unknown, the ratio of patients receiving high-dose influenza vaccine to those receiving low-dose influenza vaccine being unknown, and especially the absence of a control group. This makes it difficult to interpret the results of Sun et al. and raises questions about whether their conclusions are justified.

[0021] In Pleyer et al., Blood (2021), vol. 137(2), p. 185-189, vaccination with hepatitis B vaccine (HepB-CpG) or recombinant adjuvant-added zoster vaccine (RZV, recombinant zoster vaccine) was studied in patients with CLL receiving BTK inhibitor therapy with ibrutinib or acalabrutinib, which are BTK inhibitors. Regarding hepatitis vaccination, the authors concluded that the de novo immune response to hepatitis B vaccine was "almost absent" in CLL patients receiving BTKi and impaired in untreated patients. The effect on the response rate to RZV of BTK inhibitor therapy was much weaker (the authors of Pleyer et al. concluded that the response was "not significantly different" overall), but seroconversion was detected at a significantly lower rate in patients during BTK inhibitor treatment than in those 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 the recombinant zoster vaccine (RZV) induced both humoral and cellular immune responses in treated and untreated CLL patients, although the response rate in patients on BTKi therapy was lower compared to untreated CLL patients. The antibody response rate was significantly higher in the untreated (TN) cohort (76.8%) than in patients receiving BTKi (40.0%). The cellular response rate was also significantly higher in the TN cohort (70.0%) compared to the BTKi group (41.3%).

[0023] Thus, current in vitro and in vivo data on the mechanism of action of evobrutinib and other BTK inhibitors, as well as the vaccination data obtained for selected BTK inhibitors in CLL patients, suggest that the performance of de novo vaccination and recall vaccination may be blunted generally for BTK inhibitors and also in other situations where administration of BTK inhibitors, such as in autoimmune or other inflammatory diseases, may be beneficial.

[0024] In situations where a proper immune response to a vaccine cannot be expected, it is generally recommended to administer the vaccine well before the start and / or well after the end of immunosuppressive or immunomodulatory treatment. Usually, to have a safety margin, a gap or interval of several weeks to several months is applied between vaccination and the start and / or end of immunosuppressive treatment. Typical recommendations for vaccination in patients who will receive immunosuppressive / immunomodulatory treatment are that for inactivated vaccines, it should be at least 2 weeks, and for live vaccines, it should be ≥ 4 weeks before receiving the vaccination. Importantly, the refractory period after immunosuppression also needs to be considered, which can be up to 1 year at most, depending on the type of drug (e.g., rituximab or alemtuzumab). Except for some treatments that only result in mild immunosuppression, live vaccines are strongly contraindicated under immunosuppressive treatment (Zrzavry et al., Frontiers in Immunology (2019), vol. 10, p. 1883).

[0025] These recommendations are in line with Papp et al., Journal of Cutaneous Medicine and Surgery (2019), vol. 32, p. 50 - 74. The authors of this publication recommended evaluating the vaccination status and administering vaccines appropriate for age and condition before the start of immunosuppressive treatment in newly diagnosed patients with immune-mediated diseases. To optimize the immunogenicity of inactivated vaccines or live attenuated varicella zoster vaccines in untreated patients with immune-mediated conditions, they suggested administering the vaccination at least 2 - 4 weeks before the start of immunosuppressive therapy.

[0026] However, in many treatment situations, immunosuppressive or immunomodulatory treatments are already underway by the time vaccination is desired. The severity and unpredictability of many autoimmune and immune-related inflammatory diseases can essentially force a profound occurrence, flare, or recurrence of disease activity at any given point in time, and as a result, it is often not possible to interrupt treatment of such diseases to provide a gap or interval as a safe window for vaccination. Moreover, many of these diseases are typically incurable and rather chronic lifelong diseases, so continuous administration of immunosuppressive / immunomodulatory drugs over years, if not decades, is often necessary. In these situations, vaccination before or after the start or end of treatment is not possible.

[0027] Therefore, it is highly desirable to find a way to vaccinate patients suffering from autoimmune and other inflammatory diseases while continuously treating them with immunosuppressive / immunomodulatory drugs, i.e., a way to continuously treat such patients with immunosuppressive or immunomodulatory drugs while still being able to successfully vaccinate them.

[0028] Therefore, there is a need in the art for improved methods for treating autoimmune and inflammatory diseases. Further, there is a need in the art for improved methods for treating autoimmune diseases such as SLE and MS, particularly MS. Further, there is a need in the art for improved methods for treating autoimmune diseases with BTK inhibitors. Further, there is a need in the art for improved methods for treating autoimmune or inflammatory diseases that enable successful vaccination during treatment of such diseases. Further, there is a need in the art for improved methods for vaccinating patients having an autoimmune or inflammatory disease. Further, there is a need in the art for improved methods for vaccinating patients having an autoimmune disease treated with an immunomodulatory drug.

[0029] The present disclosure overcomes the above problems and addresses the above needs.

Summary of the Invention

[0030] Summary The present disclosure is based, in part, on the surprising observation that patients under treatment with a BTK inhibitor, particularly ibrutinib, can initiate a humoral response comparable to that of untreated patients upon vaccination against seasonal influenza or COVID-19. Further, in various autoimmune diseases such as SLE and MS, it has been observed that a humoral response comparable to that of untreated patients is induced, suggesting that the success of vaccination under ibrutinib treatment (and perhaps under treatment with closely related BTK inhibitors) can occur similarly for other autoimmune diseases and perhaps for other inflammatory diseases as well. Additionally, our analysis shows that the humoral response under BTK inhibitor treatment, particularly under treatment with ibrutinib, can be obtained not only with vaccination with recall antigens but also with novel antigens.

[0031] These surprising findings open the door for a novel method of treatment that combines administration of a BTK inhibitor and vaccination, which, through various aspects and embodiments of the present disclosure, enables addressing the above needs.

[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) administering a BTK inhibitor (Bruton's tyrosine kinase inhibitor) to the patient; (b) vaccinating the patient against an infectious disease.

[0033] 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 a patient in need of treatment for the disease who is at risk of contracting an infectious disease; (b) vaccinating a patient at risk of developing the infectious disease against the infectious disease, and (c) 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) identifying a patient in need of treatment for the disease who is at risk of developing an infectious disease, (b) vaccinating a patient at risk of developing the infectious disease against the infectious disease, and (c) treating the disease by administering a BTK inhibitor to the patient.

[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) administering a BTK inhibitor to the patient, (b) identifying that the patient is at risk of developing an infectious disease, and (c) vaccinating the patient against the infectious disease.

[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) repeatedly administering the BTK inhibitor to the patient, thereby treating the patient for the disease, (b) identifying that the patient is at risk of developing an infectious disease while undergoing repeated treatment with the BTK inhibitor, and (c) vaccinating the patient against the infectious disease during repeated treatment with the BTK inhibitor, and optionally, (d) continuing the repeated treatment with the BTK inhibitor.

[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) Administering a BTK inhibitor to the patient; (b) Vaccinating the patient against an infectious disease; and (c) Continuing to administer the BTK inhibitor to the patient.

[0038] 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 the patient; (b) Identifying that the patient is at risk of developing an infectious disease; (c) Vaccinating the patient against the infectious disease; and (d) Optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered, thereby treating the patient against the disease and reducing the risk that the patient develops the infectious disease.

[0039] 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 infectious disease while under ongoing treatment with the BTK inhibitor.

[0040] In another aspect, the present disclosure relates to a method for reducing the risk that a subject develops an infectious disease, the method comprising: (a) Administering a BTK inhibitor to the subject; and (b) Vaccinating the subject against the infectious disease.

[0041] In another aspect, the present disclosure relates to a method for reducing the risk that a subject develops an infectious disease, the method comprising vaccinating the subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0042] In another aspect, the present disclosure relates to a method of treating a disease in a patient in need thereof and reducing the risk of an infectious disease in said patient, said method comprising: (a) administering a BTK inhibitor to said patient, and (b) vaccinating said patient against said infectious disease.

[0043] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising: (a) administering said BTK inhibitor to a patient having said disease, (b) vaccinating the patient against an infectious disease.

[0044] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising: (a) identifying a patient at risk of developing an infectious disease, (b) vaccinating the patient at risk of developing said infectious disease against said infectious disease, and (c) administering said BTK inhibitor to said patient.

[0045] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein said BTK inhibitor is administered as follows: (a) administering said BTK inhibitor to a patient, (b) identifying that said patient is at risk of developing an infectious disease, and (c) vaccinating said patient against said infectious disease.

[0046] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein said BTK inhibitor is administered as follows: (a) repeatedly administering said BTK inhibitor to a patient, thereby treating said patient for said disease, (b) identifying that the patient is at risk of contracting an infectious disease while undergoing repeated treatment with the BTK inhibitor, and (c) vaccinating the patient against the infectious disease during relapse treatment with the BTK inhibitor, and optionally, (d) continuing the repeated treatment with the BTK inhibitor.

[0047] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against an infectious disease, and (c) continuing to administer the BTK inhibitor to the patient.

[0048] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) optionally, administering the BTK inhibitor to a patient, (b) identifying that the patient is at risk of contracting an infectious disease, (c) vaccinating the patient against the infectious disease, and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0049] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising administering a BTK inhibitor to a patient having the disease, the method comprising vaccinating the patient against an infectious disease while the patient is under ongoing treatment with the BTK inhibitor.

[0050] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein while a patient having the disease is under ongoing treatment with the BTK inhibitor, the patient is vaccinated against an infectious disease.

[0051] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered in combination with a vaccine.

[0052] In another aspect, the present disclosure relates to a vaccine for use in the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infectious disease.

[0053] In another aspect, the present disclosure relates to a vaccine for use in the prevention of an infectious disease by a method comprising vaccinating a subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0054] In another aspect, the present disclosure relates to a vaccine for use in the prevention of an infectious disease by a method comprising: (a) identifying a subject at risk of contracting the infectious disease, (b) vaccinating the subject at risk of contracting the infectious disease with the vaccine against the infectious disease, and (c) administering a BTK inhibitor to the subject.

[0055] In another aspect, the present disclosure relates to a vaccine for use in the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating the subject with the vaccine against the infectious disease, and (c) continuing to administer the BTK inhibitor to the subject.

[0056] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for treating a disease by a method comprising the following. (a) Administering the BTK inhibitor to a patient having the disease; (b) Vaccinating the patient against an infectious disease.

[0057] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for treating a disease by a method comprising the following. (a) Identifying a patient at risk of contracting an infectious disease; (b) Vaccinating the patient at risk of contracting the infectious disease against the infectious disease; and (c) Administering the BTK inhibitor to the patient.

[0058] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) Administering the BTK inhibitor to a patient; (b) Identifying that the patient is at risk of contracting an infectious disease; and (c) Vaccinating the patient against the infectious disease.

[0059] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture 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 patient for the disease; (b) Identifying that the patient is at risk of contracting an infectious disease while undergoing repeated treatment with the BTK inhibitor; and (c) Vaccinating the patient against the infectious disease during re-treatment with the BTK inhibitor; and optionally, (d) Continuing the repeated treatment with the BTK inhibitor.

[0060] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient; (b) vaccinating the patient against an infectious disease; and (c) continuing to administer the BTK inhibitor to the patient.

[0061] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) optionally, administering the BTK inhibitor to a patient; (b) identifying that the patient is at risk of contracting an infectious disease; (c) vaccinating the patient against the infectious disease; and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0062] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease by a method in which a patient having the disease is vaccinated against an infectious disease while undergoing ongoing treatment with the BTK inhibitor.

[0063] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject; and (b) vaccinating the subject against the infectious disease.

[0064] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising vaccinating a subject against the infectious disease, wherein the subject is vaccinated while undergoing ongoing treatment with a BTK inhibitor.

[0065] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) identifying a subject at risk of developing an infectious disease, (b) vaccinating the subject at risk of developing the infectious disease with the vaccine against the infectious disease, and (c) administering a BTK inhibitor to the subject.

[0066] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating the subject with the vaccine against the infectious disease, and (c) continuing to administer the BTK inhibitor to the subject.

[0067] Reference is now made to the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

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Mode for Carrying Out the Invention

[0089] Detailed Description Although described in detail above and below, it should be understood that the present disclosure is not limited to the specific methodologies, protocols, and reagents described by the present disclosure, as these can vary. It should also be understood that the terms used herein are for the purpose of describing particular aspects only and are not intended to limit the scope of the present disclosure, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0090] In the following, specific elements of the present disclosure will be described in more detail, including descriptions of specific embodiments. However, the various examples and preferred embodiments described should not be construed as limiting the present disclosure to the explicitly described embodiments only. This description is to be understood as supporting and encompassing embodiments that combine the explicitly described embodiments with any number of disclosed and / or preferred elements in any manner. Furthermore, any permutation and combination of all the elements described in this application should be considered to be disclosed by the description of this application, unless this results in a logical contradiction or the context indicates otherwise.

[0091] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by one of ordinary skill in the art. In general, the nomenclature and techniques referred to in the present disclosure, such as those of organic chemistry, chemical synthesis, biology, medicinal and pharmaceutical chemistry, medicine, pharmacology, or toxicology, are well-known and commonly used in the art. The methods and techniques of the present disclosure are generally carried out according to conventional methods well-known in the art, unless otherwise indicated, and as described in the references cited and discussed throughout the present disclosure.

[0092] Autoimmune disease The immune system defends the body against infections. When the immune system malfunctions, it may attack the body's healthy cells. An autoimmune disease is a condition in which the body's immune system mistakes its own healthy tissues for foreign ones and attacks them, causing inflammation, which can affect many parts of the body depending on the specific type of autoimmune disease a person has.

[0093] Details about the overview of autoimmune diseases, the current scientific understanding of the mechanisms underlying them, and their treatment in clinical practice can be obtained from general 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.

[0094] There are approximately 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. For most autoimmune diseases, there is no cure, and some of them require lifelong treatment to manage symptoms or prevent further damage to healthy tissues (Lleo et al., Autoimmunity Reviews (2010), vol. 9, p. A259 - 266).

[0095] Research into the treatment of autoimmune diseases has advanced significantly towards improving our understanding of the disease mechanisms driving the pathology. Dysregulation of B lymphocytes plays a major role in many rheumatic and neuroinflammatory diseases, but T cells and innate immune cells also play important roles in autoimmune diseases.

[0096] Systemic lupus erythematosus (SLE) SLE is a potentially fatal chronic multi-system autoimmune disease typically affecting women between puberty and menopause. SLE can affect connective tissue, joints, skin, brain, lungs, kidneys and blood vessels. There is no cure for lupus, and the disease severity ranges from mild to life-threatening. The cause of SLE is unknown, but is thought to be a combination of environmental, genetic, and hormonal factors. Some of the strongest genetic associations with SLE are single gene deficiencies of the rare complement components C1Q and C4. In most patients, SLE is a quantitative trait due to several genes that contribute to the risk of developing the disease; genome-wide association analysis has shown that several candidate loci, including interferon (IFN) regulatory factor 5 (IRF5) in SLE patients, are involved, and mutations therein are associated with increased levels of molecules of the type 1 IFN family in patients with SLE. For a review, see Kaul et al., Nature Reviews Disease Primers (2016), vol. 2(1), art. 16039.

[0097] Rheumatoid arthritis (RA) RA is a chronic disease and the most common form of autoimmune arthritis. Approximately 75% of RA patients are women, and over 1 million Americans are affected. Although less common, the symptoms in men tend to be more severe. RA causes joint pain, stiffness, swelling, leading to decreased joint movement and long-term damage to cartilage tissue and surrounding bone. Small joints in the hands and feet are most commonly affected in most cases, but other organs such as the eyes, skin, or lungs can also be affected to a lesser extent over time in some patients. What causes RA is unknown, and infections, smoking, and genetics are risk factors that may influence RA. Current treatments include drug therapy, balanced exercise, targeted rest for affected joints, and surgery to address joint and bone damage (Bullock et al., Med. Princ. Pract. (2018), vol. 27, p. 501-507).

[0098] Pemphigus vulgaris (PV) PV itself presents with blistering and pain in the skin and mucous membranes, which are caused by autoantibodies against specific proteins in these tissues. The exact cause of the disease is unknown, but several drugs including penicillamine, ACE (angiotensin-converting enzyme) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) may trigger the disease. If untreated, PV can be dangerous, and in some cases, complications including severe infections can be life-threatening. Treatment typically includes the use of corticosteroids to suppress the immune system, wound care similar to severe burns, and measures aimed at preventing infection (Scully & Challacombe, Crit. Rev. Oral. Biol. Med. (2002), vol. 13, p. 397).

[0099] Sjögren's syndrome (SJ) In Sjogren's syndrome, the body's immune cells attack the glands in the body that produce tears, saliva, and other body fluids. The amount of moisture produced by the glands decreases, causing dryness in 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 who develop Sjogren's syndrome are women. The disease may be associated with other autoimmune conditions such as rheumatoid arthritis and lupus. Treatment currently mainly focuses on alleviating individual symptoms according to the affected tissues. Interventions can include eye drops to keep the eyes moist, sprays, medicated candies and gels to keep the mouth moist, and medications that support the body in producing more tears and saliva. For an overview, see Venables, Best. Pract. Res. Clin. Rheumatol. (2004), vol. 18(3), p. 313-329.

[0100] 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 complex gene-environment interactions. The pathological hallmark of MS is the accumulation of demyelinating lesions that occur in the white and gray matter of the brain and spinal cord. The clinical symptoms and course of MS are heterogeneous; in most patients, the disease is characterized in its early phase by reversible episodes of neurological deficits (known as relapses) that typically last for several days or weeks (Clinically Isolated Syndrome (CIS) and Relapsing Remitting MS (RRMS)). Over time, the development of permanent neurological deficits and progression of clinical disability become prominent (known as Secondary Progressive MS (SPMS)). A minority of patients have a progressive disease course from onset, which is termed Primary Progressive MS (PPMS). Each subtype of MS can be classified as active or inactive based on the clinical assessment of relapse occurrence or lesion activity detected using MRI; furthermore, patients with PPMS or SPMS can be classified according to whether the disability has progressed over a given period of time. MS typically affects young adults, with onset between the ages of 20 and 40 and a higher prevalence in women, although some patients experience an initial demyelinating event during childhood or adolescence, which typically is associated with RRMS (Filippi et al., Nature Reviews Disease Primers (2018), vol. 4, art. 43).

[0101] Idiopathic Thrombocytopenic Purpura (ITP) ITP is a hematological condition characterized by low platelet counts of less than 100,000 per microliter. This platelet deficiency can be caused by decreased platelet production, immune-mediated destruction, or increased sequestration by the spleen, but typically involves autoantibodies against glycoproteins expressed on megakaryocytes, which are platelet precursor cells. The symptoms of ITP can be diverse but tend to be general symptoms of thrombocytopenia, such as petechiae, purpura, mucosal bleeding such as epistaxis, and in the most severe cases, fatal intracranial bleeding. ITP is idiopathic in 80% of cases, and primary ITP is often considered an autoimmune condition. However, in 20% of cases of ITP, it can occur secondary to a coexisting disease. For example, ITP is often seen after an infectious disease. For a review, see Samson et al., Cureus (2019), vol. 11(10), p. e5849.

[0102] Chronic urticaria (CU) CU is characterized by wheals, angioedema, or both, lasting longer than 6 weeks. CU can be further divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). CSU is defined by the absence of a specific trigger for the skin lesions, while in CIndU, the lesions are activated by a specific stimulus (e.g., symptomatic dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, or aquagenic urticarial).

[0103] The pathophysiology underlying CSU encompasses the degranulation of mast cells and basophils, which is accompanied by the release of histamine, leukotrienes, prostaglandins (PGs), and various inflammatory mediators. Urticaria is characterized by edema, mast cell degranulation, and a perivascular mixed infiltrate mainly composed of CD4+ lymphocytes, monocytes, neutrophils, eosinophils, and basophils, and is similar to the allergen-mediated late-phase reaction. The cytokine profile is characterized by increased interleukin (IL)-4, IL-5, and interferon-gamma, which suggests a mixed type 1 helper T (Th1) / type 2 helper T (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).

[0104] Myasthenia gravis (MG) Myasthenia gravis (MG) is an autoimmune disease that affects the postsynaptic membrane at the neuromuscular junction. Its main symptom is muscle weakness. Muscle weakness of the respiratory muscles can rarely occur, leading to a life-threatening condition that requires intensive treatment and respiratory support. However, with appropriate treatment, most patients with MG are in a stable state with only mild muscle weakness and can fully perform the functions of their daily lives.

[0105] 80% of patients with MG have detectable antibodies against the acetylcholine (ACh) receptor (AChR), while a very small number have antibodies against muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4) instead. Anti-LRP4 antibodies may be less specific for MG than antibodies against AChR and MuSK, and this MG subgroup is less well established than the others. Antibodies are not detected in 10-15% of patients with generalized MG, usually because the sensitivity of the assays used is too low.

[0106] MG is classified into subgroups according to clinical symptoms, age of onset, autoantibody pattern, and thymic pathology. These subgroups reflect differences in epidemiology, disease mechanism, severity, and treatment response, and assist in guiding individualized treatment. Ocular MG and MG with anti-LRP4 antibodies tend to be mild, while MuSK MG, and perhaps thymoma MG, also tend to be more severe. The thymus plays an important role in AChR-mediated MG, and thymectomy is an option for treatment of patients with this subtype. MG is induced by thymoma in 10% of patients, and thymectomy is an option for treatment of patients with thymoma or thymic hyperplasia (Gilhus et al., Nature Reviews Disease Primers (2019), vol. 5, art. 30).

[0107] 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 (AQP4-IgG) against aquaporin 4, 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); of note, MOG-IgG is also present in a subset (mainly pediatric) of patients with acute disseminated encephalomyelitis (ADEM).

[0108] AQP4-IgG-positive NMO is mainly an autoimmune astrocytopathy, but secondary damage to oligodendrocytes and neurons occurs as a result of astrocyte dysfunction and loss, and perhaps also 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 neuropathies, but cases are rare. In a small subgroup of patients, the cause remains unknown (known as idiopathic NMO).

[0109] AQP4-IgG-positive and MOG-IgG-positive NMO usually have a relapsing disease course without significant disease progression during attacks, but cases of monophasic MOG-IgG-positive disease have been reported. Untreated NMO can cause severe and persistent visual and motor dysfunction due to incomplete recovery from acute attacks (Jarius et al., Nature Reviews Disease Primers (2020), vol 6, art. 85).

