WO2016104584A1

WO2016104584A1 - Influenza vaccine composition for intradermal administration use

Info

Publication number: WO2016104584A1
Application number: PCT/JP2015/085980
Authority: WO
Inventors: 文彦武下; 晶子高浜; 良輔安中; 本川　賢司; 玄唐牛; 匡志榎本; 由加利萩原
Original assignee: 第一三共株式会社
Priority date: 2014-12-25
Filing date: 2015-12-24
Publication date: 2016-06-30
Also published as: JPWO2016104584A1; JP6719388B2; TW201628645A; JP6940649B2; JP2020122003A

Abstract

Provided is an influenza vaccine preparation for intradermal administration use, which ensures the delivery of an influenza vaccine antigen to an upper layer part of human skin to highly increase an HI antibody titer in an earlier stage in the prevention of influenza infection, and which is highly safe. An influenza vaccine preparation which can be administered using an intradermal administration device equipped with a needle tube, wherein a needle tip of the needle tube is so designed as to ensure a vaccine preparation to be administered to an upper layer part of skin; and a method for preventing influenza using the preparation.

Description

Intradermally administered influenza vaccine composition

The present invention relates to an intradermally administered influenza vaccine composition and the prevention or treatment of influenza.

Influenza virus is an RNA envelope virus having a particle size of about 100 nm in diameter belonging to the Orthomyxoviridae family, and is classified into A, B and C types based on the antigenicity of the internal protein. Influenza A viruses infect a wide range of mammals and avian animals, whereas types B and C basically infect only humans. Influenza viruses consist of a core of ribonucleic acid (RNA) associated with an internal nucleocapsid or nucleoprotein surrounded by a viral envelope having a lipid bilayer structure and an external glycoprotein. The inner layer of the viral envelope is mainly composed of matrix proteins, and the outer layer is mostly composed of host-derived lipid substances. Influenza virus RNA has a segmental structure.

Recently, types A1 H1N1 and H3N2 and type B have been reported as seasonal influenza viruses. Type A has 16 subtypes for HA and 9 types for NA due to the difference in antigenicity between hemagglutinin (HA), a glycoprotein on the surface of virus particles, and neuraminidase (NA). Has been. Type B also has HA and NA, but there is no difference enough to classify it into subtypes. Even within the same subtype, antigenicity changes due to amino acid substitutions on HA and NA, so influenza viruses escape from the human immune system and are prevalent every year, albeit at varying scales.

Influenza is a disease with strong transmission ability and high morbidity. If the disease affects patients with chronic respiratory / circulatory / kidney diseases, metabolic diseases such as diabetes, patients with impaired immune function, or elderly people, It has been reported that with the worsening of the disease, it becomes easy to develop secondary bacterial infections in the respiratory organ (Non-patent Document 1). In addition, when a child is affected, the frequency of inducing otitis media complications, febrile seizures, bronchial asthma, and the risk of developing influenza encephalitis, encephalopathy, etc. has been reported (Non-patent Document 2). For this reason, "excess death" is recognized during the influenza epidemic, and preventive measures including vaccines are important from the viewpoint of public health and medical economy.

Influenza vaccines are classified into three types: live attenuated vaccines, inactivated whole particle vaccines, inactivated component vaccines (inactivated split vaccines, inactivated subunit vaccines, etc.). Live attenuated vaccines are approved only in the United States, and only inactivated split vaccines are used in Japan.

Current influenza vaccines are largely biased to intramuscular and subcutaneous administration, and influenza vaccines are often insufficiently supplied. In recent years, intradermal administration targeting the upper layer of the skin has attracted attention. Since there are many immunocompetent cells such as dermal dendritic cells and Langerhans cells in the upper layer of the skin (Non-patent Document 3), it is expected to reduce the amount of antigen by inoculating the skin with the vaccine. (Non-Patent Documents 4 and 5).

The Manto method, known as the method of intradermal administration, is difficult to perform, and its success rate can vary depending on the skill of the inoculator who performs the injection (Non-patent Documents 6 and 7), so it is generally used as a vaccination. I can't.

Therefore, development of a device for intradermal administration that can be administered intradermally is underway (Non-patent Document 8,

Patent Documents

1, 2, and 3). Soluvia (trademark) (Becton, manufactured by “Dickinson” and “Company”) is known as a device for intradermal administration which has been successfully developed first. In fact, intradermally administered influenza vaccine (Intanza or IDflu) using Soluvia (trademark) has been approved in various countries including Europe and the United States, but on the 21st and 28th days after vaccination, it is equal to or better than intramuscular administration. It is known to show immunogenicity (Non-patent Documents 9 and 10), and the usefulness of intradermal administration has been confirmed.

In addition, many intradermally administered influenza vaccines (Patent Documents 4 and 5) are known, but none have been approved.

However, it is known that it takes about 2 to 3 weeks from the vaccination of influenza vaccine until it actually exerts a preventive effect, and there is a possibility of infection before the antibody titer increases sufficiently. desired. In addition, it has been shown that 90% or more of Soluvia (trademark) is administered intradermally in studies using pigs (Non-patent Document 11), but was administered to the upper skin layer in human clinical studies. Since the formation rate of wheal indicating about 50% and liquid leakage has been confirmed (Non-patent Document 9), more reliable intradermally administered influenza vaccine for high immunogenicity and reduction of effective dose Is desired.

EP1092444 US8663163 US8622963 WO2002 / 074336 WO2006 / 062637

An object of the present invention is to prevent the infection of influenza virus by inducing early and high HI antibody titer compared to the conventional influenza vaccine by reliably delivering the influenza vaccine antigen to the upper layer of human skin in preventing influenza infection. It is to provide an intradermally administered influenza vaccine preparation that is possible and highly receptive.

Therefore, the present inventors have conducted extensive research to solve the above problems, and as a result, influenza using an intradermal administration device designed to reliably administer a vaccine preparation to the upper layer of human skin with the needle tip of a needle tube. In clinical trials of vaccines, high HI antibody titer (antibody seroconversion rate, GMT, antibody retention rate) 7 and 21 days after vaccine administration and superiority to subcutaneous administration (antibody seroconversion) in all strains present in the vaccine composition The rate difference, the ratio of GMT) was confirmed, and it was found to be early and highly immunogenic compared to conventional influenza vaccines, and confirmed the formation of wheal that was administered to the upper skin layer with high probability . In addition, the present inventors have found in the safety test of the above test that both systemic and local reactions are acceptable compared to subcutaneous preparations, and the incidence of severe side effects is low for local reactions.

Therefore, the intradermal influenza vaccine is confirmed to have a sufficiently high antibody titer as an influenza protection level as early as 1 week after vaccination, and it is used as a highly receptive influenza vaccine, as with conventional subcutaneous preparations. it can. The present invention has been completed based on such findings.

