Methods for enhancing vaccine efficacy by administering IL-4R antagonists

Abstract

The present invention provides methods for enhancing the efficacy and / or safety of vaccines. In certain embodiments, the present invention provides methods for increasing or strengthening the immune response to a vaccine in a subject in need thereof. The methods of the present invention comprise administering to a subject in need thereof an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody, in combination with the vaccine. In certain embodiments, the methods of the present invention are used to provide enhanced protection against infectious diseases, such as whooping cough. [Selection diagram] Figure 7

Description

[Technical field]

[0001] Sequence Listing Reference This application incorporates by reference a Sequence Listing, which was filed in computer readable format as file 10209WO01-Sequence.txt, created on February 10, 2017, and contains 15,276 bytes.

[0002] The present invention relates to methods of increasing the effectiveness of a vaccine. More specifically, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist in combination with a vaccine in a subject in need thereof. [Background technology]

[0003] Vaccines are one of the most successful public health interventions in preventing disease and death due to infectious diseases. Vaccines typically contain the causative agent of the disease, its products or surrogates that act as antigens without causing disease (or in some cases, causing mild disease). For example, some current vaccines against microbial pathogens consist of live attenuated or non-pathogenic variant strains of the microorganism, or killed or otherwise inactivated organisms. Other vaccines utilize pathogen lysates such as surface carbohydrates, recombinant pathogen-derived proteins sometimes fused to other molecules, or more or less purified components of replicating viruses that produce antigens derived from the pathogen. Vaccines work by resulting in the activation of antigen-specific naive lymphocytes, which then induce an internal immune response that gives rise to antibody-secreting B cells or antigen-specific effector and memory T cells or both. This approach can result in long-lasting protective immunity that can be boosted from time to time by new exposure to the same antigenic material.

[0004] Vaccines generally contain adjuvants that help accelerate, prolong, and / or enhance antigen-specific immune responses. Some commonly used adjuvants include, but are not limited to, aluminum salts (e.g., alum, aluminum phosphate, and aluminum hydroxide), Freund's complete adjuvant, Freund's incomplete adjuvant, Ribi adjuvant, squalene, and MF59®.

[0005] There remains a need for safe and effective vaccines and / or improved vaccination strategies that enhance efficacy and provide more durable protection against pathogen exposure and challenge without causing any adverse side effects (e.g., allergic reactions). Summary of the Invention

[0006] According to certain aspects of the present invention, methods are provided for enhancing the efficacy and / or safety of a vaccine in a subject. Methods for increasing the immune response to a vaccine or increasing the duration of protective immunity of a vaccine in a subject are also included. In certain embodiments, the present invention provides methods for increasing protection against a disease in a subject and / or for preventing infection and the spread of the aforementioned disease to uninfected subjects, or for preventing the progression of a disease to another disease. The methods according to these aspects include administering an interleukin-4 receptor (IL-4R) antagonist in combination with a vaccine to a subject in need thereof. In certain embodiments, the method includes selecting a subject susceptible to a microbial infection, and administering an interleukin-4 receptor (IL-4R) antagonist in combination with a vaccine against the aforementioned microbial infection to a subject in need thereof. In certain embodiments, the IL-4R antagonist is administered before, after, or simultaneously with the vaccine in a subject in need thereof.

[0007] According to certain aspects, the present invention provides methods of preventing, treating, reducing, or ameliorating adverse side effects of a vaccine (e.g., allergic reactions) in a subject in need thereof. In certain embodiments, the present invention provides methods of preventing, reducing, or ameliorating vaccine-induced T helper 2 (Th2) responses in a subject in need thereof. In certain embodiments, the present invention provides methods of reducing vaccine-induced IgE in a subject in need thereof. Methods according to these aspects include administering an IL-4R antagonist in combination with a vaccine to a subject in need thereof.

[0008] According to certain aspects, the present invention provides a method for reducing the total number of vaccine doses, comprising administering an IL-4R antagonist in combination with the aforementioned vaccine to a subject in need thereof. In certain embodiments, the total number of vaccine doses is reduced by one or more doses, e.g., one dose, two doses, or more, compared to a subject not administered the IL-4R antagonist.

[0009] According to certain aspects, the present invention provides a method of treating atopic dermatitis in a patient without interfering with the patient's response to a vaccine. In certain embodiments, the present invention provides a method of treating atopic dermatitis in a patient without suppressing the patient's response to a vaccine. The methods according to these aspects include selecting a patient diagnosed with atopic dermatitis who has recently been or will be vaccinated with a vaccine; and administering to the patient one or more doses of an IL-4R antagonist, where the IL-4R antagonist does not reduce or attenuate the patient's response to the vaccine. In certain embodiments, administration of the IL-4R antagonist results in an improvement in one or more atopic dermatitis (AD)-related parameters selected from the group consisting of Investigator's Global Assessment (IGA); Body Surface Area Lesions of Atopic Dermatitis (BSA); Eczema Area and Severity Index (EASI); Atopic Dermatitis Assessment Score (SCORAD); 5-D Pruritus Scale; and Pruritus Numeric Rating Scale (NRS). In certain embodiments, patients with atopic dermatitis are susceptible to microbial infections, such as whooping cough, diphtheria, tetanus, tuberculosis, meningitis, etc. In certain embodiments, patients with atopic dermatitis are allergic to certain components of the vaccine or develop allergic reactions (e.g., skin reactions) to the vaccine. In certain embodiments, the patient is a child under about 3 years of age who has been diagnosed with atopic dermatitis and is in need of a vaccine against an infectious disease (e.g., whooping cough).

[0010] In certain embodiments, the vaccine is directed against Bordetella pertussis, Corynebacterium diptheriae, Clostridium tetani, Mycobacterium tuberculosis, Plasmodium spp., Bacillus anthracis, Vibrio cholera, Salmonella typhi, Borrelia spp., Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, coli, Clostridium spp., Mycobacterium leprae, Yersinia pestis, influenza virus, varicella zoster virus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), poliovirus, smallpox virus, rabies virus, rotavirus, human papillomavirus, Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, lyssavirus, measles virus, mumps virus, and rubella virus.

[0011] In certain embodiments, the vaccine is against a disease or infection selected from the group consisting of whooping cough, diphtheria, tetanus, tuberculosis, malaria, anthrax, cholera, typhoid, leprosy, Lyme disease, streptococcal infection, E. coli infection, staphylococcal infection, plague, clostridial infection, meningococcal infection, pneumococcal infection, pneumonia, meningitis, sepsis, influenza, chickenpox, HIV infection, RSV infection, polio, smallpox, rabies, rotavirus infection, papilloma, cervical cancer, Ebola, hepatitis, yellow fever, measles, mumps, and rubella infection. According to one embodiment, the vaccine is against whooping cough.

[0012] According to certain embodiments, the method of the invention comprises administering to a subject in need thereof one or more doses of an IL-4R antagonist in combination with one or more doses of a vaccine. In certain embodiments, one or more doses of an IL-4R antagonist are administered, where each dose is administered 1-12 weeks after the immediately preceding dose. In certain embodiments, each dose of an IL-4R antagonist comprises 1-50 mg / kg of the subject's body weight. In certain embodiments, each dose of an IL-4R antagonist comprises 10-600 mg of an IL-4R antagonist. In certain embodiments, each dose comprises 0.1-10 mg / kg of the subject's body weight. In certain embodiments, one or more doses of a vaccine are administered, where each dose is administered 2-24 months after the immediately preceding dose. In certain embodiments, one or more doses of a vaccine are administered at intervals of 2-15 years after the immediately preceding dose. In certain embodiments, subsequent doses of a vaccine are referred to as "booster" doses. In certain embodiments, the method comprises administering one or more doses of an IL-4R antagonist prior to each dose of the vaccine, followed by administering the IL-4R antagonist doses simultaneously with the vaccine doses. In further embodiments, the method optionally comprises administering one or more doses of an IL-4R antagonist after administering the vaccine dose.

[0013] In certain embodiments, the methods of the invention include administering an initial dose of about 10 mg to about 600 mg of an IL-4R antagonist, followed by one or more secondary doses. In certain embodiments, the initial dose and the one or more secondary doses each include about 10 mg to about 600 mg of an IL-4R antagonist. In certain embodiments, the IL-4R antagonist is administered at an initial dose of 600 mg, followed by one or more secondary doses, where each secondary dose includes 300 mg. In one embodiment, the IL-4R antagonist is administered at an initial dose of 400 mg, followed by one or more secondary doses, where each secondary dose includes 200 mg. In certain embodiments, the initial and one or more secondary doses each include 0.1 to 10 mg / kg of the IL-4R antagonist. In certain embodiments, the initial and one or more secondary doses each include 1, 2, 3, 5, or 6 mg / kg of the IL-4R antagonist. According to this aspect of the invention, the IL-4R antagonist may be administered to the subject at a dosing frequency of, for example, once per week, once per two weeks, once per three weeks, or once per four weeks. In one embodiment, each secondary dose is administered one week after the immediately preceding dose. In certain embodiments, the vaccine is administered at an initial dose followed by one or more subsequent (booster) doses, where each subsequent (booster) dose is administered 1-104 weeks after the immediately preceding dose. In certain embodiments, the one or more subsequent (booster) doses are administered 2-20 years after the immediately preceding dose.

[0014] In certain embodiments, the IL-4R antagonist is administered before, after, or simultaneously with the vaccine in a subject in need thereof. In certain embodiments, one or more doses of the IL-4R antagonist are administered before, after, or simultaneously with each dose of the vaccine. In certain embodiments, one or more doses of the IL-4R antagonist are administered before each dose of the vaccine. In certain embodiments, one or more doses of the IL-4R antagonist are administered after each dose of the vaccine. In certain embodiments, one or more doses of the IL-4R antagonist are administered before the vaccine dose, followed by an IL-4R antagonist dose administered simultaneously with the vaccine dose, optionally followed by one or more doses of the IL-4R antagonist administered after the vaccine administration.

[0015] According to certain aspects, the present invention provides a vaccination regimen in a subject, comprising administration of a vaccine starting dose, optionally followed by administration of one or more subsequent booster doses, where administration of each vaccine dose comprises administration of one or more doses of an IL-4R antagonist, followed by administration of an IL-4R antagonist dose together with said vaccine, followed by administration of one or more doses of an IL-4R antagonist. In certain embodiments, the IL-4R antagonist dose or doses are administered at weekly, biweekly, triweekly or quadrennial intervals following the immediately preceding dose.

[0016] Exemplary IL-4R antagonists that can be used in the context of the methods of the present invention include, for example, small molecule chemical inhibitors of IL-4R or its ligands (IL-4 and / or IL-13), or biologic agents that target IL-4R or its ligands. According to certain embodiments, the IL-4R antagonist is an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to the IL-4R alpha chain and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13. In one embodiment, an antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises the complementarity determining regions (CDRs) in the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair of SEQ ID NO:1 / 2. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR (HCDR1) having the amino acid sequence of SEQ ID NO: 3, an HCDR2 having the amino acid sequence of SEQ ID NO: 4, an HCDR3 having the amino acid sequence of SEQ ID NO: 5, a light chain CDR (LCDR1) having the amino acid sequence of SEQ ID NO: 6, an LCDR2 having the amino acid sequence of SEQ ID NO: 7, and an LCDR3 having the amino acid sequence of SEQ ID NO: 8. One such type of antigen-binding protein that can be used in the context of the methods of the invention is an anti-IL-4Rα antibody, such as dupilumab.

[0017] In some embodiments, the IL-4R antagonist is administered to the subject subcutaneously, intravenously, or intraperitoneally.

[0018] According to certain aspects, the present invention provides a vaccine composition comprising an adjuvant, wherein the adjuvant comprises an IL-4R antagonist. In certain embodiments, the vaccine composition further comprises a vaccine component selected from the group consisting of tetanus toxoid, diphtheria toxoid, inactivated pertussis toxin, filamentous hemagglutinin, pertactin, type 2 fimbriae, type 3 fimbriae, and formalin-inactivated respiratory syncytial virus. In certain embodiments, the vaccine composition comprises a second adjuvant (e.g., alum).

[0019] In certain embodiments, the present invention provides the use of an IL-4R antagonist of the present invention in the manufacture of a medicament for enhancing the efficacy and / or safety of a vaccine in a patient. In certain embodiments, the present invention provides the use of an IL-4R antagonist in a method for increasing the efficacy and / or safety of a vaccine, wherein the IL-4R antagonist is administered to a subject in need thereof in combination with said vaccine.