[0110] In 2015, physicians defined a broad continuum of clinical symptoms, including not only spinal cord and / or optic nerve involvement but also other indications, as neuromyelitis optica spectrum disorder (NMOSD) (because they all result from the same immunological mechanism), and at that time, the term "spectrum disorder" was added to the official name of NMO. NMOSD is a term used to encompass NMO (having both optic neuritis and myelitis), as well as limited phenotypes such as recurrent optic neuritis or myelitis. It is an autoimmune disease, and in most cases, it is mediated by antibodies against aquaporin 4 (AQP4) water channels, and for the majority of patients, serum AQP4 antibodies can be detected by immunoassay. Making a definitive diagnosis of antibody-negative NMOSD can be difficult because relapsing-remitting multiple sclerosis (RRMS), which has a higher prevalence, can present similarly. For a review, see Matthews et al., Neurology (2013), vol. 80, p. 1330.

[0111] In 2015, physicians defined a broad continuum of clinical symptoms, including not only spinal cord and / or optic nerve involvement but also other indications, as neuromyelitis optica spectrum disorder (NMOSD) (because they all result from the same immunological mechanism), and at that time, the term "spectrum disorder" was added to the official name of NMO.

[0112] Other inflammatory diseases Despite not being autoimmune diseases, there are additional inflammatory diseases that show similarities to autoimmune disorders with regard to misdirected inflammation and its clinical symptoms and underlying inflammatory responses. Examples of such inflammatory diseases that are particularly relevant to the present disclosure are discussed below.

[0113] Large-vessel vasculitis (LVV) Large-vessel vasculitis (LVV) presents as inflammation of the aorta and its major branch vessels and is the most common primary vasculitis in adults. LVV encompasses two distinct pathologies, giant cell arteritis (GCA) and Takayasu arteritis (TAK), although the phenotypic spectrum of primary LVV is complex. As nonspecific symptoms are often predominant, patients with LVV present to various healthcare providers or settings. Prompt diagnosis, expert referral, and early treatment are important for good patient prognosis. Unfortunately, disease recurrence remains common, and chronic vascular complications are a significant source of morbidity. Although accurately monitoring disease activity is difficult, advances in vascular imaging techniques and measurement of laboratory biomarkers can facilitate better matching of treatment intensity to disease activity.

[0114] GCA is a primary inflammatory condition characterized by granulomatous arteritis in temporal artery biopsy (TAB) specimens. Currently, GCA is recognized to encompass a broad phenotypic spectrum of inflammation of medium and large arteries. The nomenclature has evolved to reflect this, with terms such as large-vessel GCA (LV-GCA), cranial GCA (C-GCA), and LV-GCA with cranial complications being proposed according to the site of inflammation.

[0115] TAK was first described in 1908 as a series of retinal vascular abnormalities. Its association with the loss or reduction of peripheral pulses led to the term "pulseless disease," and autopsy studies demonstrated panarteritis involving the aorta and its major branch vessels. The initial descriptions of the disease included individuals of Japanese origin, but TAK is now recognized to occur worldwide. Furthermore, advances in our understanding of the pathophysiology of the disease have opened the way for new biological treatments targeting key mediators of the disease in both giant cell arteritis and Takayasu arteritis (Pugh et al., Nature Reviews Disease Primers (2021), vol. 7(1), art. 93).

[0116] 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, greater attention has been focused on supportive care, prevention of infection, immunosuppressive drugs, and improvement of DNA-based tissue typing. However, graft-versus-host disease (GVHD) remains the most frequent and serious complication after allogeneic HCT.

[0117] GVHD has acute and chronic forms. Acute GVHD is characterized by damage to the skin, liver, and gastrointestinal tract, while chronic GVHD has more diverse symptoms and may resemble an autoimmune syndrome, for example, eosinophilic fasciitis, scleroderma-like skin diseases, and involvement of the salivary and lacrimal glands. For the purposes of epidemiological studies, acute GVHD occurs within 100 days after transplantation, and chronic GVHD occurs after day 100 after transplantation. However, currently, it is recognized that the clinical features of chronic GVHD may occur within 100 days after transplantation and that the features of acute and chronic GVHD can coexist, leading to a new definition that focuses the diagnosis on the constellation of symptoms rather than the time of onset of symptoms (Choi et al., Immunol. Allergy Clin. North Am. (2010), vol. 30(1), p. 75-101).

[0118] Asthma Asthma is a heterogeneous disease characterized by chronic airway inflammation and various remodellings, leading to a wide range of clinical symptoms, treatment responses, and natural histories over the course of a patient's life. Asthma is associated with a history of respiratory symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary over time and in response to a wide range of stimuli such as exercise and inhaled irritants, in terms of both intensity and the limitation of expiratory airflow and airway hyperresponsiveness. At the population level, a subset of individuals with asthma shows accelerated decline in lung function over their lifetime, which presents as fixed airflow obstruction in severe chronic disease. This decline is particularly prominent in late-onset asthma. The origin and severity of asthma are driven by strong genetic and environmental factors. Most cases of asthma begin in childhood, in relation to IgE-dependent sensitization to common environmental allergens, but asthma can also present later in life. Adult-onset asthma often occurs in the absence of allergy and can be associated with NSAID intolerance, rhinosinusitis, and nasal polyps. NSAID intolerance is most likely due to a decrease in the production of prostaglandin E2, an anti-bronchoconstrictor factor under inflammatory conditions. For a review, see Holgate et al., Nature Reviews Disease Primers (2015), vol. 25(1), art. 15025.

[0119] In the clinical setting, there is a significant need for medical treatment with immunosuppressive or immunomodulatory agents for autoimmune or other inflammatory diseases. However, at the same time, such patients are at risk of infections, particularly those caused by viruses and / or bacteria.

[0120] Bacterial infection Multiple types of bacteria, particularly multiple types of pathogenic bacteria, are known that can potentially infect, and more specifically pathologically infect, one or more host species including warm-blooded animals, mammals, and humans. Generally, an infection by (pathogenic) bacteria often occurs when the body of an organism (i.e., the body of the host) is invaded by one or more of said pathogenic bacteria and the host body cannot control, or cannot sufficiently control, the replication and spread of said pathogenic bacteria within the host body or in a part or organ thereof, thereby causing a bacterial disease or disorder in the host, which results in a bacterial disease or an infectious bacterial disease in the host.

[0121] Other bacteria are characterized as opportunistic pathogens and cause disease mainly in people with immunosuppression or cystic fibrosis. Examples of these opportunistic pathogens include: Pseudomonas aeruginosa (which causes diseases such as nosocomial infections, ventilator-associated pneumonia (a type of lung infection that occurs in people using ventilators in hospitals), and various sepsis syndromes), Burkholderia cenocepacia, and Mycobacterium avium (found in fresh and salt water, in household dust, and in soil, and causing in humans a disease known as Mycobacterium avium-intracellulare infection or Mycobacterium avium complex infection only in immunocompromised subjects or those with severe lung disease).

[0122] Preferably, the bacterial infections, diseases or disorders include, but are preferably not limited to, anthrax, cholera, diphtheria, Haemophilus influenzae, meningococcal meningitis, Pertussis, plague, Pneumococcal diseases, Streptococcus pneumoniae, tetanus, tuberculosis, and typhus.

[0123] Antibacterial vaccines that may be used in the present disclosure include, without limitation, one or more of the following given vaccines, but are preferably not limited to the following given vaccines: 23-valent pneumococcal vaccine, such as Pneumovax 23 or Pneumovax 23 (Pro), 13-valent pneumococcal vaccine, such as Prevnar 13 or Prevnar 13 (Pro), meningococcal conjugate vaccine, such as Menacra or Menacra (Pro), Haemophilus b conjugate (prp-t) vaccine, such as ActHIB or ActHIB (Pro), meningococcal group B vaccine, such as Bexsero or Bexsero (Pro), adsorbed anthrax vaccine, such as Biothrax or Biothrax (Pro), Haemophilus b conjugate (prp-t) vaccine, such as Hiberix or Hiberix (Pro), Haemophilus b conjugate (prp-omp) vaccine, such as Liquid PedvaxHIB or Liquid PedvaxHIB (Pro), Haemophilus b conjugate (prp-t) vaccine / meningococcal conjugate vaccine, such as MenHibrix, meningococcal polysaccharide vaccine, 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 adsorbed tetanus toxoid, meningococcal group B 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.

[0124] Viral infection Multiple types of viruses are known that can potentially infect, and more specifically, pathologically infect, one or more host species including warm-blooded animals, mammals, and humans. Generally, viral infections, which often cause viral or infectious viral diseases in said hosts, occur when the body of an organism (i.e., the body of the host) is invaded by a pathogenic virus and infectious viral particles (such as virions) attach to and penetrate the susceptible cells of said host or the body of the subject.

[0125] Basic structural features such as genome type, virion shape, and replication site generally share the same features among virus species within the same family: · Double-stranded DNA family: Three are non-enveloped (Adenoviridae, Papillomaviridae, and Polyomaviridae), and two are enveloped (Herpesviridae and Poxviridae). All of the non-enveloped families have icosahedral capsids. · Partially double-stranded DNA viruses: Hepadnaviridae. These viruses are of the enveloped type. · One family of single-stranded DNA viruses infects humans: Parvoviridae. These viruses are non-enveloped. · Positive single-stranded RNA families: Three non-enveloped (Astroviridae, Caliciviridae, and Picornaviridae) and four enveloped (Coronaviridae, Flaviviridae, Retroviridae, and Togaviridae). All of the non-enveloped families have icosahedral nucleocapsids. · Negative single-stranded RNA families: Arenaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae. All are of the enveloped type and have helical nucleocapsids. · Double-stranded RNA genome: Reoviridae. ·The hepatitis D virus has not yet been assigned to a family but can be clearly distinguished from other families that infect humans. ·Viruses known to infect humans that have not yet been associated with a disease: Anelloviridae and Dependovirus. All of these taxa are non-enveloped single-stranded DNA viruses.

[0126] The families of viruses that infect humans provide rules that can assist physicians and medical microbiologists / virusologists. As a general rule, DNA viruses replicate in the nucleus of the cell, while RNA viruses replicate in the cytoplasm. Exceptions to this rule are known: Poxviruses replicate in the cytoplasm, and Orthomyxoviruses and hepatitis D virus (RNA viruses) replicate in the nucleus.

[0127] Some types of viruses, such as the families Bunyaviridae, Orthomyxoviridae, Arenaviridae, and Reoviridae (acronym BOAR), have a segmented genome. All of these are RNA viruses. Some viruses are transmitted almost exclusively by arthropods: Bunyaviruses, Flaviviruses, and Togaviruses. Some Reoviruses are transmitted from arthropod vectors. All of these are RNA viruses. One family of enveloped viruses causes gastroenteritis (Coronaviridae). All other viruses associated with gastroenteritis are non-enveloped.

[0128] Table 1 below summarizes some of the most clinically important pathogenic viruses, known to afflict multiple hosts including humans, as well as the type, family, exemplary transmission routes, and the infections / diseases caused by each virus. However, the clinical characteristics of viruses can vary substantially among species within the same family.

Table 1-1

Table 1-2

Table 1-3

[0129] Preferably, all of the viruses and / or viral disorders indicated above should be considered clinically relevant viruses and / or viral disorders in relation to the uses according to the invention and / or the methods of treatment according to the invention. More preferably, for example in MS, a number of vaccine-preventable infectious diseases are relevant as a risk of infection, or the prognosis is worsened by MS itself or its treatment. These mainly include hepatitis B virus (HBV) and varicella zoster virus (VZV). Other infectious diseases include measles, influenza, poliovirus, pneumococcus, diphtheria, tetanus and pertussis bacteria, COVID-2 and / or COVID-19. Vaccines against COVID-2 and / or COVID-19 are currently available and further alternatives will soon be available.

[0130] Viral infections and / or the resulting diseases can typically be detected by clinical presentation, signs and / or symptoms, which include but are not limited to severe muscle pain and joint pain, subsequent fever, or skin rash and swollen lymph nodes. Standard laboratory tests can be useful for detecting viral infections. Laboratory tests can also be useful in diagnosing bacterial infections associated with viral infections. Viral infections are generally of limited duration, and prior art treatments typically consist of reducing symptoms, and antipyretic and analgesic drugs are commonly prescribed.

[0131] However, the best protection for the subject against the prognosis of a potentially serious and harmful infection is the prevention or remission of the infection itself. The most advantageous way to prevent or remit an infection is currently considered to be vaccination of the subject who is at risk of said infection.

[0132] However, preventive measures against infectious diseases such as vaccination generally require an appropriate immune response of each body and are therefore generally recommended to be carried out well in advance of, and / or well after the end of, a major medical intervention, i.e., surgery, chemotherapy, radiotherapy, or the initiation of immunosuppressive treatment.

[0133] Therefore, preventive measures against infectious diseases such as vaccination, which require an appropriate immune response of each body, are generally recommended to be carried out well in advance of the initiation of each immunosuppressive treatment and / or well after the end of each immunosuppressive treatment if there is an end.

[0134] In this regard, vaccination is preferably the administration of a vaccine to help the immune system develop protection from a disease, preferably an infectious disease. Vaccines typically contain weakened, live, or killed / inactivated forms of the pathogen of each disease, preferably a microorganism or virus, or proteins or toxins of each organism. They help prevent the pathological condition from an infectious disease in stimulating the acquired immunity of the body. Vaccination is the most effective way to prevent infectious diseases, and therefore, preventing infectious diseases in people with a reduced immunity due to immunosuppressive treatment is generally considered important and advantageous / desirable.

[0135] Vaccines are available or at least desired for infectious disorders, including but not limited to influenza and influenza-like diseases such as parainfluenza virus (which causes croup, pneumonia, bronchiolitis and / or colds), and infections derived from coronaviruses.

[0136] Antiviral vaccines that can be used in the present disclosure include, without limitation, one or more of the following given vaccines, but are preferably not limited to the following given vaccines: 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 adult vaccine, 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), such as Shingrix or Shingrix (Pro), influenza virus vaccine (live, trivalent), such as FluMist or FluMist (Pro), influenza virus vaccine (inactivated), such as Fluzone, influenza virus vaccine (inactivated), such as Fluzone high dose or Fluzone high dose (Pro), influenza virus vaccine (inactivated), such as Fluad or Fluad (Pro), influenza virus vaccine (inactivated), such as Fluvad or Fluvad (Pro), influenza virus vaccine (live, trivalent), such as FluMistQuadrivalent, yellow fever vaccine, e.g., Stamaril or Stamaril (Pro), smallpox vaccine, e.g., ACAM2000 or ACAM2000 (Pro), influenza virus vaccine (inactivated), e.g., Afluria Quadrivalent or Afluria Quadrivalent (Pro), influenza virus vaccine (inactivated), e.g., Agriflu, measles virus vaccine, e.g., Attenuvax, human papillomavirus vaccine, e.g., Cervarix or Cervarix (Pro), smallpox vaccine, e.g., Dryvax, hepatitis B pediatric vaccine, e.g., Engerix-B for pediatric use, influenza virus vaccine (inactivated), e.g., Fluarix or Fluarix (Pro), influenza virus vaccine (inactivated), e.g., Flucelvax, influenza virus vaccine (inactivated), e.g., FluLaval or FluLaval (Pro), influenza virus vaccine (inactivated), e.g., FluLaval Preservative Free Quadrivalent, influenza virus vaccine (inactivated), e.g., FluLaval Quadrivalent or FluLaval Quadrivalent (Pro), influenza virus vaccine (inactivated), e.g., Fluzone High Dose Quadrivalent, influenza virus vaccine (inactivated), e.g., Fluzone Intradermal Quadrivalent, influenza virus vaccine (inactivated), e.g., Fluzone Quadrivalent or Fluzone Quadrivalent (Pro), hepatitis vaccine for adults, e.g., Havrix or Havrix (Pro), hepatitis vaccine for pediatric use, e.g., Havrix for pediatric use, rabies vaccine, human diploid cell, e.g., Imovax Rabies or Imovax Rabies (Pro), poliovirus vaccine (inactivated), e.g., Ipol or Ipol (Pro), Japanese encephalitis vaccine sa14-14-2 (inactivated), e.g., Ixiaro or Ixiaro (Pro), rubella virus vaccine, e.g., Meruvax II, mumps virus vaccine, e.g., Mumpsvax, rabies vaccine, purified chicken embryo cell, e.g., RabAvert or RabAvert (Pro), hepatitis B vaccine for adults, e.g., Recombivax HB for adults, hepatitis B vaccine for adults, e.g., RecombivaxHB dialysis preparations, pediatric hepatitis B vaccines, such as Recombivax HB for pediatric / adolescent use, rotavirus vaccines, such as Rotarix or Rotarix (Pro), rotavirus vaccines, such as RotaTeq or RotaTeq (Pro), adult hepatitis A vaccines, such as Vaqta or Vaqta (Pro), pediatric hepatitis A vaccines, such as Vaqta for pediatric use, varicella virus vaccines, such as Varivax or Varivax (Pro), and / or yellow fever vaccines, such as YF-Vax or YF-Vax (Pro).

[0137] Coronavirus Infections induced by coronaviruses include epidemics or pandemics caused by SARS-CoV, HCoV NL63, HCoV HKU1, MERS-CoV, and SARS-CoV-2 / COVID-19, and / or their variants or progeny.

[0138] Coronaviruses preferably consist of the subfamily Orthocoronavirinae in the order Nidovirales, realm Riboviria. They are considered to be enveloped viruses with a positive-sense single-stranded RNA genome and / or a helical symmetry nucleocapsid. The latter is typically enclosed in an icosahedral protein shell. The genome size of coronaviruses is thought to range from about 26 to 32 kilobases, which is one of the largest among RNA viruses. Furthermore, they typically have characteristic club-shaped spikes protruding from their surface, which create an image reminiscent of the sun's corona in electron micrographs and from which their name is thought to be derived.

[0139] Human coronaviruses were discovered in the 1960s and include viruses tagged as B814, 229E, IBV (infectious bronchitis virus), and OC43. This new group of viruses came to be known as coronaviruses due to their characteristic morphological appearance. Since then, multiple 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, there are also numerous animal coronaviruses that have been identified since the 1960s.

[0140] The COVID-19 pandemic has caused unprecedented disruption to normal social and economic life worldwide. As of June 2022, there have been over 500 million cases and more than 6 million deaths globally (https: / / covid19.who.int / ). The disease is caused by the novel coronavirus SARS-CoV-2, which infects cells via the angiotensin-converting enzyme receptor type 2 expressed on the cells of important tissues such as the respiratory tract and also the brain.

[0141] Vaccines against COVID-19 and / or its variants are highly desirable for use in accordance with the present disclosure. Several vaccines directed against the virus that causes COVID-19 (i.e., SARS-COV-2) are currently available, and additional vaccines are under development and nearing approval by health authorities. The actual and / or candidate approaches include: subunit vaccines containing viral proteins, particularly the surface membrane spike protein that mediates receptor adhesion; nucleic acid-based vaccines that enable host cells to produce viral antigens, i.e., the spike protein or its immunogenic portion; and whole microorganism approaches such as live attenuated vaccines, inactivated vaccines, or viral vector vaccines.

[0142] Particularly preferred for use as a vaccine according to the present invention are coronavirus vaccines, particularly COVID-19 vaccines including, but not limited to, the following: mRNA technology-based vaccines, 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 / Sputnik V (Gamaleya Institute), Ad5-nCoV (CanSino Biologics); Virus-like particle (VLP)-based vaccines, 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), preferably with an adjuvant added, NVX-CoV2373 (Novavax), preferably with an adjuvant added; 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, BBIBP-CorV (Sinopharm / Beijing Institute of Biological Products); etc. The same preferably also applies to further coronavirus vaccines, especially COVID-19 vaccines.

[0143] mRNA-based COVID-19 vaccines (COVID-19 mRNA vaccines) such as mRNA vaccines, for example, the COVID-19 mRNA vaccines of BioNTech / Pfizer and Moderna, are particularly preferred. mRNA-based vaccines contain mRNA, which is introduced into the cells in the body of the vaccinated individual and instructs these cells to make a protein (or just a piece of a protein) that causes an immune response in the body.

[0144] In contrast, non-mRNA vaccines do not contain such mRNA and instead may contain, for example, a viral vector (which causes the production of a protein or a piece of a protein inside the cells of the vaccinated individual) or a protein or protein subunit. The protein then probably causes an immune response in the body of the vaccinated individual, perhaps in conjunction with an adjuvant.

[0145] Examples of mRNA vaccines include Comirnaty® by BioNTech / Pfizer or Spikevax® by Moderna, which are mRNA-based COVID-19 vaccines. Examples of non-mRNA vaccines include Vaxzevria® / Covishield® (AstraZeneca) or Jcovden® (Janssen / Johnson & Johnson), which are non-mRNA COVID-19 vaccines.

[0146] Influenza Influenza, commonly known as "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 fatigue. These symptoms typically begin two days after exposure to the virus and most often end within less than a week. However, the cough may last longer than two weeks. In children, diarrhea and vomiting can occur, but these are not common in adults. Complications of influenza can include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of pre-existing health problems such as asthma or heart failure.

[0147] There are four types of influenza viruses: A, B, C, and D. Typically, three of the four types, namely A, B, and C, infect humans. Type D is not known to infect humans to date but is thought to have the potential to do so. Only influenza A and B cause seasonal epidemics of respiratory disease that occur every 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 subtypes of HA (H1-18) and 11 different subtypes of NA (N1-11).

[0148] Each year, that year's influenza vaccine protects against three or four strains of influenza (this number depends on which research predictions are most common for the coming influenza season). Only H1N1, H1N2, and H3N2 are the known A-type influenza virus subtypes currently circulating among humans and are included in trivalent vaccines, while an additional B-type influenza strain is included in quadrivalent vaccines.

[0149] H1N1 influenza is also known as swine influenza. The term swine influenza derives from the past when people who contracted it had direct contact with pigs. It changed when a new virus emerged that spread among people who had not been near pigs. In 2009, H1N1 spread rapidly around the world, and the World Health Organization called it a pandemic.

[0150] The H3N2 virus continues to circulate around the world as a seasonal A-type influenza virus. Seasonal H3N2 viruses associated with severe disease in the elderly undergo regular antigenic drift. In years when H3N2 is the dominant strain, there are more hospitalizations, especially among high-risk groups such as the elderly and young children.

[0151] The 2018 - 2019 trivalent influenza vaccine for the Northern Hemisphere contained the following: 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 contained an additional B / Puerto Rico / 3073 / 2013-like Yamagata lineage virus. Genetic characterization of the viruses showed that the majority of circulating A(H3N2) viruses in the United States were antigenically distinguishable from, or were drifting from, the 2018 - 19 Northern Hemisphere vaccine strain, while all circulating A(H1N1)pdm09 viruses were identical.

