US20180008702A1 - Adjuvant composition containing at least one influenza virus neutralizing and binding molecule and vaccine composition containing same - Google Patents
Adjuvant composition containing at least one influenza virus neutralizing and binding molecule and vaccine composition containing same Download PDFInfo
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- US20180008702A1 US20180008702A1 US15/533,269 US201515533269A US2018008702A1 US 20180008702 A1 US20180008702 A1 US 20180008702A1 US 201515533269 A US201515533269 A US 201515533269A US 2018008702 A1 US2018008702 A1 US 2018008702A1
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Definitions
- the present invention relates to an adjuvant composition comprising at least one binding molecule for neutralizing influenza virus and a vaccine composition comprising the same, and more particularly to an adjuvant composition including at least one human monoclonal antibody having neutralizing activity against influenza virus, which functions as an adjuvant for enhancing an immune response induced by a vaccine to thus increase the efficacy of the vaccine, and to a vaccine composition comprising the same.
- Influenza which is an illness caused by infecting the respiratory tract with an influenza virus, is common in the winter and is highly infectious and easily spread to all ages, and is also known to particularly afflict the elderly (Treanor J, 2004 , N Engl. J Med. 350(3):218-20).
- Influenza viruses which are enveloped viruses belonging to the Orthomyxoviridae family and the genome of which consists of eight negative-sense single-stranded RNA (ribonucleic acid) segments, are classified into groups A, B and C, and influenza A viruses are further divided into a number of subtypes depending on HA (hemagglutinin) and NA (neuraminidase) as the major surface proteins.
- Influenza viruses continuously produce variant viruses to thus features that may infect birds, pigs and humans depending on the types thereof and create a variety of gene combinations and mutations due to the genome comprising RNA segments. Treanor J, 2004 . N Engl. J Med. 350(3):218-20). Because of such persistent mutations, it is difficult to obtain permanent immunity, and currently, the most effective prevention method is to form immunity appropriate for a particular type annually by inoculating a vaccine against influenza virus, which is predicted to be popular every year.
- the influenza virus vaccine which is currently inoculated every year, is a trivalent or tetravalent vaccine composed of HA of H1 and H3 subtypes of influenza A and one or two kinds of HA of influenza B.
- the present inventors have ascertained that the effect of a vaccine may be increased by administering the vaccine together with the antibody for neutralizing influenza virus, which was already developed by the present inventors, and have found the new use of the already-developed antibody as the adjuvant, thus culminating in the present invention.
- the present invention is intended to provide an adjuvant composition comprising at least one binding molecule for neutralizing influenza virus.
- the present invention is intended to provide a method of producing the vaccine composition comprising the adjuvant composition and the target antigen.
- the present invention is intended to provide a method of increasing an immune response to a target antigen by administering the adjuvant composition to a host.
- the present invention is intended to provide a method of immunizing a host by administering the vaccine composition to the host.
- the present invention is intended to provide a method of preparing an immunological product from the host immunized by administering the vaccine composition to the host.
- the present invention provides an adjuvant composition comprising at least one binding molecule for neutralizing influenza virus.
- the binding molecule may bind to an epitope in a stem region of a hemagglutinin (HA) protein of influenza A virus.
- HA hemagglutinin
- the epitope of the binding molecule may be at least one selected from the group consisting of i) an epitope comprising any one amino acid residue selected from the group consisting of amino acids at positions 18, 25, 27, 32, 33, 38, 40, 54, 55, 278, 291, 292, 310, 311, 312 and 318 of an HA1 polypeptide; and ii) an epitope comprising any one amino acid residue selected from the group consisting of amino acids at positions 18, 19, 20, 21, 38, 39, 41, 42, 45, 46, 48, 49, 52, 53, 56, 57, 58, 60 and 99 of an HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at positions 18, 38, 40, 291, 292 and 318 of the HA1 polypeptide. Also, the epitope of the binding molecule may include amino acid residues at positions 18, 19, 20, 21, 41, 42, 45, 48, 49, 52 and 53 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at positions 18, 38, 40, 291, 292 and 318 of the HA1 polypeptide and may include amino acid residues at positions 18, 19, 20, 21, 41, 42, 45, 48, 49, 52 and 53 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at positions 278 and 318 of the HA1 polypeptide. Also, the epitope of the binding molecule may include amino acid residues at positions 38, 39, 41, 42, 45, 48, 49, 52, and 53 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at said positions of the HA1 polypeptide and/or the HA2 polypeptide of a first monomer of HA, and may further include amino acid residues at positions 25, 32 and 33 of the HA1 polypeptide of a second monomer adjacent to the first monomer.
