JP2016094359A - Vaccine and phylaxis kit - Google Patents
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Abstract
Description
本発明は、不活化ワクチンの特定の用法及びウイルスに対する感染防御キットに関する。 The present invention relates to specific uses of inactivated vaccines and infection protection kits against viruses.
インフルエンザは、呼吸器飛沫感染を介して拡散するインフルエンザウイルスにより引き起こされる急性の伝染性呼吸器疾患である。インフルエンザは、世界的規模で流行することがあるウイルス感染疾患の一つであり、効果的な予防法の確立が望まれる。 Influenza is an acute infectious respiratory disease caused by an influenza virus that spreads through respiratory droplet infection. Influenza is one of the viral infectious diseases that may be prevalent on a global scale, and the establishment of an effective prevention method is desired.
インフルエンザウイルスは、ウイルス粒子表面に存在する主要な表面抗原であるヘマグルチニン(ＨＡ)タンパク質又はノイラミニダーゼ(ＮＡ)タンパク質の型によって、例えばＡソ連型(Ｈ１Ｎ１)、Ａ香港型(Ｈ３Ｎ２)等の亜型に分類される。 Influenza viruses are classified into subtypes such as A Soviet type (H1N1) and A Hong Kong type (H3N2) depending on the type of hemagglutinin (HA) protein or neuraminidase (NA) protein that is a major surface antigen present on the surface of the virus particle. being classified.
トリ等の他種動物を宿主とするインフルエンザウイルスが直接ヒトへ感染することも知られるようになり（非特許文献１）、１９９７年５月以降、それまでトリで確認されていたがヒトでは見つかっていなかったＨ５Ｎ１型インフルエンザウイルスの感染者が複数確認された。今後、これがヒトからヒトへと感染するウイルスへと変異し、世界的な流行（パンデミック）が起こる可能性も否定できない。 It has also been known that influenza viruses hosted by other species of animals such as birds directly infect humans (Non-patent Document 1). Since May 1997, it has been confirmed in birds, but it was found in humans. A number of infected H5N1 influenza viruses were confirmed. In the future, there is no denying the possibility that this will be transformed into a virus that infects humans, resulting in a global pandemic.
ヒトがこのＨ５Ｎ１型インフルエンザウイルスに感染した場合、３８度以上の発熱、下痢、鼻血、歯肉出血、血痰、呼吸困難等、激烈な症状を起こし、強毒性のため、致死率が高くなることが報告されている。 It is reported that when humans are infected with this H5N1 influenza virus, it causes severe symptoms such as fever of 38 degrees or more, diarrhea, nosebleed, gingival bleeding, blood clot, dyspnea, etc. Has been.
特許文献１には、Ｈ５Ｎ１型に代表されるパンデミックインフルエンザウイルスに対して免疫する手法であって、インフルエンザウイルスを含む免疫原性組成物を、１４日未満の間隔で２回初回投与する手法が記載されている。 Patent Document 1 describes a technique for immunizing against a pandemic influenza virus typified by H5N1 type, in which an immunogenic composition containing influenza virus is initially administered twice at intervals of less than 14 days. Has been.
しかし、上述の手法では、中和抗体価の十分な上昇が期待できず、更に、ワクチン接種株以外の亜型のインフルエンザ感染を充分予防することは困難である。 However, with the above-described method, a sufficient increase in neutralizing antibody titer cannot be expected, and it is difficult to sufficiently prevent influenza infection of subtypes other than the vaccinated strain.
本発明はかかる問題点に鑑みてなされたものであって、中和抗体価の十分な上昇が期待でき、且つ、広い交叉免疫性が得られるワクチンを提供することを目的とする。 The present invention has been made in view of such problems, and an object of the present invention is to provide a vaccine that can be expected to sufficiently increase the neutralizing antibody titer and that can provide a broad cross-immunity.
本発明の第１の観点にかかるワクチンは、同一株の不活化ワクチンがヒトに対して２回接種されるように用いられるワクチンであって、前記２回接種の接種間隔を６０日以上１８０日以下とすることを特徴とする。 The vaccine according to the first aspect of the present invention is a vaccine that is used so that an inactivated vaccine of the same strain is inoculated twice into a human, and the inoculation interval between the two inoculations is 60 days to 180 days. It is characterized as follows.