[0020] Other embodiments of the present invention will become apparent from the following detailed description. [Brief description of the drawings]

[0021] [Figure 1] 1 shows the study design, including dosing and sampling schedules, for the studies in Examples 1, 2, 3, or 4. [Diagram 2] Figures 2A and 2B show serum total IgE levels in mice immunized with either TDaP containing acellular pertussis (aP) vaccine (Figure 2A), or DTP containing whole cell pertussis (wP) vaccine (Figure 2B), and treated with isotype control antibody or with anti-mouse IL-4R antibody (anti-IL-4Rα). Results are for 4-12 mice per group. One-way ANOVA statistical analysis was performed: ***p<0.001, ****p<0.0001. [Diagram 3] Figures 3A and 3B show (Figure 3A) Filamentous hemagglutinin (FHA)-specific total IgG titers in aP-immunized mice, and (Figure 3B) heat-killed Bordetella pertussis (HKBp)-specific total IgG titers in wP-immunized mice. Results are for 4-12 mice per group. *p<0.05, ****p<0.0001. [Figure 4]Figures 4A and 4B show (Figure 4A) FHA-specific IgG1 titers in aP-immunized mice, and (Figure 4B) HKBp-specific IgG1 titers in wP-immunized mice. Results are for 4-12 mice per group. One-way ANOVA statistical analysis was performed. **p<0.01, ***p<0.001, ****p<0.0001. [Diagram 5] Figures 5A and 5B show (Figure 5A) FHA-specific IgG2a titers in aP-immunized mice, and (Figure 5B) HKBp-specific IgG2a titers in wP-immunized mice. Results are the average for 4-12 mice per group. One-way ANOVA statistical analysis was performed. **p<0.01, ***p<0.001, ****p<0.0001. [Figure 6] Figures 6A and 6B show (Figure 6A) FHA-specific IgG2c titers in aP-immunized mice, and (Figure 6B) HKBp-specific IgG2c titers in wP-immunized mice. Results are for 4-12 mice per group. One-way ANOVA statistical analysis was performed. *p<0.05, ****p<0.0001. [Figure 7] Figure 1 shows that anti-IL-4Rα treatment in aP-immunized mice enhances FHA-specific interferon-gamma (IFN-γ) production by splenocytes upon restimulation. Results are the mean values ​​for 4 mice per group. Two-way ANOVA statistical analysis was performed: ***p<0.001. [Figure 8] Figures 8A and 8B show the total number of B. pertussis colony forming units (CFU) per lung in mice immunized with either aP (Figure 8A) or two doses of wP (Figure 8B) and challenged with B. pertussis by aerosol exposure, as described in the study in Example 4. Results are the mean for 4-8 mice per group at each time point (except for the wP immunized group (B), n=3 on day 14). ***p<0.001, aP+control IgG vs. aP+anti-IL-4Rα, by two-way ANOVA. [Figure 9]1 shows the study design, including dosing and sample collection schedules, for the study in Example 5. [Figure 10] Figure 1 shows the total number of B. pertussis colony forming units (CFU) per lung in mice immunized with either one dose of aP or wP vaccine and challenged with B. pertussis by aerosol exposure as described in the study in Example 5. Results are the mean for 4 mice per group at each time point (except for the untreated group on day 7, n=3). By two-way ANOVA, ***p<0.001, aP+control IgG vs. aP+anti-IL4Ra; ΔΔΔp<0.001, aP+control IgG vs. wP+control IgG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Before the invention is described, it is to be understood that the invention is not limited to the particular methods and experimental conditions described, and as such, the methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the invention is limited only by the appended claims.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. As used herein, the term "about" when used in relation to a specific referenced numerical value means that the value may differ from the referenced value by less than 1%. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.). As used herein, the terms "treat", "treating" and the like refer to relieving symptoms, removing the cause of symptoms, either temporarily or permanently, or preventing or delaying the appearance of symptoms of the named disorder or condition.

[0024] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference and are set forth in their entirety.

[0025] General Description Bacillus pertussis is a gram-negative bacterium that causes whooping cough (also called whooping cough), a highly contagious, severe, and sometimes fatal respiratory infection in infants and young children. Whooping cough was largely controlled after the introduction of the whole cell pertussis (wP) vaccine (DTP or DPT) in 1943. The wP vaccine typically contains an inactivated (heat-killed or chemically treated, usually with formalin) suspension of the whole bacterial organism. However, the wP vaccine was found to be associated with a variety of adverse side effects, including vaccine-induced fever, febrile convulsions, and central nervous system complications. Therefore, the wP vaccine was discontinued in the United States due to such safety concerns and was completely replaced by the acellular pertussis (aP) vaccine in 1997. The aP vaccine contains inactivated pertussis toxin (PT) and one or more other bacterial components [i.e., filamentous hemagglutinin (FHA), pertactin (Pn), and fimbriae (Fim)] precipitated in alum and has been widely used in developed countries since 1990. However, since the aP vaccine replaced the wP vaccine, pertussis has re-emerged as a public health concern. Reported pertussis cases among 7-10 year olds increased from 13% to 23% of reported cases, which was as high as the 42,000 cases of pertussis reported in children in 2012 (Mills et al 2014; Trends Microbiol. 22: 49-52).

[0026] Mechanisms contributing to protective immunity have been studied for wP and aP vaccines in humans and in mouse models. The immune responses observed with wP vaccines are very similar to those of naturally infected individuals or challenged mice. wP induces a T helper 1 (Th1) response (i.e., influx of neutrophils and production of IL-1, IL-12) (Redhead et al 1993, Infect. Immun. 61: 3190-8; Ross et al 2013, PLoS Pathog 9(4): e1003264.doi:10.1371 / journal.ppat.1003264). However, wP also induces IgE formation and allergic reactions. On the other hand, aP vaccines have a well-defined T helper 2 (Th2) response both in humans and in preclinical mouse models, where the Th2 response is induced via IL-4 production (Mills et al 1998, Infect. Immun. 66: 596-602). Subsequent studies have shown that Th2 responses are not essential for protective immunity in humans and mouse models, and that wP vaccines and prior infections are better than current aP vaccines in terms of acquired protective immunity because they induce Th1 responses (Ross et al 2013, PLoS Pathog 9(4): e1003264.doi:10.1371 / journal.ppat.1003264; Brummelman et al 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067). The aP vaccine fails to generate effective immunological memory, which leads to fading of protective immunity. In addition, the Th2 response induced by the aP vaccine leads to undesirable IgE and rare hypersensitivity reactions observed in children with the 4th or 5th booster dose (Brummelman et al 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067).Furthermore, antigenic variation has been observed in pertussis toxin, pertactin and fimbriae, which leads to loss of protection against some currently circulating strains (Brummelman et al 2015, FEMS Pathog. Dis. doi: 10.1093 / femspd / ftv067).

[0027] A novel animal model of experimental pertussis in baboons revealed a major deficit in protective immunity induced by aP vaccination (Warfel et al 2014, PNAS 111: 787). Studies showed that animals with previous infection were not colonized after aerosolized challenge, while the wP vaccine prevented disease and enhanced bacterial clearance compared to naive animals. In contrast, the aP vaccine produced a suboptimal immune response that prevented disease in vaccinated baboons but failed to prevent infection or transmission to naive baboons.

[0028] Various molecules, such as cytokines such as IL-1, IL-12 and GM-CSF, as well as Toll-like receptor agonists, have been investigated as potential adjuvants to increase the immunogenicity and duration of immunity provided by aP vaccines (Dunne et al 2015, Mucosal Immunol. 8: 607-17; Allen & Mills 2014, Expert Rev. Vaccines 13: 1253-64). There remains an unmet need for improved vaccine compositions and vaccination strategies to prevent Bordetella pertussis infection and transmission. The inventors herein show that administration of an IL-4R antagonist (e.g., an anti-IL-4R antibody) together with an aP vaccine results in the production of more Th1-type antigen-specific IgG isotype antibodies (e.g., IgG2a and b / c in mice, or IgG1 in humans), and a reduction in IgE and Th2-type antigen-specific IgG isotype antibodies (e.g., IgG1 in mice, or IgG4 in humans), thereby providing better protection in response to pathogen challenge. More generally, as shown herein, administration of an IL-4R antagonist (e.g., an anti-IL-4R antibody) as an adjuvant in combination with a vaccine results in a Th1 response instead of a Th2 response, thereby ensuring better efficacy of the vaccine and / or preventing adverse side effects of the vaccine (e.g., allergic reactions).

[0029] Methods for enhancing the efficacy and / or safety of vaccines The present invention includes a method comprising administering to a subject in need thereof a vaccine in combination with a pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition comprising an IL-4R antagonist comprises a pharma- ceutical acceptable carrier or excipient. In certain embodiments, the IL-4R antagonist is administered before, after and / or simultaneously with the vaccine.

[0030] As used herein, the expression "subject in need thereof" refers to a human or non-human animal susceptible to and / or in need of prophylactic protection from a microbial (e.g., bacterial or viral) infection. In the context of the present invention, the term "subject" includes subjects susceptible to an infection selected from the group consisting of whooping cough, diphtheria, tetanus, tuberculosis, malaria, anthrax, cholera, typhoid, leprosy, Lyme disease, streptococcal infection, E. coli infection, staphylococcal infection, plague, clostridial infection, meningococcal infection, pneumococcal infection, pneumonia, meningitis, sepsis, influenza, chickenpox, HIV infection, RSV infection, polio, smallpox, rabies, rotavirus infection, papilloma, cervical cancer, Ebola, hepatitis, yellow fever, measles, mumps and rubella infection.

[0031] In some embodiments, the term "subject" includes children who are 3 years old or younger. For example, the method may be used for infants who are less than 1 month, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months old. In other embodiments, the method of the present invention may be used to treat children who are about 1 year old, less than 1 year old, less than 2 years old, less than 3 years old, less than 4 years old, less than 5 years old, less than 6 years old, less than 7 years old, less than 8 years old, less than 9 years old, less than 10 years old, less than 11 years old, less than 12 years old, less than 13 years old, less than 14 years old, or less than 15 years old. In certain embodiments, the method of the present invention may be used to treat adolescents who are about 15 years old, about 16 years old, about 17 years old, about 18 years old, about 19 years old, about 20 years old, or less than 20 years old.

[0032] In certain embodiments, the term "subject" includes adults who are over 50, over 55, over 60, over 65, over 70, or over 75 years of age.

[0033] In certain embodiments, the term "subject" includes adults who are over 20, over 25, over 30, over 35, over 40, over 45, or over 50 years of age. In certain embodiments, the adults have not been previously immunized with a vaccine, such as a tetanus vaccine, a diphtheria vaccine, or a pertussis vaccine.

[0034] In certain embodiments, the term "subject" includes adults or adolescents over 10 years of age who have been immunized with a vaccine but do not need to receive a booster dose of the vaccine. In certain embodiments, the term includes adults who may have been previously immunized but who have developed compromised immunity to an infectious disease and need to receive an additional vaccine dose (e.g., a booster dose). In certain embodiments, the term "subject" includes subjects who are allergic to one or more components of the vaccine. In further embodiments, the term includes subjects who may be at increased risk of developing an allergic response to the vaccine.

[0035] In certain embodiments, the present invention provides a method of enhancing the efficacy and / or safety of a vaccine comprising administering to a subject in need thereof one or more doses of the aforementioned vaccine in combination with one or more doses of an IL-4R antagonist.

[0036] In certain embodiments, the present invention provides a method of enhancing or potentiating the immune response to a vaccine comprising administering to a subject in need thereof one or more doses of the aforementioned vaccine in combination with one or more doses of an IL-4R antagonist.

[0037] As used herein, the term "enhancing the efficacy and / or safety of a vaccine" refers to the increased protection and / or increased duration of protection provided by administration of a vaccine in combination with an IL-4R antagonist against a subsequent pathogen challenge compared to administration of the vaccine alone. In certain embodiments, the term includes one or more of the following: (a) prevention of disease caused by pathogenic bacteria or viruses; (b) reduced bacterial or viral titers in infected hosts or reduced pathogen load in infected hosts; (c) faster clearance of pathogens from infected hosts; (d) increased production of pathogen-specific Th1-type IgG isotype titers; (e) reduced or abrogated allergic responses resulting from vaccine administration; (f) reduced or suppressed production of serum IgE in hosts resulting from vaccine administration; (g) reduction in Th2 responses; (h) reduced production of pathogen-specific Th2-type IgG isotype titers; (i) reduction in the total number of vaccine doses required for protection; (j) prevention of pathogen infection and transmission and / or infectious disease; and / or (k) long-lasting (durable) resistance to subsequent pathogen load, compared to subjects administered the vaccine alone. In certain embodiments, the term includes enhancing the safety of the vaccine. In certain embodiments, the term includes prevention or reduction or abrogation of one or more IgE-mediated responses to a vaccine, including but not limited to urticaria, angioedema, anaphylaxis, gastrointestinal disorders, and discontinuation of a booster dose of a vaccine that causes a suboptimal immune response to the vaccine. In one aspect, the invention provides a method of generating an optimal immune response to a vaccine in a subject, comprising administering to a subject in need thereof an IL-4R antagonist in combination with a vaccine.