- the epitope of the binding molecule may include amino acid residues at positions 278 and 318 of the HA1 polypeptide, and amino acid residues at positions 38, 39, 41, 42, 45, 48, 49, 52, and 53 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at said positions of the HA1 polypeptide and the HA2 polypeptide of a first monomer of HA, and may further include amino acid residues at positions 25, 32 and 33 of the HA1 polypeptide of a second monomer adjacent to the first monomer.
- the epitope of the binding molecule may include amino acid residues at positions 278 and 318 of the HA1 polypeptide, and amino acid residues at positions 38, 39, 41, 42, 45, 48, 49, 52, 53, 58 and 99 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at said positions of the HA1 polypeptide and the HA2 polypeptide of a first monomer of HA, and may further include amino acid residues at positions 25, 27, 32 and 33 of the HA1 polypeptide of a second monomer adjacent to the first monomer.
- the epitope of the binding molecule may include amino acid residues at positions 54, 55, 278, 291 and 318 of the HA1 polypeptide and amino acid residues at positions 19, 20, 21, 38, 39, 41, 42, 45, 46, 48, 49, 52, 53, 56, 57 and 60 of the HA2 polypeptide.
- the epitope of the binding molecule may include amino acid residues at said positions of the HA1 polypeptide and the HA2 polypeptide of a first monomer of HA, and may further include amino acid residues at positions 25, 32, 33, 310, 311, and 312 of the HA1 polypeptide of a second monomer of HA adjacent to the first monomer of HA.
- the numbering of the amino acid positions of the epitope is based on an H3 HA numbering system.
- the binding molecule may include at least one selected from the group consisting of i) a binding molecule, comprising a light-chain variable domain including a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2 and a CDR3 region of SEQ ID NO:3, and a heavy-chain variable domain including a CDR1 region of SEQ ID NO:4, a CDR2 region of SEQ ID NO:5 and a CDR3 region of SEQ ID NO:6, as determined according to the Kabat method; and ii) a binding molecule, comprising a light-chain variable domain including a CDR1 region of SEQ ID NO:7, a CDR2 region of SEQ ID NO:8 and a CDR3 region of SEQ ID NO:9, and a heavy-chain variable domain including a CDR1 region of SEQ ID NO:10, a CDR2 region of SEQ ID NO:11 and a CDR3 region of SEQ ID NO:12,
- CDRs of the variable domains are determined using a typical method in accordance with the system devised by Kabat et al. (Reference [Kabat et al., Sequences of Proteins of Immunological Interest (5 th ), National Institutes of Health, Bethesda, Md. (1991)]).
- the CDR numbering used in the present invention was performed using the Kabat method, but the present invention also encompasses binding molecules comprising CDRs determined by other methods, including the IMGT method, the Chothia method, and the AbM method, etc.
- the binding molecule may include at least one selected from the group consisting of i) a binding molecule including a light chain comprising a polypeptide sequence of SEQ ID NO:13 and a heavy chain comprising a polypeptide sequence of SEQ ID NO:14; and ii) a binding molecule including a light chain comprising a polypeptide sequence of SEQ ID NO:15 and a heavy chain comprising a polypeptide sequence of SEQ ID NO:16.
- the binding molecule includes a binding molecule binding to an Fc receptor of a cell surface.
- the present invention provides a vaccine composition comprising the adjuvant composition and a target antigen.
- the target antigen may be a virus antigen, but is not limited thereto.
- the virus antigen is an influenza virus antigen.
- the influenza virus antigen includes an influenza A virus or influenza B virus antigen.
- the influenza virus antigen may be hemagglutinin (HA) or neuraminidase (NA) but is not limited thereto.
- the vaccine composition may include the antigen and the adjuvant composition at a weight ratio of 1:0.02 to 1:200, and preferably 1:0.2 to 1:20, but is not limited thereto.
- the weight ratio of the antigen and the adjuvant composition may be decreased or increased to modulate immunogenic activity.
- the present invention provides a vaccine composition added an additional adjuvant composition, in addition to the said adjuvant composition as well as the said adjuvant composition.