また、本発明の第２の観点にかかる感染防御キットは、請求項１乃至６の何れか１項に記載のワクチンと、前記ワクチンをヒトに対して投与するための器具と、を有することを特徴とする。 Moreover, the infection prevention kit concerning the 2nd viewpoint of this invention has the vaccine of any one of Claims 1 thru | or 6, and the apparatus for administering the said vaccine with respect to a human. Features.
本発明にかかるワクチンによれば、中和抗体価の十分な上昇が期待でき、且つ、有害事象の発生を必要以上に惹起せずに交叉免疫性を大幅に上昇させることができる。 According to the vaccine of the present invention, a sufficient increase in neutralizing antibody titer can be expected, and cross-immunity can be significantly increased without causing an adverse event more than necessary.
以下、添付の図面を参照して本発明の実施形態について具体的に説明するが、当該実施形態は本発明の原理の理解を容易にするためのものであり、本発明の範囲は、下記の実施形態に限られるものではなく、当業者が以下の実施形態の構成を適宜置換した他の実施形態も、本発明の範囲に含まれる。 Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings. However, the embodiments are for facilitating understanding of the principle of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiments, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.
生後６カ月以上13歳未満の対象者へのインフルエンザワクチンの接種は２回接種とされており、従来、その接種間隔はおよそ2〜4週間とされている。接種間隔をこのように設定する理由は、4週間程度の間隔をあけて接種した方が免疫の獲得が良好であると考えられているからである。しかしながら、本発明者らは、実験の結果、２回接種の接種間隔を従来よりも広げることにより、従来よりも中和抗体価を十分に上昇させつつ、且つ、交叉免疫性を大幅に上昇させることができるという新知見を見いだし、かかる事実に基づいて本発明を完成させた。 Inoculation of influenza vaccine to subjects who are 6 months or older and under 13 years of age is considered to be inoculated twice, and the inoculation interval is conventionally about 2 to 4 weeks. The reason for setting the inoculation interval in this way is that immunization is considered better when inoculated at intervals of about 4 weeks. However, as a result of the experiment, the inventors of the present invention significantly increased the cross-immunity while increasing the neutralizing antibody titer more than before by broadening the inoculation interval between the two inoculations. Based on this fact, the present invention has been completed.
即ち、本発明にかかるワクチンは、同一株の不活化ワクチンがヒトに対して２回接種されるように用いられるワクチンであって、２回接種の接種間隔を６０日以上１８０日以下とすることを特徴とする。 That is, the vaccine according to the present invention is a vaccine used so that an inactivated vaccine of the same strain is inoculated twice to a human, and the inoculation interval between the two inoculations is 60 days or more and 180 days or less. It is characterized by.
２回接種の接種間隔を６０日以上とすることにより、従来よりも中和抗体価を十分に上昇させつつ、且つ、交叉免疫性を大幅に上昇させることができる。一方で、２回接種の接種間隔を１８０日以下とするのは、流行期を前にして早期に有効な免疫を与えるためである。 By setting the inoculation interval of the second inoculation to 60 days or more, the neutralizing antibody titer can be sufficiently increased as compared with the conventional method, and the cross immunity can be significantly increased. On the other hand, the reason why the inoculation interval of the second inoculation is 180 days or less is to give effective immunity early in the epidemic period.