[0152] Influenza B virus is known to infect only humans and seals. This limited host range is clearly the cause of the absence of related influenza pandemics, which is in contrast to those caused by morphologically similar influenza A viruses that mutate by both antigenic drift and reassortment. Based on the antigenic characteristics of the surface glycoprotein hemagglutinin, there are two known circulating lineages of influenza B virus. These lineages are referred to as B / Yamagata / 16 / 88-like and B / Victoria / 2 / 87-like viruses. Quadrivalent influenza vaccines licensed by the CDC are currently designed to protect against both co-circulating lineages and have been shown to be more effective than previous trivalent vaccines in preventing influenza caused by influenza B virus. To further reduce the impact of this virus, "in humans, influenza B virus evolves more slowly than influenza A virus and faster than influenza C virus." Influenza B virus mutates two to three times more slowly than influenza A.

[0153] Injectable trivalent inactivated influenza vaccines are the most commonly used worldwide. Quadrivalent inactivated influenza vaccines available since the 2014 / 2015 season have been used in expanded studies. In 2011, a live attenuated influenza vaccine (LAIV) for intranasal use was approved in the EU / EEA for children and adolescents (2 - 17 years). All currently available live attenuated influenza vaccines are quadrivalent mixed vaccines that, according to WHO recommendations, contain two influenza A strains (H1N1 and H3N2 subtypes) and two influenza B strains (Victoria and Yamagata lineages).

[0154] Seasonal influenza vaccines are usually recommended for several vulnerable groups who are lower responders to immunization due to age or disease. Therefore, several attempts to improve the vaccine have been explored since 10 to 15 years ago, such as increasing the antigen dose administered, intradermal administration to activate other arms of the immune system, and adding immunostimulatory compounds such as adjuvants.

[0155] Products using these new technologies are currently approved and available in several EU / EEA countries. See the following table. For human influenza vaccines, MF59 (squalene) and AS03 (squalene and α-tocopherol) have been approved as adjuvants by regulatory authorities in the EU, Canada, and the United States. Data from several observational studies showing improved performance and reduced hospitalizations in the elderly against influenza disease and hospitalization are included in the label for adjuvant-containing trivalent influenza vaccines.

[0156] Most influenza vaccines are based on the production of influenza virus / antigen in chicken fertilized eggs, either inactivated or live attenuated. These vaccines cannot, therefore, be administered to individuals with egg allergy who may develop severe symptoms upon exposure to egg proteins. Therefore, several manufacturers have developed cell-based influenza vaccines.

[0157] Influenza A virus subtype H1N2 (A / H1N2) is a subtype of the species Influenza A virus (sometimes referred to as avian influenza virus). It is currently endemic in both human and pig populations. Only H1N1, H1N2, and H3N2 are the known influenza A virus subtypes currently circulating among humans. The virus generally does not cause more severe disease than other influenza viruses, and an abnormal increase in influenza activity is not associated with it.

[0158] H3N2 virus continues to circulate worldwide as a seasonal influenza A virus. Seasonal H3N2 viruses associated with severe disease in the elderly undergo regular antigenic drift.

[0159] Injection - based trivalent inactivated influenza vaccines have been the most commonly used in the world in the past. Influenza antigen formulations vary among manufacturers. Inactivated influenza vaccines available in the EU / EEA may contain either split - virion influenza virus products or subunit influenza products. Adjuvant - added inactivated subunit influenza vaccines for the elderly are available in some EU / EEA member states.

[0160] . An injection - based quadrivalent inactivated influenza vaccine, available in some EU / EEA countries since the 2014 / 2015 season, is expected to replace the trivalent vaccine eventually. It is available in the private market in some European countries, but vaccine approval, vaccine availability, observed vaccine effectiveness and cost can affect the rate of this replacement.

[0161] In 2011, a live attenuated influenza vaccine (LAIV) for intranasal use was approved in the EU / EEA for children and adolescents (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), according to WHO recommendations.

[0162] Global pediatric programs organized in Finland and the UK respectively offer quadrivalent LAIV for young children aged either 2 - 3 years or 2 - 11 years.

[0163] Table 2: Summary of seasonal influenza vaccines available in the EU / EEA (season 2019 / 20) [Table 2]

[0164] Table 3: Seasonal influenza vaccines available in the UK (season 2020 / 2021) [Table 3]

[0165] Appropriate influenza (virus) vaccines include, but are not limited to: Mutagrip may contain trace amounts of eggs such as ovalbumin, as well as neomycin, formaldehyde and octoxynol-9 used during the manufacturing process (according to the Spanish label).

[0166] Quadrivalent inactivated influenza vaccine (VaxigripTetra™); VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza vaccine for persons aged ≥3 years, approved in Europe in 2016. IIV4 is based on the well-established record of the trivalent split-virion influenza vaccine (Vaxigrip®). IIV4 is immunogenic and well tolerated. By adding a second B strain to the trivalent split-virion influenza vaccine, an excellent immune response is provided against the additional strain, which does not reduce the other immune responses to the three strains or negatively affect 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 what is achieved by trivalent vaccines.

[0167] VaxigripTetra (trademark) contains a buffered solution of sodium chloride, potassium chloride, disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate, and water for injection. Some components such as eggs (ovalbumin, chicken protein), neomycin, formaldehyde, octoxynol-9 may be present in very small amounts.

[0168] A single 0.5 mL dose of Alfuria quad - AFLURIA QUADRIVALENT contains sodium chloride (4.1 mg), sodium phosphate monobasic (80 mcg), sodium phosphate dibasic (300 mcg), potassium phosphate monobasic (20 mcg), potassium chloride (20 mcg), and calcium chloride (0.5 mcg). From 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).

[0169] Trivalent inactivated influenza virus vaccine and quadrivalent inactivated influenza vaccine are preferred influenza (virus) vaccines for use according to the present invention.

[0170] Particularly preferred for use as a vaccine according to the present invention is a quadrivalent influenza vaccine (split virion, inactivated), which is adapted for the prevention of influenza diseases caused by two influenza A virus subtypes and two influenza B virus types contained in the vaccine. The quadrivalent influenza vaccine (split virion, inactivated) is a vaccine administered to protect a subject or patient against influenza (influenza / flu). The quadrivalent influenza vaccine (split virion, inactivated) or a similar type of vaccine is adapted for the prevention of influenza diseases caused by two influenza A virus subtypes and two influenza B virus types contained in the vaccine. Typically, such an influenza vaccine is administered only once a year, preferably before or during the influenza season. Preferably, the influenza vaccine is administered once a year or in relation to the influenza season, but preferably according to the vaccination schedule of the present invention.

[0171] However, such an influenza vaccine can also be administered more than once a year, or once per influenza season, preferably 2 or 3 times, more preferably 2 times, in order to boost or optimize, for example, the immunization achieved or achievable by said vaccine. If such a vaccine is to be administered twice, the first dose is preferably administered at any time within the vaccination schedule described herein, preferably within the early vaccination period described herein, followed by within 1 to 3 weeks after said first administration, preferably within 1 to 3 weeks of the same early vaccination period, or within 4 weeks to 3 months after the first administration, preferably within the subsequent or subsequent vaccination period described herein, the second dose is administered.

[0172] Varicella-zoster virus Herpes zoster is caused by the same virus (varicella) that causes chickenpox in children. When this virus reactivates in adults, it can cause herpes zoster, or shingles. Zostavax (registered trademark) (live vaccine for herpes zoster) is a live vaccine useful for the prevention of herpes zoster, preferably an inactivated or recombinant VZV vaccine such as Shingrix (registered trademark) or Shingrix (Pro (registered trademark)).

[0173] Herpes zoster (HZ) often occurs following reactivation of latent varicella-zoster virus (VZV) in sensory and autonomic neurons. The incidence of HZ varies from 6-8 cases / 1000 persons / year in those aged 50-59 years to >11 cases / 1000 persons / year in those aged 70 years. The severity of HZ and its complications also increase with aging, which closely correlates with an age-related decline in VZV-specific T cell-mediated immunity (CMI), which is thought to be important in preventing reactivation of latent VZV and preventing the proliferation of the reactivated virus. HZ vaccines are thought to boost VZV-specific memory T cells and prevent them from decreasing below a currently unknown threshold required for protection against HZ. Suitable varicella-zoster vaccines are known in the art.

[0174] The live attenuated varicella zoster virus (VZV) vaccine (Zostavax, Merck Sharpe & Dohme Corp, hereinafter referred to as Zoster Vaccine Live [ZVL]) is available for preventing herpes zoster (HZ) in individuals aged ≥50 years. However, ZVL has several limiting factors. Clinical trials have shown that the efficacy of the vaccine 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. Moreover, the efficacy of ZVL against HZ decreases over time from 62% during the first year after vaccination to approximately 40% by the fifth year after vaccination.

[0175] The 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 the AS01B adjuvant system. gE was selected as a vaccine antigen because it is the most abundantly present glycoprotein expressed by VZV-infected cells and because 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., a company based in Delaware, USA) and 3-O-desacyl-4'-monophosphoryl lipid A (MPL). AS01B stimulates local and transient activation of the innate immune response, resulting in the recruitment and activation of antigen-presenting dendritic cells. QS-21 is an adjuvant that induces transient local cytokine responses in muscle and draining lymph nodes, as well as activation of dendritic cells and macrophages, in animal models. The Toll-like receptor 4 agonist MPL acts synergistically with QS-21 to enhance the immune response to co-administered antigens through the production of interferon gamma (IFN-γ).

[0176] The Phase I and Phase II trials showed that a single dose of HZ / su induced a substantial humoral and CMI response, which further increased after the second dose.

[0177] Particularly preferred for use as a vaccine according to the present invention are inactivated and / or recombinant herpes zoster vaccines or varicella zoster vaccines, preferably those having the product number EMEA / H / C / 004336 of the European Medicines Agency (EMA), wherein the active substance comprises recombinant varicella zoster virus glycoprotein E, having the International non-proprietary name (INN) or common name "herpes zoster vaccine" or "herpes zoster vaccine (recombinant, adjuvant added)", having a therapeutic area (MeSH) that includes herpes zoster, and / or an anatomical therapeutic chemical (ATC) code of J07BK03. This vaccine is known under the trade name SHINGRIX®. Preferably, the inactivated and / or recombinant herpes zoster vaccine or varicella zoster vaccine is available as a powder and a suspension, which should preferably be mixed together, for example by a physician or a nurse, before being administered to the patient, preferably by injection, for example into the upper arm muscle of the patient. Vaccination is preferably administered at intervals of about 3 weeks to about 8 months, preferably at intervals of about 4 weeks to about 6 months, and preferably comprises two separate vaccinations, two separate injections or two separate shots.

[0178] Typically, in this regard, two separate vaccinations, two separate shots or two separate injections are administered to the patient or subject: (i) at intervals of about 3 - 5 weeks or about 1 month; (ii) at intervals of about 8 - 10 weeks or about 2 months; (iii) at intervals of about 24 - 28 weeks or about 6 months; or (iv) at intervals of about 4 - 28 weeks, about 6 - 26 weeks, or about 8 - 25 weeks, or basically at intervals of up to 6 months, It is administered.

[0179] Thus, if desired or necessary in this regard, the second vaccination, dose, injection or shot is after an interval of 3 to 10 weeks, but preferably can be done within 6 months after the first vaccination, dose, injection or shot. Persons in whom the immune system does not function properly, persons under immunosuppressive therapy, and / or persons who are being treated or should be treated according to the method of treatment of the present invention and thus would benefit from a shorter vaccination schedule can have a second dose 1 to 2 months after the first dose, preferably within the vaccination period as outlined herein. This is particularly preferred with respect to inactivated or recombinant zoster vaccines, herpes zoster vaccines, varicella zoster vaccines and / or VZV vaccines, especially those vaccines that are generally administered twice to the subject or patient in order to achieve optimal protection or immunity for said subject or patient. Administration is typically by two separate vaccinations, two separate injections or two separate shots, preferably as known in the art and especially as described herein. Preferred examples of such vaccines are recombinant adjuvant-containing zoster vaccines, such as those marketed under the trade name SHINGRIX®. Such vaccines are preferably indicated for the prevention of shingles, more preferably for the prevention of shingles in adults 50 years of age and older. Such vaccines are also preferred for use as vaccines according to the present invention. The two administrations of said vaccine are preferably via injection, preferably intramuscularly, and preferably according to the following schedule: a first dose at any point within the vaccination period described herein, preferably within the early vaccination period described herein, followed by a second dose at a) any point between 1 and 6 months after the first dose, or b) any point between 2 and 6 months after the first dose, preferably within the late vaccination period described herein.

[0180] Recombinant, adjuvant - added varicella - zoster vaccine, such as SHINGRIX®, has been shown to boost the VZV - specific immune response when preferably used according to the method of the present invention, and this boost is thought to be the mechanism by which it protects the subject or patient against the said varicella - zoster and / or herpes zoster disease.

[0181] Particularly preferred in this regard is a vaccine comprising recombinant varicella - zoster virus glycoprotein E, preferably a vaccine having the International Non - proprietary Name (INN) or common name "herpes zoster vaccine" or "herpes zoster vaccine (recombinant, adjuvant - added)", such as SHINGRIX®.

[0182] Preferred for varicella - zoster virus vaccines are live vaccines or attenuated live vaccines such as Zostavax® (herpes zoster live vaccine), which can be used to prevent varicella - zoster virus (herpes zoster) in people 50 years of age and older. Also preferred in this regard are non - live varicella - zoster virus (VZV) vaccines, which preferably include, but are not limited to, inactivated VZV vaccines and recombinant VZV vaccines such as Shingrix® or Shingrix(Pro)®.

[0183] Also particularly preferred for use as a vaccine according to the present disclosure is a live herpes zoster vaccine, which is preferably an attenuated live virus vaccine, such as ZOSTAVAX® (live herpes zoster vaccine), preferably indicated for the prevention of herpes zoster (shingles), more preferably indicated for the prevention of herpes zoster (shingles) in individuals 50 years of age and older. A live herpes zoster vaccine, such as ZOSTAVAX® is preferably a lyophilized formulation of a live, attenuated varicella zoster virus (VZV) strain, such as the Oka / Merck strain of live, attenuated varicella zoster virus (VZV). ZOSTAVAX® is a sterile suspension for subcutaneous administration when reconstituted as directed. Typically, such a live herpes zoster vaccine is for single-dose use and thus is typically administered only once (i.e., as a single dose) to a subject or patient in accordance with the present invention. However, repeated administration may be recommended or prescribed by the treating physician. In any case, it is typically administered subcutaneously, preferably in the deltoid region of the upper arm of the subject or patient. Herpes zoster (HZ), commonly known as shingles or zoster, is preferably a manifestation of the reactivation of the varicella zoster virus (VZV) that causes chickenpox as a primary infection. After the initial infection, the virus remains latent in the dorsal root or cranial sensory ganglia until it reactivates to cause herpes zoster. Herpes zoster is characterized by a unilateral, painful, vesicular rash with a dermatomal distribution. The risk of developing zoster and / or shingles is thought to be related to a decline in VZV-specific immunity. Varicella zoster virus vaccine (or varicella zoster vaccine), preferably a live herpes zoster vaccine, and particularly ZOSTAVAX® have been shown to boost VZV-specific immunity, which is thought to be the mechanism by which it protects against herpes zoster and its complications.

[0184] Other diseases for which a vaccine is available or desired Additional infectious diseases for which vaccines are available or at least desirable include, but are 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, pertussis bacteria, and SARS-Covid 2. Vaccines against SARS Covid-2 are now available.

[0185] Other diseases, including smallpox, chickenpox, polio, tetanus, measles, mumps, rubella, whooping cough, and / or influenza-like disorders, are also relevant.

[0186] Vaccination Vaccination with a vaccine is a way to artificially activate the immune system to protect against infectious diseases. Activation occurs through priming the immune system with an immunogen. Stimulating an immune response with an infectious agent is known as immunization. Vaccination encompasses various methods of administering an immunogen.

[0187] Various methods for the administration of vaccines are known to those skilled in the art. Typically, vaccine administration may be oral, by injection (intramuscular, intradermal, subcutaneous), by puncture, transdermal, or intranasal. Some recent clinical trials have aimed to deliver vaccines across mucosal surfaces so that they are taken up by the general mucosal immune system, thereby avoiding the need for injection.

[0188] Most vaccines are administered to help provide future protection before a patient contracts a disease. However, some vaccines are administered after a patient has already contracted a disease. Vaccines administered after exposure to smallpox have been reported to provide some protection from the disease or reduce the severity of the disease.

[0189] Most vaccines are administered by injection because they are not reliably absorbed through the gut. Live attenuated polio, rotavirus, some typhoid, and some cholera vaccines are administered orally to produce immunity in the gut. Vaccination provides a lasting effect, but it usually takes several weeks to develop and requires an immune system capable of initiating a suitable immune response.

[0190] Vaccine type There are several different types of vaccines. Each type is designed to teach the human immune system how to fight a specific type of pathogenic microorganism - and the serious diseases they cause. When scientists make vaccines, they consider the following: how the human immune system responds to pathogens, who needs to be vaccinated against pathogenic microorganisms, and the best technology or approach for making the vaccine. Based on many of these factors, scientists determine the type of vaccine they will make. There are several main types of vaccines: for example, live-attenuated vaccines, inactivated vaccines, subunit, recombinant, polysaccharide, and conjugate vaccines, toxoid vaccines.

[0191] The most relevant types of vaccines are described in more detail below: · Live-attenuated vaccines: Live vaccines use a weakened (or attenuated) form of the pathogenic microorganism that causes the disease. Since these vaccines are very similar to the natural infections they help prevent, they create a strong and long-lasting immune response. Just one or two doses of most live vaccines can provide lifelong protection against the pathogenic microorganism and the disease it causes. However, live vaccines also have some limiting factors. For example: Since they contain small amounts of weakened live virus, some people, such as those with a weakened immune system, people with long-term health problems, or people who have had an organ transplant, should consult their healthcare provider before being administered them. Since they need to be kept cold, they are not suitable for transportation. That is, they cannot be used in countries with limited access to refrigerators. Live vaccines are used to provide protection against: measles, mumps, rubella (MMR combined vaccine), rotavirus, smallpox, chickenpox, yellow fever, intranasal influenza vaccine. · Inactivated vaccines: Inactivated vaccines use a killed version of the pathogenic microorganism that causes the disease. Inactivated vaccines usually do not provide as strong an immune (protective) response as live vaccines. Several doses over time may be needed to obtain ongoing immunity against the disease. Inactivated vaccines are used to provide protection against hepatitis A, influenza (only the shot), polio (only the shot), rabies. · Subunits, Recombinants, Polysaccharides, and Conjugate Vaccines: These vaccines use specific pieces of pathogenic microorganisms, such as their proteins, sugars, or capsids (the casing around the pathogenic microorganism). Since these vaccines use only specific pieces of the pathogenic microorganism, they can confer a very strong immune response that targets important parts of the pathogenic microorganism. They can also be used for almost everyone who needs them, including people with weakened immune systems and those with long-term health problems. One limitation of these vaccines is that booster shots may be needed to obtain ongoing protection against the disease. These vaccines are used to protect against Hib (Haemophilus influenzae type b) disease, hepatitis B, HPV (human papillomavirus), whooping cough (part of the DTaP combination vaccine), pneumococcal disease, meningococcal disease, and shingles. · Toxoid Vaccines: Toxoid vaccines use toxins (harmful products) made by pathogenic microorganisms that cause disease. They create immunity against parts of the pathogenic microorganism that cause disease, rather than against the pathogenic microorganism itself. This means that the immune response targets the toxin instead of the whole pathogenic microorganism. As with some other types of vaccines, booster shots may be needed to obtain ongoing protection against the disease. Toxoid vaccines are used to protect against diphtheria and tetanus. · DNA plasmid vaccine: It contains a small circular piece of DNA called a plasmid that carries the gene encoding the protein from the pathogen of interest. The manufacturing process for DNA plasmid vaccines is well established and enables the rapid development of experimental vaccines to address emerging or re-emerging infectious diseases. The NIAID’s Vaccine Research Center has developed candidate DNA vaccines during pandemics to address the threat of several viral diseases, including the SARS coronavirus (SARS-CoV) in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and Zika virus in 2016. The time from the selection of the viral gene to be included in the vaccine to the start of clinical studies in humans has been shortened, ranging from 20 months for SARS-CoV to slightly longer than 3 months for Zika virus. · mRNA vaccine: A vaccine based on messenger RNA (mRNA), an intermediate between DNA and protein, which is also under development. Recent technological advances have nearly overcome the problems of mRNA instability and the difficulty of delivering it into cells, and several mRNA vaccines have provided encouraging early results. For example, researchers supported by NIAID developed an experimental mRNA vaccine that protects mice and monkeys against Zika virus infection after a single dose. · 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. Some such recombinant vector vaccines have been approved to protect animals from infectious diseases, including rabies and distemper. Many of these veterinary vaccines are based on a technology developed by NIAID researchers in the 1980s that uses a weakened version of poxvirus to deliver the pathogen's genetic material. Currently, scientists supported by NIAID are developing and evaluating recombinant vector-based vaccines to protect humans from viruses such as HIV, Zika virus, and Ebola virus.

[0192] However, vaccination can cause severe clinical crises in the vaccinated body, for example, due to vaccine failure. Typically, vaccine failure is implied when an organism contracts the disease despite being vaccinated against it. Primary vaccine failure occurs when an organism's immune system does not produce antibodies when first vaccinated. A vaccine can fail if several series are administered and fail to produce an immune response. The term "vaccine failure" does not necessarily imply that the vaccine is defective. Most vaccine failures result from individual variations in the immune response, but also occur, for example, in immunosuppressed bodies under immunosuppressive treatment of patients with autoimmune diseases.

[0193] Vaccine response Effector mechanism Vaccines are found to induce effector mechanisms (cells or molecules) that can rapidly control replicating pathogens or inactivate their toxic components. The effectiveness of initial protection is mainly conferred by the induction of antigen-specific antibodies that can bind to pathogens or toxins, which are immune effectors produced by B cells. Long-term protection requires the persistence of vaccine antibodies above a protective threshold and / or the maintenance of immune memory that can be rapidly and effectively reactivated. Antigen-specific antibodies have been officially shown to confer vaccine-induced protection against many diseases. The major role of B cells in the efficacy of current vaccines should not obscure the importance of T cell responses. Most antigens and vaccines elicit B cell (humoral immunity) and T cell responses (cellular immunity).