That is, the present invention includes the following inventions.
(1) An influenza vaccine composition comprising an influenza antigen as an active ingredient and administered by an intradermal administration device having a needle tube protrusion length of 0.9 to 1.4 mm.
(2) The composition according to (1), wherein all strains present in the vaccine composition satisfy at least one of the following EMA standards:
1) In the age group between 20 and 65 years old
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 40%;
ii) GMT (geometric mean titer) change rate (magnification of GMT after inoculation from the value before the first inoculation) exceeds 2.5; and
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 70%;
2) In the age group over 65 years old,
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 30%;
ii) The rate of change in GMT (the increase rate from the pre-vaccination GMT value after vaccination) exceeds 2.0; and
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 60%.
(3) All the strains present in the vaccine composition are different in seroconversion rate (intradermal inoculation group-subcutaneous inoculation group) and ratio of GMT (geometric mean antibody titer) (intradermal inoculation group / subcutaneous inoculation group). The composition according to (1) or (2), which satisfies at least one of the following non-inferiority criteria:
1) Difference in seroconversion rate: Lower limit of 95% CI of difference in seroconversion rate exceeds -10%; and 2) Ratio of GMT: Lower limit of 95% CI of GMT ratio exceeds 2/3.
(4) The strains present in the vaccine composition have the following superiority criteria regarding the difference in seroconversion rate (intradermal inoculation group-subcutaneous inoculation group) and the ratio of GMT (intradermal inoculation group / subcutaneous inoculation group) The composition according to any one of (1) to (3), which satisfies at least one:
1) Difference in seroconversion rate: 95% CI lower limit of antibody seroconversion rate exceeds 0%; and 2) GMT ratio: 95% CI lower limit of GMT ratio exceeds 1.
(5) The composition according to any one of (2) to (4), wherein each of the strains satisfies at least one EMA standard, non-inferiority standard, or superiority standard on days 5 to 14 after vaccination.
(6) The composition according to any one of (1) to (5), wherein the HA content per each strain is 3 to 15 μg.
(7) The composition according to any one of (1) to (6), wherein the vaccine composition comprises at least an A strain (H1N1), an A strain (H3N2), and a B strain.
(8) The composition according to any one of (1) to (7), wherein the vaccine composition does not contain an adjuvant.
(9) The composition according to any one of (1) to (8), wherein the device comprises a needle assembly having the following characteristics 1) and 2).
1) a) a 26-33G needle tube having a needle tip that can puncture a living body;
b) a hub for holding the needle tube;
c) an adjustment unit provided around the needle tube and having a needle projecting surface from which the needle tip of the needle tube projects;
d) a cylindrical stabilizing portion that is arranged so as to cover the periphery of the needle tube and comes into contact with the skin when the needle tube is punctured into a living body;
e) provided on the outer peripheral surface of the stable portion, having a contact surface that comes into contact with the skin, and when the needle tube is punctured into a living body, the stable portion is pressed against the skin until the contact surface comes into contact with the skin. A guide part for guiding the pressing force to the living body of the needle tube and the stabilizing part,
2) The contact surface of the guide portion is provided at a predetermined distance from an end surface that contacts the skin in the stable portion.
(10) The composition according to any one of (1) to (9), which is a device comprising an injection needle characterized in that the device comprises the following a) to d).
a) a 26-33G needle tube having a needle tip that can puncture a living body;
b) a hub for holding the needle tube;
c) a needle projecting surface provided around the needle tube, from which the needle tip of the needle tube projects, and the length of the needle tip of the needle tube projecting from the needle projecting surface is 0.5 to 3.0 mm; An adjustment portion formed so as to have a shortest distance from the periphery of the needle projecting surface to the peripheral surface of the needle tube in a range of 0.3 to 1.4 mm;
d) A cylindrical shape provided around the needle tube at a predetermined interval from the adjustment unit, having an end surface that comes into contact with the skin when the needle tube is punctured into a living body, and covers the periphery of the needle tube and the adjustment unit The stabilizing portion is formed such that the distance from the inner wall surface to the outer peripheral surface of the adjusting portion is set in the range of 4 to 6 mm, and the inner diameter thereof is set in the range of 9 to 13 mm.
(11) The composition according to any one of (1) to (10), which exhibits a wheal formation rate of 90% or more at the administration site of a human individual.
(12) The composition according to any one of (1) to (11), wherein the administration site is the deltoid muscle of the upper arm.

This specification includes the disclosure of Japanese Patent Application No. 2014-263457, which is the basis of the priority of the present application.

According to the present invention, in preventing influenza infection, an influenza vaccine composition (antigen) is reliably delivered to the upper layer of human skin to enable early and high HI antibody titer increase and highly receptive intradermal administration. Influenza vaccine formulations can be provided.

It is a schematic diagram which shows an injection needle assembly. It is a perspective view which shows an injection needle assembly. It is a figure which shows the state which punctured the skin of the needle tube of the chemical injection device containing an injection needle assembly and a syringe. It is a schematic diagram which shows an injection needle. It is a figure which shows the device for intradermal administration used by the phase I / II test. It is a figure which shows an injection needle assembly (FIG. 6B) and its protector (FIG. 6A).

The skin is composed of the epidermis, dermis, and part of the subcutaneous tissue. The epidermis is a layer of about 50 to 200 μm from the skin surface, and the dermis is a layer of about 1.5 to 3.5 mm continuing from the epidermis to the subcutaneous tissue side. Many of the current compositions are administered subcutaneously or intramuscularly and are administered in the lower layer of the skin or deeper. The composition of the present invention is administered intradermally.

In this specification, the term “intradermal administration” means administration of the composition to the dermis of the skin, but the composition may not be localized only to the dermis. The thickness of the dermis layer varies somewhat between individuals and also varies depending on the body part. The composition may ultimately be in the dermis only or primarily in the dermis, or in the epidermis. In the present specification, “intradermal administration” and “administration (inoculation) to the upper skin layer” are synonymous.

The thickness of the upper skin portion corresponds to the depth from the skin surface to the dermis layer, and is generally in the range of 0.5 to 3.0 mm. Therefore, the composition can be administered at a position of 0.5 to 3.0 mm below the skin surface.

The thickness of the upper layer of the deltoid muscle, the site of influenza vaccine administration, is 0.9-1.6 mm in children, 1.4-2.6 mm in the distal part in adults, and 1.4-2 in the central part It is confirmed that the thickness of the upper layer of the deltoid muscle is 0.9 mm or more for children and 1.4 mm or more for adults. (Patent Documents 2 and 3). Therefore, it is preferable to administer the vaccine at a position 0.9 to 1.4 mm below the surface of the skin in the vaccine administration in the upper layer part of the deltoid muscle. Administration to this location is possible by using the intradermal administration device described below.

In this specification, “prevention” means prevention of illness and / or pathological condition, and broadly includes prevention of aggravation, reduction of symptoms and secondary prevention. In the present specification, “treatment” is obvious to those skilled in the art, but means to alleviate or improve symptoms.

