MXPA06009737A - Method of evaluating the therapeutic potential of a vaccine for mucosal administration - Google Patents

Abstract

The invention relates to a method of evaluating the therapeutic potential of a vaccination program comprising a vaccine for mucosal administration comprising one or more antigens and a vaccination protocol, the method comprising a) subjecting at least one test individual to the vaccination program, b) measuring the level of a biomarker antibody selected from the group consisting of IgA, IgG, IgE and IgX specific to the antigen in a biological sample from the test individual, and c) using the measurements obtained to evaluate the therapeutic potential of the vaccination program.

Description

METHOD FOR EVALUATING THE THERAPEUTIC POTENTIAL OF A VACCINE OF ADMINISTRATION BY THE MUCOSA TECHNICAL FIELD The present invention relates to a method for evaluating the therapeutic potential of a vaccine for administration by the mucosa comprising one or more antigens. BACKGROUND OF THE INVENTION Allergy is a major health problem in countries where the Western lifestyle is adapted. In addition, the prevalence of allergic disease is increasing in these countries. Although allergy in general can not be considered a life threatening disease, asthma annually causes a significant number of deaths. An exceptional prevalence of approximately 30% in adolescents leads to a substantial loss in quality of life, days of work and money, and guarantees a classification among the major health problems in the Western world. Allergy is a complex disease. Many factors contribute to the awareness event. Among these is the susceptibility of the individual defined by an interaction still insufficiently understood between several genes. Another important factor is exposure to the allergen above certain thresholds. Several environmental factors can be important in the sensitization process including contamination, childhood infections, infections by parasites, intestinal microorganisms, etc. Once an individual is sensitized and the allergic immune response established, the presence of only tiny amounts of allergens efficiently results in symptoms. The natural course of allergic disease is usually accompanied by aggravation at two levels. First, a progression of symptoms and severity of the disease, as well as progression of the disease, for example, hay fever to asthma. Second, dissemination in attacking allergens most often results in allergic multirectivity. Chronic inflammation leads to a general weakening of mucosal defense mechanisms resulting in non-specific irritation and eventually destruction of mucosal tissue. Infants may become sensitized primarily to food, ie milk, resulting in eczema or gastrointestinal disorders; however, more often, they often leave these symptoms spontaneously. These infants are at risk of developing inhalation allergies later in their lives. The most important sources of allergen are among the most prevalent particles of a certain size in the air that is breathed. These sources are remarkably universal and include herbal pollens and faecal particles of house dust mites, which together are responsible for approximately 50% of all allergies. Of global importance are also animal dander, that is, cat and dog dander, other pollens, such as sagebrush pollens, and micro fungi, such as Alternaria. On a regional basis still other pollens can dominate, such as birch pollen in Northern and Central Europe, ambrosia in the eastern and central United States, and Japanese cedar pollen in Japan. Insects, that is, bees and bees poison, and food, each one takes into account approximately 2% of all allergies. Allergy, that is, type I hypersensitivity, is caused by an inappropriate immunological reaction to non-pathogenic foreign substances. The major clinical manifestations of allergy include asthma, hay fever, eczema and gastrointestinal disorders. The allergic reaction is specific in the sense that a particular individual is sensitized to the particular allergen (s), while the individual does not necessarily show an allergic reaction or other known substances that cause the allergic disease. The allergic phenotype is characterized by pronounced inflammation of the mucosa of the target organ and by the presence of the allergen-specific antibody of the IgE class in the circulation and on the surface of the mast cells and basophils. 'An allergic attack is initiated by the reaction of the foreign allergen with allergen-specific IgE antibodies, when the antibodies bind to specific high affinity IgE receptors on the surface of mast cells and basophils. The mast cells and basophils contain preformed mediators, ie, histamine, tryptase and other substances, which are released in the cross-linking of two or more IgE antibodies bound to the receptor. IgE antibodies are cross-linked by the simultaneous binding of an allergen molecule. The cross-linking of the IgE bound to the receptor on the surface of mast cells also leads to the release of signaling molecules responsible for the attraction of eosinophils, allergen-specific T cells, and other cell types to the site of the allergic response. These cells interact with the allergen, IgE and effector cells, leading to a renewed onset of symptoms that occur 12-24 hours after finding the allergen (late phase reaction). The management of allergy disease includes diagnosis and treatment including prophylactic treatments. The diagnosis of the allergy is related to the demonstration of allergen specific IgE and the identification of the allergen source. In many cases a careful anamnesis can be sufficient for the diagnosis of allergy and for the identification of the source material of allergen attacker. More frequently, however, the diagnosis is supported by objective measurements, such as the skin prick test, blood test or provocation test. The therapeutic options fall into three major categories. The first opportunity is the avoidance or reduction of exposure to the allergen. While avoiding the allergen is obvious, for example, in the case of food allergens, this can be difficult or expensive, as for dust mite allergens, or it may be impossible, as for pollen allergens. The second and most widely used therapeutic option is the prescription of classic symptomatic drugs similar to antihistamines and steroids. Symptomatic drugs are safe and efficient; however, they do not alter the natural cause of the disease, nor do they control the spread of the disease. The third therapeutic alternative is the specific allergy vaccination that in most cases reduces or alleviates the allergic symptoms caused by the allergen in question. Vaccination for conventional specific allergy is a causal treatment for allergic disease. This interferes with basic immunological mechanisms that result in the persistent improvement of the patient's immune status. "Thus, the protective effect of vaccination for specific allergy extends beyond the period of treatment in contrast to treatment with symptomatic drug. Some patients who receive the treatment are cured, and in addition, most patients experience relief in the severity of the disease and the symptoms experienced, or at least one arrest in the aggravation of the disease. Thus, vaccination for specific allergy has preventive effects that reduce the risk of hay fever that develops in asthma, and reduces the risk of developing new sensitivities. The immunological mechanism involved in successful allergy vaccination is not known in detail. A specific immune response, such as the production of antibodies against a particular pathogen, is known as an adaptive immune response. This response can be distinguished from the innate immune response, which is a non-specific reaction to pathogens. An allergy vaccine is linked to address the adaptive immune response, which includes cells and molecules with antigen specificity, such as T cells and B cells that produce antibody. B cells can not mature in the cells that produce antibody without the help of T cells of the corresponding specificity. The T cells that participate in the stimulation of the allergic immune responses are mainly of the Th2 type. The establishment of a new balance between Thl and Th2 cells has been proposed to be beneficial and central to the immunological mechanism of vaccination for specific allergy. If this is caused by a reduction in Th2 cells, a shift of the .Th2 to Thl cells, or up-regulation of Thl cells is controversial. Recently, regulatory T cells have been proposed that are important for the mechanism of allergy vaccination. According to this model, regulatory T cells, ie, Th3 or Trl cells, down-regulate both Th1 and Th2 cells of the corresponding antigen specificity. Despite these ambiguities, it is generally believed that an active vaccine must have the ability to stimulate allergen-specific T cells. Vaccination for specific allergy is not, in spite of its virtues, in widespread use, mainly for two reasons. One reason is the inconvenience associated with the traditional vaccination program comprising repeated vaccinations, i.e. injections for several months. The other reason is, more importantly, the risk of allergic side reactions. Ordinary vaccinations against infectious agents are sufficiently carried out using one or a few high-dose immunizations. This strategy, however, can not be used for allergy vaccination since a pathological immune response is implicit. Vaccination for conventional specific allergy is therefore carried out using multiple subcutaneous immunizations applied over a prolonged period of time. The course is divided into two phases, the dosage upwards and the maintenance phase. In the dosage phase upwards increased doses are applied, typically over a period of 16 weeks, starting with very small doses. When the recommended maintenance dose is reached as this dose applied for the maintenance phase, typically with injections every six weeks. After each injection the patient must remain under medical attention for 30 minutes due to the risk of anaphylactic side reactions, which in principle although extremely rare could be life-threatening. In addition, the clinic must be equipped to withstand emergency treatment. There is no doubt that a vaccine based on a different route of administration would eliminate or reduce the risk for allergic side reactions inherent in the current subcutaneous base vaccine as well as facilitate more widespread use, possibly even by enabling self-vaccination in the home. Attempts to improve vaccines for specific allergy vaccinations have been made for over 30 years and include various procedures. Several procedures