[0194] CD4+ T cells are required for most antibody responses, and antibodies have a significant impact on T cell responses against intracellular pathogens. T cells are essential for the induction of high-affinity antibodies and immune memory. Cytotoxic CD8+ T lymphocytes are additional effectors that will recognize and kill infected cells or limit the spread of infectious agents by secreting specific antiviral cytokines. CD4+ T helper cells (Th) provide assistance for the generation and maintenance of B cell and CD8 responses and contribute to protection by cytokine production (e.g., TH1 cells that express IFN-gamma). Another additional type of Th subtype effector cells are follicular Th cells (Tfh) that assist in strong B cell activation and differentiation into antibody-secreting cells or TH17 cells.

[0195]

Table 4

[0196] The nature of the vaccine has a direct impact on the type of immune effectors induced that mediate protective activity The features of T-dependent responses (elicited by toxoids, proteins, inactivated or attenuated viral vaccines) are to induce higher affinity antibodies and immunological memory. In addition, attenuated vaccines / vectors usually give rise to CD8 cytotoxic T cells. Most current vaccines mediate their protective efficacy through the induction of vaccine antibodies, while vaccine-induced CD4+ T cells contribute to macrophage activation and the control of Mycobacterium tuberculosis. Current vaccines mainly mediate protection through the induction of highly specific IgG serum antibodies. Live vaccines induce serum IgA and secretory IgA levels that help limit viral shedding at mucosal surfaces. There is conclusive evidence that T cells are the major effectors for BCG in infants immunized with BCG or in adults immunized with varicella zoster. There is indirect evidence that vaccine-induced T cells contribute to the protection conferred by other vaccines.

[0197]

Table 5

[0198] Innate Immunity and Vaccination When exposed to pathogens in the tissue or at the site of injection, immature dendritic cells mature and migrate to secondary lymph nodes where they will induce B and T cell responses. The central role of mature DCs (dendritic cells) in inducing vaccine responses is to provide danger signals sufficient to induce an inflammatory effect through vaccine antigens or adjuvants. DCs, monocytes, and neutrophils express pattern recognition receptors (e.g., Toll-like receptors, TLRs) that are activated upon encountering pathogens. They regulate the expression of cell surface proteins and produce pro-inflammatory cytokines and chemokines. The inflammatory environment drives the differentiation of monocytes into macrophages and the maturation of DCs. In the absence of danger signals, DCs remain immature, and when naive cells come into contact, CD4+ cells do not differentiate into effector cells. Live vaccines most efficiently induce the innate immune system temporally and spatially via TLRs. Inactivated vaccines (e.g., proteins, glycoconjugates, inactivated microorganisms) may still contain pathogen recognition receptors, however, activation induced by the vaccine remains limited to the site of injection. After activation, DCs change their homing receptors and migrate to the draining lymph node where B and T cell responses occur.

[0199] primary antibody response In response to protein antigens, B cells that can bind to this antigen via their surface immunoglobulins undergo active activation. Initial antigen exposure induces an extrafollicular response, where B cells rapidly differentiate into plasma cells, which produce low-affinity antibodies (IgM+ / -IgG isotype), resulting in a rapid appearance of low Ig titers in the serum within days of immunization. Antigen-specific T helper cells activated by antigen-bearing DCs cause the migration of antigen-specific B cells towards follicular DCs, initiating the germinal center (GC) reaction. In the GC, B cells receive additional signals from follicular T helper (Tfh) cells and undergo strong clonal expansion and class switching from IgM to IgG, IgA, or IgE. Since B cells proliferate in the germinal center, the IgG antibody titer increases to peak levels, usually reaching after 4 weeks of immunization. The short lifespan of these plasma cells results in a rapid decline in antibody titers. A minimum interval of 3 weeks between two initial doses allows for the generation of successive waves of Ag-specific primary responses without interference.

[0200] Secondary antibody response In the secondary immune response, booster exposure to the antigen reactivates immunological memory, resulting in a rapid increase in IgG titers. Short-lived plasma cells maintain peak levels for several weeks until long-lived plasma cells that have reached a survival niche in the bone marrow continue to produce antigen-specific antibodies, which then decline with a more gradual kinetics. A minimum interval of 4 months between priming and boosting allows for the affinity maturation of memory B cells, thereby enabling a higher secondary response. This general pattern may not apply to the long-term IgG antibodies induced by live vaccines over an extended period.

[0201]

Table 6

[0202] Vaccine-induced B cell memory Memory B cells arise during the primary response to T-dependent vaccines. They persist in the absence of antigen, and re-exposure to antigen drives their differentiation into antibody-producing plasma cells. This reactivation is rapid and does not require T cell help, such that the booster response is characterized by a rapid increase to higher titers of antibodies with higher affinity for the antigen than the antibodies that arose during the primary response.

[0203]

Table 7

[0204] Vaccine-induced T cell memory

Table 8

[0205]

Table 9

[0206] Problems associated with vaccination under treatment with immunosuppressive / immunomodulatory drugs Vaccination is a powerful tool for preventing infectious diseases, reducing the risk of contracting them, and increasing the chance of a milder course of infection if one is actually contracted. However, as detailed in the background section, many immunosuppressive and immunomodulatory drugs affect the immune system such that a complete vaccination response does not occur. Thus, in these cases, vaccination will not result in the desired immunization.

[0207] In view of this situation, it is strongly recommended to avoid vaccination while being treated with a drug having a modifying effect on the immune response, or when in temporal proximity to such treatment. Instead, it is recommended to always leave a gap or interval of several weeks to several months between vaccination and the start and / or end of treatment with such immunosuppressive or immunomodulatory drugs (see the background section above).

[0208] Based on their mechanisms of action, it is likely that such problems will also occur with BTK inhibitors. This hypothesis is consistent with the vaccination data obtained with the selected BTK inhibitor, suggesting that the performance of vaccination may be blunted under treatment with BTK inhibitors (see the background section above). According to general recommendations, this also means that vaccination in temporal proximity to treatment with immunomodulatory drugs should be avoided in the case of BTK inhibitors as well.

[0209] BTK inhibitor Bruton's tyrosine kinase (BTK) is a cytoplasmic kinase of the Tec family and is expressed by hematopoietic cells and plasma cells that regulate various signals including the PI3K, MAPK and NF-κB pathways.

[0210] As discussed in the background section, BTK is expressed not only in almost all hematopoietic cells, particularly B cells, but also in macrophages and monocytes, but not in T cells. Indeed, it is an essential component of various B cell receptor (BCR) signaling pathways and regulates the differentiation of antibody-producing plasma cells, as well as the activation, proliferation, and survival of cells. In addition, BTK plays an important role in the secretion of pro-inflammatory cytokines, as well as in degranulation and histamine release.

[0211] Thus, BTK inhibition causes the blockade of various downstream cell signaling pathways associated with the development of B cell malignancies, as well as autoimmune and inflammatory diseases.

[0212] BTK is composed of 659 amino acids. The protein contains five domains. From the N-terminus to the C-terminus, they are as follows: the pleckstrin homology (PH) domain, the proline-rich TEC homology (TH) domain, the SRC homology (SH) domains (named SH3 and SH2), and finally the catalytic domain. The function of the PH domain is to mediate protein-lipid and protein-protein interactions. In contrast, the TH domain contains a zinc finger motif that is important for protein activity and stability. In the SH2 and SH3 domains, the autophosphorylation site Tyr223 is located. The catalytic domain contains two phosphorylation sites (Tyr551 and Cys481).

[0213] BTK inhibitors can be classified into two types based on their mechanism of action and binding mode: (i) irreversible inhibitors that form a covalent bond with the conserved cysteine 481 residue at the ATP binding site, and (ii) reversible inhibitors that bind to a specific pocket in the SH3 domain through weak reversible interactions (e.g., hydrogen bonds or hydrophobic interactions), causing an inactive conformation of the enzyme.

[0214] Examples of irreversible BTK inhibitors are evobrutinib, spebrutinib, remibrutinib, trebrutinib, ormutinib, branebrutinib, TAK-020 (Takeda), elsibrutinib or rilzabrutinib. Examples of reversible BTK inhibitors are ibrutinib, BMS-935177 (Bristol Meyers Squibb), BMS-986142 (Bristol Meyers Squibb) or fenebrutinib.

[0215] BTK inhibitors are reviewed, for example, in Tasso et al., Molecules (2021), vol. 26, p. 7411 or Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223, the content of which is incorporated herein by reference. See also the discussion and citations in the background section; the content thereof is also incorporated herein by reference. BTK inhibitors have great potential in the clinical treatment of diseases.

[0216] Ibrutinib was the first BTK inhibitor approved by the FDA in 2013 for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), and relapsed / refractory mantle cell lymphoma (MCL). Subsequently, it was also approved for patients with chronic graft-versus-host disease (cGVHD) in 2017. More recently, acalabrutinib and zanubrutinib were launched in 2017 and 2019, respectively, for CLL, SLL, and MCL. In addition, tirabrutinib is currently registered in Japan for the treatment of relapsed or refractory primary central nervous system lymphoma and has also received additional approval for WM and lymphoplasmacytic lymphoma. In December 2020, oraberutinib received its first approval in China for the treatment of patients with MCL, CLL, and SLL who have received at least one prior treatment. The clinical development of oraberutinib for various indications is ongoing in the United States and China. For a review of such compounds and treatments, see, for example, Tasso et al.

[0217] As detailed in the Background section, various BTK inhibitors also show great potential or are in clinical trials for the treatment of autoimmune and other inflammatory 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 (PMS), pemphigus vulgaris, Sjögren's syndrome, chronic idiopathic urticaria and idiopathic thrombocytopenia, as well as the treatment of other inflammatory diseases such as graft-versus-host disease and asthma. The BTK inhibitors evobrutinib and tolebrutinib 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). Additionally, a recent trial of tolebrutinib in myasthenia gravis (MG) has been recently published (NCT05132569).

[0218] Thus, BTK inhibitors can be successfully administered to treat various diseases, including various autoimmune and other inflammatory diseases. For details on these treatments, see, for example, Ringheim et al., Tasso et al., the references cited therein, submissions of studies at www.clinicaltrials.gov, and the publications of the corresponding studies. Accordingly, such BTK inhibitors are contemplated for use in the practice of the present disclosure.

[0219] Evobrutinib Evobrutinib is a BTK inhibitor having the structure shown in formula (I):

Chemical formula

[0220] The chemical name of ibrutinib 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.

[0221] Preferably, the naming of the active ingredient, active ingredient (active principle: API), medicine, or their International Nonproprietary Names (INN) includes all their prodrugs, salts and solvates, especially those that are functionally equivalent and / or considered appropriate alternatives from a clinical perspective.

[0222] Ibrutinib and its use in medical treatment are described, for example, in the published international patent applications WO 2012 / 170976 A2, WO 2017 / 087445 A1 and WO 2020 / 016850 A1, or in publications on clinical trials with ibrutinib, such as Montalban et al., the contents of which are incorporated herein by reference.

[0223] The 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 in WO 2012 / 170976 A2, WO 2017 / 087445 A1 and WO 2017 / 079542 A1 (Compound A225). Ibrutinib is an irreversible BTK inhibitor. It covalently binds to cysteine 481 in the active site of BTK, causing a potent and sustained inhibition of BTK enzyme activity.

[0224] Functional changes induced by BTK inhibition through ibrutinib encompass inhibition of B cell proliferation, activation, maturation, antigen presentation, cytokine / antibody production, and CNS homing. Due to inhibition of the interaction between T cells and B cells, ibrutinib also indirectly affects pathological T cell responses. In myeloid cells (monocytes, macrophages, dendritic cells) and CNS glia (microglia, astrocytes), ibrutinib acts downstream of various receptors (e.g., GM-CSF receptor, FcR), increasing anti-inflammatory signals while decreasing pro-inflammatory signals, thereby potentially promoting a more anti-inflammatory state in peripheral and CNS compartments.

[0225] Ibrutinib is under clinical investigation for autoimmune disorders and, when administered orally, it has shown good efficacy in mouse models of RA and SLE, as demonstrated by reduction in disease severity and histological damage (Caldwell et al., J. Med. Chem. (2019), vol. 62, p. 7643-7655; Haselmayer et al., J. Immunol. (2019), vol. 202, p. 2888-2906). Furthermore, ibrutinib has shown efficacy in the treatment of patients with relapsing forms of multiple sclerosis (Montalban et al.).

[0226] Ibrutinib (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 considered for use in the practice of the teachings of this disclosure. BTK inhibitors, particularly ibrutinib, can be formulated in any pharmaceutical preparation, where preferably such pharmaceutical preparation is suitable for oral administration. Representative oral formulations of BTK inhibitors are described in the product characteristics of BTK inhibitor products that have obtained marketing authorization by the FDA or EMA (refer to the United States Prescribing Information (USPI) approved by the U.S. Food and Drug Administration (FDA) or the Summary of Product Characteristics (SmPC) approved by the European Medicines Agency (EMA) respectively). Examples of ingredients for oral formulations are provided below. Processes for preparing ibrutinib are known in the art. For example, the preparation of ibrutinib is described in the published international patent application WO 2012 / 170976 A2.

[0227] The BTK inhibitor may be used in the form of a free base, a pharmaceutically acceptable salt, a solvate, or a solvate of a salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic bases or acids and organic bases or acids. Thus, a BTK inhibitor containing one or more basic groups (such as ibrutinib), i.e., groups that can be protonated, can exist in the form of a salt and can be used in the form of an addition salt with an inorganic or organic acid according to the present invention. Examples of suitable acids include the following: 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, a BTK inhibitor containing one or more acidic groups can exist in the form of a salt and can be used according to the present disclosure, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine, or amino acids, etc.).

[0228] Oral administration of ibrutinib may be in the form of capsules, tablets, oral suspensions, or syrups. Tablets or capsules may contain about 10 to 500 mg of the aforementioned BTK inhibitor (such as ibrutinib). Preferably, they may contain 30 to about 300 mg of ibrutinib, more preferably about 40 to 150 mg of ibrutinib. Tablets may contain the aforementioned amount of the compound and a binder, which may be a gelatin solution, a starch paste in water, polyvinyl polyvinyl alcohol in water, etc., and may have a typical sugar coating.

[0229] Preferably, when the term "evobrutinib" is used in connection with the present invention and is not otherwise explicitly defined, it preferably means "oral evobrutinib", i.e., the active ingredient evobrutinib to be administered orally according to the present invention. Preferably, evobrutinib to be administered orally according to the present invention is administered in the form of an oral dosage form such as a capsule, for example, a capsule filled with an evobrutinib solution, a capsule filled with evobrutinib powder, or a tablet containing evobrutinib.

[0230] . The composition of evobrutinib may further contain one or more pharmaceutically acceptable additional ingredients such as alum, stabilizers, antibacterial agents, buffers, coloring agents, flavors, adjuvants, and the like.

[0231] The composition may be in the form of tablets or lozenges formulated by conventional methods. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, a binding agent, a filler, a lubricant, a disintegrant, and a wetting agent. Binding agents include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage, 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 silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate). Tablets may be coated according to methods well known in the art.

[0232] The composition may also be a liquid formulation, including but not limited to aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The composition may also be formulated as a dry product for constitution with water or other suitable media before use. Such liquid formulations may contain additives including but not limited to suspending agents, emulsifying agents, 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 and oils. Emulsifying agents include but are not limited to lecithin, sorbitan monooleate, and acacia. Non-aqueous vehicles include but are not limited to edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include but are not limited to methyl or propyl p-hydroxybenzoate, and sorbic acid.

[0233] The above information regarding the composition, formulation, or preparation for oral administration in any pharmaceutical preparation is, where appropriate, applicable to other BTK inhibitors.

[0234] Post hoc analysis of clinical study data In the experimental section herein, a post hoc analysis of data obtained in two Phase II clinical studies using a BTK inhibitor (evobrutinib) has been conducted.

[0235] Surprisingly, regarding the treatment of various autoimmune diseases (SLE, MS) with this BTK inhibitor, during treatment with the BTK inhibitor, various vaccinations (influenza, COVID-19) were found to result in a humoral immune response similar to that of patients treated with placebo (SLE / influenza vaccine), or the induced antibody levels were consistent with the published data (MS / mRNA COVID-19 vaccine). Contrary to previous general recommendations, thus, surprisingly, subjects suffering from autoimmune disorders can receive BTK inhibitor treatment, particularly ibrutinib treatment, and yet can safely receive and / or be immunized against infectious diseases whenever vaccination against infectious diseases is necessary or desirable. In the treatment of various autoimmune diseases, the fact that such observations were made with different types of vaccines (the influenza vaccine is presumed to reflect a recall response; the COVID-19 vaccine is an mRNA vaccine and is assumed to reflect the response to a novel antigen due to the recent emergence of this virus) suggests that these findings are more widely applicable to other autoimmune diseases, and perhaps other inflammatory diseases, as well as various types of vaccines and antigens.

[0236] As a result, it was found that the immune response to vaccination can be initiated during BTK inhibitor treatment in various contexts, despite the presumed negative impact of BTK inhibitor administration on the part of the immune system involved in the initiation of such an immune response to vaccination.

[0237] Advantageously, these findings enable much higher vaccine applicability with respect to BTK inhibitor treatment, particularly ibrutinib treatment, and much greater flexibility when vaccinating regarding treatment with such BTK inhibitors. Thus, in various aspects, the present disclosure further relates to the following:

[0238] In one aspect, the present disclosure relates to a method for treating a disease in a patient in need thereof, the method comprising the following: (a) administering a BTK inhibitor (Bruton's tyrosine kinase inhibitor) to the patient, (b) vaccinating the patient against an infectious disease.

[0239] BTK inhibitors are known to those skilled in the art and are further described herein. Additional information on BTK inhibitors and their use in the treatment of diseases is available from the literature; see, for example, Ringheim et al., Frontiers in Immunology (2021), vol. 66, p. 2223; Tasso et al., Molecules (2021), vol. 26, p. 7411; and the references cited therein. Appropriate dosages will be determined by the attending physician, as they will depend on the particular patient and clinical situation.

[0240] Vaccinating is effected by administering a vaccine to the patient. Vaccines, and their use for preventing infectious diseases, are part of the expertise of those skilled in the art. The exact vaccination protocol will be determined by the attending physician based on the clinical prescription of the vaccine used and the details of the case.

[0241] As described herein, the present disclosure is directed to BTK inhibitor treatment and vaccination that are temporally proximate, or even simultaneous, without the need for a particular order of the steps of BTK inhibitor treatment and vaccination. Thus, the placement of the letters (a) and (b) of the above method (or similar placement of letters regarding BTK inhibitor treatment and vaccination in the further methods below) should not be understood in a chronological sense. Administering a BTK inhibitor to the patient and vaccinating the patient according to this treatment method can be done in any order, at overlapping times, or simultaneously, unless specifically specified otherwise.

[0242] As used herein, the term "patient" refers to a human to be treated by the methods of the present invention. As used herein, the terms "treating" or "treatment" include any effect that results in the amelioration of a disease, e.g., alleviating, reducing, modulating, improving or eliminating. Corresponding considerations apply to further aspects of the present disclosure below.

[0243] 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 a patient in need of treatment of said disease who is at risk of contracting an infectious disease, (b) vaccinating the patient at risk of contracting said infectious disease against said infectious disease, and (c) administering a BTK inhibitor to the patient.

[0244] "Identifying a patient at risk of contracting an infectious disease" (or "ascertaining that a patient is at risk of contracting an infectious disease") is a routine step for one of ordinary skill in the art. Typically, it is performed by a skilled physician (e.g., a physician in general medicine, in the field of immunology and / or in the field of autoimmune disorders) using standard laboratory procedures (including, e.g., determining antibody titers). From such antibody titers, it is possible to assess to what extent the patient is already immune to a given infection and thus to assess whether said patient is at risk of contracting such an infectious disease.

[0245] With respect to the step of identifying whether a patient is at risk of contracting an infectious disease and the step of vaccinating said patient, it is understood that the identifying step precedes the vaccinating step as the patient to receive the vaccination is identified through the identifying step.

[0246] 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 a patient in need of treatment of the disease who is at risk of developing an infectious disease, (b) vaccinating the patient at risk of developing the infectious disease against the infectious disease, and (c) treating the disease by administering a BTK inhibitor to the patient.

[0247] 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) identifying that the patient is at risk of developing an infectious disease, and (c) vaccinating the patient against the infectious disease.

[0248] 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 the patient, thereby treating the patient for the disease, (b) identifying that the patient is at risk of developing an infectious disease while the patient is undergoing repeated treatment with the BTK inhibitor, and (c) vaccinating the patient against the infectious disease during repeated treatment with the BTK inhibitor, and optionally, (d) continuing the repeated treatment with the BTK inhibitor.

[0249] As used herein, "repeated" administration of the BTK inhibitor or "repeated" treatment with the BTK inhibitor means that the BTK inhibitor is administered at regular time intervals as defined by a treatment protocol for the BTK inhibitor and the disease (which may be defined, for example, as in the drug label of the BTK inhibitor), e.g., daily.

[0250] 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 an infectious disease, and (c) continuing to administer the BTK inhibitor to the patient.

[0251] As will be understood by those skilled in the art, the step of "continuing to administer the BTK inhibitor" will occur after the step of "administering the BTK inhibitor". There can be a time during which no BTK inhibitor is administered between the completion of the step of administering the BTK inhibitor and the step of continuing to administer the BTK inhibitor (i.e., there is an interruption in the treatment with the BTK inhibitor; features defining the length of such an interruption are further disclosed below), or the step of continuing to administer the BTK inhibitor can start immediately when the step of administering the BTK inhibitor is completed (i.e., the patient is treated continuously). The step of vaccinating the patient can overlap completely or partially with the step of administering the BTK inhibitor, the step of continuing to administer the BTK inhibitor, or both.

[0252] 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 the patient, (b) identifying that the patient is at risk of contracting an infectious disease, (c) vaccinating the patient against the infectious disease, and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered, whereby treating the patient against the disease and reducing the risk that the patient contracts the infectious disease.

[0253] As used herein, "reducing the risk that the patient contracts the infection" can be either a complete reduction (i.e., the patient becomes completely immune to the infection) or a partial reduction.

[0254] 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 under ongoing treatment with the BTK inhibitor.

[0255] The route of administration of the BTK inhibitor is not particularly limited. Administration can be by any route that enables the success of the treatment of the disease. Typically, the administration of the BTK inhibitor is by oral administration, for example in the form of tablets, or by injection.