- the additional adjuvant composition may include, but is not limited to, Alum, metabolizable oils (e.g. squalene), tocols (e.g. ⁇ -tocopherol), sterols (e.g. cholesterol), saponins (e.g. QS21), Toll-like receptor ligands (e.g. poly(I:C)), an oligonucleotide having a CpG motif and/or LPS derivatives (e.g. 3D-MPL).
- Alum metabolizable oils
- tocols e.g. ⁇ -tocopherol
- sterols e.g. cholesterol
- saponins e.g. QS21
- Toll-like receptor ligands e.g. poly(I:C)
- the present invention provides a method of preparing a vaccine composition comprising the adjuvant composition and a target antigen.
- the vaccine composition may be an influenza virus vaccine composition, but is not limited thereto.
- the present invention provides a method of increasing an immune response to a target antigen by administering the adjuvant composition to a host.
- the vaccine composition may be an influenza virus vaccine composition, but is not limited thereto.
- the immune response may be induced by a cell having an Fc receptor on the surface thereof, but the present invention is not limited thereto.
- the present invention provides a method of preventing a disease caused by virus, comprising administering an effective amount of the vaccine composition containing the adjuvant composition to a subject.
- the disease caused by a virus may be a disease caused by the influenza virus.
- the present invention provides a method of immunizing a host by administering the vaccine composition to the host.
- the present invention provides a method of preparing an immunological product, comprising a) immunizing a host by administering the vaccine composition to the host and b) obtaining the immunological product from the immunized host.
- the immunological product may be T cells, B cells, or an antibody.
- the immunological product may be other kinds of cells having an Fc receptor on the cell surface, like the B cells, for example, neutrophils, macrophages, natural killer cells or dendritic cells.
- influenza virus refers to an enveloped virus belonging to the Orthomyxoviridae family and having a genome composed of eight negative-sense single-stranded RNA (ribonucleic acid) segments. Influenza viruses are classified into groups A, B and C, and are further divided into a number of subtypes depending on HA (hemagglutinin) and NA (neuraminidase) as the major surface proteins thereof 17 types of HA and 10 types of NA have been reported to date.
- HA hemagglutinin
- NA neuroaminidase
- H1 subtype includes H1N1, H1N2, H1N3, H1N4, H1N5, H1N6, H1N7, H1N8, H1N9 and H1N10.
- H2 subtype includes H2N1, H2N2, H2N3, H2N4, H2N5, H2N6, H2N7, H2N8, H2N9 and H2N10.
- H5 subtype includes H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9 and H5N10.
- H9 subtype includes H9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, H9N9 and H9N10.
- 1-13 subtype includes H3N1, H3N2, H3N3, H3N4, H3N5, H3N6, H3N7, H3N8, H3N9 and H3N10.
- H7 subtype includes H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9 and H7N10.
- hemagglutinin refers to the envelope glycoprotein of influenza virus. HA mediates the adsorption and penetration of influenza virus into a host cell. 17 HA subtypes have been reported to date.
- NA neuroaminidase
- an influenza vaccine is regarded as being the most effective method of preventing seasonal or pandemic influenza, and largely includes a live vaccine and an inactivated vaccine.
- a live vaccine a live attenuated vaccine is developed and used.
- the inactivated vaccine may include a whole virus vaccine using the entire virus in which a virus incubated from an embryonated egg or via cell culture is purified and inactivated with formalin or the like, a split vaccine in which the envelope of the virus is disrupted with ether or the like, and a subunit vaccine in which HA and NA components are purified.
- a vaccine including H1 and H3 subtypes of the influenza A group and one kind from the influenza B group is a trivalent vaccine
- a vaccine including H1 and H3 subtypes of the influenza A group and two kinds from the influenza B group is a tetravalent vaccine.
- influenza vaccine includes all live vaccines and inactivated vaccines, which are trivalent, tetravalent, seasonal, and pandemic.
- binding molecule refers to an intact immunoglobulin including monoclonal antibodies, such as chimeric, humanized or human monoclonal antibodies, fusion protein which comprising Fc of immunoglobulin or immunoglobulin which binds to antigen, for example, a variable domain including an immunoglobulin fragment that competes with the intact immunoglobulin in order to bind to the monomeric HA or trimeric HA of influenza A virus, a substrate-binding enzyme, a receptor or a protein. Regardless of the structure, an antigen-binding fragment binds with the same antigen that is recognized by the intact immunoglobulin.