不活化ワクチンは、ウイルスをホルマリン等で処理して感染性を失わせたものを材料に調整されたワクチンである。不活化ワクチンは、特に限定されるものではなく、例えば、ジフテリア・百日せき・破傷風（ＤＰＴ）三種混合ワクチン、ジフテリア・破傷風（ＤＴ）二種混合ワクチン、日本脳炎ワクチン、小児用７価肺炎球菌ワクチン、子宮頸がんワクチン、Ａ型肝炎ワクチン、Ｂ型肝炎ワクチン、不活化ポリオワクチン等であるが、好ましくはインフルエンザワクチンである。 An inactivated vaccine is a vaccine prepared using a material obtained by treating a virus with formalin or the like to lose its infectivity. The inactivated vaccine is not particularly limited. For example, diphtheria / pertussis / tetanus (DPT) triple vaccine, diphtheria / tetanus (DT) dual vaccine, Japanese encephalitis vaccine, pediatric 7-valent pneumococci Vaccines, cervical cancer vaccines, hepatitis A vaccines, hepatitis B vaccines, inactivated polio vaccines and the like, preferably influenza vaccines.
インフルエンザワクチンは、インフルエンザウイルスを発育鶏卵で培養し、その漿尿液から採取したウイルス粒子を精製して作られた感染防御抗原物質を主成分とした多価ワクチンである。精製工程中に、ホルマリンを用いて全ての微生物は不活性化される。 The influenza vaccine is a multivalent vaccine mainly composed of an infection-protecting antigenic substance, which is produced by culturing influenza virus in embryonated chicken eggs and purifying virus particles collected from the chorioallantoic fluid. During the purification process, all microorganisms are inactivated with formalin.
インフルエンザウイルスは特に限定されるものでなく、A型又はB型の何れの型も含まれる。A型インフルエンザの亜型には126種類の型が確認されているが、好ましくはＨ５Ｎ１型インフルエンザである。Ｈ５Ｎ１型インフルエンザワクチンは、ともに同一株由来である。例えば、青海株(clade2.2)、インドネシア株(clade2.1)、安徽株(clade2.3)、又はベトナム株(clade1)であり、好ましくはエジプト株(clade2.2)である。 The influenza virus is not particularly limited, and includes any type of A type or B type. Although 126 types of influenza A subtypes have been confirmed, H5N1 influenza is preferred. Both H5N1 influenza vaccines are derived from the same strain. For example, Qinghai strain (clade2.2), Indonesia strain (clade2.1), Anhui strain (clade2.3), or Vietnam strain (clade1), preferably Egyptian strain (clade2.2).
Ｈ５Ｎ１型インフルエンザワクチンは、アジュバントを含むことが可能である。アジュバントとしては、特に限定されるものではないが、例えば、水酸化アルミニウム、リン酸アルミニウム等のアルミニウム塩、キトサン、オリゴデオキシヌクレオチド、水中油型エマルジョン等を用いることが可能である。好ましくは水酸化アルミニウムであり、水酸化アルミニウムをアジュバントとして用いることにより、免疫原性を高めることができる。 The H5N1 influenza vaccine can include an adjuvant. The adjuvant is not particularly limited, and for example, aluminum salts such as aluminum hydroxide and aluminum phosphate, chitosan, oligodeoxynucleotide, oil-in-water emulsion and the like can be used. Aluminum hydroxide is preferable, and immunogenicity can be enhanced by using aluminum hydroxide as an adjuvant.
血球凝集素（ＨＡ）は、不活性化インフルエンザワクチンにおける主要な免疫原であり、ワクチン用量は、代表的には、単一放射状免疫拡散（ＳＲＤ）アッセイによって測定されるように、ＨＡレベルを参照することによって標準化される。Ｈ５Ｎ１型インフルエンザワクチンは、ＨＡ抗原の量は、特に限定されるものではないが、１用量あたり例えば１μｇ〜２００μｇであり、好ましくは１０μｇ〜３０μｇであり、より好ましくは１５μｇである。１用量は例えば０．５ｍＬである。 Hemagglutinin (HA) is the primary immunogen in inactivated influenza vaccines, and vaccine doses typically refer to HA levels as measured by a single radial immunodiffusion (SRD) assay. To be standardized. In the H5N1 influenza vaccine, the amount of the HA antigen is not particularly limited, but is, for example, 1 μg to 200 μg, preferably 10 μg to 30 μg, more preferably 15 μg per dose. One dose is, for example, 0.5 mL.