[0256] When the present disclosure states that a patient is "under ongoing treatment" with a BTK inhibitor at a particular time point, this means that the treatment with the BTK inhibitor was started prior to that particular time and continues without interruption up to and including that particular time point. In some embodiments, it means that at that particular time point, the most recent administration of the BTK inhibitor was within 72 hours. In some embodiments, it means that at that particular time point, the most recent administration of the BTK inhibitor was within 48 hours. In some embodiments, it means that at that particular time point, the most recent administration of the BTK inhibitor was within 36 hours. In some embodiments, it means that at that particular time point, the most recent administration of the BTK inhibitor was within 24 hours.

[0257] Similarly, when the present disclosure states that a particular event (e.g., vaccination) occurs while a patient is "under ongoing treatment" with a BTK inhibitor, this means that the treatment with the BTK inhibitor was initiated prior to that event and continues without interruption until or longer than the day of that event (e.g., the treatment of the patient with the BTK inhibitor is initiated and continues without interruption until the patient receives at least one dose of each vaccine). In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor was within 72 hours. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor was within 48 hours. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor was within 36 hours. In some embodiments, it means that at the time of the event, the most recent administration of the BTK inhibitor was within 24 hours. Treatment typically includes repeated administration of the BTK inhibitor at regular time intervals, e.g., daily, according to a protocol.

[0258] In another aspect, the present disclosure relates to a method for reducing the risk that a subject contracts an infectious disease, the method comprising: (a) administering a BTK inhibitor to the subject, and (b) vaccinating the subject against the infectious disease.

[0259] In some embodiments, the subject is a patient having a disease. In some embodiments, administering the BTK inhibitor to the subject is for treating the subject's disease. In some embodiments, the subject is a patient in need of such treatment.

[0260] In another aspect, the present disclosure relates to a method of reducing the risk that a subject contracts an infectious disease, the method comprising vaccinating the subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0261] In some embodiments, the subject is a patient having a disease. In some embodiments, the treatment with the BTK inhibitor is for treating a disease in a patient in need thereof. In some embodiments, the treatment comprises administering the BTK inhibitor to the subject.

[0262] In another aspect, the present disclosure relates to a method of treating a disease in a patient in need thereof and reducing the risk of an infectious disease in the patient, the method comprising: (a) administering a BTK inhibitor to the patient, and (b) vaccinating the patient against the infectious disease.

[0263] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising: (a) administering the BTK inhibitor to a patient having the disease, (b) vaccinating the patient against an infectious disease.

[0264] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising: (a) identifying a patient at risk of contracting an infectious disease, (b) vaccinating the patient at risk of contracting the infectious disease against the infectious disease, and (c) administering the BTK inhibitor to the patient.

[0265] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0266] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient; (b) identifying that the patient is at risk of developing an infectious disease; and (c) vaccinating the patient against the infectious disease.

[0267] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0268] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) repeatedly administering the BTK inhibitor to a patient, thereby treating the patient for the disease; (b) identifying that the patient is at risk of developing an infectious disease while undergoing repeated treatment with the BTK inhibitor; and (c) vaccinating the patient against the infectious disease during retreatment with the BTK inhibitor, and optionally (d) continuing the repeated treatment with the BTK inhibitor.

[0269] In some embodiments, the patient is a patient having the disease. In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient; (b) vaccinating the patient against an infectious disease; and (c) Continuing to administer the BTK inhibitor to the patient.

[0270] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0271] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) Optionally, administering the BTK inhibitor to a patient, (b) Identifying that the patient is at risk of contracting an infectious disease, (c) Vaccinating the patient against the infectious disease, and (d) Optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0272] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease. In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease by a method comprising administering a BTK inhibitor to a patient having the disease, the method comprising vaccinating the patient against an infectious disease while the patient is under ongoing treatment with the BTK inhibitor.

[0273] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the patient having the disease is vaccinated against an infectious disease while the patient is under ongoing treatment with the BTK inhibitor.

[0274] In some embodiments, the treatment with the BTK inhibitor includes administering the BTK inhibitor to the patient. In some embodiments, the method includes administering the BTK inhibitor to a patient having the disease.

[0275] In another aspect, the present disclosure relates to a BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered in combination with a vaccine. In some embodiments, the treatment is by administration of the BTK inhibitor to a patient in need thereof.

[0276] In some embodiments, the vaccine is a vaccine against an infectious disease. In some embodiments, the patient is vaccinated with the vaccine against the infectious disease. In some embodiments, the vaccine is administered to the patient.

[0277] In some embodiments, the treatment with the BTK inhibitor and the vaccination with the vaccine are performed simultaneously or sequentially. In some embodiments, the administration of the BTK inhibitor and the vaccination with the vaccine are performed simultaneously or sequentially.

[0278] In another aspect, the present disclosure relates to a vaccine for use in the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infectious disease.

[0279] As used herein, "prevention" of an infectious disease can mean complete prevention or partial prevention of said infection. Thus, "prevention" of an infectious disease can mean that, by said vaccination, the subject becomes fully immune or partially immune to said infection. Thus, "prevention" of an infectious disease means that infection is avoided, the risk of contracting the disease is reduced, or, if the patient contracts the infectious disease, the infectious disease is ameliorated (compared to the situation where such vaccination has not been performed).

[0280] In some embodiments, the subject is a patient having a disease. In some embodiments, administering a BTK inhibitor to the subject is for treating said disease. In some embodiments, administering a BTK inhibitor to the subject is for treating the disease of the subject.

[0281] In some embodiments, the subject is a patient in need of such treatment. In another aspect, the present disclosure relates to a vaccine for use in preventing an infectious disease by a method comprising vaccinating a subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0282] In some embodiments, the subject is a patient having a disease. In some embodiments, said treatment with the BTK inhibitor is for treating a disease in a patient.

[0283] In some embodiments, the patient is a patient having said disease. In some embodiments, said treatment comprises administering the BTK inhibitor to the subject.

[0284] In another aspect, the present disclosure relates to a vaccine for use in preventing an infectious disease by a method comprising: (a) Identifying a subject at risk of contracting the infectious disease; (b) Vaccinating the subject at risk of contracting the infectious disease with the vaccine against the infectious disease, and (c) Administering a BTK inhibitor to the subject.

[0285] In some embodiments, the BTK inhibitor is administered to treat a disease. In some embodiments, wherein the subject is a patient having a disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0286] In another aspect, the present disclosure relates to a vaccine for use in preventing an infectious disease by a method comprising: (a) Administering a BTK inhibitor to a subject; (b) Vaccinating the subject with the vaccine against the infectious disease, and (c) Continuing to administer the BTK inhibitor to the subject.

[0287] In some embodiments, the BTK inhibitor is administered to treat a disease. In some embodiments, the subject is a patient having a disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0288] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for treating a disease by a method comprising: (a) Administering the BTK inhibitor to a patient having the disease; (b) Vaccinating the patient against an infectious disease.

[0289] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for treating a disease by a method comprising: (a) Identifying a patient at risk of contracting an infectious disease, (b) Vaccinating the patient at risk of contracting the infectious disease against the infectious disease, and (c) Administering the BTK inhibitor to the patient.

[0290] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0291] In another aspect, the disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) Administering the BTK inhibitor to a patient, (b) Identifying that the patient is at risk of contracting an infectious disease, and (c) Vaccinating the patient against the infectious disease.

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

[0293] In another aspect, the disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) Repeatedly administering the BTK inhibitor to a patient, thereby treating the patient for the disease, (b) Identifying that the patient is at risk of contracting an infectious disease while undergoing repeated treatment with the BTK inhibitor, and (c) Vaccinating the patient against the infectious disease during recurrence treatment with the BTK inhibitor, and optionally, (d) Continuing the repeated treatment with the BTK inhibitor.

[0294] In some embodiments, the patient is a patient having the disease. In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient, (b) vaccinating the patient against an infectious disease, and (c) continuing to administer the BTK inhibitor to the patient.

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

[0296] In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) optionally, administering the BTK inhibitor to a patient, (b) identifying that the patient is at risk of contracting an infectious disease, (c) vaccinating the patient against the infectious disease, and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0297] In some embodiments, the patient is a patient having the disease. In some embodiments, the BTK inhibitor is administered to treat the disease. In another aspect, the present disclosure relates to the use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease by a method in which a patient having the disease is vaccinated against an infectious disease while undergoing ongoing treatment with the BTK inhibitor.

[0298] In some embodiments, the method includes administering the BTK inhibitor to a patient having the disease. In some embodiments, the treatment with the BTK inhibitor includes administering the BTK inhibitor to the patient.

[0299] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against the infectious disease.

[0300] In some embodiments, the subject is a patient having a disease. In some embodiments, administering the BTK inhibitor to the subject is for treating the disease. In some embodiments, administering the BTK inhibitor to the subject is for treating the subject's disease.

[0301] In some embodiments, the subject is a patient in need of such treatment. In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising vaccinating a subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0302] In some embodiments, the subject is a patient having a disease. In some embodiments, the treatment with the BTK inhibitor is for treating the disease. In some embodiments, the treatment includes administering the BTK inhibitor to the subject.

[0303] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) Identifying a subject at risk of contracting an infectious disease; (b) Vaccinating the subject at risk of contracting the infectious disease with the vaccine against the infectious disease, and (c) Administering a BTK inhibitor to the subject.

[0304] In some embodiments, the BTK inhibitor is administered to treat a disease. In some embodiments, the subject is a patient having a disease. In some embodiments, the BTK inhibitor is administered to treat the disease.

[0305] In another aspect, the present disclosure relates to the use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) Administering a BTK inhibitor to a subject; (b) Vaccinating the subject with the vaccine against the infectious disease, and (c) Continuing to administer the BTK inhibitor to the subject.

[0306] In some embodiments, the subject is a human. In some embodiments, the BTK inhibitor is administered to treat a disease. In some embodiments, the subject is a patient having a disease.

[0307] In some embodiments, the BTK inhibitor is administered to treat the disease. The following embodiments relate to any of the aspects disclosed above (i.e., any method for treating the above disease, method for reducing the risk of a subject contracting an infectious disease, BTK inhibitor for use, vaccine for use, use of a BTK inhibitor for the manufacture of a medicament, or use of a vaccine for the manufacture of a medicament), or to any of those embodiments above.

[0308] In some embodiments, the patient is vaccinated, while the patient is under ongoing BTK inhibitor treatment. In some embodiments, the vaccine is administered while the patient is under ongoing BTK inhibitor treatment.

[0309] In some embodiments, at least one dose of the vaccine is administered during treatment with the BTK inhibitor. In some embodiments, at least one dose of the vaccine is administered while the patient is under ongoing BTK inhibitor treatment.

[0310] In some embodiments, at least a portion of the vaccination procedure is performed while the patient / subject is under treatment with the BTK inhibitor. In some embodiments, treatment with the BTK inhibitor is initiated before the vaccination begins and continues until the vaccination begins.

[0311] As will be understood by those skilled in the art, in this context, the expressions "the vaccination begins" or "the vaccination is completed" refer to a complete vaccination procedure, which may include the administration of multiple individual doses to the patient. Thus, in such a context, the term "vaccination" includes the administration of all doses necessary for the completion of the vaccination procedure.

[0312] In some embodiments, treatment with the BTK inhibitor is initiated before the vaccination begins and continues until after the vaccination is completed. In some embodiments, treatment with the BTK inhibitor is initiated after the vaccination has begun and before the vaccination is completed, and continues until after the vaccination is completed.

[0313] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine and continued at least until the administration of the vaccine. In this context, "administration of the vaccine" refers to the administration of individual doses of the vaccine. Depending on the particular vaccine, in some cases, administration of a single dose of the vaccine may be sufficient to complete the vaccination procedure, while in other cases, administration of more than one dose of the vaccine may be required to complete the vaccination procedure.

[0314] In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine and continued until after administration of the vaccine. In some embodiments, the BTK inhibitor is administered before, during, and after administration of the vaccine.

[0315] In some embodiments, the vaccine is administered at a time when treatment with the BTK inhibitor has been initiated and is still ongoing. In some embodiments, there is a temporal overlap between the vaccination procedure and the BTK inhibitor treatment.

[0316] In some embodiments, the BTK inhibitor is administered during vaccination. In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine begins, and the treatment with the BTK inhibitor does not end before the administration of the vaccine begins or ends more than 4 weeks after the administration of the vaccine begins.

[0317] As used herein, for the treatment with the BTK inhibitor to start at a first time and "not end 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 to at least the second time, and implies that there is repeated administration of the BTK inhibitor (wherein, preferably, the repeated administration of the BTK inhibitor means daily, more than one administration).

[0318] As used herein, "administered essentially daily" means that administration occurs daily or nearly daily (i.e., there may be days when administration does not occur, but only on very exceptional criteria). "Administered essentially daily" is not limited with respect to the number of doses administered per day, i.e., it can be one or more doses per day.

[0319] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine is initiated, and the treatment with the BTK inhibitor does not end before the administration of the vaccine is initiated or ends more than 3 weeks after the administration of the vaccine is initiated.

[0320] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine is initiated, and the treatment with the BTK inhibitor does not end before the administration of the vaccine is initiated or ends more than 2 weeks after the administration of the vaccine is initiated.

[0321] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine is initiated, and the treatment with the BTK inhibitor does not end before the administration of the vaccine is initiated or ends more than 1 week after the administration of the vaccine is initiated.

[0322] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine is initiated, and from this point, the BTK inhibitor is administered essentially daily until 4 weeks or more before the administration of the vaccine is initiated.

[0323] In some embodiments, treatment with the BTK inhibitor is initiated before the administration of the vaccine is initiated, and from this point, the BTK inhibitor is administered essentially daily until 3 weeks or more before the administration of the vaccine is initiated.

[0324] In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and from this point, the BTK inhibitor is administered essentially daily until 2 weeks before or after the start of administration of the vaccine. In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and from this point, the BTK inhibitor is administered essentially daily until 1 week before or after the start of administration of the vaccine.

[0325] In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and from this point, the BTK inhibitor is administered essentially daily until the start of administration of the vaccine or thereafter. In some embodiments, the essentially daily administration can be one or more doses of the BTK inhibitor that are administered essentially daily.

[0326] In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and the treatment with the BTK inhibitor ends after 4 weeks before the start of administration of the vaccine. In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and the treatment with the BTK inhibitor ends within 3 weeks before the start of administration of the vaccine.

[0327] In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and the treatment with the BTK inhibitor ends within 2 weeks before the start of administration of the vaccine. In some embodiments, treatment with the BTK inhibitor is initiated before administration of the vaccine begins, and the treatment with the BTK inhibitor ends within 1 week before the start of administration of the vaccine.

[0328] In some embodiments, the treatment with the BTK inhibitor is initiated after the vaccination is started, and the treatment with the BTK inhibitor is started within less than 4 weeks after the vaccination is completed. In some embodiments, the treatment with the BTK inhibitor is initiated after the vaccination is started, and the treatment with the BTK inhibitor is started within 3 weeks after the vaccination is completed.

[0329] In some embodiments, the treatment with the BTK inhibitor is initiated after the vaccination is started, and the treatment with the BTK inhibitor is started within 2 weeks after the vaccination is completed. In some embodiments, the treatment with the BTK inhibitor is initiated after the vaccination is started, and the treatment with the BTK inhibitor is started within 1 week after the vaccination is completed.

[0330] In some embodiments, the period between the administration of the BTK inhibitor and the vaccination is less than 4 weeks. In some embodiments, the period between the administration of the BTK inhibitor and the vaccination is less than 3 weeks. In some embodiments, the period between the administration of the BTK inhibitor and the vaccination is less than 2 weeks. In some embodiments, the period between the administration of the BTK inhibitor and the vaccination is less than 1 week.

[0331] In some embodiments, vaccination is performed while the patient is under treatment with the BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 8 weeks for the administration of the vaccine. In some embodiments, vaccination is performed while the patient is under treatment with the BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 6 weeks for the administration of the vaccine.

[0332] In some embodiments, vaccination is performed while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 4 weeks for administration of the vaccine. In some embodiments, vaccination is performed while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 2 weeks for administration of the vaccine.

[0333] In some embodiments, vaccination is performed while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 1 week for administration of the vaccine. In some embodiments, vaccination is performed while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted for administration of the vaccine.

[0334] In some embodiments, during the period that the patient is under BTK inhibitor treatment, the BTK inhibitor is administered to the patient essentially daily. In some embodiments, during the period that the patient is under BTK inhibitor treatment, the BTK inhibitor is administered to the patient daily.

[0335] In some embodiments, during BTK inhibitor treatment, the patient receives repeated administration of the BTK inhibitor essentially daily. In some embodiments, during BTK inhibitor treatment, the patient receives repeated administration of the BTK inhibitor daily. In some embodiments, repeated treatment with a BTK inhibitor means administration of the BTK inhibitor essentially daily. In some embodiments, repeated administration of the BTK inhibitor means that administration of the BTK inhibitor is performed essentially daily.

[0336] In some embodiments, step (d) starts less than 8 weeks after step (a) is completed. In some embodiments, step (d) starts less than 6 weeks after step (a) is completed. In some embodiments, step (d) starts less than 4 weeks after step (a) is completed. In some embodiments, step (d) starts less than 2 weeks after step (a) is completed. In some embodiments, step (d) starts less than 1 week after step (a) is completed. In some embodiments, step (d) starts immediately after step (a) is completed.

[0337] In some embodiments, the subject is human. In some embodiments, the patient is human. In some embodiments, the subject / patient is an adult. In some embodiments, the subject / patient is 18 to 75 years old.

[0338] In some embodiments, by examining the patient / subject for a history of infectious diseases, the patient / subject is identified as being at risk of having the infectious disease. In some embodiments, by determining one or more antibody titers, which are indicators of immunity to the infectious disease, in the blood, serum or plasma of the patient / subject, the patient / subject is identified as being at risk of having the infection.

[0339] In some embodiments, the step of identifying a patient at risk of having an infectious disease or identifying that a patient is at risk of having an infection preferably includes measuring one or more antibody titers from a blood, serum or plasma sample.

[0340] In some embodiments, by the method, the patient is treated for the disease. In some embodiments, the method reduces the symptoms of the disease. In some embodiments, the administration of the BTK inhibitor is for treating a disease in a patient in need thereof.

[0341] In some embodiments, by administering the BTK inhibitor to the patient, the patient is treated for the disease. In some embodiments, by administering the BTK inhibitor to the patient, the symptoms of the disease are reduced.

[0342] In some embodiments, by the treatment, the patient is treated for the disease. In some embodiments, by the treatment, the symptoms of the disease are reduced. In some embodiments, by the treatment, the frequency of clinical exacerbation of the autoimmune disease is reduced.

[0343] In some embodiments, by the treatment, the progression of the autoimmune disease is slowed or stopped. In some embodiments, the administration of the BTK inhibitor to the patient results in the success of the treatment of the patient. In some embodiments, by the method, the risk that the patient contracts the infection is reduced. In some embodiments, by the method, prophylaxis against the infection is achieved.

[0344] In some embodiments, by the method, an immune response of the patient against the pathogen causing the infection is achieved. In some embodiments, by administering the vaccine to the patient, the risk that the patient contracts the infection is reduced. In some embodiments, by administering the vaccine to the patient, prophylaxis against the infection is achieved. In some embodiments, administering the vaccine to the patient achieves an immune response in the patient against the pathogen that causes the infection.

[0345] In some embodiments, vaccinating a patient against the infection reduces the risk that the patient will develop the infection. In some embodiments, vaccinating a patient against the infection achieves prevention of the infection. In some embodiments, vaccinating a patient against the infection achieves an immune response in the patient against the pathogen that causes the infection. In some embodiments, vaccinating a patient against the infection accomplishes complete or partial immunization against the infection.

[0346] In some embodiments, vaccinating a patient against the infection accomplishes complete immunization against the infection. In some embodiments, prevention of infection means that the subject becomes fully or partially immune to the infection. In some embodiments, prevention of infection means that the subject becomes fully immune to the infection. In some embodiments, prevention of infection means that the infection is avoided, the risk of developing the infection is reduced, or, if the patient develops the infection, the infection is ameliorated (compared to a situation where such prevention was not performed).

[0347] In some embodiments, the method is a method for vaccinating the subject and not a method for treating a disease. In some embodiments, the method is a method for vaccinating the subject and not a method for treating a disease.

[0348] In some embodiments, the BTK inhibitor is selected from the group consisting of evobrutinib, trebrutinib, fenebrutinib, and remibrutinib. In some embodiments, the BTK inhibitor is an irreversible BTK inhibitor. In some embodiments, the BTK inhibitor is a BTK inhibitor that covalently binds to cysteine 481 of BTK. In some embodiments, it has been shown in clinical studies that the BTK inhibitor enables the success of treating the disease. In some embodiments, the marketing approval for the use of the BTK inhibitor in treating the disease has been granted by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0349] 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 a mixture in any ratio of any of the above.

[0350] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human tissue within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and that exhibit a reasonable benefit / risk ratio.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] In some embodiments, the BTK inhibitor is evobrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is evobrutinib.

[0361] In some embodiments, the BTK inhibitor has the formula (I):

Chemical formula

[0362] In some embodiments, the BTK inhibitor has the formula (I): [Chemistry] It is a compound represented by the formula, or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the BTK inhibitor is of formula (I): [Chemistry] It is a compound represented by the formula.

[0364] In some embodiments, the disease is selected from the group consisting of systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenic purpura (ITP), chronic spontaneous urticaria (CSU), graft-versus-host disease (GVHD), large-vessel vasculitis (LVV), and asthma.

[0365] In some embodiments, the disease is selected from the group consisting of autoimmune diseases and inflammatory diseases. In some embodiments, the disease is selected from the group consisting of autoimmune diseases, graft-versus-host disease (GVHD), large-vessel vasculitis (LVV), and asthma.

[0366] In some embodiments, the inflammatory disease is selected from the group consisting of graft-versus-host disease (GVHD), large-vessel vasculitis (LVV), and asthma. In some embodiments, the disease is an autoimmune disease.

[0367] In some embodiments, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenic purpura (ITP), and chronic spontaneous urticaria (CSU).

[0368] In some embodiments, the autoimmune disease is selected from the group consisting of 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 thrombocytopenic purpura (ITP), and chronic spontaneous urticaria (CSU).

[0369] In some embodiments, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), neuromyelitis optica spectrum disorder (NMOSD), and myasthenia gravis (MG).

[0370] In some embodiments, the autoimmune disease is SLE (systemic lupus erythematosus) or MS (multiple sclerosis). In some embodiments, the autoimmune disease is SLE (systemic lupus erythematosus). In some embodiments, the autoimmune disease is MS (multiple sclerosis).