[0038] According to one aspect, the present invention provides a method for preventing infection and / or transmission of infectious disease to a subject.In certain embodiments, the present invention provides a method for increasing herd immunity in a population susceptible to infectious disease.The method according to this aspect comprises administering an IL-4R antagonist in combination with a vaccine to a subject in need thereof.

[0039] In certain embodiments, the present invention provides a method for preventing, treating, or reducing or ameliorating the severity of adverse side effects induced by administration of a vaccine in a subject in need thereof. Adverse side effects induced by a vaccine include, but are not limited to, injection site reactions, allergic reactions, localized swelling, swollen lymph nodes, and hypersensitivity. In certain specific embodiments, the present invention provides a method for preventing, treating, or reducing or reducing the severity of allergic responses induced by administration of a vaccine in a subject in need thereof. As used herein, the phrases "allergic response", "allergic reaction", "allergic symptoms", and the like include one or more signs or symptoms selected from the group consisting of urticaria (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, reduced peak expiratory flow (PEF), gastrointestinal disorders, flushing, swollen lips, swollen tongue, reduced blood pressure, anaphylaxis, and organ damage / failure. "Allergic response", "allergic reaction", "allergic symptoms" and the like also include immunological responses and reactions, such as, for example, increased Th2 response, increased IgE production and / or increased allergen-specific immunoglobulin production. As used herein, the term "reducing an allergic response" refers to the absence of an allergic response or a reduction in the severity of an allergic response.

[0040] In certain embodiments, the present invention includes a method of reducing serum total IgE levels induced by administration of a vaccine, comprising administering one or more doses of a vaccine in combination with one or more doses of an IL-4R antagonist. As used herein, a reduction in serum IgE levels means that the amount of IgE measured in the serum of a subject administered the vaccine and treated with an IL-4R antagonist is at least 5%, 10%, 20%, 50%, 80%, or 90% lower than the serum IgE levels measured in the same or comparable subject not treated with an IL-4R antagonist. In certain embodiments, a reduction in serum IgE levels means that no or negligible amounts of IgE are detected in the serum of the subject. As used herein, serum IgE may include total serum IgE and / or antigen-specific IgE (e.g., allergen-specific IgE).

[0041] In certain embodiments, the present invention provides a method of reducing a Th2 response induced upon administration of a vaccine in a subject in need thereof, comprising administering one or more doses of a vaccine in combination with one or more doses of an IL-4R antagonist. In certain embodiments, reducing a Th2 response includes, but is not limited to, a reduction in vaccine-induced serum IgE levels and / or reduced production of pathogen-specific Th2-type IgG isotype titers (e.g., IgG1 in mice, or IgG4 in humans).

[0042] The present invention includes a method for reducing the susceptibility of a subject to an allergic response to a vaccine. As used herein, the term "subject" refers to a subject with increased susceptibility or at higher risk of developing an allergic response, such as a subject with atopic dermatitis. In this embodiment, the term "subject" includes a subject with atopic dermatitis, a subject with higher allergen sensitization, and a subject with allergic rhinitis, asthma, or food allergy. In certain embodiments, the present invention includes a method for reducing the toxicity associated with vaccine administration in a patient with atopic dermatitis, comprising administering one or more doses of an IL-4R antagonist in combination with the aforementioned vaccine. The term "subject" also includes a subject with elevated levels of serum total and allergen-specific IgE, or serum chemokines (e.g., CCL17 or CCL27).

[0043] According to certain aspects, the present invention includes a method of increasing the duration of vaccine-induced immunity in a subject in need thereof. It is known in the art that some vaccines, e.g., acellular pertussis vaccines, show shorter duration of protection, thereby requiring regular booster doses in subjects such as older children, adolescents, adults, or the elderly. These booster doses result in undesirable hypersensitivity reactions in the subject. Thus, in certain embodiments, the present invention provides a method of reducing the total number of booster doses required to provide protection against pathogen load in a subject. The method according to this aspect includes administering the vaccine in combination with a pharmaceutical composition comprising an IL-4R antagonist. The methods disclosed herein induce similar or better immune protection against pathogen load even with reduced doses of vaccine. In certain embodiments, the present invention provides a method of reducing the total number of vaccine doses by one or more doses, e.g., one dose, two doses, three doses, or more, compared to a subject not administered an IL-4R antagonist. In a particular embodiment, administration of one dose of a vaccine in combination with one or more doses of an IL-4R antagonist is at least as effective as two doses of a vaccine without an IL-4R antagonist. In another embodiment, administration of one or two doses of a vaccine in combination with one or more doses of an IL-4R antagonist is at least as effective as three doses of a vaccine without an IL-4R antagonist.

[0044] The method of the present invention according to certain embodiments comprises administering to a subject a vaccine in combination with an IL-4R antagonist. As used herein, the expression "in combination with" means that the vaccine is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. The term "in combination with" also includes sequential or concomitant administration of an IL-4R antagonist and a vaccine.

[0045] For example, when administered "before" administration of a vaccine, the IL-4R antagonist may be administered about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week before administration of the vaccine. In certain embodiments, the IL-4R antagonist may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the vaccine. When administered "after" administration of a vaccine, the pharmaceutical composition comprising the IL-4R antagonist may be administered about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks after administration of the vaccine. In certain embodiments, the IL-4R antagonist may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the vaccine. "Concurrent" or "concomitant" administration with the vaccine means that the IL-4R antagonist is administered to the subject in a separate dosage form less than 10 minutes after (before, after, or at the same time as) administration of the vaccine, or is administered to the subject as a single combined dosage formulation including both the vaccine and the IL-4R antagonist.

[0046] The present invention includes a method for increasing the efficacy and / or safety of a vaccine, comprising administering the above-mentioned vaccine in combination with an effective amount of a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in multiple doses, for example, as part of a specific vaccination regimen.For example, the vaccination regimen may include administering multiple doses of the pharmaceutical composition to the subject about once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, or less frequently, followed by one or more doses of the vaccine.

[0047] In certain embodiments, each dose of the IL-4R antagonist comprises 1-50 mg / kg of subject's body weight, hi certain embodiments, each dose of the IL-4R antagonist comprises 10-600 mg of the IL-4R antagonist.

[0048] In a related aspect, the invention provides a vaccination regimen in a subject comprising administration of one or more doses of an IL-4R antagonist, followed by administration of a dose of the IL-4R antagonist concomitantly with the vaccine, optionally followed by administration of one or more doses of the IL-4R antagonist. In certain embodiments, the vaccination regimen comprises administration of 1-10 weekly doses of the IL-4R antagonist, followed by administration of a dose of the IL-4R antagonist concomitantly with the vaccine, followed by administration of 1-3 weekly doses of the IL-4R antagonist. In certain embodiments, the vaccination regimen comprises one or more booster doses of the vaccine. In further embodiments, each booster dose of the vaccine is administered following one or more doses of the IL-4R antagonist.

[0049] Methods for Treating Atopic Dermatitis According to certain aspects, the present invention provides a method of treating atopic dermatitis (AD) in a patient without interfering with the patient's response to a vaccine. In certain embodiments, the present invention provides a method of treating AD in a patient without suppressing the patient's response to a vaccine. In certain embodiments, the present invention provides a method of treating AD in a patient susceptible to microbial infections and / or in need of a vaccine against an infectious disease. The method according to this aspect comprises administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. In certain embodiments, the method comprises selecting a patient diagnosed with atopic dermatitis who has recently been or will be vaccinated with a vaccine, and administering to the patient one or more doses of an IL-4R antagonist, wherein the IL-4R antagonist does not reduce or attenuate the patient's response to the vaccine. As used herein, the term "patient response to a vaccine" refers to a protective immune response to the vaccine in a patient. In the context of the present invention, the term refers to the level of antibodies produced in a patient with AD who has been or has not been treated with dupilumab. As used herein, the phrase "patient in need thereof" refers to a human animal that exhibits one or more symptoms or signs of atopic dermatitis and / or has been diagnosed with atopic dermatitis. In certain embodiments, the methods of the present invention may be used to treat patients that exhibit elevated levels of one or more biomarkers associated with AD (e.g., IgE). Biomarkers associated with AD are described in U.S. Publication No. 20140072583, which is incorporated herein in its entirety. For example, the methods of the present invention include administering an IL-4R antagonist to a patient with elevated levels of IgE or TARC or periostin.In the context of the present invention, a "patient in need thereof" may include, for example, a patient who, prior to treatment, exhibits (or has exhibited) one or more AD-associated parameters, such as, for example, elevated IGA, BSA, EASI, SCORAD, 5D-pruritus, and / or NRS scores, and / or elevated levels of one or more AD-associated biomarkers, such as, for example, IgE and / or TARC. In certain embodiments, a "subject in need thereof" may include a subset of a population that may be susceptible to AD or exhibit elevated levels of AD-associated biomarkers. For example, a "subject in need thereof" may include a subset of a population defined by race or ethnicity present in the population.

[0050] In some embodiments, the method herein may be used to treat AD in children who are 1 year old or younger. For example, the method may be used to treat infants who are less than 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or less than 12 months. In other embodiments, the method may be used to treat children and / or adolescents who are 18 years old or younger. For example, the method may be used to treat children or adolescents who are less than 17 years old, less than 16 years old, less than 15 years old, less than 14 years old, less than 13 years old, less than 12 years old, less than 11 years old, less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, or less than 2 years old. In certain embodiments, the method may be used to treat AD in children who need vaccines against infectious diseases (e.g., whooping cough, diphtheria, tuberculosis, RSV, measles, mumps, and rubella).

[0051] In certain embodiments, a patient in need thereof is an adult with AD and over 20 years of age who may require a booster dose of the vaccine.

[0052] As used herein, "atopic dermatitis (AD)" refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and by scaly and dry eczema lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. The present invention encompasses methods of treating patients with mild, moderate to severe, or severe AD. As used herein, "moderate to severe AD" is characterized by extensive, extremely pruritic skin lesions that are often exacerbated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. In many cases, chronic lesions include thickened patches of skin, lichenification, and fibrous papules. Patients affected by moderate to severe AD also generally have more than 20% of the affected body skin, or 10% of the skin area, in addition to the improvement of eye, hand and body wrinkles.Moderate to severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids.Patients may also be described as having moderate to severe AD when they are resistant or refractory to treatment with either topical corticosteroids or calcineurin inhibitors or any other commonly used therapeutic agent known in the art.Patients with moderate to severe or severe AD may also show further progression or relapse of the disease.

[0053] The present invention includes a method of treating AD in patients who are resistant, unresponsive or inadequately responsive to treatment with topical corticosteroids (TCS) or calcineurin inhibitors. As used herein, the term "resistant, unresponsive or inadequately responsive to TCS or calcineurin inhibitors" refers to subjects or patients with AD treated with TCS or calcineurin inhibitors, where the TCS / calcineurin inhibitors have no therapeutic effect. In some embodiments, the term refers to reduced patient compliance and / or toxicity and side effects and / or ineffectiveness of TCS / calcineurin inhibitors administered to reduce, ameliorate or reduce symptoms of AD. In some embodiments, the term refers to patients suffering from moderate to severe AD who are refractory to treatment with TCS / calcineurin inhibitors. In some embodiments, the term refers to patients with AD that is not controlled despite treatment with TCS and / or calcineurin inhibitors. In some embodiments, a patient who is "resistant, unresponsive or insufficiently responsive to TCS or calcineurin inhibitor" may not show improvement in one or more parameters associated with AD. Examples of parameters associated with AD are described elsewhere herein. For example, treatment with TCS / calcineurin inhibitor may not result in a decrease in pruritus or EASI score or BSA score. In some embodiments, the present invention includes a method of treating moderate to severe AD in a patient who has been previously treated with TCS / calcineurin inhibitor for one month or more and does not show a decrease in one or more parameters associated with AD. For example, the method may be used to treat a patient with chronic AD who is on a stable TCS / calcineurin inhibitor dosing regimen and has a BSA score of 10% or more or an IGA score of 3 or more.