- the above fragments may be produced synthetically or by enzymatic or chemical cleavage of intact immunoglobulins, or they may be genetically engineered by recombinant DNA techniques. Such production methods are well known in the art.
- the twin “adjuvant” refers to a substance or composition that is added to a vaccine or pharmaceutically active ingredients to thus increase and/or effect an immune response. Examples thereof include an immunogenic carrier or assistant material and/or other pharmaceutically active materials or compositions.
- the term “adjuvant” should be interpreted broadly and refers to a broad range of substances or stratagems that may be incorporated into the adjuvant or may enhance the immunogenicity of the antigen administered with the adjuvant.
- the adjuvant may include, but is not limited to, an immune potentiator, an antigen delivery system or a combination thereof.
- the term “immunological product” refers to a protective immune mediator or cell generated from the host immunized by the administration of the adjuvant composition and/or the antigen, and examples thereof may include, but are not limited to, activated T cells, B cells or antibodies.
- the term “pharmaceutically acceptable excipient” means any inert substance that is combined with an active molecule such as a drug, agent, or binding molecule for preparing an admittable or convenient dosage form.
- the pharmaceutically acceptable excipient is an excipient that is non-toxic or at least less toxic to recipients at the used dosages and concentrations, and is compatible with other ingredients of the formulation comprising the drug, agent or binding molecule.
- the term “effective amount” refers to an amount of the binding molecule of the invention that is effective for increasing the effect of the vaccine upon administration with the vaccine against influenza A virus.
- Korean Patent Application Nos. 10-2011-0020061, 10-2012-0107512, and 10-2014-0036601 have confirmed their effects of increasing an immune response upon inoculation with the influenza vaccine through mouse experiments, and thus new use thereof as an adjuvant has been found.
- Korean Patent Application Nos. 10-2011-0020061, 10-2012-0107512, and 10-2014-0036601, filed by the present applicant are incorporated by reference into this application.
- a composition including at least one binding molecule for neutralizing influenza virus can enhance the effect of a vaccine, and can thus be used as an adjuvant for increasing an immune response upon administration of a vaccine and is very effective at preventing diseases caused by viruses.
- FIG. 1 shows the ELISA results of a specific antibody titer against H1N1 influenza virus in a serum that is sampled 13 days, 17 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 1);
- FIG. 2 shows the ELISA results of a specific antibody titer against H1N1 HA protein and H1N1 influenza virus in a serum that is sampled 28 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 3);
- FIG. 3 shows changes in the survival rate and body weight of the immunized mouse after inoculating the immunized mouse with 10MLD 50 of H1N1 influenza virus
- FIG. 4 shows the ELISA results of a specific antibody titer against H1N1 influenza virus in a serum that is sampled 13 days, 20 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 5);
- FIG. 5 shows changes in the survival rate and body weight of the immunized mouse after inoculating the immunized mouse with 10MLD 50 of H1N1 influenza virus
- FIG. 6 shows the ELISA results of a specific antibody titer against H1N1 influenza virus in a serum that is sampled 13 days, 20 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 7);
- FIG. 7 shows changes in the survival rate and body weight of the immunized mouse after inoculating the immunized mouse with 10MLD 50 of H1N1 influenza virus
- FIG. 8 shows the ELISA results of a specific antibody titer against H3N2 influenza virus in a serum that is sampled 13 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H3N2 vaccine composition at an interval of two weeks (Table 9);
- FIG. 9 shows changes in the survival rate and body weight of the immunized mouse after inoculating the immunized mouse with 10MLD 50 of H3N2 influenza virus
- FIG. 10 shows the ELISA results of a specific antibody titer against H1N1 influenza virus in a serum is sampled 13 days, 20 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 11);
- FIG. 11 shows the results of measurement the proportion of the B cell population among immune cells in the spleen 1 day, 3 days and 7 days after the second intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 14);
- FIG. 12 shows the results of measurement the proportion of the B cell population among immune cells in the inguinal lymph node 1 day, 3 days and 7 days after the second intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 14);
- FIG. 13 shows the results of measurement the proportion of the B cell population in the spleen and lymph nodes 1 day and 3 days after inoculation with H1N1 virus 4 weeks after the second intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 15);
- FIG. 14 shows the ELISA results of a specific antibody titer against H1N1 influenza virus in a serum that is sampled 13 days, 20 days and 27 days after the first intramuscular injection under the condition that each mouse is intramuscularly injected twice with an H1N1 vaccine composition at an interval of two weeks (Table 16).