have targeted the allergen itself through the modification of IgE reactivity. Other procedures have been directed to the formulation and route of administration for the vaccine. The testing of new allergens, allergen formulations and treatment protocols is both labor-intensive and time consuming, since it requires in vivo testing in animals and / or humans, including clinical trials. In particular, clinical trials to test the therapeutic efficacy of new vaccines or treatment protocols are labor and time consuming, since they traditionally involve a high number of patients, a long treatment period, which for example for pollen allergy. it includes the pollen season and a period before the pollen season, and a wide range of doses. In addition, clinical trials require government approval of the clinical study to be carried out and the enrollment of appropriate test persons. Also, clinical trials of vaccines, for example, allergy vaccines, depend on the monitoring and evaluation of clinical symptoms, which are highly subjective parameters, and therefore the results of such experiments involve a certain degree of uncertainty. The aim of the present invention is to provide an improved method for evaluating the therapeutic potential of a vaccination protocol or a vaccine for mucosal administration, for example, a vaccine for administration for oromucose, ie, sublingual. BRIEF DESCRIPTION OF THE INVENTION This objective is achieved by the present invention, comprising i. to. the following aspects: A method for evaluating the therapeutic potential of a vaccination program comprising a vaccine for administration by the mucosa comprising one or more antigens and a vaccination protocol, the method comprising a) subjecting at least one individual test the vaccination program, b) measure the level of a biomarker antibody selected from the group consisting of IgA, IgG, IgE and IgX specific to the antigen in a biological sample of the test individual, and c) use the measurements obtained to evaluate the therapeutic potential of the vaccination program. A vaccine obtainable by the method according to any of claims 1-35. A method for evaluating the effect of vaccination for specific mucosal allergy (SAV) of an individual, the method comprising a) subjecting the individual to SAV by the mucosa, b) measuring the level of a biomarker antibody selectable from the group which consists of IgA, IgG, IgE and IgX specific to the antigen in a biological sample of the individual, and c) use the measurements obtained to evaluate the effect of the SAV. The invention is based on the surprising experimental discovery that the mucosal administration of an allergy vaccine is followed by a distinct and reliable increase in the blood fluid concentration of both IgE, IgG, IgA and IgX specific to the allergen in question, while the administration by the mucosa of a vaccine does not give rise to any of the changes for a number of other measurable markers of the response of the immune system. Experimental results suggest that IgE body fluid concentrations, Antigen-specific IgG, IgA and IgX are strong and effective markers for the therapeutic effect of a vaccine. Thus, the present invention provides a possibility to test new allergen candidates, new vaccine formulations and as new vaccination protocols when analyzing a biological sample from an animal or test individual in vitro. By carrying out, for example, such in vitro analysis before clinical trials it is possible to exclude the protocol of non-effective vaccinations, vaccines and doses prior to performing the clinical experiments and thereby reduce the degree of clinical experiments to thereby make the development of new vaccines more feasible. Also, the invention has provided a new and additional parameter for evaluating the therapeutic potential of a vaccine or vaccination protocol, a parameter that is also easily measurable and quantifiable and therefore very reliable. In particular, the method can be used in relation to clinical experiments to obtain additional information or to obtain alternative information to other parameters, such as clinical symptoms, and in this way make the clinical trial more reliable. As will be presented from the foregoing, the method can be used at any stage of vaccine development from the classification of new allergen candidates, for example, recombinant and modified recombinant allergens, to clinical vaccine experiments for the purpose of obtain vaccine authorizations in the market. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the level of IgE for a group of patients treated with placebo for four points at the time of the administration period. Fig. 2 shows the IgE level for a group of patients treated with a dose of 2500 SQ for four points at the time of the administration period. Fig. 3 shows the IgE level for a group of patients treated with a dose of 25000 SQ for four points at the time of the administration period. Fig. 4 shows the level of IgE for a group of patients treated with a dose of 75,000 SQ for four points at the time of the administration period. Fig. 5 shows the IgA level for a group of patients treated with placebo for four points at the time of the administration period. Fig. 6 shows the IgA level for a group of patients treated with a dose of 2500 SQ for four points at the time of the administration period. Fig. 7 shows the IgA level for a group of patients treated with a dose of 25000 SQ for four points at the time of the administration period. Fig. 8 shows the level of IgA for a group of patients treated with a dose of 75,000 SQ for four points at the time of the administration period. Fig. 9 shows the IgG level for a group of patients treated with placebo for four points at the time of the administration period. Fig. 10 shows the IgG level for a group of patients treated with a dose of 2500 SQ for four points at the time of the administration period. Fig. 11 shows the IgG level for a group of patients treated with a dose of 25000 SQ for four points at the time of the administration period. Fig. 12 shows the level of IgG for a group of patients treated with a dose of 75,000 SQ for four points at the time of the administration period. Fig. 13 shows the level of IgE for a group of patients treated with placebo at the beginning of and in 1-2 weeks after a period of treatment. Fig. 14 shows the IgE level for a group of patients treated with a 1000000 SQ dose at the beginning of and in 1-2 weeks after a period of treatment. Fig. 15 shows the IgE level for Treatment Groups 1-4 of the Intention-To-Treat (ITT) population at three time points during the treatment period. Fig. 16 shows the IgE level for Treatment Groups 1 and 6 of the Intention-To-Treat population (ITT) at three points of time during the treatment period. Fig. 17 shows the level of IgE for Treatment Groups 1-4 of the population Per Protocol (PP) at three points of time during the treatment period. Fig. 18 shows the level of IgE for Treatment Groups 1, 5 and 6 of the population Per Protocol (PP) at three points of time during the treatment period. Fig. 19 shows the IgX level for Treatment Groups 1-4 of the Intention-To-Treat (ITT) population at three time points during the treatment period. Fig. 20 shows the IgX level for Treatment Groups 1, 5 and 6 of the Intention-To-Treat (ITT) population at three points of time during the treatment period. Fig. 21 shows the IgX level for Treatment Groups 1-4 of the Por-Protocol (PP) population at three points of time during the treatment period. Fig. 22 shows the IgX level for Treatment Groups 1, 5 and 6 of the Por-Protocol (PP) population at three points of time during the treatment period. DETAILED DESCRIPTION OF THE INVENTION Evaluation of the therapeutic potential of a vaccine program The evaluation of the therapeutic potential of a vaccination program can be based on 1) measurements of IgE, IgA, IgG or IgX alone, 2) measurements of two of the four biomarker antibodies, 3) measurements of three of the four biomarker antibodies, or 4) measurements of all four biomarker antibodies. The evaluation of the obtained measurements can be carried out by comparison with a reference biomarker antibody level profile of reference, for example, by preparing a graph of the biomarker antibody level against time to produce a time curve. The measurements obtained are used to evaluate the therapeutic potential of a vaccination program since it is tested. The vaccination program has two main components, viz. the vaccination protocol and the vaccine, with each having a number of parameters, which may be the test subject in the method of the invention. The vaccination protocol involves two parameters of, for example, the classification and selection of persons for the study, the circumstances under which the administration of the vaccine takes place, the route of administration, the doses of antigen used, the frequency and duration of the vaccination. administration, etc. The vaccine involves the parameters of one or more antigens, the adjuvant, if it is present in the vaccine formulation, that is, the excipients of the formulation. The method of the invention can be used to evaluate the therapeutic potential of 1) the vaccination protocol using a conventional vaccine, 2) the vaccine using a conventional vaccination protocol or 3) the combination of the vaccination protocol and the vaccine. In one embodiment of the method of the invention, the biomarker antibody is IgE. It is preferred that the level of IgE be increased more than 50%, more preferably more than 100%, more preferably more than 200%, more preferably more than 300% and more preferably more than 400% compared to the level in the start of the vaccination program. It is further preferred that the increase in IgE level occur within twelve weeks, preferably within ten weeks, more preferably within eight weeks, more preferably within six weeks and much more preferably within four weeks from the start of the vaccination program. In a particular embodiment of the invention, the level of IgE has a maximum value followed by a decrease. It is preferred that the maximum value of the IgE level occurs within twelve weeks, preferably within ten weeks, more preferably within eight weeks, 'more preferably within six weeks, more preferably within four weeks from the start of the vaccination program. It is preferred that the level of IgE decrease to a level below 90%, preferably below 80%, more preferably below 70%, more preferably below 60% and much more preferably below 50% of the maximum value. It is preferred that the decrease in IgE level occurs within 26 weeks, preferably within 20 weeks, more