[0054] In certain embodiments, the present invention provides a method in which administration of an IL-4R antagonist results in an improvement in one or more parameters associated with AD. Examples of "parameters associated with AD" include (a) Investigator's Global Assessment (IGA); (b) Atopic Dermatitis Body Surface Area Lesions (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Pruritus Numeric Rating Scale (NRS). Parameters associated with AD are described in US Publication No. 20140072583, which is incorporated herein in its entirety. "Improvement in parameters associated with AD" refers to a decrease from baseline in one or more of IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, or NRS. As used herein, the term "baseline" refers to the numerical value of a parameter associated with AD for a subject prior to or at the time of administration of a pharmaceutical composition of the present invention with respect to a parameter associated with AD.

[0055] To determine whether a parameter associated with AD has been "improved," the parameter is quantified at baseline and at one or more time points following administration of a pharmaceutical composition of the invention. For example, parameters associated with AD may be measured at the end of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 85th day; or at the end of the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th week or more after an initial treatment with a pharmaceutical composition of the invention. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the parameter associated with AD.

[0056] Interleukin-4 receptor antagonist The method of the present invention includes administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor", "IL-4Rα antagonist", "IL-4R blocker", "IL-4Rα blocker", etc.) is any agent that binds to or interacts with IL-4Rα or IL-4R ligand, and any agent that inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptor. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 13. Type 1 IL-4 receptor is a dimeric receptor that includes an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor that includes an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, while type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that can be used in the methods of the present invention may function by blocking signal transduction mediated by IL-4, signal transduction mediated by IL-13, or signal transduction mediated by both IL-4 and IL-13. Thus, the IL-4R antagonists of the present invention may prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptors.

[0057] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor bodies" (e.g., engineered molecules that contain the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0058] Anti-IL-4Rα antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains linked together by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region is made up of three domains, C H 1. C H 2 and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further divided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). H and V L consists of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to the human germline sequence or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a comparative analysis of two or more CDRs.

[0059] As used herein, the term "antibody" also includes antigen-binding fragments of complete antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived, for example, from complete antibody molecules using any suitable standard technique, such as proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated by using chemical or molecular biology techniques, for example, to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0060] Non-limiting examples of antigen-binding fragments include (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) a minimal recognition unit consisting of amino acid residues mimicking a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetraspecific antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed within the expression "antigen-binding fragment" as used herein.

[0061] An antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame with one or more framework sequences. L Domain and Related V H In an antigen-binding fragment having a domain, H and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer and may have a V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a dimer of monomeric V H or V L It may contain domains.

[0062] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the invention include: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -C H 2;(x)VL -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any arrangement of the variable and constant domains, including any of the exemplary arrangements listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be linked to each other and / or to one or more monomeric V H or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association (eg, via disulfide bonds) between the domains.

[0063] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies will typically contain at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format may be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present invention using routine techniques available in the art. For example, the present invention includes methods that include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present invention include, for example, scFv-based or antibody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob-into-hole, common light chain (such as common light chain with knob-into-hole), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include, but are not limited to, bispecific formats (for a review of the aforementioned formats, see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, where unnatural amino acids with orthogonal chemical reactivity are used to create site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0064] The antibody used in the method of the present invention may be a human antibody. As used herein, the term "human antibody" is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibody of the present invention may include amino acid residues (e.g., mutations induced by in vitro random or site-specific mutagenesis or by in vivo somatic mutations), e.g., in CDRs and in particular CDR3, that are not encoded by human germline immunoglobulin sequences. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, are grafted onto human framework sequences.

[0065] The antibody used in the method of the present invention may be a recombinant human antibody. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector introduced into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created, or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), which results in the V H and V L The amino acid sequence of the region is H and V LWhile derived from and related to the sequence, it is a sequence that may not naturally occur within the human antibody germline repertoire in vivo.

[0066] According to certain embodiments, the antibody used in the method of the present invention specifically binds to IL-4Rα. The term "specifically binds" and the like means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4Rα, as used in the context of the present invention, has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM as measured in a surface plasmon resonance assay. D An isolated antibody that specifically binds human IL-4Rα may, however, have cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0067] According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4Rα antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies described in U.S. Patent No. 7,608,693. In certain exemplary embodiments, an anti-IL-4Rα antibody or an antigen-binding fragment thereof that can be used in the context of the methods of the present invention comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO:1 and a LCVR comprising SEQ ID NO:2. According to certain exemplary embodiments, the methods of the invention comprise the use of an anti-IL-4R antibody (referred to as "dupilumab" and known in the art) comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence of SEQ ID NOs:3-4-5-6-7-8, or a biological equivalent thereof. In certain embodiments, the methods of the invention involve the use of an anti-IL-4R antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is the fully human anti-IL-4R antibody known as dupilumab.According to certain exemplary embodiments, the method of the present invention includes the use of dupilumab, or a biological equivalent thereof. As used herein, the term "biological equivalent" refers to an anti-IL-4R antibody or an IL-4R binding protein or a fragment thereof that is a pharmaceutical equivalent or pharmaceutical alternative whose rate and / or degree of absorption is not significantly different from that of dupilumab when administered in single or multiple doses at the same molar dose under similar experimental conditions. In the context of the present invention, the term refers to an antigen binding protein that binds to IL-4R that does not have a clinically meaningful difference from dupilumab in their safety, purity and / or potency.

[0068] In certain specific embodiments, the methods of the invention comprise the use of an anti-mouse anti-IL-4R antibody or antigen-binding fragment thereof comprising the HCVR sequence of SEQ ID NO: 11 and the LCVR sequence of SEQ ID NO: 12. In an exemplary embodiment, the methods of the invention comprise the use of an anti-mouse anti-IL-4R antibody in increasing the efficacy and / or safety of a pertussis vaccine in a Bordetella pertussis aerosol-challenged mouse model.

[0069] In certain specific embodiments, the methods of the invention comprise the use of an anti-monkey anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising the HCVR sequence of SEQ ID NO: 14 and the LCVR sequence of SEQ ID NO: 15. In an exemplary embodiment, the methods of the invention comprise the use of an anti-monkey anti-IL-4R antibody in increasing the efficacy and / or safety of a pertussis vaccine in a clinically relevant juvenile baboon model.

[0070] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, the antibody referred to as AMG317 and known in the art (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or any of the anti-IL-4Rα antibodies described in U.S. Pat. No. 7,186,809, U.S. Pat. No. 7,605,237, U.S. Pat. No. 7,608,693, or U.S. Pat. No. 8,092,804.

[0071] The anti-IL-4Rα antibody used in the context of the method of the present invention may have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibody for use in the method of the present invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibody of the present invention may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. The expression "neutral pH" as used herein means a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0072] In certain instances, "reduced binding to IL-4R at acidic pH compared to neutral pH" refers to the K D K values ​​for antibody binding to IL-4Rα at acidic pH D For example, an antibody or antigen-binding fragment thereof may be expressed in terms of a ratio of values ​​(or vice versa). DA ratio of about 3.0 or greater may be considered for purposes of the present invention to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0073] Antibodies with pH-dependent binding characteristics may be obtained by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level may result in an antibody with pH-dependent characteristics. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues, an antibody with reduced antigen binding at acidic pH compared to neutral pH may be obtained. As used herein, the expression "acidic pH" refers to pH 6.0 or less.

[0074] Pharmaceutical Compositions The present invention includes a method comprising administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical composition of the present invention is formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, etc. A large number of suitable formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, a formula known to all pharmacists. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cationic or anionic) containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0075] The dose of the antibody administered to the patient according to the method of the present invention may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is typically calculated by body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies may be empirically determined; for example, patient progress can be monitored by periodic evaluation, and the dose can be adjusted accordingly. Furthermore, inter-species adjustments of the dosage can be made using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Certain exemplary doses of anti-IL4R antibodies and administration regimens, including the same, that can be used in the context of the present invention are disclosed elsewhere herein.

[0076] A variety of delivery systems are known and can be used to administer pharmaceutical compositions containing IL-4R antagonists, such as encapsulation in liposomes, microparticles, microcapsules, mutant viruses, recombinant cells capable of expressing receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous layers (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other biologically active agents.

[0077] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, for subcutaneous delivery, a pen delivery device is easily applied in delivering the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a container within the device. Once the container is emptied of the pharmaceutical composition, the entire device is discarded.

[0078] A number of reusable pen and autoinjector delivery devices have application in the subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic), to name just a few. These and other injectable pens include, but are not limited to, the HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Company, Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices having application in subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the SOLOSTAR™ Pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ Pen (Abbott Laboratories, Abbott Park, Ill.), to name just a few.

[0079] In certain circumstances, pharmaceutical compositions can be delivered in controlled release systems. In one embodiment, pumps can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed close to the target of the composition, thereby requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0080] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared by dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous or oily medium that is usually used for injections. The aqueous medium for injection includes, for example, physiological saline, an isotonic solution containing glucose and an auxiliary, which may be used in combination with a suitable solubilizer such as alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. The oily medium includes, for example, sesame oil, soybean oil, etc., which may be used in combination with a solubilizer such as benzyl benzoate, benzyl alcohol, etc. The injection drug prepared in this way can be filled into a suitable ampule.

[0081] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms with unit doses corresponding to the dose of the active ingredient. Such dosage forms with unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0082] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present invention are disclosed, for example, in US Pat. No. 8,945,559.

[0083] Vaccine Compositions In certain embodiments, the present invention provides a vaccine composition comprising a vaccine adjuvant, wherein the vaccine adjuvant comprises an IL-4R antagonist. As used herein, the term "adjuvant" refers to any substance that acts to accelerate, prolong, or enhance an antigen-specific immune response when used in combination with a specific vaccine antigen. In the context of the present invention, an adjuvant (e.g., an IL-4R antagonist) has the property of increasing the efficacy of a vaccine in a subject compared to a subject receiving a vaccine that does not contain an IL-4R antagonist. In certain embodiments, the use of an IL-4R antagonist increases the safety of the administered vaccine, for example, by reducing the risk of an allergic reaction to a vaccine component. In certain embodiments, the use of an IL-4R antagonist as an adjuvant can reduce the total number of administered doses of a vaccine. For example, administration of one dose of a vaccine composition with an adjuvant (i.e., an IL-4R antagonist) according to the present invention is as efficient as administration of two doses of a vaccine without an adjuvant according to the present invention. Similarly, administration of one or two doses of a vaccine according to the invention with an adjuvant according to the invention is as efficient as administration of three doses of a vaccine without an adjuvant according to the invention. In certain embodiments, the vaccine composition comprises a second adjuvant (e.g., alum).

[0084] In certain embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof described herein. In certain exemplary embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0085] Immunogens or antigens suitable for use in the vaccine compositions of the invention may be selected from the group consisting of inactivated pathogens, attenuated pathogens, immunogenic subunits (e.g., proteins, polypeptides, peptides, epitopes, haptens), or recombinant expression vectors comprising a plasmid with an immunogenic insert. In one embodiment of the invention, the immunogen is an inactivated or killed microorganism. In certain embodiments, the vaccine composition is selected from the group consisting of Bordetella pertussis, Corynebacterium diptheriae, Clostridium tetani, Mycobacterium tuberculosis, Plasmodium spp., Bacillus anthracis, Vibrio cholerae, Salmonella typhi, Borrelia spp., Streptococcus pneumoniae, and the like. pneumoniae, Staphylococcus aureus, Escherichia coli, Clostridium spp., Mycobacterium leprae, Yersinia pestis, influenza virus, Varicella-zoster virus, human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), poliovirus, smallpox virus, rabies virus, rotavirus, human papillomavirus, Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, lyssavirus, measles virus, mumps virus, and rubella virus. In certain embodiments, the vaccine composition comprises a vaccine component selected from the group consisting of tetanus toxoid, diphtheria toxoid, inactivated pertussis toxin, filamentous hemagglutinin, pertactin, type 2 fimbria, type 3 fimbria, and formalin-inactivated respiratory syncytial virus.