Examples of the influenza vaccine of the present invention include a live attenuated vaccine, an inactivated whole particle vaccine, and an inactivated component vaccine. Live vaccines actually infect attenuated viruses to gain immunity and have the advantage of maintaining a strong and long-term immune memory, but still have safety issues. An inactivated vaccine is used after chemically or physically inactivating a virus. Whole particle vaccines contain not only antigenic substances but also various microorganism-derived substances. Inactivated component vaccines are component vaccines (including split vaccines and subunit vaccines) from which target antigens essential for protective immunity are extracted. The influenza vaccine of the present invention is preferably an inactivated whole particle vaccine or an inactivated component vaccine, and most preferably an inactivated split vaccine.

Production of a suitable inactivated influenza vaccine composition for use in the present invention can be carried out by subjecting a vaccine strain to a culture medium or a culture medium containing the culture medium (cells, etc.) or an animal that has been grown on an animal as needed. To obtain a stock solution. The stock solution is subjected to various necessary tests, and further concentration adjustment, stabilizers, etc. are added from the stock solution. Specifically, the following methods are mentioned.
(I) culture of influenza virus strain (preferably culture using embryonated chicken eggs); (ii) collection of virus-containing substance from the culture (eg, allantoic fluid); (iii) purification of collected substance ( (Iv) inactivation treatment of the purified product; (v) removal of undesirable substances by filtration; (vi) dilution / mixing; (vii) preservative / stabilization. Addition of agents.

The above steps are performed in the order of description, but are not necessarily continuous.

The influenza vaccine of the present invention contains at least three different influenza strains (usually two A strains and one B strain), and is usually trivalent or higher. The influenza vaccine of the present invention contains HA antigens derived from two or more influenza virus strains, preferably 3 or 4 strains, more preferably 2 types A strains and 1 or 2 types B strains . As one aspect, it contains three influenza virus strains (H1N1, H3N2, and B strains) selected by the National Institute of Infectious Diseases as vaccine production strains, and further includes another type B strain Also good.

The influenza vaccine composition according to the present invention is preferably useful for prevention of human influenza vaccine virus infection, and in addition to the active ingredient (virus strain), a pharmaceutically acceptable excipient, solvent, stabilizer, Buffers, dispersants and the like can be included.

The influenza vaccine according to the present invention contains the same or lower hemagglutinin (HA) than conventional vaccines, and exhibits an early antibody titer increase and high immunogenicity. The HA content of each influenza strain in a single vaccine administration dose is 3 to 15 μg, for example, 6 to 15 μg, specifically 6, 9 or 15 μg (preferably 15 μg) of influenza strain HA. The influenza vaccine according to the present invention may contain an adjuvant or an immunostimulant (such as an adjuvant), but exhibits an early antibody titer increase and high immunogenicity even without an adjuvant. In this specification, an adjuvant is an auxiliary agent that promotes an immune response, and means a substance that nonspecifically enhances the immune response to an antigen when administered to a living body together with the antigen.

The volume of one dose of the influenza vaccine composition according to the present invention is 0.025 ml to 2.5 ml, more preferably 0.05 ml to 0.5 ml. For example, a 0.1 ml dose is about 1/5 of the volume of a conventional subcutaneously injected influenza vaccine dose. The volume of liquid that can be administered intradermally is optionally determined by the site of injection. For injections into the deltoid region, a maximum volume of 0.1 ml is the preferred volume, but in the lower back, for example, about 0.2 ml can be administered.

In this specification, “wheal” refers to a bulge that physically occurs in the skin with injection of a chemical solution or the like immediately after inoculation with the above composition or vaccine (medicine, etc.). It is known that wheal is formed when a drug such as a vaccine is administered to the upper skin layer (clinical immunity 20: 223-227-1988).

By administration of the influenza vaccine composition according to the present invention, wheal is formed at the inoculation site of a human individual, but the formation rate of wheal is 80% or more, preferably 85% or more, more preferably 90% or more. Yes, more preferably 95% or more.

The number of times of administration of the influenza vaccine composition according to the present invention is usually one or two inoculations / year, but is not limited thereto. In the case of 2 doses / year, it is recommended to inoculate at intervals of 1-4 weeks.

US Food and Drug Administration (FDA) Guidance インフルエンザ for Industry ： Clinical data needed to support the Food and Drug Administration (FDA) Evaluation Guidelines for Seasonal Inactivated Influenza Vaccine Efficacy (Immunogenicity) Evaluation criteria set forth in licensure of seasonal inactivated influenza vaccines. May 2007, European Medicines Agency (EMA) influenza vaccine evaluation guidance (Note for guidance on harmonisation of requirements for influenza vaccines. (CPMP / BWP / 214/96), EMA Evaluation Guidance) and the evaluation standards of the Japanese Ministry of Health, Labor and Welfare (Pharmaceutical Diet Examination 0527 No. 5 May 27, 2010 "Infectious Disease Prevention Vaccine Clinical Trials Guidelines ") are known.

Currently, the evaluation criteria for the immunogenicity of seasonally inactivated influenza vaccines in Japan include the evaluation criteria indicated in the FDA's seasonally inactivated influenza vaccine evaluation guidance and the EMA evaluation criteria indicated in the EMA guidance. HI antibody titer (immunogenicity) is often evaluated with reference to EMA standards. In clinical trials of the influenza vaccine composition according to the present invention, evaluation is performed using a standard referring to the EMA evaluation standard. In other words, the EMA standards for the age group of 20 to 65 years old are used for the evaluation of the age group of 18 to 60 years old, and the age group of 61 years or older for the evaluation of the age group of 65 years or older. In Japan, the usage and dosage of seasonal influenza vaccines are categorized by age from 6 months to under 3 years, from 3 years to under 13 years, and from 13 years. In Europe, each strain contained in the influenza vaccine composition can be approved if it satisfies at least one of the above three EMA criteria.

The influenza vaccine composition according to the present invention satisfies a part or all of the standard with reference to the EMA standard. Standards based on EMA evaluation criteria are as follows.
1) Age group between 20 and 65 years old:
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 40%.
ii) The change rate of GMT (geometric mean antibody titer) (the increase rate from the pre-vaccination value of GMT after inoculation) exceeds 2.5.
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 70%.
2) Ages 65 and over:
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 30%.
ii) The rate of change in GMT (the rate of increase from the pre-vaccination GMT value after vaccination) exceeds 2.0.
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 60%.

The influenza vaccine composition according to the present invention can be administered as follows according to the administration of the vaccine composition (HA content per strain is any of 6 to 15 μg, preferably 9 to 15 μg, most preferably 12 to 15 μg). Meet any of the criteria from A) to (E).
(A) All strains in the vaccine composition meet at least one of the three EMA criteria in the age group of 1) or 2) above.
(B) Meet the criteria of (A) above and all strains in the vaccine composition will meet at least two of the three EMA criteria in the age group of 1) or 2) above.
(C) In the above age group 1) or 2), all the strains in the vaccine composition are in the above 5 days (Day 5) to 14 days (Day 14), preferably Day 7 to Day 10 (for example, Day 7 and Day 10). Meet EMA standards in (A) or (B).
(D) Satisfy the criteria of (C) above, and at least 5 days after inoculation (Day 5) to 14 days (Day 14), preferably Day 7 to Day 10 (for example, Day 7 and Day 10) in the age group of 1) or 2) above One stock meets three EMA standards.
(E) Satisfy the above criteria (C) or (D) and in the age group 1) or 2) 5 days after inoculation (Day 5) to 14 days after (Day 14), preferably Day 7 to Day 10 (for example, Day 7, At Day 10), at least two strains (eg, H1N1 and H3N2 strains) meet the three EMA standards.