preferably within 16 weeks, more preferably within 12 weeks, more preferably within 8 weeks and much more preferably within of 4 weeks from the time of maximum value. In another embodiment of the invention, the IgE level remains at approximately the optimum value once it has been reached. In a further preferred embodiment of the invention, the biomarker antibody is IgA. It is preferred that the IgA level be increased more than 50%, preferably more than 100%, more preferably more than 200%, more preferably more than 300% and much more preferably more than 400% compared to the level in the start of the vaccination program. It is preferred that the increase in IgA level occurs within 20 weeks, preferably within 16 weeks, more preferably within 12 weeks and much more preferably within 8 weeks from the start of administration. In still a preferred embodiment of the invention, the biomarker antibody is IgG. It is preferred that the IgG level be increased more than 50%, preferably more than 100%, more preferably more than 200%, more preferably more than 300% and much more preferably more than 400% compared to the level in the start of the vaccination program. It is preferred that the increase in IgG level occurs within 20 weeks, preferably within 16 weeks, more preferably within 12 weeks and much more preferably within 8 weeks from the start of administration. In a further preferred embodiment of the invention the biomarker antibody is IgX. In a preferred embodiment of the invention, IgX is expressed as the ratio of the IgE level as measured in an immunoassay with competition of other components of the biological sample to the IgE level as measured in an immunoassay without competition. In this embodiment of the invention, it is preferred that the IgX level be decreased more than 4%, preferably more than 6%, more preferably more than 8%, more 'preferably more than 10%, more preferably more than 12%. % and much more preferably more than 14% compared to the level at the start of the vaccination program. It is further preferred that the decrease in IgX level occurs within 24 weeks, preferably within 16 weeks, more preferably within 12 weeks and much more preferably within 8 weeks from the start of administration. The expressions "IgE level", "IgA level", "IgG level" and "IgX level" used above may refer to the levels of the individual test subjects, or, when a group of individuals undergo the vaccination program, the weighted levels of the group or part of the group, such as the average levels of them. Frequently the level of IgA, IgE, IgG and IgX varies from one individual to another, and therefore it is preferred to use a group of two or more, preferably five or more, more preferably ten or more individuals for the test of a vaccination program. Vaccination Protocol In one embodiment of the invention, the vaccination protocol comprises the daily administration of the vaccine to the test individual. In another embodiment of the invention, the vaccination protocol comprises the administration of the vaccine every second day, every third day or every fourth day. For example, the vaccination protocol comprises administering the vaccine for a period of more than 4 weeks, preferably more than 8 weeks, more preferably more than 12 weeks, more preferably more than 16 weeks, more preferably more than 20 weeks, more preferably more than 24 weeks, more preferably more than 30 and much more preferably more than 36 weeks. The period of administration can be a continuous period. Alternatively, the period of administration is a discontinuous period interrupted by one or more periods of non-administration. Preferably, the (total) period of non-administration is shorter than the (total) administration period. In a further embodiment of the invention, the vaccine is administered to the test subject once a day, alternatively, the vaccine is administered to the test individual twice a day. The vaccine can be a unidose vaccine. Measurement of IgE, IgA, IgG and IgX In one embodiment of the invention, the measurement of the level of IgA, IgE and / or antigen specific in a biological sample is carried out by means of ELISA comprising the steps of 1) coating the allergen on an ELISA plate and wash, 2) add the biological sample, incubate and wash, 3) add a conjugate of an enzyme and anti-IgA / IgG / IgE antibody, incubate and wash, 4) add an enzyme substrate, incubate and stop the reaction, and 5) measure the level of substrate reacted. In another embodiment of the invention, the measurement of the level of IgA, IgE and / or IgG specific to the antigen is a biological sample is carried out by a two-site immunoassay (competition immunoassay) comprising the steps of (a) providing a mixture of a liquid phase and a solid-phase complex of four components composed of (i) the antibody of the sample, (ii) a class-specific antibody directed against the antibody to be detected bound to a solid phase, (iii) a ligand in the form of an antigen, an antibody or a hapten, and (iv) a tag compound, to form a four-component solid phase complex, (b) separate the solid phase complex from four phase components liquid, (c) washing the separated four-component solid phase to remove compounds not bound to the complex, (d) performing a detection / measurement of the four-component complex labeled, washed. The immunoassay of two sites can be carried out in a number of variant methods. Optionally, a washing step can be carried out after the market of the reactants (i) and (ii) before the addition of the reactants (iii) and (iv) and / or after the mixing of the reactants (i). ), (ii) and (iii). The solid phase can be, for example, a particulate carrier, such as paramagnetic particles. The label compound can be, for example, a chemiluminescent compound, such as an acridinium ester. The ligand can be linked to biotin in or a functional derivative thereof, and the label compound can be a chemiluminescent compound covalently linked to avidin, streptavidin or a functional derivative thereof, in which case the detection / measurement of the complex of four marked components, washing is carried out at the initiation of a chemiluminescent reaction in the complex and upon detection / measurement of the resulting chemiluminescence, if any.

The immunoassay can be carried out using, for example, an ADVIA Centaur (Bayer). A particular embodiment of the two-site immunoassay (non-competition immunoassay) comprises the steps of (a) mixing (i) the biological sample with (ii) a class-specific antibody directed against the antibody that is detected bound to a solid phase for form a mixture of a liquid phase and a two-component solid phase complex. (b) separating the solid phase complex from two components of the liquid phase and washing the solid phase complex from two separate components to remove compounds not bound to the complex. (c) adding (iii) a ligand in the form of an antigen, an antibody or a hapten, and (iv) a tag compound, to form a four-component solid phase complex. (d) separates the solid phase complex from four components of the liquid phase, (e) washing the separated four-component solid phase to remove compounds not bound to the complex. (f) performing a detection / measurement of the four-component complex labeled, washed. Another particular embodiment of the two-site immunoassay (competition immunoassay) comprises a two-site immunoassay for an antibody using a chemiluminescent label and a ligand bound to biotin, the method comprising the steps of (a) mixing the biological sample with an antigen. of ligand, antibody or hapten bound to biotin or a functional derivative thereof, a class-specific antibody directed against the antibody that is detected bound to paramagnetic particles and a chemiluminescent acridinium compound bound to avidin, streptavidin or a functional derivative thereof for form a four-component solid-phase complex, (b) magnetically separate the four-component solid phase from the liquid phase, (c) wash the four-component solid phase to remove compounds not bound to the complex, (d) initiate a chemiluminescent reaction, if any, in the separated solid phase and detect / measure the chemiluminum resulting inception, if there is one. A further particular embodiment of the two-site immunoassay (non-competition immunoassay) comprises the steps of (a) mixing (i) the biological sample with (ii) a class-specific antibody directed against the antibody that is detected bound to the paramagnetic particles to form a mixture of a liquid phase and a two-component solid phase complex. (b) magnetically separating the solid phase complex from two components of the liquid phase and washing the solid phase complex from two separate components to remove compounds not bound to the complex. (c) adding (iii) a ligand in the form of an antigen, an antibody or a hapten bound to biotin or a functional derivative thereof, and (iv) a chemiluminescent acridinium compound bound to avidin, streptavidin or a derivative or functional of the same brand, to form a solid phase complex of four components. (d) magnetically separating the four-component solid-phase complex from the liquid phase, (e) washing the separated four-component solid phase to remove compounds not bound to the complex. • (f) initiate a chemiluminescent reaction, if any, in the washed solid phase, and detect / measure the resulting chemiluminescence, if any. Preferably, IgX is expressed as the ratio of IgE level as measured in an immunoassay with competition of other components of the biological sample to the IgE level as measured in an immunoassay without competition. In this case, immunoassay without competition can be one of the non-competition immunoassay modalities of two sites as described above, wherein a washing step is carried out after mixing the biological sample and the specific antibody of class is directed against the antibody that is detected bound to a the solid phase, ie, the washing is carried out before the addition of the allergen in order to avoid the competition of the non-IgE antibodies of the biological sample in the IgE antibody binding of the sample to the allergen. The immunoassay with competition can be one of the competition immunoassay modalities of two sites mentioned in the above. Preferably, the biological sample is selected from the group consisting of blood, plasma, serum, urine, saliva and nasal secretion. Vaccine formulations and routes of administration In a preferred embodiment of the invention, the vaccine is selected from the group consisting of vaccines formulated to be adapted for administration via the oromucosa, the mucosa of the respiratory system, the