[0086] The vaccine composition of the present invention comprises at least one pharma- ceutically acceptable carrier. The term "pharma-ceutically acceptable carrier" refers to a carrier that can be administered to a patient together with an antigen, does not destroy its pharmacological activity, and is non-toxic when administered in a dose sufficient to deliver a pharma- ceutically effective amount of the compound. Useful pharma-ceutically acceptable vehicles or excipients are standard. Remington's Pharmaceutical Sciences by E. W. Martin, Mack Publishing Co., Easton, Pa., 15th Edition (1975) describes compositions and formulations suitable for pharmaceutical delivery of vaccines. In general, the nature of the vehicle or excipient will depend on the particular mode of administration employed. For example, parenteral formulations usually contain pharma-ceutically and physiologically acceptable injectable liquids as vehicles, such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, and the like. For solid compositions (e.g., lyophilized troche, powder, pill, tablet, or capsule forms), conventional non-toxic solid vehicles or excipients may include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral vehicles or excipients, the immunogen composition to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0087] As will be appreciated by those of skill in the art, vaccines are suitably formulated to be compatible with the intended route of administration. Examples of suitable routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, oral (e.g., buccal, inhalation, nasal and pulmonary spray), intradermal, transdermal (topical), transmucosal, and intraocular administration.

[0088] Dosage regimen The methods of the invention according to certain embodiments include administering to a subject a vaccine in combination with an IL-4R antagonist (e.g., an anti-IL-4R antibody). As used herein, the expression "in combination" means that the vaccine is administered before, after, or simultaneously with the IL-4R antagonist. The term "in combination" also includes sequential or simultaneous administration of the IL-4R antagonist and the vaccine.

[0089] For example, when administered "before" an IL-4R antagonist, the vaccine may be administered less than 72 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the IL-4R antagonist. When administered "after" an IL-4R antagonist, the vaccine may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than about 72 hours after administration of the IL-4R antagonist. "Concurrent administration" with an IL-4R antagonist means that the vaccine is administered to the subject in a separate dosage form within less than 5 minutes of (before, after, or at the same time as) administration of the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation containing both the vaccine and the IL-4R antagonist.

[0090] The present invention includes methods that include administering to a subject an IL-4R antagonist at a dosing frequency of about 4 times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently, so long as a therapeutic response is achieved. In certain embodiments that include administration of an anti-IL-4R antibody, weekly dosing in an amount of about 25 mg, 50 mg, 150 mg, or 300 mg can be utilized.

[0091] According to certain embodiments of the present invention, multiple doses of IL-4R antagonist may be administered to a subject over a defined time course. The method according to this aspect of the present invention comprises sequentially administering multiple doses of IL-4R antagonist to a subject. As used herein, "sequential administration" means that each dose of IL-4R antagonist is administered to a subject at different points in time, e.g., on different days separated by a predefined interval (e.g., hours, days, weeks or months). The present invention includes methods that include sequential administration of one initial dose of IL-4R antagonist to a patient, followed by one or more secondary doses of IL-4R antagonist, and optionally followed by one or more tertiary doses of IL-4R antagonist.

[0092] The terms "initial dose", "secondary dose", and "tertiary dose" refer to the time sequence of administration of an IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses varies from each other during the course of treatment (e.g., adjusted upwards or downwards, as necessary). In certain embodiments, the initial dose comprises a first amount of an antibody or antigen-binding fragment thereof, and one or more secondary doses each comprise a second amount of an antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second amount of the antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the beginning of the treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered less frequently. For example, the IL-4R antagonist may be administered to a patient in need thereof at a loading dose of about 300 mg to about 600 mg, followed by one or more maintenance doses of about 25 mg to about 300 mg. According to one embodiment, the initial dose and the one or more secondary doses each comprise between 10 mg and 600 mg of the IL-4R antagonist, e.g., between 100 mg and 400 mg of the IL-4R antagonist, e.g., 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg of the IL-4R antagonist.

[0093] In one exemplary embodiment of the invention, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, or more) weeks after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to the dose of IL-4R antagonist administered to a patient prior to administration of the immediately following dose in a multiple administration sequence with no intervening doses.

[0094] The method according to this aspect of the invention may include administering any total number of secondary and / or tertiary doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only one secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only one tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0095] In embodiments comprising multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-6 weeks after the immediately preceding dose. Similarly, in embodiments comprising multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to the patient can vary over the course of the dosing regimen.

[0096] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject in combination with a vaccine by the method of the present invention is generally an immunologically effective amount. As used herein, the phrase "immunologically effective amount" refers to an amount of IL-4R antagonist that causes an increase in the effectiveness of the vaccine or an enhanced or increased immune response to the vaccine. In the context of the present invention, the phrase "immunologically effective amount" refers to an amount of IL-4R antagonist that causes one or more of the following: (a) faster clearance of microbial pathogens from infected hosts; (b) a reduction in IgE levels induced by the vaccine; (c) an increase in Th1-type antigen-specific IgG; (d) a reduction in Th2-type antigen-specific IgG levels; (e) a reduction in the total number of vaccine doses; and / or (f) better protection against pathogen challenge and delay of infection upon pathogen challenge. In certain embodiments, the term "immunologically effective amount" includes a prophylactically or therapeutically effective amount of an IL-4R antagonist, which means the amount required for an effective immune response to prevent, treat, or alleviate a symptom or sign of an infectious disease. In certain embodiments, the phrase "immunologically effective amount" means an amount of an IL-4R antagonist that results in a detectable improvement in one or more symptoms or signs in a patient with atopic dermatitis, asthma, nasal polyposis, chronic sinusitis, eosinophilic esophagitis, or allergy.

[0097] In the case of an anti-IL-4R antibody, an immunologically effective amount is about 0.05 mg to about 600 mg of an anti-IL-4R antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about The amount of the compound can be about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In certain embodiments, 10 mg, 25 mg, 50 mg, 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody is administered to a subject.

[0098] The amount of IL-4R antagonist contained within an individual dose may be expressed in terms of milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight. EXAMPLES

[0099] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0100] Example 1: Administration of anti-IL-4R antibody significantly reduces serum total IgE induced by pertussis vaccine In this example, the effect of anti-IL-4R antibodies on total serum IgE levels induced by whole cell pertussis (wP) or acellular pertussis (aP) vaccines was evaluated using a Bordetella pertussis aerosol challenge infection model. It is known in the art that tetanus as well as wP and aP vaccines induce a log-scale boost in IgE in some patients. Table 1 lists the components of the aP and wP vaccines used in the examples herein.

[0101] [Table 1]

[0102] C57BL / 6 mice were immunized with either TDaP [Adacel® (Sanofi Pasteur)] or DTP vaccine (Serum Institute of India, Pune, India) on days −42 and −14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or isotype control antibody was initiated 1 week prior to the first immunization and continued once a week until day 7. The treatment regimen is summarized in FIG. 1. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12.

[0103] Serum was collected from naive and immunized mice (12 mice per group) on day 0. Total IgE levels were analyzed by ELISA. Total serum IgE levels were determined by ELISA using biotin-conjugated anti-mouse IgE antibodies and peroxidase-conjugated streptavidin. Antibody levels are expressed as total IgE (μg / mL) determined from a standard curve.

[0104] Treatment of mice with anti-IL-4Rα significantly reduced total serum IgE levels in mice immunized with TDaP (aP) and DTP (wP) vaccines compared to mice treated with an isotype control antibody (Figure 2). Reductions in serum IgE indicate a vaccine-induced reduction in Th2 responses and / or prevention or reduction in allergic reactions.

[0105] Example 2: Effect of anti-IL-4R antibody treatment on antigen-specific serum IgG antibodies in mice vaccinated with pertussis vaccine In this example, the effect of anti-IL-4R antibodies on antigen-specific serum antibodies induced by whole cell pertussis (wP; Th1 immune response) or acellular pertussis (aP; Th2 immune response) vaccines was evaluated using a Bordetella pertussis aerosol challenge infection model. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days −42 and −14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or isotype control antibody was initiated 1 week prior to the primary immunization and continued weekly until day 7. The treatment regimen is summarized in FIG. 1. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody comprising an HCVR with the amino acid sequence of SEQ ID NO: 11 and an LCVR with the amino acid sequence comprising SEQ ID NO: 12. Serum was collected on the day of challenge from naive and immunized mice (four mice per group per experiment). Antigen-specific serum antibodies were analyzed by ELISA using plate-bound heat-killed Bordetella pertussis or FHA (5 mg / mL). Bound antibodies were detected using biotin-conjugated anti-mouse IgG, IgG1, IgG2a or IgG2c antibodies and peroxidase-conjugated streptavidin. Antibody levels are expressed as the mean endpoint titers determined by extrapolation of the linear portion of the titration curves to 2 SD above the background values ​​obtained with non-immunized mouse sera.

[0106] Serum IgG specific to heat-killed Bordetella pertussis was analyzed in mice treated with wP, whereas serum IgG specific to filamentous hemagglutinin (FHA) was analyzed in mice treated with aP. Immunization with aP or wP induced Bordetella pertussis-specific IgG; total IgG titers were not altered by treatment with anti-IL-4Rα in mice immunized with aP, and a very small (although significant) increase in antigen-specific total IgG was observed in mice immunized with wP (Figure 3). Immunization with aP induced primarily IgG1 anti-FHA antibodies (indicative of a Th2-specific response), which was significantly reduced by anti-IL-4Rα treatment (Figure 4). FHA-specific IgG2a and IgG2c titers (indicative of a Th1 response) were significantly enhanced by treatment with anti-IL-4Rα; titers were significantly higher in aP-immunized mice treated with anti-IL-4Rα when compared to aP-immunized mice treated with isotype control antibody (Figures 5 and 6). There were no significant differences in heat-killed Bordetella pertussis (HK-BP)-specific IgG1 antibody titers between experimental groups immunized with wP, but there was a slightly significant increase in HK-BP-specific IgG2a and IgG2c titers in groups treated with anti-IL4Rα compared to isotype control antibody. This increase in IgG2a and IgG2c titers is not significant for individual experiments (each consisting of 4 mice per group) but is significant when the results of multiple experiments are pooled.

[0107] Thus, anti-IL-4Rα treatment reduced the Th2 response and enhanced the Th1 response induced by immunization with the aP vaccine; this was reflected in a switch from serum IgG1 to IgG2a / c antibodies and a decrease in IgE concentrations.

[0108] Example 3: Effect of anti-IL-4R antibodies on antigen-specific production of cytokines In this example, the effect of anti-IL-4R antibodies on antigen-specific production of cytokines after splenocyte ex vivo restimulation was tested using a Bordetella pertussis aerosol challenge infection model. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days −42 and −14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or isotype control antibody was initiated 1 week prior to the first immunization and continued once a week until day 7. The treatment regimen is summarized in FIG. 1. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12. Serum was collected from naive and immunized mice (four mice per group per experiment) on the day of challenge (day 0). Antigen-specific cytokine production by splenocytes was analyzed by ELISA. Splenocytes were prepared from mouse spleens by mechanical disruption of splenic tissue. Splenocytes were cultured with the indicated numbers or concentrations of heat-killed Bordetella pertussis or purified FHA. Supernatants were removed 72 hours later and IL-13, IL-17 and IFNγ concentrations were determined by ELISA.

[0109] Spleen cells from aP-immunized mice treated with anti-IL-4Rα produced significantly higher interferon-gamma (IFNγ) in response to FHA stimulation in a dose-dependent manner than mice treated with isotype control (Figure 7). IFNγ concentrations were detected in spleen cells from all anti-IL-4Rα-treated mice, but lower in 1 of 4 aP-immunized mice treated with isotype control. There was a trend toward reduced IL-13 in spleen cells from aP-immunized mice treated with anti-IL-4Rα (data not shown). We did not detect FHA-specific IL-17. Bordetella pertussis-specific IL-17 and IFNγ production by splenocytes from wP-immunized mice after restimulation was similar across all immunization groups (data not shown).

[0110] Example 4: Treatment with anti-IL-4R antibodies enhances the efficacy of pertussis vaccines In this example, the protective efficacy of anti-IL-4R antibodies as adjuvants for whole cell pertussis (wP) or acellular pertussis (aP) vaccines was evaluated using a Bordetella pertussis aerosol challenge infection model. C57BL / 6 mice were immunized with either acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)] or whole cell pertussis (wP) (DTP, Serum Institute of India, Pune, India) on days −42 and −14 prior to aerosol challenge (day 0) with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibodies ("anti-IL-4Rα") or isotype control antibodies was initiated 1 week prior to the first immunization and continued weekly until day 7. The treatment regimen is summarized in FIG. 1. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12.