Of the above criteria, preferably (B) is satisfied, more preferably (C) is satisfied, further preferably (D) is satisfied, and most preferably (E) is satisfied.

In addition, when we meet standard about subjects 20 years old and younger than 65 years old, we do not meet standard about elderly person (65 years old or older) or we meet standard about elderly person (65 years old or older), 0 years old For subjects under 65 years of age, the criteria may not be met.

The influenza vaccine composition according to the present invention can be incorporated into the vaccine by administration of the vaccine composition (HA content per strain is any of 6 μg to 15 μg, preferably 9 to 15 μg, most preferably 12 to 15 μg). Each existing strain meets some or all of the following non-inferiority criteria in the age group of 0 to 65 years old or the elderly (65 years and older).
1) Difference in antibody seroconversion rate (intradermal inoculation group-subcutaneous inoculation group): 95% CI lower limit of seroconversion rate difference exceeds -10% 2) GMT ratio (intradermal inoculation group / subcutaneous inoculation group) : 95% CI lower limit of GMT ratio exceeds 2/3 (CI: confidence interval)
That is, the influenza vaccine composition according to the present invention satisfies any of the following criteria (A) to (E).
(A) All strains in the vaccine composition meet at least one non-inferiority criterion in the age group of 20 years old and younger than 65 years old, or elderly (65 years old and older).
(B) All strains satisfy the two non-inferiority criteria in the age group of 20 years old and younger than 65 years old or elderly people (65 years old and older) who meet the above criteria (A).
(C) In the age group of 20 years old or older and less than 65 years old or elderly people (65 years old or older) 5 days after inoculation (Day5) to 14 days later (Day14), preferably Day7 to Day10 (for example, Day7, Day10) Stocks satisfy the non-inferiority criteria of (A) or (B) above.
(D) In the age group of 20 years old or older and less than 65 years old or elderly people (65 years old or older) who meet the above criteria (C), 5 days after inoculation (Day 5) to 14 days later (Day 14), preferably Day 7 to On Day 10 (eg Day 7, Day 10) all strains in the vaccine composition meet at least two of the three EMA criteria.
(E) Satisfy the above criteria (C) or (D) and in the age group of 20 years old or older and under 65 years old or elderly people (65 years old or older) 5 days after inoculation (Day 5) to 14 days later (Day 14), Preferably at least one strain, more preferably at least two strains (eg H1N1 strain, H3N2 strain) in the vaccine composition meet three EMA criteria from Day 7 to Day 10 (eg Day 7, Day 10).

The influenza vaccine composition according to the present invention can be incorporated into the vaccine by administration of the vaccine composition (HA content per strain is any of 6 μg to 15 μg, preferably 6, 9, 15 μg, most preferably 15 μg). For each strain present, meet some or all of the following superiority criteria:
1) Difference in antibody seroconversion rate (intradermal inoculation group-subcutaneous inoculation group): The lower limit of 95% CI of the difference in antibody seroconversion rate exceeds 0%.
2) GMT ratio (intradermal group / subcutaneous group): The lower limit of 95% CI of the GMT ratio is above 1.

That is, the influenza vaccine composition according to the present invention satisfies any of the following criteria (A) to (E).
(A) The strain in the vaccine composition meets at least one and preferably two superiority criteria in the age group of 20 years old or older and less than 65 years old or elderly people (65 years old or older).
(B) All strains in the vaccine composition meet at least one, preferably two superiority criteria, in the age group of 20 years old and younger than 65 years old, or elderly (65 years old and older).
(C) In the age group of 20 years old or older and less than 65 years old or the elderly (65 years old or older), the day 5 to day 14 (Day14), preferably Day7 to Day10 (for example, Day7, Day10) All strains in the vaccine composition meet the superiority criteria of (A) or (B) above.
(D) Satisfy the above criteria (C) and in the age group of 0 to 65 years old or elderly (65 years and over) 5 days after inoculation (Day 5) to 14 days after (Day 14), preferably Day 7 to On Day 10 (eg Day 7, Day 10) all strains in the vaccine composition meet at least two of the three EMA criteria.
(E) 5 to 14 days after inoculation (Day 14), preferably Day 7 or more in the age group of 20 years old or older and less than 65 years old or elderly person (65 years old or older) At Day 10 (eg, Day 7, Day 10), at least one strain, more preferably at least two strains (eg, H1N1 strain, H3N2 strain) in the vaccine composition meet three EMA criteria.

The intradermal administration device according to the present invention is an intradermal administration device in which the protruding length of the needle tube is 0.9 to 1.4 mm.

An intradermal administration device according to the present invention includes an injection needle or drug injection device described in US8663163 (Patent No. 5430646), or an injection needle assembly or drug injection device described in US8622963 (Patent No. 55366195) (this book) Intradermal administration device, which is to be incorporated herein. The drug injection device has a syringe 9 that can be filled with a syringe or a needle assembly and a drug. The syringe 9 is also called a syringe for intradermal injection.

For example, an intradermal administration device A including a needle assembly 1 having the following features 1) and 2).
1)
a) a 26-33G needle tube 2 having a needle tip capable of puncturing a living body;
b) a hub 3 for holding the needle tube 2;
c) an adjusting portion 4 provided around the needle tube 2 and having a needle projecting surface 4b from which the needle tip of the needle tube 2 projects;
d) a cylindrical stabilizing portion 6 which is arranged so as to cover the periphery of the needle tube 2 and comes into contact with the skin when the needle tube 2 is punctured into a living body;
e) A contact surface 7a that is provided on the outer peripheral surface of the stabilizing portion 6 and that contacts the skin. When the needle tube 2 is punctured into a living body, the stabilizing portion 6 is kept on the skin until the contact surface 7a contacts the skin. A guide portion 7 for guiding the pressing force to the living body of the needle tube 2 and the stabilizing portion 6 by being pressed against the living body;
With
2) The contact surface 7a of the guide portion 7 is provided at a predetermined distance from the end surface 6c that contacts the skin in the stabilizing portion 6.

Further, the intradermal administration device according to the present invention includes a syringe 9 connected to the needle assembly 1 having the characteristics 1) and 2) and the needle tube 2 of the above a). Is an intradermal administration device A.

The length (projection length) L by which the needle tip of the needle tube 2 projects from the needle projecting surface 4b is 0.9 to 1.4 mm, preferably 1.0 to 1.2 mm.

The needle tube 2 is preferably 30 to 33G.