mucosa of the digestive system , the rectal mucosa and the genital mucosa. Preferably, the vaccine is formulated to be adapted for administration by the oromucosal route. In a particular embodiment of the invention, the vaccine is selected from the group consisting of vaccines formulated with a solution, a suspension, a dispersion, an emulsion, rapid dispersion dosage forms, drops, lozenges, a spray, an aerosol, a tablet, a chewable tablet, granules, a powder, a gel, a paste, a syrup, a cream, an ointment, a bar, implants, vagitors, suppositories or uteritories. Preferably, the vaccine is formulated as a fast dispersing dosage form. The formulation may be any conventional formulation suitable for mucosal administration, and in particular the formulation may comprise conventional excipients and adjuvants. Antigens The vaccine antigen evaluated according to the method of the present invention can be any antigen that induces an immune response upon exposure to an individual. In a preferred embodiment of the invention, the antigen is selected from the group consisting of a respiratory antigen, a digestive antigen, a microbial antigen and an insect antigen. In a particular embodiment of the invention, the antigen is a respiratory antigen. In a particular embodiment, the antigen is an allergen, for example, an inhalant allergen or an insect allergen. Other examples of antigens are allergoids, peptides, haptens, carbohydrates, peptide nucleic acids (PNAs, a synthetic genetic imitation classification) and infectious antigens, such as viral or bacterial material, as well as analogs or derivatives thereof. Examples of nutritional substances are vitamins, enzymes, minor elements and minor minerals as well as analogues or derivatives thereof. Examples of medicaments are antibodies, antibiotics, peptides, salts, hormones, hemolytics, hemostats, enzymes, enzyme inhibitors, psychopharmaceuticals, opiates and barbiturates, as well as analogues or derivatives thereof. Allergens In a preferred embodiment of the invention the allergen is any naturally occurring protein that has been reported to induce allergic reactions, ie, mediated by IgE in its repeated exposure to an individual. Examples of naturally occurring allergens include pollen allergens (tree, bush, weed and grass pollen allergens), insect allergens (inhalant, saliva and poisonous allergens, for example mite allergens, cockroach allergens and gnats). hymenoptera venom allergens), hair allergens and animal dander (for example, dog, cat, horse, rat, mouse, etc.) and food allergens. The important pollen allergens of trees, grasses and herbs are such that they originate from the taxonomic orders of Fagales, Oléales, Piñales and Platanaceae including i. to. birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), cedar (Cryptomeria and Juniperus), plane tree (Bananas), the order of Poales including i. to. herbs of the genera Lolium, Phelum, Poa, Cynodon, Dactylis, Holcus, Phalaris, Sécale and Sorghum, the orders of Asterales and Urticales including i. to. herbs of the genera Ambrosia, Artemisia and Parietaria., Other important inhalation allergens are those of domestic dust mite of the genus Dermatophagoides and Euroglyphus, storage mites for example Lepidoglyphys, Glycyphagus and Tyrophagus, those of cockroaches, gnats and fleas for example Blatella , Periplaneta, Chironomus and Ctenocephalides, and those of mammals such as cat, dog and horse, venom allergens including such that originate from stinging or pungent insects such as those of the taxonomic order of Hymenoptera including bees (superfamily) Apidae), wasps (Vespidae superfamily) and ants (Superfamily Formicoidae). The important fungal inhalation allergens are i. to. such that they originate from the genera Alternaría and Cladosporium. In a more preferred embodiment of the invention the allergen is Bet v 1, Aln g 1, Cor a 1 and Carb b 1, Que a 1, Cy j 1, Cry j 2, Cup a 1, Cup s 1, Jun a 1 , Jun to 2, Jun to 3, Ole e 1, Lig v 1, Pia I 1, Pia to 2, Amb a 1, Amb a 2, Amp t 5, Art v 1, Art v2, Par j 1, Par j 2, Par j 3, Sal k 1, Ave e 1, Cyn d 1, Cyn d 7, Dac g 1, Fes p 1, Hol I 1, Lol p 1 and 5, Pha a 1, Pas n 1, Phl p 1, Phl p 5, Phl p 6, Poa p 1, Poa p 5, Sec c 1, Sec c 5, Sor h 1, Der f 1, Der f 2, Der p 1, Der p 2, Der p 7, Der m 1, Eur m 2, Gly d 1, Lep d 2, Bio t 1, Tyr p 2, Bla g 1, Bla g 2, Per a 1, Fed d 1, Can f 1, Can f 2, Bos d 2, Equ c 1, Equ c 2, Equ c 3, Mus m 1, Rat n 1, Apis m 1, Api m 2, Ves v 1, Ves v 2, Ves v 5, Dol m 1, Dil m 2, Dol m 5, Pol a 1, Pol a 2, Pol a 5, Sol i 1, Sol I 2, Sol I 3 and Sun I 4, Alt a 1, Cía h 1, Asp f 1, Bos d 4, Mal d 1, Gly m 1, Gly m 2, Gly m 3, Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5 or hybrids intermingled from the molecular reproduction of any of these. In the most preferred embodiment of the invention, the allergen is a grass pollen allergen or a dust mite allergen or an ambrosia allergen or a cedar pollen or a cat allergen or a birch allergen. In yet another embodiment of the invention, the fast dispersing solid dosage form comprises at least two different types of allergens either originating from the same allergic source or originating from different allergic sources, for example, group allergens. 1 and group 5 of grass or allergens of group 1 and group 2 of mites of different species of mites and grasses repeatedly, weed antigens similar allergens of short and giant ragweed, different allergens and fungi similar to alternaria and cladosporium, tree allergens similar to birch, hazel, carpel, oak and alder allergens, food allergens similar to peanut, soy and milk allergens. The allergen incorporated in the fast dispersing solid dosage form can be in the form of an extract, a purified allergen, a modified allergen, a recombinant allergen or a mutant of a recombinant allergen. An allergenic extract can naturally contain one or more isoforms of the same allergen, while a recombinant allergen typically only represents an isoform of an allergen. A preferred embodiment the allergen is in the form of an extract. In another preferred embodiment the allergen is a recombinant allergen. In a further preferred embodiment the allergen 'is a mutant that binds low IgE that occurs naturally or a mutant that binds recombinant low IgE. The allergens may be present in equimolar amounts or the ratio of the allergens present may preferably vary up to 1:20. In a further embodiment of the invention the allergen that binds low IgE is an allergen according to WO 99/47680, WO 02/40676 or WO 03/096869. Infectious Antigens In a preferred embodiment of the invention, the microbial agent is a virus, a bacterium, a fungus, a parasite or any part thereof. Examples of microbial agents are Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondii, Cytomegalovirus, Chlamydia species, Streptococcal species, Norwaik Virus, Escherischia coli, Helicobacter pylori, Helicobacter felis, Rotavirus, Neisseria gonorrhea, Neisseria meningititis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes Simplex, Clostridia Species, Respiratory Syncytial Virus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross River Virus, JC Virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi, Pasteurella haemolítica, poliovirus, influenza virus, Vibrio cholerae and Salmonella enterica serovar Typhi. Additional examples of microbial agents are those that prevent or reduce the symptoms of the following diseases: Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles , Lyme Disease, Traveler's Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies, Parainfluenza, Rubella, Yellow Fever, Disinterity, Legionnaires Disease, Toxoplasmosis, Q Fever, Hemorrhagic Fever, Argentine Hemorrhagic Fever, Caries , Chagas Disease, Urinary Tract Infection caused by E. coli, Pneumococcal Disease, Mumps and Chikungunya Method for evaluating the effect of SAV in an individual The invention also relates to a method for evaluating the effect of Vaccination for Specific Allergy (SAV) in an individual, the method comprising a) subjecting an individual to SAV, • b ) measure the level of a biomarker antibody selected from the group consisting of IgA, IgG, IgE and IgX specific to the antigen in a biological sample of the individual, and c) use the measurements obtained to evaluate the effect of the SAV. The evaluation of the SAV effect is carried out in the same manner as described in relation to the method for evaluating the therapeutic potential of the vaccination program. DEFINITIONS In relation to the present invention, the following expressions are used: "Biological sample" means any body fluid, such as blood, plasma, serum, urine and saliva, which is excreted, secreted or transported within a biological organism. The term "allergy" means any type 1, 2, 3 or 4 hypersensitivity allergy to an antigen. The term "digestive antigen" means any antigenic agent that enters into contact with the mucosa of the digestive system, in particular the mucosa of the oral cavity, pharynx, larynx, stomach and intestine. The term "respiratory antigen" means any antigenic agent that comes into contact with the mucosa of the respiratory system, in particular the mucosa of the nose, the oral cavity, the pharynx, the larynx, the trachea and the lungs. The term "antigen" means any antigen, to which an individual may be exposed, and refers to any compound or substance that occurs naturally or synthetically or a part or fraction thereof that has been reported may be shown to induce an immune response in the expression of an individual. The term "allergen" means any allergen, to which an individual may be expressed, and refers to any naturally occurring protein or protein mixture that has been reported to induce allergic, ie, IgE-mediated, reactions in the exposure repeated to an individual. The allergen evaluated may be in the form of an allergen extract, a purified allergen, a modified allergen, a recombinant allergen, a recombinant mutant allergen, any allergen fragment above 10 amino acids or any combination thereof. The term "rapid dispersion dosage form" refers to dosage forms that disintegrate in less than about 90 seconds, preferably in less than 60 seconds, preferably less than 30 seconds, more preferably in less than 20, even more preferably less than 10 seconds in the oral cavity, even more preferred in less than 5, much more preferably in less than about 2 seconds of being placed in the oral cavity. The term "oromucose" means the mucosa of the oral cavity and the pharynx of the patient. The expression "mucosa of the respiratory system" means the mucosa of the nose, the oral cavity, the pharynx, the larynx, the trachea and the