[0111] Colony forming unit (CFU) levels per lung were assessed 0, 3, 7, 10, and 14 days after Bordetella pertussis challenge. Briefly, the course of infection was followed and CFU counts were performed in lungs from groups of four mice at multiple intervals after challenge. Lungs were aseptically removed and homogenized in 1 mL of sterile saline on ice. Undiluted and serially diluted homogenates from individual lungs were spotted in triplicate onto Bordet-Jung agar plates and the number of CFU was calculated after 5 days of incubation. The limit of detection was approximately 0.3 log per lung for groups of four mice at each time point. 10 It was CFU.

[0112] Immunization with the wP vaccine conferred the highest level of protection against aerosol challenge with live Bordetella pertussis (Figure 8). Anti-IL-4Rα treatment in wP-immunized mice cleared infection similar to wP-immunized mice treated with isotype control. Anti-IL-4Rα treatment significantly enhanced the efficacy of the aP vaccine; mice immunized with aP vaccine and treated with anti-IL-4α had significantly lower lung bacterial burdens on day 3 when compared to mice treated with isotype control. Anti-IL-4Rα treatment increased the efficacy of the aP vaccine by one-third based on the area under the clearance curve. The results of this example suggest that IL-4R blockade is generally a useful therapeutic strategy to enhance the protective effect of vaccines that induce Th2 responses.

[0113] Example 5: Administration of anti-IL-4R antibodies enhances the efficacy of a single dose of vaccine In this example, a Bordetella pertussis aerosol challenge infection model was used to evaluate the effect of anti-IL-4R antibodies on the efficacy of a single dose of vaccine.

[0114] C57BL / 6 mice were immunized once with either aP vaccine (Adacel® TDaP; Sanofi Pasteur) or wP vaccine (DTP, Serum Institute of India, Pune, India) 3 weeks prior to aerosol challenge with a virulent strain of Bordetella pertussis. Treatment with anti-mouse IL-4R antibody ("anti-IL-4Rα") or isotype control antibody was initiated 1 week prior to immunization and continued once a week for the duration of the study. The treatment regimen is summarized in FIG. 9. The anti-IL-4Rα antibody used in this example was an antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12.

[0115] Mice were then challenged with Bordetella pertussis; lung CFUs were assessed at days 0, 3, 7, 14, and 21 post-infection. Briefly, the course of infection was followed and CFU counts were performed in lungs from groups of four mice at multiple intervals post-challenge. Lungs were aseptically removed and homogenized in 1 mL of sterile saline on ice. Undiluted and serially diluted homogenates from individual lungs were spotted in triplicate onto Bordet-Jung agar plates and the number of CFUs was calculated after 5 days of incubation. The limit of detection was approximately 0.3 log per lung for groups of four mice at each time point. 10 It was CFU.

[0116] Immunization with the wP vaccine conferred the highest level of protection against aerosol challenge with live Bordetella pertussis (Figure 10), and efficacy of the wP vaccine was not altered by anti-IL-4Rα treatment. Anti-IL-4Rα treatment significantly enhanced the efficacy of the aP vaccine, even when the vaccine was reduced to a single dose. Mice immunized with aP and treated with anti-IL-4α had cleared bacterial infection by day 14, whereas mice immunized with aP and treated with isotype control still maintained a 4 log 10 bacterium and did not completely clear the infection by day 21. Anti-IL-4Rα treatment increased the efficacy of the aP vaccine by one-third based on the area under the clearance curve.

[0117] Anti-IL-4Rα significantly enhanced the efficacy of the aP vaccine, with Bordetella pertussis infection completely cleared by day 14. The single-dose immunization protocol clearly accounts for the increased efficacy of the aP vaccine in combination with anti-IL4Rα treatment.

[0118] Example 6: Effect of low doses of anti-IL-4R antibodies on Th1 responses to acellular pertussis vaccine In this example, the effect of anti-IL-4R antibodies on serum total and antigen-specific antibodies induced by aP vaccine is evaluated in a mouse model (described herein in Examples 1-5). C57BL / 6 mice are immunized with an acellular pertussis (aP) vaccine [Adacel® TDaP (Sanofi Pasteur)]. Mice are treated with an anti-mouse IL-4R antibody ("anti-IL-4Rα") or an isotype control antibody prior to primary immunization (see below). The anti-IL-4Rα antibody used in this example is an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12.

[0119] In a first experiment, 1-5 doses of anti-IL-4R antibody are administered to animals in different groups at 25 mg / kg mouse body weight prior to vaccination with aP. One group of animals is further administered anti-IL-4R antibody at the same time as the aP vaccine. One group of animals is further administered a booster dose of aP vaccine 4 weeks after the priming dose.

[0120] In another experiment, 1-5 doses of anti-IL-4R antibody are administered to animals in different groups at 10 mg per kg of mouse body weight prior to vaccination with aP. One group of animals is further administered anti-IL-4R antibody at the same time as the aP vaccine. One group of animals is further administered a booster dose of aP vaccine 4 weeks after the priming dose.

[0121] In another experiment, 1-5 doses of anti-IL-4R antibody are administered at 1 mg per kg of mouse body weight to animals in different groups prior to vaccination with aP. One group of animals is further administered anti-IL-4R antibody at the same time as the aP vaccine. One group of animals is further administered a booster dose of aP vaccine 4 weeks after the priming dose.

[0122] Serum is collected from naive and immunized mice 7 and 21 days after vaccination. Antigen-specific serum antibodies are analyzed by ELISA using plate-bound heat-killed Bordetella pertussis or FHA (5 mg / mL). Bound antibodies are detected using biotin-conjugated anti-mouse IgG, IgG1, IgG2a or IgG2c antibodies and peroxidase-conjugated streptavidin. Antibody levels are expressed as mean endpoint titers determined by extrapolation of the linear portion of the titration curves to 2 SD above background values ​​obtained with non-immunized mouse sera.

[0123] Mice administered low doses of anti-IL-4R antibodies prior to and / or concomitantly with aP vaccine administration are expected to show a switch from serum IgG1 to serum IgG2a / c antibodies and a decrease in IgE concentrations. Furthermore, it is expected that even a single dose of anti-IL-4R antibodies administered prior to vaccination with aP vaccine will result in a reduction in serum IgG1 levels and an increase in serum IgG2a / c levels and a decrease in IgE levels (i.e., a switch from Th2 to Th1 responses). Thus, low doses of anti-IL-4Rα treatment prior to and / or during vaccination will reduce the Th2 response and enhance the Th1 response induced by immunization with aP vaccine.

[0124] Example 7: IL-4R blockade as an adjuvant for aP vaccine in an infant baboon model The efficacy of anti-IL-4R antibodies as adjuvants for an acellular pertussis (aP) vaccine was evaluated in a clinically relevant infant baboon model (Warfel et al 2014, PNAS 111: 787). The anti-IL-4Rα antibody used in this example was an anti-monkey IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO: 14 and an LCVR having the amino acid sequence comprising SEQ ID NO: 15 (referred to herein as "mAb1").

[0125] The study design is summarized in Table 2.

[0126] [Table 2]

[0127] Baboons are immunized intramuscularly with human doses of aP or wP at 2, 4 and 6 months of age. For studies using aP, animals are vaccinated with Daptacel (Sanofi Pasteur) or Infanrix (GlaxoSmithKline). For studies using wP, animals are vaccinated with triple antigen (Serum Institute of India). Non-vaccinated animals are also age-matched. All animals receive fixed doses of placebo or mAb1 subcutaneously at 1, 2, 3, 4, 5 and 6 months of age, except for group 5, which receives fixed doses of mAb1 at 2, 4 and 6 months of age (Table 2). Whole blood is collected for serum and PBMC at 1, 2, 3, 4, 5 and 6 months of age. Serum is raised for mAb1 levels and for pertussis-specific total IgG, IgG1, IgG4 and IgE levels. Animals are challenged at 6-8 months of age with Bordetella pertussis.

[0128] Animals treated with anti-IL-4R antibodies prior to vaccination with aP are expected to show an increase in pertussis-specific IgG1 levels (Th1 specific) and a decrease in pertussis-specific IgG4 levels (Th2 specific). More importantly, animals treated with anti-IL-4R antibodies prior to vaccination with aP vaccine are protected against disease upon Bordetella pertussis challenge, as evidenced by faster clearance of bacterial infection from the lungs.

[0129] Example 8: Clinical trial of acellular pertussis vaccine in combination with anti-IL-4R antibody in adolescents aged 10-15 years The efficacy of anti-IL-4R antibodies as adjuvants is measured in clinical trials in adolescents aged 10-15 years. One objective of the trial is to study the efficacy of an acellular pertussis vaccine (TDaP, Adacel®, Sanofi Pasteur) in combination with dupilumab. Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NO:3-8.

[0130] Study treatment includes a 400mg loading dose of dupilumab on day 1, followed by a 200mg weekly dose; or a double dose of placebo on day 1, followed by a weekly placebo dose. Study subjects receive 200mg injections of dupilumab or placebo subcutaneously on days 8, 15, 22, 29, 36, and 43. On day 29, all subjects receive one dose of TDaP (Adacel®, sanofi) vaccine. Subjects are monitored for allergic reactions to the vaccine. Vaccine-specific serum Ig titers are checked 1, 4, 8, 16, and 24 weeks after vaccine injection.

[0131] The efficacy variables measured in this test include: (a) IgE titer; (b) FHA-specific total IgG titer; and (c) FHA-specific IgG1, and IgG4 titers.

[0132] The primary endpoint of the study is the proportion of subjects treated with dupilumab who have a positive response to the vaccine on day 43. A positive response is defined as one or more of the following, compared to placebo: (i) lower IgE titers in test subjects treated with dupilumab; (ii) higher vaccine-specific (e.g., anti-FHA) IgG4 titers in test subjects treated with dupilumab; and (iii) a lower number of adverse events (allergic reactions) in test subjects treated with dupilumab.

[0133] At the end of the study, subjects treated with dupilumab have one or more of the following: (a) lower IgE titers compared to placebo; (b) higher anti-FHA total IgG titers compared to placebo; (c) lower IgG4 and higher IgG1 titers compared to placebo. More than 50% of subjects in the study show a positive response to the vaccine.

[0134] Example 9: Clinical trial of a booster dose of acellular pertussis vaccine in combination with anti-IL-4R antibody in children under 10 years of age The efficacy of anti-IL-4R antibodies as adjuvants is measured in clinical trials in children under the age of 10. One objective of the study is to test the efficacy of acellular pertussis vaccine (DTaP, Sanofi Pasteur) in combination with dupilumab. Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NO:3-8.

[0135] Study treatment includes a 50 mg loading dose of dupilumab on day 1, followed by a 25 mg dose; or a double placebo dose on day 1, followed by a placebo dose. Study subjects receive subcutaneous injections of 25 mg dupilumab (or placebo) every other week on days 15, 29, 43, 57, 71, 85, 99, and 113; followed by injections of secondary doses on days 141, 155, 162, 169, 176, and 183. All subjects receive a vaccine dose (DTaP) on day 43, followed by booster doses on days 113 and 176.

[0136] Subjects are monitored for allergic reactions to the vaccine. Vaccine-specific serum Ig titers are checked 1, 4 and 8 weeks after each vaccine dose.

[0137] The efficacy variables measured in this test include: (a) IgE titer; (b) FHA-specific total IgG titer; and (c) FHA-specific IgG1, and IgG4 titers.

[0138] The primary endpoint of the study is the proportion of subjects treated with dupilumab who have a positive response to the vaccine on day 1. A positive response is defined as one or more of the following, compared to placebo: (i) lower IgE titers in test subjects treated with dupilumab; (ii) higher vaccine-specific (e.g., anti-FHA) IgG1 titers in test subjects treated with dupilumab; and (iii) a lower number of adverse events (allergic reactions) in test subjects treated with dupilumab.

[0139] At the end of the study, subjects treated with dupilumab have one or more of the following: (a) lower IgE titers compared to placebo; (b) higher anti-FHA total IgG titers compared to placebo; (c) lower IgG4 and higher IgG1 titers compared to placebo. More than 50% of subjects in the study show a positive response to the vaccine. More than 50% of subjects treated with dupilumab show higher IgG1 titers.

[0140] Example 10: Clinical trial to examine vaccine responses in adults with atopic dermatitis treated with dupilumab This was a 32-week randomized, double-blind, placebo-controlled, parallel-group study evaluating immune responses to adsorbed tetanus toxoid Adacel® (tetanus, diphtheria, and acellular pertussis [TDaP]) and Menomune (meningococcal polysaccharide vaccine) vaccinations in adults with moderate to severe AD treated with subcutaneously administered dupilumab. Eligible patients (194 patients) were randomized in a 1:1 ratio to receive dupilumab or placebo for 16 weeks. Randomization was stratified by baseline disease severity (moderate vs. severe IGA). Treatment duration was 16 weeks, followed by a follow-up period of 16 weeks.