A blade surface 2a for making the needle tip an acute angle is formed at the tip of the needle tube 2, and the length of the blade surface 2a in the direction in which the needle tube 2 extends is called a bevel length BL, and the bevel length BL Is preferably 0.5 to 1.4 mm. More preferably, it is 0.9 mm (children) or less, which is the thinnest thickness of the upper skin layer, that is, the bevel length BL is in the range of 0.5 to 0.9 mm.

The material of the needle tube 2 is not limited, and examples include stainless steel, aluminum, aluminum alloy, titanium, titanium alloy, and other metals.

It is preferable that at least a part of the needle tube 2 has a tapered structure.

The tube hole of the needle tube 2 communicates with the hub 3. The hub 3 may take any form as long as it can be connected to the syringe 9.

The adjustment part 4 is formed in a columnar shape. The needle tube 2 passes through the adjustment unit 4, and the axis of the needle tube 2 and the axis of the adjustment unit 4 coincide. The adjustment unit 4 is fixed in close contact with the peripheral surface of the needle tube 2. One end surface of the adjusting portion 4 is a hub facing surface 4a facing the hub 3, and the other end surface is a flat needle projecting surface 4b from which the needle tip of the needle tube 2 projects. The needle protrusion surface 4b of the adjustment unit 4 defines the depth at which the needle tube 2 is punctured in contact with the surface of the skin when the needle tube 2 is punctured into the upper skin portion. That is, the depth at which the needle tube 2 is punctured into the skin is determined by the length protruding from the needle protrusion surface 4b of the needle tube 2 (hereinafter referred to as “projection length L”). The adjusting unit 4 may be fixed in close contact with the peripheral surface of the needle tube 2 by applying the adhesive 5 to the concave portion for the adhesive with the needle tube 2 penetrating, but the fixing method is limited to the adhesive. Instead, it may be fixed by welding or the like. The needle projecting surface 4b of the adjusting unit 4 is preferably set such that the distance S from the peripheral edge of the needle projecting surface 4b to the peripheral surface of the needle tube 2 is in the range of 0.3 to 1.4 mm. The adjustment unit 4 is preferably formed separately from the needle tube 2 and is fixed in close contact with the peripheral surface of the needle tube 2. Further, it is preferable that the adjustment unit 4 is formed separately from the needle tube 2 and is fixed in close contact with the peripheral surface of the needle tube 2.

The stabilizing part 6 has a shape in which two cylinders having different diameters are connected in the axial direction. A needle tube 2, a hub 3, and an adjustment unit 4 are disposed in the cylindrical hole of the stabilization unit 6. The stabilizing portion 6 includes a fixing portion 6 a that is fixed to the hub 3 and a contact portion 6 b that covers the periphery of the needle tube 2 and the adjusting portion 4. And the hub 3 is accommodated in the cylindrical hole of the fixing | fixed part 6a. Further, a contact portion 6b is continuously provided on one side in the axial direction of the fixed portion 6a.

A guide portion 7 is integrally formed on the outer peripheral surface of the contact portion 6 b in the stable portion 6. The guide part 7 is provided continuously along the circumferential direction of the outer peripheral surface of the stabilizing part 6. The guide portion 7 is formed as a ring-shaped flange that protrudes from the outer peripheral surface of the stabilizing portion 6 toward the outside in the radial direction substantially perpendicularly. The guide portion 7 has a contact surface 7a that comes into contact with the skin. By pressing the stable portion 6 until the contact surface 7a of the guide portion 7 comes into contact with the skin, the force with which the stable portion 6 and the needle tube 2 press the skin can always be secured above a predetermined value. The pressing force is preferably 0.5 to 20N. It is preferable that the end surface 6c in contact with the skin in the stable portion 6 and the needle protruding surface 4b of the adjusting portion 4 are located on the same plane. Moreover, it is preferable that the stable part 6 is integrally formed with the hub 3.

When the inner diameter d of the stabilizing portion 6 is set to 12 to 14 mm, the distance between the contact surface of the guide portion 7 and the end surface of the stabilizing portion 6 that contacts the skin is defined as y (guide portion height), Assuming that the guide portion length in the guide portion 7 in the substantially vertical direction from the stable portion 6 is x, y and x are:
1.0Ln (x) +1.2 <y <3.1Ln (x) +3.2
It is preferable to satisfy the relationship.

When the inner diameter of the stable portion 6 is set to 11 mm, the distance between the contact surface 7a of the guide portion 7 and the end surface 6c of the stable portion 6 that contacts the skin is the stable portion 6 in the guide portion 7. When the guide portion 7 length x, which is the length in the substantially vertical direction from the center, is 0.5 mm, it is preferably set in the range of 0.75 to 2.6 mm.

The distance T from the inner wall surface of the stabilizing portion 6 to the outer peripheral surface of the adjusting portion 4 is preferably set in the range of 4 to 15 mm.

Examples of the intradermal administration device according to the present invention include an intradermal administration device B including an injection needle 1 ′ provided with the following a) to d).
a) a 26-33G needle tube 2 having a needle tip that can be punctured into a living body;
b) a hub 3 for holding the needle tube 2;
c) It is provided around the needle tube 2 and has a needle projecting surface 4b from which the needle tip of the needle tube 2 projects, and the length of the needle tip of the needle tube 2 projecting from the needle projecting surface 4b is 0.5. An adjusting portion 4 formed in a range of ˜3.0 mm and a shortest distance from the periphery of the needle protruding surface 4b to the peripheral surface of the needle tube 2 being in the range of 0.3 to 1.4 mm; ,
d) An end face 6c provided around the needle tube 2 at a predetermined interval from the adjustment unit 4 and in contact with skin when the needle tube 2 is punctured into a living body, and the needle tube 2 and the adjustment unit 4 The distance T from the inner wall surface to the outer peripheral surface of the adjusting portion 4 is set to be in the range of 4 to 6 mm, and the inner diameter d is in the range of 9 to 13 mm. And a stabilizing part 6 set to the following.

Further, the intradermal administration device according to the present invention includes a skin including a drug injection device, characterized in that it includes an injection needle 1 ′ provided with a) to d) and a syringe 9 connected to the needle tube 2 of a). This is an internal administration device B.

In the intradermal administration device B, the needle tube 2, the hub 3, the adjustment unit 4, and the stabilization unit 6 are the same as those in the intradermal administration device A described above.

The syringe 9 is connected to the injection needle assembly 1 or the injection needle 1 '. The syringe 9 is connected to the injection needle assembly 1 or the hub 3 of the injection needle 1 'via a connector.

The devices A and B which are intradermal administration devices including the needle assembly 1 or the needle 1 ′ and the syringe 9 may be filled with a drug such as a vaccine when used, and are prefilled with a drug filled in advance. It may be a syringe. A prefilled syringe is preferable.