投与方法は特に限定されるものではないが、例えば経鼻、皮下、皮内、経皮、眼内、粘膜、又は、経口投与であり、好ましくは、筋肉内投与である。 The administration method is not particularly limited, and for example, nasal, subcutaneous, intradermal, transdermal, intraocular, mucosal, or oral administration, preferably intramuscular administration.
また、本実施形態にかかる感染防御キットは、上記のワクチンと、ワクチンをヒトに対して投与するための器具と、を有する。ヒト患者に対してワクチンを投与するための器具は、特に限定されるものではないが、例えば、注射器、吸入器、ネブライザー、ピペット等である。 Moreover, the infection prevention kit concerning this embodiment has said vaccine and the instrument for administering a vaccine with respect to a human. The device for administering the vaccine to the human patient is not particularly limited, and examples thereof include a syringe, an inhaler, a nebulizer, and a pipette.
感染防御キットは、ワクチンを投与するのを助ける医薬的に許容され得る賦形剤を含有することも可能である。賦形剤は、例えば、生理食塩水、グリセロール、デキストロース、ラクトース、スクロース、デンプン末、アルカン酸のセルロースエステル、セルロースアルキルエステル、タルク、ステアリン酸、ステアリン酸マグネシウム、酸化マグネシウム、リン酸及び硫酸のナトリウム及びカルシウム塩、ゼラチン、アカシアガム、アルギン酸ナトリウム、ポリビニルアルコール、ポリビニルピロリドン等である。 Infection protection kits can also contain pharmaceutically acceptable excipients that assist in administering the vaccine. Excipients include, for example, saline, glycerol, dextrose, lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sodium sulfate And calcium salt, gelatin, acacia gum, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone and the like.
インフルエンザウイルスエジプト株をホスホマイシンナトリウム、ゲンタマイシン硫酸塩、ミノサイクリン塩酸塩、ジベカシン硫酸塩及びプレドニゾロンとともに発育鶏卵で増殖させ、得られたウイルスを採取し、ろ過法、超遠心法等で精製し、ホルマリンで不活化した後、免疫原性を高めるために水酸化アルミニウムゲルに吸着させ不溶性として製造される沈降インフルエンザワクチンH5N1「ビケン」エジプト株Clade2.2を使用した。 Influenza virus Egypt strains are grown in foster eggs together with fosfomycin sodium, gentamicin sulfate, minocycline hydrochloride, dibekacin sulfate and prednisolone.The resulting virus is collected, purified by filtration, ultracentrifugation, etc. After activation, the precipitated influenza vaccine H5N1 “Biken” Egyptian strain Clade2.2, which was adsorbed on aluminum hydroxide gel and manufactured as insoluble, was used to enhance immunogenicity.
Ｈ５Ｎ１型を対象とするワクチン未接種者を対象に上記エジプト株を３週、６０日、９０日、１８０日間隔で２回接種した。インフルエンザウイルスのＨＡ含量は３０μｇ／ｍｌであり、０．５ｍＬを（１回摂取量１５μｇ）上記間隔をあけて上腕三角筋に２回注射した。 The above-mentioned Egyptian strain was inoculated twice at intervals of 3 weeks, 60 days, 90 days, and 180 days for non-vaccinated persons targeting H5N1. The HA content of influenza virus was 30 μg / ml, and 0.5 mL (a single intake of 15 μg) was injected twice into the deltoid triceps at the above interval.
被験者は、３週の試験間隔が５０名、６０日の試験間隔が３０名、９０日の試験間隔が３０名、１８０日の試験間隔が２９名であった。 The subjects had a test interval of 3 weeks at 50 people, a test interval of 60 days at 30 people, a test interval of 90 days at 30 people, and a test interval of 180 days at 29 people.
被験者は、女性８１名（５８．０％）（平均年齢３５．０歳）、及び、男性５８名（４２．０％）（平均年齢３４．９歳）であった。女性では、２９歳以下は３２人、３０歳代は２２人、４０歳代は１９人、５０歳代は８人、６０歳以上は０人であった。男性では、２９歳以下は２４人、３０歳代は１５人、４０歳代は１２人、５０歳代は７人、６０歳以上は０人であった。 The subjects were 81 females (58.0%) (average age 35.0 years) and 58 males (42.0%) (average age 34.9 years). Among women, there were 32 people under 29 years old, 22 people in their 30s, 19 people in their 40s, 8 people in their 50s, and 0 people over 60 years. Among men, 24 were under 29, 15 were in their 30s, 12 were in their 40s, 7 were in their 50s, and 0 were over 60.