[0141] Test Purpose The primary objective of the study was to evaluate T cell-dependent vaccine responses in patients with moderate to severe atopic dermatitis (AD) not adequately controlled with topical medications treated with dupilumab 300 mg subcutaneously (SC) once weekly.

[0142] Secondary objectives of the study were to evaluate (i) T cell-dependent vaccine responses in patients with moderate to severe AD treated with SC dupilumab 300 mg once weekly; (ii) the safety of co-administered vaccine and SC dupilumab in patients with moderate to severe AD; and (iii) the efficacy of dupilumab in patients with moderate to severe AD.

[0143] The primary endpoint in the study was the proportion of patients with a positive response to tetanus toxoid (Adacel [TDaP] vaccine) at study week 16 (i.e., 4 weeks after immunization). A positive response was defined as a 4-fold or greater increase in anti-tetanus IgG titers from baseline 4 weeks after administration of Adacel for patients with a baseline titer ≥ 0.1 IU / mL, or a titer ≥ 0.2 IU / mL for patients with a baseline titer < 0.1 IU / mL.

[0144] Secondary endpoints were: (i) the proportion of patients with a positive response at study week 16, with a positive response defined as a ≥2-fold increase in anti-tetanus IgG titer from pre-vaccination baseline for patients with a pre-vaccination tetanus antibody titer of ≥0.1 IU / ml, or a titer of ≥0.2 IU / ml for patients with a pre-vaccination titer <0.1 IU / ml; (ii) Menomune response: an SBA titer of ≥8 for serogroup C (Immunological Basis for Immunization Series Module 15: Meningococcal Disease, World Health Organization). 2010);(iii) proportion of patients achieving Investigator Global Assessment (IGA)(0-1) at Week 16;(iv) proportion of patients achieving at least a 50% reduction in Eczema Area and Severity Index (EASI) score at Week 16;(v) proportion of patients achieving at least a 75% reduction in Eczema Area and Severity Index (EASI) score at Week 16;(vi) change from baseline in maximum pruritus numerical rating scale (NRS) at Week 16;(vii) change from baseline in BSA at Week 16;(viii) change from baseline in Global Symptom Score (GISS) at Week 1 (ix) change from baseline in GISS infiltration / papulation at week 16; (x) change from baseline in GISS desquamation at week 16; (xi) change from baseline in GISS lichenification at week 16; (xii) change from baseline to week 16 in Patient-Oriented Eczema Evaluation Score (POEM); (xiii) occurrence of serious treatment-emergent adverse events (TEAEs) during week 20; (xiv) occurrence of study drug discontinuation due to TEAEs during week 20; and (xv) occurrence of skin infections during week 20.

[0145] Test Design The study consisted of a screening period, a treatment period, and a follow-up period. Patients received weekly injections of dupilumab from day 1 to week 15. After providing appropriate training in self-injection, patients / caregivers self-injected dupilumab for several weeks and no clinic visits were scheduled (weeks 5, 6, 7, 9, 10, 11, 13, 14, and 15). Sites contacted patients by phone to conduct visits at weeks 5, 6, 7, 9, 10, 11, 13, 14, and 15. At week 12, patients received Adacel (TDaP) and Menomune vaccines. Responses to vaccination (anti-tetanus IgG titers and serum bactericidal antibody (SBA) titers to meningococcal serogroups) were assessed after 4 weeks.

[0146] Patients who used or did not use palliatives, mild to higher potency topical corticosteroids, and / or topical calcineurin inhibitors were potentially eligible for enrollment. Patients were treated with topical AD therapy and / or with low-dose systemic corticosteroids (prednisone or equivalent ≤ 10 mg) at any time during the study and could continue study drug. A single treatment course of high-dose systemic corticosteroids (any steroid dose prednisone or equivalent > 10 mg) was used as rescue medication for up to 14 days after initiation and completed between days 1 and week 10 during the study, although study drug was temporarily discontinued during this time. Patients treated with high-dose systemic corticosteroids for AD could reinitiate study drug 5 half-lives after stopping systemic corticosteroids, as long as the patient did not experience a clinically significant adverse event (AE) associated with the specific immunosuppressant and after consultation and consent from the medical monitor. After weeks 10 to 16, high-dose systemic corticosteroids were prohibited.

[0147] For the dupilumab cohort, patients received a loading dose of 600 mg SC on day 1, followed by 300 mg qw weeks 1-15.

[0148] For the placebo cohort, patients received a loading dose, SC, on day 1, followed by weekly placebo SC doses from weeks 1 to 15.

[0149] Adacel (TDaP) Vaccine: Patients were vaccinated with the Adacel (TDaP) vaccine, IM, at 12 weeks.

[0150] Menomune vaccine: Patients were vaccinated with Menomune vaccine, SC, at 12 weeks.

[0151] Adacel (Tdap), manufactured by Sanofi Pasteur, was provided in prefilled syringes. Each 0.5 mL dose contained 5 Lf (agglutinating units) of tetanus toxoid (T), 2 Lf of diphtheria toxoid (d), and acellular pertussis antigens (2.5 μg detoxified pertussis toxin, 5 μg filamentous hemagglutinin [FHA], 3 μg pertactin [PRN], and 5 μg types 2 and 3 fimbriae [FIM]). Other components per 0.5 mL dose included 1.5 mg aluminum phosphate (0.33 mg aluminum) as an adjuvant, ≦5 μg residual formaldehyde, <50 ng residual glutaraldehyde, and 3.3 mg (0.6% v / v) of 2-phenoxyethanol (not as a preservative). The antigens were the same as in DAPTACELR, diphtheria and tetanus toxoids, and adsorbed acellular pertussis vaccine (DTaP), but the Adacel (Tdap) vaccine was formulated with reduced amounts of diphtheria and detoxified pertussis toxins. Menomune, manufactured by Sanofi Pasteur, was provided as single-dose vials for SC use. The single-dose diluent (0.6 mL) contained sterile, pyrogen-free, distilled water without preservatives. The multi-dose diluent (6 mL) contained sterile, pyrogen-free, distilled water and thimerosal, a mercury derivative, added as a preservative for the reconstituted vaccine.

[0152] Study population The target population included adults with moderate to severe AD whose disease was not adequately controlled with topical medications, including those who were not suitable candidates for treatment with effective topical therapies.

[0153] Inclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) male or female adults aged 18-64 years with chronic AD (per the American Academy of Dermatology Consensus Criteria, [Eichenfeld 2004]) that had been present for at least 3 years prior to the screening visit; (2) patients with a documented recent history (within 6 months prior to the screening visit) of an inadequate response to a satisfactory course of outpatient treatment with topical AD medications or for whom topical AD therapy was otherwise not recommended (e.g., due to side effects or safety risks); (3) Eczema Area and Severity Index (EASI) score ≥ 16 at the screening and baseline visits; (4) Investigator Global Assessment (IGA) score ≥ 3 (IGA scale 0-4) at the screening and baseline visits; and (5) body surface area lesions of AD improvement ≥ 10% at the screening and baseline visits.

[0154] Note about the second criterion: Inadequate response was defined as failure to achieve and maintain remission or a state of low disease activity (IGA 0 = eliminated to 2 = equivalent to mild) despite treatment with a daily regimen of moderate-to-higher potency topical corticosteroids (with or without topical calcineurin inhibitors, as appropriate) applied for at least 28 days or the maximum duration recommended by the product prescribing information (e.g., 14 days for extra-potent topical corticosteroids), whichever is shorter. Patients with documented systemic treatment for AD in the past 6 months were also considered inadequate responders to topical treatment and were eligible for treatment with dupilumab after appropriate resolution. Serious side effects or safety risks outweighed the possible benefits of treatment and included intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic effects, as assessed by the investigator or the patient's physician. Acceptable documentation included in contemporaneous charts describes investigator documentation based on recorded topical prescriptions and treatment outcomes or communication with the patient's primary care physician. If documentation was insufficient, potential patients were rescreened after such documentation was obtained (e.g., patients who demonstrated failure to complete a 28-day course of mid- to higher-potency topical corticosteroids [with or without topical calcineurin inhibitors]).

[0155] Patients could be enrolled in the study with or without emollients, topical corticosteroids + / - topical calcineurin inhibitors, but had to meet the following requirements: (i) patients treated with topical AD medications at baseline had to be on a stable dosing regimen for at least 14 days or the maximum duration of treatment recommended by the prescribing information, whichever is shorter; and (ii) patients not treated with topical AD medications at baseline may not have used them within 7 days prior to the baseline visit.

[0156] Methods and Evaluation Efficacy of dupilumab in this population was assessed by measurement of tetanus IgG titers and meningococcal serogroup SBA titers, quality of life questionnaires, and patient-reported outcomes. Response to the vaccine was assessed by measurement of tetanus IgG titers and meningococcal serogroup SBA titers.

[0157] Analysis variables The following demographic and baseline characteristic variables were summarized:

[0158] Demographic variables: age at screening (years), age group (<65, >=65), sex, ethnicity, race, baseline weight (kg), height (m), and BMI (kg / m2).

[0159] Baseline characteristics: (i) duration of AD disease, (ii) immunoglobulin isotypes (total IgG, IgM, IgA, and IgE), anti-tetanus IgG titers, and SBA titers for groups A, C, Y, and W-135 polysaccharide antigens, (iii) atopic dermatitis (AD)-related parameters, including pruritus numerical rating scale (NRS), investigator's global assessment (IGA) score, eczema area and severity index (EASI) score, general symptom score (GISS), atopic dermatitis body surface area (BSA) lesions, patient global assessment of disease status, and patient directed eczema evaluation score (POEM). AD-related parameters are described in U.S. Publication No. 2014 / 0072583, which is incorporated herein by reference in its entirety.

[0160] Statistical Plan The full analysis set (FAS) included all randomized patients who received any study drug; it was based on treatment assigned (randomization). Efficacy endpoints were analyzed using the FAS. The safety analysis set (SAF) included all randomized patients who received any study drug; it was based on treatment received (treated). Treatment compliance / administration and all clinical safety variables were analyzed using the SAF. Responders to tetanus vaccine at week 16 of the study were investigated by comparing the proportion of positive responders between dupilumab and placebo using the Cochran-Mantel-Haenszel (CMH) test stratified by randomization strata (disease severity). 90% CIs are presented with exploratory p-values. For continuous endpoints, a mixed effects model with repeated measures (MMRM) was used. The model included factors for treatment (fixed effects), randomization strata (disease severity), study visit, treatment by visit exchange, and relevant baseline values. Statistical inferences were derived from the MMRM. Least squares means and 90% CIs were derived from the MMRM model and no p values ​​were provided.

[0161] result Demographic and baseline characteristics are presented in Tables 3-6.

[0162] [Table 3]

[0163] [Table 4]

[0164] [Table 5]

[0165] [Table 6]

[0166] Positive response to tetanus toxoid at week 16 in the dupilumab treatment arm The proportion of patients (83.3%) was similar to that in the placebo-treated arm (83.7%). The 90% CI for the difference between the treatment arms was (-9.41%, 8.69%).

[0167] Secondary measures of response included: the proportion of patients with a positive response to tetanus vaccination, defined as a 2-fold or greater increase in anti-tetanus IgG titers 4 weeks after vaccination (week 16); and the proportion of patients with a positive response to Menomune, defined as a serum bactericidal antibody (SBA) response to serogroup C of ≥8 4 weeks after vaccination (week 16).

[0168] A similar proportion of patients in the dupilumab-treated group (95.6%) achieved a 2-fold or greater increase in anti-tetanus IgG titers compared to placebo-treated patients (94.6%). Uniform responses to Menomune vaccine were also observed for both treatment groups; 86.7% of dupilumab-treated patients achieved an SBA>8 compared to 87.0% for placebo-treated patients. The 90% CIs for the differences between treatment groups in tetanus toxoid (2-fold or greater increase) and Menomune responses were (-4.29%, 6.27%) and (-8.54%, 7.96%), respectively. However, patients treated with dupilumab showed reduced toxicity associated with tetanus toxoid (e.g., skin reactions) compared to placebo.

[0169] The results of other secondary efficacy endpoints are presented in Table 7.

[0170] [Table 7]

[0171] Further analyses will include total IgE, and FHA-specific IgG1 and IgG4 titers in placebo- and dupilumab-treated patients. Patients treated with dupilumab are expected to have lower IgE titers compared to placebo.