As one aspect of the device, there is a device comprising the injection needle assembly 1 shown in FIGS. 1 and 2, or the injection needle 1 'shown in FIG. 4 and a syringe 9 connected thereto. FIG. 3 shows a schematic view of a device in which a syringe is connected to the injection needle assembly 1. The injection needle assembly 1 or injection needle 1 ′ in the device is composed of a needle tube 2 and a needle base, and is provided with a mechanism for setting a puncture depth appropriate for intradermal injection, and punctures the skin for intradermal injection. A sterile needle assembly or needle to perform. The needle base includes a needle hub (hub 3), a rear connector for connecting the syringe 9, and an elastic member. The needle hub (hub 3) includes a stopper portion that defines the puncture depth of the needle tube 2 into the skin, a limiter portion that stabilizes the pressing of the injection into the skin without inhibiting the penetration into the skin, and the needle assembly 1 Or it has the flange part used as the standard of the force which presses injection needle 1 'against skin. The stopper portion is also referred to as an adjustment portion 4, the limiter portion is also referred to as a stabilization portion 6, and the flange portion is also referred to as a guide portion 7. The injection needle assembly 1 or injection needle 1 ′ is connected to the intradermal injection syringe 9 by the rear connector 11. A female screw or a male screw is provided at the proximal end portion of the rear connector 11, and the injection agent leaks from the connection portion of the injection needle assembly 1 or injection needle 1 'and the intradermal injection syringe 9 due to the injection pressure of the intradermal injection. To prevent the damage. Further, an elastic member is provided for reducing a dead space generated in the gap between the luer taper fitting between the injection needle assembly 1 or the injection needle 1 ′ and the syringe 9 for intradermal injection. The intradermal injection syringe 9 is a syringe barrel mainly used for injection or the like. The intradermal injection dedicated syringe 9 is shaped to hold the outer cylinder and press the pusher with the thumb so that it is stable when it is pressed vertically against the skin and injected, and the intradermal injection needle is applied by the injection pressure of the intradermal injection. In order to prevent the injection from leaking from the connection part 9 for the intradermal injection dedicated syringe 9, a screw is provided at the base of the tube tip.

Furthermore, the intradermal administration device of the present invention may have a protector 12 (FIG. 6A) for holding the injection needle assembly 1 or the injection needle 1 '. The injection needle assembly 1 or the injection needle 1 ′ is held in the protector 12, and the protector 12 holding the injection needle assembly 1 or the injection needle 1 ′ is covered with a top film 13, and the injection needle assembly 1 therein. Alternatively, the injection needle 1 ′ is protected aseptically. In use, the top film 13 is peeled off, and the intradermal injection syringe 9 is connected to the rear connector of the injection needle assembly 1 or the injection needle 1 'to be used as an intradermal administration device. The needle assembly 1 and the needle 1 'are preferably disposable.

The intradermal administration device 1 of the present invention can be manufactured based on the descriptions in US8663163 (Japanese Patent No. 5430646) and US8622963 (Japanese Patent No. 55366195).

As another aspect of the device, there is a device comprising an injection needle assembly 1 or an injection needle 1 'and a syringe 9 dedicated to intradermal injection that is preliminarily filled with an injection connected thereto.

The device is useful for intradermal administration of various drugs such as vaccines.

Intradermal administration is performed as follows.

The injection needle assembly 1 or the injection needle 1 ′ is connected to the intradermal injection syringe 9 filled with various medicines such as vaccines via the rear connector of the injection needle assembly 1 or the injection needle 1 ′. It is pressed against the skin to which the medicine is to be administered, for example, the skin of the deltoid muscle in the case of a vaccine and injected. By this operation, a medicine such as a vaccine can be administered intradermally.

Compositions containing various antigens, proteins or pharmaceutical active ingredients administered by the intradermal administration device according to the present invention, treatment or prevention of various diseases such as infectious diseases and cancers comprising the step of administering the composition to an individual Methods, use of various antigens for the treatment or prevention, and the like are also encompassed by the present invention.

The clinical trial in this specification refers to a phase I / II trial or a phase III trial for healthy adults and the elderly.

The primary endpoint in the Phase I / II study is the HI antibody titer, and antibodies are classified by manufacturing strain (H1N1, H3N2, B) and group age (20 to 65 years, 65 years and older). Percentage of seroconversions (“HI antibody titer is less than 1:10 before inoculation and 1:40 or more after inoculation” or “HI antibody titer is 1:10 or more before inoculation and the change rate is 4 times or more”) ), GMT change rate (magnification increase from pre-inoculation value of GMT), antibody retention rate (ratio of subjects with HI antibody titers greater than 1:40).

Phase III study or post-marketing clinical study is the difference in seroconversion rate of HI antibody titer and ratio of GMT for each virus strain (H1N1, H3N2, and B) on Day 21. The evaluation method was the difference in seroconversion rate of HI antibody titer for each virus strain (H1N1, H3N2, and B) on Day 21 (intradermal inoculation group-subcutaneous inoculation group) and GMT ratio (intradermal inoculation group) / Non-inferiority of VN-100 against subcutaneous injections is examined with (subcutaneous group) as the primary endpoint for immunogenicity. The non-inferiority criteria for non-inferiority verification are set as follows.
1) Difference in antibody seroconversion rate: Lower limit of 95% CI of difference in antibody seroconversion rate exceeds -10%
2) GMT ratio: The lower limit of 95% CI of the GMT ratio is more than 2/3. If non-inferiority is verified, the following superiority criteria are evaluated as secondary measures.
1) Difference in antibody seroconversion rate: Lower limit of 95% confidence interval of difference in antibody seroconversion rate (intradermal inoculation group-subcutaneous inoculation group) exceeds 0%
2) The ratio of GMT: The lower limit of the 95% confidence interval of the ratio of GMT (intradermal group / subcutaneous group) exceeds 1. Furthermore, as a secondary endpoint, each virus strain on Day 7 (H1N1 type, H3N2 type) , And B), the same analysis as the main endpoint such as the difference in seroconversion rate of HI antibody titer and GMT ratio is performed.

Hereinafter, the present invention will be described specifically by way of examples. However, these examples do not limit the technical scope of the present invention.
[Example 1: Production of investigational drug]
Three influenza virus strains selected as vaccine production strains by the National Institute of Infectious Diseases were administered into the allantoic cavity of the developing chicken eggs, and the allantoic fluid collected after the culture was used as the virus suspension. The HA suspension was purified by concentrating (ultrafiltration), purifying (sucrose density gradient centrifugation), virus particle degradation (ether treatment), and the like. The HA fraction suspension was inactivated with formalin and used as the inactivated HA fraction suspension. Adjust the osmotic pressure of the suspension of the inactivated HA fraction (ultrafiltration), and use aseptically filtered solution as the vaccine stock solution. The vaccine stock solutions prepared for each of the three strains were mixed, and the final bulk was prepared by adding a phosphate buffered sodium chloride solution (PBS) to adjust the HA antigen amount to a specified concentration. The final bulk was dispensed into glass vials to make a preparation (0.1 ml). A / California / 7/2009 (X-179A), A / Texas / 50/2012 (X-223), and B / Massachusetts / 2/2012 (BX-51B) are used for the manufacture of investigational drugs. It was.
[Example 2: Healthy adults and elderly subjects immunogenicity and wheal formation in Phase I / II study]
In healthy adults and the elderly, the HA content was 6, 9, or 15 μg per strain of the investigational drug once or 15 μg of the investigational drug was intradermally inoculated, and the dosage was examined. In addition, the immunogenicity was compared using as a control one or two inoculations of influenza HA vaccine subcutaneous injection preparation of 15 μg per strain as HA content.