[0371] In some embodiments, the autoimmune disease is multiple sclerosis (MS), which includes one or more indications selected from the group consisting of relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

[0372] In some embodiments, the autoimmune disease is selected from the group consisting of relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS).

[0373] In some embodiments, the autoimmune disease is relapsing multiple sclerosis (RMS). In some embodiments, the disease is a disease that can be treated by the BTK inhibitor. In some embodiments, the fact that the treatment with the BTK inhibitor is ongoing over a particular period of time means that, for at least this period of time, the BTK inhibitor is being administered essentially daily.

[0374] In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 72 hours. In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 48 hours. In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 36 hours. In some embodiments, being under ongoing treatment with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 24 hours.

[0375] In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 72 hours. In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 48 hours. In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 36 hours. In some embodiments, "ongoing treatment" with the BTK inhibitor means that the most recent administration of the BTK inhibitor was within 24 hours.

[0376] In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 20 mg to 300 mg. As will be understood by those skilled in the art, the daily dose may be administered in a single administration or in multiple administrations that together result in the complete 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.

[0377] In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 20 mg to 200 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 25 mg to 150 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 85 mg to 95 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 25 mg to 50 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 50 mg to 75 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 75 mg to 100 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 100 mg to 150 mg.

[0378] In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 100 mg to 125 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 125 mg to 150 mg. In some embodiments, the BTK inhibitor is administered in a daily dose in the range of 90 mg to 130 mg. In some embodiments, the BTK inhibitor is administered in a daily dose of about 90 mg.

[0379] As used herein, the term "about" when used in connection with a number, range, or quantity is used to mean "circa" or "approximately" that number, range, or quantity. The meaning of these terms is well known in the art and indicates that for each number, range, or quantity, variance, deviation, and / or variability, e.g., up to plus / minus 15% variance, deviation, and / or variability, is included. In some embodiments, the term "about" indicates up to plus / minus 5% variance, deviation, and / or variability.

[0380] In some embodiments, the BTK inhibitor is administered at a daily dose of 90 mg. In some embodiments, the daily dose of the BTK inhibitor is administered in a single unit dosage form. The unit dosage form may be, for example, a tablet (for oral administration) or a single injection shot (for administration by injection). Thus, if a patient is administered a daily dose of 100 mg by taking one tablet of 100 mg in the morning, this would be an administration of the daily dose in a single unit dosage form. On the other hand, if a patient is administered a daily dose of 100 mg by taking one tablet of 50 mg in the morning and one tablet of 50 mg in the evening, this would be an administration of the daily dose in two unit dosage forms.

[0381] In some embodiments, the daily dose of the BTK inhibitor is administered in two unit dosage forms, which are administered independently and together constitute the daily dose. In some embodiments, the daily dose of the BTK inhibitor is administered in two or more unit dosage forms, which are administered independently and together constitute the daily dose. In some embodiments, the daily dose of the BTK inhibitor is administered in a single unit dosage form or in two unit dosage forms that are administered independently and together constitute the daily dose.

[0382] In some embodiments, each unit dosage administered per day contains the same amount of the BTK inhibitor. In some embodiments, the unit dosage(s) is / are tablets or capsules.

[0383] In some embodiments, 65 - 85 mg of the BTK inhibitor is administered once daily. In some embodiments, 70 - 80 mg of the BTK inhibitor is administered once daily. In some embodiments, about 75 mg of the BTK inhibitor is administered once daily. In some embodiments, 75 mg of the BTK inhibitor is administered once daily. In some embodiments, the once-daily administration of the BTK inhibitor is administered in a single unit dose.

[0384] In some embodiments, 40 - 85 mg of the BTK inhibitor is administered twice daily. In some embodiments, 45 - 80 mg of the BTK inhibitor is administered twice daily. In some embodiments, about 50 - about 75 mg of the BTK inhibitor is administered twice daily. In some embodiments, 50 - 75 mg of the BTK inhibitor is administered twice daily. In some embodiments, 40 - 60 mg of the BTK inhibitor is administered twice daily.

[0385] In some embodiments, 45 - 55 mg of the BTK inhibitor is administered twice daily. In some embodiments, about 50 mg of the BTK inhibitor is administered twice daily. In some embodiments, 50 mg of the BTK inhibitor is administered twice daily. In some embodiments, 65 - 85 mg of the BTK inhibitor is administered twice daily. In some embodiments, 70 - 80 mg of the BTK inhibitor is administered twice daily.

[0386] In some embodiments, about 75 mg of the BTK inhibitor is administered twice a day. In some embodiments, 75 mg of the BTK inhibitor is administered twice a day. In some embodiments, about 45 mg of the BTK inhibitor is administered twice a day. In some embodiments, 45 mg of the BTK inhibitor is administered twice a day. In some embodiments, the twice-daily administration of the BTK inhibitor means that two single unit doses of the same amount are administered per day.

[0387] In some embodiments, the BTK inhibitor is administered in such a manner that the concentration of the BTK inhibitor in the plasma of the patient resulting from the administration is equivalent to the concentration of the BTK inhibitor in the plasma achieved when the BTK inhibitor is administered orally as a tablet according to a dosing / administration regimen as defined in any of the above embodiments.

[0388] In some embodiments, the BTK inhibitor is administered in such a manner that the concentration of the BTK inhibitor in the plasma of the patient resulting from the administration is equivalent to the concentration of the BTK inhibitor in the plasma achieved when the BTK inhibitor is administered orally as a tablet twice a day at 40 mg to 85 mg.

[0389] In some embodiments, the BTK inhibitor is administered in such a manner that the concentration of the BTK inhibitor in the plasma of the patient resulting from the administration is equivalent to the concentration of the BTK inhibitor in the plasma achieved when the BTK inhibitor is administered orally as a tablet twice a day at 40 mg to 85 mg under the condition of being given a meal.

[0390] In some embodiments, the BTK inhibitor is administered in a manner such that the therapeutic effect of the BTK inhibitor is equivalent to the therapeutic effect achieved when the BTK inhibitor is administered orally as a tablet according to a dosing / administration regimen as defined in any of the above embodiments.

[0391] In some embodiments, "administration in a manner such that" means "administration in such an amount, in such a formulation, and according to such an administration regimen". In some embodiments, the BTK inhibitor is administered with food on each occasion on which the BTK inhibitor is administered.

[0392] In some embodiments, the BTK inhibitor is administered without food on each occasion on which the BTK inhibitor is administered. In some embodiments, the BTK inhibitor is administered to a patient who has consumed food within 1 hour before the BTK inhibitor is administered.

[0393] In some embodiments, the BTK inhibitor is administered to a patient who has consumed food within 1 hour before the BTK inhibitor is administered and / or to a patient who has consumed food within 1 hour after the BTK inhibitor is administered.

[0394] In some embodiments, the BTK inhibitor is administered to a patient who has not consumed food within 1 hour before the BTK inhibitor is administered and who does not consume food within 1 hour after the BTK inhibitor is administered.

[0395] In some embodiments, the BTK inhibitor is administered orally. In some embodiments, the BTK inhibitor is administered as a tablet(s) or capsule(s). In some embodiments, the BTK inhibitor is administered as a tablet(s).

[0396] In some embodiments, the vaccination is performed by administering a vaccine. In some embodiments, the vaccination is performed by administering a vaccine to a subject / patient. In some embodiments, the patient is vaccinated by administering a vaccine to the patient.

[0397] In some embodiments, the vaccine is selected from the group consisting of an inactivated vaccine, an attenuated live vaccine, a live vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine, and a toxoid vaccine, or a combination thereof.

[0398] In some embodiments, the vaccine is selected from the group consisting of an attenuated live vaccine and a live vaccine, or a combination thereof. In some embodiments, the vaccine is an inactivated vaccine. In some embodiments, the vaccination is performed with a selected vaccine.

[0399] In some embodiments, the vaccination is performed with a vaccine selected from the group consisting of an inactivated vaccine, an attenuated live vaccine, a live vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine, and a toxoid vaccine, or a combination thereof.

[0400] In some embodiments, the vaccination is performed with a vaccine selected from the group consisting of an attenuated live vaccine and a live vaccine, or a combination thereof. In some embodiments, the vaccination is performed with a vaccine that is an inactivated vaccine.

[0401] In some embodiments, the vaccine is selected from the group consisting of an anthrax vaccine, a cholera vaccine, a diphtheria vaccine, a Haemophilus influenzae vaccine, a meningococcal meningitis vaccine, a pertussis vaccine, a plague vaccine, a pneumococcal disease vaccine, a Streptococcus pneumoniae vaccine, a tetanus vaccine, a tuberculosis vaccine, and a typhoid vaccine.

[0402] 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.

[0403] In some embodiments, the vaccine is a recombinant adjuvanted zoster vaccine. In some embodiments, the vaccine is a recombinant adjuvanted zoster vaccine comprising recombinant varicella zoster virus glycoprotein E.

[0404] In some embodiments, the vaccine is SHINGRIX®. In some embodiments, the patient is antibody-negative for varicella zoster virus, preferably antibody-negative for varicella zoster virus before vaccination and / or before initiation of the BTK inhibitor treatment.

[0405] In some embodiments, the vaccine is an influenza virus vaccine selected from the group consisting of 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.

[0406] In some embodiments, the vaccine is a quadrivalent influenza virus vaccine. In some embodiments, the vaccine is selected from the group consisting of a coronavirus vaccine, a COVID-19 vaccine, a SARS-COVID-19 vaccine, and a SARS-CoV-2 vaccine.

[0407] In some embodiments, the vaccine is a coronavirus vaccine. In some embodiments, the vaccine is a COVID-19 vaccine. In some embodiments, the vaccine is an mRNA vaccine. In some embodiments, the vaccine is not an mRNA vaccine. In some embodiments, the vaccine is a non-mRNA vaccine. In some embodiments, the vaccine is a non-mRNA COVID-19 vaccine.

[0408] In some embodiments, the vaccine is an mRNA-based vaccine. In some embodiments, the vaccine is a virus vector-based vaccine. In some embodiments, the vaccine is a protein-based vaccine. In some embodiments, the vaccine is not an mRNA-based vaccine. In some embodiments, the vaccine is an mRNA-based COVID-19 vaccine. In some embodiments, the vaccine is not an mRNA-based COVID-19 vaccine.

[0409] In some embodiments, the vaccine is the mRNA vaccine against COVID-19 of BioNTech / Pfizer, or the mRNA vaccine against COVID-19 of Moderna. In some embodiments, the vaccine is Comirnaty® of BioNTech / Pfizer or Spikevax® of Moderna, or the same vaccine distributed under a different name.

[0410] In some embodiments, the vaccine is Comirnaty® by BioNTech / Pfizer or Spikevax® by Moderna or the same vaccine. In some embodiments, the vaccine is an mRNA vaccine against COVID-19 by BioNTech / Pfizer. In some embodiments, the vaccine is Vaxzevria® / Covishield® (AstraZeneca) or the same vaccine distributed under a different name.

[0411] In some embodiments, the vaccine is Vaxzevria® (AstraZeneca) or the same vaccine. In some embodiments, the vaccine is Jcovden® (Janssen / Johnson & Johnson) or the same vaccine distributed under a different name. In some embodiments, the vaccine is Jcovden® (Janssen / Johnson & Johnson) or the same vaccine.

[0412] In some embodiments, prior to vaccination, the patient is antibody-negative for antibodies against the target antigen of the vaccination. In some embodiments, prior to vaccination, the patient is seronegative for antibodies generated in the immune response to the vaccine. In some embodiments, the antigen to which the patient is exposed during vaccination is a novel antigen to the patient.

[0413] In some embodiments, the patient's immune response to the vaccination is a de novo response. In some embodiments, prior to the vaccination, the patient is antibody - positive for antibodies against the target antigen of the vaccination. In some embodiments, prior to the vaccination, the patient is sero - positive for antibodies generated in the immune response to the vaccine.

[0414] In some embodiments, the antigen to which the patient is exposed during vaccination is a recall antigen for the patient. In some embodiments, the patient's immune response to the vaccination is a recall response. In some embodiments, the vaccine is a vaccine against an infectious disease.

[0415] In some embodiments, the infectious disease is a viral infectious disease. In some embodiments, the viral infectious disease is selected from the group consisting of 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).

[0416] In some embodiments, the hepatitis is hepatitis A and / or hepatitis B. In some embodiments, the hepatitis is hepatitis B. In some embodiments, the infectious disease is a bacterial infectious disease.

[0417] In some embodiments, the bacterial infectious disease is selected from the group consisting of anthrax infection, cholera, diphtheria, Haemophilus influenzae infection, meningococcal meningitis, whooping cough, plague, pneumococcal disease, Streptococcus pneumoniae infection, pneumococcal pneumonia, tetanus, tuberculosis, and typhus exanthematicus.

[0418] In some embodiments, the infectious disease is a coronavirus infectious disease. In some embodiments, the infectious disease is selected from the group consisting of SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and COVID-19 (coronavirus disease 2019).

[0419] In some embodiments, the infectious disease is COVID-19. In some embodiments, the infectious disease is caused by a virus belonging to the realm Riboviria. In some embodiments, the infectious disease belongs to the realm Riboviria and is caused by a virus belonging to the order Nidovirales within that realm.

[0420] In some embodiments, the infectious disease belongs to the realm Riboviria, belongs to the order Nidovirales within that realm, and is caused by a virus belonging to the family Coronaviridae within that order.

[0421] In some embodiments, the infectious disease belongs to the realm Riboviria, belongs to the order Nidovirales within that realm, belongs to the family Coronaviridae within that order, and is caused by a virus belonging to the subfamily Orthocoronavirinae within that family.

[0422] In some embodiments, the infectious disease is caused by a coronavirus. In some embodiments, the infectious disease is caused by a virus selected from the group consisting of 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).

[0423] In some embodiments, the infectious disease is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In some embodiments, the infectious disease is influenza. In some embodiments, the infectious disease is seasonal influenza. In some embodiments, the infectious disease is varicella-zoster infection. In some embodiments, the infectious disease is herpes zoster infection. In some embodiments, the infectious disease is varicella. In some embodiments, the infectious disease is shingles.

[0424] In some embodiments, the vaccine is a vaccine against an infectious pathogen. In some embodiments, the infectious disease is an infectious disease caused by an infectious pathogen. In some embodiments, the infectious disease is caused by an infectious pathogen.

[0425] In some embodiments, the infectious pathogen is a virus belonging to the realm Riboviria. In some embodiments, the infectious pathogen is a virus belonging to the realm Riboviria and the order Nidovirales. In some embodiments, the infectious pathogen is a virus belonging to the realm Riboviria, the order Nidovirales, and the family Coronaviridae. In some embodiments, the infectious pathogen is a virus belonging to the realm Riboviria, the suborder Nidovirineae, the family Coronaviridae, and the subfamily Orthocoronavirinae.

[0426] In some embodiments, the infectious pathogen is a coronavirus. In some embodiments, the infectious pathogen is a virus selected from the group consisting of 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). In some embodiments, the infectious pathogen is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0427] In some embodiments, the vaccine is selected from the group consisting of: 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, a killed virus-based SARS-CoV-2 / COVID-19 virus vaccine.

[0428] In some embodiments, the vaccine is selected from the group consisting of 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.

[0429] In some embodiments, the vaccine is an mRNA-based SARS-CoV-2 / COVID-19 virus vaccine. In some embodiments, the vaccine is Comirnaty® (manufactured by BioNTech / Pfizer) or Spikevax® (manufactured by Moderna). In some embodiments, the vaccine is Comirnaty®. In some embodiments, the vaccine is Spikevax®.

[0430] In some embodiments, the infectious pathogen is an influenza virus. In some embodiments, the infectious pathogen is an influenza virus of the HIA strain (human influenza A) or the HIB strain (human influenza B). In some embodiments, the infectious pathogen is an influenza virus of the HIA strain (human influenza A). In some embodiments, the infectious pathogen is an influenza virus of the HIA strain (human influenza A), subtype A (H1N1). In some embodiments, the infectious pathogen is an influenza virus of the HIA strain (human influenza A), subtype A (H3N2).

[0431] In some embodiments, the infectious pathogen is an influenza virus of the HIB strain (human influenza B). In some embodiments, the infectious pathogen is an influenza virus of the HIB strain (human influenza B), lineage B / Yamagata. In some embodiments, the infectious pathogen is an influenza virus of the HIB strain (human influenza B), lineage B / Victoria. In some embodiments, the infectious pathogen is the varicella-zoster virus.

[0432] In some embodiments, the vaccine is administered by intramuscular injection. In some embodiments, the vaccine is administered orally. In some embodiments, the vaccine is administered as a nasal spray.

[0433] In some embodiments, the vaccination consists of administering a single dose of the vaccine. In some embodiments, the vaccination consists of administering two separate doses of the vaccine administered on different days. In some embodiments, the vaccination consists of administering one dose of the vaccine, or two separate doses of the vaccine administered on different days. In some embodiments, the vaccination comprises administering a single dose of the vaccine, or separate doses of 2 to 6 different vaccines administered on different days. In some embodiments, administering the dose(s) of the vaccine comprises administering the dose(s) to a patient.

[0434] In some embodiments, the two doses, or the 2 to 6 doses, are each administered on different days within 1 week to 12 months. In some embodiments, the two doses, the separate doses of 2 to 6, are each administered on different days within 1 week to 6 months. In some embodiments, the two doses, the separate doses of 2 to 6, are each administered on different days within 1 to 12 weeks. In some embodiments, the two doses, the separate doses of 2 to 6, are each administered on different days within 1 to 6 weeks. In some embodiments, the two doses, the separate doses of 2 to 6, are each administered on different days within 1 to 4 weeks.

[0435] In some embodiments, the separate two doses, the separate doses of 2 to 6, are each administered on different days separated by a period of at least 2 weeks. In some embodiments, the separate two doses, the separate doses of 2 to 6, are each administered on different days separated by a period of at least 4 weeks. In some embodiments, the separate two doses are administered to a patient on different days separated by a period of at least 2 weeks.

[0436] In some embodiments, the vaccination optionally includes administration of a booster vaccination. In some embodiments, the vaccination includes administration of a booster vaccination. In some embodiments, the vaccination does not include administration of a booster vaccination. In some embodiments, administration of the vaccine optionally includes administration of a booster vaccination. In some embodiments, administration of the vaccine includes administration of a booster vaccination. In some embodiments, administration of the vaccine does not include administration of a booster vaccination.

[0437] A booster vaccination is a dose of vaccine administered to an individual who has already received a primary vaccination (or series of vaccinations). Booster vaccinations are recommended when protection from a primary vaccination wanes over time and serve to maintain or increase the protective immune response achieved by the primary vaccination. For example, after a primary vaccination against tetanus, a booster vaccination for tetanus vaccination is typically recommended every 10 years, at which point memory cells specific to tetanus lose their function or undergo apoptosis. The recommended time intervals between administration of a primary vaccination and a booster vaccination for a particular vaccine are known to physicians with expertise in each medical field and can also be obtained from the product label of the vaccine or the company that manufactures and sells the vaccine. In the case of mRNA-based COVID-19 vaccines such as Comirnaty® by BioNTech / Pfizer or Spikevax® by Moderna, a booster dose may be administered, for example, approximately 6 months after the administration of the previous COVID-19 vaccination.

[0438] In some embodiments, the booster vaccination is administered before the BTK inhibitor is administered. In some embodiments, the booster vaccination is administered after the BTK inhibitor has been administered.

[0439] In some embodiments, the booster vaccination is administered while the patient is undergoing repeated treatment with the BTK inhibitor. In some embodiments, the booster vaccination is administered while the patient is under ongoing BTK inhibitor treatment.

[0440] In some embodiments, the treatment with the BTK inhibitor lasts for at least two weeks. In some embodiments, the treatment with the BTK inhibitor lasts for at least one month. In some embodiments, the treatment with the BTK inhibitor lasts for at least two months. In some embodiments, the treatment with the BTK inhibitor lasts for at least three months. In some embodiments, the treatment with the BTK inhibitor lasts for at least six months. In some embodiments, the treatment with the BTK inhibitor lasts for at least twelve months.

[0441] Due to the fact that most of the autoimmune and other inflammatory diseases discussed herein are rarely ultimately cured and are thus of a chronic nature, the treatment period with the BTK inhibitor may extend for one year or more, typically for several years, where the BTK inhibitor is preferably administered to the patient without significant breaks or interruptions, or essentially without significant breaks or interruptions, as described above and / or below herein. However, there may be exceptional cases where the treatment period is limited as defined in the following embodiments.

[0442] In some embodiments, the treatment with the BTK inhibitor lasts for up to twelve months. In some embodiments, the treatment with the BTK inhibitor lasts for up to six months. In some embodiments, the treatment with the BTK inhibitor lasts for up to three months. In some embodiments, the treatment with the BTK inhibitor lasts for up to two months. In some embodiments, treatment with the BTK inhibitor lasts for up to one month. In some embodiments, treatment with the BTK inhibitor lasts for up to two weeks.

[0443] In some embodiments, for the duration of time that the treatment with the BTK inhibitor lasts, the patient is under continuous treatment with the BTK inhibitor without intermittent periods during which treatment with the BTK inhibitor is not performed.

[0444] In some embodiments, by administering the BTK inhibitor to the patient or subject, the patient or subject is treated for the disease. In some embodiments, by administering the BTK inhibitor to the patient or subject, the patient or subject is treated for the disease.

[0445] In some embodiments, treatment with a BTK inhibitor is performed by administering a BTK inhibitor. In some embodiments, by administering a BTK inhibitor, the patient is treated with the BTK inhibitor.

[0446] In some embodiments, at the time when the vaccination is initiated, treatment with the BTK inhibitor is ongoing for at least one week. In some embodiments, at the time when the vaccination is initiated, treatment with the BTK inhibitor is ongoing for at least two weeks. In some embodiments, at the time when the vaccination is initiated, treatment with the BTK inhibitor is ongoing for at least one month. In some embodiments, at the time when the vaccination is initiated, treatment with the BTK inhibitor is ongoing for at least two months.

[0447] In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for at least 3 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for at least 6 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for at least 12 months.

[0448] In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 12 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 6 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 3 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 2 months. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 1 month. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 2 weeks. In some embodiments, at the time when the vaccination starts, the treatment with the BTK inhibitor is ongoing for up to 1 week.

[0449] In some embodiments, the treatment with the BTK inhibitor continues for at least 1 week after the vaccination is completed. In some embodiments, the treatment with the BTK inhibitor continues for at least 2 weeks after the vaccination is completed. In some embodiments, treatment with the BTK inhibitor continues for at least 1 month after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for at least 2 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for at least 3 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for at least 6 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for at least 12 months after completion of the vaccination.