２回接種後採血し、Ｈ５Ｎ１型インフルエンザウイルス４株に対する交叉免疫性並びに中和抗体価を検討した。 Blood samples were collected after the second inoculation, and cross immunity and neutralizing antibody titer against four H5N1 influenza viruses were examined.
結果を図１〜図４及び表１〜表５に示す。図１は、ベトナム株に対しての中和抗体価の逆累積度数分布図である。図２は、インドネシア株に対しての中和抗体価の逆累積度数分布図である。図３は、エジプト株に対しての中和抗体価の逆累積度数分布図である。図４は、安徽株に対しての中和抗体価の逆累積度数分布図である。 The results are shown in FIGS. 1 to 4 and Tables 1 to 5. FIG. 1 is a reverse cumulative frequency distribution diagram of neutralizing antibody titers against Vietnamese strains. FIG. 2 is a reverse cumulative frequency distribution diagram of neutralizing antibody titers against Indonesian strains. FIG. 3 is a reverse cumulative frequency distribution diagram of neutralizing antibody titers against Egypt strains. FIG. 4 is a reverse cumulative frequency distribution diagram of neutralizing antibody titers against Anhui strains.
表１は、ベトナム株に対しての中和抗体価の頻度分布である。表２は、インドネシア株に対しての中和抗体価の頻度分布である。表３は、エジプト株に対しての中和抗体価の頻度分布である。表４は、安徽株に対しての中和抗体価の頻度分布である。表５は、幾何平均抗体価増加倍率を示す。括弧内は９５％信頼区間である。 Table 1 shows the frequency distribution of neutralizing antibody titers against Vietnamese strains. Table 2 shows the frequency distribution of neutralizing antibody titers against Indonesian strains. Table 3 shows the frequency distribution of neutralizing antibody titers against Egypt strains. Table 4 shows the frequency distribution of neutralizing antibody titers against Anhui strains. Table 5 shows the geometric mean antibody titer increase magnification. The brackets are 95% confidence intervals.
エジプト株での幾何平均抗体価増加倍率は、３週後で１６．７倍（９５％信頼区間１２．４−２２．４）、６０日後で２３．２倍（９５％信頼区間１４．５−３７．０）、９０日後で３４．３倍（９５％信頼区間２１．４−５５．０）、１８０日後で５２．９倍（９５％信頼区間３５．３−７９．２）であり、優れた免疫原性があることが確認された。また、交叉免疫性についても優れていることが確認去され、特に接種間隔が１８０日の場合に優れた交叉免疫性を示した。 Geometric mean antibody titer increase in Egyptian strains was 16.7 times after 3 weeks (95% confidence interval 12.4-22.4), 23.2 times after 60 days (95% confidence interval 14.5- 37.0), 34.3 times after 90 days (95% confidence interval 21.4-55.0), and 52.9 times after 180 days (95% confidence interval 35.3-79.2), excellent. Were confirmed to be immunogenic. Moreover, it was confirmed that the cross immunity was also excellent, and the cross immunity was excellent particularly when the inoculation interval was 180 days.
インフルエンザワクチンの製造及び開発分野において利用できる。 It can be used in the field of influenza vaccine production and development.
Claims (7)
前記２回接種の接種間隔を６０日以上１８０日以下とすることを特徴とするワクチン。 A vaccine used so that an inactivated vaccine of the same strain is inoculated twice to a human,
A vaccine characterized in that the inoculation interval of the second inoculation is 60 days or more and 180 days or less.
前記ワクチンをヒトに対して投与するための器具と、を有することを特徴とする感染防御キット。 The vaccine according to any one of claims 1 to 6,
And a device for administering the vaccine to humans.
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