In each group of investigational drugs, the HA content of 0.1, 9 or 15 μg of the investigational drug per strain as 0.1 μmL of the investigational drug was applied to the deltoid region of the upper arm as shown in FIGS. 5 and 6 (US8663163 (Patent No. 5430646). ), US8622963 (Japanese Patent No. 55366195)) was used for intradermal inoculation (intradermal inoculation group or this investigational drug inoculation group). On the other hand, in the HA vaccine subcutaneous inoculation group, 0.5 mL of a subcutaneous injection preparation of 15 μg per strain as the HA content was subcutaneously inoculated on the arm extension side.

The period from the first vaccination to the post-examination was designated as the study drug inoculation period, and a double-blind study was conducted between the groups inoculated with this study drug. The first inoculation group was inoculated on Day 0, and the second inoculation group was inoculated on Day 0 and Day 21.

The study drug was inoculated to a total of 600 people, 100 people in each group (20 to 65 years old: 50 people, 65 years old and over: 50 people).

The primary endpoint is the HI antibody titer, and the antibody seroconversion rate (“HI antibody titer”) by manufacturing strain (H1N1 strain, H3N2 strain, B strain) and group age (20 to 65 years, 65 years and older) Is the ratio of subjects who were less than 1:10 before vaccination and 1:40 or more after vaccination ”or“ HI antibody titer was 1:10 or more and vaccination was 4 times or more before vaccination ”, GMT change rate (GMT Fold increase from pre-inoculation value) and antibody retention (ratio of subjects with HI antibody titers greater than 1:40).

The following immunogenicity evaluation items were collected before Day 10 (Day 0), Day 10 (only in the 1st inoculation group), Day 21 and Day 42 (in the 2nd inoculation group only). The actual average blood collection date is as follows.
This study drug 6 μg inoculation group (intradermal inoculation group): Average 7.1 Japanese investigational drug 9 μg inoculation group (intradermal inoculation group): Average 7.1 Japanese investigational drug 15 μg inoculation group (intradermal inoculation group): Average 7.1 days subcutaneous 15 μg inoculation group : Average 7.1 Japanese investigational drug 6, 9, 15 μg inoculation group (intradermal inoculation group) and subcutaneous inoculation group (total): Average 7.1 days <Study result>
1) Antibody seroconversion rate of HI antibody titers Tables 1 and 2 show the HI antibody titers by production strain (H1N1, H3N2 and B strains) and by group age (20 to 65 years, 65 years and older). The seroconversion rate was shown.

In the seroconversion rate of Day 21 in the single inoculation group, the 6 μg and 9 μg inoculation groups of the study drug were similar to the subcutaneous inoculation group in both age groups, and the 15 μg inoculation group of the study drug was higher than the subcutaneous inoculation group Was recognized. The antibody seroconversion rate on Day 10 was similar except for H1N1 at age 65 and older.
2) GMT change rate of HI antibody titers Tables 3 and 4 show the HI antibody titers by production strain (H1N1, H3N2 and B strains) and by group age (20 to 65 years, 65 years and older). GMT change rate is shown.

In the GMT change rate of Day 21 in the 1-time inoculation group, the 6 μg and 9 μg inoculation groups of the study drug were similar to the subcutaneous inoculation group in both age groups, and the 15 μg inoculation group of the investigational drug tended to be higher than the subcutaneous inoculation group Was recognized. The same tendency was observed in the GMT change rate on Day 10.

In addition, the GMT transition was that Day 21 was higher than Day 10 for any dose and any type in the single inoculation group, but the 15 μg inoculation group of the investigational drug on Day 10 was the subcutaneous inoculation group A higher value was shown, and an early increase in antibody titer was confirmed by intradermal inoculation. In both groups, Day 21 and Day 42 GMTs were similar in both groups.
3) Antibody ownership ratio of HI antibody titers Tables 5 and 6 show HI antibody titers by manufacturing strain (H1N1, H3N2, and B strains) and by group age (20 to 65 years, 65 years and older). Antibody retention was shown.

Regarding the antibody retention rate on Day 21 in the single inoculation group, type A (H1N1 type and H3N2 type) was as high in both age groups and in all inoculation groups. In the B group, in the age group of 20 to 65 years, all groups were similar, but in the group of 65 years and older, the study drug group (intradermal group) was higher than the subcutaneous group.
4) Immunogenicity by age (20 to 65 years old, 65 years old and above) As shown in Tables 1-6, all inoculation groups are immunized in the age group of 65 years or older from 20 years old to under 65 years old. Although the originality was low, in both ages, the 15 μg group receiving the study drug tended to be higher than the subcutaneous group, comparing the study drug group (intradermal group) with the subcutaneous group There was no difference by age group in terms of.
5) Conformity result of HI antibody titer (EMA evaluation standard)
In type A (H1N1 type, H3N2 type), all three items were matched in Day 10 and Day 21 in all groups in both age groups.

In type B, in Day 21 in the population of 20 years old and younger than 65 years, the seroconversion rate and GMT change rate met the standard in all groups, and the antibody retention rate met the standard in the 6 μg inoculation group of the investigational drug, The 9 μg and 15 μg doses of the investigational drug in the single inoculation group were slightly below 70% of the EMA evaluation criteria. All the EMA3 standards met in the population over 65 years old. On the other hand, on Day 10, the seroconversion rate and GMT change rate met the criteria in at least 15 μg of the study drug in the group of 20 years old and younger than 65 years, and the seroconversion rate and GMT change rate in all groups in the group of 65 years of age and older. The GMT change rate met the criteria, whereas the subcutaneous group did not fit any of the three items.

In the twice-inoculation group, both the study drug (15 μg) inoculation group and the subcutaneous inoculation group met all EMA evaluation criteria on both Day 21 and Day 42.
6) Formation of wheal The investigator or study investigator confirmed the presence or absence of bulges (whisles) that physically occur on the skin following the injection of drug solution immediately after inoculation. As a result, the formation rate of wheal at the site of inoculation of this study drug was 97.2% (483/497), confirming that it was inoculated into the upper skin layer with high probability.
[Example 3: Healthy adult and elderly subjects immunogenicity in phase I / II study]
In the same manner as in Example 2, for healthy adults and the elderly, as a HA content, 6, 9, or 15 μg of the investigational drug per strain is administered once or 15 μg of the investigational drug is intradermally inoculated twice. The dose was examined. At the same time, the safety was compared by using one or two inoculations of influenza HA vaccine subcutaneous injection preparation of 15 μg per strain as HA content as a control.