[0450] In some embodiments, treatment with the BTK inhibitor continues for up to 12 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 6 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 3 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 2 months after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 1 month after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 2 weeks after completion of the vaccination. In some embodiments, treatment with the BTK inhibitor continues for up to 1 week after completion of the vaccination.

[0451] Also disclosed with respect to the above subject matter are: [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; (b) vaccinating the patient against an infectious disease.

[0452] [2] A method for treating a disease in a patient in need thereof, the method comprising: (a) identifying a patient in need of treatment of the disease who is at risk of contracting an infectious disease; (b) vaccinating the patient at risk of contracting the infectious disease against the infectious disease, and (c) administering a BTK inhibitor to the patient.

[0453] [3] A method for treating a disease in a patient in need thereof, the method comprising: (a) identifying a patient in need of treatment of the disease who is at risk of contracting an infectious disease; (b) vaccinating the patient at risk of contracting the infectious disease against the infectious disease, and (c) treating the disease by administering a BTK inhibitor to the patient.

[0454] [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) identifying that the patient is at risk of contracting an infectious disease, and (c) vaccinating the patient against the infectious disease.

[0455] [5] A method for treating a disease in a patient in need thereof, the method comprising: (a) repeatedly administering the BTK inhibitor to the patient, thereby treating the patient for the disease; (b) identifying that the patient is at risk of contracting an infection while undergoing repeated treatment with the BTK inhibitor, and (c) vaccinating the patient against the infection during retreatment with the BTK inhibitor, and optionally, (d) continuing the repeated treatment with the BTK inhibitor.

[0456] [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 an infection, and (c) continuing to administer the BTK inhibitor to the patient.

[0457] [7] A method for treating a disease in a patient in need thereof, the method comprising: (a) optionally, administering a BTK inhibitor to the patient, (b) identifying that the patient is at risk of contracting an infection, (c) vaccinating the patient against the infection, and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered, thereby treating the patient for the disease and reducing the risk that the patient will contract the infection.

[0458] [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 under ongoing treatment with the BTK inhibitor.

[0459] [9] A method for reducing the risk that a subject will contract an infection, the method comprising: (a) Administering a BTK inhibitor to the subject, and (b) Vaccinating the subject against the infectious disease.

[0460]

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

[0461]

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

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

[0462]

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

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

[0463]

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

[0464]

[14] The method according to item

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

[0465]

[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.

[0466]

[16] The method according to any one of items

[13] to

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

[0467]

[17] A method for treating a disease in a patient in need thereof and reducing the risk of an infectious disease in the patient, the method comprising: (a) Administering a BTK inhibitor to the patient, and (b) Vaccinating the patient against the infectious disease.

[0468] A BTK inhibitor for use in the treatment of a disease by a method comprising: (a) administering the BTK inhibitor to a patient having the disease; (b) vaccinating the patient against an infectious disease.

[0469]

[19] A BTK inhibitor for use in the treatment of a disease by a method comprising: (a) identifying a patient at risk of developing an infectious disease; (b) vaccinating the patient at risk of developing the infectious disease against the infectious disease; and (c) administering the BTK inhibitor to the patient.

[0470]

[20] The BTK inhibitor for use according to item

[19] , wherein the patient is a patient having the disease.

[0471]

[21] The BTK inhibitor for use according to either

[19] or

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

[0472]

[22] A BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) administering the BTK inhibitor to a patient; (b) identifying that the patient is at risk of developing an infectious disease; and (c) vaccinating the patient against the infectious disease.

[0473]

[23] The BTK inhibitor for use according to item

[22] , wherein the patient is a patient having the disease.

[0474]

[24] The BTK inhibitor for use according to either item

[22] or

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

[0475]

[25] A BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) Repeatedly administering the BTK inhibitor to a patient, thereby treating the patient for the disease; (b) Identifying that the patient is at risk of contracting an infection while undergoing repeated treatment with the BTK inhibitor; and (c) Vaccinating the patient against the infection during re-treatment with the BTK inhibitor, and optionally (d) Continuing the repeated treatment with the BTK inhibitor.

[0476]

[26] The BTK inhibitor for use according to item

[25] , wherein the patient is a patient having the disease.

[0477]

[27] A BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) Administering the BTK inhibitor to a patient; (b) Vaccinating the patient against an infection; and (c) Continuing to administer the BTK inhibitor to the patient.

[0478]

[28] The BTK inhibitor for use according to item

[27] , wherein the patient is a patient having the disease.

[0479]

[29] The BTK inhibitor for use according to either item

[27] or

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

[0480]

[30] A BTK inhibitor for use in the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) Optionally, administering the BTK inhibitor to a patient; (b) Identifying that the patient is at risk of contracting an infection; (c) vaccinating the patient against the infectious disease, and (d) optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0481]

[31] The BTK inhibitor for use according to item

[30] , wherein the patient is a patient having the disease.

[0482]

[32] The BTK inhibitor for use according to either item

[30] or

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

[0483]

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

[0484]

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

[0485]

[35] The BTK inhibitor for use according to item

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

[0486]

[36] The BTK inhibitor for use according to either item

[34] or

[35] , wherein the method includes administering the BTK inhibitor to a patient having the disease.

[0487]

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

[0488]

[38] A BTK inhibitor for use according to item

[37] , wherein said treatment is by administration of said BTK inhibitor to a patient in need thereof, said BTK inhibitor.

[0489]

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

[37] to

[38] , wherein said vaccine is a vaccine against an infectious disease.

[0490]

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

[37] to

[39] , wherein said patient is vaccinated with said vaccine against said infectious disease.

[0491]

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

[37] to

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

[0492]

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

[37] to

[41] , wherein said treatment with said BTK inhibitor and vaccination with said vaccine are performed simultaneously or sequentially.

[0493]

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

[37] to

[42] , wherein administration of said BTK inhibitor and vaccination with said vaccine are performed simultaneously or sequentially.

[0494]

[44] A vaccine for use in the prevention of an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against said infectious disease.

[0495]

[45] A vaccine for use according to item

[44] , wherein said subject is a patient having a disease.

[0496]

[46] A vaccine for use according to item

[45] , wherein administering a BTK inhibitor to said subject is for treating said disease.

[0497]

[47] A vaccine for use in the use according to any one of items

[44] to

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

[0498]

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

[44] to

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

[0499]

[49] A vaccine for use in the prevention of an infectious disease by a method comprising vaccinating the subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor.

[0500]

[50] A vaccine for use in the use according to item

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

[0501]

[51] A vaccine for use in the use according to any one of items

[49] or

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

[0502]

[52] A vaccine for use in the use according to item

[51] , wherein the patient is a patient having the disease.

[0503]

[53] A vaccine for use in the use according to any one of items

[49] to

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

[0504]

[54] A vaccine for use in the prevention of an infectious disease by a method comprising: (a) identifying a subject at risk of contracting the infectious disease; (b) vaccinating the subject at risk of contracting the infectious disease with the vaccine against the infectious disease; and (c) administering a BTK inhibitor to the subject.

[0505]

[55] A vaccine for use as described in item

[54] , wherein the BTK inhibitor is administered for treating a disease.

[0506]

[56] A vaccine for use as described in either item

[54] or

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

[0507]

[57] A vaccine for use as described in any one of items

[54] to

[56] , wherein the BTK inhibitor is administered for treating the disease.

[0508]

[58] A vaccine for use in preventing an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, (b) vaccinating the subject with the vaccine against the infectious disease, and (c) continuing to administer the BTK inhibitor to the subject.

[0509]

[59] A vaccine as described in item

[58] , wherein the BTK inhibitor is administered for treating a disease.

[0510]

[60] A vaccine for use as described in either item

[58] or

[59] , wherein the subject is a patient having the disease.

[0511]

[61] A vaccine for use as described in any one of items

[58] to

[60] , wherein the BTK inhibitor is administered for treating the disease.

[0512]

[62] Use of a BTK inhibitor for manufacturing a medicament for treating a disease by a method comprising: (a) administering the BTK inhibitor to a patient having the disease, (b) vaccinating the patient against an infectious disease.

[0513]

[63] Use of a BTK inhibitor for manufacturing a medicament for treating a disease by a method comprising: (a) Identifying a patient at risk of developing an infection, (b) Vaccinating the patient at risk of developing the infection against the infection, and (c) Administering the BTK inhibitor to the patient.

[0514]

[64] Use according to item

[63] , wherein the patient is a patient having the disease.

[0515]

[65] Use according to either item

[63] or

[64] , wherein the BTK inhibitor is administered for treating the disease.

[0516]

[66] Use of a BTK inhibitor for the manufacture of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) Administering the BTK inhibitor to a patient, (b) Identifying that the patient is at risk of developing an infection, and (c) Vaccinating the patient against the infection.

[0517]

[67] Use according to item

[66] , wherein the patient is a patient having the disease.

[0518]

[68] Use according to either item

[66] or

[67] , wherein the BTK inhibitor is administered for treating the disease.

[0519]

[69] Use of a BTK inhibitor for the manufacture of a medicament for treating a disease, wherein the BTK inhibitor is administered as follows: (a) Repeatedly administering the BTK inhibitor to a patient so as to treat the patient for the disease, (b) Identifying that the patient is at risk of developing an infection while undergoing repeated treatment with the BTK inhibitor, and (c) Vaccinating the patient against the infection during repeated treatment with the BTK inhibitor, and optionally, (d) Continuing the repeated treatment with the BTK inhibitor.

[0520]

[70] The use according to item

[69] , wherein the patient is a patient having the disease.

[0521]

[71] Use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered as follows: (a) Administering the BTK inhibitor to a patient; (b) Vaccinating the patient against an infectious disease; and (c) Continuing to administer the BTK inhibitor to the patient.

[0522]

[72] The use according to item

[71] , wherein the patient is a patient having the disease.

[0523]

[73] The use according to any one of items

[71] or

[72] , wherein the BTK inhibitor is administered for treating the disease.

[0524]

[74] Use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease, wherein the BTK inhibitor is administered by the following method: (a) Optionally, administering the BTK inhibitor to a patient; (b) Identifying that the patient is at risk of suffering from an infectious disease; (c) Vaccinating the patient against the infectious disease; and (d) Optionally, administering the BTK inhibitor to the patient, provided that the method includes one or more treatment periods during which the BTK inhibitor is administered.

[0525]

[75] The use according to item

[74] , wherein the patient is a patient having the disease.

[0526]

[76] The use according to any one of items

[74] or

[75] , wherein the BTK inhibitor is administered for treating the disease.

[0527]

[77] Use of a BTK inhibitor for the manufacture of a medicament for the treatment of a disease by a method, wherein, while a patient having said disease is under ongoing treatment with said BTK inhibitor, said patient is vaccinated against an infectious disease, said use of the BTK inhibitor.

[0528]

[78] The use according to

[77] , wherein said method comprises administering said BTK inhibitor to a patient having said disease.

[0529]

[79] The use according to any one of items

[77] or

[78] , wherein said treatment with said BTK inhibitor comprises administering said BTK inhibitor to said patient.

[0530]

[80] Use of a vaccine for the manufacture of a medicament for preventing an infectious disease by a method comprising: (a) administering a BTK inhibitor to a subject, and (b) vaccinating the subject against said infectious disease.

[0531]

[81] The use according to item

[80] , wherein said subject is a patient having a disease.

[0532]

[82] The use according to any one of items

[80] or

[81] , wherein administering the BTK inhibitor to said subject is for treating said disease.

[0533]

[83] The use according to any one of items

[80] to

[82] , wherein administering the BTK inhibitor to said subject is for treating the disease of said subject.

[0534]

[84] The use according to any one of items

[80] to

[83] , wherein said subject is a patient in need of such treatment.

[0535] The use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising vaccinating the subject against the infectious disease, wherein the subject is vaccinated while under ongoing treatment with a BTK inhibitor, the use of said vaccine.

[0536]

[86] The use according to item

[85] , wherein the subject is a patient having a disease.

[0537]

[87] The use according to item

[86] , wherein the treatment with the BTK inhibitor is for treating the disease.

[0538]

[88] The use according to any one of items

[85] to

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

[0539]

[89] The use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) Identifying a subject at risk of contracting an infectious disease; (b) Vaccinating the subject at risk of contracting the infectious disease with the vaccine against the infectious disease; and (c) Administering a BTK inhibitor to the subject.

[0540]

[90] The use according to item

[89] , wherein the BTK inhibitor is administered for treating a disease.

[0541]

[91] The use according to any one of items

[89] or

[90] , wherein the subject is a patient having a disease.

[0542]

[92] The use according to any one of items

[89] to

[91] , wherein the BTK inhibitor is administered for treating the disease.

[0543]

[93] The use of a vaccine for the manufacture of a medicament for the prevention of an infectious disease by a method comprising: (a) Administering a BTK inhibitor to a subject; (b) vaccinating the subject with the vaccine against the infectious disease, and (c) continuing to administer the BTK inhibitor to the subject.

[0544]

[94] The use according to item

[93] , wherein the subject is a human.

[0545]

[95] The use according to either item

[93] or

[94] , wherein the BTK inhibitor is administered for treating a disease.

[0546]

[96] The use according to any one of items

[93] to

[95] , wherein the subject is a patient having a disease.

[0547]

[97] The use according to any one of items

[93] to

[96] , wherein the BTK inhibitor is administered for treating the disease.

[0548]

[98] While the patient is under ongoing BTK inhibitor treatment, the patient receives vaccination, the method according to any one of items [1] to

[17] , or the BTK inhibitor for the use according to any one of items

[18] to

[43] , or the vaccine for the use according to any one of items

[44] to

[61] , or the use according to any one of items

[62] to

[97] .

[0549]

[99] While the patient is under ongoing BTK inhibitor treatment, the vaccine is administered, the method according to any one of items [1] to

[17] or

[98] , or the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] , the vaccine for the use according to any one of items

[44] to

[61] or

[98] , or the use according to any one of items

[62] to

[98] .

[0550] The method according to any one of items [1] to

[17] or

[98] to

[99] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[99] , or the use of a vaccine for the 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.

[0551] The method according to any one of items [1] to

[17] or

[98] to

[0100] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0100] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0100] , or the use according to any one of items

[62] to

[0100] , wherein at least one dose of the vaccine is administered while the patient is under ongoing BTK inhibitor treatment.

[0552] The method according to any one of items [1] to

[17] or

[98] to

[0101] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0101] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0101] , or the use according to any one of items

[62] to

[0101] , wherein at least a part of the vaccination procedure is carried out while the patient / subject is under treatment with the BTK inhibitor.

[0553] The method according to any one of items [1] to

[17] or

[98] to

[0102] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0102] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0102] , or the use according to any one of items

[62] to

[0102] , wherein the BTK inhibitor treatment starts before the vaccination starts and continues until after the vaccination starts.

[0554]

[0104] The BTK inhibitor treatment starts before the start of the vaccination and continues until after the completion of the vaccination, and is the method according to any one of items [1] to

[17] or

[98] to

[0103] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0103] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0103] , or the use according to any one of items

[62] to

[0103] .

[0555]

[0105] The BTK inhibitor treatment starts after the start of the vaccination and before the completion of the vaccination, and continues until after the completion of the vaccination, and is the method according to any one of items [1] to

[17] or

[98] to

[0104] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0104] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0104] , or the use according to any one of items

[62] to

[0104] .

[0556]

[0106] The treatment with the BTK inhibitor starts before the administration of the vaccine and continues at least until the administration of the vaccine, and is the method according to any one of items [1] to

[17] or

[98] to

[0105] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0105] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0105] , or the use according to any one of items

[62] to

[0105] .

[0557]

[0107] Treatment with the BTK inhibitor starts before administration of the vaccine and continues until after administration of the vaccine, for the method according to any one of items [1] to

[17] or

[98] to

[0106] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0106] , or for the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0106] , or for the use according to any one of items

[62] to

[0106] .

[0558]

[0108] The BTK inhibitor is administered before, during, and after administration of the vaccine, for the method according to any one of items [1] to

[17] or

[98] to

[0107] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0107] , or for the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0107] , or for the use according to any one of items

[62] to

[0107] .

[0559]

[0109] The vaccine is administered at a time when treatment with the BTK inhibitor has started and is still ongoing, for the method according to any one of items [1] to

[17] or

[98] to

[0108] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0108] , or for the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0108] , or for the use according to any one of items

[62] to

[0108] .

[0560]

[0110] There is a temporal overlap between the vaccination procedure and the BTK inhibitor treatment, for the method according to any one of items [1] to

[17] or

[98] to

[0109] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0109] , or for the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0109] , or for the use according to any one of items

[62] to

[0109] .

[0561]

[0111] The BTK inhibitor is the one for use in the method according to any one of items [1] to

[17] or

[98] to

[0110] , or for use according to any one of items

[18] to

[43] or

[98] to

[0110] , which is administered during the vaccination, or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0110] , or the use according to any one of items

[62] to

[0110] .

[0562]

[0112] The treatment with the BTK inhibitor is started before the administration of the vaccine starts, and here, the treatment with the BTK inhibitor does not end before the administration of the vaccine starts, or ends after 4 weeks before the administration of the vaccine starts, the method according to any one of items [1] to

[17] or

[98] to

[0111] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0111] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0111] , or the use according to any one of items

[62] to

[0111] .

[0563]

[0113] The treatment with the BTK inhibitor is started before the administration of the vaccine starts, and here, the treatment with the BTK inhibitor does not end before the administration of the vaccine starts, or ends after 3 weeks before the administration of the vaccine starts, the method according to any one of items [1] to

[17] or

[98] to

[0112] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0112] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0112] , or the use according to any one of items

[62] to

[0112] .

[0564]

[0114] The method according to any one of items [1] to

[17] or

[98] to

[0113] , or the use according to any one of items

[18] to

[43] or

[98] to

[0113] , or the use according to any one of items

[44] to

[61] or

[98] to

[0113] , or the use according to any one of items

[62] to

[0113] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started, and wherein the treatment with the BTK inhibitor does not end before the administration of the vaccine is started or ends after 2 weeks before the administration of the vaccine is started.

[0565]

[0115] The method according to any one of items [1] to

[17] or

[98] to

[0114] , or the use according to any one of items

[18] to

[43] or

[98] to

[0114] , or the use according to any one of items

[44] to

[61] or

[98] to

[0114] , or the use according to any one of items

[62] to

[0114] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started, and wherein the treatment with the BTK inhibitor does not end before the administration of the vaccine is started or ends after 1 week before the administration of the vaccine is started.

[0566]

[0116] The method according to any one of items [1] to

[17] or

[98] to

[0115] , or the use according to any one of items

[18] to

[43] or

[98] to

[0115] , or the use according to any one of items

[44] to

[61] or

[98] to

[0115] , or the use according to any one of items

[62] to

[0115] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started, and from this point on, the BTK inhibitor is administered essentially daily until 4 weeks before the administration of the vaccine is started or later.

[0567]

[0117] Treatment with the BTK inhibitor is initiated before the administration of the vaccine begins, and from this point onwards, the BTK inhibitor is administered essentially daily until 3 weeks before or after the administration of the vaccine begins, the method according to any one of items [1] to

[17] or

[98] to

[0116] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0116] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0116] , or the use according to any one of items

[62] to

[0116] .

[0568]

[0118] Treatment with the BTK inhibitor is initiated before the administration of the vaccine begins, and from this point onwards, the BTK inhibitor is administered essentially daily until 2 weeks before or after the administration of the vaccine begins, the method according to any one of items [1] to

[17] or

[98] to

[0117] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0117] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0117] , or the use according to any one of items

[62] to

[0117] .

[0569]

[0119] Treatment with the BTK inhibitor is initiated before the administration of the vaccine begins, and from this point onwards, the BTK inhibitor is administered essentially daily until 1 week before or after the administration of the vaccine begins, the method according to any one of items [1] to

[17] or

[98] to

[0118] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0118] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0118] , or the use according to any one of items

[62] to

[0118] .

[0570]

[0120] The treatment with the BTK inhibitor is started before the administration of the vaccine is initiated, and from this point onwards, the BTK inhibitor is administered essentially daily until the administration of the vaccine is initiated or thereafter, for the method according to any one of items [1] to

[17] or

[98] to

[0119] , or for the use of the BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0119] , or for the use of the vaccine according to any one of items

[44] to

[61] or

[98] to

[0119] , or for the use according to any one of items

[62] to

[0119] .

[0571]

[0121] The fact that the administration is essentially daily can be that one or more doses of the BTK inhibitor are administered essentially daily, for the method according to any one of items [1] to

[17] or

[98] to

[0120] , or for the use of the BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0120] , or for the use of the vaccine according to any one of items

[44] to

[61] or

[98] to

[0120] , or for the use according to any one of items

[62] to

[0120] .

[0572]

[0122] The treatment with the BTK inhibitor is started before the administration of the vaccine is initiated, and here, the treatment with the BTK inhibitor ends after 4 weeks from the start of the administration of the vaccine, for the method according to any one of items [1] to

[17] or

[98] to

[0121] , or for the use of the BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0121] , or for the use of the vaccine according to any one of items

[44] to

[61] or

[98] to

[0121] , or for the use according to any one of items

[62] to

[0121] .

[0573]

[0123] The method according to any one of items [1] to

[17] or

[98] to

[0122] , or the use according to any one of items

[18] to

[43] or

[98] to

[0122] , or the use according to any one of items

[44] to

[61] or

[98] to

[0122] , or the use according to any one of items

[62] to

[0122] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started and, herein, the treatment with the BTK inhibitor ends within 3 weeks before the administration of the vaccine is started.

[0574]

[0124] The method according to any one of items [1] to

[17] or

[98] to

[0123] , or the use according to any one of items

[18] to

[43] or

[98] to

[0123] , or the use according to any one of items

[44] to

[61] or

[98] to

[0123] , or the use according to any one of items

[62] to

[0123] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started and, herein, the treatment with the BTK inhibitor ends within 2 weeks before the administration of the vaccine is started.

[0575]

[0125] The method according to any one of items [1] to

[17] or

[98] to

[0124] , or the use according to any one of items

[18] to

[43] or

[98] to

[0124] , or the use according to any one of items

[44] to

[61] or

[98] to

[0124] , or the use according to any one of items

[62] to

[0124] , wherein the treatment with the BTK inhibitor is started before the administration of the vaccine is started and, herein, the treatment with the BTK inhibitor ends within 1 week before the administration of the vaccine is started.