- H1N1 split vaccine was administered alone, or in combination with an adjuvant Alum (1 mg) typically used as an adjuvant or a CT120 antibody (0.5 ⁇ g, 1 ⁇ g, 5 ⁇ g, 10 ⁇ g) or a CT149 antibody (0.5 ⁇ g, 1 ⁇ g, 5 ⁇ g, 10 ⁇ g) as an adjuvant, after which the antibody titer against influenza virus in each mouse was measured.
- the H1N1 vaccine composition was intramuscularly injected twice to mice at an interval of two weeks, after which the immune response induced in each test group was observed. 13 days, 17 days and 27 days after the first intramuscular injection, the serum was sampled from each test group and the antibody titer thereof was measured through ELISA.
- the antibody able to detect a virus corresponding to the vaccine administered as a whole was produced in a larger amount in the groups administered with the vaccine in combination with CT120, CT149 or Alum than in the group administered only with the vaccine.
- the amounts of the produced antibodies were similar in the group administered with 5 ⁇ g of CT120 or 10 ⁇ g of CT149 and the group administered with Alum, and the group administered with 1 ⁇ g or 0.5 ⁇ g of CT149 produced the antibody in a large amount compared to the group administered with Alum.
- HI assay hemagglutinin inhibition assay
- Group 1 PBS N.D. N.D. N.D. Group 2 PBS CT 120 10 ⁇ g N.D. N.D. N.D. Group 3 PBS CT 149 10 ⁇ g N.D. N.D. N.D. Group 4 H1N1 split vaccine — N.D. N.D. 40 0.2 ⁇ g Group 5 H1N1 split vaccine CT 120 10 ⁇ g N.D. N.D. 40 0.2 ⁇ g Group 6 H1N1 split vaccine CT 120 5 ⁇ g N.D. N.D. 80 0.2 ⁇ g Group 7 H1N1 split vaccine CT120 1 ⁇ g N.D. N.D.
- H1N1 split vaccine CT120 0.5 ⁇ g N.D. N.D. 40 0.2 ⁇ g Group 9 H1N1 split vaccine CT149 10 ⁇ g N.D. N.D. 80 0.2 ⁇ g Group 10 H1N1 split vaccine CT149 5 ⁇ g N.D. N.D. 40 0.2 ⁇ g Group 11 H1N1 split vaccine CT149 1 ⁇ g N.D. 40 160 0.2 ⁇ g Group 12 H1N1 split vaccine CT149 0.5 ⁇ g N.D. N.D. 160 0.2 ⁇ g Group 13 H1N1 split vaccine Alum N.D. 20 80 0.2 ⁇ g
- the groups administered with 5 ⁇ g of CT120 and 10 ⁇ g of CT149 (Groups 6 and 9) exhibited an HI titer similar to that of the group administered with Alum (Group 13), and the groups administered with 1 ⁇ g and 0.5 ⁇ g of CT149 (Groups 11 and 12) exhibited high HI titer compared to the group administered with Alum.
- CT120 or CT149 When CT120 or CT149 was administered together upon injection of the influenza virus vaccine, an immunogenicity-enhancing effect similar or superior to that of the Alum adjuvant was manifested. Thereby, CT120 and CT149 can be found to be effective as the influenza virus vaccine adjuvant.
- H1N1 vaccine 0.1 ⁇ g Alum i.m. 5
- Group 11 Standard 0.3 ⁇ g — i.m. 5
- Group 12 H1N1 vaccine 0.05 ⁇ g — i.m. 5
- Group 13 H1N1 vaccine 0.05 ⁇ g Alum i.m. 5
- Group 14 H1N1 vaccine 0.01 ⁇ g — i.m. 5
- Group 15 H1N1 vaccine 0.01 ⁇ g Alum i.m. 5
- Group 16 0.03 ⁇ g — i.m. 5
- the H1N1 vaccine composition was intramuscularly injected twice to mice at an interval of two weeks, after which the immune response induced in each test group was observed. 28 days after the first intramuscular injection, the serum was sampled from each test group and the antibody titer against HA protein and virus in the serum was measured through ELISA and the neutralizing antibody titer was measured through HI assay.