Adverse events (adverse events, laboratory values, body temperature) that occurred between the time of study drug inoculation and 21 days after the last inoculation (post-examination) were collected. Adverse events appearing at and around the injection site were taken as injection site adverse events, and adverse events other than injection site adverse events were taken as systemic adverse events. Injection site redness, injection site swelling, injection site hardening, injection site ecchymosis, injection site pain, injection site heat, injection site pruritus, and systemic adverse events among fever, chills, fatigue Sensation, headache, and rash were defined as specific adverse events.
<Test results>
Adverse events occurred in 531 out of 600 patients (inoculated with 6 μg of the investigational drug: 94% [94/100], inoculated with 9 μg of the investigational drug: 96% [96/100], administered with 15 μg of the investigational drug once: 93% [93/100], The investigational drug 15 μg 2 times inoculation group: 96% [96/100], Subcutaneous inoculation group: 72% [72/100], Subcutaneous inoculation group: 80% [80/100] ). Injection site adverse events occurred frequently in the study drug inoculation group, but the incidence of severe injection sites was lower in the study drug inoculation group than in the subcutaneous inoculation group, and all recovered within 22 days without treatment. did. There was no significant difference in the incidence of systemic adverse events between the study drug group and the subcutaneous group.

Based on the above, regarding the safety during the study drug inoculation period, there was no significant difference in the frequency of adverse events between the doses in the study drug inoculation group, and no significant problems were observed compared to the subcutaneous injection of influenza HA vaccine. . In particular, the local reaction was found to have a low incidence of severe side effects.

DESCRIPTION OF SYMBOLS 1 Injection needle assembly 1 'Injection needle 2 Needle tube 2a Blade surface 3 Hub 4 Adjustment part (stopper part)
4a Hub facing surface 4b Needle protruding surface 5 Adhesive 6 Stable part (limiter part)
6a Fixed part 6b Contact part 6c End face 7 Guide part (flange part)
7a Contact surface 9 Syringe 10 Intradermal administration device 11 Rear connector 12 Protector 13 Top film BL Bevel length L Protrusion length S Distance from the peripheral edge of the needle protrusion surface to the peripheral surface of the needle tube T Outer surface of the adjustment portion to the outer peripheral surface of the adjustment portion Distance x Guide length y Guide height d Inner diameter All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

An influenza vaccine composition comprising an influenza antigen as an active ingredient and administered by an intradermal administration device having a needle tube protrusion length of 0.9 to 1.4 mm.
2. The composition of claim 1, wherein all strains present in the vaccine composition meet at least one of the following EMA criteria:
1) In the age group between 20 and 65 years old
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 40%;
ii) GMT (geometric mean titer) change rate (magnification of GMT after inoculation from the value before the first inoculation) exceeds 2.5; and
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 70%;
2) In the age group over 65 years old,
i) Antibody seroconversion rate (% of subjects whose antibody titer is “less than 1:10 before the first vaccination and 1:40 or more after vaccination” or “1:10 or more before the first vaccination and the change rate is 4 times or more”) (%)) Exceeds 30%;
ii) The rate of change in GMT (the increase rate from the pre-vaccination GMT value after vaccination) exceeds 2.0; and
iii) The antibody retention rate (ratio of subjects with antibody titers of 1:40 or more (%)) exceeds 60%.
For all strains present in the vaccine composition, the difference in seroconversion rate (intradermal inoculation group-subcutaneous inoculation group) and GMT (geometric mean antibody titer) ratio (intradermal inoculation group / subcutaneous inoculation group) The composition according to claim 1 or 2, which satisfies at least one of the non-inferiority criteria of:
1) Difference in seroconversion rate: lower limit of 95% CI of difference in seroconversion rate exceeds -10%; and 2) Ratio of GMT: Lower limit of 95% CI of GMT ratio exceeds 2/3.
The strain present in the vaccine composition is at least one of the following superiority criteria for the difference in seroconversion rate (intradermal inoculation group-subcutaneous inoculation group) and the ratio of GMT (intradermal inoculation group / subcutaneous inoculation group) The composition according to any one of claims 1 to 3, wherein
1) Difference in seroconversion rate: 95% CI lower limit of antibody seroconversion rate exceeds 0%; and 2) GMT ratio: 95% CI lower limit of GMT ratio exceeds 1.
The composition according to any one of claims 2 to 4, wherein each of the strains meets at least one EMA standard, non-inferiority standard or superiority standard 5 to 14 days after vaccination.
The composition according to any one of claims 1 to 5, wherein the HA content per each strain is any one of 6 to 15 µg.
The composition according to any one of claims 1 to 6, wherein the vaccine composition comprises at least an A strain (H1N1), an A strain (H3N2), and a B strain.
The composition according to any one of claims 1 to 7, wherein the vaccine composition does not contain an adjuvant.
The composition according to any one of claims 1 to 8, wherein the device comprises a needle assembly having the following characteristics 1) and 2).
1)
a) a 26-33G needle tube having a needle tip that can puncture a living body;
b) a hub for holding the needle tube;
c) an adjustment unit provided around the needle tube and having a needle projecting surface from which the needle tip of the needle tube projects;
d) a cylindrical stabilizing portion that is arranged so as to cover the periphery of the needle tube and comes into contact with the skin when the needle tube is punctured into a living body;
e) provided on the outer peripheral surface of the stable portion, having a contact surface that comes into contact with the skin, and when the needle tube is punctured into a living body, the stable portion is pressed against the skin until the contact surface comes into contact with the skin. A guide part for guiding the pressing force to the living body of the needle tube and the stabilizing part,
2) The contact surface of the guide portion is provided at a predetermined distance from an end surface that contacts the skin in the stable portion.
The composition according to any one of claims 1 to 9, which is a device comprising an injection needle characterized in that the device comprises the following: a) to d).
a) a 26-33G needle tube having a needle tip that can puncture a living body;
b) a hub for holding the needle tube;
c) a needle projecting surface provided around the needle tube, from which the needle tip of the needle tube projects, and the length of the needle tip of the needle tube projecting from the needle projecting surface is 0.5 to 3.0 mm; An adjustment portion formed so as to have a shortest distance from the periphery of the needle projecting surface to the peripheral surface of the needle tube in a range of 0.3 to 1.4 mm;
d) A cylindrical shape provided around the needle tube at a predetermined interval from the adjustment unit, having an end surface that comes into contact with the skin when the needle tube is punctured into a living body, and covers the periphery of the needle tube and the adjustment unit The stabilizing portion is formed such that the distance from the inner wall surface to the outer peripheral surface of the adjusting portion is set in the range of 4 to 6 mm, and the inner diameter thereof is set in the range of 9 to 13 mm.
The composition according to any one of claims 1 to 10, which exhibits a rash formation rate of 90% or more in the upper layer of the skin of a human individual.
The composition according to any one of claims 1 to 11, wherein the administration site is the deltoid region of the upper arm.