[0172] Patients on dupilumab had significantly lower total IgE compared to placebo (Table 8).

[0173] [Table 8]

[0174] IgE levels in response to TDaP vaccine components [pertussis toxin (PT), pertussis pertactin (PRN) and tetanus toxoid (TT)] were analyzed. In addition to vaccine-specific IgE, two allergens were included in the analysis (Fel d 1; cat allergen, and Bet v 1; birch allergen). Allergic antibody responses to allergens and TDaP antigens were assessed by measuring Fel d 1, Bet v 1, tetanus toxoid (TT), pertussis toxin (PT) and pertussis pertactin (PRN) IgE levels via a modified Luminex® antibody assay. Sera from weeks 12 (at the time of TDaP immunization), 16 (end of treatment period), and 32 (end of study) were treated with GullSORB™ and incubated with Fel d 1, Bet v 1, TT, PT, or PRN coated microparticles. Bound specific IgE levels were detected via anti-hIgE antibodies conjugated with R-phycoerythrin (PE) and expressed as TDaP TT-, PT-, or PRN- or allergen Fel d 1- or Bet v 1-specific IgE mean fluorescence intensity (MFI). Values ​​3 SD above the mean of negative control sera were considered IgE positive for the respective TDaP antigen or allergen.

[0175] IgE responses to Fel d 1 tended to be lower, and IgE responses to Bet v 1 were significantly lower in individuals treated with dupilumab, especially at week 32 (end of study). 54 and 12.1% of individuals treated with dupilumab vs. 65.2% and 30.4% of individuals treated with placebo were positive for Fel d 1-specific IgE (p=0.067) and Bet v 1-specific IgE (p<0.001), respectively, at week 32. The allergic status of the patients to these allergens was unknown.

[0176] Dupilumab- and placebo-treated patients had similar TDaP-specific IgE MFI, but placebo-treated patients showed a higher frequency of induction of TDaP-specific IgE responses. Table 9 shows TDaP-specific IgE seropositivity in placebo- and dupilumab-treated patients at weeks 12 (time of TDaP immunization), 16 (end of treatment period), and 32 (end of study).

[0177] [Table 9]

[0178] As shown in Table 9, the majority of patients treated with dupilumab (62.16%) were seronegative for vaccine-specific IgE at the end of the study (week 32) compared to placebo (34.78%).

[0179] Overall, individuals treated with dupilumab had a significant drop in total IgE (-54.7% from baseline) compared to placebo-treated individuals (-7.2%) by the end of the study (p=<0.0001). Patients treated with dupilumab were less likely to develop TDaP-specific IgE responses. By week 32 (end of study), 37.8% dupilumab-treated patients vs. 65.22% placebo-treated patients had developed TDaP-specific IgE antibodies (the majority of patients were TDaP IgE positive for all three vaccine antigens measured).

[0180] FHA-specific IgG1 and IgG4 titers were determined at weeks 4, 16, and 32 in placebo- and dupilumab-treated patients. Patients in dupilumab showed a significant increase in FHA-specific IgG1 at weeks 4 and 16 after vaccination, but no treatment-specific response was observed. It was outlined that, due to their age, patients may have received a full course of wP in their childhood. If true, this indicated that there was a Th1 bias in wP-primed patients that was maintained into adulthood.

[0181] safety Treatment-emergent AEs (TEAEs, AEs that occurred during treatment and follow-up and worsened in severity compared to baseline) and potentially treatment-emergent clinically significant values ​​(PCSV) in laboratory variables, ECG, and vital signs were examined. There were three serious TEAEs in three dupilumab patients (3.1%). There was one stage IV mycosis fungoides, one squamous cell carcinoma, and one serum sickness-like reaction. There were no serious treatment-emergent adverse events in the placebo group. The incidence of treatment-emergent adverse events was lower in the dupilumab group compared to the placebo group (55.7% vs. 61.9%, respectively). Overview of adverse events by MedDRA system organ class (SOC) did not show any suggestive patterns of adverse drug effects on specific organ systems. The most commonly reported SOCs were "infections and infestations" (32.0% for placebo vs. 35.1% for dupilumab), "general disorders and administration site conditions" (7.2% for placebo vs. 16.5% for dupilumab), "skin and subcutaneous tissue disorders" (16.5% for placebo vs. 7.2% for dupilumab), "respiratory, thoracic, and mediastinal disorders" (10.3% for placebo vs. 7.2% for dupilumab), and "gastrointestinal disorders" (5.2% for placebo vs. 11.3% for dupilumab). The most common TEAEs included upper respiratory tract infections (14.4% for placebo vs. 11.3% for dupilumab), atopic dermatitis (11.3% for placebo vs. 1.0% for dupilumab), and nasopharyngitis (5.2% for placebo vs. 4.1% for dupilumab). The dupilumab-treated group showed a lower incidence of injection site reactions, localized swelling or lymph node swelling associated with the vaccine injection compared to placebo.

[0182] conclusion Dupilumab did not suppress patient responses to T cell-dependent vaccine (dTap) and T cell-independent vaccine (Menomune). Responses of patients treated with dupilumab 300 mg qw to T cell-dependent vaccine (dTap) and T cell-independent vaccine (Menomune) were comparable to those of patients treated with placebo. All secondary efficacy endpoints showed statistically significant favorable outcomes in the dupilumab group. Dupilumab 300 mg qw was safe and well tolerated. The safety profile of dupilumab was found to be consistent with that seen from previous studies.

[0183] Example 11: Duration of Th1 vs. Th2 responses to pertussis vaccines in human subjects

[0184] This example examines the duration of Th1 / Th2 responses to pertussis vaccine in human subjects primed with whole cell (wP) or acellular pertussis (aP) vaccines during childhood. Individuals primed with wP or aP vaccines were divided into six groups. Individuals primed with wP or aP are boosted with wP, aP or no vaccine (control). Antibody isotypes (total and antigen-specific IgG isotypes and IgE) are tested in the groups. Initial studies examined T cell responses in these individuals (Bancroft et al 2016; 304-305: 35-43).

[0185] Individuals primed with wP are expected to exhibit antibody isotypes specific for Th1 responses (increase in antigen-specific serum IgG1 levels) regardless of whether they are boosted with aP or wP. Similarly, individuals primed with aP exhibit antibody isotypes specific for Th2 responses (increase in antigen-specific serum IgG4 levels) regardless of aP / wP boost. This indicates that responses triggered in response to initial vaccination with aP (Th2-specific response) or wP (Th1-specific response) persist throughout adulthood.

[0186] Based on the results, it is suggested that an IL-4R antagonist be administered at and / or before the priming dose. Individuals administered the aP vaccine are administered an anti-IL-4R antibody prior to and / or concomitantly with the aP vaccine to imprint a Th1 response at the time of initial vaccination.

[0187] Example 12: Comparison of anti-IL-4R antibodies as adjuvants with other adjuvants

[0188] This example examines the effectiveness of an anti-IL-4R antibody as an adjuvant compared to other adjuvants. The anti-IL-4Rα antibody used in this example was an anti-mouse IL-4R antibody comprising an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence comprising SEQ ID NO:12 ("anti-IL-4Rα").

[0189] Mice are immunized with ovalbumin as a model antigen in combination with different adjuvants such as alum, AS04, AS03, MF59 and anti-IL-4Rα. Serum total and antigen-specific antibodies are analyzed. Administration of anti-IL-4Rα is expected to boost ovalbumin immunity and induce Th1 responses compared to ovalbumin itself.

[0190] In another experiment, anti-IL-4Rα is administered in combination with ovalbumin and alum. Alum is known in the art to induce Th2 responses. Here, administration of anti-IL4Rα is expected to act as an immunological modulator / blocker specific for alum, causing a switch in Th1 responses.

[0191] The present invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in a method of vaccination against whooping cough, the method comprising: administering the pharmaceutical composition comprising the IL-4R antagonist in combination with an acellular pertussis vaccine to a subject in need thereof; The IL-4R antagonist is an antibody or antigen-binding fragment thereof that binds to IL-4Rα and comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3); said HCDR1 comprises the amino acid sequence of SEQ ID NO:3; said HCDR2 comprises the amino acid sequence of SEQ ID NO:4; said HCDR3 comprises the amino acid sequence of SEQ ID NO:5; the LCDR1 comprises the amino acid sequence of SEQ ID NO:6; the LCDR2 comprises the amino acid sequence of SEQ ID NO:7; the LCDR3 comprises the amino acid sequence of SEQ ID NO:8; The above pharmaceutical composition.

2. (a) the IL-4R antagonist is administered to the subject as a single dose prior to or simultaneously with the vaccine; or (b) one or more doses of said IL-4R antagonist are administered prior to the vaccine; or (c) one or more doses of the IL-4R antagonist are administered prior to the vaccine, followed by a dose of the IL-4R antagonist administered subcutaneously simultaneously with the vaccine; or (d) one or more doses of the IL-4R antagonist are administered prior to the vaccine, followed by a dose of the IL-4R antagonist administered subcutaneously simultaneously with the vaccine, followed by a dose or doses of the IL-4R antagonist administered after the vaccine; The pharmaceutical composition of claim 1.

3. (a) each dose of the IL-4R antagonist is administered subcutaneously at a dose of about 1-50 mg / kg body weight of the subject; or (b) each dose of the IL-4R antagonist is administered subcutaneously in a dose of 10-600 mg; The pharmaceutical composition according to claim 1 or 2.

4. The IL-4R antagonist (a) at a dose of 50 mg, 100 mg, 200 mg, or 300 mg; or (b) twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks; or (c) an initial dose of 600 mg followed by one or more secondary doses, each secondary dose containing 300 mg; or (d) an initial dose of 400 mg followed by one or more secondary doses, each secondary dose containing 200 mg; The pharmaceutical composition according to any one of claims 1 to 3, which is administered.

5. 2. The pharmaceutical composition of claim 1, wherein the vaccine is administered at an initial dose, followed by one or more subsequent (booster) doses, each subsequent (booster) dose being administered 2 to 24 months after the immediately preceding dose.

6. (a) the subject is a child or adolescent under the age of 18, or (b) The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject is an adult aged 50 or older.

7. The IL-4R antagonist (a) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2; (b) an antibody or antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; or (c) dupilumab or a bioequivalent thereof; The pharmaceutical composition according to any one of claims 1 to 6, 8. (a) the pharmaceutical composition is contained in a syringe; or (b) the pharmaceutical composition is contained in a pen delivery device; or (c) the pharmaceutical composition is contained in an automatic injection delivery device. The pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical composition of claim 8, wherein the pen delivery device is a pre-filled pen delivery device.

10. A vaccine component comprising an acellular pertussis antigen, and 1. A vaccine composition comprising an adjuvant that increases T helper 1 (Th1) type antigen-specific IgG isotype antibodies in a subject against said vaccine component, The adjuvant comprises an IL-4R antagonist; The IL-4R antagonist is an antibody or antigen-binding fragment thereof that binds to IL-4Rα and comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3); The HCDR1 comprises the amino acid sequence of SEQ ID NO:3, and the HCDR2 comprises the amino acid sequence of SEQ ID NO:

4. wherein HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence of SEQ ID NO:7, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8; The IL-4R antagonist is present in an amount of 10 to 600 mg. The above vaccine composition.

11. 11. The vaccine composition of claim 10, wherein the acellular pertussis antigen comprises inactivated pertussis toxin, filamentous hemagglutinin, pertactin, type 2 fimbria, or type 3 fimbria.

12. The vaccine composition of claim 10, wherein the acellular pertussis antigen comprises inactivated pertussis toxin.

13. The vaccine composition according to any one of claims 10 to 12, further comprising a second adjuvant.

14. 14. The vaccine composition of claim 13, wherein the second adjuvant is alum.

15. The IL-4R antagonist comprises: (a) the heavy chain variable region (HCVR) comprises the amino acid sequence of SEQ ID NO:1 and the light chain variable region (LCVR) comprises the amino acid sequence of SEQ ID NO:2; (b) an antibody or antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; or (c) dupilumab or a biological equivalent thereof; The vaccine composition according to any one of claims 10 to 14,

16. (a) the vaccine composition is contained in a syringe; or (b) the vaccine composition is contained in a pen delivery device; or (c) the vaccine composition is contained in an automatic injection delivery device. A vaccine composition according to any one of claims 10 to 15.

17. 17. The vaccine composition of claim 16, wherein the pen delivery device is a pre-filled pen delivery device.

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