- the antibody titer was increased in approximate proportion to the amount of the antigen that was added, and the antibody titer was higher when the Alum adjuvant was added therewith. Furthermore, there was no great difference between the antibody titer against HA protein and the antibody titer against H1N1 virus.
- the HI titer was increased in the test groups administered with the antigen and Alum compared to the test groups administered only with the antigen. Furthermore, in the test groups having an antigen concentration of 0.1 ⁇ g (Groups 9 and 10) and the test groups having an antigen concentration of 0.05 ⁇ g (Groups 12 and 13), the HI titer was increased 8 times and 4 times respectively when the Alum adjuvant was further added compared to when only the antigen was added, whereby a difference in the vaccine effects with or without the adjuvant was clearly confirmed.
- 10MLD 50 of CA/04/09 H1N1 virus was inoculated to the immunized mouse nasal cavity and allowed to infect it, after which changes in the survival rate and body weight of each mouse were measured for 15 days.
- the protective immunity effect against influenza virus was high at all concentrations in the test groups administered with the antigen and the adjuvant compared to the test group administered only with the antigen. Furthermore, as for the test groups of two antigen concentrations (0.1 ⁇ g and 0.05 ⁇ g) at which the vaccine effect was significantly different in the presence or absence of the adjuvant through HI titer measurement, in the 0.1 ⁇ g test groups, the test group administered only with the antigen exhibited a survival rate of 80% and the test group administered with the antigen and the adjuvant showed a survival rate of 100%. On the other hand, in the 0.05 ⁇ g test groups, the test group administered only with the antigen exhibited a survival rate of 60% and the test group administered with the antigen and the adjuvant showed a survival rate of 100%.
- the HI titer results were different but a difference in the protective immunity effects depending on whether or not the adjuvant was present was low, and thus, 0.05 ⁇ g, at which differences in the HI titer results and the protective immunity effects were significant depending on whether or not the adjuvant was present, was determined as the ultimate antigen concentration. Subsequently, animal testing was performed to evaluate the adjuvant effect using the same.
- the mouse-form antibody was manufactured by replacing the constant region of the Fc region in CT120 or CT149, which is the human IgG1 form, with the IgG1 or IgG2a region of the mouse.
- CT120 and CT120 were determined by selecting the concentrations effective as the adjuvant through the preliminary test (not described herein).
- the H1N1 vaccine (cell-based) was mixed with the therapeutic antibody at various concentrations, reacted at 37° C. for 1 hr, and intramuscularly injected twice to mice at an interval of 2 weeks, as shown in Table 5 below. 13 days, 20 days, and 27 days after the first intramuscular injection, the serum was sampled in each test group and the antibody titer against H1N1 virus in the serum and the neutralizing antibody titer were measured through ELISA and HI assay, respectively.
- the antibody titer against H1N1 virus was higher in the test group using the mouse-form CT120 (mIgG2a) as the adjuvant than in the test group using CT120 as the adjuvant. Furthermore, in the case of the test group using CT120 (mIgG2a), the antibody titer was high compared to the test group using Alum as the adjuvant, and the antibody titer was drastically increased in the serum (D20 of FIG. 5 ) sampled 3 weeks after the first immunization.
- the HI titer was generally increased a maximum of 4 times depending on the concentration in the test group using CT120 (mIgG2a) as the adjuvant compared to the test group using CT120 as the adjuvant.
- 10MLD 50 of CA/04/09 H1N1 virus was inoculated to the immunized mouse nasal cavity and allowed to infect it, after which changes in the survival rate and body weight of each mouse were measured for 15 days.
- the survival rate was higher than in the test group using CT120 as the adjuvant or the test group using only the antigen, and the changes in body weight were the lowest.
- the test group using, as the adjuvant, 0.5 ⁇ g of CT120 (mIgG2a), having the highest antibody titer and HI titer results exhibited a survival rate of 100%, which is 30% higher than that of the test group using Alum as the adjuvant.
- CT120 (mIgG2a) can be found to be more effective as the adjuvant compared to CT120 and to manifest the greatest effect when administered at a concentration of 0.5 ⁇ g.
- Example 3-1-1 the concentration at which the adjuvant effect was exhibited in the preliminary test (not described herein) for CT149 was determined, and the same testing as in Example 3-1-1 was carried out.
- the adjuvant effect of CT149 was generally weak, unlike CT120, and the antibody titer similar to the test group using the Alum adjuvant was represented in the test group using 0.5 ⁇ g of CT149 (mIgG2a).