lungs. The expression "mucosa of the digestive system" means the mucosa of the oral cavity, pharynx, larynx, stomach and intestine. The term "genital mucosa" means the vaginal and urinal mucosa. The term "therapeutic potential" means capable of partially or completely preventing or treating an immunological disease mediated by antigen, or capable of partially or completely alleviating symptoms or inhibiting the causes of symptoms of an immunological disease mediated by antigen. The term "IgX" means a parameter that directly or indirectly expresses the level of non-allergen-specific IgE antibody, such as IgG4, present in the biological sample, which can compete with IgE at the allergen link. IgX may be, for example, the level of absolute IgX or the IgE ratio as measured in an immunoassay with competition (interference) of other components of the biological sample at the IgE level as measured in an immunoassay without competition. EXAMPLES EXAMPLE 1: TREATMENT OF ALLERGIC PATIENTS TO GRASS POLLEN WITH NON-COMPRESSED SUBLINGUAL TABLETS OF DISPERSION R REQUEST Background A vaccine against grass pollen allergy using a Fleum pratense extract as an allergically active substance is known to be effective in a formulation for subcutaneous administration, wherein the allergen is formulated together with an aluminum hydroxide gel as an adjuvant. Purpose To test the therapeutic potential (efficacy) of a new formulation of Fleum pratense extract in the form of a tablet freeze dried, non-compressed, fast dispersed for sublingual administration, the tablet that does not contain adjuvant. The tablet contained fish gelatin as the matrix forming agent. The efficacy study is a clinical part of a clinical phase I study, which also includes a safety study. Vaccination Protocol Test persons 48 adult test persons between 18 and 65 years of age who suffer from moderate to severe allergic rhinoconjunctivitis in the grass pollen season and who have no symptoms outside the season. The inclusion criteria were 1) the clinical history of the test person, 2) a positive skin prick test (> 3mm on a Soluprick © SQ-U HEP Felum pratense) and 3) positive IgE specific against Fleum pratense (CAP class 2 or higher). Dosage and administration program The 48 test persons were divided into four groups A, B, C and D each comprising 12 people. Group A (2,500 SQ-U) is treated with a tablet containing 2,500 SQ-U and two placebo tablets. Group B (25,000 SQ-U) is treated with a tablet containing 25,000 SQ-U and two placebo tablets. Group C (75,000 SQ-U) is treated with three tablets containing 25,000 SQ-U. Group D is treated with three placebo tablets. The three tablets were administered once each day for 8 weeks. The 8 weeks of treatment were followed by 10 weeks of no treatment and then the same treatment is carried out and the initial 8 weeks are continued in 15 weeks. Before the efficacy test 45 of people have participated in a safety study, where 30 people have been given increased doses of 2,500 to 1,125,000 SQ-U and 15 people have been given placebo. Measurements Blood serum samples were obtained after 0, 3-5 and 7-8 weeks of the 8-week treatment period as well as 2 weeks after the end of the 15-week treatment period. The level of IgE, IgA and IgC were measured using the tests summarized below. Test procedure for measuring IgE IgE was measured in an ADVIA Centaur (Bayer) using a two-site immunoassay with the following procedure: (a) mixing the liquid sample with a class-specific antibody directed against the antibody that is detected bound to paramagnetic particles to form a first complex of solid phase, b) wash, (c) add the allergen Fleum pratense bound to biotin to form a second solid phase complex (d) add a chemiluminescent acridinium compound bound to streptavidin to form a third phase complex. solid, (e) magnetically separate the solid phase from the liquid phase, (f) wash, (g) initiate a chemiluminescent reaction, if any, in the separated solid phase and (h) measure the chemiluminescence emitted, which is indicative of the presence of the antibody in the sample. Test procedure to measure IgA and IgG 1 .. Coating. 100 μl of Phl p extract (10 μg / ml) is added to the cavities of an ELISA plate (NUNC Maxisorp 439454). The plates are allowed to stand until the next day at 2-8 ° C. 2. Washing. The coated plates are washed with a buffer solution. 3. Blocking. 200 μl of 2% Casein buffer is added to each well and incubated at room temperature for one hour on a shaking table. After incubation, the Casein buffer is removed. 4. Serum The serum sample is diluted, and 100 μl of diluted sample is added to the cavity of a plate and incubated at room temperature for two hours on a shaking table. 5. Washing. 6. Conjugate. 100 μl of HRP mouse antihuman IgG / IgA diluted 1: 1000 in 0.5% Casein buffer is added to each well and allowed to stand at room temperature for one hour on a shaking table. 7. Washing 8. Substrate: 100 μl of TMP (3, 3 ', 5, 5' -Tetramethylbenzidine, Jem-En-Tec TMB ONE) is added to each well and incubated at 20 min. 9. Detention. 100 μl of 0.5 M H2SO4 is added to each well to stop the reaction. 10. Measurement. The resulting reaction mixture is subjected to a spectrophotometric measurement at a final point of 450 nm (Bio Kinetics Reader EL-340). Results The results are shown in Figs. 1-12, wherein Fig. 1-4 shows the IgE levels for groups A, B, C and D, respectively, Figs. 5-8 show the IgA levels for groups A, B, C and D, respectively, and Is Figs. 9-12 shows the IgG levels for groups A, B, C and D, respectively, and where each figure indicates the level of antibody (kU / L for IgE and the relative titer as compared to a reference serum of an allergic patient for IgA and IgG) for the four points of time of the measurement (week 0, week 4 (samples obtained in 3-5 weeks), week 8 (samples obtained in 7-8 weeks) and Final (two weeks after at the end of the 15-week treatment period.) The antibody level is the mean value for the treated group, and from Fig. 1-4 the following appears: In Treatment Group A (Placebo) no increase in the level of IgE is recorded during the administration period.

Treatment group B (2500 SQ), a continuous increase in the IgE level from 29 to 58 is recorded during the period.

For Treatment Group C (25000 SQ), a continuous increase of 31 to 94 is observed. Finally, for Treatment Group D (75000SQ), the IgE level rises sharply from 34 to 0 weeks at a maximum value of 168 in 4 weeks, and then drops to 159 in 8 weeks and in addition to 86 in the Final. The time profile for Group D is considered to represent a desired profile, which means a Vaccination for Effective specific allergy. From Figs. 5-8 it is presented that no increase in the IgA level is recorded for treatment groups A and B. For Groups C and D of treatment the level of IgA is permanently increased during the administration period. From Figs. 9-12 shows that no increase in the IgG level is recorded for treatment groups A and B. For treatment groups C and D, the level of IgG is permanently increased during the administration period. The results shown in Fig. 1-12 are also listed in Table 1. Table 1 EXAMPLE 2: TREATMENT OF ALLERGIC PATIENTS TO GRASS POLLEN WITH NON-COMPRESSED, QUICK-DISPERSED SUBLINGUAL TABLETS Background A vaccine against grass pollen allergy using an extract of Flem pratense as an allergenic active substance is known to be effective in a formulation for subcutaneous administration, wherein the allergen is formulated together with an aluminum peroxide gene as an adjuvant. Purpose To test the therapeutic potential (efficacy) of a new formulation of Fleum pratense extract in the form of freeze-dried, non-compressed, fast-dispersed tablet for lingual administration, the tablet containing no adjuvant. The tablet contained fish gelatin as matrix forming agent. The efficacy study is part of a clinical phase I study, which also includes a safety study. Vaccination Protocol Test persons 9 adult test persons between 18 and 65 years of age who suffer from moderate to severe allergic rhinoconjunctivitis in the grass pollen season and who have no symptoms outside the season. The inclusion criteria were 1) the clinical history of the test person, 2) a positive skin prick test (> 3mm on a Soluprick © SQ-U HEP Felum pratense) and 3) positive IgE specific against Fleum pratense (CAP class 2 or higher). Dosage and administration schedule The 6 test subjects were treated with a number of tablets corresponding to a daily dose of 1,000,000 SQ-U for a period of 28 days and 3 people were treated with placebo for the same period. Measurements Biological samples were obtained at the beginning of and in 1-2 weeks after the last day of treatment. The level of IgE was measured using the assay described in Example 1. Results The results are shown in Figs. 13-14, where Fig. 13 shows the IgE level for the group of patients treated with placebo at the start of and in 1-2 weeks after a treatment period, and where Fig. 14 shows the level of IgE for group of patients treated with a dose of 1000000 SQ at the beginning of and in 1-2 weeks after a period of treatment. As will be presented -from Fig. 13, the IgE level is unchanged during the treatment period for the placebo group, while the IgE level increases from approximately 0.31 to approximately 1.79. EXAMPLE 3: TREATMENT OF ALLERGIC PATIENTS TO GRASS POLEN WITH NON-COMPRESSED SUBLINGUAL TABLETS OF QUICK DISPERSION Background A vaccine against a grass pollen allergy using an extract of Flem pratense as an allergenic active substance is known to be effective in a formulation for administration subcutaneous, wherein the allergen is formulated together with an aluminum hydroxide gene as an adjuvant. Purpose To test the therapeutic potential (efficacy) of a new formulation of Fleum pratense extract in the form of a freeze-dried tablet, non-compressed, fast-dispersed tablet for sublingual administration, the tablet containing no adjuvant. The tablet contained fish gelatin as matrix forming agent. The efficacy study constitutes a part of a clinical phase IIb-III study. Vaccination Protocol Test persons 855 adult test persons between 18 and 65 years of age who suffer from moderate to severe allergic rhinoconjunctivitis at the grass pollen season and who have no symptoms outside the station. The inclusion criteria were 1) the clinical history of the test person, 2) a Positive Skin Puncture Test (> 3mm on a Soluprick © SQ-U HEP Felum pratense) and 3) positive IgE specific against Fleet pratense (CAP class 2 or higher). Test persons lived in Denmark, Germany, Sweden, Norway, Belgium, Austria, England, Switzerland and Canada.