[0576]

[0126] The method according to any one of items [1] to

[17] or

[98] to

[0125] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0125] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0125] , or the method according to any one of items

[62] to

[0125] , wherein the treatment with the BTK inhibitor starts after the vaccination is started, and here, the treatment with the BTK inhibitor starts within less than 4 weeks after the vaccination is completed.

[0577]

[0127] The method according to any one of items [1] to

[17] or

[98] to

[0126] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0126] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0126] , or the use according to any one of items

[62] to

[0126] , wherein the treatment with the BTK inhibitor starts after the vaccination is started, and here, the treatment with the BTK inhibitor starts within 3 weeks after the vaccination is completed.

[0578]

[0128] The method according to any one of items [1] to

[17] or

[98] to

[0127] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0127] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0127] , or the method according to any one of items

[62] to

[0127] , wherein the treatment with the BTK inhibitor starts after the vaccination is started, and here, the treatment with the BTK inhibitor starts within 2 weeks after the vaccination is completed.

[0579]

[0129] The treatment with the BTK inhibitor starts after the vaccination is initiated, and here, the treatment with the BTK inhibitor starts within 1 week after the vaccination is completed, the method according to any one of items [1] to

[17] or

[98] to

[0128] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0128] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0128] , or the use according to any one of items

[62] to

[0128] .

[0580]

[0130] The period between the administration of the BTK inhibitor and the vaccination is less than 4 weeks, the method according to any one of items [1] to

[17] or

[98] to

[0129] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0129] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0129] , or the use according to any one of items

[62] to

[0129] .

[0581]

[0131] The period between the administration of the BTK inhibitor and the vaccination is less than 3 weeks, the method according to any one of items [1] to

[17] or

[98] to

[0130] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0130] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0130] , or the use according to any one of items

[62] to

[0130] .

[0582]

[0132] The period between the administration of the BTK inhibitor and the vaccination is less than 2 weeks, the method according to any one of items [1] to

[17] or

[98] to

[0131] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0131] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0131] , or the use according to any one of items

[62] to

[0131] .

[0583]

[0133] The method according to any one of items [1] to

[17] or

[98] to

[0132] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0132] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0132] , or the use according to any one of items

[62] to

[0132] , wherein the period between the administration of the BTK inhibitor and vaccination is less than 1 week.

[0584]

[0134] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 8 weeks for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0133] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0133] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0133] , or the use according to any one of items

[62] to

[0133] .

[0585]

[0135] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 6 weeks for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0134] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0134] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0134] , or the use according to any one of items

[62] to

[0134] .

[0586]

[0136] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 4 weeks for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0135] , or a BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0135] , or the use according to any one of items

[44] to

[61] or

[98] to

[0135] , or the use according to any one of items

[62] to

[0135] .

[0587]

[0137] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 2 weeks for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0136] , or a BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0136] , or a vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0136] , or the use according to any one of items

[62] to

[0136] .

[0588]

[0138] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted or is interrupted for less than 1 week for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0137] , or a BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0137] , or a vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0137] , or the use according to any one of items

[62] to

[0137] .

[0589]

[0139] Vaccination is carried out while the patient is under treatment with a BTK inhibitor, and the treatment with the BTK inhibitor is not interrupted for the administration of the vaccine, the method according to any one of items [1] to

[17] or

[98] to

[0138] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0138] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0138] , or the use according to any one of items

[62] to

[0138] .

[0590]

[0140] During the period when the patient is under BTK inhibitor treatment, the BTK inhibitor is administered to the patient essentially daily, the method according to any one of items [1] to

[17] or

[98] to

[0139] , or the BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0139] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0139] , or the use according to any one of items

[62] to

[0139] .

[0591]

[0141] During the period when the patient is under BTK inhibitor treatment, the BTK inhibitor is administered to the patient daily, the method according to any one of items [1] to

[17] or

[98] to

[0140] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0140] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0140] , or the method according to any one of items

[62] to

[0140] .

[0592]

[0142] During treatment with a BTK inhibitor, for the method according to any one of items [1] to

[17] or

[98] to

[0141] , or for the use of a BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0141] , or for the use of a vaccine according to any one of items

[44] to

[61] or

[98] to

[0141] , or for the use according to any one of items

[62] to

[0141] , in which the patient receives repeated administration of the BTK inhibitor, essentially every day.

[0593]

[0143] During treatment with a BTK inhibitor, for the method according to any one of items [1] to

[17] or

[98] to

[0142] , or for the use of a BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0142] , or for the use of a vaccine according to any one of items

[44] to

[61] or

[98] to

[0142] , or for the use according to any one of items

[62] to

[0142] , in which the patient receives repeated administration of the BTK inhibitor every day.

[0594]

[0144] For the method according to any one of items [1] to

[17] or

[98] to

[0143] , or for the use of a BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0143] , or for the use of a vaccine according to any one of items

[44] to

[61] or

[98] to

[0143] , or for the use according to any one of items

[62] to

[0143] , in which repeated treatment with a BTK inhibitor means administration of the BTK inhibitor essentially every day.

[0595]

[0145] For the method according to any one of items [1] to

[17] or

[98] to

[0144] , or for the use of a BTK inhibitor according to any one of items

[18] to

[43] or

[98] to

[0144] , or for the use of a vaccine according to any one of items

[44] to

[61] or

[98] to

[0144] , or for the use according to any one of items

[62] to

[0144] , in which repeated administration of the BTK inhibitor means that administration of the BTK inhibitor is essentially carried out every day.

[0596]

[0146] The method according to any one of item [5] or [7] or

[98] to

[0145] , or the BTK inhibitor for use according to any one of item

[25] to

[26] or

[30] to

[32] or

[98] to

[0145] , or the use according to any one of item

[69] to

[70] or

[74] to

[76] or

[98] to

[0145] , wherein step (d) starts less than 8 weeks after step (a) has ended.

[0597]

[0147] The method according to any one of item [5] or [7] or

[98] to

[0146] , or the BTK inhibitor for use according to any one of item

[25] to

[26] or

[30] to

[32] or

[98] to

[0146] , or the use according to any one of item

[69] to

[70] or

[74] to

[76] or

[98] to

[0146] , wherein step (d) starts less than 6 weeks after step (a) has ended.

[0598]

[0148] The method according to any one of item [5] or [7] or

[98] to

[0147] , or the BTK inhibitor for use according to any one of item

[25] to

[26] or

[30] to

[32] or

[98] to

[0147] , or the use according to any one of item

[69] to

[70] or

[74] to

[76] or

[98] to

[0147] , wherein step (d) starts less than 4 weeks after step (a) has ended.

[0599]

[0149] The method according to any one of item [5] or [7] or

[98] to

[0148] , or the BTK inhibitor for use according to any one of item

[25] to

[26] or

[30] to

[32] or

[98] to

[0148] , or the use according to any one of item

[69] to

[70] or

[74] to

[76] or

[98] to

[0148] , wherein step (d) starts less than 2 weeks after step (a) has ended.

[0600] Item [5] or [7] or

[98] to

[0149] , or a BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[0149] , or use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[0149] , wherein step (d) starts within less than one week after step (a) has ended, and the method according to any one of items [5] or [7] or

[98] to

[0149] , or a BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[0149] , or use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[0149] , wherein step (d) starts immediately after step (a) has ended.

[0601] Item [5] or [7] or

[98] to

[0150] , or a BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[0150] , or use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[0150] , wherein step (d) starts immediately after step (a) has ended, and the method according to any one of items [5] or [7] or

[98] to

[0150] , or a BTK inhibitor for use according to any one of items

[25] to

[26] or

[30] to

[32] or

[98] to

[0150] , or use according to any one of items

[69] to

[70] or

[74] to

[76] or

[98] to

[0150] , wherein step (d) starts immediately after step (a) has ended.

[0602] The method according to any one of items [1] to

[17] or

[98] to

[0151] , or a BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0151] , or a vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] , or use according to any one of items

[62] to

[0151] , wherein the subject is a human.

[0603] The method according to any one of items [1] to

[17] or

[98] to

[0152] , or a BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0152] , or a vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] , or use according to any one of items

[62] to

[0152] , wherein the patient is a human.

[0604]

[0154] For use of a BTK inhibitor for the method according to any one of items [1] to

[17] or

[98] to

[0153] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0153] , or for a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0153] , or for the use according to any one of items

[62] to

[0153] , wherein the subject / patient is an adult.

[0605]

[0155] For use of a BTK inhibitor for the method according to any one of items [1] to

[17] or

[98] to

[0154] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0154] , or for a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0154] , or for the use according to any one of items

[62] to

[0154] , wherein the subject / patient is between 18 and 75 years old.

[0606]

[0156] For use of a BTK inhibitor for the method according to any one of items [1] to

[17] or

[98] to

[0155] , or for the use according to any one of items

[18] to

[43] or

[98] to

[0155] , or for a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0155] , or for the use according to any one of items

[62] to

[0155] , wherein the patient / subject is identified as having a risk of suffering from the infectious disease by examining the patient / subject for a history of infectious diseases.

[0607] By determining one or more antibody titers that are indicators of immunity to the infectious disease in the blood, serum, or plasma of the patient / subject, the patient / subject is identified as being at risk of contracting the infection, the method according to any one of items [1] to

[17] or

[98] to

[0156] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0156] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] or

[0145] or

[0152] to

[0156] , or the use according to any one of items

[62] to

[0156] .

[0608] Identifying a patient at risk of contracting an infectious disease or identifying that a patient is at risk of contracting an infection, the step preferably includes measuring one or more antibody titers from a blood, serum, or plasma sample, the method according to any one of items [1] to

[17] or

[98] to

[0157] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0157] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0157] , or the use according to any one of items

[62] to

[0157] .

[0609]

[0159] By the method, the patient is treated for the disease, the method according to any one of items [1] to

[17] or

[98] to

[0158] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0158] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0158] , or the use according to any one of items

[62] to

[0158] .

[0610]

[0160] The method according to any one of items [1] to

[17] or

[98] to

[0159] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0159] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0159] , or the use according to any one of items

[62] to

[0159] , wherein the symptoms of the disease are alleviated by the method.

[0611]

[0161] The method according to any one of items [1] to

[17] or

[98] to

[0160] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0160] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0160] , or the use according to any one of items

[62] to

[0160] , wherein the administration of the BTK inhibitor is for treating a disease in a patient in need thereof.

[0612]

[0162] The method according to any one of items [1] to

[17] or

[98] to

[0161] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0161] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0161] , or the use according to any one of items

[62] to

[0161] , wherein the patient is treated for the disease by administering the BTK inhibitor to the patient.

[0613] The method according to any one of items [1] to

[17] or

[98] to

[0162] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0162] , wherein the symptoms of the disease are alleviated by administering the BTK inhibitor to the patient, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0162] , or the use according to any one of items

[62] to

[0162] .

[0614] The method according to any one of items [1] to

[17] or

[98] to

[0163] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0163] , wherein the patient is treated for the disease by the treatment, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0163] , or the use according to any one of items

[62] to

[0163] .

[0615] The method according to any one of items [1] to

[17] or

[98] to

[0164] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0164] , wherein the symptoms of the disease are alleviated by the treatment, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0164] , or the use according to any one of items

[62] to

[0164] .

[0616] The method according to any one of items [1] to

[17] or

[98] to

[0165] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0165] , wherein the frequency of clinical exacerbation of the autoimmune disease is reduced by the treatment, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0165] , or the use according to any one of items

[62] to

[0165] .

[0617]

[0167] By the treatment, the progression of the autoimmune disease is slowed or stopped, the method according to any one of items [1] to

[17] or

[98] to

[0166] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0166] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0166] , or the use according to any one of items

[62] to

[0166] .

[0618]

[0168] The administration of the BTK inhibitor to the patient results in the success of the treatment of the patient, the method according to any one of items [1] to

[17] or

[98] to

[0167] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0167] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0167] , or the use according to any one of items

[62] to

[0167] .

[0619]

[0169] By the method, the risk that the patient suffers from the infectious disease is reduced, the method according to any one of items [1] to

[17] or

[98] to

[0168] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0168] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0168] , or the use according to any one of items

[62] to

[0168] .

[0620]

[0170] The method according to any one of items [1] to

[17] or

[98] to

[0169] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0169] , by which prevention against the infectious disease is achieved, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0169] , or the use according to any one of items

[62] to

[0169] .

[0621]

[0171] The method according to any one of items [1] to

[17] or

[98] to

[0170] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0170] , by which the immune response of the patient against the pathogen causing the infectious disease is achieved, or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0170] , or the use according to any one of items

[62] to

[0170] .

[0622]

[0172] The method according to any one of items [1] to

[17] or

[98] to

[0171] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0171] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0171] , or the use according to any one of items

[62] to

[0171] , by which the risk that the patient contracts the infectious disease is reduced by administering the vaccine to the patient.

[0623] The method according to any one of items [1] to

[17] or

[98] to

[0172] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0172] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0172] , or the use according to any one of items

[62] to

[0172] , wherein prevention against the infectious disease is achieved by administering the vaccine to the patient.

[0624] The method according to any one of items [1] to

[17] or

[98] to

[0173] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0173] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0173] , or the use according to any one of items

[62] to

[0173] , wherein an immune response of the patient against the pathogen causing the infectious disease is achieved by administering the vaccine to the patient.

[0625] The method according to any one of items [1] to

[17] or

[98] to

[0174] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0174] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0174] , or the use according to any one of items

[62] to

[0174] , wherein the risk that the patient contracts the infectious disease is reduced by vaccinating the patient against the infection.

[0626] The method according to any one of items [1] to

[17] or

[98] to

[0175] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0175] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0175] , or the use according to any one of items

[62] to

[0175] , wherein prevention against the infection is achieved by vaccinating a patient against the infection.

[0627] The method according to any one of items [1] to

[17] or

[98] to

[0176] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0176] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0176] , or the use according to any one of items

[62] to

[0176] , wherein an immune response of a patient against a pathogen causing the infection is achieved by vaccinating the patient against the infection.

[0628] The method according to any one of items [1] to

[17] or

[98] to

[0177] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0177] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0177] , or the use according to any one of items

[62] to

[0177] , wherein complete or partial immunization against the infection is accomplished by vaccinating a patient against the infection.

[0629] The method according to any one of items [1] to

[17] or

[98] to

[0178] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0178] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0178] , or the use according to any one of items

[62] to

[0178] , wherein a patient is vaccinated against said infection to achieve complete immunization against said infectious disease.

[0630] Prevention of infection means that the subject becomes fully or partially immune to said infectious disease. The method according to any one of items [1] to

[17] or

[98] to

[0179] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0179] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0179] , or the use according to any one of items

[62] to

[0179] .

[0631] Prevention of infection means that the subject becomes fully immune to said infectious disease. The method according to any one of items [1] to

[17] or

[98] to

[0180] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0180] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0180] , or the use according to any one of items

[62] to

[0180] .

[0632]

[0182] Prevention of 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 improved (compared to a situation where such prevention has not been carried out), the method according to any one of items [1] to

[17] or

[98] to

[0181] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0181] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0181] , or the use according to any one of items

[62] to

[0181] .

[0633]

[0183] The method according to any one of items [1] to

[17] or

[98] to

[0182] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0182] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0182] , or the use according to any one of items

[62] to

[0182] , wherein the method is a method for vaccinating the subject and not a method for treating a disease.

[0634]

[0184] The method according to any one of items [1] to

[17] or

[98] to

[0183] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0183] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0183] , or the use according to any one of items

[62] to

[0183] , wherein the BTK inhibitor is selected from the group consisting of evobrutinib, trebrutinib, fenebrutinib, and remibrutinib.

[0635]

[0185] The method according to any one of items [1] to

[17] or

[98] to

[0184] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0184] , wherein the BTK inhibitor is an irreversible BTK inhibitor, or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0184] , or the method according to any one of items

[62] to

[0184] .

[0636]

[0186] The method according to any one of items [1] to

[17] or

[98] to

[0185] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0185] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0185] , or the use according to any one of items

[62] to

[0185] , wherein the BTK inhibitor is a BTK inhibitor that covalently binds to cysteine 481 of BTK.

[0637]

[0187] The method according to any one of items [1] to

[17] or

[98] to

[0186] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0186] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0186] , or the use according to any one of items

[62] to

[0186] , wherein the BTK inhibitor has been shown in clinical studies to enable the successful treatment of the disease.

[0638] The use of the BTK inhibitor in the treatment of the disease, wherein the marketing approval is granted by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA), for the method described in any of items [1] to

[17] or

[98] or

[98] to

[0187] , or for the use of a BTK inhibitor for the use described in any of items

[18] to

[43] or

[98] to

[0187] , or for the use of a vaccine for the use described in any of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0187] , or for the use described in any of items

[62] to

[0187] .

[0639] The method described in any of items [1] to

[17] or

[98] to

[0188] , or for the use of a BTK inhibitor for the use described in any of items

[18] to

[43] or

[98] to

[0188] , or for the use of a vaccine for the use described in any of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0188] , or for the use described in any of items

[62] to

[0188] , 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 a mixture in any ratio of any of the above.

[0640] The method according to any one of items [1] to

[17] or

[98] to

[0189] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0189] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0189] , or the use according to any one of items

[62] to

[0189] , 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.

[0641]

[0191] The method according to any one of items [1] to

[17] or

[98] to

[0190] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0190] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0190] , or the use according to any one of items

[62] to

[0190] , 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.

[0642]

[0192] The method according to any one of items [1] to

[17] or

[98] to

[0191] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0191] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0191] , or the use according to any one of items

[62] to

[0191] , 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.

[0643]

[0193] The method according to any one of items [1] to

[17] or

[98] to

[0192] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0192] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0192] , or the use according to any one of items

[62] to

[0192] , 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.

[0644]

[0194] The method according to any one of items [1] to

[17] or

[98] to

[0193] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0193] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0193] , or the use according to any one of items

[62] to

[0193] , 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.

[0645]

[0195] The method according to any one of items [1] to

[17] or

[98] to

[0194] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0194] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0194] , or the use according to any one of items

[62] to

[0194] , 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 thereof in any ratio.

[0646]

[0196] The method according to any one of items [1] to

[17] or

[98] to

[0195] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0195] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0195] , or the use according to any one of items

[62] to

[0195] , 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.

[0647]

[0197] The method according to any one of items [1] to

[17] or

[98] to

[0196] , or the use of the BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0196] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0196] , or the use according to any one of items

[62] to

[0196] , 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.

[0648]

[0198] The method according to any one of items [1] to

[17] or

[98] to

[0197] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0197] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0197] , or the use according to any one of items

[62] to

[0197] , wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, or a mixture thereof in any ratio.

[0649]

[0199] The method according to any one of items [1] to

[17] or

[98] to

[0198] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0198] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0198] , or the use according to any one of items

[62] to

[0198] , wherein the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof.

[0650]

[0200] The method according to any one of items [1] to

[17] or

[98] to

[0199] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0199] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0199] , or the use according to any one of items

[62] to

[0199] , wherein the BTK inhibitor is ibrutinib.

[0651] The method according to any one of items [1] to

[17] or

[98] to

[0199] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0199] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0199] , or the use according to any one of items

[62] to

[0199] , wherein the BTK inhibitor is of formula (I):

Chemical formula

[0652] The method according to any one of items [1] to

[17] or

[98] to

[0201] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0201] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0201] , or the use according to any one of items

[62] to

[0201] , wherein the BTK inhibitor is of formula (I):

Chemical formula

[0653] The method according to any one of items [1] to

[17] or

[98] to

[0202] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0202] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0202] , or the use according to any one of items

[62] to

[0202] , wherein the BTK inhibitor is of formula (I):

Chemical formula

[0654]

[0204] The method according to any one of items [1] to

[17] or

[98] to

[0203] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0203] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0203] , or the use according to any one of items

[62] to

[0203] , wherein the disease is selected from the group consisting of systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), pemphigus vulgaris (PV), Sjögren's syndrome (SJ), idiopathic thrombocytopenic purpura (ITP), chronic spontaneous urticaria (CSU), graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma.

[0655]

[0205] The method according to any one of items [1] to

[17] or

[98] to

[0204] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0204] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0204] , or the use according to any one of items

[62] to

[0204] , wherein the disease is selected from the group consisting of autoimmune diseases and inflammatory diseases.

[0656]

[0206] The method according to any one of items [1] to

[17] or

[98] to

[0205] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0205] , or the vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0205] , or the method according to any one of items

[62] to [

[0205] ], wherein the disease is selected from the group consisting of autoimmune diseases, graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma.

[0657]

[0207] The inflammatory disease is selected from the group consisting of graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma, the method according to any one of items [1] to

[17] or

[98] to

[0206] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0206] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0206] , or the use according to any one of items

[62] to

[0206] .

[0658]

[0208] The disease is an autoimmune disease, the method according to any one of items [1] to

[17] or

[98] to

[0207] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0207] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0207] , or the use according to any one of items

[62] to

[0207] .

[0659]

[0209] The autoimmune disease is selected from the group consisting of 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), the method according to any one of items [1] to

[17] or

[98] to

[0208] , or the BTK inhibitor for use according to any one of items

[18] to

[43] or

[98] to

[0208] , or the vaccine for use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0208] , or the use according to any one of items

[62] to

[0208] .

[0660]

[0210] The method according to any one of items [1] to

[17] or

[98] to

[0209] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0209] , or the use of a vaccine for the use according to any one of items

[44] to

[61] or

[98] to

[0145] or

[0152] to

[0209] , or the use according to any one of items

[62] to

[0209] , wherein the autoimmune disease is selected from the group consisting of 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), idiopathic thrombocytopenic purpura (ITP), and chronic spontaneous urticaria (CSU).

[0661]

[0211] The method according to any one of items [1] to

[17] or

[98] to

[0210] , or the use of a BTK inhibitor for the use according to any one of items

[18] to

[43] or

[98] to

[0210] , or the use of a vaccine for the use according to any one of items

[44] to...

Claims

[Claim 1] A BTK inhibitor for use in the treatment of autoimmune or inflammatory diseases, wherein the BTK inhibitor is provided by the following method: (a) Optionally administer the BTK inhibitor to the patient. (b) Identifying that the patient is at risk of contracting an infectious disease, (c) Vaccinating the patient against the infectious disease, (d) Optionally administer the BTK inhibitor to the patient. It is administered by, However, the method includes one or more treatment periods in which the BTK inhibitor is administered. Here, the inflammatory diseases are selected from the group consisting of graft-versus-host disease (GVHD), large vessel vasculitis (LVV), and asthma. And, hereof, the patient is vaccinated while the patient is undergoing ongoing BTK inhibitor treatment, or, hereof, the period between the administration of the BTK inhibitor and the vaccination is less than four weeks. The aforementioned BTK inhibitor.

Images