- the HI titer was not significantly increased in the test group using CT149 or CT149 (mIgG2a) as the adjuvant, and as in the results of antibody titer measured through ELISA, the HI titer in the test group using 0.5 ⁇ g of CT149 (mIgG2a) (Group 10) was the same as that in the test group using the Alum adjuvant (Group 11).
- 10MLD 50 of CA/04/09 H1N1 virus was inoculated to the immunized mouse nasal cavity and allowed to infect it, after which changes in the survival rate and body weight of each mouse were measured for 15 days.
- the test group using 0.5 ⁇ g of CT149 (mIgG2a) as the adjuvant exhibited a survival rate of 80%, which is 10% higher than when using Alum.
- the extent of changing the body weight was not significantly improved compared to when using Alum.
- CT120 (mIgG2a) exhibited an outstanding adjuvant effect for the H1N1 vaccine, especially the greatest effect when used at a concentration of 0.5 ⁇ g.
- CT149 (mIgG2a) was used at 0.5 ⁇ g, the adjuvant effect was exhibited, but was lower than that of CT120 (mIgG2a).
- CT120 and CT149 as the adjuvant for H1N1 vaccine were confirmed through Examples 1 to 3, and, using another influenza virus strain, Philippines/2/82 (H3N2), H3N2 vaccine (cell-based) was produced, and animal testing was performed to evaluate the effects of CT120 and CT149 as the adjuvant for H3N2 vaccine.
- H3N2 vaccine in an amount ranging from 0.01 ⁇ s to 1 ⁇ g was administered alone or in combination with the Alum adjuvant, after which the antibody titers were measured through ELISA and the neutralizing antibody titers were measured through HI. Furthermore, in order to evaluate the protective immunity effect, each mouse was infected with mouse-adapted Philippines/2/82 (H3N2) virus and changes in the survival rate and body weight thereof were measured.
- H3N2 vaccine 0.05 ⁇ g — i.m. 5
- Group 11 H3N2 vaccine 0.05 ⁇ g Alum i.m. 5
- Group 12 H3N2 vaccine 0.01 ⁇ g — i.m. 5
- Group 13 H3N2 vaccine 0.01 ⁇ g Alum i.m. 5
- the H3N2 vaccine composition was intramuscularly injected twice to mice at an interval of two weeks, after which the immune response induced in each test group was observed. 2 weeks after each intramuscular injection, the serum was sampled from each test group and the antibody titer against H3N2 virus in the serum was measured through ELISA and the neutralizing antibody titer was measured through HI assay.
- the antibody titer was increased in proportion to the amount of the antigen that was added, and the antibody titer was higher when used together with the Alum adjuvant.
- the HI titer was higher in the test group using the antigen and Alum than in the test group using only the antigen.
- the test groups using 0.01 ⁇ g and 0.05 ⁇ g of the antigen (Groups 12 and 10)
- the HI titer could not be measured, but the HI titers were increased to 160 and 640 in the test groups further added with the Alum as adjuvant (Groups 13 and 11), respectively.
- 10MLD 50 of A/Philippines/2/82 H3N2 virus was inoculated to the immunized mouse nasal cavity and allowed to infect it, after which changes in the survival rate and body weight of each mouse were measured for 15 days.
- the therapeutic influenza antibody was concluded to function as an adjuvant for enhancing the effect of the influenza vaccine.
- animal testing for the mechanism for generating the adjuvant effect was performed.
- Group 2 H1N1 vaccine 0.05 ⁇ g — i.m. 10
- Group 4 PBS CT 120 (mIgG2a) 0.5 ⁇ g i.m. 10
- Group 5 H1N1 vaccine 0.05 ⁇ g Alum i.m.
- Group 7 H1N1 vaccine 0.05 ⁇ g CT 120 (mIgG2a) 0.1 ⁇ g i.m.
- H1N1 vaccine was mixed with various concentrations of CT120 (mIgG2a) or CT120 (mIgG2a) F(ab′)2, reacted at 37° C. for 1 hr, and intramuscularly injected twice to mice at an interval of 2 weeks as shown in Table 11, after which the immune response induced in each test group was observed. 13 days, 20 days and 27 days after the first intramuscular injection, the serum was sampled in each test group and the antibody titer against H1N1 virus in the serum and the neutralizing antibody titer against H1N1 virus were measured through ELISA and HI, respectively.