Dosage and administration program The 855 test persons were divided into six groups 1, 2, 3, 4, 5 and 6 comprising 136, 136, 139, 141, 1509 and 153 people, respectively. Group 1 was treated with placebo and active antihistamine. Group 2 was treated with an allergen dose of 2500 SQ and active antihistamine. Group 3 was treated with an allergen dose of 25,000 SQ and active antihistamine. Group 4 was treated with an allergen dose of 75,000 SQ and active antihistamine. Group 5 was treated with placebo and placebo antihistamine.

Group 6 was treated with a dose of allergen of 75,000 SQ and antihistamine of placebo. The treatment was carried out daily for approximately 8 weeks before the early start of the pollen station of Fleum pratense (pretreatment period), through the pollen season and for a week after the pollen season (Post period). -treatment). The duration of the pollen season varied from 12 days in Tronheim (Norway) to 86 days in Karisruhe, Germany. Measurements Blood samples were removed at the start of the pretreatment period (Pretreatment in Fig. 15-22), at the start of the pollen season (Treatment in Figs. 15-22) and at the end of the Post-treatment period. Treatment (Post-treatment in Figs 15-22). The IgE level was measured using the assay described in Example 1. The IgX parameter was determined as IgE level (competition) / IgE level (without competition). The level of IgE (without competition) was measured using the assay described in Example 1. IgE (competition) level was measured using the following test procedure: (a) mixing the liquid sample with a class-specific antibody directed against the antibody that is detected linked to paramagnetic particles to form a first complex of the solid phase. (b) adding the Fleum pratense allergen bound to biotin to form a second solid phase complex. (c) adding a chemiluminescent acridinium compound linked to streptavidin to form a third solid phase complex. (d) magnetically separating the solid phase from the liquid phase. (e) washing (f) initiating a chemiluminescent reaction, if any, in the separated solid phase and (h) measuring the chemiluminescence emitted, which is indicative of the presence of the antibody in the sample. Results The IgE results are shown in those in Figs. 15-18 and Table 2 and 3, where Fig. 15 shows the IgE level for Groups 1-4 for the ITT population, Fig. 16 shows the IgE level for groups 1, 5 and 6 for the ITT population, Fig. 17 shows the IgE level for Groups 1-4 for the PP population and Fig. 18 shows the IgE level for groups 1, 5 and 6 for the PP population. ITT means intention to treat and includes all the people - who start in the study, and PP means by Protocol and includes all the people treated according to the planned protocol. Table 2 contains all the values of Figs. 15 and 16 and Table 3 contains all the values of Figs. 15, 17 and 18. As will be presented in Figs. 15-18 and Tables 2 and 3, for Groups 1 and 5 no increase in the IgE level of the Pretreatment to the Treatment is recorded, and an increase in small and a level of IgE of the Treatment to the Post-treatment is recorded . For Group 2 a moderate permanent increase in the level of IgE is recorded. For Groups 3, 4 and 6 an acute increase in the IgA level from Pretreatment to Treatment is recorded followed by a leveled phase of the Post-treatment Treatment. For Group 4, the level of IgE decreases slightly during the level phase. The time profile of Group 3, 4 and 6, particularly Group 4, is considered to represent a desired profile, which means an effective Specific Allergy Vaccination. The IgX results are shown in Figs. 19-22 and Tables 4 and 5, where Fig. 19 shows the IgX level for Groups 1-4 for the ITT population, Fig. 20 shows the IgX level for groups 1, 5 and 6 for the ITT population, Fig. 21 shows the IgX level for Groups 1-4 for the PP population and Fig. 22 shows the IgX level for groups 1, 5 and 6 for the PP population. ITT means intention to treat and includes all persons who initiate the study, and PP means by Protocol and includes all persons, treated in accordance with the planned protocol. Table 4 contains all the values of Figs. 19 and 20 and Table 5 contains all the values of Figs. 21 and 22. As will be presented in Figs. 19-22 and the Tables 4 and 5, for Groups 1 and 5 no decrease in the IgX level of Pretreatment to Treatment is recorded, and a small decrease in the IgX level for Post Treatment Treatment is recorded. For Groups 2 and 3 a moderate permanent decrease in the level of IgX is recorded. For Groups 4 and 6 a sharp decrease in the IgX level from Pretreatment to Treatment is recorded followed by a less severe decrease in Post-treatment Treatment. For Group 4, most of the decrease in IgX level occurs in the Pretreatment to Treatment period. The time profile of Groups 4 and 6, particularly Group 4, is considered to represent a desired profile, which means an effective Specific Allergy Vaccination. or Table 2. grass-specific gE (kU / L) for ITT Population Group - \ Group 2 Group 3 Group 4 Group, 5 Group Q Placebo 2500SQ 25000SQ 75000SQ Placebo 75000SQ + Astive + Active + Astive + Active + Placebo + Total Placebo Visit (N = 136) (N = 136), (N = 139) (N = 141) (N = 150) (N = 153) (N = 855) Pretreatment N 136 135 139 139 148 153 850 Medium (SD) 25.7 (34.4) 3.8 (47.2) 27.2 (34.6) 27.1 (45.8) 18.8 (28.0) 29.1 (44.4) 26.9 (39.8) ^ dio -] 2.4 14.0 12.7 12.4 10.1 10.6 12.0 P5% -P95% 1.3-109.0 1.6-120.9 0.8-115.4 1.1-97.2 0.5-71.4 0.7-133.8 0.8-107.4 Min-Max 0.3-201.5 0.2-271.8 0.4-207.1 0.4-360.6 0.1-185.6 0.2-229.6 0.1-360.6 Treatment N 130 131 130 131 142 145 809 Medium (SD) 22.7 (29.5) 57.1 (87.5) 88.3 (104.6) 103.0 (126.1) 17.5 (28.3) 105.7 (133.2) 65.8 (101.4) Medium 11.2 24.9 46.4 63.4 9.3 57.0 26.6 P5% -P95% 0.9-92.8 1.6-173.1 1.9-326.8 3.0-355.5 0.4-63.5 2.7-340.2 1, 2-258.8 Min-Max 0.2-148.8 0.2-702.1 0.5-563.3 1.1-705.6 0.0-233.4 0.5-901.7 0.0-901 J I > .o l After treatment N 130 131 130 133 142 146 812 Medium (SD) 40J (53.1) 74.8 (96.1) 94.1 (107.5) 99.5 (129.4) 30.2 (46.7) 111.1 (136.7) 75.2 (105.6) Medium 18.9 38.6 53.7 58.3 15.4 59.7 36.1 P5% -P95% 1.5-154.1 2.8-250.2 2.8-360.0 3.3-350.6 1.0-101.6 4.5-356: 0 1.9-290.1 Min-Max- 0.3-286.8 0.3-675.5 1.6-554.9 1.5-7157 0.0-278.9 1.1-928.8 0.0-928.8 Table 3. Herbic specific IgE (kU / L) for PP population Group * (Group 2 Group 3 Group 4 Group 5 Group Q Placebo 2500SQ 25000SQ 75000SQ Placebo 75000SQ + Active + Active + Active + Astive + Piacebo + Total Placebo Visit (N = 122) (N = 122) (N = 125) (N = 124) (N = 128) (N = 127) (N = 748) Pretreatment N 122 121 125 122 127 127 744 Medium (SD) 25.3 (35.0) 34.7 (48.6) 25.7 (34.5) 27.7 (48.1) 19.4 (287) 26.4 (40.3) 26.5 (39.9) Medium 12 1 14.1 11, 0 11.9 11.1 10.5 11, 6 t O P5% -P95% 1.3-109.0 1.6-120.9 0.8-103.1 1, 5-97.2 0.4-71.4 0.6-107.1 0.8-109.0 Min-Max 0.3-201.5 0.2-271.8 0.4-207.1 0.4-360.6 0.1-185.6 0.2-219.0 0.1-360.6 Treatment N 122 121 123 123 127 127 743 Medium (SD) 22.3 (29.2) 58.9 (90.2) 857 (102.5) 102.4 (127.9) 17.6 (28.9) 104.1 (133.2) 65.2 (101.4) Medium 11.2 25.0 44.9 63.3 9.3 57.0 267 P5% -P95% 0.9-92.8 17-173.1 1.9-280.4 3.4-355.5 0.4-63.5 27-327.4 1.3-251.3 Min-Max 0.2-148.8 0.2-702.1 0.5-563.3 1, 1-705.6 0.0-233.4 0.5-9017 0.0-9017 Post treatment N 122 121 121 123 127 126 740 Medium (SD) 40.9 (54.3) 77.8 (98.8) 92.2 (1057) 98.4 (131.2) 29.2 (44.4) 1077 (136.5) 74.3 (105.3) Medium 18.5 38.6 53.2 57.8 15.7 53.2 34.9 P5% -P95% 1, 5-154.1 3.2-250.2 2.8-3247 3.3-350.6 07-94.0 3.1-356.0 2.0-288.4 Min-Max 0.3-286.8 0.5-675.5 1.6-554.9 1, 5-7157 0.0-278.9 1.1-928.8 0.0-928.8 t t Ul O Table . Grass-specific IgX for ITT Population Group 1 Group 2 Group 3 Group 4 Group 5 Group Q Placebo 2,500 SQ 25,000 SQ 75,000 SQ Placebo 75,000 SQ + Active + Active + Active + Astive + P | aCßb? + PlßCß O Total Visit (N = 136) (N = 136). (N = 139) (N = 141) (N = 150) (N = 153) (N = 855) Pre-treatment N 136 135 139 139 148 153 850.

Medium (SD) 1.097 (0.15) 1.101 (0.15) 1.111 (0.16) 1.075 (0.13) 1.101 (0.21) 1.091 (0.18) 1.096 (0.16) Medium 1.08 1.08 1.09 1.07 1.07 1.08 1.08 P5% -P95% 0.88-1.37 0.90-1.37 0.90-1.42 0.87-1.30 0.87-1.44 0.85-1, 39 0.88-1, 38 Min-Max 0.80-175 0.81-1, 64 0.66-178 079-1.44 0.67-2.68 0.57-1.69 0.57-2.68 Treatment N 130 131 130 131 142 145 809 Medium (SD) 1,107 1,082 (0.14) 1,060 (0.17) 0.988 (0.13) 1,113 (0.25) 0.990 (0.16) 1.056 (0.18) Medium 1.09 1.06 1.02 1.00 1.07 0.97 1.03 P5% - P95 % 0.88-1.41 0.90-1.35 0.88-1.46 0.80-1.20 0.86-1.46 077-1.25 0.83-1.35 t Ul t Min-Max 077-176 0.83-1.53 0.64-176 0.55-1.39 079-3.19 0.47-1.48 0.47-3.19 Post-treatment N 130 131 130 133 142 146 812 Medium (SD) 1.087 (0.16) 1.058 (0.14) 1.015 (0.16) 0.964 (0.16) 1.110 (0.27) 0.934 (0.17) 1.027 (0.19) Medium 1.07 1.03 '0.99 0.95 1.07 0.95 1.02 P5% -P95% 0.87-1.35 0.88-1.33 0.81-1.38 071-1.20 0.87-1.44 0.67-1.19 0.78-1.32 Min-Max 076-1.65 070-1.62 0.56-1.64 0.53-1.65 0.80-3.48 0.29- 1.24 0.29-3.48 Ul Ul Table 5. Grass-specific IgX for Population PP Group 1 Group 2 Group I 3 Group 4 Group 5 Group Q Placebo 2,500 SQ 25,000 SQ 75,000 SQ Placebo 75,000 SQ + Astive + Active + Active + Active + Placebo + Total Placebo Visit (N = 122) (N = 122) - (N = 125) (N = 124) (N = 128) (N = 127) (N = 748) Pretreatment N 122 121 125 122 127 127 744 to t Ul Medium (SD) 1.103 (0.15) 1.103 (0.15) 1.114 (0.17) 1.070 (0.12) 1.103 (0.22) 1.088 (0.18) 1.097 (0.17) Medium 1.08 1, 10 1.09 1.07 1, 07 1.07 1.08 P5% - P95% 0.89 -1.37 0: 90-1.37 0.91-1.42 0.88-1.29 0.87-1.44 0.84-1.40 0.88-1.39 Min-Max 0.80-175 0.81-1.64 '0.66-178 079-1.44 0.67-2.68 0.57-1.69 0.57- 2.68 Treatment N 122 121 123 123 127 127 743 Medium (SD) 1.110 (0.16) 1.086 (0.13) 1.060 (0.17) 0.985 (0.13) 1.117 (0.25) 0.989 (0.16) 1.058 (0.18) M ^ ÍO .09 1.06 1, 02 1.00 1.07 0.97 1.04 P5% -P95% 0.88-1.41 0.90-1.35 0.88-1, 46 0.80-1.20 0.86-1.40 077-1.25 0.83-1.35 Min-Max 077-176 0.83-1.53 0.64-176 0.55-1.39 0.81-3.19 0.47-1.48 0.47-3.19 Post treatment N 122 121 121 123 127 126 740 Medium (SD) 1,090 (0.16) 1,057 (0.13) 1,014 (0.17) 0.960 (0.16) 1,113 (0.28) 0.929 (0.17) 1.027 (0.20) Medium 1.07 1.04 0.99 0.94 1.07 0.95 1.02 P5% -P95% 0.88-1.35 0.88-1, 32 0.81-1.38 071-1.20 0.87-1.44 0.65-1.19 079-1.32 Min-Max 076-1.65 070-1.62 0.56-1.64 0.53-1, 65 0.80-3.48 0.29-1.24 0.29-3.48

Claims (44)

1. CLAIMS 1. A method for evaluating the therapeutic potential of a vaccination program comprising a vaccine for administration by the mucosa, comprising one or more antigens and a vaccination protocol, the method characterized in that it comprises a) subjecting at least a test individual to the vaccination program, b) measure the level of a biomarker antibody selected from the group consisting of IgA, IgG, IgE and IgX specific to the antigen in a biological sample of the test individual, and c) use the measurements obtained for evaluate the therapeutic potential of the vaccination program.
2. 2. A method according to claim 1, characterized in that the evaluation of the obtained measurements is carried out by comparison with a reference biomarker antibody level profile of reference.
3. 3. A method according to claim 1 or 2, characterized in that the biomarker antibody is IgE.
4. 4. A method according to claim 2 or 3, characterized in that the level of IgE is increased more than 50%, preferably more than 100%, more preferably more than 200%, more preferably more than 300% and more preferably more than 400% compared to the level at the start of the vaccination program.
5. 5. A method according to claim 4, characterized in that the increase in the level of IgE occurs within twelve weeks, preferably within ten weeks, more preferably within eight weeks, preferably within four weeks from the start of the vaccination program.
6. 6. A method according to any of claims 2-5, characterized in that the level of IgE has a maximum value followed by a decrease.
7. 7. A method according to claim 6, characterized in that the maximum value of the IgE level occurs within twelve weeks, preferably within ten weeks, more preferably within eight weeks, and more preferably within four weeks. since the beginning of the vaccination program.
8. 8. A method according to claim 6 or 7, characterized in that the level of IgE decreases to a level below 90 %%, preferably below 80%, more preferably below 60%, more preferably below 50% and much more preferably below the maximum value.
9. 9. A method according to claim 8, characterized in that the decrease in IgE level occurs within 26 weeks, preferably within 20 weeks, more preferably within 16 weeks, more preferably within 12 weeks, and more preferably within 8 weeks and much more preferably within 4 weeks from the time of the maximum value.
10. 10. A method according to any of the preceding claims, characterized in that the biomarker antibody is IgA.
11. 11. A method according to claim 10, characterized in that the level of IgA is increased more than 50%, preferably more than 100%, more preferably more than 200%, more preferably more than 300% and much more than preference more than 400% compared to the level at the start of the vaccination program.