- the antibody titer was relatively low when using CT120 (mIgG2a) F(ab′)2, and the antibody titer difference was not significantly different in any of the test groups.
- the HI titer in all of the test groups using CT120 (mIgG2a) F(ab′)2 as the adjuvant (Groups 8 to 11) was similar to that of the test group (Group 2) in which the H1N1 vaccine was administered alone without the adjuvant.
- the test groups (Groups 6 and 7) using intact CT120 (mIgG2a) as the adjuvant exhibited HI titers of 160 and 80, respectively, which are increased 8 times and 4 times compared to the test group in which the H1N1 vaccine was administered alone (Group 2).
- the Fc region of the antibody was found to play an important role as the influenza vaccine adjuvant.
- the Fc region of the influenza antibody was confirmed to play an important function as the adjuvant in Example 5. Accordingly, animal testing was performed to discover cells having an immune response varying depending on the binding to the Fc region, among immune cells that express the Fc receptor. Used as the amount of the antibody was mouse-form CT120 (mIgG2a) 0.5 ⁇ g, which exhibited the greatest effect as the H1N1 vaccine adjuvant in Example 3.
- the H1N1 vaccine and the adjuvant were mixed, reacted at 37° C. for 1 hr, and intramuscularly injected twice to mice at an interval of 2 weeks, as set forth in Table 14. 1 day, 3 days and 7 days thereafter, the spleen and the inguinal lymph node in each mouse were separated and thus the number of various immune cells and the corresponding cell proportion were measured.
- the CT120 adjuvant was confirmed to enhance B cell immunity in Example 6-1. Based thereon, animal testing for evaluating whether the CT120 adjuvant is able to be associated with the protective immunity of B cells even in a state of viral inoculation was performed.
- the H1N1 vaccine composition was intramuscularly injected twice to mice at an interval of 2 weeks. After 4 weeks, 10MLD 50 of CA/04/09 H1N1 virus was inoculated to the immunized mouse nasal cavity. 1 day and 3 days after viral infection, the spleen and the internal lymph node in each mouse were separated and the B cell proportion in all the cells was measured using a flow cytometer.
- the B cell population was increased by about 10% in the test group using both the H1N1 vaccine and CT120 compared to the PBS control.
- the B cell population was significantly increased compared to the PBS control, but was not greatly increased compared to the test group using CT120.
- immature B cells namely B-1 cells (CD19+B220 ⁇ ) were present in the other groups, but only B-2 cells (CD19+B220+) developed from the B-1 cells were present in the test group using the H1N1 vaccine and CT120.
- lymph nodes as in the spleen, the B cell proportion was not drastically increased, but was significantly increased in three repeated experiments.
- CT120 was confirmed to be effective as the influenza vaccine adjuvant, and this effect was compared with the effect of a currently useful influenza vaccine adjuvant.
- the currently commercially available seasonal influenza vaccine adjuvant is MF59, Fluad of Novartis.
- AddaVaxTM InvivoGen, Catalog # vac-adx-10) having the same composition as MF59 was used.
- H1N1 vaccine was mixed with CT120 (mIgG2a) or AddaVax having the same composition as the commercially available adjuvant, reacted at 37° C. for 1 hr, and intramuscularly injected twice to mice at an interval of 2 weeks, as set forth in Table 16, and the immune response induced in each test group was then observed. 13 days, 20 days and 27 days after the first intramuscular injection, the serum was sampled in each test group and the antibody titer against H1N1 virus in the serum and the neutralizing antibody titer against H1N1 virus were measured through ELISA and HI, respectively.
- H1N1 vaccine 0.05 ⁇ g Alum 160 Group 6 H1N1 vaccine 0.05 ⁇ g CT 120 (mIgG2a) 0.5 ⁇ g 160 Group 7 H1N1 vaccine 0.05 ⁇ g CT 120 (mIgG2a) 0.1 ⁇ g 80 Group 8 H1N1 vaccine 0.05 ⁇ g AddaVax 100% 160 Group 9 H1N1 vaccine 0.05 ⁇ g AddaVax 10% 20 Group 10 H1N1 vaccine 0.05 ⁇ g AddaVax 1% N.D.
- 10MLD 50 of CA/04/09 H1N1 virus was inoculated to the immunized mouse nasal cavity and allowed to infect it, after which the mouse survival rate was measured for 15 days.
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