12. 12. A method according to claim 11, characterized in that the increase in IgA level occurs within 20 weeks, preferably within 16 weeks, more preferably within 12 weeks, and much more preferably within 8 weeks from the beginning of the administration.
13. 13. A method according to any of the preceding claims, characterized in that the biomarker antibody is IgG.
14. 14. A method in accordance with the claim 13, characterized in that the level of IgG is increased more than 50%, preferably within 100%, more preferably more than > 200%, more preferably more than 300% and much more preferably more than 400% compared to the level at the start of the vaccination program.
15. 15. A method according to claim 14, characterized in that the increase in the level of IgG occurs within 20 weeks, preferably within 16 weeks, more preferably within 12 weeks, and much more preferably within 8 weeks from the start of administration.
16. 16. A method according to any of the preceding claims, characterized in that the biomarker antibody is IgX.
17. 17. A method according to claim 16, characterized by IgX is expressed as the ratio of IgE level as measured in an immunoassay with competition of other components of the biological sample to the IgE level as measured in an immunoassay without competition. .
18. 18. A method according to claim 17, characterized in that the level of IgX decreases more than 4%, preferably more than 6%, more preferably more than 8%, more preferably more than 10%, more preferably more of 12% and much more preferably more than 14% compared to the level at the start of the vaccination program.
19. 19. A method according to claim 18, characterized in that the decrease in IgX level occurs within 24 weeks, preferably within 16 weeks, more preferably within 12 weeks, and much more preferably within 8 weeks from the beginning of the administration.
20. 20. A method according to any of the preceding claims, characterized in that the vaccination protocol comprises administering the vaccine to the test individual every day, every second day, every third day or every fourth day.
21. 21. A method in accordance with the claim 20, characterized in that the vaccination protocol comprises administering the vaccine for a period of more than 4 weeks, preferably more than 8 weeks, more preferably more than 12 weeks, more preferably more than 16 weeks, more preferably more of 20 weeks, more preferably more than 24 weeks, more preferably more than 30 weeks and much more preferably more than 36 weeks.
22. 22. A method according to claim 21, characterized in that the period of administration is a continuous period.
23. 23. A method in accordance with the claim 21, characterized in that the period of administration is a discontinuous period interrupted by one or more periods of non-administration.
24. 24. A method according to claim 23, characterized in that the period of non-administration is shorter than the period of administration.
25. 25. A method according to any of claims 20-24, characterized in that the vaccine is administered to the test individual once a day.
26. 26. A method according to any of claims 20-25, characterized in that the vaccine is administered to the test individual twice a day.
27. 27. A method according to any of claims 20-26, characterized in that the vaccine is a vaccine unit dose.
28. 28. A method according to any of claims 1-27, characterized in that the vaccine is selected from the group consisting of vaccines formulated to be adapted for administration by the oromucosal route, the mucosa of the respiratory system, the mucosa of the digestive system, rectal mucosa and genital mucosa.
29. 29. A method according to claim 28, characterized in that the vaccine is formulated to be adapted for administration by the oromucose route.
30. 30. A method according to any of the preceding claims, characterized in that the vaccine is selected from the group consisting of vaccines formulated as a solution, a suspension, rapid dispersion dosage forms, drops and pills.
31. 31. A method in accordance with the claim 30, characterized in that the vaccine is formulated as a fast dispersing dosage form.
32. 32. A method according to any of the preceding claims, characterized in that the antigen is selected from the group consisting of a respiratory antigen, a digestive antigen, a microbial antigen and an insect antigen.
33. 33. A method in accordance with the claim 32, characterized in that the antigen is a respiratory antigen.
34. 34. A method in accordance with the claim 32 or 33, characterized in that the antigen is an allergen.
35. 35. A method in accordance with the claim 34, characterized in that the allergen is an inhalant allergen.
36. 36. A method according to any of the preceding claims, characterized in that the measurement of the level of biomarker antibody IgA, IgG and / or IgE specific for the antigen in a biological sample is carried out by means of an ELISA comprising the steps of 1. ) coat the allergen on an ELISA plate and wash, 2) add the biological sample, incubate and wash, 3) add a conjugate and an enzyme and antibiomarker antibody, incubate and wash, 4) add an enzyme substrate, incubate and stop the reaction, and 5) measure the level of substrate reacted.
37. 37. A method according to any of claims 1-35, characterized in that the measurement of the level of IgA, IgE and / or IgG specific to the antigen in a biological sample is carried out by a two-site immunoassay comprising the steps (a) mixing (i) the biological sample with (ii) a class-specific antibody directed with the antibody that is detected bound to a solid phase to form a mixture of a liquid phase and a two-component solid phase complex, (b) separating the solid phase complex from two components of the liquid phase and washing the solid phase complex from two separate components to remove compounds not bound to the complex, (c) adding (iii) a ligand in the form of an antigen, an antibody or a hapten, and (iv) a tag compound, to form a four-component solid phase complex. (d) separating the solid-phase complex from four components of the liquid phase, (e) washing in the separated four-component solid phase to remove compounds not bound to the complex, (f) performing a detection / measurement of the complex of four. marking, washing components.
38. 38. A method in accordance with the claim 37, characterized in that the two-site immunoassay comprises a two-site immunoassay for an antibody using a chemiluminescent label and a ligand bound to biotin, the method comprising the steps of (a) mixing (i) the biological sample with (ii) a class-specific antibody directed against the antibody that is detected bound to paramagnetic particles to form a mixture of a liquid phase and a two-component solid-phase complex, (b) magnetically separate the solid-phase complex from two-phase components liquid and wash the solid phase complex of two separate components to remove the compounds not bound to the complex, (c) add (iii) a ligand in the form of an antigen, an antibody or a hapten linked to biotin or a functional derivative of the same and (iv) a chemiluminescent acridinium compound bound to avidin, streptavidin or a functional derivative thereof, to form a solid phase complex. It has four components. (d) magnetically separating the four-component solid-phase complex from the liquid phase, (e) washing the separated four-component solid phase to remove compounds not bound to the complex, (f) initiating a chemiluminescent reaction, if any, in the washed solid phase, and detect / measure the resulting chemiluminescence, if any.
39. 39. A method according to any of the preceding claims, characterized in that IgX is determined as the ratio of the level of IgE as measured in an immunoassay with competition of other components of the biological sample to the level of IgE as measured in an immunoassay. without competition.
40. 40. A method in accordance with the claim 39, characterized in that IgE is measured in an immunoassay with competition is measured in an immunoassay comprising the steps of: (a) mixing the biological sample with a ligand, antibody or hapten antigen bound to biotin or a functional derivative thereof, a class-specific antibody directed against the antibody that is detected bound to paramagnetic particles and a chemiluminescent acridinium compound bound to avidin, streptavidin or a functional derivative thereof to form a four-component solid-phase complex, (b) magnetically separate the phase solid of four components of the liquid phase, (c) wash the solid phase of four separate components to remove compounds not bound to the complex, (d) initiate a chemiluminescent reaction, if any, on the separated solid phase and detect / measure the resulting chemiluminescence, if any.
41. 41. A method according to claim 39 or 40, characterized in that IgE as measured in an immunoassay without competition is measured in an immunoassay comprising the steps of: (a) mixing (i) the biological sample with (ii) a class-specific antibody directed against the antibody that is detected bound to paramagnetic particles to form a mixture of a liquid phase and a two-component solid phase complex, (b) magnetically separate the two-component solid phase complex from the liquid phase and washing the two-component solid phase complex to remove the compounds not bound to the complex, (c) adding (iii) a ligand in the form of an antigen, an antibody or a hapten linked to biotin or a functional derivative thereof and (iv) a chemiluminescent acridinium compound bound to avidin, streptavidin or a functional derivative thereof, to form a four-component solid-phase complex, (d) separating Gnostically the solid-phase complex of four components of the liquid phase, (e) washing the separated four-component solid phase to remove compounds not bound to the complex, (f) initiating a chemiluminescent reaction, if any, into the solid phase washed, and detect / measure the resulting chemiluminescence, if any.
42. 42. A method according to any of the preceding claims, characterized in that the biological sample is selected from the group consisting of blood, plasma, serum, urine, saliva and nasal secretion.
43. 43. A vaccine, characterized in that it can be obtained by the method according to any of claims 1-42.
44. 44. A method to evaluate the effect of Vaccination for Specific Allergy (SAV) by the mucosa in an individual, the method characterized because it comprises a) subjecting the individual to the SAV by the mucosa, b) measuring the level of a biomarker antibody selected from the group consisting of IgA, IgG, IgE and IgX specific to the antigen in a biological sample of the individual, and c) using the measurements obtained to evaluate the effect of the SAV.